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Savara is an orphan lung disease company.
−Removed: Our current drug development pipeline is comprised of Molgradex, an inhaled granulocyte-macrophage colony-stimulating factor (“GM-CSF”) in Phase 3 development for autoimmune pulmonary alveolar proteinosis (“aPAP”), in Phase 2a development for nontuberculous mycobacterial (“NTM”) lung infection, in Phase 2a development for the treatment of NTM lung infection in people living with cystic fibrosis (“CF”), and AeroVanc, an inhaled vancomycin in Phase 3 development for persistent methicillin-resistant Staphylococcus aureus (“MRSA”) lung infection in individuals living with cystic fibrosis (“CF”).
−Removed: Our strategy involves expanding our pipeline of potentially best-in-class products through indication expansion, strategic development partnerships and product acquisitions, with the goal of becoming a leading company in the orphan lung disease market.
−Removed: Our management team has significant experience in orphan drug development and pulmonary medicine, navigating the regulatory environment, identifying unmet needs, developing and acquiring new product candidates and effectively advancing them to approvals, and commercialization.
−Removed: The table below summarizes the current status and anticipated milestones for our primary drug development candidates.
+Added: Our lead program, molgramostim nebulizer solution (“molgramostim,” formerly referred to as Molgradex), is an inhaled granulocyte-macrophage colony-stimulating factor (“GM-CSF”) in Phase 3 development for autoimmune pulmonary alveolar proteinosis (“aPAP”).
+Added: Our management team has significant experience in orphan drug development and pulmonary medicine, identifying unmet needs, and effectively advancing product candidates to approval and commercialization.
Corporate Strategy
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Key elements of our strategy include:
−Removed: Advancing the current pipeline .
−Removed: Advancing Savara’s development pipeline is our highest priority and includes:
−Removed: Molgradex for aPAP―Working with the U.S.
−Removed: Food and Drug Administration (“FDA”) to plan an additional Phase 3 clinical study that will evaluate the efficacy and safety of Molgradex for the treatment of aPAP and ensuring all aspects of our manufacturing are validated and can produce product at commercial scale.
−Removed: Molgradex NTM program – Determining the next steps for the program based on the top line microbiology results from the OPTIMA study and results from the ongoing ENCORE study.
−Removed: AeroVanc―Continuing to enroll patients until Q2 2020 for AVAIL, the Phase 3 study of inhaled vancomycin for the treatment of MRSA lung infection in people living with CF.
−Removed: Top line results from the study are expected in early 2021.
−Removed: Expanding the product pipeline through strategic product acquisitions .
−Removed: In addition to evaluating indication expansion opportunities with our current programs, our strategy also includes growing our development pipeline through strategic partnerships and product acquisitions.
−Removed: A key priority has been to enhance the delivery of known chemical entities or drug classes (e.g., reformulation of an existing drug so that it can be delivered directly into the lungs) for the treatment of serious or life-threatening lung diseases.
−Removed: While we have developed an internal core competency in inhaled drug development, we are technology and route-of-delivery agnostic.
−Removed: Future product acquisition decisions will be based on the unmet medical need within a specific disease, market opportunity, and the ability to rapidly develop and commercialize the product candidate.
−Removed: Outsource capital intensive operations.
−Removed: We will continue to pursue the development and manufacturing of our product candidates by outsourcing most clinical development work and all manufacturing operations.
+Added: Advancing the molgramostim aPAP program and the Phase 3 IMPALA 2 clinical trial.
+Added: The IMPALA 2 trial design has been endorsed by regulatory authorities in approximately 14 countries across North America, Europe, and Asia and is expected to initiate by the end of the second quarter of 2021.
+Added: Ensuring all aspects of our manufacturing are validated and can produce product at commercial scale.
+Added: As is good practice, we are pursuing the development of a second source manufacturer of molgramostim to ensure drug substance supply and mitigate approvability risk.
+Added: Outsourcing capital-intensive operations.
+Added: We will continue to pursue the development and manufacturing of our product candidates by outsourcing most clinical development work and manufacturing operations.
We believe our business model enables the effective and capital-efficient development of our pipeline through the use of high-quality specialist vendors and consultants.
−Removed: Molgradex – aPAP
−Removed: Our lead product candidate, Molgradex, an inhaled formulation of recombinant human GM-CSF, is being developed for the treatment of aPAP.
−Removed: Pulmonary alveolar proteinosis (“PAP”) is a rare lung disease characterized by the build-up of lung surfactant in the alveoli (or air sacs) of the lungs.
+Added: Molgramostim – aPAP
+Added: Our lead product candidate, molgramostim, an inhaled formulation of recombinant human GM-CSF, is being developed for the treatment of aPAP.
+Added: Pulmonary alveolar proteinosis (“PAP”) is a rare lung disease characterized by the build-up of surfactant in the alveoli (or air sacs) of the lungs.
There are different types of PAP, of which aPAP is the most common.
−Removed: In 2019, we announced that IMPALA, the Phase 3 clinical study of Molgradex for the treatment of aPAP, did not meet its primary endpoint of alveolar-arterial oxygen gradient, (A-a)DO 2, improvement compared to placebo and that the FDA indicated the data in our briefing package did not provide sufficient evidence of efficacy and safety.
−Removed: While we will need to provide additional evidence to meet the FDA’s requirements, we believe the totality of data from the IMPALA study suggest that Molgradex has the potential to address significant unmet need in this rare disease.
−Removed: These data extend beyond the primary endpoint and include:
−Removed: Multiple key secondary and exploratory endpoints that either achieved statistical significance or trended in favor of the active drug arms,
−Removed: Results from the open-label period of the study that demonstrated a sustained treatment effect, or continued improvement, after longer term exposure to Molgradex, and
−Removed: Adverse event frequencies that were similar to placebo.
−Removed: We consider Molgradex to have a compelling risk-benefit profile and remain confident in the future of the program.
−Removed: Our highest priority is to continue discussions with the regulatory agencies to plan an additional Phase 3 study of Molgradex in aPAP.
−Removed: In May 2019, the FDA granted Molgradex for the treatment of aPAP Fast Track Designation which facilitates the expedited development and review of new drugs or biologics intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs.
−Removed: In December 2019, the FDA also granted the program Breakthrough Therapy Designation which provides a process for expediting the development and review of drugs that are intended to treat a serious condition and for which preliminary evidence indicates that the drug may demonstrate substantial improvement over the available therapy.
−Removed: Additionally, Molgradex has been granted Orphan Drug Designation for the treatment of aPAP in the U.S.
−Removed: and the EU, which allows for seven and ten years of exclusivity from approval, respectively.
−Removed: Savara has exclusive access to the PARI Investigational eFlow Nebulizer System for this indication along with a proprietary cell bank for molgramostim, a non-glycosylated form of GM-CSF and the active drug substance of Molgradex.
−Removed: There are estimated to be at least 2,200 PAP patients in the U.S., with the vast majority having aPAP.
−Removed: The disease process underlying aPAP involves an autoimmune response against GM-CSF, a naturally occurring protein that functions to clear excess surfactant from the alveoli.
−Removed: More specifically, the anti-GM-CSF autoantibodies associated with aPAP suppress the stimulating activity of GM-CSF on lung macrophages, resulting in the accumulation of excess surfactant which obstructs gas exchange and results in shortness of breath and decreased exercise tolerance.
−Removed: Patients may also experience chronic cough, acute cough or chest pain, as well as episodes of fever, especially if secondary lung infection develops.
−Removed: In the long term, the disease can lead to serious complications, including lung fibrosis and the need for a lung transplant.
−Removed: Currently, there are no therapies approved for the treatment of aPAP.
−Removed: The current standard-of-care is a surgical procedure called whole lung lavage (“WLL”), which entails washing out the lungs with saline, segment-by-segment, under general anesthesia.
−Removed: By nature, WLL is an invasive and inconvenient procedure that requires highly experienced physicians and hospitalization at specialist sites.
−Removed: Based on published investigator-sponsored treatment experience with inhaled GM-CSF and data from the IMPALA study, we believe Molgradex has the potential to replace the inactivated GM-CSF in aPAP patients, thereby restoring the surfactant clearing activity of the alveolar macrophages.
−Removed: If approved, Molgradex could become the first-line treatment for aPAP.
−Removed: The IMPALA clinical study was a Phase 3 randomized, double-blind, placebo-controlled study that completed in June 2019.
−Removed: It was designed to compare the efficacy and safety of Molgradex with placebo in patients with aPAP.
−Removed: The study enrolled 138 patients and was conducted in 18 countries, including the U.S., Japan, and throughout Europe.
−Removed: IMPALA’s primary endpoint was (A-a)DO 2 , a commonly used measure of oxygenation impairment, and also included three key secondary endpoints and multiple other secondary and exploratory endpoints designed to assess improvement in the disease pathology, pathophysiology, clinical symptoms, and function.
−Removed: Patients were randomized to receive treatment for up to 24 weeks in one of t hree treatment arms:
−Removed: 1) Molgradex 300 µg administered once daily, 2) Molgradex 300 µg and matching placebo administered daily every other week, or 3) inhaled placebo administered once daily.
−Removed: For details on the results of the IMPALA study, please see the “Clinical Development of Molgradex―aPAP:
−Removed: Phase 3 IMPALA Study” section included in this report.
−Removed: In March 2018, the IMPALA-X clinical study was initiated.
−Removed: This open-label extension study allowed patients who have completed the IMPALA study to continue treatm ent for up to three additional years and will provide additional data on the long-term safety and use of Molgradex in patients with aPAP.
−Removed: In February 2020, IMPALA-X enrollment was complete, with 60 patients out of a total of 64 eligible patients enrolle d.
−Removed: Molgradex - NTM
−Removed: Molgradex is also being investigated for the treatment of NTM lung infection.
−Removed: Top line microbiology results were recently announced for the open-label, non-controlled Phase 2a study called OPTIMA.
−Removed: NTM lung infection is a rare and serious lung disorder associated with increased rates of morbidity and mortality.
−Removed: Nontuberculous mycobacteria are naturally occurring organisms, and NTM lung infection can occur when the organism (found in the environment) is inhaled and an individual develops a slowly progressive and destructive lung disease.
−Removed: NTM lung infection is typically characterized by cough, fatigue, and weight loss.
−Removed: NTM infections often become chronic and require long courses of multiple antibiotics, and despite aggressive treatment regimens, treatment failure rates are high and recurrence of infection common.
−Removed: Chronic NTM lung infection can have a significant impact on quality of life.
−Removed: There are up to 80,000 individuals affected by NTM in the U.S., and the most common types of NTM lung infection involve Mycobacterium avium complex (“MAC”), and Mycobacterium abscessus (“MABSC”).
−Removed: There have been few advancements in new systemic treatments for NTM lung infection.
−Removed: NTM lung infections are a considerable therapeutic challenge due to the unique ability of these bacteria to evade the normal killing mechanisms of alveolar macrophages, a type of immune cell responsible for killing bacteria in the lungs.
−Removed: There is increasing scientific literature suggesting that GM-CSF plays an important role in enhancing the ability of macrophages to clear mycobacteria.
−Removed: 1 For instance, GM-CSF knock out mice inoculated with MABSC develop a chronic lung disease resembling human chronic infection, whereas wild type mice with intact GM-CSF production typically clear the bacteria quickly and fail to develop chronic infection.
−Removed: In animal studies, GM-CSF has been shown to kill NTM with similar efficacy compared to commonly used NTM antibiotics, and the simultaneous use of GM-CSF with antibiotics can further improve the antibacterial effect of either GM-CSF or antibiotics given alone.
−Removed: In two published clinical case reports in the European Respiratory Journal by Dr.
−Removed: Wylam of the Mayo Clinic, 2 inhaled GM-CSF was shown to eradicate or dramatically reduce the bacterial burden in patients with chronic MABSC lung infection.
−Removed: This suggests that the promising animal data may be translatable to humans, and the potential therapeutic role of GM-CSF in NTM lung infection warrants more intensive investigation.
−Removed: The multi-center OPTIMA study in non-CF patients was initiated in Q1 2018 and investigated the efficacy of Molgradex on reduction of NTM bacterial load in sputum, NTM sputum culture conversion to negative, exercise capacity, patient reported outcomes and safety.
−Removed: Two groups of subjects were recruited into the study, both of which received Molgradex 300 µg administered once daily.
−Removed: Treatment group one consisted of patients who remained sputum culture positive while currently on a multidrug NTM guideline-based anti-mycobacterial regimen, which had been ongoing for at least six-months prior to the baseline visit.
−Removed: Treatment group two consisted of patients who remained sputum culture positive, but either stopped a multidrug NTM guideline-based anti-mycobacterial regimen at least 28 days prior to screening due to lack of response or intolerance, or never started such treatment.
−Removed: The primary endpoint was sputum culture conversion during the treatment period, d efined as at least three consecutive negative sputum samples.
−Removed: Interim results from the OPTIMA study were disclosed in December 2018.
−Removed: Based on the microbiological data and safety profile, which provides the basis to continue treating patients for a longer period of time, the duration of the OPTIMA study was extended from 24 to 48 weeks, with a 12-week follow up period at the end of treatment.
−Removed: In March 2020, top line microbiology results from OPTIMA were announced that showed five out of 24 patients (21%) with MAC infection achieved a sputum culture conversion, defined as at least three consecutive sputum samples without growth of nontuberculous mycobacteria by week 48.
−Removed: For details on the results of the OPTIMA study, please see the “Clinical Development of Molgradex―NTM:
−Removed: Phase 2a OPTIMA Study” section included in this report.
−Removed: deSilva T.I., et al.
−Removed: Journal of Infection (2007) 54 (e207-e210);
−Removed: Hallstrand T.S., et al.
−Removed: European Respiratory Journal (2004) 24 (367-370);
−Removed: Groote et al, J Antimicrob Chemother.
−Removed: 2014 Apr;69(4):1057-64.;
−Removed: Bermudez, et al.
−Removed: The Journal of Infectious Diseases, Volume 169, Issue 3, 1 March 1994, Pages 575–580.
−Removed: Scott et al, European Respiratory Journal (2018) (DOI:
−Removed: 10.1183/13993003.02127-2017).
−Removed: In Q3 2018, the IND application for Molgradex in CF-affected patients with chronic NTM lung infection was accepted by the FDA.
−Removed: A Phase 2a study of Molgradex in CF-affected patients with NTM lung infection, called ENCORE, was initiated in Q1 2019.
−Removed: ENCORE is an open-label, non-controlled, multi-center, Phase 2a clinical study of Mo lgradex in patients living with CF who have persistent pulmonary NTM lung infection.
−Removed: ENCORE will enroll approximately 30 patients (≥18 years of age) with chronic MAC or MABSC infection, with all patients having either antibiotic refractory infection, intol erance to standard NTM antibiotics, or not currently meeting recommendations for antibiotic treatment.
−Removed: The study comprises a 48-week treatment period of 300 µg of Molgradex once daily and a 24-week follow up period.
−Removed: The primary endpoint in the study is spu tum culture conversion, defined as at least three consecutive negative NTM sputum samples with a four-week interval between each.
−Removed: Secondary endpoints include:
−Removed: (i) the number of patients with sputum smear conversion to negative, defined as at least three co nsecutive negative acid-fast bacilli (“AFB”) stained sputum smears on microscopy among patients who were smear positive at baseline, (ii) the reduction of bacterial load in sputum, and (iii) other microbiological indicators, pulmonary measures, and patient reported outcomes.
−Removed: Our second Phase 3 product candidate, AeroVanc, is a vancomycin hydrochloride inhalation powder.
−Removed: AeroVanc is the first inhaled antibiotic in development for the treatment of persistent MRSA lung infection in individuals living with CF.
−Removed: AeroVanc was granted Orphan Drug Designation and Qualified Infectious Disease Product (“QIDP”) status for the treatment of persistent MRSA lung infection in individuals living with CF in the U.S.
−Removed: Orphan Drug Designation makes AeroVanc eligible for seven years of exclusivity from approval in the U.S., and the QIDP designation makes AeroVanc eligible for an additional five years of exclusivity in the U.S.
−Removed: In 2017, a composition of matter patent covering AeroVanc was issued by the U.S.
−Removed: Patent and Trademark Office (“USPTO”), which affords us important protection for the program in the largest market for the product (the U.S.), augments our market protection strategy, and will not expire earlier than 2032.
−Removed: CF is a genetic disease that involves sticky mucus buildup in the lungs, persistent lung infections, and permanent and progressive respiratory disability.
−Removed: There are approximately 30,000 individuals affected by CF in the U.S.
−Removed: and with a prevalence of approximately 26% of people living with CF infected by MRSA, this lung infection has become increasingly common.
−Removed: Persistent MRSA infection in people living with CF is associated with increased use of intravenous (“IV”) antibiotics, increased hospitalizations, a more rapid rate of decline in lung function, and shortened life-expectancy.
−Removed: Due to the lung pathology associated with CF, persistent MRSA lung infection is difficult to eradicate or manage using oral or IV antibiotics and there is currently no standard-of-care to manage this condition.
−Removed: Whereas inhaled antibiotics have become a cornerstone of treating Pseudomonas aeruginosa (“Pseudomonas”), the most prevalent chronic pathogen in individuals living with CF, there are no approved inhaled antibiotics addressing MRSA lung infection.
−Removed: In a randomized, double-blind, placebo-controlled Phase 2 study in individuals living with CF with persistent MRSA infection, AeroVanc met a primary endpoint to reduce MRSA density in sputum and showed encouraging trends of improvement in lung function and respiratory symptoms, as well as prolongation of the time-to-use of other antibiotics, with best responses in patients under 21 years of age.
−Removed: AeroVanc is currently being investigated in a pivotal Phase 3 clinical study, called AVAIL, in the U.S.
−Removed: and Canada for the treatment of persistent MRSA lung infection in individuals living with CF.
−Removed: Study enrollment began in late 2017 and is targeted to enroll approximately 200 patients (150 patients ≤ 21 years old, 50 patients > 21 years old).
−Removed: During Period 1 of the study, patients are randomly assigned in a blinded 1:1 fashion to receive either AeroVanc (30 mg) twice daily, or placebo, by inhalation for 24 weeks or 3 dosing cycles.
−Removed: A dosing cycle is defined as 28 days of treatment followed by 28 days of observation.
−Removed: During Period 2 of the study, patients receive open-label AeroVanc (30 mg) twice daily for an additional 24 weeks or 3 dosing cycles, to evaluate the long-term safety of AeroVanc.
−Removed: The primary endpoint is the mean absolute change in Forced Expiratory Volume in the first second (“FEV1”) percent predicted from baseline, which will be analyzed sequentially at week 4 (the end of cycle 1), week 12 (the end of cycle 2), and at week 20 (the end of cycle 3).
−Removed: Analysis of the primary endpoint will be based on patients 6‒21 years of age.
−Removed: Secondary endpoints include:
−Removed: (i) time-to-use of another antibiotic medication (oral, IV, and/or inhaled) for pulmonary infection, (ii) the number of successful FEV1-response cycles a patient achieves over Period 1 (weeks 4, 12, and 20), (iii) relative change from baseline in FEV1 percent predicted at weeks 4, 12, and 20, (iv) change from baseline in Cystic Fibrosis Questionnai re-Revised scores at weeks 4, 12, and 20 and (v) change from Baseline in Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Symptom Score at weeks 4, 12, and 20.
−Removed: We will continue to enroll patients in the AVAIL study until Q2 2020.
−Removed: We anticipate enrolling approximately 140-145 out of the expected 150 patients in the primary analysis population.
−Removed: Top line results from the study are expected in early 2021.
+Added: In June 2019, we announced that IMPALA, the Phase 3 clinical trial of molgramostim for the treatment of aPAP, did not meet its primary endpoint of alveolar-arterial oxygen gradient, or (A-a)DO 2 , improvement compared to placebo and that the U.S.
+Added: Food and Drug Administration (“FDA”) indicated data from the IMPALA trial did not provide sufficient evidence of efficacy and safety.
+Added: The totality of data from the IMPALA trial – which extends beyond the primary endpoint – gives us confidence that molgramostim has the potential to address a significant unmet need in this rare disease.
+Added: These data include:
+Added: Multiple key secondary and exploratory endpoints that either achieved nominal statistical significance or trended in favor of the active drug arms;
+Added: Results from the open-label period of the trial that demonstrated a sustained treatment effect, or continued improvement, after longer term exposure to molgramostim.
+Added: Additionally, patients who had been on placebo during the double-blind period of the trial and switched to treatment with molgramostim during the open-label period, showed improvements that eventually caught up with those seen in patients who received molgramostim during the double-blind period;
+Added: Molgramostim being generally well tolerated.
+Added: In September 2020, results from the IMPALA trial were published in the New England Journal of Medicine.
+Added: We consider molgramostim to have a favorable risk-benefit profile and remain confident in the future of the program, including the upcoming Phase 3 IMPALA 2 trial.
+Added: In May 2019, the FDA granted Fast Track Designation to molgramostim for the treatment of aPAP.
+Added: Fast Track Designation facilitates the development and expedites the review of new drugs or biologics intended to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs.
+Added: In December 2019, although the IMPALA data did not meet the regulatory requirement for approval, the FDA granted a Breakthrough Therapy Designation (“BTD”) for molgramostim in aPAP based on data from the 24-week double-blind treatment period from our IMPALA trial.
+Added: Additionally, molgramostim was granted Orphan Drug Designation for the treatment of aPAP in the U.S.
+Added: and the European Union (“EU”), which allows for seven and ten years of exclusivity from approval, respectively.
+Added: Savara has exclusive access to the PARI eFlow ® Nebulizer System for this indication along with a proprietary cell bank for molgramostim, a non-glycosylated form of GM-CSF.
+Added: Molgramostim – NTM
+Added: Molgramostim was also being investigated in cystic fibrosis (“CF”) and non-CF patients for the treatment of nontuberculous mycobacterial (“NTM”) lung infection, a rare and serious lung disorder.
+Added: The most common types of NTM lung infection involve Mycobacterium avium complex (“MAC”) and Mycobacterium abscessus (“MABSC”).
+Added: Savara has conducted two exploratory clinical trials of molgramostim in patients with persistent pulmonary NTM lung infection.
+Added: An open-label, non-controlled, Phase 2a trial in non-CF patients
+Added: An open-label, non-controlled, Phase 2a clinical trial in patients with CF
+Added: The OPTIMA trial investigated the efficacy of molgramostim on reduction of NTM bacterial load in sputum, NTM sputum culture conversion to negative, exercise capacity, patient reported outcomes, and safety.
+Added: The primary endpoint was sputum culture conversion during the treatment period.
+Added: In March 2020, we disclosed top line microbiology results showing that OPTIMA did not meet the primary endpoint.
+Added: Data showed five out of 24 patients (21%) with MAC infection achieved a sputum culture conversion, defined as at least three consecutive sputum samples without growth of nontuberculous mycobacteria by week 48.
+Added: The ENCORE trial investigated the efficacy of molgramostim on reduction of NTM bacterial load in sputum, NTM sputum culture conversion to negative, and other microbiological indicators, pulmonary measures, and patient reported outcomes.
+Added: In September 2020, we announced the decision to discontinue the ENCORE trial based on confounding factors that compromised the ability of the trial to achieve its primary purpose of investigating the efficacy of molgramostim on NTM sputum culture conversion to negative.
+Added: Such factors included the impact of COVID-19 on patient recruitment and continued participation in the trial as well as the availability of the new triple-combination CFTR modulator, approved during the treatment period of ENCORE, which became a preferred treatment option for many CF patients.
+Added: Trial recruitment was terminated at the end of March 2020 with 14 patients enrolled out of a target of 30.
+Added: Ten out of 14 patients were on the triple-combination CFTR modulator, nine patients started it during the trial, and one patient was on the triple-combination modulator from baseline.
+Added: The decision to discontinue the trial was not based on safety concerns.
+Added: Due to the early discontinuation of the trial, not all patients completed the planned 48-week treatment period.
+Added: Based on preliminary data as of September 2020 from 12 patients who progressed at least beyond 20 weeks of treatment, five patients on the triple-combination CFTR modulator achieved a sputum culture conversion, defined as at least three consecutive sputum samples without growth of NTM.
+Added: All of those patients had started the triple-combination modulator during the trial prior to culture conversion.
+Added: Sputum culture conversions were not observed in patients who were on molgramostim without the triple-combination modulator.
+Added: Data disclosed from the ENCORE trial have not been validated and are subject to the final trial report.
+Added: Based on the results of the exploratory ENCORE and OPTIMA trials, we decided to continue focusing molgramostim development efforts on our lead indication, aPAP, and do not plan to conduct further development activities related to molgramostim in NTM.
+Added: Vancomycin hydrochloride inhalation powder
+Added: Vancomycin inhalation powder (“vancomycin,” formerly referred to as AeroVanc) was the first inhaled antibiotic in development for the treatment of persistent methicillin-resistant Staphylococcus aureus (“MRSA”) lung infection in individuals living with CF and was being investigated in a randomized, double-blind, placebo-controlled Phase 3 clinical trial called AVAIL.
+Added: The primary endpoint was the absolute change from baseline in Forced Expiratory Volume in one second (FEV 1 ) percent predicted at weeks 4, 12, and 20.
+Added: Secondary endpoints included:
+Added: (i) time-to-first pulmonary exacerbation requiring use of another antibiotic, (ii) frequency of pulmonary infection, (iii) patient reported outcome measures Cystic Fibrosis Questionnaire-Revised (CFRQ-R) and Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Infection Symptom Score (CFRSD-CRISS), and (iv) relative change in FEV 1 and area under the curve FEV 1 .
+Added: In December 2020, we announced the AVAIL trial did not meet the primary endpoint of mean absolute change from baseline in FEV 1 percent predicted analyzed sequentially at week 4, 12, and 20.
+Added: According to statistical hierarchy, if the trial did not show a statistically significant improvement in FEV 1 , the sequence of analysis would end.
+Added: Data from the trial showed a mean change from baseline in FEV 1 percent predicted compared to placebo of 1.4 at week 4 (p=0.33), 1.3 at week 12 (p=0.33), and 3.0 at week 20 (p=0.07) in the primary analysis population of patients 6-21 years of age.
+Added: Additionally, treatment with vancomycin did not result in a reduction in the frequency of pulmonary exacerbations versus placebo.
+Added: The exacerbation rate per year was 2.3 for both groups (risk ratio 1.0, 95% CI 0.7, 1.4).
+Added: Vancomycin was generally well tolerated.
+Added: Based on the AVAIL results, we have discontinued further development of the vancomycin program.
+Added: Inhaled liposomal ciprofloxacin (“Apulmiq”)
+Added: In March 2020, we entered into an exclusive license and collaboration agreement with Grifols, S.A.
+Added: (“Grifols”) for Apulmiq (inhaled liposomal ciprofloxacin).
+Added: Apulmiq is a late-stage (Phase 3-ready) investigational inhaled antibiotic for the treatment of non-cystic fibrosis bronchiectasis (“NCFB”).
+Added: Under the terms of the agreement, Savara obtained the worldwide rights to develop and
+Added: commercialize Apulmiq.
+Added: However, as part of our December 2020 pipeline simplification strategy that focuse d resources on molgramostim in aPAP and the IMPALA 2 trial, we discontinued the Apulmiq clinical development program.
Detailed Program Descriptions
Background on aPAP
−Removed: Autoimmune PAP, known as aPAP, is a specific disease belonging to a family of distinct rare lung diseases collectively referred to as PAP syndrome.
−Removed: aPAP represents about 90% of all patients with PAP syndrome and is estimated to affect up to seven out of a million people in the U.S.
−Removed: 3 , with similar or higher prevalence rates reported elsewhere in the world.
+Added: Autoimmune PAP, known as aPAP, is a specific disease belonging to a family of distinct rare lung diseases collectively referred to as PAP.
+Added: Autoimmune PAP represents about 90% of all patients with PAP and the estimated prevalence of PAP is seven cases per million people in the U.S.
+Added: 1 , with similar or higher prevalence reported elsewhere in the world.
For example, Japan, a country that undertakes a more centralized approach to diagnosing and treating aPAP, has seen a consistent increase in patients being diagnosed with the disease.
−Removed: It is now estimated the prevalence rate in Japan could be three times the original estimate of 7 per million.
−Removed: 4 PAP is characterized by the build-up of lung surfactant in the alveoli, or air sacs, of the lungs.
+Added: It is now estimated the prevalence in Japan could be four times the original estimate of seven cases per million.
+Added: 2 PAP is characterized by the build-up of surfactant in the alveoli, or air sacs, of the lungs.
The surfactant consists of proteins and lipids and is an important physiological substance that lines the inside of the alveoli to prevent the lungs from collapsing.
The lungs continuously produce new active surfactant.
−Removed: In a healthy lung, the old and inactivated surfactant is cleared and digested by immune cells called alveolar macrophages.
−Removed: However, in lungs of patients with aPAP, the macrophages fail to clear the surfactant from the alveoli, leading to gradual accumulation of excess surfactant in the alveoli.
−Removed: The root cause of aPAP is an autoimmune response against a naturally occurring protein in the body, GM-CSF.
