−Removed: We are a biopharmaceutical company focused on the discovery, development and commercialization of innovative therapies for diseases of the eye.
−Removed: We have worldwide rights to a portfolio of innovative products and product candidates that include two marketed products utilizing our proprietary mucus penetrating particle, or MPP, drug delivery technology, which we refer to as our AMPPLIFY ® technology, to address medical needs for the front of the eye.
−Removed: Our product candidates and programs include a proprietary regenerative biotherapy for severe ocular diseases and a pipeline of preclinical new chemical entities, or NCEs, targeted to address front and back of the eye diseases.
−Removed: Our two marketed products are EYSUVIS ® (loteprednol etabonate ophthalmic suspension) 0.25%, for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease, and INVELTYS ® (loteprednol etabonate ophthalmic suspension) 1%, a topical twice-a-day ocular steroid for the treatment of post-operative inflammation and pain following ocular surgery.
−Removed: Both products apply our AMPPLIFY technology to loteprednol etabonate, or LE, a corticosteroid designed for ocular applications.
−Removed: The AMPPLIFY technology uses selectively-sized nanoparticles that each have a proprietary coating.
−Removed: We believe that these two key attributes enable even distribution of drug particles on mucosal surfaces and significantly increase drug delivery to target tissues by enhancing mobility of drug particles through mucus and preventing drug particles from becoming trapped and eliminated by mucus.
−Removed: EYSUVIS is the first and only FDA-approved prescription product with an indication for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease.
−Removed: Food and Drug Administration, or FDA, approved EYSUVIS in October 2020, and we commenced a full promotional launch of EYSUVIS in January 2021.
−Removed: We believe that EYSUVIS’ broad mechanism of action, rapid onset of relief of both signs and symptoms, favorable tolerability profile and potential to be complementary to existing therapies offer a favorable profile for the management of dry eye flares and other dry eye associated conditions that would benefit from short-term treatment of dry eye signs and symptoms.
−Removed: We further believe that these features of EYSUVIS are attractive to prescribing clinicians and EYSUVIS could become the preferred first-line prescription therapy for the short-term treatment of the signs and symptoms of dry eye disease, including the treatment of dry eye flares that affect the vast majority of dry eye patients.
−Removed: INVELTYS is the first and only FDA-approved ocular corticosteroid product with a twice-a-day dosing regimen for the treatment of post-operative inflammation and pain following ocular surgery.
−Removed: The FDA approved INVELTYS in August 2018, and we commercially launched the product in January 2019.
−Removed: INVELTYS has the highest concentration (1%) of LE on the market in the United States and is formulated with our AMPPLIFY technology, which enables INVELTYS to deliver 3.75x more drug to the target ocular tissue compared to an active comparator.
−Removed: We believe INVELTYS offers advantages over existing post-surgical treatment options.
−Removed: Upon the consummation of our acquisition of Combangio, Inc., or Combangio, on November 15, 2021, we acquired Combangio’s product candidate, CMB-012, which we now refer to as KPI-012.
−Removed: KPI-012 is our lead product candidate and is currently in clinical development for the treatment of persistent corneal epithelial defects, or PCED, a rare disease of impaired corneal healing.
−Removed: We believe the multifactorial mechanism of action of KPI-012 also makes it a platform technology, and we are evaluating KPI-012 for potential expansion to indications for rare front of the eye diseases, such as limbal stem cell deficiency, chemical burns and Sjogren’s Syndrome, as well as select rare back of the eye diseases, such as retinitis pigmentosa and optic neuritis.
−Removed: For a description of the financial terms of the acquisition of Combangio, see “Item 7., Management’s Discussion and Analysis of Financial Condition and Results of Operations”.
−Removed: We are also progressing our pipeline of proprietary NCE preclinical development programs targeted to address both front and back of the eye diseases.
−Removed: These preclinical development programs include KPI-287, our receptor Tyrosine Kinase Inhibitor, or TKI, and our selective glucocorticoid receptor modulators, or SEGRMs.
−Removed: KPI-287 is designed to inhibit the vascular endothelial growth factor, or VEGF, and platelet derived growth factor, or PDGF, pathways, and is administered by suprachoroidal injection for the treatment of retinal diseases, including wet age-related macular degeneration, or wet AMD, diabetic macular edema, or DME, and retinal vein occlusion, or RVO.
−Removed: SEGRMs are a novel class of therapies designed to modify the downstream activity of the
−Removed: glucocorticoid receptors to exhibit the anti-inflammatory and immunomodulatory properties of the corticosteroid class of therapies while markedly reducing their associated side effects, which we are developing for the treatment of inflammatory diseases.
−Removed: The following table describes our marketed products and the stage of each of our current clinical and preclinical development programs:
−Removed: We have retained worldwide commercial rights for EYSUVIS, INVELTYS, KPI-012 and our preclinical development programs.
−Removed: Starting with FDA approval of INVELTYS, we have built a commercial infrastructure with our own focused, specialty sales force which now includes approximately 100 field-based commercial sales personnel.
−Removed: Our sales representatives promote both EYSUVIS and INVELTYS.
−Removed: We own and/or exclusively license patents relating to EYSUVIS, INVELTYS, KPI-012, our preclinical development programs and our AMPPLIFY technology, including U.S.
+Added: We are a clinical-stage biopharmaceutical company dedicated to the research, development and commercialization of innovative therapies for rare and severe diseases of the eye.
+Added: Our product candidate, KPI-012, which we acquired from Combangio, Inc., or Combangio, on November 15, 2021, is a mesenchymal stem cell secretome, or MSC-S, and is currently in clinical development for the treatment of persistent corneal epithelial defects, or PCED, a rare disease of impaired corneal healing.
+Added: Based on the positive results of a Phase 1b clinical safety and efficacy trial of KPI-012 in patients with PCED, along with favorable preclinical safety and efficacy results, we submitted an investigational new drug application, or IND, to the U.S.
+Added: Food and Drug Administration, or FDA, which was accepted in December 2022.
+Added: In February 2023, we dosed our first patient in our CHASE ( C orneal H ealing A fter SE cretome therapy) Phase 2b clinical trial of KPI-012 for PCED in the United States, and we are targeting reporting top-line safety and efficacy data from this trial in the first quarter of 2024.
+Added: If the results of the CHASE Phase 2b clinical trial are positive, and subject to discussion with regulatory authorities, we believe this trial could serve as the first of two pivotal trials required to support the submission of a Biologics License Application, or BLA, to the FDA.
+Added: We believe the multifactorial mechanism of action of KPI-012 also makes MSC-S a platform technology.
+Added: We are evaluating the potential development of KPI-012 for additional rare front-of-the-eye diseases, such as for the treatment of Limbal Stem Cell Deficiency and ocular manifestations of moderate-to-severe Sjögren’s.
+Added: In addition, we have initiated preclinical studies under our KPI-014 program to evaluate the utility of our MSC-S platform for inherited retinal degenerative diseases, such as Retinitis Pigmentosa and Stargardt Disease.
+Added: In connection with the determination to focus our research and development efforts on KPI-012, in 2022, we determined to cease the development of our preclinical pipeline programs that are unrelated to our MSC-S platform.
+Added: We expect to commercialize in the United States any of our product candidates that receive marketing approval.
+Added: We previously developed and commercialized two marketed products, EYSUVIS ® (loteprednol etabonate ophthalmic suspension) 0.25%, for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease, and INVELTYS ® (loteprednol etabonate ophthalmic suspension) 1%, a topical twice-a-day ocular steroid for the treatment of post-operative inflammation and pain following ocular surgery.
+Added: Both products applied a proprietary mucus-penetrating particle drug delivery technology, which we referred to as the AMPPLIFY ® Drug Delivery Technology.
+Added: On July 8, 2022, we closed the transaction, or the Alcon Transaction, contemplated by the asset purchase agreement, dated as of May 21, 2022, or the Asset Purchase Agreement, by and between us, Alcon Pharmaceuticals Ltd.
+Added: and Alcon Vision, LLC, which we refer to collectively as Alcon, pursuant to which Alcon purchased the rights to manufacture, sell, distribute, market and commercialize EYSUVIS and INVELTYS and to develop, manufacture, market and otherwise exploit the AMPPLIFY Drug Delivery Technology, which we collectively refer to as the Commercial Business.
+Added: Alcon also assumed certain liabilities with respect to the Commercial Business at the closing of the Alcon Transaction.
+Added: Alcon paid us an upfront cash payment of $60.0 million upon the closing of the Alcon Transaction.
+Added: Pursuant to the Asset Purchase Agreement, we are also eligible to receive from Alcon up to four commercial-based sales milestone payments as follows:
+Added: (1) $25.0 million upon the achievement of $50.0 million or more in aggregate worldwide net sales of EYSUVIS and INVELTYS in a calendar year from 2023 to 2028, (2) $65.0 million upon the achievement of $100.0 million or more in aggregate worldwide net sales of EYSUVIS and INVELTYS in a calendar year from 2023 to 2028, (3) $75.0 million upon the achievement of $175.0 million or more in aggregate worldwide net sales of EYSUVIS and INVELTYS in a calendar year from 2023 to 2029 and (4) $160.0 million upon the achievement of $250.0 million or more in aggregate worldwide net sales of EYSUVIS and INVELTYS in a calendar year from 2023 to 2029.
+Added: Each milestone payment will only become payable once, if at all, upon the first time such milestone is achieved, and only one milestone payment will be paid with respect to a calendar year.
+Added: In the event that more than one milestone is achieved in a calendar year, the higher milestone payment will become payable and the lower milestone payment will become payable only if the corresponding milestone is achieved again in a subsequent calendar year.
+Added: To date, we have not received any milestone payments pursuant to the Asset Purchase Agreement.
+Added: On July 8, 2022, we announced that we had committed to a course of action to terminate 113 employees, consisting of our entire commercial sales force and certain employees in our commercial, scientific, manufacturing, finance and administrative functions.
+Added: The determination to proceed with the workforce reduction was made in the context of the closing of the Alcon Transaction and the changes to the scope of our research and development activities of KPI-012 as more fully described above.
+Added: The workforce reduction was completed by the end of 2022.
+Added: The following table describes the stage of each of our development programs:
+Added: We have retained worldwide commercial rights for our MSC-S platform, including KPI-012 and KPI-014.
+Added: We own and/or exclusively license patents relating to this platform, including U.S.
and foreign issued patents and pending patent applications.
−Removed: The expiration dates of issued U.S.
−Removed: patents covering EYSUVIS and INVELTYS are in 2033.
The expiration dates of the issued U.S.
−Removed: patents that we control covering KPI-012 are in 2040, and a portfolio of additional U.S.
−Removed: patent applications covering KPI-012 is currently in prosecution.
−Removed: The expiration dates of issued U.S.
−Removed: patents relating to our AMPPLIFY technology are in 2025 through 2036.
−Removed: Our goal is to become a leading biopharmaceutical company focused on the discovery, development and commercialization of innovative therapies primarily for diseases of the front and back of the eye.
+Added: patents that we control covering KPI-012 are scheduled to expire no earlier than 2040, and a portfolio of additional U.S.
+Added: patent applications covering the MSC-S platform is currently in prosecution.
+Added: Our goal is to become a leading biopharmaceutical company dedicated to the research, development and commercialization of innovative therapies for rare and severe diseases of the front and back of the eye.
Key elements of our strategy include:
−Removed: ● Maximize the commercial potential of EYSUVIS and INVELTYS.
−Removed: EYSUVIS is the first and only FDA-approved prescription product with an indication for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease.
−Removed: EYSUVIS was approved in October 2020, and we commenced a full promotional launch in January 2021.
−Removed: We estimate that approximately 17.2 million people in the United States have been diagnosed with dry eye disease.
−Removed: We believe that EYSUVIS’ broad mechanism of action, rapid onset of relief of both signs and symptoms, favorable tolerability profile and potential to be complementary to existing therapies, offers a favorable profile for the management dry eye associated conditions that would benefit from short-term treatment.
−Removed: We further believe that EYSUVIS could become
−Removed: the preferred first-line prescription therapy for treating dry eye flares, which affect the vast majority of dry eye patients.
−Removed: We also expect to explore commercialization of EYSUVIS for the treatment of dry eye disease in certain markets outside of the United States, utilizing a variety of collaboration, distribution and other marketing arrangements with one or more third parties.