−Removed: Pulmonary macrophages need to be stimulated by GM-CSF to function properly, but in aPAP, GM-CSF is deactivated by antibodies against GM-CSF, rendering the macrophages unable to perform their tasks, including the clearance of surfactant from the alveoli.
+Added: In a healthy lung, the surfactant is cleared by immune cells called alveolar macrophages.
+Added: However, in lungs of patients with aPAP, the macrophages fail to clear the surfactant from the alveoli, leading to gradual accumulation of surfactant in the alveoli.
+Added: The root cause of aPAP is an autoimmune response against GM-CSF, a naturally occurring protein in the body.
+Added: Pulmonary macrophages need to be stimulated by GM-CSF to function properly, but in aPAP, GM-CSF is neutralized by antibodies against GM-CSF, rendering the macrophages unable to perform their tasks, including the clearance of surfactant from the alveoli.
aPAP most commonly affects men in early middle age, but both sexes and patients of any age can be affected.
−Removed: As a result of the accumulation of excess surfactant, gas exchange in the lungs is obstructed, and patients start to experience shortness of breath and decreased exercise tolerance.
+Added: As a result of the accumulation of surfactant, gas exchange in the lungs is obstructed, and patients start to experience shortness of breath and decreased exercise tolerance.
Typically, shortness of breath is first observed upon exertion, but as the disease progresses, shortness of breath can be experienced even when a person is at rest.
−Removed: Patients may experience chronic cough, as well as episodes of fever, chest pain, or coughing blood, especially if secondary lung infection develops.
+Added: Patients may experience cough, as well as episodes of fever, especially if secondary lung infection develops.
In the long-term, the disease can lead to serious complications, including lung fibrosis and the need for lung transplant.
−Removed: Mortality due to aPAP has decreased over the last decades with better clinical management, but in rare cases serious lung infections or respiratory insufficiency may lead to death.
Current treatment options for aPAP
−Removed: The current standard-of-care for aPAP is a surgical procedure called Whole Lung Lavage (“WLL”), which entails washing out the lungs with saline under general anesthesia.
−Removed: WLL is an invasive and inconvenient procedure that is performed at specialist sites and requires highly experienced physicians.
−Removed: The procedure, conducted in an operating room under general anesthesia, necessitates hospitalization and admission to intensive care afterwards.
−Removed: In many patients, WLL only provides temporary symptomatic relief, and once the lungs refill with surfactant, the WLL procedure needs to be repeated.
−Removed: As there are no approved drug treatments available for aPAP, there is a high need for a convenient and efficacious medicinal treatment.
−Removed: We believe that inhalation of GM-CSF directly into the lungs has the potential to replace the inactivated GM-CSF, thereby restoring the surfactant clearing activity of the alveolar macrophages and resulting in the potential to considerably improve oxygenation and exercise tolerance.
−Removed: An injectable form of GM-CSF, sargramostim, is approved and on the market in the U.S.
−Removed: for IV and subcutaneous administration for the treatment of neutropenia caused by cancer chemotherapy, but there are currently no approved inhalation formulations of GM-CSF.
+Added: The current standard-of-care for aPAP is a procedure called Whole Lung Lavage (“WLL”), which entails washing out the lungs with saline, one lung at a time, under general anesthesia.
+Added: WLL is an invasive and inconvenient procedure that is performed by highly experienced physicians at specialist sites and necessitates hospitalization and admission to intensive care afterwards.
+Added: In many patients, WLL may only provide temporary symptomatic relief.
+Added: Once the lungs refill with surfactant, the WLL procedure needs to be repeated.
+Added: As there are no approved pharmaceutical treatments available for aPAP, there is a high need for a convenient and efficacious medicinal treatment.
+Added: We believe that inhalation of molgramostim activates macrophages in the lung alveoli, thus potentially restoring the surfactant clearing activity of the alveolar macrophages and considerably improving oxygenation and exercise tolerance.
+Added: Sargramostim, an injectable form of GM-CSF, is approved in the U.S.
+Added: for intravenous (“IV”) and subcutaneous administration (“SC”) treatment of neutropenia caused by cancer chemotherapy and other related indications.
+Added: Currently, there are no approved inhalation formulations of GM-CSF.
+Added: GM-CSF products administered systemically (e.g., by injection), including molgramostim, are unlikely to benefit patients with aPAP because autoimmune PAP patients have circulating antibodies against GM-CSF.
+Added: These antibodies would likely neutralize systemically administered GM-CSF before reaching the alveolar space in the lung, unless a very large (perhaps impractical) amount of GM-CSF is injected to overwhelm the circulating anti-GM-CSF antibody.
Trapnell BC, Avetisyan R, Carey B, Zhang W, Kaplan P, Wang H.
5 unchanged sentences
ERJ Open Res.
−Removed: The potential bene fits of inhaled GM-CSF in aPAP, together with the availability of sargramostim for off-label compounding, have stimulated independent clinicians and academic researchers in the U.S., Europe, and Japan to study the safety and efficacy of GM-CSF, administere d by inhalation, in aPAP patients.
−Removed: In addition to our Phase 3 IMPALA study of Molgradex (molgramostim), the largest placebo-controlled study in this patient population (n=138), several investigator-sponsored, open-label clinical studies and case studies of inhaled GM-CSF treatment have been published, with promising results on the efficacy and safety of the treatment.
−Removed: 5 , 6 , 7 In total, treatment of nearly 150 aPAP patients with inhaled GM-CSF has been reported in open-label studies or retrospective cohorts, as well as several individual case reports.
−Removed: The recently published data originate from a study called PAGE.
−Removed: It was a randomized, double-blind, placebo-controlled, 25-week study of inhaled sargramostim in 64 patients with mild-to-moderate disease.
−Removed: A modest bu t significant effect was observed in the primary endpoint, change from baseline in (A-a)DO 2 .
−Removed: Secondary endpoints, including changes from baseline in vital capacity, diffusing capacity for carbon monoxide (“DLCO”), six-minute walk distance (“6MWD”), and aPA P serum biomarkers, showed directional, but in most cases not statistically significant, treatment effects over placebo.
−Removed: Overall, for the first time, this study showed in a placebo-controlled setting, proof-of-concept for GM-CSF inhalation therapy in aPAP.
−Removed: Results from these investigator-sponsored clinical studies and case studies indicate that both molgramostim and sargramostim have the potential for a positive impact on oxygenation and clinical symptoms in aPAP patients.
−Removed: According to our review of published literature, few safety issues related with molgramostim or sargramostim inhalation in patients with aPAP have been reported.
+Added: The potential benefits of inhaled GM-CSF in aPAP, together with the availability of sargramostim for off-label compounding, have prompted independent clinicians and academic researchers in the U.S., Europe, and Japan to study the safety and efficacy of inhaled GM-CSF in aPAP patients.
+Added: In addition to our Phase 3 IMPALA trial of molgramostim, the largest placebo-controlled trial in this patient population (n=138), several investigator-sponsored, open-label clinical trials and case studies of inhaled GM-CSF treatment have been published, with promising results on the efficacy and safety of the treatment.
+Added: 3 , 4 , 5 In total, treatment of nearly 150 aPAP patients with inhaled GM-CSF ha ve been reported in open-label trials or retrospective cohorts, as well as several individual case reports.
+Added: In PAGE, a randomized, double-blind, placebo-controlled, 25-week clinical trial of inhaled sargramostim in 64 patients with mild-to-moderate disease, a significant effect was observed in the primary endpoint, which was change from baseline in (A-a)DO 2 .
+Added: Secondary endpoints, including changes from baseline in diffusing capacity for carbon monoxide ( “ DLCO ” ), six-minute walk distance ( “ 6MWD ” ), and aPAP serum biomarkers, showed directional, but in most cases not statistically significant, treatment effects over placebo.
+Added: Overall, for the first time, the PAGE trial showed in a placebo-controlled setting, proof-of-concept for GM-CSF inhalation therapy in aPAP.
+Added: Results from these investigator-sponsored clinical trials and case studies indicate that GM-CSF may have a positive impact on oxygenation and clinical symptoms in aPAP patients.
+Added: For details on the results of the IMPALA trial, please see the “Clinical Development of Molgramostim―aPAP:
+Added: Phase 3 IMPALA Trial ” section included in this report .
+Added: According to our review of published literature, few safety issues related with GM-CSF inhalation in patients with aPAP have been reported.
However, there is still limited information available on the long-term safety of inhaled GM-CSF.
In indications other than aPAP, more than 100 patients, mainly with a cancer diagnosis, have received inhaled sargramostim in doses up to 4000 µg/day.
−Removed: Pulmonary toxicity was the most frequently reported toxicity at high doses.
−Removed: An increase in both number and severity of adverse events with increasing dose have been observed.
−Removed: However, due to the underlying diseases, it was often difficult for the investigators to assess causality of the adverse event cases.
−Removed: Molgradex Product Description
−Removed: Molgradex is a novel inhaled formulation of recombinant human GM-CSF being developed for the treatment of aPAP.
−Removed: The active drug substance, molgramostim, is a non-glycosylated form of GM-CSF.
−Removed: GM-CSF is an endogenous growth factor that stimulates the proliferation and differentiation of hematopoietic cells (blood and immune cells), mainly granulocytic and monocytic cell lines, which serve as the body’s first line of defense against bacteria and viruses, and also function to clear cellular debris and waste substances from the body.
+Added: Pulmonary adverse event was the most frequently reported adverse event at high doses.
+Added: An increase in both the number and severity of adverse events with an increasing dose has been observed.
+Added: However, due to the underlying diseases, it was often difficult for investigators to assess causality of the adverse event cases.
+Added: Product Description
+Added: Molgramostim is a non-glycosylated form of recombinant human GM-CSF that we are developing as an inhaled formulation for the treatment of aPAP.
+Added: GM-CSF is an endogenous growth factor that stimulates the proliferation and differentiation of hematopoietic cells (blood immune cells), mainly granulocytic and monocytic cell lines, which defend against bacteria and viruses, and clear cellular debris and waste substances from the body.
Molgramostim is produced in a strain of Escherichia coli bearing a genetically engineered plasmid containing a human GM-CSF gene.
−Removed: Molgradex is a sterile nebulizer solution in a vial containing 300 µg of molgramostim designed to be administered once daily by inhalation via a high efficiency Investigational eFlow Nebulizer System (PARI Pharma GmbH, Germany).
−Removed: The PARI eFlow Nebulizer system for use with investigational drug products is a reusable electronic inhalation system that has been optimized for administration of Molgradex.
−Removed: Molgradex was granted Orphan Drug Designation by the FDA in October 2012, and by the EMA in July 2013, for the treatment of aPAP.
−Removed: Molgradex was also granted Fast Track Designation and Breakthrough Therapy Designation by the FDA in May 2019 and December 2019, respectively, for the treatment of aPAP.
−Removed: Since 2014, Molgradex has been available in several European countries for the treatment of aPAP for named patients following unsolicited physician requests.
−Removed: We anticipate that Molgradex will be used as a long-term therapy in patients with aPAP.
+Added: Our product is a drug-device combination consisting of molgramostim nebulizer solution (drug component) and a nebulizer (device component).
+Added: Molgramostim nebulizer solution is vialed as a sterile formulation containing 300 µg of molgramostim in 1.2 mL solution.
+Added: Molgramostim nebulizer solution is administered once daily by inhalation via a high efficiency nebulizer, the eFlow ® Nebulizer System (PARI Pharma GmbH).
+Added: The eFlow ® Nebulizer System is a reusable electronic inhalation system that has been optimized for administration of molgramostim nebulizer solution.
+Added: The eFlow ® consists of a controller unit (AC or battery powered), a nebulizer handset, and a connection cord.
+Added: The controller unit has a life span of multiple years and the handset is replaced monthly with a new unit.
+Added: Molgramostim was granted Orphan Drug Designation by the FDA (October 2012) and by the EMA (July 2013) for the treatment of aPAP.
+Added: It was also granted Fast Track Designation and Breakthrough Therapy Designation by the FDA in May 2019 and December 2019, respectively.
+Added: Since 2014, molgramostim has been available in several European countries for the treatment of aPAP for named patients following unsolicited physician requests.
+Added: We anticipate that molgramostim will be used as a long-term therapy in patients with aPAP.
The optimal duration of treatment is currently not known and is likely to vary between patients depending on disease severity and the natural course of their disease.
−Removed: Treatment with Molgradex may not entirely eliminate the need for WLL in all patients.
−Removed: However, based on interviews we conducted, PAP centers that have experimented with long-term inhaled GM-CSF have seen a considerable reduction of WLL procedures.
−Removed: In the IMPALA study, we observed a reduced number of WLL procedures in the active treatment arms, but the difference was not statistically significant due to the relatively low number of the procedures.
−Removed: In the open-label extension period (Period 2) of the study, when all patients received active drug, there was a further reduction of WLL procedures, suggesting that prolonged treatment with Molgradex may considerably reduce the need for WLL.
+Added: Treatment with molgramostim may not entirely eliminate the need for WLL in all patients.
+Added: In the IMPALA trial, we observed a reduced number of WLL procedures in the active treatment arms, but the difference was not statistically significant due to the relatively low number of the procedures (approximately 10%).
+Added: In the open-label extension period (Period 2) of the trial, when all patients received active drug, there was a further reduction of WLL procedures.
+Added: This suggests that prolonged treatment with molgramostim may reduce the need for WLL.
Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, et al.
9 unchanged sentences
Clin Drug Investig 34(8):
−Removed: Molgradex Key Advantages
−Removed: Based on data from the completed Phase 3 IMPALA study and building upon the published investigator-sponsored treatment experience with inhaled GM-CSF, we believe Molgradex has the potential to become the treatment of choice for aPAP.
−Removed: Molgradex has the following characteristics that may contribute to the clinical profile of the product candidate, as well as facilitate potential regulatory approval and successful commercialization.
−Removed: Specifically, Molgradex offers:
+Added: Molgra mostim Key Advantages
+Added: Based on data from the completed Phase 3 IMPALA trial and building upon the published investigator-sponsored treatment experience with inhaled GM-CSF, we believe molgramostim has the potential to become the treatment of choice for aPAP.
+Added: Molgramostim has the following characteristics that may contribute to the clinical profile of the product candidate, as well as facilitate potential regulatory approval and successful commercialization.
+Added: Specifically, molgramostim offers:
A strong product foundation that applies both a previously approved active drug substance class and drug delivery technology.
−Removed: GM-CSF delivery directly to the lungs, the primary site of macrophage function deficiency, which could result in high clinical efficacy with limited systemic adverse effects.
+Added: GM-CSF delivered directly to the lungs, the primary site of macrophage function deficiency, which could result in high clinical efficacy with limited systemic adverse effects.
A high-efficiency nebulizer that provides a fast and convenient method of administration.
This is highly desirable for long-term treatment in a chronic disease, such as aPAP.
−Removed: Eligibility for strong market protection via orphan drug status, potential eligibility for biologic exclusivity in the U.S., a proprietary cell bank used in the production of the drug substance, and an exclusive device supply agreement.
−Removed: Clinical Development of Molgradex ‒ aPAP
−Removed: Phase 3 IMPALA Study
−Removed: In June 2019 we announced the results of a pivotal Phase 3 clinical study of Molgradex, called IMPALA, that was conducted in 18 countries including the U.S., Japan, and various European countries.
−Removed: IMPALA was a randomized, double-blind, placebo-controlled study designed to compare the efficacy and safety of Molgradex with placebo in patients with aPAP.
+Added: Eligibility for strong market protection via orphan drug status, potential eligibility for biologic exclusivity in the U.S., and Fast Track and Breakthrough Therapy Designations.
+Added: A proprietary cell bank used in the production of the drug substance.
+Added: An exclusive agreement for a device that is optimized for administration of molgramostim nebulizer solution.
+Added: Clinical Development of Molgramostim ‒ aPAP
+Added: Phase 3 IMPALA Trial
+Added: IMPALA was a Phase 3 randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of molgramostim in patients with aPAP.
+Added: Conducted in 18 countries including the U.S., Japan, and various European countries, it was the largest controlled clinical trial of molgramostim for the treatment of aPAP.
Patients were randomized to receive treatment for up to 24 weeks in one of three treatment arms:
−Removed: 1) Molgradex 300 µg administered once daily, 2) Molgradex 300 µg and matching placebo administered daily every other week, or 3) inhaled placebo administered once daily.
−Removed: At the end of the 24-week double-blind period, all patients received Molgradex 300 ug administered daily in 7-day intermittent cycles in a 24-week open-label follow up period.
−Removed: The primary endpoint of the study was (A-a)DO 2 , a commonly used measure of oxygenation impairment.
+Added: 1) molgramostim 300 µg administered once daily (“continuous dosing arm”), 2) molgramostim 300 µg and matching placebo administered daily every other week (“intermittent dosing arm”), or 3) inhaled placebo administered once daily.
+Added: At the end of the 24-week double-blind period, all patients received molgramostim 300 ug administered daily in every other week intermittent cycles in a 24-week open-label follow up period.
+Added: The primary endpoint of the trial was (A-a)DO 2 , a commonly used measure of oxygenation impairment.
In addition, three key secondary endpoints―St.
George’s Respiratory Questionnaire (“SGRQ”), 6MWD, and time to/requirement for WLL― along with multiple other secondary and exploratory endpoints were assessed to determine improvement in the disease pathology, pathophysiology, clinical symptoms, and function.
−Removed: The pathogenesis of aPAP is well known and GM-CSF’s effect on the disease, as evaluated by (A-a)DO 2 , dyspnea, 6MWD, pulmonary function tests, CT scores, and biomarkers, is well documented through published clinical studies.
−Removed: When looking at the totality of evidence, we believe that data from the IMPALA study demonstrate reversal of lung pathology and pathophysiology, improvement in clinical outcomes, and reduction of the need for rescue treatment, with a clear dose-frequency dependency in favor of the continuous dosing arm.
+Added: The pathogenesis of aPAP is well known and GM-CSF’s effect on the disease, as evaluated by (A-a)DO 2 , dyspnea, 6MWD, pulmonary function tests, computed tomography (“CT”) scores, and biomarkers, is well documented through published clinical trials.
+Added: While IMPALA did not meet its primary endpoint, when looking at the totality of evidence, we believe that data from the IMPALA trial demonstrate reversal of lung pathology and pathophysiology, improvement in clinical outcomes, and reduction of the need for rescue treatment, with a clear dose-frequency dependency in favor of the continuous dosing arm.
Such results are detailed below:
−Removed: Lung Pathology― Reversal of disease pathology and reduction of surfactant accumulation was demonstrated in the Full Analysis Set Population (FAS) with improvement in CT scans as measured by Ground Glass Opacity (GGO) scores.
+Added: Lung Pathology―Reversal of disease pathology and reduction of surfactant accumulation was demonstrated in the Full Analysis Set (“FAS”) population with improvement in CT scans as measured by Ground Glass Opacity (“GGO”) scores.
Results from IMPALA also demonstrated positive biomarker data, with improvements seen in most of the key biomarkers known to be associated with the severity of aPAP .
Lung Pathophysiology― In the FAS population, a n average (A-a)DO 2 improvement of 12.1 mmHg was observed in the continuous dosing arm, compared to an average (A-a)DO 2 improvement of 8.8 mmHg in the placebo arm.
−Removed: With an estimated 4.6 mmHg treatment difference, the study did not meet its primary endpoint.
−Removed: Notably, one-third of patients in IMPALA were prescribed supplemental oxygen, continuously or as necessary, during the study.
−Removed: The study protocol recommended that supplemental oxygen not be used immediately before or during arterial blood sampling to minimize influence on (A-a)DO 2 values.
−Removed: For ethical reasons, the protocol did allow patients to remain on supplemental oxygen during blood sampling if they could not tolerate discontinuation due to the severity of their respiratory condition.
−Removed: This was conditionally allowed only if they received the same oxygen flow rate as used at baseline at all subsequent visits (n=4 patients, two in the placebo group and one in each of the active groups).
−Removed: In these four patients, (A-a)DO 2 values distributed quite differently compared to the remaining study population―ranging from highly negative to highly positive.
+Added: estimated 4.6 mmHg treatment difference, the trial did not meet its primary endpoint.
+Added: Notably, one-third of patients in IMPALA were prescribed supplemental oxygen, continuously or as necessary, during the trial.
+Added: The trial protocol recommended that supplemental oxygen not be used immediately before or during arterial blood sampling to minimize influence on (A-a)DO 2 values.
+Added: The protocol did allow patients to remain on supplemental oxygen during blood sampling if they could not tolerate discontinuation due to the severity of their respiratory condition.
+Added: This was conditionally allowed only if they received the same oxygen flow rate used at baseline at all subsequent visits (n=4 patients, two in the placebo arm and one in each of the active arm s).
+Added: In these four patients, (A-a)DO 2 values distributed quite differently compared to the remaining trial population―ranging from highly negative to highly positive.
In a revised analysis that excluded these four patients, a statistically significant average (A-a)DO 2 improvement was observed in the continuous dosing arm compared with the placebo arm.
Impaired gas transfer and oxygenation are key pathophysiologic features of aPAP and are associated with symptoms of shortness of breath and limitations in exercise capacity.
−Removed: In addition to (A-a)DO 2 , DLCO was assessed in the FAS as a secondary endpoint to evaluate the efficacy of Molgradex on gas transfer.
+Added: In addition to (A-a)DO 2 , DLCO was assessed in the FAS as a secondary endpoint to evaluate the efficacy of molgramostim on gas transfer.
Patients in the continuous dosing arm showed a mean improvement of 11.6% predicted in DLCO, whereas the intermittent dosing and placebo arms showed a 7.7% predicted and 3.9% predicted improvement, respectively.
−Removed: The estimated treatment difference of 7.9 % predicted (p=0.007) between the con tinuous dosing arm and placebo was statistically significant, and in keeping with the (A-a)DO 2 improvement, suggests improved gas exchange in the lungs.
−Removed: Clinical Outcomes―In the FAS population, a n average improvement of 12.3 points in the SGRQ, a patient-reported outcomes/quality-of-life measure and a key secondary endpoint, was observed in the continuous dosing arm compared to an average improvement of 4.7 points in the placebo arm .
+Added: The estimated treatment difference of 7.9% predicted (p=0.007) between the continuous dosing arm and placebo was statistically significant, and in keeping with the (A-a)DO 2 improvement, and suggests improved gas exchange in the lungs.
+Added: Clinical Outcomes―In the FAS population, a n average improvement of 12.3 points in the SGRQ, a patient-reported outcomes/health status measure and a key secondary endpoint, was observed in the continuous dosing arm compared to an average improvement of 4.7 points in the placebo arm .
The estimated treatment difference was 7.6 points which was statistically significant (p < 0.05).
4 unchanged sentences
Given that some patients received more than one WLL, the total number of WLLs observed in the continuous dosing arm was 9, with 7 observed in the intermittent dosing arm and 17 in the placebo arm.
−Removed: Consistency of Endpoints in the FAS― A range of primary and secondary endpoints were selected to determine the potential treatment effect of Molgradex on aPAP.
−Removed: Patients in the continuous dosing arm demonstrated consistent improvements across all of the key endpoints compared to placebo, with the majority of the measures achieving statistical significance .
−Removed: A dose-frequency dependency was observed, with continuous daily administration of Molgradex generally resulting in higher efficacy than intermittent dosing.
−Removed: Safety and Tolerability― The number of treatment emergent adverse events (TEAEs) in the FAS population, including serious adverse events, occurred with similar frequency and severity in the active arms compared to placebo and did not indicate any notable safety concerns.
−Removed: In March 2018, the IMPALA-X clinical study was initiated.
−Removed: This open-label extension study allowed patients who have completed the IMPALA study to continue treatment for up to three additional years and will provide additional data on the long-term safety and use of Molgradex in patients with aPAP.
−Removed: In February 2020, IMPALA-X enrollment was complete, with 60 patients out of a total of 64 eligible patients enrolled.
−Removed: Results from the open-label period of the study announced in March 2020, demonstrated a sustained treatment effect, or continued improvement, after longer term exposure to Molgradex.
+Added: Consistency of Endpoints in the FAS― A range of primary and secondary endpoints were selected to determine the potential treatment effect of molgramostim on aPAP.
+Added: Patients in the continuous dosing arm demonstrated consistent improvements across all the key endpoints compared to placebo, with the majority of the measures achieving statistical significance .
+Added: A dose-frequency dependency was observed, with continuous daily administration of molgramostim generally resulting in higher efficacy than intermittent dosing.
+Added: Safety and Tolerability― The percentage of patients with adverse events were similar in the treatment arms, except for the percentage of patients with chest pain, which was higher in the continuous dosing arm compared to placebo .
+Added: Results from the open-label period of the IMPALA trial, announced in March 2020, demonstrated a sustained treatment effect, or continued improvement, after longer term exposure to molgramostim.
A summary of the results can be found below.
−Removed: During the double-blind period, a dose frequency dependency was observed with continuous administration of Molgradex resulting in higher efficacy than intermittent dosing.
−Removed: Results from the open-label period noted below therefore focus on the group that had received a continuous dose (OD) of Molgradex during the double-blind period versus those that had received placebo (PBO)―both of which received intermittent dosing during the open-label period.
−Removed: Patients who had been in the OD treatment group during double-blind period :
−Removed: (A-a)DO 2 improvement from baseline continued in these patients during the open-label period of the study, with progressively larger improvements at weeks 48 and 72 of the study.
+Added: During the double-blind period, a dose frequency dependency was observed with continuous administration of molgramostim resulting in higher efficacy than intermittent dosing.
+Added: Results from the open-label period noted below, therefore, focus on the group that had received a continuous dose of molgramostim during the double-blind period versus those that had received placebo, both of which received intermittent dosing during the open-label period.
+Added: Patients who had been in the continuous dosing group during the double-blind period :
+Added: (A-a)DO 2 improvement from baseline continued in these patients during the open-label period of the trial, with progressively larger improvements at weeks 48 and 72.
Likewise, progressively larger improvements from baseline were observed in DLCO and SGRQ at weeks 48 and 72.
−Removed: Patients who had been in the PBO group during double-blind period:
−Removed: PBO patients that transitioned to active drug showed similar average improvements in (A-a)DO 2 , DLCO, and SGRQ in the open-label period as compared to the OD group during the double-blind period, reaching similar level of improvement with the OD group by week 72.
+Added: Patients who had been in the placebo group during the double-blind period:
+Added: Placebo patients that transitioned to active drug showed similar average improvements in (A-a)DO 2 , DLCO, and SGRQ in the open-label period as compared to the continuous dosing group during the double-blind period, reaching similar levels of improvement to the continuous dosing group by week 72.
Similar trends were seen in the 6MWD at weeks 48 and 72, but the data were less conclusive.
−Removed: During the double-blind period of the study, 33 WLL procedures were required, 9 in the continuous group compared to 17 in the placebo group.
−Removed: During the 48-week open-label period of the study, during which time all patients received active drug, only 5 WLL procedures were conducted.
−Removed: Background on NTM
−Removed: NTM lung infection is a rare and serious lung disorder associated with increased rates of morbidity and mortality.
−Removed: Nontuberculous mycobacteria are naturally occurring organisms and NTM lung infection can occur when an individual inhales the organism from their environment and develops a slowly progressive and destructive lung disease.
−Removed: NTM lung infection is typically characterized by cough, fatigue, and weight loss.
−Removed: NTM infections often become chronic and require long courses of multiple antibiotics and, despite aggressive treatment regimens, treatment failure rates are high and recurrence of infection common.
−Removed: Chronic NTM lung infection can have a significant impact on quality of life.
−Removed: There are up to 80,000 individuals affected by NTM in the U.S, and the most common types of NTM lung infection involve MAC and MABSC.
−Removed: There have been few advancements in new systemic treatments for NTM lung infection.
−Removed: However, in 2018 the FDA granted accelerated approval of an inhaled form of amikacin directly to the lung.
−Removed: In a 2017 Phase 3 study, the drug was shown to be effective in approximately one third of treatment refractory patients with pulmonary MAC infection.
−Removed: This suggests that administration of high local concentrations of drug directly at the site of infection provides an attractive new avenue to improve clinical outcomes in this and other difficult-to-treat chronic lung infections.
−Removed: NTM lung infections are a considerable therapeutic challenge due to the unique ability of these bacteria to evade the normal killing mechanisms of alveolar macrophages, a type of immune cells responsible for killing bacteria in the lungs.
−Removed: There is increasing scientific literature suggesting that GM-CSF plays an important role in enhancing the ability of macrophages to clear mycobacteria.
−Removed: 8 For instance, GM-CSF knock out mice inoculated with MABSC develop a chronic lung disease resembling human chronic infection, whereas wild type mice with intact GM-CSF production typically clear the bacteria quickly and fail to develop chronic infection.
−Removed: In animal studies, GM-CSF has been shown to kill NTM with similar efficacy compared to commonly used NTM antibiotics, and the simultaneous use of GM-CSF with antibiotics can further improve the antibacterial effect of either GM-CSF or antibiotics given alone.
−Removed: In two published clinical case reports in the European Respiratory Journal by Dr.
−Removed: Wylam of the Mayo Clinic, 9 inhaled GM-CSF was shown to eradicate or dramatically reduce the bacterial burden in patients with refractory MABSC lung infection.