−Removed: INVELTYS is the first and only FDA approved ocular corticosteroid product with a twice-a-day dosing regimen for the treatment of post-operative inflammation and pain following ocular surgery.
−Removed: Other approved topical ocular corticosteroid products for this indication are dosed three or four times a day.
−Removed: In January 2019, we began to commercialize INVELTYS in the United States with our own focused, specialty sales force.
−Removed: ● Advance the clinical development of, and seek and obtain regulatory approval for, KPI-012 for the treatment of PCED and other indications .
−Removed: KPI-012 is a novel, human bone-marrow derived mesenchymal stem cells, or MSC, secretome currently in clinical development for the treatment of PCED.
+Added: ● Advance the clinical development of, and seek regulatory approval for, KPI-012 for the treatment of PCED .
+Added: KPI-012 is a novel, human bone-marrow derived MSC-S currently in clinical development for the treatment of PCED.
A PCED is a persistent non-healing corneal defect or wound that is refractory to conventional treatments.
−Removed: Based on the positive results of a Phase 1b clinical efficacy trial of KPI-012 in patients with PCED, we plan to submit an investigational new drug, or IND, application to the FDA for KPI-012 and, subject to regulatory clearance, commence a Phase 2/3 clinical trial of KPI-012 for PCED in the United States in the fourth quarter of 2022.
−Removed: If the results of our planned Phase 2/3 clinical trial of KPI-012 are positive, and subject to discussions with regulatory authorities, we believe this trial can serve as the first of two required pivotal trials.
−Removed: If so, we plan to conduct an additional Phase 3 pivotal trial in PCED patients to support the potential submission of a biologics license application, or BLA, to the FDA.
+Added: Based on the positive results of a Phase 1b clinical safety and efficacy trial of KPI-012 in patients with PCED, along with favorable preclinical safety and efficacy results, we submitted an IND to the FDA, which was accepted in December 2022.
+Added: In February 2023, we dosed our first patient in the CHASE Phase 2b clinical trial of KPI-012 for PCED in the United States.
+Added: If the results of the CHASE Phase 2b clinical trial are positive, and subject to discussions with regulatory authorities, we believe this trial could serve as the first of two pivotal trials required to support the submission of a BLA to the FDA.
If approved, we intend to commercialize KPI-012 with a small, targeted, internal sales force in the United States.
−Removed: We also expect to explore commercialization of KPI-012 for the treatment of PCED in certain markets outside the United States utilizing a variety of collaboration, distribution and other marketing arrangements with one or more third parties.
−Removed: We further believe that the multifactorial nature of KPI-012 also makes it a platform technology, and we are evaluating KPI-012 for potential expansion to indications for rare front of the eye diseases, such as limbal stem cell deficiency, chemical burns and Sjogren’s Syndrome, as well as select rare back of the eye diseases, such as retinitis pigmentosa and optic neuritis.
−Removed: ● Advance our pipeline of preclinical development programs.
−Removed: We are also progressing our pipeline of proprietary NCE preclinical development programs targeting both front and back of the eye diseases.
−Removed: These programs include KPI-287, our TKI product candidate that inhibits the VEGF and PDGF pathways, for the treatment of retinal diseases, including wet AMD, and our SEGRMs, which are a novel class of therapies designed to modify the downstream activity of the receptors to exhibit the anti-inflammatory and immunomodulatory properties while markedly reducing side effects associated with corticosteroids .
−Removed: We own all intellectual property and worldwide rights to these preclinical development programs.
−Removed: Prior to initiating IND-enabling studies, we may consider potential collaborative partnership opportunities to advance product candidates we develop, including through these programs.
+Added: We also expect to explore commercialization of KPI-012 for the treatment of PCED in certain markets outside the United States utilizing a variety of collaboration, distribution, co-promotion and other marketing arrangements with one or more third parties.
+Added: ● Advance KPI-012 for additional rare ocular surface disease indications and KPI-014 for rare inherited retinal diseases.
+Added: We are also evaluating the potential of KPI-012 to treat other rare front-of-the-eye diseases, such as Limbal Stem Cell Deficiency and ocular manifestations of moderate-to-severe Sjögren’s.
+Added: In addition, we have initiated preclinical studies of KPI-014, our preclinical program evaluating the utility of our MSC-S platform for inherited retinal degenerative diseases, such as Retinitis Pigmentosa and Stargardt Disease.
● Business development through selective transactions.
−Removed: We plan to pursue value-driven business development opportunities as they arise in order to enhance our business and product pipeline, which may include strategically acquiring preclinical or clinical product candidates, particularly in the ophthalmic area.
−Removed: We also plan to explore a variety of transactions to maximize the value of our assets, including out-licensings, collaborations, divestitures, distributions and other development and marketing arrangements with one or more third parties for our products and product candidates.
−Removed: EYSUVIS for Dry Eye Disease
−Removed: Dry Eye Disease Overview
−Removed: Dry eye disease is a chronic, episodic, multifactorial disease affecting the tears and ocular surface that can result in tear film instability, inflammation, discomfort, visual disturbance and ocular surface damage.
−Removed: While the precise cause of dry eye disease is not fully understood, it often involves impairment of the lacrimal unit, which consists of the lacrimal glands, ocular surface and the sensory and motor nerves that connect them, and has a significant inflammatory
−Removed: There is significant published research that suggests that inflammation plays a major role in the development of dry eye disease.
−Removed: Dry eye disease can have a significant impact on quality of life and can potentially cause long-term damage to the ocular surface.
−Removed: Due to the impact of dry eye disease on tear film dynamics, the condition can affect performance of common vision-related activities such as reading, using a computer and driving, and can lead to complications associated with visual impairment.
−Removed: Dry eye disease is commonly treated by ophthalmologists and optometrists.
−Removed: A significant number of dry eye disease patients experience acute, episodic exacerbations of their symptoms, which are commonly referred to as flares, at various times throughout the year that can cause significant discomfort and disability.
−Removed: A dry eye flare is defined as a rapid onset, inflammation-driven response to a variety of triggers that typically cannot be adequately managed with the patient’s ongoing therapy.
−Removed: As illustrated in the graphic below, these flares can be triggered by numerous factors, such as environmental stimuli related to exposure to allergens, pollution, wind and low humidity.
−Removed: Intense visual concentration, such as watching television or working at a computer, can also trigger flares.
−Removed: Other potential triggers include hormonal changes, contact lens wear, smoking and sleep deprivation, which cause ocular surface inflammation and impact tear production and/or tear film stability.
−Removed: We estimate dry eye disease affects approximately 38 million people in the United States based on an estimated dry eye disease prevalence of 14.5% described below and applied to the population of the United States over 20 years old.
−Removed: Based on third-party academic research, we believe dry eye disease results in approximately $55 billion in direct and indirect costs in the United States each year, of which approximately $3.8 billion are direct medical costs.
−Removed: The exact prevalence of dry eye disease is unknown due to the difficulty in defining the disease and the lack of a single diagnostic test to confirm its presence.
−Removed: The Beaver Dam Offspring Study, a major epidemiological study published in 2014 in the American Journal of Ophthalmology , reported that in a cohort of over 3,000 patients, dry eye disease was self-reported by 14.5% of the patients.
−Removed: The prevalence of dry eye disease increases with age, and we expect that the number of dry eye disease cases will increase as the U.S.
−Removed: population continues to age.
−Removed: Epidemiology and market research commissioned by us indicate that there are an estimated 17.2 million patients with a diagnosis of dry eye disease in the United States.
−Removed: We also commissioned three surveys of 503, 297, and 500 dry eye disease patients, which we refer to as our patient surveys, in 2017, 2018, and 2020, respectively.
−Removed: The patient surveys included a representative set of dry eye patients based on demographics and disease characteristics, such as age, sex and therapeutic history.
−Removed: The patients represented a broad
−Removed: range of dry eye disease severity.
−Removed: Based upon our review of the patient surveys as well as independent studies conducted in 2020 and 2021 of 774 and 756 dry eye sufferers, respectively, we believe dry eye disease is a burdensome disease that has a significant impact on the quality of life of patients with dry eye disease.
−Removed: Limitations of Existing Treatments for Dry Eye Disease
−Removed: The most commonly used treatments for dry eye disease in the United States are over-the-counter eye drops, often referred to as “artificial tears” or lubricating eye drops, and four prescription pharmaceutical products, Restasis ® , Xiidra ® , Cequa TM and Tyrvaya TM .
−Removed: Most over-the-counter artificial tears are palliative in nature and are intended to supplement insufficient tear production or improve tear film instability.
−Removed: Artificial tears typically provide only short term or temporary relief by lubricating the eyes and helping to maintain moisture on the outer surface of the eye.
−Removed: Artificial tears do not treat the underlying inflammatory components of dry eye disease.
−Removed: In addition to over-the-counter artificial tears, Restasis, Xiidra, Cequa and Tyrvaya are sometimes prescribed as a chronic therapy for the treatment of dry eye disease.
−Removed: We believe that less than 10% of patients diagnosed with dry eye disease in the United States use a chronic therapy to treat their disease.
−Removed: Restasis and Cequa are each topically applied, ophthalmic formulations of the immunosuppressant cyclosporine.
−Removed: Restasis and Cequa are not approved for the treatment of the signs and symptoms of dry eye disease, but rather for increasing tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with dry eye disease.
−Removed: Restasis frequently causes burning upon instillation, and, according to the package insert, 17% of patients in clinical trials of Restasis reported ocular burning upon instillation.
−Removed: Cequa frequently causes pain upon instillation, and, according to the package insert, 22% of patients in clinical trials of Cequa reported pain upon instillation of drops.
−Removed: Xiidra is a topically applied, ophthalmic formulation of lifitegrast, a small molecule LF1a antagonist, which was approved by the FDA in July 2016 for the treatment of the signs and symptoms of dry eye disease.
−Removed: In clinical trials, the most common adverse reactions (incidence rate of approximately 5% to 25%) following the use of Xiidra were instillation-site irritation, dysgeusia, and decreased visual acuity.
−Removed: Tyrvaya (varenicline solution) nasal spray is a cholinergic agonist that was approved by the FDA in October 2021 to increase tear production and treat the signs and symptoms of dry eye disease.
−Removed: According to the Tyrvaya package insert, 82% of patients reported sneezing upon instillation.
−Removed: Tyrvaya, like Xiidra, Restasis and Cequa, is typically used chronically for dry eye patients who have continuous symptoms.
−Removed: As each of these medications have a relatively long onset of action, they are not generally used for the short-term treatment of episodic dry eye flares.
−Removed: We believe there is a larger proportion of dry eye patients whose symptoms are primarily episodic as opposed to chronic, and for whom a chronic therapy is not necessary and for whom EYSUVIS, an FDA-approved therapy for short-term use, can address a significant unmet need.
−Removed: For example, our patient surveys and the independent study of 774 dry eye sufferers indicate that approximately 75% to 90% of surveyed patients experience dry eye flares, with flares lasting on average approximately four days and occurring approximately six times per year.
−Removed: These results are also consistent with the 2021 independent, multi-sponsor survey of 756 dry eye sufferers indicating that they suffer a median of 5.25 flares per year lasting on average 4.9 days.
−Removed: In our 2021 survey of 201 eye care professionals, or ECPs, all reported that their patients have dry eye flares, but many underestimated the actual number of patients with flares.
−Removed: In addition, according to our patient surveys, the most common reason given by patients for discontinuing the two leading branded dry eye treatments were insufficient efficacy, side effects and product price.
−Removed: EYSUVIS Opportunity in Dry Eye Disease
−Removed: EYSUVIS received FDA approval for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease in October 2020 utilizing a two-week course of therapy administered four times a day.
−Removed: We commenced our full promotional launch of EYSUVIS in January 2021.
−Removed: We believe that EYSUVIS has a favorable profile for the management of dry eye disease flares and other dry eye associated conditions, including the following attributes:
−Removed: ● Broad mechanism of action.
−Removed: LE is a corticosteroid.
−Removed: Corticosteroids are known for their broad anti-inflammatory properties.
−Removed: ● Rapid onset of relief.
−Removed: In our Phase 2 and Phase 3 clinical trials, patients treated with EYSUVIS reported reductions in ocular discomfort within days of initiation of treatment.
−Removed: ● Favorable safety and tolerability profile.
−Removed: LE is one of the safest topical ocular steroids available due to its unique pharmacokinetics.
−Removed: LE was designed to be metabolized after exerting its anti-inflammatory action in the eye.
−Removed: The metabolism of LE to inactive metabolites reduces exposure of the trabecular meshwork, an area of tissue located in the anterior chamber that is responsible for draining the aqueous humor from the eye, to active steroid, thus reducing the risk of an increase in IOP relative to other steroids.
−Removed: EYSUVIS was well-tolerated across four clinical trials, with adverse events and IOP increases comparable to that observed with vehicle.
−Removed: ● Specifically targeting relief of episodic dry eye flares.
−Removed: The mechanism of action and rapid onset of relief of EYSUVIS in dry eye disease is distinct from that of artificial tears and chronic therapies like Restasis, Xiidra, Cequa and Tyrvaya.
−Removed: Therefore, we expect EYSUVIS to be used as a stand-alone short course therapy to provide rapid relief of dry eye flares by improving ocular discomfort (a dry eye symptom) and reducing ocular redness (a dry eye sign).
−Removed: ● Potentially complementary to existing therapies.
−Removed: We believe that patients on chronic therapies also experience dry eye flares and could potentially benefit from using EYSUVIS in addition to their maintenance therapy.
−Removed: We believe that these attributes make EYSUVIS attractive to prescribing clinicians for treating patients that suffer from dry eye flares, and that EYSUVIS could become the preferred first-line prescription therapy for the short-term treatment of the signs and symptoms of dry eye disease, including the treatment of dry eye flares.
−Removed: Our current estimates of potential future revenue from sales of EYSUVIS are based, in part, on current prescription trends, anticipated changes in payer coverage, market growth assumptions and physician market research data we have commissioned that examines intent to prescribe.
−Removed: These estimates may be impacted by the current COVID-19 pandemic.
−Removed: The extent of the impact of the COVID-19 pandemic on our commercialization efforts will depend on the length and severity of this pandemic and the impact on our customers, employees, vendors and government agencies, which is uncertain and cannot be predicted.
−Removed: EYSUVIS Clinical Development Program
−Removed: EYSUVIS was evaluated in four clinical trials.
−Removed: In January 2018, we announced topline results from two completed Phase 3 clinical trials, which we refer to as STRIDE 1 and STRIDE 2 (STRIDE - S hort T erm R elief I n D ry E ye), evaluating the safety and efficacy of EYSUVIS versus vehicle (placebo) in patients with dry eye disease.
−Removed: In STRIDE 1, statistical significance was achieved for the primary sign endpoint of conjunctival hyperemia and the primary symptom endpoint of ocular discomfort severity change from baseline to day 15 in the intent to treat, or ITT, population;
−Removed: in addition, statistical significance was also achieved in STRIDE 1 for a second pre-specified primary symptom endpoint of ocular discomfort severity change from baseline to day 15 in patients with more severe baseline ocular discomfort.
−Removed: In STRIDE 2, statistical significance was achieved for the primary sign endpoint of conjunctival hyperemia, but statistical significance was not achieved for the primary symptom endpoint of ocular discomfort severity.
−Removed: EYSUVIS was generally well tolerated in both STRIDE 1 and STRIDE 2, with no clinically significant treatment-related adverse events observed during the course of either trial, and with elevations in intraocular pressure, or IOP, in both trials similar to placebo.
−Removed: In October 2018, we submitted a New Drug Application, or NDA, to the FDA for EYSUVIS.
−Removed: In August 2019, we announced that we received a complete response letter, or CRL, from the FDA regarding this NDA.
−Removed: The FDA indicated that efficacy data from an additional clinical trial would be needed to support a resubmission of the NDA.
−Removed: Based upon the previous recommendation of the FDA, we had initiated an additional Phase 3 clinical trial, STRIDE 3, in the third quarter of 2018.
−Removed: In March 2020, we announced top line results from STRIDE 3, achieving statistical significance in the pre-specified primary endpoints of change from baseline to day 15 in ocular discomfort severity in the overall ITT population and in a pre-defined subgroup of patients with more severe baseline ocular discomfort.
−Removed: In addition, statistical significance was achieved for conjunctival hyperemia at day 15.
−Removed: Consistent with prior clinical
−Removed: experience, EYSUVIS was well-tolerated in STRIDE 3, with adverse events and intraocular pressure increases comparable to vehicle.
−Removed: The positive results from STRIDE 3 for both signs and symptoms of dry eye disease, along with the positive data from the previous clinical trials of EYSUVIS, served as the basis for our NDA resubmission in April 2020.
−Removed: EYSUVIS received FDA approval for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease in October 2020.
−Removed: EYSUVIS Customer Concentration
−Removed: Three customers comprised 10% or more of our revenue attributable to EYSUVIS during the year ended December 31, 2021 and 2020.
−Removed: These customers comprised 48%, 26% and 23% of our revenue, respectively, during the year ended December 31, 2021 and 35%, 32% and 29% of our revenue, respectively, during the year ended December 31, 2020.
−Removed: INVELTYS for Post-Operative Inflammation and Pain
−Removed: Post-Operative Inflammation and Pain Overview
−Removed: Ocular inflammation and pain are common complications following ocular surgery.
−Removed: In 2019, Marketscope, a third-party provider of market data, projected that the number of ocular surgeries in the United States would grow to approximately 10.1 million by 2024.
−Removed: The COVID-19 pandemic impacted the ocular surgery market, and in 2020, there were only 7.0 million ocular surgeries reported by Marketscope, representing a decline of approximately 1.4 million from approximately 8.4 million ocular surgeries reported in 2019.
−Removed: In November 2021, Marketscope reported that ocular surgeries were projected to reach pre-COVID levels by the end of 2021.
−Removed: Commonly performed ocular surgeries include cataract, cornea, refractive, oculoplastic and glaucoma procedures.
−Removed: Tissue damage caused by ocular surgery leads to the production of prostaglandins, lipids that aid in recovery at the site of an injury, and increases in blood flow to the affected area, which contribute to inflammation.
−Removed: The standard of care for postoperative inflammation and pain includes anti-inflammatory drugs such as corticosteroids, which improve patient comfort and accelerate recovery through disruption of the inflammatory cascade.
−Removed: INVELTYS was approved by the FDA on August 22, 2018 for the treatment of post-surgical inflammation and pain following all ocular surgery, and was commercially launched in the United States in January 2019.
−Removed: INVELTYS is the first and only twice-daily ocular corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery.
−Removed: Limitations of Existing Treatments for Post-Operative Inflammation and Pain
−Removed: Loteprednol etabonate, or LE, is a unique steroid that was designed to limit side effects, such as increases in IOP and cataract formation, that are associated with other ocular steroids.
−Removed: The first LE containing product, Lotemax ® , was approved by the FDA in 1998.
−Removed: Subsequent gel and ointment formulations of Lotemax were approved by the FDA for the treatment of post-operative inflammation and pain following ocular surgery.
−Removed: Durezol ® is a topical steroid approved by the FDA for the treatment of inflammation and pain associated with ocular surgery.
−Removed: Durezol eye drops are dosed four times a day for two weeks followed by dose tapering based on patient response.
−Removed: The first generic formulations of loteprednol suspension 0.5% (Lotemax suspension) and loteprednol ophthalmic gel 0.5% (Lotemax Gel) were launched in May 2019 and February 2021, respectively, and the first generic version of Durezol was launched in September 2021.
−Removed: The most commonly used ocular steroids, including Lotemax products and Durezol, are approved for the treatment of post-operative inflammation and pain with a three or four-times-a-day dosing regimen.
−Removed: This dosing regimen can be burdensome for patients as they are taking multiple eye drops following surgery, and a three or four times-a-day dosing regimen may reduce patient compliance with the prescribed medication.
−Removed: Other than INVELTYS, there is currently no marketed ocular steroid product with an approved twice-a-day dosing regimen.
−Removed: INVELTYS Opportunity in Post-Operative Inflammation and Pain
−Removed: We believe that INVELTYS has a favorable profile for the treatment of post-operative inflammation and pain following ocular surgery, including the following attributes:
−Removed: ● Twice daily dosing.
−Removed: INVELTYS is the first and only twice-daily ocular corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery.
−Removed: All other ocular corticosteroid products for the treatment of postoperative inflammation and pain are approved for dosing three or four times-a-day.
−Removed: INVELTYS has the highest concentration (1%) of LE on the market in the United States and is formulated with our AMPPLIFY technology, which enables INVELTYS to deliver 3.75x more drug to the target ocular tissue compared to an active comparator.
−Removed: Given the generally accepted view that less frequent dosing leads to higher patient compliance, we believe the ability to achieve a significant reduction in inflammation and pain following surgery with a twice-a-day product is a key differentiating attribute of INVELTYS.
−Removed: ● Favorable safety and tolerability profile.
−Removed: LE is one of the safest topical ocular steroids available due to its unique pharmacokinetics.
−Removed: LE was designed to be metabolized after exerting its anti-inflammatory action in the eye.
−Removed: The metabolism of LE to inactive metabolites reduces exposure of the trabecular meshwork to the active steroid, thus reducing risk of IOP increase relative to other steroids.
−Removed: In our completed Phase 3 clinical trials, INVELTYS was well tolerated with similar increases in IOP, a common side effect of steroids, compared to placebo and with no treatment-related serious adverse events observed during the course of either Phase 3 trial.
−Removed: Our current estimates of potential future revenue from sales of INVELTYS are based, in part, on current prescription trends, anticipated changes in payer coverage, market growth assumptions and physician market research data we have commissioned that examines intent to prescribe.
−Removed: These estimates may be impacted by the current COVID-19 pandemic.
−Removed: The extent of the impact of COVID-19 on our commercialization efforts will depend on the length and severity of this pandemic and the impact on our customers, employees, vendors and government agencies, which is uncertain and cannot be predicted.
−Removed: INVELTYS Clinical Development Program
−Removed: In each of the two Phase 3 clinical trials of INVELTYS in patients who had undergone cataract surgery, administration of INVELTYS two times a day for 14 days achieved statistical significance for both primary efficacy endpoints of complete resolution of inflammation at day eight maintained through day 15 with no need for rescue medication and complete resolution of pain at day eight maintained through day 15 with no need for rescue medication.
−Removed: In each of these trials, INVELTYS was well tolerated with similar increases in IOP, a common side effect of steroids, compared to placebo and with no treatment-related significant adverse events observed during the course of either trial.
−Removed: INVELTYS Customer Concentration
−Removed: Three customers comprised 10% or more of our revenue attributable to INVELTYS during the years ended December 31, 2021 and 2020.
−Removed: These customers comprised 47%, 30% and 21% of our revenue, respectively, during the year ended December 31, 2021 and 40%, 28% and 28% of our revenue, respectively, during the year ended December 31, 2020.
+Added: We plan to pursue value-driven business development opportunities as they arise in order to enhance our business and product pipeline, which may include opportunistically in-licensing or acquiring the rights to complementary products, product candidates and technologies, particularly for the treatment of rare ophthalmic diseases.
+Added: We also plan to explore a variety of transactions to maximize the value of our assets, including out-licensing transactions, collaborations, distributions and other development and marketing arrangements with one or more third parties for our product candidates.
Our Clinical-Stage Product Candidate
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Persistent Corneal Epithelial Defects Overview
−Removed: Persistent corneal epithelial defects, or PCED, is a persistent non-healing corneal defect or wound that is refractory to conventional treatments.
−Removed: PCED is a disease of impaired corneal healing and can be the result of numerous etiologies, including (but not limited to) neurotrophic keratitis, or NK, microbial/viral keratitis, surgical epithelial debridement, corneal transplant surgery, limbal stem cell deficiency, mechanical/thermal trauma and exposure
+Added: PCED is a persistent non-healing corneal defect or wound that is refractory to conventional treatments.
+Added: PCED is a disease of impaired corneal healing and can be the result of numerous etiologies, including (but not limited to) neurotrophic keratitis, or NK, microbial/viral keratitis, surgical epithelial debridement, corneal transplant surgery, limbal stem cell deficiency, mechanical/thermal trauma and exposure keratopathy.
Normal healing is a highly regulated multifactorial process that involves numerous biologic pathways and molecules, including growth factors, cell signaling, proliferation, migration and extracellular matrix remodeling.