−Removed: This suggests that the promising animal data may be translatable to humans, and the potential therapeutic role of GM-CSF in NTM lung infection warrants more intensive investigation.
−Removed: Among the various NTM species, MABSC is a particularly challenging clinical problem, as it is one of the most resistant organisms to antibiotics.
−Removed: Importantly, GM-CSF is not an antibiotic that targets the bacteria.
−Removed: Rather, it is an anti-infective immunotherapy that targets the human immune response, not the bacteria directly, thus avoiding the increasing problem of antibiotic resistance.
−Removed: Clinical Development of Molgradex ‒ NTM
−Removed: Phase 2a OPTIMA Study
−Removed: A Phase 2a multi-center clinical study in non-CF patients, called OPTIMA, was initiated in Q1 2018 and investigated the efficacy of Molgradex on reduction of NTM bacterial load in sputum, NTM sputum culture conversion to negative, exercise capacity, patient reported outcomes, and safety.
−Removed: OPTIMA is an open-label, non-controlled, multi-center, Phase 2a clinical study of Molgradex in 32 subjects (≥18 years of age) with persistent NTM lung infection.
−Removed: OPTIMA enrolled subjects with chronic MAC or MABSC infection, with all patients having either antibiotic refractory infection or intolerance to standard NTM antibiotics.
−Removed: The study initially consisted of a 24-week treatment period and a 12-week follow up period.
−Removed: Two groups of subjects were recruited into the OPTIMA study, both of which received Molgradex 300 µg administered once daily.
−Removed: Treatment group one consisted of patients who remained sputum culture positive while currently on a multidrug NTM guideline-based anti-mycobacterial regimen, which had been ongoing for at least six-months prior to the baseline visit.
−Removed: Treatment group two consisted of patients who remained sputum culture positive, but either stopped a multidrug NTM guideline-based anti-mycobacterial regimen, at least 28 days prior to screening due to lack of response or intolerance, or never started such treatment.
−Removed: Interim results from the OPTIMA study were disclosed in December 2018.
−Removed: Based on the microbiological data and safety profile, which provides the basis to continue treating patients for a longer period of time, the duration of the OPTIMA study was extended from 24 to 48 weeks, with a 12-week follow up period at the end of treatment.
−Removed: deSilva T.I., et al.
−Removed: Journal of Infection (2007) 54 (e207-e210);
−Removed: Hallstrand T.S., et al.
−Removed: European Respiratory Journal (2004) 24 (367-370);
−Removed: Groote et al, J Antimicrob Chemother.
−Removed: 2014 Apr;69(4):1057-64.;
−Removed: Bermudez, et al.
−Removed: The Journal of Infectious Diseases, Volume 169, Issue 3, 1 March 1994, Pages 575–580.
−Removed: Scott et al, European Respiratory Journal (2018) (DOI:
−Removed: 10.1183/13993003.02127-2017).
−Removed: The primary endpoint in the study is sputum culture conversion, defined as at least three consecutive sputum samples without growth of NTM.
−Removed: Secondary endpoints include:
−Removed: (i) the number of patients with sputum smear conversion to ne gative, defined as at least three consecutive negative AFB stained sputum smears on microscopy among patients who were smear positive at baseline, (ii) the number of patients with durable sputum culture conversion, defined as sputum culture conversion at o r before week 48 and culture still negative for growth of NTM at 12-week follow up, (iii) the number of patients with durable sputum smear conversion, defined as sputum smear conversion at or before week 48 and AFB stained smear still negative for NTM at 1 2-week follow up among patients who were smear positive at baseline, and (iv) other microbiological indicators, exercise capacities , and patient reported outcomes.
−Removed: In March 2020 top line microbiology results from the OPTIMA were announced.
−Removed: In the study, 24 patients had MAC infection and 8 patients had MABSC infection.
−Removed: Of the patients with MAC infection, 11 were in treatment group one and 13 were in treatment group two.
−Removed: Of the patients with MABSC infection, 3 were in treatment group one and 5 were in treatment group two.
−Removed: Results from the Intention-to-Treat (ITT) population showed that 5 out of 24 patients (21%) with MAC infection achieved a sputum culture conversion, defined as at least three consecutive sputum samples without growth of nontuberculous mycobacteria by week 48.
−Removed: Two of these patients, one from each treatment group, remained culture negative through the 12-week follow-up period.
−Removed: Sputum culture conversions were not observed in patients with MABSC infection.
−Removed: Among the 32 patients, 14 experienced serious adverse events (SAEs), one of which was considered potentially treatment related.
−Removed: The most common SAE was infective exacerbation of bronchiectasis.
−Removed: Three patients died during the study, with all deaths being considered unlikely related to the study treatment.
−Removed: In Q3 2018, the IND application for Molgradex in CF-affected patients with chronic NTM lung infection was accepted by the FDA.
−Removed: A Phase 2a study of Molgradex in CF-affected patients with NTM lung infection, called ENCORE, was initiated in Q1 2019.
−Removed: ENCORE is an open-label, non-controlled, multi-center, Phase 2a clinical study of Molgradex in patients living with CF who have persistent pulmonary NTM lung infection.
−Removed: ENCORE will enroll approximately 30 patients (≥18 years of age) with chronic MAC or MABSC infection, with all patients having either antibiotic refractory infection, intolerance to standard NTM antibiotics, or not currently meeting recommendations for antibiotic treatment.
−Removed: The study comprises a 48-week treatment period of 300 µg of Molgradex once daily and a 24-week follow up period.
−Removed: The primary endpoint in the study is sputum culture conversion, defined as at least three consecutive negative NTM sputum samples with a four-week interval between each.
−Removed: Secondary endpoints include:
−Removed: (i) the number of patients with sputum smear conversion to negative, defined as at least three consecutive negative AFB stained sputum smears on microscopy among patients who were smear positive at baseline, (ii) the reduction of bacterial load in sputum, and (iii) other microbiological indicators, pulmonary measures, and patient reported outcomes.
−Removed: Overview of AeroVanc
−Removed: Background on MRSA Infection in CF
−Removed: CF is a genetic disease characterized, in part, by the prevalence of thick, sticky mucus produced in the lung, frequent lung infections, and a resultant decline in pulmonary function.
−Removed: As the disease progresses, patients’ lungs are typically infected with bacteria that are difficult to eradicate.
−Removed: Inhaled antibiotics have become a cornerstone for the treatment of the most common chronic pathogen, pseudomonas, in order to control the infection and improve lung function and quality of life.
−Removed: In recent years, MRSA lung infection has become increasingly common in CF, with a prevalence rate of 26% according to the most recent (2017) data report of the Cystic Fibrosis Foundation.
−Removed: Importantly, persistent MRSA lung infection has been associated with worse clinical outcomes in CF, including a more rapid rate of decline in lung function 10 and a shorter life expectancy.
−Removed: 11 The increasing prevalence and high clinical impact of MRSA infection in CF have resulted in an unmet need for improved therapies to help address the condition.
−Removed: Considering the established practice of treating chronic Pseudomonas infection in CF using inhaled antibiotics, all of which have limited activity against MRSA, it would be logical to attempt treatment of chronic MRSA infection with an inhaled antibiotic that is active against MRSA.
−Removed: We believe that AeroVanc is the first inhaled antibiotic being developed to specifically treat MRSA infection of the lungs.
−Removed: Dasenbrook EC, Merlo CA, Diener-West M, et al.
−Removed: “Persistent Methicillin-resistant Staphylococcus aureus and Rate of FEV1 Decline in Cystic Fibrosis.” Am J Respir Crit Care Med 2008;178, 814-821.
−Removed: Dasenbrook EC, Checkley W, Merlo CA, et al.
−Removed: “Association Between Respiratory Tract Methicillin-Resistant Staphylococcus aureus and Survival in Cystic Fibrosis.” JAMA 2010;303, 2386-2392.
−Removed: Current MRSA T reatment O ptions in CF
−Removed: Persistent MRSA lung infection in people living with CF is difficult to eradicate or manage using oral or IV antibiotics.
−Removed: Currently, there is no standard of care to manage the infection despite the high need.
−Removed: 12 In contrast to the established treatment of pseudomonas infection with inhaled antibiotics, there is no FDA-approved inhaled antibiotic treatment available for MRSA infection.
−Removed: For people living with CF who have MRSA infection, IV vancomycin or linezolid are the most commonly used drugs for the treatment of acute pulmonary exacerbation, and these drugs may be used in combination with other IV antibiotics in patients with simultaneous gram-negative infections, such as Pseudomonas.
−Removed: For MRSA lung infection, vancomycin is available exclusively in IV form, and while highly effective against MRSA and other gram-positive bacteria, chronic home-based use of IV vancomycin is not practical, and chronic use has been associated with systemic toxicity, especially renal toxicity and ototoxicity.
−Removed: According to our research, there is increasing clinical need to treat chronic MRSA infection in CF.
−Removed: In the absence of an inhaled antibiotic, there is emerging use of oral anti-MRSA antibiotics in an attempt to suppress the MRSA infection and reduce the occurrence of acute pulmonary exacerbations.
−Removed: According to our survey of CF specialists in the U.S., 27% of those surveyed regularly use antibiotics targeting MRSA as a suppressive treatment (any dosage form) in patients with frequent exacerbations or other symptoms for which MRSA is considered a cause or contributing factor.
−Removed: This practice is emerging despite the absence of established consensus or guidelines relating to the use of oral anti-MRSA antibiotics in CF, or evidence of efficacy established in controlled studies.
−Removed: As with current inhaled anti-pseudomonal drugs, we believe that there is significant clinical advantage in delivering an anti-MRSA antibiotic, such as vancomycin, directly to the site of infection to maximize the clinical efficacy, reduce systemic exposure and the risk of adverse effects, and to enable convenient use of the product outside of the hospital setting.
−Removed: The aerosolized IV form of vancomycin, administered by nebulization, has been used in multiple published small clinical studies, mainly to treat ventilator-associated pneumonia in an intensive care setting.
−Removed: In these studies, and case reports, nebulized vancomycin had good antibacterial efficacy and was generally well tolerated.
−Removed: According to our research, in recent years many of the leading CF centers in the U.S.
−Removed: have explored the use of inhaled vancomycin to treat MRSA on a chronic basis, by nebulizing the IV form of vancomycin.
−Removed: The experience gained from this type of treatment has been encouraging and provides anecdotal reports of the safety and clinical utility of inhaled vancomycin for a period of several years in some patients.
−Removed: Similarly, in the 1990’s, nebulized IV tobramycin was explored as a treatment of pseudomonas infections in people living with CF.
−Removed: This exploration resulted in the development of the most widely used inhaled antibiotic worldwide, TOBI, which is a cornerstone of chronic treatment of pseudomonas lung infection in CF.
−Removed: We believe that inhaled antibiotics, as well as other palliative treatments, will continue to have a central role in the management of CF.
−Removed: Various disease modifying drugs, such as CF Transmembrane Conductance Regulator (“CFTR”) modulators, that attempt to address the underlying cause of CF, (i.e., restore or improve the function of the CFTR protein that is defective or dysfunctional in individuals living with CF) have recently been launched.
−Removed: Such disease-modifying drugs, on average, result in improvement in lung function and, potentially, slow the rate of lung function decline.
−Removed: Nevertheless, patients on these drugs are expected to continue to have chronic infections that require antibiotic treatment, and their lung function is expected to continue to decline.
−Removed: Feedback from the CF Foundation and key opinion leaders suggests that managing chronic infection and inflammation continue to be key challenges in the management of CF and addressing these issues should remain a high priority for new drug development.
−Removed: AeroVanc Product Description
−Removed: AeroVanc is a novel inhaled formulation of vancomycin being developed for the treatment of persistent MRSA lung infection in individuals with CF.
−Removed: Vancomycin is a glycopeptide antibiotic that was discovered in the mid-1950’s and is commonly used in the prophylaxis and treatment of infections caused by gram-positive bacteria.
−Removed: Vancomycin acts by inhibiting proper cell wall synthesis of aerobic and anaerobic gram-positive bacteria and is generally not active against gram-negative bacteria.
−Removed: AeroVanc is delivered via a capsule containing a proprietary dry powder formulation of vancomycin hydrochloride intended for oral inhalation with the AeroVanc inhaler.
−Removed: The AeroVanc inhaler is a commercialized, hand-held, manually operated, breath-activated device manufactured by Plastiape S.p.A.
−Removed: (Lecco, Italy).
−Removed: Zobell JT, Epps KL, Young DC, Montague M, Olson J, Ampofo K, Chin MJ, Marshall BC, Dasenbrook E.
−Removed: “Utilization of antibiotics for methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.” Pediatric Pulmonology (June 2015) Volume 50, Issue 6, pages 552–559.
−Removed: We anticipate that AeroVanc , if approved, will be used predominantly to suppress chronic MRSA lung infection which has the potential to improve patients’ lung function and respirato ry symptoms, and to prolong the time to pulmonary exacerbation and need of systemic antibiotics.
−Removed: AeroVanc would not be intended to replace IV vancomycin or other IV antibiotics in the treatment of acute pulmonary exacerbations associated with MRSA.
−Removed: However , long-term AeroVanc use has the potential to reduce the occurrence of these exacerbations and , thereby , reduce the need for IV treatments and hospitalizations.
−Removed: If approved, we believe AeroVanc in CF will be broadly adopted based on a high level of interest for the product from direct clinician surveys, as well as market research of key opinion leaders in the field of CF.
−Removed: Notably, a clear majority of the surveyed CF physicians in the U.S.
−Removed: (94%) indicated they expect to prescribe AeroVanc for MRSA lung infection, if approved by the FDA.
−Removed: Likewise, according to U.S.
−Removed: payer interviews, an AeroVanc launch would receive reimbursement support given the high unmet need in an orphan indication and a current lack of comparable products.
−Removed: AeroVanc Key Advantages
−Removed: There are a number of important characteristics that, we believe, contribute to AeroVanc’s overall clinical profile and may facilitate regulatory approval and, potentially, successful commercialization.
−Removed: Specifically, AeroVanc offers:
−Removed: A strong product foundation that applies both a previously approved active drug substance and drug delivery technology.
−Removed: High concentration of antibiotic delivered directly to the lungs (the primary site of infection) which, we believe, can result in higher clinical efficacy and reduced systemic toxicity, as compared with oral or IV delivery of antibiotics.
−Removed: Capsule-based powder inhaler that provides a fast and convenient method of administration, which is attractive to the CF population, who have a high treatment burden.
−Removed: Eligibility for strong market protection via orphan drug status, QIDP status, a formulation patent, and an exclusive device supply agreement.
−Removed: Clinical Development of AeroVanc
−Removed: Phase 3 Study
−Removed: AeroVanc is currently being investigated in a pivotal Phase 3 clinical study, called AVAIL, in the U.S.
−Removed: and Canada for the treatment of persistent MRSA lung infection in people living with CF.
−Removed: The study began enrolling patients at U.S.
−Removed: and Canadian clinical sites in late 2017.
−Removed: AVAIL is currently enrolling approximately 200 patients (150 patients ≤ 21 years old, 50 patients > 21 years old), subject to potential enrollment reductions discussed below, to evaluate the long-term safety of AeroVanc.
−Removed: During Period 1 of the study, patients are randomly assigned in a blinded 1:1 fashion to receive either AeroVanc (30 mg) twice daily, or placebo, by inhalation for 24 weeks or 3 dosing cycles.
−Removed: A dosing cycle is defined as 28 days of treatment followed by 28 days of observation.
−Removed: During Period 2 of the study, patients receive open-label AeroVanc (30 mg) twice daily for an additional 24 weeks or 3 dosing cycles.
−Removed: The primary endpoint is the mean absolute change in FEV1 percent predicted from baseline, which will be analyzed sequentially at week 4 (the end of Cycle 1), week 12 (the end of Cycle 2), and at week 20 (the end of Cycle 3).
−Removed: Analysis of the primary endpoint will be based on patients 6‒21 years of age.
−Removed: Secondary endpoints include:
−Removed: (i) time-to-use of another antibiotic medication (oral, IV, and/or inhaled) for pulmonary infection, (ii) the number of successful FEV1-response cycles a patient achieves over Period 1 (weeks 4, 12, and 20), (iii) relative change from baseline in FEV1 percent predicted at weeks 4, 12, and 20, (iv) change from baseline Cystic Fibrosis Questionnaire-Revised scores at weeks 4, 12, and 20 and (v) change from baseline in Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Symptom Score scores at weeks 4, 12, and 20.
−Removed: We will continue to enroll patients in the AVAIL study until Q2 2020.
−Removed: We anticipate enrolling approximately 140-145 out of the expected 150 patients in the primary analysis population.
−Removed: Top line results from the study are expected in early 2021.
−Removed: Completed Clinical Studies
−Removed: Phase 2 Study
−Removed: In a Phase 2 clinical study in CF patients with persistent MRSA lung infection, AeroVanc met a primary endpoint to reduce MRSA density in sputum and showed encouraging trends of improvement in lung function, prolongation of the time to use of other antibiotics, and improvement in respiratory symptoms, with best responses in patients below 21 years of age.
−Removed: The consistency of the responses across the different endpoints, as well as the magnitude of change in the younger patients, supported the advancement of AeroVanc into a Phase 3 clinical study.
−Removed: The results of the Phase 2 study were summarized and presented to the FDA in an End of Phase 2 Meeting, and the agency subsequently provided detailed guidance on the design and analysis of our current Phase 3 study, which is described above under the heading “Phase 3 study.”
−Removed: The Phase 2 study evaluated the safety and efficacy of AeroVanc in CF patients with persistently positive MRSA lung infection.
−Removed: The 28-day, randomized, double-blind, placebo-controlled study enrolled 87 patients.
−Removed: Patients received AeroVanc 32 mg twice daily (“BID”) or 64 mg BID, with an eight-week follow-up.
−Removed: The study was conducted at 40 sites in the U.S.
−Removed: Quantitative MRSA cultures from spontaneously expectorated sputum samples were used as the primary endpoint of the study.
−Removed: The average baseline values in both active drug cohorts, as well as the placebo cohorts, were high ranging from 6.78 ‒ 7.65 log 10 colony-forming units (“CFU”) /mL.
−Removed: In the primary endpoint analyses (modified intent-to-treat population), a reduction from baseline in MRSA CFU was observed in the 32 mg and 64 mg dose cohorts pooled, compared to placebo by -0.52 log 10 CFU/mL and -0.06 log 10 CFU/mL for the AeroVanc and placebo doses, respectively (p = 0.0312);
−Removed: in the 64 mg dose cohort by -0.63 log 10 CFU/mL and 0.16 log 10 CFU/mL for the AeroVanc and placebo doses, respectively (p = 0.0145);
−Removed: in the 32 mg dose cohort by -0.25 log 10 CFU/mL and -0.30 log 10 CFU/mL for the AeroVanc and placebo doses, respectively (p = 0.8352).
−Removed: MICs of vancomycin for MRSA cultured from the sputum samples were determined using a broth microdilution technique at baseline, at each visit during the administration of AeroVanc, as well as at the post-administration follow-up time points.
−Removed: The distribution of MIC values was very narrow, with MIC 50 and MIC 90 both at 0.5 µg/mL at baseline.
−Removed: At baseline, all strains were susceptible to vancomycin, with MIC values of 1 µg/mL, and there were no notable changes in the MIC distribution at any of the time points following the baseline sample.
−Removed: This suggests the susceptibility of MRSA to vancomycin was not affected by the 28 days of pulmonary administration of AeroVanc.
−Removed: Vancomycin peak and trough concentrations in sputum at Day 8 and Day 29 were in high excess over the generally accepted level of MIC (mean C trough /MIC ratio > 35) after multiple dosings in all patients at both dose levels, with apparent dose-dependency but no notable difference in C trough between the two time points.
−Removed: The most frequent adverse events reported were respiratory related.
−Removed: The AeroVanc 32 mg BID dose was well tolerated, with no significant difference in adverse events as compared with placebo.
−Removed: However, a higher incidence of adverse events, most frequently consistent with signs and symptoms of bronchoconstriction, and a significantly higher rate of premature study drug discontinuations were seen in adult patients at the 64 mg BID dose, as compared with patients receiving 32 mg of AeroVanc or placebo.
−Removed: Discontinuations were most commonly due to drug intolerability (mainly bronchoconstriction and/or chest tightness) or pulmonary exacerbation and typically occurred within the first two weeks from the start of drug administration.
−Removed: Based on the observed clinical results in the 32 mg cohort of patients below 21 years of age, the high vancomycin concentrations in sputum observed at both dose levels, and the high frequency of discontinuation in adult patients at the 64 mg dose, the Phase 3 study is further evaluating the 32 mg dose and enrollment is focused on patients below 21 years of age.
−Removed: Human Factor Study
−Removed: We have performed a human factor study with fourteen people living with CF (ages 12 ‒ 56 years old) to better understand patient reactions to the AeroVanc inhaler device, drug capsule and written instructions.
−Removed: Study participants represented a variety of sex and ethnicity demographics, as well as dominant hand preference.
−Removed: Patients were given the device, capsules and instructions to simulate use (without drug) and provide feedback.
−Removed: In summary, all patients were able to use the device properly and no device design issues were identified that could impact proper use.
+Added: During the double-blind period of the trial, 33 WLL procedures were required, with nine in the continuous group compared to 17 in the placebo group.
+Added: During the 48-week open-label period of the trial, during which time all patients received active drug, only five WLL procedures were conducted.
+Added: IMPALA-X Extension Trial
+Added: In March 2018, the IMPALA-X clinical trial was initiated.
+Added: IMPALA-X was an open-label extension trial that allowed patients who completed the IMPALA trial to continue treatment for up to three additional years.
+Added: In August 2020, we disclosed that we were stopping the IMPALA-X trial in which approximately 60 patients were being treated with molgramostim 300 µg according to the intermittent, every other week dosing regimen.
+Added: Some patients from IMPALA-X may be eligible to enroll in the Phase 3 IMPALA 2 trial.
+Added: Phase 3 IMPALA 2 Trial
+Added: IMPALA 2 is a Phase 3, 48-week, randomized, double-blind, placebo-controlled clinical trial designed to compare the efficacy and safety of molgramostim 300 µg administered once daily by inhalation with matching placebo in patients with aPAP.
+Added: The primary endpoint is the change from baseline in percent predicted DLCO, a gas exchange measure.
+Added: Three secondary endpoints will evaluate clinical measures of direct patient benefit:
+Added: SGRQ Total Score, SGRQ Activity Component Score, and exercise capacity using a treadmill test.
+Added: Other efficacy endpoints will include (A-a)DO 2 (another gas exchange measure), supplemental oxygen use, WLL frequency, patient and clinician global impression of disease severity and disease change, chest CT scan to assess lung opacity, blood biomarkers, etc.
+Added: IMPALA 2 is expected to enroll a total of 160 patients who will be randomized to receive treatment for up to 48 weeks in one of two arms:
+Added: molgramostim 300 µg administered once daily or inhaled placebo administered once daily.
+Added: The primary time point for efficacy assessment will be at week 24, however, efficacy will be assessed through week 48 to show durability of effect.
+Added: Safety will be assessed through week 48.
+Added: Following the 48-week double-blind treatment period, patients will roll over to a 48-week open-label period and will receive molgramostim 300 µg administered once daily.
+Added: The IMPALA 2 trial design has been endorsed by regulatory authorities in approximately 14 countries across North America, Europe, and Asia and is anticipated to start by the end of the second quarter of 2021.
+Added: The trial will be conducted at approximately 50 sites and is expected to fully enroll in approximately 20 months following initiation.
+Added: Top line data are anticipated in the second quarter of 2024.
+Added: While we are working to initiate IMPALA 2 as quickly and as safely as possible, the impact of the COVID-19 pandemic continues to evolve and may adversely impact trial timelines, even with mitigation strategies in place.
+Added: In January 2021, we engaged Parexel International (IRL) Limited (“Parexel”), a global contract research organization (“CRO”) to support our IMPALA 2 clinical trial development activities.
Manufacturing and Supply
−Removed: We do not own or operate manufacturing facilities to produce clinical or commercial quantities of any of our product candidates.
−Removed: We have fee-for-service contracts with well-established drug substance manufacturers, as well as drug product manufacturers covering all steps of the manufacturing process of our product candidates.
−Removed: We expect to continue with this outsourcing model for the foreseeable future.
+Added: We do not own or operate manufacturing facilities to produce clinical or commercial quantities of our molgramostim product candidate.
+Added: We have fee-for-service contracts with a well-established drug substance manufacturer and drug product manufacturer that covers all steps of the manufacturing process of molgramostim.
+Added: We expect to continue with this outsourcing model for the foreseeable future and plan to pursue a second source manufacturer to reduce production risks and ensure drug substance supply.
All of our manufacturing and supply vendors conduct their operations under current Good Manufacturing Practices (“cGMP”), a regulatory standard for the manufacture of pharmaceuticals.
−Removed: Molgradex Manufacturing
−Removed: The drug substance in Molgradex, molgramostim, is currently manufactured by GEMA Biotech S.A.
−Removed: (Buenos Aires, Argentina).
−Removed: All clinical and nonclinical studies to date have used material sourced from GEMA Biotech S.A.
−Removed: and validation activities are ongoing to prepare for commercial manufacturing.
−Removed: Patheon UK Limited (Ferentino, Italy), a division of Thermo Fisher Scientific Inc., has been selected as the commercial drug product manufacturer.
−Removed: Technology transfer is ongoing, and the planning of process validation activities has been initiated.
−Removed: Molgradex is administered to the lungs using the investigational eFlow® Nebulizer System, manufactured by PARI Pharma GmbH (Stamberg, Germany).
−Removed: The eFlow nebulizer has been CE certified (CE 0123) according to the Medical Devices Directive 93/42/EEC (as ame nded by Directive 2007/47/EC) as a class IIa device.
+Added: Molgramostim drug substance is currently manufactured by GEMA Biotech S.A.
+Added: in Buenos Aires, Argentina (“GEMA”).
+Added: All clinical and nonclinical trials to-date have used material sourced from GEMA and validation activities are ongoing to prepare for commercial manufacturing.
+Added: Patheon UK Limited in Ferentino, Italy (“Patheon”), a division of Thermo Fisher Scientific Inc., has been selected as the commercial drug product manufacturer.
+Added: Technology transfer and process validation activities with Patheon UK Limited are complete.
+Added: Molgra mostim is administered to the lungs using the eFlow ® Nebulizer System, manufactured by PARI Pharma GmbH in Stamberg, Germany (“PARI”) .
+Added: The eFlow ® N ebulizer System has been Conformité Européenne ( “ CE ” ) certified (CE 0123) according to the Medical Devices Directive 93/42/EEC (as amended by Directive 2007/47/EC) as a class IIa device.
The device has a 510(k) approval in the U.S.
as a general device.
−Removed: We have an exclusive license and a long-term supply agreement with PARI Pharma GmbH , as further discussed below, covering the eFlow nebul izer for the administration of recombinant human GM-CSF.
−Removed: AeroVanc Manufacturing
−Removed: AeroVanc is a high-performance inhalation powder formulation of vancomycin hydrochloride, applying a commercially-available capsule inhaler.
−Removed: The drug substance used in AeroVanc, vancomycin hydrochloride USP, is produced using microbial fermentation followed by purification, and is sourced from Xellia Pharmaceuticals ApS (Copenhagen, Denmark), a commercial manufacturer with two manufacturing facilities (one in China and one in Denmark).
−Removed: Both sites use the same cell line and manufacturing processes and produce material of comparable quality.
−Removed: A long-term commercial supply agreement has been established with Xellia Pharmaceuticals ApS.
−Removed: AeroVanc inhalation powder is a spray-dried powder containing a ratio of 9:1 by weight of vancomycin hydrochloride and l-leucine.
−Removed: L-leucine is an essential amino acid and has generally regarded as safe, GRAS, status as a food additive.
−Removed: Formulation studies showed that the addition of l-leucine improves inhalation performance in vitro, as measured by improved emitted dose and fine particle dose.
−Removed: The powder manufacturing is carried out by Hovione LLC (East Windsor, NJ), a vendor with two operational sites (one in the U.S.
−Removed: and one in Europe).
−Removed: Both of the facilities have the same base equipment, which could be upgraded to produce material of comparable quality.
−Removed: The proprietary AeroVanc spray drying process creates very fine particles (smaller than five microns) required for efficient delivery to the lungs.
−Removed: Proprietary nozzle and cyclone technologies were developed to meet product performance and manufacturing throughput requirements.
−Removed: The powder production process has been successfully scaled-up from laboratory to commercial equipment.
−Removed: The drug product is manufactured from bulk AeroVanc powder by GlaxoSmithKline Trading Services Limited (“GSK”).
−Removed: At this final stage of manufacturing, AeroVanc powder is conditioned and automatically filled into 16 mg capsules of vancomycin.
−Removed: The capsules are then packaged into aluminum foil blisters to protect them from light and moisture.
−Removed: A long-term commercial supply agreement has been established with GSK for the finished product.
−Removed: The inhaler device used for AeroVanc is manufactured by Plastiape S.p.A.
−Removed: (Lecco, Italy).
−Removed: The device was approved in the U.S.
−Removed: as part of the Aridol ® new drug application (NDA 022368) on October 5, 2010.