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KPI-012 Opportunity in Persistent Corneal Epithelial Defects
−Removed: KPI-012 is a novel, human bone-marrow derived MSC secretome composed of biologically active components secreted from the MSCs, such as growth factors, protease inhibitors, matrix proteins and neurotropic factors, that have been shown in preclinical studies by Combangio and others to facilitate corneal healing.
+Added: KPI-012 is a novel, human bone-marrow derived MSC secretome composed of biologically active components secreted from the MSCs, such as growth factors, protease inhibitors, matrix proteins and neurotropic factors, that have been shown in preclinical studies by Combangio to facilitate corneal healing.
KPI-012 is cell-free and produced from a proprietary cell bank.
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We believe that KPI-012’s multi-factorial mechanism of action has the potential to normalize the impaired healing in PCED and other severe ocular surface diseases driven by impaired healing.
−Removed: As such, KPI-012 offers a potentially promising approach for the treatment of PCED and other ocular surface diseases across multiple etiologies.
+Added: As such, we believe KPI-012 offers a potentially promising approach for the treatment of PCED and other ocular surface diseases across multiple etiologies.
Key biological factors contained in KPI-012 and their potential wound healing functions are shown below:
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Matrix Proteins
+Added: (Fibronectin)
Build a molecular scaffold in the wound bed for cells to migrate and adhere to
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Promote maintenance of neurons to support corneal health
−Removed: The multifactorial mechanism of action of KPI-012 is thought to be responsible for the significant wound healing activity observed in Combangio’s preclinical animal models and in the Phase 1b clinical trials.
−Removed: KPI-012 has received orphan drug designation from the FDA, for the treatment of PCED, and we believe KPI-012 should meet the criteria for fast-track and breakthrough designations.
−Removed: Preliminary Clinical Development Plan for KPI-012
+Added: The multifactorial mechanism of action of KPI-012 is thought to be responsible for the significant wound healing activity observed in Combangio’s preclinical animal models and in the completed Phase 1b clinical trial.
+Added: KPI-012 has received orphan drug designation from the FDA for the treatment of PCED.
+Added: Clinical Development Plan of KPI-012
We are initially developing KPI-012 for the treatment of PCED.
−Removed: Combangio completed a Phase 1b clinical efficacy trial in nine patients with PCED in Mexico City.
−Removed: Based on the results of this Phase 1b clinical trial, we plan to submit an IND application to the FDA for KPI-012 and, subject to regulatory clearance, commence a Phase 2/3 clinical trial of KPI-012 for PCED in the United States in the fourth quarter of 2022.
−Removed: Our planned Phase 2/3 randomized, placebo-controlled clinical trial of KPI-012 will evaluate the safety and efficacy of various dosing regimens of KPI-012 in patients diagnosed with PCED.
−Removed: If the results of our planned Phase 2/3 clinical trial of KPI-012 are positive, and subject to discussions with regulatory authorities, we believe this trial can serve as the first of two required pivotal trials.
−Removed: If so, we plan to conduct an additional Phase 3 pivotal trial in PCED patients to support the potential submission of a BLA to the FDA.
+Added: Combangio completed a Phase 1b clinical efficacy trial in nine patients with PCED in Mexico City, Mexico.
+Added: Based on the results of this Phase 1b clinical trial, we initiated a full preclinical development program and submitted an IND application to the FDA for KPI-012, which was accepted in December 2022.
+Added: In February 2023, we dosed our first patient in the CHASE Phase 2b clinical trial of KPI-012.
+Added: The trial includes two patient cohorts, with the initial cohort involving an open label evaluation in two PCED patients to establish safety of the high dose KPI-012 (3 U/ml given QID) to be administered in the study.
+Added: If no dose-limiting toxicity is observed after one week of dosing in these two patients, then the second cohort of approximately 90 patients will be initiated as a multicenter, randomized, double-masked, vehicle-controlled, parallel-group trial in PCED patients with varying underlying etiologies to evaluate the safety and efficacy of two doses of KPI-012 ophthalmic solution (1 U/ml and 3 U/ml) compared to vehicle when dosed topically four times per day for 56 days.
+Added: The trial will have an 8-week treatment period with evaluations at frequent times during the dosing period and at 10 weeks and 26 weeks.
+Added: The trial is expected to enroll approximately 90 adult patients with PCED, and the primary endpoint of the trial will be complete healing of the PCED at Week 8 as measured by corneal fluorescein staining using a central-reading center assessment of corneal fluorescing staining photographs.
+Added: We are targeting reporting top-line safety and efficacy data from the CHASE Phase 2b clinical trial in the first quarter of 2024.
+Added: If the results are positive, and subject to discussions with regulatory authorities, we believe this trial can serve as the first of two pivotal trials required to support the submission of a BLA to the FDA.
Phase 1b Clinical Trial Results of KPI-012
−Removed: Combangio conducted two Phase 1b clinical trials with KPI-012 in Mexico City, Mexico during 2020 and 2021, one in 3 subjects without active corneal disease who were dosed twice a day (25 ng/mL FNE) for one week and another in nine patients with PCED, or the PCED cohort, who were dosed twice a day (25 ng/ml FNE) for up to 8 weeks.
+Added: Combangio conducted a Phase 1b clinical trial of KPI-012 in Mexico City, Mexico during 2020 and 2021, one in three subjects without active corneal disease who were dosed twice a day (1 U/mL) for one week and another in nine patients with PCED, or the PCED cohort, who were dosed twice a day (1 U/mL) for up to eight weeks.
Key inclusion criteria for the PCED cohort included:
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- Keratoconjunctivtis sicca
−Removed: - Sjogren’s Syndrome
+Added: - Sj ö gren’s
- Corneal cross-linking
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● Any previous treatment was stopped except for the study medication
−Removed: The subjects were treated with KPI-012 topically twice a day, with the subjects in the safety cohort without active corneal disease treated for one week and patients in the PCED cohort treated between one to eight weeks.
−Removed: KPI-012 was generally well tolerated during both trials, with only one subject experiencing treatment-related TEAEs (mild and transient itching, red eye, and blurred vision after study drug administration).
+Added: The subjects in the Phase 1b trial were treated with KPI-012 topically twice a day, with the subjects in the safety cohort without active corneal disease treated for one week and patients in the PCED cohort treated between one to eight weeks.
+Added: KPI-012 was generally well tolerated during both trials, with only one subject experiencing treatment-related adverse events (mild and transient itching, red eye and blurred vision after study drug administration).
There were no deaths or treatment-related serious adverse events during either trial.
One subject in the PCED cohort had to withdraw from the trial due to a protocol screening violation.
−Removed: As depicted in Figure 1 below, six of the eight patients in the PCED cohort (75%) who completed the trial achieved complete healing of the lesion after four weeks of treatment, with one additional patient experiencing some clinical improvement but not complete healing.
+Added: As depicted in Figure 1 below, six of the eight patients in the PCED cohort (75%) who completed the trial achieved complete healing of the lesion after four weeks of treatment, with the two other patients experiencing some clinical improvement but not complete healing.
Four of eight patients in the PCED cohort (50%) achieved complete healing of the lesion after one week of treatment and the other two patients achieved complete healing within two to four weeks of initiation of treatment with KPI-012.
All six of the patients who achieved complete healing remained healed through the follow-up period of the trial, which ranged between eight to 19 weeks.
−Removed: Of the two patients who did not show complete healing in the trial, clinical investigators noted some clinical improvement in one of the patients (Patient 2-05), but the corneal staining images did not show complete healing of the defect.
−Removed: Patient 2-04 had a PCED in a blind eye which was perhaps too severe to respond to a pharmaceutical intervention.
−Removed: Patient 2-05 had a PCED that had existed for 871 days before treatment;
−Removed: corneal specialists have advised that it is rare for a PCED to have persisted for this duration and that it could be indicative of systemic disease.
+Added: Of the two patients who did not show complete healing in the trial, clinical investigators noted some clinical improvement in both patients, but the corneal staining images did not show complete healing of the defect.
Summary of Phase 1b clinical trial of KPI-012 for PCED, including representative images for a healed patient study eye.
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KPI-012 Preclinical Studies and Results
−Removed: KPI-012 has been evaluated by Combangio in a number of preclinical studies.
+Added: KPI-012 was evaluated by Combangio in a number of preclinical studies.
In these studies, KPI-012 promoted rapid ocular re-epithelialization and mitigated scarring and neovascularization in a number of well-established animal models.
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(B) Treatment with KPI-012 resulted in more rapid complete healing and a greater percentage of completely healed eyes (dashed line), relative to vehicle-treated eyes (solid line).
−Removed: Rabbit Tolerability Study
−Removed: To evaluate tolerability of KPI-012, Combangio conducted a 15-day good laboratory practice toxicology study following ocular instillation of KPI-012 in rabbits.
−Removed: The purpose of the study was to determine the ocular and systemic toxicity of KPI-012 following repeated topical ocular instillation for 15 days.
−Removed: One group of rabbits was administered KPI-012 three times a day via topical ocular instillation to the right eye (the low dose) and another group was administered KPI-012 six times a day via topical ocular instillation to the right eye (the high dose), in each case with a one-week recovery period.
−Removed: The left eye served as a contralateral control and received vehicle at the same frequency as the KPI-012-treated right eye.
−Removed: All rabbits survived to the end of the study, and no gross lesions and abnormalities were recorded.
−Removed: There were no observed test article-related findings on body weight, intraocular pressure, clinical pathology, gross pathology, organ weights, ophthalmologic examination or ocular histopathology.
−Removed: The data of the toxicology study supported that repeated daily topical administration of KPI-012, at both three times a day and six times a day for 15 days, was well-tolerated and resulted in no overt toxicities in rabbits.
−Removed: Other Potential Indications for KPI-012
−Removed: We believe the multifactorial mechanism of action of KPI-012 also makes it a platform technology, and we are evaluating KPI-012 for potential expansion to indications for rare front of the eye diseases, such as limbal stem cell deficiency, chemical burns and Sjogren’s Syndrome, as well as select rare back of the eye diseases, such as retinitis pigmentosa and optic neuritis.
−Removed: The wound-healing mechanism of action of KPI-012 also potentially enables partnering opportunities in chronic and/or severe indications outside of the eye such as diabetic foot ulcer.
−Removed: Our Preclinical Development Programs
−Removed: We are progressing a pipeline of proprietary NCE preclinical development programs, targeted to address both front and back of the eye diseases, including our TKI program for retinal diseases, and our SEGRM program.
−Removed: TKI Program for Retinal Disease
−Removed: Retinal Disease Overview
−Removed: There are a range of retinal diseases and conditions that adversely affect vision, including age-related macular degeneration, or AMD, diabetic retinopathy, or DR, diabetic macular edema, or DME, and retinal vein occlusion, or
−Removed: These diseases frequently result in damage to the vasculature of the eye, leading to poor function and/or leaking of existing vessels and often leading to proliferation of new, abnormal and leaky blood vessels in the back of the eye.
−Removed: These conditions can lead to retinal damage, scarring, and irreversible loss of vision.
−Removed: Age-Related Macular Degeneration (AMD)
−Removed: AMD is a degeneration of the macula of the retina that leads to impairment and loss of central vision.
−Removed: There are two categories of AMD:
−Removed: “Dry” AMD, which involves slow deterioration of the retina with submacular drusen, atrophy, loss of macular function and central vision impairment;
−Removed: and “wet” AMD, which involves the leakage of existing blood vessels often accompanied by the growth of abnormal and leaky blood vessels under the retina and macula, resulting in edema, tissue damage and rapid loss of central vision.
−Removed: If untreated, neovascularization in wet AMD patients typically results in significant vision loss and the formation of a scar under the macular region of the retina.
−Removed: Most cases begin as Dry AMD, which can progress to wet AMD.
−Removed: Wet AMD is a leading cause of blindness in people over the age of 55 in the United States and the European Union.
−Removed: The incidence of wet AMD increases substantially with age, and we expect that the number of cases of wet AMD will increase with growth of the elderly population in the United States.
−Removed: The current standard of care for wet AMD is intravitreal injection of biologic agents that target VEGF, one of the key proteins involved in neovascularization.
−Removed: Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME)
−Removed: DR is an ocular complication of diabetes involving changes of retinal blood vessels that lead to significant visual impairment.
−Removed: These changes include dysfunction of retinal vasculature (nonproliferative retinopathy), with vascular occlusion and increased permeability, leading to retinal hypoxia and DME.