−Removed: A cosmetically modified version of the device was approved in the U.S.
−Removed: as part of the Arcapta ® Neohaler ® new drug application (NDA 022383) on July 1, 2011.
−Removed: An exclusive long-term commercial supply agreement has been established with Plastiape S.p.A.
−Removed: We have worked with our manufacturing partners to scale up processes, improve yields and production rates, and transfer processes to commercial facilities with commercial equipment.
−Removed: We have produced the supplies for the AVAIL pivotal Phase 3 clinical study using the same manufacturing sites, equipment and processes that will be used for commercial supply.
+Added: We have an exclusive license and a long-term supply agreement with PARI, as further discussed below, covering the eFlow ® N ebulizer System for the administration of recombinant human GM-CSF .
Commercialization
−Removed: We own exclusive rights to Molgradex and AeroVanc in the U.S.
−Removed: and all other major markets, except for Japan, where we have licensed the Molgradex rights to Nobelpharma Co., Ltd.
−Removed: (“Nobelpharma”), located in Tokyo, Japan, and which is described further below.
−Removed: We recently received notification from Nobelpharma of its intent to terminate the license agreement which will be effective on August 21, 2020.
−Removed: However, we continue plan to pursue clinical and regulatory approvals for our products in the U.S.
−Removed: and EU, and to independently commercialize AeroVanc and Molgradex in the U.S.
−Removed: In doing so, we may engage with strategic partners to help implement optimal sales and promotion activities.
−Removed: Our commercialization strategy will target key prescribing physicians, as well as provide patients with support programs to ensure product access.
−Removed: Pending EMA approval, we expect to commercialize Molgradex and AeroVanc in certain key markets in the EU and may engage with strategic partners to optimize sales and promotion activities in the remaining EU territories.
−Removed: License and Supply Agreements
−Removed: Plastiape S.p.A.
−Removed: In September 2012, we entered into a supply agreement related to AeroVanc with Plastiape S.p.A, which was subsequently amended in June 2016 (the “Plastiape Agreement”).
−Removed: Pursuant to the terms of the Plastiape Agreement, Plastiape S.p.A.
−Removed: will supply dry powder inhalers to us on an exclusive basis for use with vancomycin for the diagnosis, management, prevention or treatment of lung diseases.
−Removed: Pricing under the Plastiape Agreement is on a per unit basis, with the per unit price decreasing as the volume increases.
−Removed: Xellia Pharmaceuticals ApS
−Removed: In September 2016, we entered into a supply agreement related to the supply of the Active Pharmaceutical Ingredients (“API”) for AeroVanc with Xellia Pharmaceuticals ApS (the “Xellia Agreement”).
−Removed: Pursuant to the Xellia Agreement, we are obligated to purchase all of our requirements of the API from Xellia Pharmaceuticals ApS.
−Removed: The pricing under the Xellia Agreement is a set price per kg, with the price decreasing upon the commercial launch of AeroVanc.
+Added: Savara owns exclusive rights to molgramostim in the U.S.
+Added: and all other major markets.
+Added: We continue to pursue clinical and regulatory approvals for molgramostim in the U.S., EU, and Japan and to independently commercialize molgramostim in the U.S.
+Added: In doing so, we may engage with strategic partners to collaborate on implementing optimal sales and promotion activities.
+Added: Our commercialization strategy will target key prescribing physicians and centers, as well as provide patients with support programs to ensure product access.
+Added: Pending European Medicines Agency (“EMA”) approval, we expect to commercialize molgramostim in the EU and may engage with strategic partners to optimize sales and promotion activities in other EU territories.
+Added: Key License and Other Agreements
+Added: We entered into a Master Services Agreement (“MSA”) with Parexel on March 5, 2021, pursuant to which Parexel will provide contract research services related to our clinical trials.
+Added: The MSA has an initial term of five years.
+Added: We may terminate the MSA and/or any work order without cause on 60 days’ prior written notice to Parexel, and either party may terminate the MSA or any work order (i) upon 30 days’ notice in the event of the other party’s uncured breach, or (ii) immediately upon the occurrence of any of the following:
+Added: (a) continuation of the services would pose an undue risk to the health and/or wellbeing of a study participant, (b) any certificate, authorization, approval or exemption from a regulatory authority required for the conduct of the services is revoked, suspended, or expires without renewal, (c) in the reasonable opinion of such party, the continuation of the services would be in violation of applicable law, or (d) the other party becomes insolvent.
+Added: Contemporaneously with entering the MSA, we executed a work order with Parexel, under which Parexel will provide services related to the IMPALA 2 trial.
+Added: Under that work order, we expect to pay Parexel service fees and pass-through expenses estimated to be approximately $31 million over the course of the IMPALA 2 clinical trial.
PARI Pharma GmbH
−Removed: In November 2014, Serendex, predecessor-in-interest to our Savara ApS subsidiary, entered into a license and collaboration agreement related to Molgradex with PARI Pharma GmbH (“PARI”), (collectively the “PARI License Agreement”), which we assumed as part of the Serendex Acquisition (as defined in Item 1, subheading “Acquisition of Serendex Pharmaceuticals,” of this report).
−Removed: Under the PARI License Agreement, we have a worldwide, exclusive license to commercialize PARI’s investigational eFlow Nebulizer device for the pulmonary delivery of any liquid formulation containing Human Granulocyte Macrophage Colony Stimulating Factors (“hGM-CSF”) as the sole active pharmaceutical ingredient for nebulization for aPAP.
−Removed: Additionally, we have the option to change the device, subject to certain conditions, to PARI’s eFlow Technology Nebulizer CS and, until marketing approval, the option to negotiate an extension to the license to cover commercialization of the drug for pulmonary delivery via the PARI eFlow Inline device for the treatment of certain other indications.
−Removed: On July 23, 2018, we entered into Amendment No.
−Removed: 1 (the “PARI Amendment”), effective May 23, 2018, to the PARI License Agreement which adds NTM lung infection to the indications included in the license and allows us to add other pulmonary infections to the included indications in the future.
−Removed: Under the terms of the PARI License Agreement, we are not permitted to work with third parties to develop any inhalation device or nebulizer for the pulmonary delivery of a pharmaceutical product containing hGM-CSF as the sole active ingredient.
+Added: We have a license and collaboration agreement related to molgramostim with PARI Pharma GmbH (the “PARI License Agreement”).
+Added: Under the PARI License Agreement, we have a worldwide, exclusive license to commercialize PARI’s eFlow Nebulizer System for the pulmonary delivery of any liquid formulation containing human GM-CSF (“hGM-CSF”) as the sole active pharmaceutical ingredient for nebulization for aPAP.
+Added: Additionally, we have the option to change the device, subject to certain conditions, to PARI’s eFlow Technology Nebulizer Closed System (“CS”) and, until marketing approval, the option to negotiate an extension to the license to cover commercialization of the drug for pulmonary delivery via the PARI eFlow Inline device for the treatment of certain other indications.
+Added: Following an amendment in 2018 (the “PARI Amendment”), we have the option to add other pulmonary infections to the included indications in the future.
+Added: Under the terms of the PARI License Agreement, Savara is not permitted to work with third parties to develop any inhalation device or nebulizer for the pulmonary delivery of a pharmaceutical product containing GM-CSF as the sole active ingredient.
This restriction extends until (i) in the European Economic Area, marketing approval of the product in Europe or the U.S., whichever is later, or (ii) in the rest of the world, the term of the PARI License Agreement.
−Removed: In consideration of rights granted by PARI, Serendex paid a one-time upfront fee and agreed to pay an hourly rate for work performed by PARI under work orders issued pursuant to the PARI License Agreement.
−Removed: Additionally, we are obligated to make future milestone payments to PARI based upon (i) the successful completion of certain clinical trials, (ii) submissions for regulatory approval in the U.S, the European Union or Japan, and (iii) the first marketing approval for the product in the U.S., the European Union or Japan.
−Removed: The PARI Amendment expanded the development milestones in the agreement to include NTM and any additional pulmonary indications.
+Added: In consideration of rights granted by PARI, our predecessor paid a one-time upfront fee and we pay an hourly rate for work performed by PARI.
+Added: Additionally, we are obligated to make future milestone payments to PARI based upon (i) the successful completion of certain clinical trials, (ii) submissions for regulatory approval in the U.S, the EU or Japan, and (iii) the first marketing approval for the product in the U.S., EU or Japan.
+Added: The PARI Amendment expanded the development milestones in the agreement to include any additional pulmonary indications for which we use the device.
If we successfully commercialize any product candidate subject to the PARI License Agreement in a country, we are responsible for royalty payments equal to a percentage of net sales.
−Removed: We are obligated to make such royalty payments until the later of (i) the expiration of the last valid claim in an issued patent covering a portion of the PARI device in the applicable country or (ii) 15 years after the first commercial sale of Molgradex with the PARI device in that country (the “PARI Royalty Period”).
+Added: We are obligated to make such royalty payments until the later of (i) the expiration of the last valid claim in an issued patent covering a portion of the PARI device in the applicable country or (ii) 15 years after the first commercial sale of molgramostim with the PARI device in that country (the “PARI Royalty Period”).
If there is no such valid patent claim covering the applicable PARI device, the royalty owed to PARI will be decreased by a specified percentage.
The license term extends on a country-by-country basis until the end of the PARI Royalty Period or until mutually agreed by the parties.
−Removed: In April 2015, Serendex entered into a commercial supply agreement with PARI (the “PARI Supply Agreement”) related to the supply of the investigational PARI eFlow Technology Nebulizer and related accessories for commercial use with our products after marketing approval is obtained.
−Removed: We assumed the PARI Supply Agreement as part of the Serendex Acquisition (as defined in Item 1, subheading “Acquisition of Serendex Pharmaceuticals ,” of this report).
−Removed: Pursuant to the terms of the PARI Supply Agreement, we are obligated to purchase from PARI (i) within the European Economic Area, (a) during the first five years from marketing approval, all of our requirements for the device and related accessories and (b) thereafter 80% and (ii) in the rest of the world, all of our requirements during the PARI Royalty Period.
−Removed: Pricing is on a per unit basis, with a reduction in price once purchasing volumes reach over 5,000 for devices and starter kits and over 40,000 for nebulizer handsets in a twelve-month period.
+Added: We also have a commercial supply agreement with PARI (the “ PARI Supply Agreement ” ) related to the supply of the PARI eFlow Nebulizer and related accessories for commercial use with our products after marketing approval is obtained.
+Added: Pursuant to the PARI Supply Agreement, we are obligated to purchase from PARI (i) within the European Economic Area, (a) during the first five years from marketing approval, all of our requirements for the device and related accessories and (b) therea fter 80% and (ii) in the rest of the world, all of our requirements during the PARI Royalty Period.
+Added: Pricing is on a per unit basis, with a reduction in price once certain purchasing volumes are met .
GEMA Biotech S.A.
−Removed: On April 26, 2019, we entered into a Manufacture and Supply Agreement (the “GEMA Agreement”) with GEMABIOTECH SAU, a corporation organized under the laws of Argentina (“GEMA”), pursuant to which GEMA will supply the active pharmaceutical ingredient for our Molgradex product (the “API”).
−Removed: The Agreement supersedes the Supply and License Agreement between Savara ApS (as defined in Item 1, subheading “Acquisition of Serendex Pharmaceuticals ,” of this report) and GEMA dated December 10, 2012, as amended on February 22, 2016 and September 20, 2017.
−Removed: Under the GEMA Agreement, GEMA shall manufacture and supp ly the API exclusively for us for commercial sale and continue to supply the API to us for clinical studies and research and development activities.
−Removed: Pursuant to the terms of the GEMA Agreement, GEMA agreed to undertake the actions required to comply with t he requirements of the FDA and other similar regulatory authorities and obtain the approvals necessary to manufacture and supply the API to us for commercial sale.
−Removed: Additionally, GEMA transferred and assigned to us all right, title and interest in and to th e master cell bank and working cell bank necessary to produce the API.
−Removed: As consideration for the rights granted by GEMA, we are required to pay GEMA an agreed upon price per vial of 1 gram of the API.
−Removed: Additionally, we are obligated to make milestone payments to GEMA upon (i) the effective date of the GEMA Agreement, (ii) completion of certain developmental activities, (iii) successful completion of an audit by the FDA, and (iv) marketing approval of a product containing the API.
+Added: In April 2019, we entered into a Manufacture and Supply Agreement with GEMA pursuant to which GEMA will supply the active pharmaceutical ingredient (“API”) for molgramostim exclusively to us for commercial sale and continue to supply the API to us for clinical trials and research and development activities.
+Added: Additionally, GEMA transferred and assigned to us all right, title, and interest in and to the master cell bank and working cell bank necessary to produce the API.
+Added: Pursuant to the terms of the GEMA Agreement, GEMA agreed to undertake the actions required to comply with the requirements of the FDA and other similar regulatory authorities and obtain the approvals necessary to manufacture and supply the API to us for commercial sale.
+Added: In addition to an agreed upon price per vial of 1 gram of the API, we paid GEMA a milestone payment upon the effective date of the agreement and are required to make milestone payments upon (i) completion of certain developmental activities, (ii) successful completion of an audit by the FDA, and (iii) marketing approval of a product containing the API.
If we successfully commercialize a product containing the API in a country, we must pay GEMA a single digit percentage royalty on annual net sales.
1 unchanged sentence
The term of the GEMA Agreement continues until the twentieth anniversary of the date of receipt of marketing approval for a product containing the API in any country and may be extended for additional twelve-month terms by the agreement of both parties.
−Removed: We may terminate the GEMA Agreement immediately if (i) products containing the API will not be sold or will be withdrawn from the market, (ii) the FDA or other regulatory authority withdraws marketing approval for or fails to approve products incorporating the API, (iii) three or more batches of API supplied in any six month period fail to conform to specifications, (iv) GEMA receives notice of deficiencies in its manufacturing and fails to adequately respond, or (v) GEMA fails to achieve compliance with the requirements of the FDA and other regulatory authorities necessary to manufacture and supply the API to the Company for commercial sale.
+Added: We may terminate the GEMA Agreement immediately if (i) products containing the API will not be sold or will be withdrawn from the market, (ii) the FDA or other regulatory authority withdraws marketing approval for or fails to approve products incorporating the API, (iii) three or more batches of API supplied in any six month period fail to conform to specifications, (iv) GEMA receives notice of deficiencies in its manufacturing and fails to adequately respond, or (v) GEMA fails to achieve compliance with the requirements of the FDA and other regulatory authorities necessary to manufacture and supply the API to us for commercial sale.
Patheon UK Limited
−Removed: On June 26, 2019, we entered into a Master Manufacturing Services Agreement (the “Master Manufacturing Agreement”) with Patheon UK Limited (“Patheon”).
−Removed: The Master Manufacturing Agreement governs the general terms under which Patheon, or one of its affiliates, will provide manufacturing services to us for the drug products specified by us from time to time.
−Removed: We expect to enter into one or more related Product Agreements (each a “Product Agreement”) pursuant to the Master Manufacturing Agreement to govern the terms and conditions of Patheon’s manufacture of commercial supplies of Molgradex, our lead product candidate.
−Removed: Pursuant to the Master Manufacturing Agreement, we have agreed to order from Patheon at least a certain percentage of our commercial requirements for a product under a Product Agreement.
−Removed: Each Product Agreement that the we may enter into from time to time will be governed by the terms of the Master Manufacturing Agreement, unless expressly modified in such Product Agreement.
−Removed: The Master Manufacturing Agreement has an initial term ending December 31, 2024, and will automatically renew after the initial term for successive terms of two years each if there is a Product Agreement in effect, unless we give notice of our intention to terminate the Master Manufacturing Agreement at least 12 months prior to the end of the then current term or Patheon gives notice of its intention to terminate the Master Agreement at least 24 months prior to the end of the then current term.
−Removed: Unless otherwise agreed in a Product Agreement, Product Agreements will automatically renew after the initial term for successive terms of two years each unless either party gives notice of its intention to terminate a Product Agreement at least 18 months prior to the end of its then current term.
−Removed: Either party may terminate the Master Manufacturing Agreement or a Product Agreement upon written notice if the other party (i) has failed to remedy a material breach within a specified time or (ii) is declared insolvent or bankrupt, voluntarily files a petition of bankruptcy or assigns such agreement for the benefit of creditors.
−Removed: We may terminate a Product Agreement upon 30 days’ prior written notice if any governmental agency takes any action that prevents the Company from selling the relevant product in the relevant territory or upon six months’ prior written notice if it does not intend to order manufacturing services due to a product’s discontinuance in the market.
−Removed: Patheon may terminate the Master Manufacturing Agreement or a Product Agreement if we assign such agreement to an assignee that is unacceptable to Patheon for certain reasons, for failure of our timely payment of invoices, or if we forecast zero volume for six months.
−Removed: Nobelpharma Co., Ltd.
−Removed: Serendex entered into a license agreement on May 12, 2016, as assumed by us in the Serendex Acquisition (as defined in Item 1, subheading “Acquisition of Serendex Pharmaceuticals ,” of this report), which was amended on June 4, 2018 (the “Nobelpharma Agreement”), with Nobelpharma Co.
−Removed: (“Nobelpharma”) under which Nobelpharma received an exclusive right to import, market, sell, distribute and promote Molgradex in Japan for the treatment of aPAP.
−Removed: In return, Nobelpharma will pay us marketing and regulatory-based milestone payments totaling $10.5 million and sales-based royalties equal to thirty-five percent (35%) of the National Health Insurance price determined by the Ministry of Health Labor and Welfare in Japan.
−Removed: Pursuant to the Nobelpharma Agreement, we are obligated to fund Nobelpharma fifty percent (50%), up to a maximum of approximately $0.8 million, of the external costs associated with specific regulatory and filing activities to be conducted by Nobelpharma regarding the commercialization of Molgradex for the treatment of aPAP in Japan .
−Removed: We received notification from Nobelpharma of its terminat ion of the license agreement effective on August 21, 2020 .
−Removed: Mayo Foundation for Medical Education Services and Research
−Removed: Under an agreement with the Mayo Foundation for Medical Education Services and Research, entered into on October 8, 2018, we are subject to certain milestone payments for the use of proprietary information and material in specific intellectual property filings related to the application of Molgradex in the treatment of NTM.
−Removed: We will owe royalties to the foundation based on net sales of Molgradex for the treatment of NTM equal to one half of one percent (0.5%) when the intellectual property filings are published and one quarter of one percent (0.25%) prior to the publication or in the event publication does not occur, with respect to the specified intellectual property filings.
+Added: We have entered into an agreement and related work orders with Patheon under which Patheon manufactures our molgramostim product candidate for clinical trials.
+Added: We may terminate the agreement at any time for any business reason.
+Added: In June 2019, we entered into a Master Manufacturing Services Agreement (the “Master Manufacturing Agreement”) with Patheon and expect in the future to enter into one or more related Product Agreements (each a “Product Agreement) pursuant to the Master Manufacturing Agreement to govern the terms and conditions of Patheon’s manufacture of commercial supplies of molgramostim.
+Added: Under the terms of the Master Manufacturing Agreement, we have agreed to order from Patheon at least a certain percentage of our commercial requirements.
+Added: The Master Manufacturing Agreement has an initial term ending December 31, 2024, and will automatically renew after the initial term for successive terms of two years each if there is a Product Agreement in effect, unless a party has given notice of termination.
+Added: Either party may terminate the Master Manufacturing Agreement upon the other party’s uncured material breach or insolvency.
+Added: Patheon may terminate the Master Manufacturing Agreement if we assign such agreement to an assignee that is unacceptable to Patheon for certain reasons, for failure of our timely payment of invoices, or if we forecast zero volume for six months.
+Added: Inhaled liposomal ciprofloxacin (Apulmiq)
+Added: In March 2020, we entered into an exclusive license and collaboration agreement with Grifols for Apulmiq for the treatment of NCFB.
+Added: Under the terms of the agreement, Savara obtained an exclusive, worldwide, royalty-bearing license, with rights to sublicense, patent rights and know-how owned or controlled by Grifols to develop and commercialize Apulmiq.
+Added: The term of the license continues until the Royalty Term (as defined in the license agreement) expires in all countries for all products containing Apulmiq.
+Added: Grifols may terminate the license immediately if (1) we or one of our affiliates files a challenge to a patent owned by Grifols or (2) we fail to develop Apulmiq for 12 consecutive months.
+Added: Either party can terminate for the other party’s material breach following a cure period or upon certain insolvency events.
+Added: As part of our December 2020 pipeline optimization strategy that focused our resources on molgramostim in aPAP and the IMPALA 2 trial, we discontinued the Apulmiq clinical development program.
Government Regulation
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Government Regulation of Drugs
−Removed: The process required by the FDA before drug product candidates may be marketed in the U.S.
+Added: The process required by the FDA before drug product candidates, like ours, may be marketed in the U.S.
generally involves the following:
3 unchanged sentences
Performance of adequate and well-controlled human clinical trials to establish the safety, purity and potency of the proposed product candidate for its intended purpose.
−Removed: Preparation of and submission to the FDA of an NDA, after completion of all required clinical trials.
−Removed: A determination by the FDA within 60 days of its receipt of an NDA to file the application for review.
+Added: Preparation of and submission to the FDA of a Biologics License Application (“BLA”), after completion of all required clinical trials.
+Added: A determination by the FDA within 60 days of its receipt of a BLA to file the application for review.
Satisfactory completion of an FDA Advisory Committee review, if applicable.
Satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMPs and to assure that the facilities, methods and controls are adequate to preserve the product’s continued safety, purity and potency, and of selected clinical investigational sites to assess compliance with current Good Clinical Practices (“cGCP”);
−Removed: FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the U.S., which must be updated annually and when significant changes are made.
+Added: FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S., which must be updated annually and when significant changes are made.
The testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if at all.
1 unchanged sentence
An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.
−Removed: The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.
−Removed: The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product;
+Added: The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials.
+Added: The IND also includes results of animal and in vitro trials assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product candidate;
chemistry, manufacturing, and controls information;
4 unchanged sentences
Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.
−Removed: Clinical trials involv e the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with cGCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.
−Removed: Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
−Removed: A separate submission to the ex isting IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.
−Removed: Furthermore, an independent IRB, for each site proposing to conduct the clinical trial , must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.
+Added: Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with cGCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.
+Added: Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
+Added: A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.
+Added: Furthermore, an independent IRB, for each site proposing to conduct the clinical trial, must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the trial until completed.
Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.
−Removed: Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.
−Removed: There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.
−Removed: For purposes of NDA approval, human clinical trials are typically conducted in three sequential phases that may overlap.
+Added: Some trials also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data
+Added: safety monitoring board, which provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.
+Added: There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.
+Added: For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap.
Additionally, in certain instances, a fourth phase, post approval, may be necessary or required.
5 unchanged sentences
In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product.
−Removed: Phase 4 studies may be required as a condition to approval of the NDA.
+Added: Phase 4 trials may be required as a condition to approval of the BLA.
Phase 1, Phase 2 and Phase 3 testing may not be completed successfully within a specified period, if at all, and there can be no assurance that the data collected will support FDA approval or licensure of the product.
2 unchanged sentences
Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
−Removed: NDA Submission and Review by the FDA
−Removed: Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.
−Removed: The NDA must include all relevant data available from pertinent preclinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.
−Removed: Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of a use of the product, or from a number of alternative sources, including studies initiated by investigators.
−Removed: The submission of an NDA requires payment of a substantial user fee to the FDA, and the sponsor of an approved NDA is also subject to annual product and establishment user fees.
+Added: BLA Submission and Review by the FDA
+Added: Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications.
+Added: The BLA must include all relevant data available from pertinent preclinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.
+Added: Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of the product, or from a number of alternative sources, including trials initiated by investigators.
+Added: The submission of a BLA requires payment of a substantial user fee to the FDA, and the sponsor of an approved BLA is also subject to annual product and establishment user fees.
These fees are typically increased annually.
A waiver of user fees may be obtained under certain limited circumstances.
−Removed: Within 60 days following submission of the application, the FDA reviews an NDA to determine if it is substantially complete before the agency accepts it for filing.
−Removed: The FDA may refuse to file any NDA that it deems incomplete or not properly reviewable at the time of submission and may request additional information.
−Removed: In this event, the NDA must be resubmitted with the additional information.
−Removed: Once an NDA has been filed, the FDA’s goal is to review the application within ten months after it accepts the application for filing, or, if the application relates to an unmet medical need in a serious or life-threatening indication, six months after the FDA accepts the application for filing.
+Added: Within 60 days following submission of the application, the FDA reviews a BLA to determine if it is substantially complete before the agency accepts it for filing.
+Added: The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information.
+Added: In this event, the BLA must be resubmitted with the additional information.
+Added: Once a BLA has been filed, the FDA’s goal is to review the application within ten months after it accepts the application for filing, or, if the application relates to an unmet medical need in a serious or life-threatening indication, six months after the FDA accepts the application for filing.
The review process is often significantly extended by FDA requests for additional information or clarification.
−Removed: The FDA reviews an NDA to determine, among other things, whether a product is safe and effective for the indication being pursued, and the facility in which it is manufactured, processed, packed, or held meets standards designed to assure the product’s continued
−Removed: safety and effectiveness.
−Removed: The FDA may convene an advisory committee to provide clinical insight on appl ication review questions.
−Removed: Before approving a n NDA, the FDA will typically inspect the facility or facilities where the product is manufactured.
+Added: The FDA reviews a BLA to determine, among other things, whether a product is safe and effective for the indication being pursued, and the facility in which it is manufactured, processed, packed, or held meets standards designed to assure the product’s continued safety and effectiveness.
+Added: The FDA may convene an advisory committee to provide clinical insight on application review questions.
+Added: Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured.
The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
−Removed: Additionally, before approving a n NDA, the FDA will typically inspect one or more clinical sites to assure compliance with cGC P.
+Added: Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with cGCP.
If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information.
2 unchanged sentences
The FDA may not grant approval on a timely basis, or at all, and we may encounter difficulties or unanticipated costs in our efforts to secure necessary governmental approvals, which could delay or preclude us from marketing our products.
−Removed: After the FDA evaluates an NDA and conducts inspections of manufacturing facilities where the investigational product and/or our drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter.
+Added: After the FDA evaluates a
+Added: BLA and conducts inspections of manufacturing facilities where the investigational product and/or our drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter.
An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.
1 unchanged sentence
A Complete Response Letter may request additional information or clarification.
−Removed: The FDA may delay or refuse approval of an NDA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.
+Added: The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.
If regulatory approval of a product is granted, such approval may entail limitations on the indicated uses for which such product may be marketed.
−Removed: For example, the FDA may approve the NDA with a Risk Evaluation and Mitigation Strategy (“REMS”) to mitigate risks, which could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.
+Added: For example, the FDA may approve the BLA with a Risk Evaluation and Mitigation Strategy (“REMS”) to mitigate risks, which could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.
The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications.
Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing regulatory standards is not maintained or if problems occur after the product reaches the marketplace.
−Removed: The FDA may require one or more Phase 4 post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further marketing of the product based on the results of these post-marketing studies.
+Added: The FDA may require one or more Phase 4 post-marketing trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further marketing of the product based on the results of these post-marketing trials.
In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of its products under development.
1 unchanged sentence
Specifically, new drug products are eligible for Fast Track Designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition.
−Removed: For a fast track product, the FDA may consider sections of the NDA for review on a rolling basis before the complete application is submitted if relevant criteria are met.
−Removed: A fast track designated product candidate may also qualify for priority review, under which the FDA sets the target date for FDA action on the NDA at six months after the FDA accepts the application for filing.
+Added: For a fast track product, the FDA may consider sections of the BLA for review on a rolling basis before the complete application is submitted if relevant criteria are met.
+Added: A fast track designated product candidate may also qualify for priority review, under which the FDA sets the target date for FDA action on the BLA at six months after the FDA accepts the application for filing.
Priority review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition.
1 unchanged sentence
Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.
−Removed: Under the accelerated approval program, the FDA may approve an NDA on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
−Removed: Post-marketing studies or completion of ongoing studies after marketing approval are generally required to verify the biologic’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.
+Added: Under the accelerated approval program, the FDA may approve a BLA on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
+Added: Post-marketing trials or completion of ongoing trials after marketing approval are generally required to verify the biologic’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.
In addition, the U.S.
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and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller or more efficient clinical trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment.
−Removed: Breakthrough designation also allows the sponsor to file sections of the NDA for review on a rolling basis.
−Removed: We may seek designation as a breakthrough therapy for some or all of our product candidates.
−Removed: On December 23, 2019, the FDA awarded us breakthrough therapy designation for Molgradex for the treatment of aPAP.
−Removed: Fast t rack designation, priority review and breakthrough therapy designation do not change the standards for approval but may expedite the development or approval process.
+Added: Breakthrough designation also allows the sponsor to file sections of the BLA for review on a rolling basis.
+Added: Fast Track Designation, priority review and Breakthrough Therapy Designation do not change the standards for approval but may expedite the development or approval process.
The review and approval process with respect to our drug candidates may also be significantly delayed in the event of government shutdowns, if any.
Orphan Drug Status
−Removed: Under the Orphan Drug Act, the FDA may grant orphan drug designation to drug candidates intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the U.S., or more than 200,000 individuals in the U.S.
+Added: Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation to drug candidates intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the U.S., or more than 200,000
+Added: individuals in the U .S.
and for which there is no reasonable expectation that costs of research and development of the drug for the indication can be recovered by sales of the drug in the U .S .
−Removed: Orphan drug designation must be requested before submitting an NDA.
+Added: Orphan Drug Designation must be requested before submitting a BLA .
After the FDA grants Orphan Drug Designation , the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.
Although there may be some increased communication opportunities, Orphan Drug Designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.
−Removed: If a drug candidate that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications, including a full NDA, to market the same drug for the same indication for seven years, except in very limited circumstances, such as if the second applicant demonstrates the clinical superiority of its product or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
+Added: If a drug candidate that has Orphan Drug Designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same drug for the same indication for seven years, except in very limited circumstances, such as if the second applicant demonstrates the clinical superiority of its product or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition.
−Removed: Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the NDA application user fee.
+Added: Among the other benefits of Orphan Drug Designation are tax credits for certain research and a waiver of the BLA application user fee.
Orphan drug exclusivity could block the approval of our drug candidates for seven years if a competitor obtains approval of the same product as defined by the FDA or if our drug candidate is determined to be contained within the competitor’s product for the same indication or disease.
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Breakthrough Designation
−Removed: In December 2019, the FDA granted the use of Molgradex for the treatment of aPAP program Breakthrough Therapy Designation which provides a process for expediting the development and review of drugs that are intended to treat a serious condition and for which preliminary evidence indicates that the drug may demonstrate substantial improvement over the available therapy.
−Removed: GAIN Act Exclusivity for Antibiotics
−Removed: In 2012, Congress passed legislation known as the Generating Antibiotic Incentives Now Act (the “GAIN Act”).
−Removed: This legislation is designed to encourage the development of antibacterial and antifungal drug products that treat pathogens that cause serious and life-threatening infections.
−Removed: To that end, the new law grants an additional five years of exclusivity upon the approval of an NDA for a drug product designated by FDA as a QIDP.
−Removed: Thus, for a QIDP with Orphan Drug Designation, the periods of five-year exclusivity and seven-year orphan drug exclusivity, would become 12 years.
−Removed: A QIDP is defined in the GAIN Act to mean “an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections, including those caused by (1) an antibacterial or antifungal resistant pathogen, including novel or emerging infectious pathogens or (2) certain qualifying pathogens.” A “qualifying pathogen” is a pathogen that has the potential to pose a serious threat to public health (such as resistant Gram-positive pathogens, multi-drug resistant Gram-negative bacteria, multi-drug resistant tuberculosis, and C.
−Removed: difficile) and that is included in a list established and maintained by the FDA.
−Removed: A drug sponsor may request the FDA to designate its product as a QIDP any time before the submission of an NDA.
−Removed: The FDA must make a QIDP determination within 60 days of the designation request.
−Removed: A product designated as a QIDP will be granted priority review by the FDA and can qualify for “fast track” status.
−Removed: The five year exclusivity extension under the GAIN Act for drug products designated by the FDA as QIDPs does not apply to:
−Removed: a supplement to an application under FDCA Section 505(b) for any QIDP for which an extension is in effect or has expired;
−Removed: a subsequent application filed with respect to a product approved by the FDA for a change that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength;
−Removed: or a product that does not meet the definition of a QIDP under Section 505(g) based upon its approved uses.
+Added: In December 2019, the FDA granted the use of molgramostim for the treatment of aPAP program Breakthrough Therapy Designation which provides a process for expediting the development and review of drug candidates that are intended to treat a serious condition and for which preliminary evidence indicates that the drug candidate may demonstrate substantial improvement over the available therapy.
Post-Approval Requirements
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We cannot be certain that we or our present or future suppliers will be able to comply with the cGMP regulations and other FDA regulatory requirements.
−Removed: If our present or future suppliers are not able to comply with these requirements, the FDA may, among other things, halt our clinical trials, require us to recall a product from distribution, or withdraw approval of the NDA.
+Added: If our present or future suppliers are not able to comply with these requirements, the FDA may, among other things, halt our clinical trials, require us to recall a product from distribution, or withdraw approval of the BLA.
Future FDA and state inspections may identify compliance issues at our facilities or at the facilities of our contract manufacturers that may disrupt production or distribution, or require substantial resources to correct.
−Removed: In addition, discovery of previously unknown problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer or holder of an approved NDA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action that could delay or prohibit further marketing.
−Removed: The FDA may withdraw approval of an NDA if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.
+Added: In addition, discovery of previously unknown problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer or holder of an approved BLA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action that could delay or prohibit further marketing.
+Added: The FDA may withdraw approval of a BLA if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.
Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;
−Removed: imposition of post-market studies or clinical studies to assess new safety risks;
+Added: imposition of post-marketing trials or clinical trials to assess new
+Added: safety risks;
or imposition of distribution restrictions or other restrictions under a REMS program.
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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;
−Removed: fines, warning letters or holds on post-approval clinical studies;
+Added: fines, warning letters or holds on post-approval clinical trials;
refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals;
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Government Regulation of Combination Products
−Removed: Our products under development will be regulated as combination products, which means that they are comprised of two or more different components that, if marketed individually, would be subject to different regulatory paths and would require approval of independent marketing applications by the FDA.
+Added: Our product candidates under development will be regulated as combination products, which means that they are comprised of two or more different components that, if marketed individually, would be subject to different regulatory paths and would require approval of independent marketing applications by the FDA.
A combination product, however, is assigned to a center within the FDA that will have primary jurisdiction over its regulation on a determination of the combination product’s primary mode of action, which is the single mode of action that provides the most important therapeutic action.
36 unchanged sentences
Failure to submit required information may result in civil monetary penalties of up to an aggregate of $179,495 per year (or up to an aggregate of $1,176,638 per year for “knowing failures”), for all payments, transfers of value or ownership or investment interests that are not timely, accurately and completely reported in an annual submission.
−Removed: On October 24, 2018, President Trump signed into law the “Substance Use-Disorder Prevention that Promoted Opioid Recovery and Treatment for Patients and Communities Act” which in part (under a provision entitled “Fighting the Opioid Epidemic with Sunshine”) extends the reporting and transparency requirements under Open Payments to physician assistants, nurse practitioners, and other mid-level practitioners (with reporting requirements going into effect in 2022 for payments made in 2021).
+Added: On October 24, 2018, former President Trump signed into law the “Substance Use-Disorder Prevention that Promoted Opioid Recovery and Treatment for Patients and Communities Act” which in part (under a provision entitled “Fighting the Opioid Epidemic with Sunshine”) extends the reporting and transparency requirements under Open Payments to physician assistants, nurse practitioners, and other mid-level practitioners (with reporting requirements going into effect in 2022 for payments made in 2021).
Additionally, entities that do not comply with mandatory reporting requirements may be subject to a corporate integrity agreement.
19 unchanged sentences
Adoption of price controls and cost containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could limit our net revenue and results.
−Removed: We may need to conduct expensive clinical studies to demonstrate the comparative cost-effectiveness of our products.
+Added: We may need to conduct expensive clinical trials to demonstrate the comparative cost-effectiveness of our products.
The product candidates that we develop may not be considered cost-effective and thus may not be covered or sufficiently reimbursed.
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These changes include, among others, the Budget Control Act of 2011, which mandates aggregate reductions to Medicare payments to providers of up to 2% per fiscal year effective April 1, 2013, and due to subsequent legislative amendments, will remain in effect through 2029 unless additional Congressional action is taken.
−Removed: In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
+Added: In January 2013, former President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
These laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our product candidates, if approved, and, accordingly, our financial operations.
−Removed: There have been judicial and Congressional challenges to certain aspects of the Affor dable Care Act, and we expect additional challenges and amendments in the future.
−Removed: The Trump Administration and the U.S.
−Removed: Congress may take further action regarding the Affordable Care Act, including, but not limited to, repeal or replacement.
+Added: There have been judicial and Congressional challenges to certain aspects of the Affordable Care Act, and we expect additional challenges and amendments in the future.
On December 18, 2019, the U.S.
Court of Appeals for the 5th Circuit upheld the District Court ruling that the individual mandate was unconstitutional and remanded the case to the District Court to determine whether the remaining provisions of the ACA are invalid.
+Added: The decision was appealed, and the case is currently under consideration by the U.S.
+Added: Supreme Court.
It is unclear how this decision, subsequent appeals, and other efforts to repeal and replace the ACA will impact the healthcare industry or our business operations.
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We also rely on trade secrets that may be important to the development of our business.
−Removed: We own issued patents and additional pending patent applications worldwide for a proprietary formulation of AeroVanc.
+Added: We own issued patents and additional pending patent applications worldwide for a proprietary formulation of vancomycin.
The patents and pending applications are derived from a PCT application (Pub.
WO2012159103) entitled “Dry Powder Vancomycin Compositions and Associated Methods.” In February 2017, the United States Patent and Trademark Office issued United States Patent No.
−Removed: 9,572,774 for “Dry Powder Vancomycin Compositions and Associated Methods” which will provide key intellectual property protection in the U.S.
−Removed: for the AeroVanc program and will expire no earlier than 2032.
−Removed: This affords us important composition of matter protection for our AeroVanc program in the U.S., the largest market for the product, and is a key component of our market protection strategy which also includes Orphan Drug and QIDP protection.
−Removed: We also have corresponding patent applications for AeroVanc in different stages of prosecution in other key markets throughout the world.
−Removed: As of December 31, 2019, patents have issued in the U.S., Canada, Australia, China, Israel, Japan, Mexico, New Zealand, South Korea and Singapore.
−Removed: As of December 31, 2019, we have patent applications pending in the U.S., Argentina, Brazil, Europe, Hong Kong and India.
−Removed: We have pending patent applications and issued patents in the U.S.
−Removed: and other countries covering the formulation of AeroVanc.
−Removed: However, these patents may not provide us with significant competitive advantages, because the validity or enforceability of the patents may be challenged and, if instituted, one or more of the challenges may be successful.
−Removed: Patents may be challenged in the U.S.
−Removed: under post-grant review proceedings, inter partes re-examination, ex parte re-examination, or challenges in district court.
−Removed: Patents issued in foreign jurisdictions may be subjected to comparable proceedings lodged in various foreign patent offices, or courts.
−Removed: These proceedings could result in either loss of the patent or loss or reduction in the scope of one or more of the claims of the patent.
−Removed: Even if a patent issues and is held valid and enforceable, competitors may be able to design around our patents, such as by using pre-existing or newly developed technology, in which case competitors may not infringe our issued claims and may be able to market and sell products that compete directly with us before and after our patents expire.
+Added: 9,572,774 for “Dry Powder Vancomycin Compositions and Associated Methods” that will expire no earlier than 2032.
+Added: We also have corresponding patent applications for vancomycin in different stages of prosecution in other key markets throughout the world.
+Added: However, in connection with our decision to discontinue the development of the vancomycin program, we may choose to abandon certain vancomycin-related applications in the future.
Our success will, in part, depend on the ability to obtain and maintain patent and other proprietary rights in commercially important technology, inventions and know-how related to our business, the validity and enforceability of our patents, the continued confidentiality of our trade secrets as well as our ability to operate without infringing the valid and enforceable patents and proprietary rights of third parties.
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For example, significant aspects of our processes and proprietary technology portfolio are based on unpatented trade secrets and know-how.
−Removed: Trade secrets and know-how can be difficult to protect.
+Added: secrets and know-how can be difficult to protect.
We seek to protect our proprietary technology and processes, in part, by confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and commercial partners.
12 unchanged sentences
We are not aware of any other companies developing an inhaled form of GM-CSF.
−Removed: A glycosylated GM-CSF product, sargramostim (Leukine), is available on the market in the U.S., intended for IV or subcutaneous delivery in patients with neutropenia following cancer chemotherapy.
−Removed: Leukine has not been approved for the treatment of aPAP or any other acute or chronic lung disease but may be administered off-label.
+Added: A glycosylated GM-CSF product, sargramostim (Leukine ® ), is available on the market in the U.S., intended for IV or SC delivery in patients with neutropenia following cancer chemotherapy.
+Added: Leukine ® has not been approved for the treatment of aPAP or any other acute or chronic lung disease but is sometimes used as a pharmacy-compounded product (injectable product compounded for inhalation delivery).
The drug substance in Leukine ® , sargramostim, has been used in a nonclinical research project conducted by NIH/TRND in collaboration with the University of Cincinnati College of Medicine on the potential application of inhaled GM-CSF as a treatment for aPAP.
−Removed: No clinical studies have been conducted to date under this collaboration project.
−Removed: We are aware of a multicenter clinical study of inhaled Leukine, using a standard commercially available nebulizer, which is currently ongoing in Japan, conducted by a consortium of independent clinical investigators.
−Removed: It is not known to us if this study, together with other possibly available related clinical or nonclinical information, may be, or will be, used to support a potential new product approval in Japan.
−Removed: If such a new product would be approved and launched in Japan, we believe it has the potential to present a material competitive threat to the commercial success of Molgradex in Japan.
+Added: No clinical trials have been conducted to date under this collaboration project.
+Added: We are aware of a multicenter clinical trial of inhaled Leukine ® , using a standard commercially available nebulizer, which was conducted by a consortium of independent clinical investigators 6 .
+Added: It is not known to us if this trial, together with other possibly available related clinical or nonclinical information, may be, or will be, used to support a potential new product approval in Japan.
+Added: If such a new product would be approved and launched in Japan, we believe it has the potential to present a material competitive threat to the commercial success of molgramostim in Japan.
In addition, in November 2018, Partner Therapeutics, Inc., a commercial biotechnology company, was granted Orphan Drug Designation to Leukine ® for the treatment of PAP by the FDA.
−Removed: We are not aware of any other companies developing inhaled forms of vancomycin.
−Removed: There are several inhaled antibiotics on the market or in development, but we are not aware of any other inhaled antibiotic product that would be specifically developed for the treatment of MRSA infection.
−Removed: Certain inhaled antibiotics in development, including levofloxacin, and ciprofloxacin inhalation formulations, may possess some level of in vitro or in vivo activity against MRSA, even though the compounds are not generally considered MRSA-antibiotics.
−Removed: It is therefore possible that such products, if approved, may present a competitive threat to AeroVanc.
−Removed: A combination product containing fosfomycin and tobramycin for inhalation (“FTI”) was developed by Gilead Sciences (Foster City, CA), and shown in a Phase 2 study to possess activity against Gram-negative and Gram-positive bacteria, including MRSA.
−Removed: Gilead Sciences terminated the development of the product, and licensed it to CURx Pharmaceuticals (San Diego, CA) in February 2014.
−Removed: No clinical studies on FTI have been initiated by CURx Pharmaceuticals.
−Removed: If FTI is developed, and approved, for the treatment of MRSA lung infection in CF, we believe it has the potential to present a material competitive threat to the commercial success of AeroVanc.
−Removed: Many small and large pharmaceutical companies have intravenously or orally administered MRSA-antibiotics on the market, and/or in development.
−Removed: Whereas such antibiotics are important in the treatment of many acute and chronic MRSA-infections, such as skin and soft tissue infections, pneumonia, or endocarditis, we do not believe these products are practical or sufficiently efficacious and/or safe for long-term management of chronic MRSA lung infection in individuals living with CF.
−Removed: Therefore, we do not believe these products and product candidates are a material competitive threat to the commercial success of AeroVanc.
−Removed: As of March 12, 2020, we had 39 full-time employees and one part-time employee, as well as several full-time or part-time consultants.
+Added: Employees and Human Capital
+Added: We are committed to attracting and retaining the best possible talent.
+Added: As of March 8, 2021, we had 27 employees as well as several consultants.
+Added: Of our employees, 14 are located in Denmark and 13 are located in the U.S.
None of our employees are represented by a labor union or covered by a collective bargaining agreement.
We consider our relationship with our employees to be good.
−Removed: Acquisition of Serendex Pharmaceuticals
−Removed: On July 15, 2016, we completed an acquisition (the “Serendex Acquisition”) through a Business Transfer Agreement, dated May 13, 2016 (the “BTA”) under which we acquired certain assets, including Molgradex (an inhalation formulation of recombinant human GM-CSF for the treatment of aPAP), liabilities, employees, and subsidiaries of Serendex Pharmaceuticals A/S (“Serendex”), a public limited company organized under the laws of Denmark.
−Removed: The purchase price consists of 1,965,400 shares of our common stock and $21.5 million of contingent cash consideration based upon the achievement of certain milestones (the “Milestone Payments”).
−Removed: On May 27, 2019, we entered into an Amendment (the “BTA Amendment”) to the BTA between Aravas, our wholly owned subsidiary, and Serenova A/S, formerly Serendex Pharmaceuticals A/S (“Serenova”).
−Removed: The BTA Amendment modifies the BTA Agreement to provide for the issuance of 1,105,216 shares of our common stock (the “Settlement Shares”), which represented the equivalent of $12.5 million in shares of our common stock based on the volume weighted-average trading price of our common stock for the ten trading days ending May 23, 2019, within five business days of the effective date of the BTA Amendment in lieu of the Milestone Payments.
−Removed: The BTA Amendment further provides that Serenova will not sell, contract to sell, or otherwise transfer or dispose of the Settlement Shares until the earlier of (i) marketing approval of our Molgradex product by the FDA or (ii) twelve months following the date of the BTA Amendment.
+Added: Attraction, Development and Retention
+Added: We believe our future success will depend in large part on our continued ability to attract and retain highly skilled employees.
+Added: Our compensation program, including salary, bonus, benefits as well as short and long-term incentives, is designed to help us to attract and retain individuals whose skills are important to our current and long-term success.
+Added: Our total compensation package is generally positioned within the competitive ranges of our peer market, with differences generally based on tenure, skills, and performance needed to attract and retain key talent.
+Added: In 2020, we implemented a spot bonus program that allows employees to nominate their colleagues for cash awards in recognition of notable achievements.
+Added: We believe that continued professional growth and development are essential to helping our team stay on top of current rules, laws, trends and events which impact their duties.
+Added: We seek to develop our employee talent within the organization through access to training, continuous learning programs and other development initiatives, such as our LEAD2020 program administered during 2020.
+Added: This program helped employees assess their strengths and identify areas of improvement while also allowing a 360 assessment of their managers.
+Added: Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S, et al.
+Added: (2019) Inhaled GM-CSF for Pulmonary Alveolar Proteinosis.
+Added: N Engl J Med.
+Added: 2019 Sep 5;381(10):923-932.
+Added: 10.1056/NEJMoa1816216.
+Added: Diversity and Inclusion
+Added: We value diverse backgrounds and viewpoints and are committed to equal opportunity.
+Added: We aim to recruit, hire, place, develop, compensate, and advance people based on the needs of our organization and the qualifications, performance, skills, and experience of our people.
+Added: Currently, women represent approximately 63% of our employees and 50% of our leadership team.
+Added: We expect to continue to enhance our workforce diversity and advance the development of diverse talent.
+Added: We consistently evaluate the opportunity for diversity for both our employee workforce and our board of directors.
+Added: Upon beginning employment with Savara, all employees receive training on workplace diversity and inclusion.
+Added: Health and Safety
+Added: The health and safety of our employees is a top priority, and our goal is to provide a safe and healthy work environment for all personnel.
+Added: In dealing with the COVID-19 pandemic, we have provided our employees the ability to work virtually in order to best manage business and personal responsibilities and halted non-essential travel.
+Added: We have enhanced our internal communications with regular “town hall” meetings to ensure connectivity to our workforce.
+Added: We have set specific guidelines for our employees to follow when they determine they need to use our facilities.
+Added: These guidelines include, among others, limiting the number of people in our office at one time and social distancing.
+Added: We will continue to manage this situation with a focus towards the safety of our employees.
Merger and Corporate Information
9 unchanged sentences
The SEC maintains a website that contains reports, proxy and information statements, and other information regarding our filings at http://www.sec.gov .
−Removed: “Savara Inc.,” the Savara logo, “AeroVanc,” and “Molgradex” are unregistered trademarks of Savara Inc.
+Added: “Savara Inc.” and the Savara logo are unregistered trademarks of Savara Inc.
or its subsidiaries in the U.S.
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Use or display by us of other parties’ trademarks, service marks, trade names, trade dress or products is not intended to and does not imply a relationship with, or endorsements or sponsorship of, us by the trademark, service mark, trade name, trade dress or product owners.
−Removed: Ris k Factors.
−Removed: Investment in our common stock involves a high degree of risk and uncertainty.
−Removed: Our business, operating results, growth prospects and financial condition are subject to various risks, many of which are not exclusively within our control, that may cause actual performance to differ materially from historical or projected future performance.
−Removed: We urge investors to consider carefully the risks described below, together with all of the information in this report and our other public filings, before making investment decisions regarding our securities.
−Removed: Each of these risk factors, as well as additional risks not presently known to us or that we currently deem immaterial, could adversely affect our business, operating results, growth prospects or financial condition, as well as the trading price of our common stock, in which case you may lose all or part of your investment.
−Removed: Risks Related to Our Capital Requirements and Financial Condition
−Removed: We have incurred significant losses since inception and expect that we will continue to incur losses for the foreseeable future, which makes it difficult to assess our future viability.
−Removed: We are a clinical development-stage biopharmaceutical company and we have not been profitable since we commenced operations and may not ever achieve profitability.
−Removed: In addition, we have limited history as an organization and have not yet demonstrated an ability to successfully overcome many of the risks and uncertainties frequently encountered by companies in new and rapidly evolving fields, particularly in the biopharmaceutical industry.
−Removed: Drug development is a highly speculative undertaking and involves a substantial degree of risk.
−Removed: To date, we have not obtained any regulatory approvals for any of our product candidates, commercialized any of our product candidates, or generated any product revenue.
−Removed: We have devoted significant resources to research and development and other expenses related to our ongoing clinical trials and operations, in addition to acquiring product candidates.
−Removed: For the year ended December 31, 2019, we incurred a net loss of $78.2 million, and net cash used in operating activities was $45.1 million.
−Removed: At December 31, 2019, our cash, cash equivalents and short-term investment securities were $121.8 million, and working capital was $113.2 million.
−Removed: At December 31, 2019, we had an accumulated deficit of $207.9 million.
−Removed: We expect to continue to incur substantial operating losses for the next several years as we seek to advance our product candidates through clinical development, global regulatory approvals, and commercialization.
−Removed: No revenue from operations will likely be available until, and unless, one of our product candidates is approved by the FDA or another regulatory agency and successfully marketed, or we enter into an arrangement that provides for licensing revenue or other partnering-related funding, outcomes which we may not achieve.
−Removed: We will require additional financing to obtain regulatory approval for Molgradex and AeroVanc, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce, or terminate our product development efforts or other operations.
−Removed: Since our Aravas subsidiary was formed in 2007, most of our resources have been dedicated to the development and acquisition of our product candidates, Molgradex and AeroVanc.
−Removed: Under our current operating plan, we believe that our existing capital resources will be sufficient to fund our planned operations into 2022.
−Removed: However, we may raise additional capital, including through our “at the market offering” program to fund new studies, including an additional Phase 3 for Molgradex in aPAP, programs, or acquisitions, or to address changes in our existing development programs.
−Removed: We cannot estimate with reasonable certainty the actual amounts necessary to successfully complete the development and commercialization of our product candidates and there is no certainty that we will be able to raise the necessary capital on reasonable terms or at all.
−Removed: Our capital requirements for the foreseeable future will depend in large part on, and could increase significantly as a result of, our expenditures on our development programs.
−Removed: Future expenditures on our development programs are subject to many uncertainties, and will depend on, and could increase significantly as a result of, many factors, including:
−Removed: the number, size, complexity, results, and timing of our drug development programs;
−Removed: the timing and terms of any collaborative or other strategic arrangement that we may establish;
−Removed: the number of clinical and nonclinical studies necessary to demonstrate acceptable evidence of the safety and efficacy of our product candidates;
−Removed: changes in standards of care which could increase the size and complexity of our clinical studies;
−Removed: the number of patients who participate, the rate of enrollment, and the ratio of randomized to evaluable patients in each clinical study;
−Removed: the ability to locate patients to participate in a study given the limited number of patients available for orphan or ultra-orphan indications;
−Removed: the number and location of sites and the rate of site initiation in each study;
−Removed: the duration of patient treatmen t and follow-up;
−Removed: the potential for additional safety monitoring or other post-marketing studies that may be requested by regulatory agencies;
−Removed: the time and cost to manufacture clinical trial material and commercial product, including process development and scale-up activities, and to conduct stability studies, which can last several years;
−Removed: the degree of difficulty and cost involved in securing alternate manufacturers or suppliers of drug product, components, or delivery devices, as necessary to meet FDA requirements and/or commercial demand;
−Removed: the costs, requirements, timing of, and the ability to, secure regulatory approvals;
−Removed: the extent to which we increase our workforce and the costs involved in recruiting, training, and incentivizing new employees;
−Removed: the costs related to developing, acquiring, and/or contracting for sales, marketing, and distribution capabilities, supply chain management capabilities, and regulatory compliance capabilities, if we obtain regulatory approval for a product candidate and commercialize it without a partner;
−Removed: the costs involved in evaluating competing technologies and market developments or the loss in sales in case of such competition;
−Removed: the costs involved in establishing, enforcing, or defending patent claims and other proprietary rights.
−Removed: Additional capital may not be available when we need it, on terms that are acceptable to us or at all.
−Removed: If adequate funds are not available to us on a timely basis, we will be required to delay, limit, reduce, or terminate our establishment of sales and marketing, manufacturing or distribution capabilities, development activities, other activities that may be necessary to commercialize our product candidates, or conduct preclinical or clinical studies.
−Removed: If we raise additional capital through marketing and distribution arrangements or other collaborations, strategic alliances, or licensing arrangements with third parties, we may have to relinquish certain valuable rights to our product candidates, technologies, future revenue streams, or research programs or grant licenses on terms that may not be favorable to us.
−Removed: If we raise additional capital through public or private equity offerings, the ownership interest of our stockholders will be diluted and the terms of any new equity securities may have preferential rights over our common stock.
−Removed: In particular, due to the price per share of our common stock, any sale of our equity securities to raise significant capital would result in substantial ownership dilution to our stockholders.
−Removed: If we raise additional capital through debt financing, it may be subject to covenants limiting or restricting our ability to take specific actions, such as incurring additional debt or making capital expenditures, or subject to specified financial ratios, any of which could restrict our ability to develop and commercialize our product candidates or operate as a business.
−Removed: Any future acquisitions that we make could disrupt our business and harm our financial condition.
−Removed: We expect to evaluate, from time to time, potential strategic acquisitions of complementary businesses, products, or technologies.
−Removed: In addition, we expect to evaluate joint ventures, licensing opportunities, and other collaborative projects.
−Removed: We may not be able to identify appropriate acquisition candidates or strategic partners, or successfully negotiate, finance, or integrate acquisitions of any businesses, products, or technologies.
−Removed: Furthermore, the integration of any acquisition and management of any collaborative project may divert our management’s time and resources from our core business and disrupt our operations.
−Removed: Any cash acquisition we pursue would diminish the funds otherwise available to us for other uses.
−Removed: Any acquisition using our stock would dilute our stockholders’ ownership interests.
−Removed: If we engage in acquisitions of companies, products or technologies in order to execute our business strategy, we may need to raise additional capital.
−Removed: We may raise additional capital in the future through one or more financing vehicles that may be available to us including (i) new collaborative agreements;
−Removed: (ii) expansions or revisions to existing collaborative relationships;
−Removed: (iii) private financings;
−Removed: (iv) other equity or debt financings;
−Removed: (v) monetizing assets;
−Removed: and/or (vi) the public offering of securities.
−Removed: If we are required to raise additional capital in the future, it may not be available on favorable financing terms within the time required, or at all.
−Removed: If additional capital is not available on favorable terms when needed, we will be required to raise capital on adverse terms or significantly reduce operating expenses through the restructuring of our operations or deferral of strategic business initiatives.
−Removed: If we raise additional capital through a public offering of securities or equity, a substantial number of additional shares may be issued, which may negatively affect our stock price and these additional shares will dilute the ownership interest of our current investors.
−Removed: Our loan agreement contains covenants which may adversely impact our business;
−Removed: the failure to comply w ith such covenants could cause our outstanding debt to become immediately payable.
−Removed: On April 28, 2017, we entered into a Loan and Security Agreement, as subsequently amended on October 31, 2017, December 4, 2018, and January 31, 2020 between us and Aravas, as co-borrowers, and Silicon Valley Bank (the “Amended Loan Agreement”).
−Removed: The Amended Loan Agreement includes a number of restrictive covenants, including restrictions on incurring additional debt, making investments, granting liens, disposing of assets, paying dividends, and redeeming or repurchasing capital stock, subject to certain exceptions.
−Removed: Collectively, these covenants could constrain our ability to grow our business through acquisitions or engage in other transactions.
−Removed: In addition, the Amended Loan Agreement includes covenants requiring, among other things, that we provide financial statements, comply with all laws, pay all taxes, and maintain insurance and the satisfaction of an equity-based milestone.