−Removed: The disease can further progress to proliferative retinopathy with retinal neovascularization, hemorrhage and retinal detachment.
−Removed: Among an estimated 19.8 million adults in the United States aged forty years and older known to have diabetes, the prevalence rate for DME is 3.8%, or approximately 746,000 people.
−Removed: DME is the leading cause of visual impairment and blindness in Americans between 20 and 74 years old.
−Removed: Retinal Vein Occlusion (RVO)
−Removed: RVO is a blockage of the small veins that carry blood away from the retina.
−Removed: The disease can cause sudden blurring or vision loss in all or part of one eye.
−Removed: RVO has been estimated to affect 16 million people worldwide.
−Removed: Limitations of Existing Treatments for Retinal Disease
−Removed: VEGF is a signaling protein that plays a critical role in the formation of new blood vessels and increased permeability, two pathological processes that contribute to the vision loss associated with certain retinal diseases.
−Removed: Several TKIs have been investigated in AMD patients in clinical trials.
−Removed: These inhibitors have been administered in a variety of ways, including intravitreal injection, oral administration, and topical dosing.
−Removed: To date, no TKIs have been approved in the United States for the treatment of ocular diseases.
−Removed: We believe that there is a substantial market opportunity for a safe and effective VEGF receptor TKIs to treat various retinal diseases, such as AMD, DR, DME, RVO and related neovascular diseases.
−Removed: The PDGF family of signaling proteins function through the PDGF receptor, a receptor tyrosine kinase, or RTK, that plays a critical role in the formation of new blood vessels and fibrotic scar, two pathological processes that contribute to the vision loss associated with ocular disease.
−Removed: The combined inhibition of both VEGF and PDGF signaling pathways through their respective RTK are believed to be beneficial in treating certain retinal diseases.
−Removed: The most common treatments for retinal diseases involve administration of biologic agents that block the VEGF pathway and prevent or retard the blood vessel leakage and/or proliferation.
−Removed: Unfortunately, clinicians must inject these biologic agents directly into the eye via frequent intravitreal injections, or IVTs, to maintain vision.
−Removed: Sales of the two leading IVT biologic agents used to treat eye diseases associated with abnormal blood vessel proliferation, Genentech’s Lucentis ® and Regeneron’s Eylea ® , were $1.9 billion and $4.9 billion, respectively, in the United States in 20208.
−Removed: A new biologic form of Novartis’ Beovu ® was approved in October 2019 and had approximately $200 million in worldwide sales in 2020.
−Removed: An effective therapeutic to treat retinal diseases with improved dosing regimen would bring significant benefits to patients.
−Removed: TKI Program for the Potential Treatment of Wet AMD, DR, DME and RVO
−Removed: Through our TKI program we have developed several novel, potent, and selective TKIs, including KPI-287, which can inhibit the VEGF pathway and the platelet derived growth factor, or PDGF, pathway.
−Removed: In vitro assays show that KPI-287 has a sub-nanomolar potency against the VEGF receptor-2 kinase and good selectivity against other growth factor receptor kinases, cell cycle kinases and other off-target receptors.
−Removed: We are developing KPI-287 via suprachoroidal injection for the treatment of various retinal diseases.
−Removed: In preclinical rabbit studies, topical administration of KPI-287 achieved concentrations in tissues in the retina and the choroid well above the concentrations required for in vitro inhibition of 50% of the VEGF receptor 2 kinase activity.
−Removed: As shown in the figures below, the concentrations observed in these rabbit studies were higher than the concentrations observed in similar rabbit studies with topical administration of axitinib, which is the most common TKI currently being developed for retinal disease.
−Removed: Tissues collected after a single topical dose 5% KPI-287 suspension vs 5% axitinib suspension in Dutch Belted rabbits
−Removed: In addition, in a rabbit model of VEGF induced vascular leakage, topically applied KPI-287 reduced leakage to an extent similar to that achieved with an IVT injection of Genentech’s Avastin, a recombinant human monoclonal antibody that binds to VEGF.
−Removed: Avastin is approved as an anticancer agent, but is widely used off-label in ophthalmic diseases.
−Removed: In this model, vascular leakage of fluorescein was induced by IVT injections of VEGF.
−Removed: The extent of fluorescein leakage observed in various treatment groups was scored in a blinded fashion on a scale from 0 to 4, with 0
−Removed: being no leakage and 4 being heavy leakage.
−Removed: As shown in the photographs below, the magnitude of the effect achieved with topical administration of KPI-287 5.0% was similar to that observed with IVT injection of Avastin.
−Removed: In addition, the magnitude of effect observed with KPI-287 was greater than the magnitude of effect observed with topical administration of axitinib in studies similar to those we have conducted.
−Removed: Axitinib (5% q4 hr) or KPI-287 (5% QID) dosed topically days 1 through 6, with VEGF challenge on day 3, and efficacy evaluation (fluorescein angiography) on day 6 (72 hrs post VEGF challenge).
−Removed: IVT Avastin used as positive control .
−Removed: We are currently conducting additional preclinical studies with KPI-287 administered via suprachoroidal administration to evaluate both the pharmacokinetics and efficacy over six months following a suprachoroidal injections.
−Removed: These studies are designed to evaluate the potential of KPI-287 for sustained durable delivery inhibiting VEGF induced ocular disease associated with vision loss.
−Removed: We believe that an effective therapy with an improved delivery for patients with retinal diseases such as AMD, DR, DME and RVO will be a significant advancement in the treatment of these diseases and could increase patient compliance and reduce treatment burden in patients suffering from these sight threatening diseases.
−Removed: SEGRM Program for Inflammatory Diseases
−Removed: Activation of the glucocorticoid receptor can result in regulation of gene expression along both the transactivation, or TA, and transrepression, or TR, pathways.
−Removed: There is considerable third-party scientific evidence that the TR pathway alone may be sufficient for anti-inflammatory and immunomodulatory activity.
−Removed: Furthermore, we believe the TA pathway is likely responsible for the adverse effects associated with ocular and systemic administration of corticosteroids, including elevated IOP, hypertension, and osteoporosis.
−Removed: SEGRMs are a novel class of compounds designed to selectively regulate gene expression through the TR pathway while avoiding or minimizing the TA pathway.
−Removed: As a result, we believe our SEGRM program has the potential for anti-inflammatory and immunomodulatory activity comparable to corticosteroids while markedly reducing their associated side effects.
−Removed: We plan to study our SEGRMs for the potential treatment of inflammatory diseases.
−Removed: Our SEGRM program is currently in the lead optimization stage, and we are aiming to identify a development candidate for the program.
−Removed: Our AMPPLIFY Technology
−Removed: Opportunities in Drug Delivery across Eye and other Mucosal Barriers
−Removed: The body is surrounded by boundary tissues that play the important physiological role of preventing foreign bodies from penetrating into the body.
−Removed: The mucus that coats these tissues, the eyes, lung, cervical/vaginal tract and gastrointestinal tract, for example, serves as a protective barrier to trap and eliminate particulate matter, such as viruses, bacteria and allergens, before these agents can enter the underlying tissues and cause infections or elicit reactions.
−Removed: However, in playing this pivotal role of protection, mucus can also hinder medical treatments by limiting the penetration of medications to mucus-protected tissues, thereby reducing their therapeutic effect.
−Removed: Mucus also makes it difficult to treat many ophthalmic diseases.
−Removed: The body can rapidly eliminate drugs delivered to the eye via the tear film protecting the surface of the eye, which can significantly limit the effectiveness of these drugs.
−Removed: This is the case both for drugs designed to treat conditions in the front of the eye, such as dry eye disease and post- operative inflammation and pain, as well as for drugs designed to treat conditions in the back of the eye, such as retinal diseases.
−Removed: We believe that our proprietary MPP technology, which we refer to as our AMPPLIFY technology, has the potential to address this clear unmet medical need for more efficient delivery of drugs.
−Removed: Our AMPPLIFY technology may have applications to other areas of the body that are protected by mucus, such as the lung, cervical/vaginal tract and gastrointestinal tract.
−Removed: We have demonstrated in preclinical studies that AMPPLIFY technology can be used to increase mucus penetration of over 15 classes of drugs.
−Removed: MPP Technology
−Removed: Our MPPs are selectively sized nanoparticles, with average diameters of approximately 330 nanometers, and have noncovalent proprietary coatings.
−Removed: We believe that these two key attributes enable even distribution of drug particles on mucosal surfaces and significantly increase drug delivery to target tissues by enhancing mobility of drug particles through mucus and preventing drug particles from becoming trapped and eliminated by mucus.
−Removed: We believe this enables enhanced efficacy at equal or lower doses as well as less frequent dosing for improved patient convenience and compliance.
−Removed: In a preclinical study, MPPs or conventional particles in a hypotonic solution were administered intravaginally to mice.
−Removed: Ten minutes after administration, the vaginal tissues were dissected and stained.
−Removed: The image on the left below shows the distribution of the conventional particles and the image on the right below shows the distribution of the MPPs.
−Removed: The conventional particles aggregated in the lumenal mucus and did not reach the target tissues.
−Removed: In contrast, the MPPs coated the entire vaginal epithelium, including all the target surfaces.
−Removed: Ensign et al., Mucus-Penetrating Nanoparticles for Vaginal Drug Delivery Protect Against Herpes Simplex Virus, Science Translational Medicine, June 14, 2012.
−Removed: Also, for ophthalmic applications, while a significant portion of conventionally formulated ophthalmic drugs are rapidly eliminated via the tear film, we have shown that our MPPs are capable of achieving higher concentration on the surface of the eye, thereby enabling the active drug substance to reach cells in the underlying ocular tissue at higher levels.
−Removed: We aim to leverage our MPP technology, to enhance delivery of drugs into the eye.
−Removed: In preclinical studies, KPI-121 demonstrated favorable pharmacokinetic characteristics and increased drug penetration into ocular tissues as compared to a branded form of LE.
−Removed: In a preclinical study of ocular inflammation in rabbits, KPI-121 0.5% administered four times a day, or QID, showed a larger reduction of inflammation as compared to a branded form of LE 0.5% given QID, as measured by the mean aqueous humor cell counts after intravitreal injection of lipopolysaccharide.
−Removed: We also administered either 0.4% KPI-121 or 0.5% branded LE to the eyes of two groups of rabbits.
−Removed: As illustrated in the line graph below, the concentrations of LE in aqueous humor, a transparent gelatinous fluid that fills the anterior and posterior chambers between the lens and the cornea, of the rabbit eyes treated with KPI-121 were more than three times higher than the rabbit eyes treated with branded LE 30 minutes after dosing, at a 20% lower concentration.
−Removed: LE in Aqueous Humor
−Removed: We administered KPI-121 0.5%, LE suspension 0.5%, or 0.5% of an LE non-MPP nanoparticle, to the eyes of three groups of rabbits and measured the amount of LE that was delivered to the cornea.
−Removed: The non-MPP nanoparticle was similar in size to our MPP nanoparticles but lacked the proprietary surface coating used in our MPP nanoparticles.
−Removed: As illustrated in the line graph below, concentrations of LE in the cornea of the rabbit eyes treated with KPI-121 were more than three times higher than the concentrations in rabbits treated with branded LE between 20 and 40 minutes after dosing.
−Removed: In addition, the rabbit eyes treated with the non-MPP nanoparticles had concentrations of LE similar to that in the rabbit eyes treated with branded LE and did not display the improved drug bioavailability properties observed with KPI-121.
−Removed: We believe these results highlight the importance of our proprietary MPP technology and show that KPI-121’s improved pharmacokinetic profile has the potential to reduce the dosing strength and/or frequency of administration of LE with KPI-121 as compared to LE suspension 0.5%.
−Removed: We also have demonstrated the potential of our MPP nanoparticles to increase the mucus penetration of over fifteen classes of drugs.
−Removed: While our primary focus is in ophthalmology, in preclinical studies, our MPP technology has been effective in delivering drugs to the lungs, cervical/vaginal tract, gastrointestinal tract and other mucus-protected
−Removed: We have the ability to vary the rate of drug release as appropriate for the targeted disease state and tissue.
−Removed: As a result, drugs can be delivered either in rapid release formulations or as sustained release formulations that slowly release drug over a time period that ranges from hours to days.