−Removed: If we are not able to comply with these covenants, the outstanding loans under the Amended Loan Agreement could become immediately due and payable and would have a material adverse effect on our liquidity, financial condition, operating results, business, and prospects and cause the price of our common stock to decline.
−Removed: We have significant IPR&D and future impairment of IPR&D may have a significant adverse impact on our future financial condition and results of operations.
−Removed: Our goodwill was fully impaired during the year ended December 31, 2019.
−Removed: As of December 31, 2019, we had IPR&D of approximately $11.1 million.
−Removed: These intangible assets have been previously impaired and remain subject to additional impairment analyses whenever an event or change in circumstances indicates the carrying amount of such an asset may not be recoverable.
−Removed: We test our goodwill, if any, and IPR&D for impairment annually, or more frequently if an event or change in circumstances indicates that the asset may be impaired.
−Removed: If an impairment is identified, we would be required to record an impairment charge with respect to the impaired asset to our consolidated statements of operations and comprehensive loss.
−Removed: A significant impairment charge could have a material negative impact on our financial condition and results of operations.
−Removed: We will continue to evaluate our intangible assets for potential impairment in accordance with our accounting policies.
−Removed: For instance, we determined that a triggering event occurred during the second and fourth quarter of 2019.
−Removed: In each instance, our stock price experienced significant declines requiring the impairment testing of our goodwill which resulted in an impairment charge of $7.4 million in the second quarter of 2019 and $19.4 million in the fourth quarters of 2019, reducing the carrying value of our goodwill to its fair value, which was determined to be zero.
−Removed: (See Note 2 of the consolidated financial statements).
−Removed: Events giving rise to impairment are difficult to predict and are an inherent risk in the pharmaceutical industry.
−Removed: Some of the potential risks that could result in impairment of our goodwill and IPR&D include negative clinical study results, adverse regulatory developments, delay or failure to obtain regulatory approval, additional development costs, changes in the manner of our use or development of our product candidates, competition, earlier than expected loss of exclusivity, pricing pressures, higher operating costs, changes in tax laws, prices that third parties are willing to pay for our IPR&D or similar assets in an arm’s-length transaction being less than the carrying value of our IPR&D, and other market and economic environment changes or trends.
−Removed: Events or changes in circumstances may lead to significant impairment charges on our goodwill, if any, and/or IPR&D in the future, which could materially adversely affect our financial condition and results of operations.
−Removed: Risks Related to Our Business Strategy and Operations
−Removed: We are substantially dependent upon the clinical, regulatory, and commercial success of our product candidates, Molgradex and AeroVanc.
−Removed: Clinical drug development involves a lengthy and expensive process with an uncertain outcome, results of earlier studies and trials may not be predictive of future trial results, and our clinical trials may fail to adequately demonstrate to the satisfaction of regulatory authorities the safety and efficacy of our product candidates.
−Removed: The success of our business is dependent on our ability to advance the clinical development of Molgradex for the treatment of patients with aPAP, treatment of patients with NTM lung infection, and its expansion into NTM lung infection with people living with CF, and AeroVanc for the treatment of MRSA infection in the lungs of CF patients.
−Removed: The topline results of the Molgradex Phase 3 clinical study for the treatment of aPAP, designated as IMPALA, were announced on June 12, 2019.
−Removed: The study did not meet its primary endpoint of alveolar-arterial oxygen gradient (“A-aDO2”) compared to placebo.
−Removed: The continuous treatment arm (Molgradex 300 µg administered once daily continuously over 24 weeks) did show a 12.1 mmHG improvement which is similar to what has been observed in previously published studies, but a larger-than-expected placebo effect was also seen (8.8 mmHg improvement).
−Removed: However, results from IMPALA did show statistically significant improvement in two secondary endpoints:
−Removed: George’s Respiratory Questionnaire (“SGRQ”) and diffusing capacity of the lungs for carbon monoxide (“DLCO”).
−Removed: Two other secondary endpoints were numerically in favor of the continuous dosing arm of Molgradex but were not statistically significant (six-minute walk distance and time to whole lung lavage), while adverse event frequencies were similar between the treatment arms and placebo.
−Removed: On October 1, 2019, we received a written response from the FDA in connection with a Type C meeting regarding the Molgradex development program for aPAP and results from the IMPALA study in which the FDA indicated that the data provided in the briefing pac kage for the Type C meeting did not provide sufficient evidence of efficacy and safety.
−Removed: On December 23, 2019, the FDA granted us Breakthrough Therapy designation for Molgradex for the treatment of aPAP, a process designed to expedite the development and review of drugs that are intended to treat a serious condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
−Removed: As such, we are working to determine the next steps for our Molgradex development program focusing on the scope and design of an additional Phase 3 study.
−Removed: The timing and cost of commencement and the likelihood of success of such additional Phase 3 study is currently not known.
−Removed: The Molgradex studies for (i) the treatment of NTM lung infection, designated as OPTIMA, and the treatment of NTM lung infection in people living with CF, designated ENCORE, are in Phase 2a development.
−Removed: The AeroVanc Phase 3 study, designated as AVAIL, started in the U.S.
−Removed: and Canada in the third quarter of 2017.
−Removed: We anticipate enrolling approximately 140-145 out of the expected 150 patients in the primary analysis population.
−Removed: Top line results from the study are expected in the first half of 2021
−Removed: Clinical testing is expensive, can take many years to complete, and its outcome is inherently uncertain.
−Removed: A failure of one or more of our clinical trials can occur at any time during the clinical trial process as demonstrated by our recent IMPALA study results.
−Removed: The results of preclinical studies and early clinical trials of our product candidates may not be predictive of the results of later-stage clinical trials.
−Removed: There is a high failure rate for drugs proceeding through clinical trials, and product candidates in later stages of clinical trials may fail to show the required safety and efficacy despite having progressed through preclinical studies and initial clinical trials.
−Removed: A number of companies in the pharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier clinical trials, and we cannot be certain that we will not face similar setbacks.
−Removed: Even if our clinical trials are completed, the results may not be sufficient to obtain regulatory approval for our product candidates.
−Removed: Given the developmental nature of our product candidates, we are subject to risks associated with initiating, completing, and achieving positive outcomes from our current and future clinical trials, including:
−Removed: slow implementation, enrollment, and completion of the clinical trials;
−Removed: inability to enroll enough patients in the clinical trials;
−Removed: low patient compliance and adherence to dosing and reporting requirements, for example, incomplete reporting of patient reported outcomes in the clinical trials or missed doses;
−Removed: lack of safety and efficacy in the clinical trials;
−Removed: delays in manufacture of supplies for both drug and device components due to delays in formulation, process development, or manufacturing activities;
−Removed: requirements for additional nonclinical or clinical studies based on changes to formulation and/or changes to regulatory requirements;
−Removed: requirements for additional clinical studies based on inconclusive or negative clinical results or changes in market, standard of care, and/or regulatory requirements.
−Removed: If we successfully complete the necessary clinical trials for our product candidates, our success will be subject to the risks associated with obtaining regulatory approvals, product launch, and commercialization, including:
−Removed: FDA rejection of our NDA and Biologics License Application (“BLA”) submissions for our product candidates;
−Removed: regulatory rejection in the EU, Japan, and other markets;
−Removed: delays during regulatory review and/or requirements of additional Chemistry, Manufacturing, and Controls, nonclinical, or clinical studies, resulting in increased costs and/or delays in marketing approval and subsequent commercialization of the product candidates in the U.S.
−Removed: and other markets;
−Removed: inability to consistently manufacture commercial supplies of drug and delivery devices resulting in slowed market development and lower revenue;
−Removed: poor commercial sales due to:
−Removed: the inability of our future sales organization or our potential commercialization partners to effectively sell the product candidates;
−Removed: our lack of success in educating physicians and patients about the benefits, administration, and use of our product candidates;
−Removed: the availability, perceived advantages, relative cost, relative safety, and relative efficacy of other products or treatments for the targeted indications of the product candidates;
−Removed: low patient demand for the product candidates;
−Removed: poor prescription coverage and inadequate reimbursement for our product candidates;
−Removed: our inability to enforce our intellectual property rights in our product candidates;
−Removed: reduction in the safety profile of our product candidates following approval.
−Removed: Many of these clinical, regulatory, and commercial matters are beyond our control and are subject to other risks described elsewhere in this “ Risk Factors ” section.
−Removed: Accordingly, we cannot assure that we will be able to advance our product candidates further through final clinical development, or obtain regulatory approval of, commercialize, or generate significant revenue from them.
−Removed: If we cannot do so, or are significantly delayed in doing so, our business will be materially harmed.
−Removed: If we fail to attract and retain senior management and key scientific personnel, we may be unable to successfully develop and commercialize our product candidates.
−Removed: We have historically operated with a limited number of employees that manage third parties for most development activities.
−Removed: Institutional knowledge is concentrated within a small number of employees.
−Removed: Our success depends on our continued ability to attract, retain, and motivate highly qualified management, clinical, and scientific personnel.
−Removed: Our future success is highly dependent upon the contributions of our senior management, as well as our senior scientists and other members of our senior management team.
−Removed: The loss of services of any of these individuals, who all have at-will employment arrangements with us, could delay or prevent the successful development of our product pipeline, completion of our planned clinical trials, or the commercialization of our product candidates.
−Removed: Replacing key employees may be a difficult, costly, and protracted process, and we may not have other personnel with the capacity to assume all the responsibilities of a key employee upon his/her departure.
−Removed: Transition periods can be difficult to manage and may cause disruption to our business.
−Removed: In addition, there may be intense competition from other companies and organizations for qualified personnel.
−Removed: Other companies and organizations with which we compete for personnel may have greater financial and other resources and different risk profiles than us, and a history of successful development and commercialization.
−Removed: If we cannot attract and retain skilled personnel, as needed, we may not achieve our development and other goals.
−Removed: In addition, the success of our business will depend on our ability to develop and maintain relationships with respected service providers and industry-leading consultants and advisers.
−Removed: If we cannot develop and maintain such relationships as needed, the rate and success at which we can develop and commercialize product candidates may be limited.
−Removed: In addition, our outsourcing strategy, which has included engaging consultants that spend considerable time to manage key functional areas, may subject us to scrutiny under labor laws and regulations, which may divert management time and attention and have an adverse effect on our business and financial condition.
−Removed: We do not have, and do not have plans to establish commercial manufacturing facilities.
−Removed: We completely rely on third parties for the manufacture and supply of our clinical trial drug and delivery device supplies and, if approved, commercial product materials.
−Removed: The loss of any of these vendors or a vendor’s failure to provide us with an adequate supply of clinical trial or commercial product material in a timely manner and on commercially acceptable terms, or at all, could harm our business.
−Removed: We outsource the manufacture of our product candidates and do not plan to establish our own manufacturing facilities.
−Removed: To manufacture our product candidates, we have made numerous custom modifications at contract manufacturing organizations (“CMOs”), making us highly dependent on these CMOs.
−Removed: For clinical and commercial supplies, if approved, we have supply agreements with third party CMOs for drug substance, finished drug product, drug delivery devices and other necessary components of our product candidates.
−Removed: While we have secured long-term commercial supply agreements with many of the third party CMOs, we would need to negotiate agreements for commercial supply with several important CMOs, and we may not be able to reach agreement on acceptable terms.
−Removed: In addition, we rely on these third parties to conduct or assist us in key manufacturing development activities, including qualification of equipment, developing and validating methods, defining critical process parameters, releasing component materials, and conducting stability testing, among other things.
−Removed: If these third parties are unable to perform their tasks successfully in a
−Removed: timely manner, whether for technical, financial, or other reasons, we may be unable to secure clinical trial material, or commercial sup ply material if approved, which likely would delay the initiation, conduct, or completion of our clinical studies or prevent us from having enough commercial supply material for sale, which would have a material and adverse effect on our business.
−Removed: For exam ple, in December 2019, a novel strain of COVID-19 coronavirus was reported to have surfaced in Wuhan, China, the impacts of which are unknown and rapidly evolving.
−Removed: The extent to which the coronavirus impacts our ability to procure sufficient supplies for t he development and commercialization of our products and product candidates will depend on the severity and duration of the spread of the coronavirus, and the actions undertaken to contain the coronavirus or treat its effects.
−Removed: All manufacturers of our clinical trial material and, if approved, commercial product, including drug substance manufacturers, must comply with cGMP requirements enforced by the FDA through its facilities inspection program and applicable requirements of foreign regulatory authorities.
−Removed: These requirements include quality control, quality assurance, and the maintenance of records and documentation.
−Removed: Manufacturers of our clinical trial material may be unable to comply with these cGMP requirements and with other FDA, state, and foreign regulatory requirements.
−Removed: While we and our representatives generally monitor and audit our manufacturers ’ systems, we do not have full control over their ongoing compliance with these regulations.
−Removed: Although the responsibility to maintain cGMP compliance is shared between us and the third-party manufacturer, we bear ultimate responsibility for our supply chain and compliance with regulatory standards.
−Removed: Failure to comply with these requirements may result in fines and civil penalties, suspension of production, suspension or delay or failure to obtain product approval, product seizure or recall, or withdrawal of product approval.
−Removed: Currently, we do not have alternative vendors to back up our primary vendors of clinical trial material or, if approved, commercial supply material.
−Removed: Identification of and discussions with other vendors may be protracted and/or unsuccessful, or these new vendors may be unsuccessful in producing the same results as the current primary vendors producing the material.
−Removed: Therefore, if our primary vendors become unable or unwilling to perform their required activities, we could experience protracted delays or interruptions in the supply of clinical trial material and, ultimately, product for commercial sale, which would materially and adversely affect our development programs, commercial activities, operating results, and financial condition.
−Removed: In addition, the FDA or regulatory authorities outside of the U.S.
−Removed: may require that we have an alternate manufacturer of a drug product before approving it for marketing and sale in the U.S.
−Removed: or abroad and securing such alternate manufacturer before approval of an NDA or BLA could result in considerable additional time and cost prior to NDA or BLA approval.
−Removed: Any new manufacturer or supplier of finished drug product or its component materials, including drug substance and delivery devices, would be required to qualify under applicable regulatory requirements and would need to have sufficient rights under applicable intellectual property laws to the method of manufacturing of such product or ingredients required by us.
−Removed: The FDA or foreign regulatory agency may require us to conduct additional clinical studies, collect stability data, and provide additional information concerning any new supplier, or change in a validated manufacturing process, including scaling-up production, before we could distribute products from that manufacturer or supplier or revised process.
−Removed: For example, if we were to engage a third party other than our current CMOs to supply the drug substance or drug product for future clinical trial or commercial product, the FDA or regulatory authorities outside of the U.S.
−Removed: may require us to conduct additional clinical and nonclinical studies to ensure comparability of the drug substance or drug product manufactured by our current CMOs to that manufactured by the new supplier.
−Removed: Changing of suppliers or equipment is particularly challenging for companies like us, with inhalation products, because any change could alter the performance of the drug product.
−Removed: The manufacture of pharmaceutical products requires significant expertise and capital investment, including the development of advanced manufacturing techniques and process controls.
−Removed: Manufacturers of pharmaceutical products often encounter difficulties in production, particularly in scaling-up initial production.
−Removed: These problems include difficulties with production costs and yields, quality control, including stability of the product candidate and quality assurance testing, and shortages of qualified personnel.
−Removed: Some of our product candidates have not been manufactured at the scale we believe will be necessary to maximize its commercial value and, accordingly, we may encounter difficulties in attempting to scale-up production and may not succeed in that effort on a timely basis or at all.
−Removed: In addition, the FDA or other regulatory authorities may impose additional requirements as we scale up initial production capabilities, which may delay our scale-up activities and/or add expense.
−Removed: If our manufacturers encounter any of the aforementioned difficulties or otherwise fail to comply with their contractual obligations or there are delays entering commercial supply agreements due to capital constraints, we may have insufficient quantities of material to support ongoing and/or planned clinical studies or to meet commercial demand, if approved.
−Removed: In addition, any delay or interruption in the supply of materials necessary or useful to manufacture our product candidates could delay the completion of our clinical studies, increase the costs associated with our development programs, and depending upon the period of delay, require us to commence new clinical studies at significant additional expense or terminate the studies completely.
−Removed: Delays or interruptions in the supply of commercial product could result in increased cost of goods sold and lost sales.
−Removed: We cannot provide assurance that manufacturing or quality control problems will not arise in connection with the manufacture of our clinical trial material or commercial product, if approved, or that third-party manufacturers will be able to maintain the necessary governmental licenses and approvals to continue manufacturing such clinical trial material or commercial product, as applicable.
−Removed: In addition, Molgradex and AeroVanc are currently
−Removed: manufactured entirely or partially outside the U.S.
−Removed: and, as a result, we may experience interruptions in supply due to shipping or customs difficulties or regional instability.
−Removed: Furthermore, changes in currency fluctuations, shipping costs, or import tariffs could adversely affect cost of goods sold.
−Removed: Any of the above factors could cause us to delay or suspend anticipated or ongoing trials, regulatory submissions or commercialization of our product candidates, entail higher costs, or result in being unable to effectively commercialize our products.
−Removed: Our dependence upon third parties for the manufacture of our clinical trial material may adversely affect our future costs and our ability to develop and commercialize our product candidates on a timely and competitive basis.
−Removed: We rely significantly on third parties to conduct our nonclinical testing and clinical studies and other aspects of our development programs and if those third parties do not satisfactorily perform their contractual obligations or meet anticipated deadlines, the development of our product candidates could be adversely affected.
−Removed: We do not employ personnel or possess the facilities necessary to conduct many of the activities associated with our programs.
−Removed: We engage consultants, advisors, contract research organizations (“CROs”), CMOs, and others to assist in the design and conduct of nonclinical and clinical studies of our product candidates, with interpretation of the results of those studies and with regulatory activities, and we expect to continue to outsource all or a significant amount of such activities.
−Removed: As a result, many important aspects of our development programs are and will continue to be outside our direct control, and our third-party service providers may not perform their activities as required or expected, including the maintenance of good clinical practice (“GCP”), good laboratories practice (“GLP”), and cGMP compliance, which are ultimately our responsibility to ensure.
−Removed: Further, such third parties may not be as committed to the success of our programs as our own employees and, therefore, may not devote the same time, thoughtfulness, or creativity to completing projects or problem-solving as our own employees would.
−Removed: To the extent we are unable to successfully manage the performance of third-party service providers, our business may be adversely affected.
−Removed: The CROs that we engage to execute our clinical studies play a significant role in the conduct of the studies, including the collection and analysis of study data, and we likely will depend on CROs and clinical investigators to conduct future clinical studies and to assist in analyzing data from completed studies and developing regulatory strategies for our product candidates.
−Removed: Individuals working at the CROs with which we contract, as well as investigators at the sites at which our studies are conducted, are not our employees, and we have limited control over the amount or timing of resources that they devote to their programs.
−Removed: In addition, our CROs may be affected by business or workforce interruptions for many reasons, including as a result of an outbreak of the coronavirus or another infectious disease, over which they and we have limited control.
−Removed: If our CROs, study investigators, and/or third-party sponsors fail to devote sufficient time and resources to studies of our product candidates, if we and/or our CROs do not comply with all GLP and GCP regulatory and contractual requirements, or if their performance is substandard, we may delay commencement and/or completion of these studies, submission of applications for regulatory approval, regulatory approval, and commercialization of our product candidates.
−Removed: Failure of CROs to meet their obligations to us could adversely affect development of our product candidates.
−Removed: In addition, CROs we engage may have relationships with other commercial entities, some of which may compete with us.
−Removed: Through intentional or unintentional means, our competitors may benefit from lessons learned on our projects that could ultimately harm our competitive position.
−Removed: Moreover, if a CRO fails to properly, or at all, perform our activities during a clinical study, we may not be able to enter into arrangements with alternative CROs on acceptable terms or in a timely manner, or at all.
−Removed: Switching CROs may increase costs and divert management time and attention.
−Removed: In addition, there likely would be a transition period before a new CRO commences work.
−Removed: These challenges could result in delays in the commencement or completion of our clinical studies, which could materially impact our ability to meet our desired and/or announced development timelines and have a material adverse impact on our business and financial condition.
−Removed: We currently have limited marketing capabilities and no sales organization.
−Removed: If we are unable to establish sales and marketing capabilities on our own or through third parties, we will be unable to successfully commercialize our products, if approved, or generate product revenue.
−Removed: To commercialize our products, if approved, in the U.S.
−Removed: and other jurisdictions we seek to enter, we must build our marketing, sales, managerial, and other non-technical capabilities, or make arrangements with third parties to perform these services, and we may not be successful in doing so.
−Removed: If our products receive regulatory approval, we expect to market such products in the U.S.
−Removed: through a focused, specialized sales force, which will be costly and time consuming.
−Removed: Institutionally, we have no prior experience in the marketing and sale of pharmaceutical products and there are significant risks involved in building and managing a sales organization, including our ability to hire, retain, and incentivize qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel, and effectively manage a geographically dispersed sales and marketing team.
−Removed: Outside of the U.S., we may consider collaboration arrangements.
−Removed: If we are unable to enter into such arrangements on acceptable terms or at all, we may not be able to successfully commercialize our products in certain markets.
−Removed: Any failure or delay in the development of our internal sales, marketing, and distribution capabilities would adversely impact the commercialization of our products.
−Removed: If we are not successful in commercializing our products, either on our own or through collaborations with one or more third parties, our future product revenue will suffer and we would incur significant additional losses.
−Removed: To establish a sales and marketing infrastructure and expand our manufacturing capabilities, we will need to increase the size of our organization, and we may experience difficulties in managing this growth.
−Removed: As of March 12, 2020, we had 39 full-time employees, including 28 employees engaged in research and development.
−Removed: As we advance our product candidates through the development process and to commercialization, we will need to continue to expand our development, regulatory, quality, managerial, sales and marketing, operational, finance, and other resources to manage our operations and clinical trials, continue our development activities, and commercialize our product candidates, if approved.
−Removed: As our operations expand, we expect that we will need to manage additional relationships with various manufacturers and collaborative partners, suppliers, and other organizations.
−Removed: Due to our limited financial resources and our limited experience in managing a company with such anticipated growth, we may not be able to effectively maintain or manage the expansion of our operations or recruit and train additional qualified personnel.
−Removed: In addition, the physical expansion of our operations may lead to significant costs and may divert our management attention and resources.
−Removed: Any inability to manage growth could delay the execution of our development and strategic objectives, or disrupt our operations, which could materially impact our business, revenue, and operating results.
−Removed: Our product candidates may cause undesirable side effects or adverse events or have other properties that could delay or prevent our clinical development, regulatory approval, or commercialization.
−Removed: Undesirable side effects or adverse events caused by our product candidates could interrupt, delay, or halt clinical studies and could result in the denial of regulatory approval by the FDA or other regulatory authorities for any or all indications, and in turn prevent us from commercializing our product candidates.
−Removed: A significant challenge in clinical development is that the patient population in early studies, where small numbers of patients are required, is different from the patient population observed in later stage studies, where larger groups of patients are required.
−Removed: For example, patients in earlier stage studies may be more sick, compliant, or otherwise motivated than patients in larger studies.
−Removed: As such, efficacy or safety results may differ significantly between studies.
−Removed: Side-effects seen at high doses in earlier studies of AeroVanc, such as bronchoconstriction or other airway irritation, may be seen in significant numbers at the lower doses selected for later studies.
−Removed: Also, for AeroVanc, while not observed in the Phase 2 clinical study, the emergence of vancomycin-resistant MRSA could occur during the longer dosing period of AeroVanc that is currently implemented in the Phase 3 clinical study.
−Removed: If this or other undesirable side effects occur, they could possibly prevent approval, which would have a material and adverse effect on our business.
−Removed: If any of our product candidates receive marketing approval and we or others later identify undesirable side effects caused by the product:
−Removed: regulatory authorities may require the addition of labeling statements, such as a “ black box ” warning or a contraindication;
−Removed: regulatory authorities may withdraw their approval of the product;
−Removed: we may be required to change the way the product is administered, conduct additional clinical studies, or change the labeling of the product;
−Removed: our reputation may suffer.
−Removed: Any of these events could prevent us from achieving or maintaining market acceptance of the affected product or could substantially increase the costs and expenses of commercializing the product, which in turn could delay or prevent us from generating significant revenue from its sale.
−Removed: We may not achieve our projected development goals in the time frames we have announced.
−Removed: We have set goals for accomplishing certain objectives material to the successful development of our product candidates.
−Removed: The actual timing of these events may vary due to many factors, including delays or failures in our nonclinical testing, clinical studies, and manufacturing and regulatory activities and the uncertainties inherent in the regulatory approval process.
−Removed: From time to time we create estimates for the completion of enrollment of or announcement of data from clinical studies of our product candidates.
−Removed: However, predicting the rate of enrollment or the time from completion of enrollment to announcement of data for any clinical study requires us to make significant assumptions that may prove to be incorrect.
−Removed: As an example, we have experienced enrollment delays in our AeroVanc program.
−Removed: Our estimated enrollment rates and the actual rates may differ materially and the time required to complete enrollment of any clinical study may be considerably longer than we estimate.
−Removed: Such delays may adversely affect our financial condition and results of operations.
−Removed: Even if we complete a clinical study with successful results, we may not achieve our projected development goals in the time frames we initially anticipate or announce.
−Removed: If a development plan for a product candidate becomes more extensive and costly than anticipated, we may determine that the associated time and cost are not financially justifiable and, as a result, may disc ontinue development in a particular indication or of the product candidate as a whole.
−Removed: In addition, even if a study did complete with successful results, changes may occur in regulatory requirements or policy during the period of product development and/or regulatory review of an NDA or BLA that relate to the data required to be included in NDAs or BLAs which may require additional studies that may be costly and time consuming.
−Removed: Any of these actions may be viewed negatively, which could adversely impact our financial condition.
−Removed: Further, throughout development, we must provide adequate assurance to the FDA and other regulatory authorities that we can consistently develop and produce our product candidates in conformance with GLP, GCP, cGMP, and other regulatory standards.
−Removed: As discussed above, we rely on CMOs for the manufacture of clinical, and future commercial, quantities of our product candidates.
−Removed: If future FDA or other regulatory authority inspections identify cGMP compliance deficiencies at these third-party facilities, production of our clinical trial material or, in the future, commercial product, could be disrupted, causing potentially substantial delay in or failure of development or commercialization of our product candidates.
−Removed: Our employees, independent contractors and consultants, principal investigators, CROs, CMOs and other vendors, and any future commercial partners may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements, which could cause significant liability for us and harm our reputation.
−Removed: We are exposed to the risk that our employees, independent contractors and consultants, principal investigators, CROs, CMOs and other vendors, and any future commercial partners may engage in fraudulent conduct or other misconduct, including intentional failures to comply with FDA regulations or similar regulations of comparable foreign regulatory authorities, to provide accurate information to the FDA or comparable foreign regulatory authorities, to comply with manufacturing standards required by cGMP or our standards, to comply with federal and state healthcare fraud and abuse laws and regulations and similar laws and regulations established and enforced by comparable foreign regulatory authorities, and to report financial information or data accurately or disclose unauthorized activities to them.
−Removed: The misconduct of our employees and other service providers could involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation.
−Removed: Although we have adopted a code of business conduct and ethics, it is not always possible to identify and deter such misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.
−Removed: If any such actions are instituted against them, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business and results of operations, including the imposition of significant fines or other sanctions.
−Removed: For example, if one of our manufacturing partners were placed under a consent decree, we may be hampered in our ability to manufacture clinical or commercial supplies.
−Removed: Our business and operations would suffer in the event of third-party computer system failures, cyber-attacks on third-party systems, or deficiency in our cyber-security.
−Removed: We rely on information technology (“IT”) systems, including third-party “ cloud based ” service providers, to keep financial records, maintain laboratory data, clinical data and corporate records, communicate with staff and external parties, and operate other critical functions.
−Removed: This includes critical systems such as email, other communication tools, electronic document repositories, and archives.
−Removed: If any of these third-party IT providers are compromised due to computer viruses, unauthorized access, malware, natural disasters, fire, terrorism, war and telecommunication failures, electrical failures, cyber-attacks, or cyber-intrusions over the internet, then sensitive emails or documents could be exposed or deleted.
−Removed: Similarly, we could incur business disruption if our access to the internet is compromised and we are unable to connect with third-party IT providers.
−Removed: The risk of a security breach or disruption, particularly through cyber-attacks or cyber-intrusion by computer hackers, foreign governments, or cyber-terrorists, has generally increased as the number, intensity, and sophistication of attempted attacks and intrusions from around the world have increased.
−Removed: In addition, we rely on those third parties to safeguard important confidential personal data regarding our employees and patients enrolled in our clinical trials.
−Removed: If a disruption event were to occur and cause interruptions in a third-party IT provider ’ s operations, it could result in a disruption of our drug development programs.
−Removed: For example, the loss of clinical trial data from completed, ongoing, or planned clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data.
−Removed: To the extent that any disruption or security breach results in loss or damage to our data or applications or inappropriate disclosure of confidential or proprietary information, we could incur liability and development of our product candidates could be delayed or could fail.
−Removed: We have experienced and may continue to experience attempts to breach our security and attempts to introduce malicious software into our IT systems;
−Removed: however, to date and to our knowledge, such attacks have not resulted in any material damage to us.