+Added: Other Potential Indications for KPI-012 and for KPI-014
+Added: We believe the multifactorial mechanism of action of KPI-012 also makes it a platform technology, and we are evaluating the potential development of KPI-012 for additional rare front of the eye diseases, such as for the treatment of Limbal Stem Cell Deficiency and ocular manifestations of moderate-to-severe Sjögren’s.
+Added: In addition, we have initiated preclinical studies under our KPI-014 program to evaluate the utility of our MSC-S platform for inherited retinal degenerative diseases, such as Retinitis Pigmentosa and Stargardt Disease.
+Added: Limbal stem cell deficiency, or LSCD, is an ocular surface disease characterized by the loss or deficiency of stem cells in the junction of the cornea and limbus, where they play an essential role in the generation and repopulation of corneal epithelial cells.
+Added: When the limbal stem cell population is reduced or depleted, the ability of the corneal epithelium to repair and renew itself is compromised, which can result in recurrent epithelial breakdown, neovascularization, conjunctival overgrowth and other sequalae that can lead to loss of corneal clarity and vision impairment, as well as significant pain and diminished quality of life.
+Added: There are currently no approved pharmaceutical products for the treatment of LSCD.
+Added: Approximately 70% of LSCD patients – or about 70,000 patients in the United States – have partial LSCD, meaning they have some level of remaining limbal stem cells but still suffer significant pathology and symptomology.
+Added: We believe these patients may be appropriate candidates for KPI-012 to maintain the integrity of the ocular surface and to avoid the vision impairment and pain associated with the disease.
+Added: In addition to the effects of KPI-012 on corneal healing observed in both animal models and in PCED patients, there is data in the literature that suggest that MSC-S can restore the limbal stem cell niche, which would be of significant benefit in both partial or complete LSCD.
+Added: Sjögren’s is a chronic multisystem autoimmune disease characterized by insufficient fluid production in certain glands of the body leading to substantial dryness, primarily of the eyes and the mouth.
+Added: Approximately 90% of Sjögren’s patients suffer from ocular manifestations and experience significant ocular symptoms, which often impact a patient’s daily life and productivity, and as a result, the quality of life in Sjögren’s patients can be significantly diminished.
+Added: Despite current treatment options, many Sjögren’s patients do not achieve significant improvement in their ocular symptoms.
+Added: We believe there is a significant unmet need for new therapies that can provide meaningful improvement in the ocular symptoms, visual impairment and quality of life to the approximately 50% of Sjögren’s patients, or roughly 95,000 people in the United States, who suffer with moderate-to-severe disease.
+Added: We are also looking to leverage the manufacturing and delivery expertise gained from KPI-012 development to develop a unique secretome formulation – designated as KPI-014 – specific for retinal disease.
+Added: The initial focus for the program is to target inherited retinal diseases, such as Retinitis Pigmentosa and Stargardt Disease.
+Added: MSC-S therapies have shown great promise to treat inherited retinal diseases, or IRDs, with the recognition that they function through their secretome (i.e., the secretion of paracrine factors that enhance retinal cell function and survival).
+Added: We believe an MSC-S engineered for intravitreal delivery may provide an improved treatment option for IRDs as compared to the traditional MSC-based approach.
+Added: IRDs are associated with mutations in over 280 different genes, where each IRD has one or more mutations that cause disease onset and results in vision loss.
+Added: It is projected that over 200,000 individuals in the United States alone suffer from IRDs.
+Added: While significant progress has been made with gene therapies, these are typically limited to a single gene or mutation.
+Added: With over 280 different IRD-associated genes, a therapy broadly effective for most IRDs does not currently exist, leaving patients with little-to-no options to slow disease progression and vision loss.
+Added: We are developing KPI-014 with the goal of providing a broad, genotype-agnostic, therapeutic benefit to reduce vision loss and improve quality of life for patients suffering from IRDs.
The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.
While we believe that our technologies, knowledge, experience and scientific resources provide us with competitive advantages, we face competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions.
−Removed: Our products compete, and any product candidates that we successfully develop and commercialize will compete, with existing therapies and new therapies that may become available in the future.
+Added: Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.
Our competitors include large pharmaceutical and biotechnology companies, and specialty pharmaceutical and generic drug companies.
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Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
−Removed: The key competitive factors affecting the success of EYSUVIS, INVELTYS, KPI-012 and any other product candidates that we develop are the product or product candidate’s efficacy, safety, method of administration, convenience, price, the level of generic competition and the availability of insurance coverage and reimbursement from government and other third-party payors.
+Added: The key competitive factors affecting the success of KPI-012 and any other product candidates that we develop are the product candidate’s efficacy, safety, method of administration, convenience, price, the level of generic competition and the availability of insurance coverage and reimbursement from government and other third-party payors.
Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than our products.
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In addition, our ability to compete may be affected because in many cases insurers or other third-party payors seek to encourage the use of generic products.
−Removed: Competition in Dry Eye Disease
−Removed: The current disease management approaches for dry eye disease in the United States includes non-pharmaceutical therapies and pharmaceutical therapies.
−Removed: Non-pharmaceutical therapies include over the counter artificial tear eye drops, which are palliative and used on an intermittent or chronic basis to provide short-term symptomatic relief of dryness and irritation;
−Removed: hot compresses for the eye and lid hygiene management;
−Removed: devices, such as punctal plugs that are inserted into the tear ducts to inhibit tear drainage, resulting in more moisture on the surface of the eye.
−Removed: Pharmaceutical therapies for dry eye disease include on label prescription drugs, including Restasis ® , Xiidra ® , Cequa TM and Tyrvaya™ which are the only prescription pharmaceutical products other than EYSUVIS that are approved in the United States for use in patients with dry eye disease;
−Removed: off label prescription drugs, including topical steroid drops and/or other similar products, which are sometimes prescribed for treatment of dry eye disease;
−Removed: and various drugs that are produced by compounding pharmacies.
−Removed: Generic versions of Restasis have been available in the United States since February 2022.
−Removed: Restasis and Cequa are both topical cyclosporine formulations that are approved for increasing tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with dry eye disease.
−Removed: Xiidra is a topical anti-inflammatory therapy approved for treatment of the signs and symptoms of dry eye disease.
−Removed: Tyrvaya (varenicline solution) nasal spray is a cholinergic agonist that was approved by the FDA in October 2021 to increase tear production and treat the signs and symptoms of dry eye disease.
−Removed: EYSUVIS is indicated for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease, which includes dry eye flares.
−Removed: Any product that is developed for the treatment of the signs and/or symptoms of dry eye disease could directly compete with EYSUVIS.
−Removed: There are several product candidates in preclinical and clinical
−Removed: development in the United States for the treatment of dry eye disease.
−Removed: These product candidates are being developed by pharmaceutical, biotechnology, specialty pharmaceutical and generic drug companies of various sizes, such as Aldeyra Therapeutics’ reproxalap ophthalmic solution, Novaliq’s CyclAsol and NOV03, which has been licensed to Bausch Health Companies Inc.
−Removed: Based on publicly available information, we have identified various other product candidates in clinical development for the chronic treatment of dry eye disease in the United States.
−Removed: If any of these product candidates is approved and such product candidate either effectively treats the signs and symptoms of dry eye disease or reduces the frequency of flares in dry eye patients, it could reduce patient demand for EYSUVIS.
−Removed: Competition in Inflammation and Pain Following Ocular Surgery
−Removed: Following ocular surgery, topical steroids are commonly prescribed to manage and prevent complications from post-operative inflammation.
−Removed: Topical steroid drops are the main competition to INVELTYS for the treatment of inflammation and pain following ocular surgery.
−Removed: The current branded market leaders for topical steroids in the United States, based on revenue, are Lotemax ® products and Durezol ® .
−Removed: Generic topical steroid formulations consist mainly of products containing prednisolone, fluorometholone or dexamethasone.
−Removed: In addition, the first generic formulations of loteprednol suspension 0.5% (Lotemax suspension) and loteprednol ophthalmic gel 0.5% (Lotemax Gel) were launched in May 2019 and February 2021, respectively, and the first generic version of Durezol was launched in September 2021.
−Removed: There are also non-topical formulations of ocular steroids that have been approved and/or marketed.
−Removed: Eyepoint Pharmaceutical launched Dexycu ® , an intraocular suspension of dexamethasone for the treatment of post-operative inflammation, in July 2019.
−Removed: Also in July 2019, Ocular Therapeutix launched Dextenza ® , an intracanalicular insert of dexamethasone, for the treatment of ocular pain and inflammation following ophthalmic surgery.
−Removed: There are also a number of companies in the United States developing products and therapies in preclinical research and clinical development for the treatment of inflammation and pain following ocular surgery.
−Removed: In addition, there are various formulations of steroids that are produced by compounding pharmacies and that are in drop form or are injected into the eye following ocular surgery.
Competition in PCED
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Each administration of Oxervate requires the use of a vial containing the drug product, a vial adapter, a single-use pipette and disinfectant wipes.
−Removed: To our knowledge, there is currently only one product candidate in active clinical development for the treatment of a broad PCED population.
−Removed: ST266, an eye drop, is currently being studied in a Phase 2b clinical trial in patients with PCED and is being developed by Noveome Biotherapeutics Inc.
−Removed: ST266 is a secretome produced from amnion-derived epithelial cells from donated full-term placentas.
−Removed: A number of companies are pursuing development of product candidates for the treatment of NK.
−Removed: Competition in Retinal Disease
−Removed: Several therapies have been developed to block the effects of VEGF by binding to and sequestering the protein.
−Removed: These include Regeneron Pharmaceuticals, Inc.’s Eylea, Genentech, Inc.’s Lucentis and Avastin, and Novartis’ Beovu.
−Removed: Avastin is approved as an anticancer agent, but is widely used off-label in ophthalmic diseases.
−Removed: All of these therapies are administered by intravitreal injections and must be regularly dosed for optimal efficacy.
−Removed: In addition to the anti-VEGF therapies, there also are marketed drug delivery systems, or DDS, that are used to treat retinal diseases, notably:
−Removed: Ozurdex ® , which releases dexamethasone, a corticosteroid, and is marketed by Allergan;
−Removed: Iluvien ® , which releases fluocinolone acetonide, a corticosteroid, and is marketed by Alimera Sciences;
−Removed: and Yutiq TM , which releases fluocinolone acetonide, a corticosteroid, and is marketed by Eyepoint.
−Removed: There are several wet-AMD product candidates in clinical development, including those being developed by F.
−Removed: Hoffmann-La Roche AG, Kodiak Sciences, Clearside Biomedical, Eyepoint Pharmaceuticals, and Ocular Therapeutix.
−Removed: There are also a number of preclinical research programs being conducted by third parties to develop treatments for retinal diseases.
−Removed: We expect that product candidates currently in clinical development, or that could enter clinical development in the near future, may represent significant competition if approved.
−Removed: These product candidates may provide efficacy, safety, convenience and other benefits that are not provided by currently marketed therapies.
−Removed: Competition in Ocular Surface Disease
−Removed: Ocular surface conditions, which include dry eye disease, are currently treated with a variety of therapies, including branded and generic corticosteroids and non-steroidal anti-inflammatory drugs.
−Removed: Corticosteroids are frequently used for the treatment of anterior segment conditions, including dry eye disease and for the treatment of post-surgical inflammation.
−Removed: Corticosteroids are also frequently used for the treatment of wet-AMD and diabetic eye disease as second line to the anti-VEGF therapies.
−Removed: We are developing our SEGRM program to be an alternative to corticosteroids for the treatment of a variety of inflammatory diseases.
+Added: To our knowledge, there are currently only two product candidates in active clinical development for the treatment of a broad PCED population.
+Added: KIO-201, a chemically modified form of the natural polymer hyaluronic acid administered as an eye drop, is currently being studied in a Phase 2 clinical trial in patients with PCED by Kiora Pharmaceuticals, Inc.
+Added: Nexagon, an antisense oligonucleotide that inhibits connexin43, is currently being studied in a Phase 2 clinical trial in patients with PCED resulting from severe ocular chemical and/or thermal injuries, by Amber Ophthalmics.
+Added: A number of companies are pursuing development of product candidates for the treatment of NK, including ReGenTree, LLC (Timbetasin), Recordati S.p.A.
+Added: (Udonitrectag) and Claris Biotherapeutics, Inc.
+Added: Competition in L imbal Stem Cell Deficiency and Sjögren’s
+Added: Competitive products and product candidates in LSCD include two stem cell-based approaches.