−Removed: We are continually working to maintain reliable systems to control costs and improve our operations.
−Removed: Our efforts include, but are not limited to, the following:
−Removed: firewalls, antivirus protection, patches, log monitors, routine backups with offsite retention of storage media, system audits, data partitioning, and routine password modifications.
−Removed: Our internal IT systems environment continues to evolve and our business policies and internal security controls may not keep pace as new threats emerge.
−Removed: No assurance can be given that our efforts to continue to enhance our systems will be successful.
−Removed: If we fail to comply with data protection laws and regulations, we could be subject to government enforcement actions (which could include civil or criminal penalties), private litigation and/or adverse publicity, which could negatively affect our operating results and business.
−Removed: A number of state, national, and foreign laws and regulations apply to the collection, use, retention, protection, disclosure, transfer, and other processing of personal data.
−Removed: Due to our Danish subsidiary, Savara ApS, our clinical trial activities, and operations in Europe, we are subject to data protection laws in the EU, including the General Data Protection Regulation (“GDPR”).
−Removed: The GDPR, which became effective on May 25, 2018, has caused the EU requirements for the protection of personal data to become more stringent and increased the penalties for noncompliance.
−Removed: Penalties can consist of fines up to 20 million euros or 4% of global annual revenues, whichever is higher.
−Removed: As a result, we have been required to implement additional mechanisms to ensure compliance with the new EU data protection rules, which may cause us to incur additional costs.
−Removed: Similarly, in June 2018, California enacted the California Consumer Privacy Act of 2018 (the “CCPA”), which became effective in January 2020.
−Removed: The CCPA, among other things, requires covered companies to provide new disclosures to California consumers and afford such consumers new rights to opt-out of certain sales of personal information.
−Removed: The CCPA creates a private right of action for statutory damages for certain breaches of information.
−Removed: The California Attorney General has proposed regulations under the CCPA, but these regulations have yet to be finalized.
−Removed: Aspects of the CCPA and its interpretation and enforcement remain unclear at this time.
−Removed: In addition, other states have enacted or proposed legislation that regulates the collection, use, and sale of personal information, and such regimes might not be compatible with either the GDPR or the CCPA.
−Removed: We may be required to implement additional mechanisms to comply with the CCPA or such other state laws, which may be difficult to implement and may require us to incur additional costs.
−Removed: If we or our vendors fail to comply with applicable data privacy laws, including the GDPR or the CCPA, we could be subject to government enforcement actions and significant penalties against us, and our business could be adversely impacted.
−Removed: If we or our vendors fail to comply with applicable data privacy laws, including the GDPR, we could be subject to government enforcement actions and significant penalties against us, and our business could be adversely impacted.
−Removed: Our operations and financial results could be adversely impacted by might be interrupted by the occurrence of a natural disaster, war, system malfunction, terrorism, war, telecommunication and electrical failures or other catastrophic event, or public health crises, such as the 2019 Novel Coronavirus (COVID-19) outbreak in China and the rest of the world including the United States.
−Removed: Our corporate headquarters is located in a single commercial facility in Austin, Texas, USA.
−Removed: We maintain a second office in a single commercial facility in Denmark where many of our product development staff are located.
−Removed: Important documents and records, including copies of our regulatory documents and other records for our product candidates, are located both at a secure offsite document storage facility as well at our own facilities and we depend on our facilities for the continued operation of our business.
−Removed: Natural disasters and other catastrophic events, such as wildfires and other fires, earthquakes and extended power interruptions, terrorist attacks, public health crises, or severe weather conditions could significantly disrupt our operations and result in additional, unplanned expense.
−Removed: As a small company with limited resources, we have not prepared or implemented a formal business continuity or disaster recovery plan and any natural disaster or catastrophic event could disrupt our business operations and result in setbacks to our development programs.
−Removed: Even though we believe we carry commercially reasonable insurance, we might suffer losses that are not covered by or exceed the coverage available under these insurance policies.
−Removed: In December 2019, a novel strain of coronavirus (COVID-19) was reported to have surfaced in Wuhan, China, resulting in significant disruptions to Chinese manufacturing and supply chain as well as travel restrictions in many countries.
−Removed: While the extent of the impact of the current COVID-19 coronavirus outbreak on our business and financial results is uncertain, a continued and prolonged public health crisis such as the COVID-19 coronavirus outbreak could have a negative impact on our business, financial condition and operating results.
−Removed: As a result of the COVID-19 coronavirus outbreak, there could be delays in the manufacturing supply chain for our product candidates, including delays in procurement of materials for certain of our clinical studies due to the outbreak, delays in clinical trials or recruitment, or in a more severe scenario, our business, financial condition and operating results could be more severely affected.
−Removed: Given the dynamic nature of these circumstances, the duration of any business disruption or potential impact to our business of the COVID-19 coronavirus is difficult to predict.
−Removed: Risks Related to Drug Development and Commercialization
−Removed: We depend on the successful completion of clinical studies of our product candidates, and any positive results in prior clinical studies do not ensure that ongoing or future clinical studies will be successful.
−Removed: Pharmaceutical products are subject to stringent regulatory requirements covering quality, safety, and efficacy.
−Removed: The burden of proof is on the manufacturer, such as us, to show with substantial clinical data that the risk/benefit profile for any new drug is favorable.
−Removed: Only after successfully completing extensive pharmaceutical development, nonclinical testing, and clinical studies may a product be considered for regulatory approval.
−Removed: Clinical studies are expensive, difficult to design and implement, they can take many years to complete, and outcomes are inherently uncertain.
−Removed: A drug product may fail to demonstrate positive results at any stage of testing despite having progressed satisfactorily through nonclinical testing and initial clinical studies.
−Removed: There is significant risk in clinical development where later stage clinical studies are designed and powered based on the analysis of data from earlier studies, with these earlier studies involving a smaller number of patients, and the results of the earlier studies being driven primarily by a subset of responsive patients.
−Removed: In addition, interim results of a clinical study do not necessarily predict final results.
−Removed: Further, clinical study data frequently are susceptible to varying interpretations.
−Removed: Medical professionals and/or regulatory authorities may analyze or weigh study data differently than the sponsor company, resulting in delay or failure to obtain marketing approval for a product candidate.
−Removed: Additionally, the possible lack of standardization across multiple investigative sites may induce variability in the results which can interfere with the evaluation of treatment effects.
−Removed: If we license rights to develop our product candidates to independent third parties or otherwise permit such third parties to evaluate our product candidates in clinical studies, we may have limited control over those clinical studies.
−Removed: Any safety or efficacy concern identified in a third-party sponsored study could adversely affect our or another licensee ’ s development of our product candidate and prospects for its regulatory approval, even if the data from that study are subject to varying interpretations and analyses.
−Removed: There is significant risk that ongoing and future clinical studies of our product candidates are unsuccessful such as the recently announced results of the IMPALA study.
−Removed: Negative or inconclusive results could cause the FDA and other regulatory authorities to require us to repeat or conduct additional clinical studies, which could significantly increase the time and expense associated with development of that product candidate or cause us to elect to discontinue one or more clinical programs.
−Removed: For example, as a result of our IMPALA study results and related correspondence from the FDA, we are planning an additional Phase 3 study of Molgradex for the treatment of aPAP.
−Removed: Failure to complete a clinical study of a product candidate or an unsuccessful result of a clinical study could have a material adverse effect on our business.
−Removed: Molgradex and AeroVanc have received Orphan Drug Designation by the FDA and Molgradex has also received Orphan Drug Designation in Europe.
−Removed: While orphan designation provides certain benefits, there are also associated risks.
−Removed: Molgradex has received Orphan Drug Designation in the U.S.
−Removed: by the FDA and in Europe by the EMA for the treatment of aPAP, and AeroVanc has been granted Orphan Drug Designation in the U.S.
−Removed: by the FDA for the treatment of MRSA lung infection in patients with CF.
−Removed: Orphan Drug Designation will not shorten the regulatory review or reduce the clinical data requirements needed to obtain approval.
−Removed: If approval is received to market either Molgradex or AeroVanc for the respective indications, the FDA will not approve a similar product, with the same active ingredient, to Molgradex or AeroVanc for seven years and the EMA will not approve a similar product to Molgradex for ten years, unless we are unable to produce enough supply to meet demand in the marketplace or another similar product, with the same active ingredient, is deemed clinically superior.
−Removed: Similar product candidates, with the same active ingredient and route of delivery, may be granted Orphan Drug Designation during the development of the respective products, but the Orphan Drug exclusivity is granted only to the first of such products approved, which means there is risk that a competitor product candidate may receive approval and Orphan Drug exclusivity before us, thus preventing us from marketing one or more of our product candidates until the exclusivity of the competing product expires.
−Removed: Also, the Orphan Drug status will not prevent a competitor with a different active ingredient from competing with our product candidates.
−Removed: If we are prevented from marketing one or more product candidates due to a competitor ’ s Orphan Drug exclusivity, this would have a material adverse effect on our business.
−Removed: Delays in commencement and completion of clinical studies are common and have many causes.
−Removed: Delays in clinical studies of our product candidates would likely increase overall development costs and jeopardize our ability to obtain regulatory approval and successfully commercialize any approved products.
−Removed: Clinical testing typically is expensive, can take many years to complete, and its outcome is inherently uncertain.
−Removed: Clinical studies may not commence on time or be completed on schedule, if at all.
−Removed: The commencement and completion of clinical studies can be delayed for a variety of reasons, including:
−Removed: inability to raise sufficient funding to initiate or continue a clinical study;
−Removed: delays in obtaining regulatory approval to commence a clinical study;
−Removed: delays in identifying and reaching agreement on acceptable terms with prospective CROs, clinical study sites, and investigators, which agreements can be subject to extensive negotiation and may vary significantly among study sites;
−Removed: delays in obtaining regulatory approval in a prospective country;
−Removed: delays in obtaining ethics committee approval to conduct a clinical study at a prospective site;
−Removed: delays in reaching agreements on acceptable terms with prospective CMOs or other vendors for the production and supply of clinical trial material and, if necessary, drug administration devices, which agreements can be subject to extensive negotiation;
−Removed: delays in the production or delivery of sufficient quantities of clinical trial material or drug delivery devices from our CMOs and other vendors to initiate or continue a clinical study;
−Removed: delays due to product candidate recalls as the result of stability failure, excessive product complaints, or other failures of the product candidate during its use or testing;
−Removed: invalidation of clinical data caused by premature unblinding or integrity issues;
−Removed: invalidation of clinical data caused by mixing up of the active drug and placebo through randomization or manufacturing errors;
−Removed: delays on the part of our CROs, CMOs, and other third-party contractors in developing procedures and protocols or otherwise conducting activities in accordance with applicable policies and procedures and in accordance with agreed upon timelines;
−Removed: delays in identifying and hiring or engaging, as applicable, additional employees or consultants to assist in managing clinical study-related activities;
−Removed: delays in recruiting and enrolling individuals to participate in a clinical study, which historically can be challenging in orphan diseases;
−Removed: delays caused by patients dropping out of a clinical study due to side effects, concurrent disorders, difficulties in adhering to the study protocol, unknown issues related to different patient profiles than in previous studies, such as the reduced age limit required for inclusion into the AeroVanc Phase 3 study, or otherwise;
−Removed: delays in having patients complete participation in a clinical study, including returning for post-treatment follow-up;
−Removed: delays resulting from study sites dropping out of a trial, providing inadequate staff support for the study, problems with shipment of study supplies to clinical sites, or focusing its staff ’ s efforts on enrolling studies that compete for the same patient population;
−Removed: suspension of enrollment at a study site or the imposition of a clinical hold by the FDA or other regulatory authority following an inspection of clinical study operations at study sites or finding of a drug-related serious adverse event;
−Removed: delays in quality control/quality assurance procedures necessary for study database lock and analysis of unblinded data;
−Removed: delays, inconsistencies, or negative results in statistical analyses of clinical study data.
−Removed: Patient enrollment, a critical component to successful completion of a clinical study, is affected by many factors, including the size and nature of the study population, the proximity of patients to clinical sites, the eligibility criteria for the study, the design of the clinical study, ongoing studies competing for the same patient population and clinicians and patients ’ perceptions as to the potential advantages of the drug being studied in relation to available alternatives, including therapies being investigated by other companies which may be viewed as more beneficial or important to study, fear of being randomized to the placebo arm, and changes in standard of care.
−Removed: Challenges to complete enrollment can be exacerbated in orphan indications, like those being pursued by us, with a limited number of qualifying patients and the lack of clinical sites with the necessary expertise and experience to conduct our studies.
−Removed: Further, completion of a clinical study and/or its results may be adversely affected by failure to retain patients who enroll in a study but withdraw due to adverse side effects, perceived lack of efficacy, belief that they are on placebo, improvement in condition before treatment has been completed, for personal reasons, without reason, or by patients who fail to return for or complete post-treatment follow-up.
−Removed: We are currently experiencing slower than expected enrollment in our Phase 3 AeroVanc study due to several factors including patient availability and patients experiencing exacerbations prior to randomization, and therefore, precluding them from enrolling in the study.
−Removed: The COVID-19 coronavirus outbreak may cause further delays in our clinical trials and have a negative impact on our business, financial condition and operating results.
−Removed: Clinical studies may not begin on time or be completed in the time frames we anticipate and m ay be costlier than we anticipate for a variety of reasons, including one or more of those described above.
−Removed: The length of time necessary to successfully complete clinical studies varies significantly and is difficult to predict accurately.
−Removed: We may make stat ements regarding anticipated timing for completion of enrollment in and/or availability of results from our clinical studies, but such predictions are subject to a number of significant assumptions and actual timing may differ materially for a variety of r easons, including patient enrollment rates, length of time needed to prepare raw study data for analysis and then to review and analyze it, and other factors described above.
−Removed: If we experience delays in the completion of a clinical study, if a clinical stud y is terminated, or if failure to conduct a study in accordance with regulatory requirements or the study ’ s protocol leads to deficient safety and/or efficacy data, the regulatory approval and/or commercial prospects for our product candidates may be harme d, and our ability to generate product revenue will be delayed.
−Removed: In addition, any delays in completing our clinical studies likely will increase our development costs.
−Removed: Further, many of the factors that cause, or lead to, a delay in the commencement or compl etion of clinical studies have in the past and may in the future ultimately lead to the denial of regulatory approval of a product candidate.
−Removed: Even if we ultimately commercialize our product candidates, the standard of care may have changed or other therapi es for the same indications may have been introduced to the market in the interim and may establish a competitive threat to us or diminish the need for our products.
−Removed: Clinical studies are very expensive, difficult to design and implement, often take many years to complete, and the outcome is inherently uncertain.
−Removed: Clinical development of pharmaceutical products for humans is generally very expensive, takes many years to complete, and failures can occur at any stage of clinical testing.
−Removed: We estimate that clinical development of our product candidates will take several additional years to complete, but because of the variety of factors that can affect the design, timing and outcome of clinical studies, we are unable to estimate the exact funds required to complete research and development, obtain regulatory approval, and commercialize all of our product candidates.
−Removed: We will need significant additional capital to continue to advance our products as per current business plans.
−Removed: Failure at any stage of clinical testing is not uncommon and we may encounter problems that would require additional, unplanned studies or cause us to abandon a clinical development program.
−Removed: In addition, a clinical study may be suspended or terminated by us, an IRB, a data safety monitoring board, the FDA, or other regulatory authorities due to a number of factors, including:
−Removed: lack of adequate funding to continue the study;
−Removed: failure to conduct the study in accordance with regulatory requirements or the study ’ s protocol;
−Removed: inspection of clinical study operations or sites by the FDA or other regulatory authorities resulting in the imposition of a clinical hold;
−Removed: unforeseen safety issues, including adverse side effects;
−Removed: changes in governmental regulations or administrative actions.
−Removed: Changes in governmental regulations and guidance relating to clinical studies may occur and we may need to amend study protocols to reflect these changes, or we may amend study protocols for other reasons.
−Removed: Amendments may require us to resubmit protocols to IRBs for re-examination and approval or renegotiate terms with CROs, study sites and investigators, all of which may adversely impact the costs or timing of or our ability to successfully complete a trial.
−Removed: There is significant uncertainty regarding the regulatory approval process for any investigational new drug, substantial further testing and validation of our product candidates and related manufacturing processes may be required, and regulatory approval may be conditioned, delayed, or denied, any of which could delay or prevent us from successfully marketing our product candidates and substantially harm our business.
−Removed: Pharmaceutical products generally are subject to rigorous nonclinical testing and clinical studies and other approval procedures mandated by the FDA and foreign regulatory authorities.
−Removed: Various federal and foreign statutes and regulations also govern or materially influence the manufacturing, safety, labeling, storage, record keeping, and marketing of pharmaceutical products.
−Removed: The process of obtaining these approvals and the subsequent compliance with appropriate U.S.
−Removed: and foreign statutes and regulations is time-consuming and requires the expenditure of substantial resources.
−Removed: Molgradex is currently in Phase 3 clinical testing in the U.S., Europe, and Japan.
−Removed: The clinical study results were released by us on June 12, 2019 and did not meet all of the statistical goals and protocol end points.
−Removed: On October 1, 2019, we received a written response from the FDA in connection with a Type C meeting regarding the Molgradex development program for aPAP and results from the IMPALA Phase 3 study in which the FDA indicated that the data provided in the briefing package for the Type C meeting did not provide sufficient evidence of efficacy and safety for the treatment of aPAP.
−Removed: On December 23, 2019, the FDA provided communication to us regarding the granting of Breakthrough Therapy designation, a process
−Removed: designed to expedite the development and review of drugs that are intended to treat a serious condition and pr eliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on clinically significant endpoint(s), for Molgradex for the treatment of aPAP.
−Removed: As such, we are working with the FDA and EMA to determine the scope and design of a n additional P hase 3 study for the Molgradex development program for the treatment of aPAP.
−Removed: T he scope, powering, cost , and timing of the additional study is not currently definitive, but the additional Phase 3 study will require us to expend substantial additional resource s, significantly extend the timeline for clinical development prior to market approval, and may result in failure to achieve the clinical development of Molgradex for the treatment of aPAP .
−Removed: We have commenced the Phase 3 trial of AeroVanc, the success of which will be needed for FDA approval to market AeroVanc in the U.S.
−Removed: to treat persistent MRSA lung infection in individuals living with CF.
−Removed: While significant communication with the FDA on the Phase 3 study design has occurred, even if the Phase 3 clinical study meets all of its statistical goals and protocol end points, the FDA may not view the results as robust and convincing.
−Removed: They may require additional clinical studies and/or other costly studies, which could require us to expend substantial additional resources and could significantly extend the timeline for clinical development prior to market approval.
−Removed: Additionally, we are conducting a two-year nonclinical carcinogenicity study on the AeroVanc powder, required by the FDA.
−Removed: The results of this study will not be known until a short time prior to potential submission of an NDA or BLA for AeroVanc.
−Removed: If the carcinogenicity study cannot be completed for technical or other reasons, or provides results that the FDA determines to be concerning, this may cause a delay or failure in obtaining approval for AeroVanc.
−Removed: Significant uncertainty exists with respect to the regulatory approval process for any investigational new drug, including Molgradex and AeroVanc.
−Removed: Regardless of any guidance the FDA or foreign regulatory agencies may provide a drug’s sponsor during its development, the FDA or foreign regulatory agencies retain complete discretion in deciding whether to accept an NDA or BLA or the equivalent foreign regulatory approval submission for filing or, if accepted, whether to approve an NDA or BLA.
−Removed: There are many components to an NDA or BLA or marketing authorization application submission in addition to clinical study data.
−Removed: For example, the FDA or foreign regulatory agencies will review the sponsor’s internal systems and processes, as well as those of its CROs, CMOs, and other vendors, related to development of its product candidates, including those pertaining to its clinical studies and manufacturing processes.
−Removed: Before accepting an NDA or BLA for review or before approving the NDA or BLA, the FDA or foreign regulatory agencies may request that we provide additional information that may require significant resources and time to generate and there is no guarantee that our product candidates will be approved for any indication for which we may apply.
−Removed: The FDA or foreign regulatory agencies may choose not to approve an NDA or BLA for a variety of reasons, including a decision related to the safety or efficacy data, manufacturing controls or systems, or for any other issues that the agency may identify related to the development its product candidates.
−Removed: Even if one or more Phase 3 clinical studies are successful in providing statistically significant evidence of the efficacy and safety of the investigational drug, the FDA or foreign regulatory agencies may not consider efficacy and safety data from the submitted studies adequate scientific support for a conclusion of effectiveness and/or safety and may require one or more additional Phase 3 or other studies prior to granting marketing approval.
−Removed: If this were to occur, the overall development cost for the product candidate would be substantially greater and competitors may bring products to market before us, which could impair our ability to generate revenues from the product candidates, or even seek approval, if blocked by a competitor’s Orphan Drug exclusivity, which would have a material adverse effect on our business, financial condition, and results of operations.
−Removed: Further, development of our product candidates and/or regulatory approval may be delayed for reasons beyond our control.
−Removed: For example, U.S.
−Removed: federal government shut-downs or budget sequestrations, such as ones that occurred during January 2018 and December 2018 through January 2019, may result in significant reductions to the FDA’s budget, employees, and operations, which may lead to slower response times and longer review periods, potentially affecting our ability to progress development of our product candidates or obtain regulatory approval for our product candidates.
−Removed: Further, regulatory oversight and actions may be disrupted or delayed in regions particularly impacted by the coronavirus if regulators and industry professionals are expending significant and unexpected resources addressing the outbreak.
−Removed: Even if the FDA or foreign regulatory agencies grant approvals for our product candidates, the conditions or scope of the approval(s) may limit successful commercialization of the product candidates and impair our ability to generate substantial sales revenue.
−Removed: For example, the FDA may approve label claims for AeroVanc with age restrictions and/or treatment duration limitations, or Molgradex with restrictions for use only by patients unresponsive to the current standard of care.
−Removed: They may limit the label of Molgradex or AeroVanc to a subset of patients based on a review of which patient groups had the greatest efficacious response in clinical studies.
−Removed: Such label restriction may be undesirable and may limit successful commercialization.
−Removed: The FDA or foreign regulatory agencies may also only grant marketing approval contingent on the performance of costly post-approval nonclinical or clinical studies, or subject to warnings or contraindications that limit commercialization.
−Removed: Additionally, even after granting approval, the manufacturing processes, labeling, packaging, distribution, adverse event reporting, storage, advertising, promotion, and recordkeeping for our products will be subject to extensive and ongoing regulatory requirements.
−Removed: These requirements include submissions of safety and other post-marketing information and reports, registration, and continued compliance with cGMP, GCP, international conference on harmonization regulations, and GLP, which are regulations and guidelines that are enforced by the FDA or foreign regulatory agencies for all clinical development and for any clinical studies that we conduct post-approval.
−Removed: The FDA or foreign regulatory agencies may decide to
−Removed: withdraw approval, add warnings, or narrow the approved indications in the product label, or establish risk management programs that could restrict distribution of our products.
−Removed: These actions could result from, among other things, safety concerns, including unexpected side effects or drug interaction problems, or concerns over misuse of a product.
−Removed: If any of these actions were to occur following approval, we may have to discontinue commercialization of the product, limit our sales and marketing efforts, implement risk minimization procedure s, and/or conduct post-approval studies, which in turn could result in significant expense and delay or limit our ability to generate sales revenues.
−Removed: Regulations may be changed prior to submission of a marketing application that require higher hurdles than currently anticipated.
−Removed: These may occur as a result of drug scandals, recalls, or a political environment unrelated to our products.
−Removed: Even if we receive regulatory approval for a product candidate, we may face regulatory difficulties that could materially and adversely affect our business, financial condition, and results of operations.
−Removed: Even if initial regulatory approval is obtained, as a condition to the initial approval, the FDA or a foreign regulatory agency may impose significant restrictions on a product ’ s indicated uses or marketing or impose ongoing requirements for potentially costly post-approval studies or marketing surveillance programs, any of which would limit the commercial potential of the product.
−Removed: Our product candidates also will be subject to ongoing FDA requirements related to the manufacturing processes, labeling, packaging, storage, distribution, advertising, promotion, record-keeping, and submission of safety and other post-market information regarding the product.
−Removed: For instance, the FDA may require changes to approved drug labels, require post-approval clinical studies, and impose distribution and use restrictions on certain drug products.
−Removed: In addition, approved products, manufacturers and manufacturers ’ facilities are subject to continuing regulatory review and periodic inspections.
−Removed: If previously unknown problems with a product are discovered, such as adverse events of unanticipated severity or frequency, or problems with the facility where the product is manufactured, the FDA may impose restrictions on that product or us, including requiring withdrawal of the product from the market.
−Removed: If we or a CMO of ours fail to comply with applicable regulatory requirements, a regulatory agency may:
−Removed: issue warning letters or untitled letters;
−Removed: impose civil or criminal penalties;
−Removed: suspend or withdraw regulatory approval;
−Removed: suspend or terminate any ongoing clinical studies;
−Removed: refuse to approve pending applications or supplements to approved applications;
−Removed: exclude our product from reimbursement under government healthcare programs, including Medicaid or Medicare;
−Removed: impose restrictions or affirmative obligations on our or our CMO ’ s operations, including costly new manufacturing requirements;
−Removed: close the facilities of a CMO;
−Removed: seize or detain products or require a product recall.
−Removed: If any of our product candidates for which we receive regulatory approval fails to achieve significant market acceptance among the medical community, patients, or third-party payers, the revenue we generate from its sales will be limited and our business may never achieve profitability.
−Removed: Our success will depend in substantial part on the extent to which our product candidates, if approved, are accepted by the medical community and patients and reimbursed by third-party payers, including government payers.
−Removed: The degree of market acceptance with respect to each of our approved products, if any, will depend upon a number of factors, including:
−Removed: the safety and efficacy of our products as demonstrated in clinical studies;
−Removed: acceptance in the medical and patient communities of our products as a safe and effective treatment;
−Removed: the product ’ s taste, ease of use, or features associated with the delivery device;
−Removed: the perceived advantages of our product over alternative treatments, including with respect to the incidence and severity of any adverse side effects and the cost of treatment;
−Removed: the indications for which our product is approved;
−Removed: claims or other information (including limitations or warnings) in a product ’ s approved labeling;
−Removed: reimbursement and coverage policies of government and other third-party payers;
−Removed: pricing and cost-effectiveness of our product relative to alternative treatments;
−Removed: availability of alternative treatments;
−Removed: smaller-than-expected market size due to lack of disease awareness of a rare disease, or the patient population with a specific rare disease being smaller than anticipated;
−Removed: inappropriate diagnostic efforts due to limited knowledge and/or resources among clinicians;
−Removed: difficulties identifying patients;
−Removed: the prevalence of off-label substitution of chemically equivalent products or alternative treatments;
−Removed: the resources we devote to marketing our product and restrictions on promotional claims we can make with respect to the product.
−Removed: We cannot predict with reasonable accuracy whether physicians, patients, healthcare insurers, health maintenance organizations, or the medical community in general, will accept or utilize any of our products, if approved.
−Removed: If our product candidates are approved but do not achieve an adequate level of acceptance by these parties, we may not generate sufficient revenue to become or remain profitable.
−Removed: In addition, our efforts to educate the medical community and third-party payers regarding benefits of our products may require significant resources and may never be successful.
−Removed: If we determine that a product candidate may not achieve adequate market acceptance or that the potential market size does not justify additional expenditures on the program, we may reduce our expenditures on the development and/or the process of seeking regulatory approval of the product candidate while we evaluate whether and on what timeline to move the program forward.
−Removed: Even if we receive regulatory approval to market one or more of our product candidates in the U.S., we may never receive approval or commercialize our products outside of the U.S., which would limit our ability to realize the full commercial potential of our product candidates.
−Removed: In order to market products outside of the U.S., we must establish and comply with the numerous and varying regulatory requirements of other countries regarding safety and efficacy.
−Removed: Approval procedures vary among countries and can involve additional product testing and validation and additional administrative review periods.
−Removed: The time required to obtain approval in other countries generally differs from that required to obtain FDA approval.
−Removed: The regulatory approval process in other countries may include all of the risks detailed above regarding FDA approval in the U.S., as well as other risks.
−Removed: Regulatory approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country may have a negative effect on the regulatory process in others.
−Removed: Failure to obtain regulatory approval in other countries or any delay or setback in obtaining such approval could have the same adverse effects detailed above regarding FDA approval in the U.S.
−Removed: As described above, such effects include the risks that our product candidates may not be approved for all indications requested, which could limit the uses of our product candidates and have an adverse effect on product sales, and that such approval may be subject to limitations on the indicated uses for which the product may be marketed or require costly, post-marketing follow-up studies.
−Removed: Conversely, if the product candidates do receive approval outside the U.S.
−Removed: in the future, we may not meet the FDA requirements in the U.S.
−Removed: for approval.
−Removed: We must comply with the U.S.
−Removed: Foreign Corrupt Practices Act and similar foreign anti-corruption laws.
−Removed: Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
−Removed: It is illegal to pay, offer to pay, or authorize the payment of anything of value to any foreign government official, government staff member, political party, or political candidate in an attempt to obtain or retain business or to otherwise influence a person working in an official capacity.