+Added: ABCB5+ limbal stem cells, which are being studied in Phase 1/2 clinical trials and are being developed by RHEACELL GmbH & Co.
+Added: KG, utilize allogeneic limbal stem cells derived from human corneal rims, which are expanded ex-vivo and manufactured as an advanced-therapy medicinal product.
+Added: Holoclar utilizes autologous limbal stem cells derived from the healthy portion of the patient’s eye.
+Added: Holoclar is approved in the European Union for treatment of LSCD caused by ocular burns and is developed by Chiesi.
+Added: To our knowledge, there are no products in development focused on Partial Limbal Stem Cell Deficiency.
+Added: Competitive pharmaceutical products in moderate-to-severe Sjögren’s include cyclosporine, lifitegrast, ophthalmic cortisone and systemic immunosuppressants.
+Added: To our knowledge, there are only two topical ophthalmic product candidates in active clinical development for ocular manifestations of moderate-to-severe Sjögren’s.
+Added: Lacripep TM , a synthetic peptide fragment of lacritin being developed by Tear Solutions, recently completed a Phase 2 clinical trial in patients with primary Sjögren’s-associated ocular surface disease.
+Added: Oxervate ® (cenegermin-bkbj) is currently being evaluated in Phase 3 clinical trials in patients with severe Sjögren’s dry eye disease.
+Added: Several systemic pharmaceutical product candidates are also in clinical development for the treatment of Sjögren’s, including Dazodalibep (Horizon Therapeutics), SAR-441344 (Sanofi), Ianalumab (Novartis), Branebrutinib (Novartis), Iscalimab (Novartis) and OSE-127 (OSE Immuno Therapeutics).
Sales and Marketing
−Removed: In January 2019, we began commercializing INVELTYS in the United States with our own focused, specialty sales force.
−Removed: During late 2020 and in 2021, we expanded our sales force, which now includes approximately 100 field-based commercial sales personnel.
−Removed: Our sales force promotes EYSUVIS and INVELTYS.
We have not yet established our own commercial organization or distribution capabilities specific to KPI-012.
We believe that we will be able to commercialize KPI-012, if approved, for the treatment of PCED with a small, targeted, internal sales force in the United States and potentially other major markets.
−Removed: We expect to explore commercialization of EYSUVIS and potentially other product candidates, including KPI-012, if approved, in certain markets outside the United States utilizing a variety of collaboration, co-promotion distribution and other marketing arrangements with one or more third parties.
+Added: We expect to explore commercialization of KPI-012, if approved, in certain markets outside the United States utilizing a variety of collaboration, distribution, co-promotion, distribution and other marketing arrangements with one or more third parties.
Manufacturing and Supply
−Removed: We do not own or operate manufacturing facilities for the production of commercial quantities or preclinical or clinical supply of EYSUVIS, INVELTYS or any product candidates, including KPI-012.
−Removed: We utilize our substantial inhouse expertise and know-how to develop and scale up our manufacturing processes before these processes are transferred to third-party contract manufacturers, and to understand and establish controls of critical process parameters.
−Removed: We also have personnel with deep product development experience who actively manage the third-party contract manufacturers producing EYSUVIS, INVELTYS and KPI-012 and plan to use such personnel to manage third-party contract manufacturers for any products that we may develop in the future.
−Removed: EYSUVIS and INVELTYS Manufacturing
−Removed: EYSUVIS and INVELTYS are currently manufactured at qualified contract manufacturing facilities in compliance with current good manufacturing practice, or cGMP, regulations.
−Removed: Our third-party manufacturers are subject to FDA inspections from time to time.
−Removed: We have supply agreements in place with these contract manufacturers to support commercial, clinical and registration manufacturing, release testing, registration stability, and labeling and packaging.
−Removed: Woodstock Commercial Supply Agreement.
−Removed: In June 2016, we entered into a Commercial Supply Agreement, or the Woodstock Agreement, which we amended in February 2018, March 2020 and December 2020, with Woodstock Sterile Solutions, Inc.
−Removed: (formerly known as Catalent Pharma Solutions, LLC), or Woodstock, pursuant to which Woodstock has agreed to manufacture and supply to us, and we have agreed to purchase from Woodstock, a combined minimum amount of EYSUVIS and INVELTYS for commercial use.
−Removed: The Woodstock Agreement had an initial term of eight years from August 22, 2018, which is the date INVELTYS was approved for commercial sale in the United States.
−Removed: Pursuant to the March 2020 amendment, the initial term was extended through June 30, 2030.
−Removed: The Woodstock Agreement is subject to three-year automatic renewal periods after the initial term, absent termination by either party in accordance with the terms of the Woodstock Agreement.
−Removed: The Woodstock Agreement provides for pricing structured on a tiered basis, with the price reduced as the volume of products ordered increases.
−Removed: Prior to the March 2020 amendment, we had annual minimum purchase requirements for each of EYSUVIS and INVELTYS.
−Removed: However, pursuant to the March 2020 amendment, the annual minimum purchase requirements are now determined on an aggregate basis for the two products.
−Removed: We may cancel any purchase order under the Woodstock Agreement, subject to our minimum purchase obligations.
−Removed: Each party has the right to terminate the Woodstock Agreement for customary reasons such as material breach and bankruptcy.
−Removed: The Woodstock Agreement contains provisions relating to compliance by Woodstock with cGMP, indemnification, confidentiality, dispute resolution and other customary matters for an agreement of this kind.
−Removed: Altasciences Commercial Supply Agreement.
−Removed: In October 2017, we entered into an Amended and Restated Master Services Agreement, or the Altasciences Agreement, with Alliance Contract Pharma, LLC, which was assigned to Altasciences company, or Altasciences, pursuant to which Altasciences has agreed to provide to us, and we have agreed to purchase from Altasciences, bulk intermediates.
−Removed: The Altasciences Agreement provides for pricing structured on a tiered basis, with the price reduced as the volume of product ordered increases.
−Removed: Under the Altasciences Agreement, we will provide a forecast of orders for the quantities we believe we will require, and forecasted quantities will become binding at a certain point before the firm delivery date set forth in the forecast.
−Removed: Unless earlier terminated pursuant to its terms, the Altasciences Agreement has an initial term of ten years, after which it continues until terminated.
−Removed: Each party has the right to terminate the Altasciences Agreement for customary reasons such as material breach and bankruptcy.
−Removed: In addition, we have the right to terminate the Altasciences Agreement at any time for any or no reason upon sufficient advance notice, in which case we would owe payment to Altasciences for any firm orders and certain raw materials.
−Removed: The Altasciences Agreement contains provisions relating to compliance by Altasciences with cGMP, indemnification, confidentiality, dispute resolution and other customary matters for an agreement of this kind.
−Removed: Chemo Iberica Manufacturing and Supply Agreement.
−Removed: In January 2017, we entered into a Manufacturing and Supply Agreement, or the Chemo Agreement, with Chemo Iberica SA, or Chemo, pursuant to which Chemo has agreed to manufacture and supply to us, and we have agreed to purchase from Chemo, bulk supply of LE, with pricing structured on a per-kilogram basis.
−Removed: Under the Chemo Agreement, we will provide a forecast of orders for the quantities of LE we believe we will require, and we commit to purchasing 75% of the forecasted quantities.
−Removed: We can alter portions of a forecast at any time, except that, without Chemo’s consent, we cannot alter a portion of the forecast less than ninety days before the period to which such portion pertains.
−Removed: Unless earlier terminated pursuant to its terms, the Chemo Agreement has an initial term of seven years, after which it renews in two year increments unless either party gives notice of nonrenewal at least one year in advance.
−Removed: Each party has the right to terminate the Chemo Agreement for customary reasons such as material breach and bankruptcy.
−Removed: The Chemo Agreement contains provisions relating to compliance by Chemo with cGMP, indemnification, confidentiality, dispute resolution and other customary matters for an agreement of this kind.
−Removed: KPI-012 Manufacturing
We do not own or operate, and currently have no plans to establish, any manufacturing facilities for KPI-012.
We rely, and expect to continue to rely, on third parties for the manufacture of both drug substance and finished drug product for KPI-012 for preclinical and clinical testing, as well as for commercial manufacture of KPI-012 if it receives marketing approval.
−Removed: We also rely, and expect to continue to rely, on third parties for packaging, labeling, sterilization, storage, distribution and other production logistics.
−Removed: We have only limited agreements in place with respect to the manufacturing of KPI-012, and these arrangements do not extend to commercial supply.
+Added: We utilize our substantial in-house expertise and know-how to develop and scale-up our manufacturing processes before these processes are transferred to third-party contract manufacturers, and to understand and establish controls of critical process parameters.
+Added: We also have personnel with deep product development experience who actively manage the third-party contract manufacturers producing KPI-012 and plan to use such personnel to manage third-party contract manufacturers for any products that we may develop in the future.
+Added: We also rely, and expect to continue to rely, on third parties for packaging, labeling, sterilization, storage, distribution and other production logistics for KPI-012.
+Added: We have only limited supply agreements in place with respect to the manufacturing of KPI-012, and these arrangements do not extend to commercial supply.
We obtain supplies of drug substance and finished drug product for KPI-012 on a purchase order basis and do not have long term committed supply arrangements with respect to KPI-012.
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Biologic products must be made consistently and in compliance with a clearly defined manufacturing process.
−Removed: KPI-012 is a bone-marrow derived mesenchymal stem cell secretome therapeutic composed of biologically active components, including protease inhibitors and growth factors, and is produced from a proprietary cell bank.
+Added: KPI-012 is a bone-marrow derived MSC-S therapeutic composed of biologically active components, including protease inhibitors and growth factors, and is produced from a proprietary cell bank.
The manufacturing process for KPI-012 is comprised of three stages:
−Removed: (1) cultivation of mesenchymal stem cells from a working cell bank and production of unprocessed conditioned media (cell-free secretome), (2) production of drug substance as a chemically defined solution and (3) formulation and filling of drug product.
−Removed: While the drug product for Combangio’s early research and Phase 1b clinical trials was cultivated using a planar culture model, we plan to implement a bioreactor cultivation model for our planned clinical trials and for commercial supply of KPI-012.
−Removed: We are continuing the process of scaling up our manufacturing processes and capabilities with our third-party manufacturers to support longer term clinical development.
+Added: (1) cultivation of MSCs from a working cell bank and production of unprocessed conditioned media (cell-free secretome), (2) production of drug substance as a chemically defined solution and (3) formulation and filling of drug product.
+Added: While the drug product for Combangio’s early research and Phase 1b clinical trial was cultivated using a planar culture model, we implemented a bioreactor cultivation model for our ongoing CHASE Phase 2b clinical trial of KPI-012.
+Added: We also plan to utilize a bioreactor cultivation model for our planned clinical trials and for commercial supply of KPI-012.
+Added: We are continuing the process of scaling up our manufacturing processes and capabilities with our third-party manufacturers to support longer
+Added: term clinical development.
We do not currently have arrangements in place for redundant supply or a second source for bulk drug substance.
KPI-012 drug product is manufactured from a vial of a working cell bank, which in turn was produced from a vial of master cell bank.
−Removed: KPI-012 master cell bank and working cell bank is stored in two separate locations.
+Added: KPI-012 master cell bank and working cell bank are stored in two separate locations.
It is possible that we could lose the cell bank in both locations and have our manufacturing severely impacted by the need to replace the cell bank.
Intellectual Property
−Removed: Our success depends significantly on our ability to obtain and maintain proprietary protection for our products, product candidates, technology and know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights.
+Added: Our success depends significantly on our ability to obtain and maintain proprietary protection for our products, product candidates, technology and knowhow, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights.
We seek to protect our proprietary position by, among other methods, filing U.S.
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We also rely on trade secrets, know--how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.
−Removed: As of March 1, 2022, we owned 47 U.S.
+Added: As of February 15, 2023, we owned 49 U.S.
issued patents and 9 U.S.
patent applications, as well as 55 foreign issued patents and 41 foreign patent applications (including Patent Cooperation Treaty, or PCT, applications).
−Removed: We exclusively licensed a total of 38 U.S.
−Removed: issued patents and 14 U.S.
−Removed: patent applications, as well as 54 foreign issued patents and 26 foreign patent applications including original filings, continuations and divisional applications.
+Added: We exclusively licensed one U.S.
+Added: patent application, as well as two foreign patent applications including original filings, continuations and divisional applications.