−Removed: Other countries, such as the U.K., have similar laws with which we must comply.
−Removed: We face the risk that an employee or agent could be accused of violating one or more of these laws, particularly in geographies where significant overlap exists between local government and healthcare industries.
−Removed: Such an accusation, even if unwarranted, could prove disruptive to our developmental and commercialization efforts.
−Removed: Risks Related to Our Intellectual Property
−Removed: Our success will depend on obtaining and maintaining effective patent and other intellectual property protection for our product candidates and proprietary technology.
−Removed: AeroVanc has received a U.S.
−Removed: Patent Notice of Allowance for its formulation in the U.S., AeroVanc ’ s primary market.
−Removed: AeroVanc has either been issued patents or is prosecuting patent applications in numerous countries outside the U.S.
−Removed: We have no patent protection for Molgradex for the treatment of aPAP, and primarily rely on the Orphan Drug exclusivity as our primary barrier to competition.
−Removed: Molgradex for the treatment of NTM has issued patents ex-U.S.
−Removed: (under prosecution in the U.S.) with an additional international patent application pending.
−Removed: Both Molgradex and AeroVanc utilize proprietary delivery devices with exclusive supply agreements.
−Removed: Molgradex receives additional protection via a proprietary cell bank used in the production of the drug substance.
−Removed: Our success will depend on our ability to:
−Removed: obtain and maintain patent and other exclusivity rights with respect to our products and their uses;
−Removed: prevent third parties from infringing upon our proprietary rights;
−Removed: maintain proprietary know-how and trade secrets;
−Removed: operate without infringing upon the patents and proprietary rights of others;
−Removed: obtain appropriate licenses to patents or proprietary rights held by third parties if infringement would otherwise occur, or if necessary, to secure exclusive rights to them, both in the U.S.
−Removed: and in foreign countries.
−Removed: The patent and intellectual property positions of biopharmaceutical companies generally are highly uncertain, involve complex legal and factual questions, and have been and continue to be the subject of much litigation.
−Removed: There is no guarantee that we have or will develop or obtain the rights to products or processes that are patentable, that patents will issue from any pending applications or that claims allowed will be sufficient to protect the technology we develop or have developed or that is used by us, our CMOs, or our other service providers.
−Removed: In addition, any patents that are issued to us may be limited in scope or challenged, invalidated, infringed, or circumvented, including by our competitors, and rights we have under issued patents may not provide competitive advantages to us.
−Removed: If competitors can develop and commercialize technology and products similar to ours, our ability to successfully commercialize our technology and products may be impaired.
−Removed: Patent applications in the U.S.
−Removed: are confidential for a period of time until they are published, and publication of discoveries in scientific or patent literature typically lags actual discoveries by several months.
−Removed: As a result, we cannot be certain that the inventors listed in any patent or patent application owned by us were the first to conceive of the inventions covered by such patents and patent applications (for U.S.
−Removed: patent applications filed before March 16, 2013), or that such inventors were the first to file patent applications for such inventions outside the U.S.
−Removed: and, after March 15, 2013, in the U.S.
−Removed: In addition, changes in or different interpretations of patent laws in the U.S.
−Removed: and foreign countries may affect our patent rights and limit the number of patents we can obtain, which could permit others to use our discoveries or to develop and commercialize our technology and products without any compensation to us.
−Removed: Our AeroVanc patent is specific to the formulation of the AeroVanc powder.
−Removed: While this may prevent identical products from entering the market, it may not preclude someone skilled in the art from inventing an alternate formulation approach with comparable or improved characteristics.
−Removed: We also rely on unpatented know-how and trade secrets and continuing technological innovation to develop and maintain our competitive position, which we seek to protect, in part, through confidentiality agreements with employees, consultants, collaborators, and others.
−Removed: We also have invention or patent assignment agreements with our employees and certain consultants.
−Removed: The steps we have taken to protect our proprietary rights, however, may not be adequate to preclude misappropriation of or otherwise protect our proprietary information or prevent infringement of our intellectual property rights, and we may not have adequate remedies for any such misappropriation or infringement.
−Removed: In addition, it is possible that inventions relevant to our business could be developed by a person not bound by an invention assignment agreement with us or independently discovered by a competitor.
−Removed: We also intend to rely on regulatory exclusivity for protection of our product candidates, if approved for commercial sale.
−Removed: Implementation and enforcement of regulatory exclusivity, which may consist of regulatory data protection and market protection, varies widely from country to country.
−Removed: Failure to qualify for regulatory exclusivity, or failure to obtain or maintain the extent or duration of such protections that we expect for our product candidates, if approved, could affect our decision on whether to market the products in a particular country or countries or could otherwise have an adverse impact on our revenue or results of operations.
−Removed: For Molgradex, which is administered via nebulization, we may rely on regulatory exclusivity for the combination of Molgradex and its delivery system.
−Removed: However, there is no assurance that our Molgradex product and its delivery system, if approved, will benefit from this type of market protection.
−Removed: We may rely on trademarks, trade names, and brand names to distinguish our products, if approved for commercial sale, from the products of our competitors.
−Removed: We intend to seek approval for new names for AeroVanc and Molgradex that meet the FDA ’ s and foreign regulatory requirements.
−Removed: However, our trademark applications may not be approved.
−Removed: Third parties may also oppose our trademark applications or otherwise challenge our use of the trademarks, in which case we may expend substantial resources to defend our proposed or approved trademarks and may enter into agreements with third parties that may limit our use of our trademarks.
−Removed: In the event that our trademarks are successfully challenged, we could be forced to rebrand our product, which could result in loss of brand recognition and could require us to devote significant resources to advertising and marketing these new brands.
−Removed: For example, we filed a trademark for the name “ Savara ” and were challenged.
−Removed: We decided to terminate the application, but we may revisit such filings at a future date.
−Removed: Further, our competitors may infringe our trademarks or we may not have adequate resources to enforce our trademarks.
−Removed: Our success depends on our ability to prevent competitors from duplicating or developing and commercializing equivalent versions of our product candidates, but patent protectio n may be difficult to obtain and any issued claims may be limited.
−Removed: We have pending patent applications and issued patents in the U.S.
−Removed: and other countries covering the formulation of AeroVanc.
−Removed: However, these patents may not provide us with significant competitive advantages, because the validity or enforceability of the patents may be challenged and, if instituted, one or more of the challenges may be successful.
−Removed: Patents may be challenged in the U.S.
−Removed: under post-grant review proceedings, inter partes re-examination, ex parte re-examination, or challenges in district court.
−Removed: Patents issued in foreign jurisdictions may be subjected to comparable proceedings lodged in various foreign patent offices, or courts.
−Removed: These proceedings could result in either loss of the patent or loss or reduction in the scope of one or more of the claims of the patent.
−Removed: Even if a patent issues and is held valid and enforceable, competitors may be able to design around our patents, such as by using pre-existing or newly developed technology, in which case competitors may not infringe our issued claims and may be able to market and sell products that compete directly with us before and after our patents expire.
−Removed: We have filed for patent protection in the U.S.
−Removed: and other countries to cover various methods of therapeutic use of our product candidates, including the use of Molgradex for treating NTM lung infections and AeroVanc for the treatment of MRSA infection in the lungs of CF patients.
−Removed: The potential use and potential therapeutic benefits of systemically administered GM-CSF for systemic NTM disease have been described in case reports in published literature, and therefore the use of an inhaled form of GM-CSF may be considered to lack novelty and an inventive step, and thereby to be unpatentable.
−Removed: The patent prosecution process is expensive and time-consuming.
−Removed: We and any future licensors and licensees may not apply for or prosecute patents on certain aspects of our product candidates at a reasonable cost, in a timely fashion, or at all.
−Removed: We may not have the right to control the preparation, filing, and prosecution of some patent applications related to our product candidates or technologies.
−Removed: As a result, these patents and patent applications may not be prosecuted and enforced in a manner consistent with our best interests.
−Removed: It is also possible that we or any future licensors or licensees will fail to identify patentable aspects of inventions made in the course of development and commercialization activities before it is too late to obtain patent protection on them.
−Removed: Further, it is possible that defects of form in the preparation or filing of our patent applications may exist, or may arise in the future, such as with respect to proper priority claims, inventorship, assignment, or claim scope.
−Removed: If there are material defects in the form or preparation of our patents or patent applications, such patents or applications may be invalid or unenforceable.
−Removed: In addition, one or more parties may independently develop similar technologies or methods, duplicate our technologies or methods, or design around the patented aspects of our products, technologies, or methods.
−Removed: Any of these circumstances could impair our ability to protect our products, if approved, in ways which may have an adverse impact on our business, financial condition, and operating results.
−Removed: Furthermore, the issuance of a patent is not conclusive as to its inventorship, scope, validity, or enforceability, and our owned and licensed patents may be challenged in the courts or patent offices in and outside of the U.S.
−Removed: Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated, or held unenforceable, in whole or in part, which could limit our ability to use our patents to stop others from using or commercializing similar or identical products or technology, or limit the duration of the patent protection of our technology and drugs.
−Removed: Given the amount of time required for the development, testing, and regulatory review of new drug candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized.
−Removed: As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing drugs similar or identical to ours once Orphan Drug and QIDP exclusivities have expired.
−Removed: See the section entitled “ Risks Related to Our Industry ” for further description of Orphan Drug and QIDP exclusivities.
−Removed: Enforcement of intellectual property rights in certain countries outside the U.S.
−Removed: has been limited or non-existent.
−Removed: Future enforcement of patents and proprietary rights in many other countries will likely be problematic or unpredictable.
−Removed: Moreover, the issuance of a patent in one country does not assure the issuance of a similar patent in another country.
−Removed: Claim interpretation and infringement laws vary by nation, so the extent of any patent protection is uncertain and may vary in different jurisdictions.
−Removed: Obtaining and maintaining patent protection depends on compliance with various procedural, document submission, fee payment, and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
−Removed: Periodic maintenance fees, renewal fees, annuity fees, and various other governmental fees on patents and applications are required to be paid to the United States Patent and Trademark Office (“USPTO”), and various governmental patent agencies outside of the U.S.
−Removed: in several stages over the lifetime of the patents and applications.
−Removed: The USPTO and various non-U.S.
−Removed: governmental patent agencies require compliance with a number of procedural, documentary, fee payment, and other similar provisions during the patent application process and after a patent has been issued.
−Removed: There are situations in which non-compliance can result in decreased patent term adjustment or in abandonment or lapse of the patent or patent application, leading to partial or complete loss of patent rights in the relevant jurisdiction.
−Removed: Third parties may c laim that our products, if approved, infringe on their proprietary rights and may challenge the approved use or uses of a product or its patent rights through litigation or administrative proceedings, and defending such actions may be costly and time consu ming, divert management attention away from our business, and result in an unfavorable outcome that could have an adverse effect on our business.
−Removed: Our commercial success depends on our ability and the ability of our CMOs and component suppliers to develop, manufacture, market, and sell our products and product candidates and use our proprietary technologies without infringing the proprietary rights of third parties.
−Removed: Numerous U.S.
−Removed: and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are or may be developing products.
−Removed: Because patent applications can take many years to publish and issue, there currently may be pending applications, unknown to us, that may later result in issued patents that our products, product candidates, or technologies infringe, or that the process of manufacturing our products or any of our respective component materials, or the component materials themselves, infringe, or that the use of our products, product candidates, or technologies infringe.
−Removed: We or our CMOs or component material suppliers may be exposed to, or threatened with, litigation by a third party alleging that our products, product candidates, and/or technologies infringe its patents and/or other intellectual property rights, or that one or more of the processes for manufacturing our products or any of our respective component materials, or the component materials themselves, or the use of our products, product candidates, or technologies, infringe its patents and/or other intellectual property rights.
−Removed: If a third-party patent or other intellectual property right is found to cover our products, product candidates, technologies, or our uses, or any of the underlying manufacturing processes or components, we could be required to pay damages and could be unable to commercialize our products or use our technologies or methods unless we are able to obtain a license to the patent or intellectual property right.
−Removed: A license may not be available to us in a timely manner or on acceptable terms, or at all.
−Removed: In addition, during litigation, the third-party alleging infringement could obtain a preliminary injunction or other equitable remedy that could prohibit us from making, using, selling, or importing our products, technologies, or methods.
−Removed: There generally is a substantial amount of litigation involving patent and other intellectual property rights in the industries in which we operate and the cost of such litigation may be considerable.
−Removed: We can provide no assurance that our product candidates or technologies will not infringe patents or rights owned by others, licenses to which might not be available to us in a timely manner or on acceptable terms, or at all.
−Removed: If a third party claims that we or our CMOs or component material suppliers infringe its intellectual property rights, we may face a number of issues, including, but not limited to:
−Removed: infringement and other intellectual property claims which, with or without merit, may be expensive and time consuming to litigate and may divert management ’ s time and attention from our business;
−Removed: substantial damages for infringement, including the potential for treble damages and attorneys ’ fees, which we may have to pay if it is determined that the product and/or its use at issue infringes or violates the third party ’ s rights;
−Removed: a court prohibiting us from selling or licensing the product unless the third party licenses its intellectual property rights to us, which it may not be required to do;
−Removed: if a license is available from the third party, we may have to pay substantial royalties, fees and/or grant cross-licenses to the third party;
−Removed: redesigning our products or processes so they do not infringe, which may not be possible or may require substantial expense and time.
−Removed: There may be issued or filed claims covering our products, product candidates, or technology or those of our CMOs or component material suppliers or the use of our products, product candidates, or technologies.
−Removed: Additionally, such patents may be issued or filed in the future.
−Removed: Because of the large number of patents issued and patent applications filed in the industries in which we operate, there is a risk that third parties may allege they have patent rights encompassing our products, product candidates, or technologies, or those of our CMOs or component material suppliers, or uses of our products, product candidates, or technologies.
−Removed: In the future, it may be necessary for us to enforce our proprietary rights, or to determine the scope, validity, and unenforceability of other parties ’ proprietary rights, through litigation or other dispute proceedings, which may be costly, and to the extent we are unsuccessful, adversely affect our rights.
−Removed: In these proceedings, a court or administrative body could determine that our claims, including those related to enforcing patent rights, are not valid or that an alleged infringer has not infringed our rights.
−Removed: The uncertainty resulting from the mere institution and continuation of any patent or other proprietary rights-related litigation or interference proceeding could have a material and adverse effect on our business prospects, operating results, and financial condition.
−Removed: Risks Relate d to Our Industry
−Removed: We expect competition in the marketplace for our product candidates, should any of them receive regulatory approval.
−Removed: Molgradex and AeroVanc have received Orphan Drug Designation from the FDA and Molgradex has received Orphan Drug Designation from the EMA.
−Removed: Orphan Drug Designation will provide market exclusivity in the U.S.
−Removed: for seven years and ten years in Europe, but only if (i) Molgradex and AeroVanc receive market approval before a competitor using the same active compound for the same indication, (ii) we are able to produce sufficient supply to meet demand in the marketplace, and (iii) another product with the same active ingredient is not deemed clinically superior.
−Removed: AeroVanc has also received QIDP status extending market exclusivity by an additional five years in addition to any other exclusivity obtained in the U.S.
−Removed: The industries in which we operate (biopharmaceutical, specialty pharmaceutical, biotechnology, and pharmaceutical) are highly competitive and subject to rapid and significant change.
−Removed: Developments by others may render potential application of any of our product candidates in a particular indication obsolete or noncompetitive, even prior to completion of its development and approval for that indication.
−Removed: If successfully developed and approved, we expect our product candidates will face competition.
−Removed: We may not be able to compete successfully against organizations with competitive products, particularly large pharmaceutical companies.
−Removed: Many of our potential competitors have significantly greater financial, technical, and human resources than us, and may be better equipped to develop, manufacture, market, and distribute products.
−Removed: Many of these companies operate large, well-funded research, development, and commercialization programs, have extensive experience in nonclinical and clinical studies, obtaining FDA and other regulatory approvals and manufacturing and marketing products, and have multiple products that have been approved or are in late-stage development.
−Removed: These advantages may enable them to receive approval from the FDA or any foreign regulatory agency before us and prevent us from competing due to their orphan drug protections.
−Removed: Smaller companies may also prove to be significant competitors, particularly through collaborative arrangements with large pharmaceutical and biotechnology companies.
−Removed: Furthermore, heightened awareness on the part of academic institutions, government agencies, and other public and private research organizations of the potential commercial value of their inventions have led them to actively seek to commercialize the technologies they develop, which increases competition for investment in our programs.
−Removed: Competitive products may be more effective, easier to dose, or more effectively marketed and sold than ours, which would have a material adverse effect on our ability to generate revenue.
−Removed: We are subject to uncertainty relating to healthcare reform measures and reimbursement policies that, if not favorable to our products, could hinder or prevent our products’ commercial success, if any of our product candidates are approved.
−Removed: The unavailability or inadequacy of third-party payer coverage and reimbursement could negatively affect the market acceptance of our product candidates and the future revenues we may expect to receive from those products.
−Removed: The commercial success of our product candidates, if approved, will depend on the extent to which the costs of such products will be covered by third-party payers, such as government health programs, commercial insurance, and other organizations.
−Removed: Third-party payers are increasingly challenging the prices and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy.
−Removed: These challenges to prices may be problematic to us since our products are targeted for a small number of patients (those suffering from orphan diseases) thus requiring us to charge very high prices in order to recover development costs and achieve a profit on our revenue.
−Removed: If these third-party payers do not consider our products to be cost-effective compared to other therapies, we may not obtain coverage for our products after approval as a benefit under the third-party payers ’ plans or, even if we do, the level of coverage or payment may not be sufficient to allow us to sell our products on a profitable basis.
−Removed: Significant uncertainty exists as to the reimbursement status for newly approved drug products, including coding, coverage, and payment.
−Removed: There is no uniform policy requirement for coverage and reimbursement for drug products among third-party payers in the U.S., therefore coverage and reimbursement for drug products can differ significantly from payer to payer.
−Removed: The coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payer separately, with no assurance that coverage and adequate payment will be applied consistently or obtained.
−Removed: The process for determining whether a payer will cover and how much it will reimburse a product may be separate from the process of seeking approval of the product or for setting the price of the product.
−Removed: Even if reimbursement is provided, market acceptance of our products may be adversely affected if the amount of payment for our products proves to be unprofitable for healthcare providers or less profitable than alternative treatments or if administrative burdens make our products less desirable to use.
−Removed: Third-party payer reimbursement to providers of our products, if approved, may be subject to a bundled payment that also includes the procedure of administering our products or third-party payers may require providers to perform additional patient testing to justify the use of our products.
−Removed: To the extent there is no separate payment for our product(s), there may be further uncertainty as to the adequacy of reimbursement amounts.
−Removed: The continuing efforts of governments, private insurance companies, and other organizations to contain or reduce costs of healthcare may adversely affect:
−Removed: our ability to set an appropriate price for our products;
−Removed: the rate and scope of adoption of our products by healthcare providers;
−Removed: our ability to generate revenue or achieve or maintain profitability;
−Removed: the future revenue and profitability of our potential customers, suppliers, and collaborators;
−Removed: our access to additional capital.
−Removed: Our ability to successfully commercialize our products will depend on the extent to which governmental authorities, private health insurers, and other organizations establish what we believe are appropriate coverage and reimbursement for our products.
−Removed: The containment of healthcare costs has become a priority of federal and state governments worldwide and the prices of drug products have been a focus in this effort.
−Removed: For example, there have been several recent U.S.
−Removed: Congressional inquiries and proposed bills designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs, and President Trump has stated that reducing drug pricing is a priority for his administration.
−Removed: We expect that federal, state, and local governments in the U.S., as well as in other countries, will continue to consider legislation directed at lowering the total cost of healthcare.
−Removed: In addition, in certain foreign markets, the pricing of drug products is subject to government control and reimbursement may in some cases be unavailable or insufficient.
−Removed: It is uncertain whether and how future legislation, whether domestic or abroad, could affect prospects for our product candidates or what actions federal, state, or private payers for healthcare treatment and services may take in response to any such healthcare reform proposals or legislation.
−Removed: Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures may prevent or limit our ability to generate revenue, attain profitability, or commercialize our product candidates, especially in light of our plans to price our product candidates at a high level.
−Removed: Furthermore, we expect that healthcare reform measures that may be adopted in the future are unpredictable, and the potential impact on our operations and financial position is uncertain, but may result in more rigorous coverage criteria, lower reimbursement, and additional downward pressure on the price we may receive for approved products.
−Removed: Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payers.
−Removed: The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our products, if approved.
−Removed: We face potential product liability exposure and, if successful claims are brought against us, we may incur substantial liability for a product or product candidate and may have to limit its commercialization.
−Removed: In the future, we anticipate that we will need to obtain additional or increased product liability insurance coverage and it is uncertain whether such increased or additional insurance coverage can be obtained on commercially reasonable terms, if at all.
−Removed: Our business (in particular, the use of our product candidates in clinical studies and the sale of any products for which we obtain marketing approval) will expose us to product liability risks.
−Removed: Product liability claims might be brought against us by patients, healthcare providers, pharmaceutical companies, or others selling or involved in the use of our products.
−Removed: If we cannot successfully defend ourselves against any such claims, we will incur substantial liabilities.
−Removed: Regardless of merit or eventual outcome, liability claims may result in:
−Removed: decreased demand for our products and loss of revenue;
−Removed: impairment of our business reputation;
−Removed: delays in enrolling patients to participate in our clinical studies;
−Removed: withdrawal of clinical study participants;
−Removed: a “ clinical hold, ” suspension or termination of a clinical study or amendments to a study design;
−Removed: significant costs of related litigation;
−Removed: substantial monetary awards to patients or other claimants;
−Removed: the inability to commercialize our products and product candidates.
−Removed: We maintain limited product liability insurance for our clinical studies, but our insurance coverage may not reimburse us or may not be sufficient to reimburse us for all expenses or losses we may suffer.
−Removed: Moreover, insurance coverage is becoming increasingly expensive and, in the future, we may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses.
−Removed: We expect that we will expand our insurance coverage to include the sale of commercial products if we obtain marketing approval for any of our product candidates, but we may be unable to obtain product liability insurance on commercially acceptable terms or may not be able to maintain such insurance at a reasonable cost or in sufficient amounts to protect us against potential losses.
−Removed: Large judgments have been awarded in class action lawsuits based on drug products that had unanticipated side effects.
−Removed: A successful product liability claim or series of claims brought against us, if judgments exceed our insurance coverage, could consume a significant portion of our cash and adversely affect our business.
−Removed: Risks Related to our Common Stock
−Removed: Our stock price is expected to continue to be volatile.
−Removed: The market price of our common stock has experienced substantial declines since we announced the top-line results of our IMPALA Phase 3 study of Molgradex for aPAP on June 12, 2019, and our stock price has been and is expected to continue to be subject to significant volatility and fluctuations.
−Removed: Market prices for securities of early-stage pharmaceutical, biotechnology, and other life sciences companies have historically been particularly volatile.
−Removed: Some of the factors that may cause the market price of our common stock to fluctuate include:
−Removed: failed or inconclusive data results from our clinical studies;
−Removed: our ability to obtain regulatory approvals for our product candidates, and delays or failures to obtain such approvals;
−Removed: failure to meet or exceed any financial and development projections that we may provide to the public;
−Removed: failure to meet or exceed the financial and development projections of the investment community;
−Removed: failure of any of our product candidates, if approved, to achieve commercial success;
−Removed: failure to maintain our existing third-party license and supply agreements;
−Removed: failure by us or our licensors to prosecute, maintain, or enforce our intellectual property rights;
−Removed: changes in laws or regulations applicable to our product candidates;
−Removed: any inability to obtain adequate supply of our product candidates or the inability to do so at acceptable prices;
−Removed: adverse regulatory authority decisions;
−Removed: introduction of new products, services, or technologies by our competitors;
−Removed: if securities or industry analysts do not publish research or reports about our business, or if they issue adverse or misleading opinions regarding our business and stock;
−Removed: failure to obtain sufficient capital to fund our business objectives;
−Removed: sales of our common stock by us or our stockholders in the future;
−Removed: trading volume of our common stock;
−Removed: the perception of the pharmaceutical industry by the public, legislatures, regulators, and the investment community;
−Removed: announcements of significant acquisitions, strategic partnerships, joint ventures, or capital commitments by us or our competitors;
−Removed: disputes or other developments relating to proprietary rights, including patents, litigation matters, and our ability to obtain patent protection for our technologies;
−Removed: additions or departures of key personnel;
−Removed: significant lawsuits, including patent or stockholder litigation;
−Removed: changes in the market valuations of similar companies;
−Removed: general market or macroeconomic conditions;
−Removed: announcements by commercial partners or competitors of new commercial products, clinical progress or the lack thereof, significant contracts, commercial relationships, or capital commitments;
−Removed: adverse publicity relating to the CF, aPAP, or NTM markets generally, including with respect to other products and potential products in such markets;
−Removed: the introduction of technological innovations or new therapies that compete with our products;
−Removed: changes in the structure of health care payment systems;
−Removed: period-to-period fluctuations in our financial results.
−Removed: Moreover, the stock markets in general have experienced substantial volatility that has often been unrelated to the operating performance of individual companies.
−Removed: These broad market fluctuations may also adversely affect the trading price of our common stock.
−Removed: In the past, following periods of volatility in the market price of a company’s securities, such as the decline in our stock price, stockholders have often instituted class action securities litigation against those companies.
−Removed: Such litigation, if instituted, could result in substantial costs and diversion of management attention and resources, which could significantly harm our profitability and reputation.
−Removed: If we fail to satisfy all applicable Nasdaq continued listing requirements, including the $1.00 minimum closing bid price requirement, our common stock may be delisted from Nasdaq, which could have an adverse impact on the liquidity and market price of our common stock.
−Removed: Our common stock is currently listed on the Nasdaq Global Select Market, which has qualitative and quantitative continued listing requirements, including corporate governance requirements, public float requirements, and a $1.00 minimum closing bid price requirement.
−Removed: If our common stock trades at closing bid prices below $1.00 for 30 consecutive business days, or if we are unable to satisfy any of the other continued listing requirements, Nasdaq may take steps to delist our common stock.
−Removed: Such a delisting would likely have an adverse effect on the market liquidity of our common stock, decrease the market price of our common stock, result in the potential loss of confidence by investors, suppliers, customers and employees and fewer business development opportunities, and adversely affect our ability to obtain financing for the continuation of our operations.
−Removed: For example, on November 15, 2019, we received written notice from The Nasdaq Stock Market LLC indicating that, for the last thirty consecutive business days, the bid price for our common stock had closed below the minimum $1.00 per share requirement for continued listing on the Nasdaq Global Select Market under Nasdaq Listing Rule 5550(a)(2).
−Removed: However, on December 10, 2019, we received written notice from The Nasdaq Stock Market LLC stating that because our shares had a closing bid price at or above $1.00 per share for a minimum of ten consecutive business days, our stock had regained compliance with the minimum bid price requirement of $1.00 per share for continued listing on the Nasdaq Global Select Market, as set forth in NASDAQ Listing Rule 5450(a)(1).
−Removed: We will continue to incur costs and demands upon management as a result of complying with the laws and regulations affecting public companies.
−Removed: We will continue to incur significant legal, accounting and other expenses, including costs associated with public company reporting requirements.
−Removed: We will also continue to incur costs associated with corporate governance requirements, including requirements under the Sarbanes-Oxley Act, as well as rules implemented by the SEC and Nasdaq.
−Removed: These rules and regulations may also make it difficult and expensive for us to obtain directors ’ and officers ’ liability insurance.
−Removed: As a result, it may be more difficult for us to attract and retain qualified individuals to serve on our board of directors or as executive officers, which may adversely affect investor confidence in us and cause our business or stock price to suffer.
−Removed: We do not expect to pay any cash dividends in the foreseeable future.
−Removed: We expect to retain any future earnings to fund the development and growth of our business and do not expect to pay any cash dividends.
−Removed: As a result, capital appreciation, if any, of our common stock will be stockholders ’ sole source of gain, if any, for the foreseeable future.
−Removed: We have completed certain transactions that likely have resulted in an ownership change under Section 382 of the In ternal Revenue Code limiting the use of our net operating loss carryforwards and certain other tax attributes.
−Removed: If a corporation undergoes an “ ownership change ” within the meaning of Sections 381, 382, and 383 of the Internal Revenue Code, the corporation ’ s net operating loss carryforwards and certain other tax attributes arising from before the ownership change are subject to limitations on use after the ownership change.
−Removed: In general, an ownership change occurs if there is a cumulative change in the corporation ’ s equity ownership by certain stockholders that exceeds fifty percentage points over a rolling three-year period.
−Removed: Similar rules may apply under state tax laws.
−Removed: Our net operating loss carryforwards and certain other tax attributes will be subject to limitations on use.
−Removed: Additional ownership changes in the future could result in additional limitations on our net operating loss carryforwards.
−Removed: Consequently, even if we achieve profitability, we may not be able to utilize a material portion of our net operating loss carryforwards and other tax attributes, which could have a material adverse effect on cash flow and results of operations.
−Removed: Unresolved Staff Comments.
−Removed: We do not have any unresolved comments issued by the SEC staff.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.