Our patent portfolio includes the following patents and patent applications that we own or exclusively license:
−Removed: patents and three U.S.
−Removed: patent applications, relating to our MPP technology, which we refer to as our AMPPLIFY technology, including those related to EYSUVIS and INVELTYS, in-licensed from The Johns Hopkins University, or JHU, six related foreign patents jointly owned by us and JHU, four related foreign patent applications jointly owned by us and JHU, 20 related foreign patents owned by us and 27 related foreign patent applications owned by us, which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire in 2033;
−Removed: patent and one U.S.
−Removed: patent application relating to our AMPPLIFY technology, and nine related foreign patents and five related foreign patent applications, which are owned by us, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire in 2033;
patents and two U.S.
−Removed: patent applications relating to pharmaceutical compositions including KPI-012 for treating ocular conditions, and 13 related foreign patent applications including a pending PCT application, which are owned by us, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire beginning in 2040;
+Added: patent applications relating to pharmaceutical compositions including KPI-012 for treating ocular conditions, and 18 related foreign patent applications, which are owned by us, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire beginning in 2040;
patent application, related to secreted stem cell factors for tissue repairment and regeneration, and two related foreign patent applications, which are exclusively in-licensed from Stanford University, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire beginning in 2038;
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patent applications, relating to TKI compounds, including KPI-287, and their uses, and 50 related foreign patents, and 23 foreign related patent applications, including pending PCT applications, which are owned by us, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, which are expected to expire beginning in 2034 through 2038;
−Removed: patents relating to antibiotic compounds and their uses, and five related foreign patents and one related foreign patent application, which are owned by us, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire in 2034;
−Removed: patents and five U.S.
−Removed: patent applications, relating to methods for treating an eye disease or disorder by injecting or instilling a drug delivery system, and 18 related foreign patents, and 22 related foreign patent applications, which are exclusively sub-licensed from GrayBug Vision, Inc., and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire beginning in 2031 through 2035;
−Removed: patents and five U.S.
−Removed: patent applications, related to our AMPPLIFY technology, and 34 related foreign patents and four related foreign patent applications, which are exclusively in-licensed from JHU, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire beginning in 2025 through 2036.
−Removed: The term of individual patents depends upon the legal term for patents in the countries in which they are granted.
+Added: patents relating to antibiotic compounds and their uses, and five related foreign patents, which are owned by us, and which, if granted with respect to the patent applications, and if the appropriate maintenance, renewal, annuity or other governmental fees are paid, are expected to expire in 2034.The term of individual patents depends upon the legal term for patents in the countries in which they are granted.
In most countries, including the United States, the patent term is generally 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country.
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We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.
−Removed: License Agreements
−Removed: The Johns Hopkins University
−Removed: In November 2009, we entered into an exclusive license agreement with JHU, which was amended in November 2012, May 2014, August 2014, June 2018 and July 2020 and amended in part in October 2014 by the JHU settlement agreement described below.
−Removed: We refer to the amended license agreement with JHU as the JHU license agreement.
−Removed: Pursuant to the JHU license agreement, JHU granted us an exclusive, worldwide, sublicensable license under specified patent rights covering various aspects of MPP technology, to research, develop, make, use and sell products and provide services in any field.
−Removed: JHU also granted us a non-exclusive license to use specified know-how with limits on JHU’s right to license the know-how to other commercial entities.
−Removed: Financial Terms
−Removed: In connection with the JHU license agreement, we paid JHU an upfront license fee in the low tens of thousands of dollars and issued to JHU a low single digit percentage of our common stock.
−Removed: We also reimbursed JHU for the prosecution and maintenance costs incurred by JHU for the licensed patent rights prior to our entering into the JHU license agreement, and we are responsible for all of the ongoing costs relating to the prosecution and maintenance of the JHU patent rights licensed to us.
−Removed: We paid JHU fees in the low tens of thousands of dollars upon entering into certain of the amendments to the JHU license agreement.
−Removed: In connection with the JHU license agreement and the JHU settlement agreement described below, we are obligated to make certain future payments to JHU.
−Removed: We paid JHU $112,500 in minimum annual royalty and running fees in the aggregate in 2021.
−Removed: We are obligated to pay JHU annual minimum royalties that will not exceed approximately $112,500 per year in the future.
−Removed: In addition, we must pay JHU a tiered royalty rate in the low single digits on annual net sales by us or our affiliates of products or services covered by a valid issued claim, or certain pending claims, of a licensed JHU patent right in the country of sale, from which we may, under specified circumstances, offset portions of amounts we must pay as royalties on other patent rights in order to commercialize a licensed product or licensed service up to a maximum reduction of a mid double digit percentage.
−Removed: We must also pay a percentage, in the high single digits, of certain consideration we or our affiliates receive from sublicensing rights under the licensed JHU intellectual property, subject to specified offsets and deductions.
−Removed: We may offset against each minimum annual payment the royalties and sublicense income that we pay to JHU in the preceding twelve-month period.
−Removed: We are obligated to pay JHU milestone fees not to exceed $750,000 in connection with the commercial sales of EYSUVIS in the U.S., and certain ex-US countries in the aggregate, if certain development and commercial events are achieved.
−Removed: We also are obligated to pay to JHU certain remaining milestone payments for the development of a third and fourth product under the JHU license agreement, which will not exceed approximately $1.7 million in the aggregate, if certain development and commercial events are achieved.
−Removed: The JHU patent rights sublicensed to us by GrayBug under the JHU settlement agreement described below are considered in the same way as the JHU patent rights directly licensed to us by JHU for purposes of determining these payments.
−Removed: Diligence Obligations
−Removed: We are required to use commercially reasonable efforts to develop and introduce the licensed products and licensed services to the market, including developing licensed products suitable for different indications, consistent with sound and reasonable business practice and judgment, and, after introducing a licensed product or licensed service into the market, we must endeavor to keep licensed products and licensed services reasonably available to the public consistent with sound and reasonable business practice and judgment.
−Removed: Term and Termination
−Removed: The JHU license agreement will expire on a country-by-country basis upon the expiration of the last to expire licensed patent in such country or, if no licensed patent issues in such country, then in November 2029.
−Removed: Either we or JHU may terminate the JHU license agreement for the other party’s breach that is not cured within specified time periods or if the other party is subject to certain bankruptcy protections.
−Removed: In addition, we may terminate the JHU license agreement, for any reason, upon 90 days’ prior written notice to JHU.
−Removed: Assignment and Exclusive License
−Removed: In April 2017 we assigned to JHU certain Kala-owned patent applications and our interest in certain patents and patent applications formerly co-owned by JHU and Kala, unifying ownership of the assigned patent rights in JHU’s name.
−Removed: As part of the assignment of these patent rights to JHU, Kala was granted an exclusive, non-royalty bearing, sub-licensable license from JHU under all of the patent rights Kala assigned in this transaction, which will expire upon the expiration of the last to expire licensed patent under the new license.
−Removed: No fees were paid to JHU for this exclusive license.
−Removed: GrayBug Vision, Inc.
−Removed: and The Johns Hopkins University
−Removed: A dispute arose between us, JHU, and GrayBug Vision, Inc.
−Removed: (formerly known as GrayBug, LLC and GrayBug, Inc.), or GrayBug, over rights licensed to us and GrayBug under certain patent rights owned by JHU.
−Removed: In October 2014, we, GrayBug, and JHU resolved this matter by entering into a Settlement and License Agreement, which was amended in January 2015, which we refer to as the JHU settlement agreement.
−Removed: Under the JHU settlement agreement, GrayBug granted us, under specified patent rights that are exclusively licensed to GrayBug by JHU in all fields, an exclusive, worldwide royalty-free sublicense in the field of use of a particle with specified characteristics for delivery of a biologically active material through mucus, mucin, or a mucosal barrier where such delivery does not involve administration via injection to the eye, which we refer to as the Kala sublicense field.
−Removed: In December 2017 and April 2019, GrayBug terminated its exclusive license from JHU as to two patent families among these patent rights.
−Removed: Pursuant to the JHU settlement agreement, these patent rights were to be automatically directly licensed to us under the terms of the JHU license agreement unless we specifically declined to accept such automatic direct license.
−Removed: While we did not accept the automatic direct license to one of the patent families as it does not directly relate to EYSUVIS, INVELTYS or any other potential drug candidates, we accepted the automatic direct license to the other patent family and are now responsible for all future patent prosecution costs for these patent rights.
−Removed: In turn, pursuant to the JHU settlement agreement we granted GrayBug, under specified patent rights that are exclusively licensed to us by JHU in all fields, an exclusive, worldwide royalty-free sublicense in the field of use of a particle with specified characteristics for delivery of a biologically active material to the eye via injection, excluding any particle comprising or consisting of LE, which we refer to as the GrayBug sublicense field.
−Removed: In addition, JHU granted us, under the terms of the JHU license agreement, an exclusive, sublicensable, worldwide license under certain additional specified patent rights relating to further aspects of MPP technology in the Kala sublicense field.
−Removed: JHU also granted to GrayBug a similar license under these same patent rights in the GrayBug sublicense field.
−Removed: In January 2017, GrayBug terminated its license under all but one patent family in these additional specified patent rights, and in July 2017, GrayBug terminated its license under the remaining patent family.
−Removed: As a result, for those patent rights terminated by GrayBug, we are now licensed in both the Kala sublicense field and the GrayBug sublicense field.
−Removed: JHU also granted us certain rights to obtain a non-exclusive license to certain additional patent rights and, if we obtain such a license, we would have the exclusive right to negotiate for a specified time period an exclusive license under such patent rights in the Kala sublicense field.
−Removed: Under the JHU settlement agreement, we agreed not to exercise our rights under the JHU patent rights licensed or sublicensed to us to use a particular active ingredient.
−Removed: Each party to the JHU settlement agreement may sublicense the rights granted to it pursuant to the JHU settlement agreement, subject to notice requirements and the requirement that any such sublicense must involve some aspect of collaboration, joint research, development, manufacture, partnership or the like.
−Removed: In any event, sublicenses beyond a specified number of tiers are not permitted without the original licensing party’s written consent.
−Removed: We, GrayBug and JHU each released the others, and certain persons affiliated with them, from any claims and losses known to the releasing party as of the effective date of the JHU settlement agreement in connection with the dispute that led to the JHU settlement agreement.
−Removed: Financial Terms
−Removed: The JHU settlement agreement also amended certain of our financial obligations under the JHU license agreement, which we have reflected in the description above.
−Removed: Neither we nor GrayBug owe the other any royalties, milestone payments or other payments with respect to the sublicenses and other rights granted to each other.
−Removed: JHU agreed that we are not responsible for paying to JHU any sublicense fees or other payments due under our JHU license agreement that may otherwise have arisen as a result of our granting GrayBug the sublicenses under the JHU settlement agreement.
−Removed: For the specified patent rights directly licensed to us by JHU in the Kala sublicense field under the JHU settlement agreement, we reimbursed JHU for a portion of the patent prosecution and maintenance costs incurred prior to entering the JHU settlement agreement, and we are responsible for all of the ongoing prosecution and maintenance costs of any of these JHU patent rights for which there is no other direct licensee of JHU, such as the JHU patent rights licensed to us in both the Kala sublicense field and the GrayBug sublicense field.
−Removed: Term and Termination
−Removed: The JHU settlement agreement will expire upon the expiration of all the patent rights that are the subject of the JHU settlement agreement.
−Removed: We may terminate one or more of the licenses or sublicenses granted to us in the JHU settlement agreement on a country-by-country basis for convenience upon 30 days’ prior written notice to GrayBug.
−Removed: We or GrayBug may terminate one or more the sublicenses granted to the other party under the JHU patent rights if the other party, or its employees, officers, directors, agents or representatives, takes certain steps to oppose, attempt to invalidate or prevent the issuance of any of the patent rights directly licensed to the terminating party by JHU.
−Removed: Stanford University
+Added: Licensing and Other Arrangements
+Added: Stanford University License Agreement
As part of our acquisition of Combangio, we acquired Combangio’s exclusively in-licensed patent portfolio from Stanford University.
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Our obligation to pay royalties will continue, on a country-by-country and licensed product-by-licensed product basis, until the last-to-expire valid claim of a licensed patent covering such licensed product in the country of manufacture and sale.
−Removed: Additionally, we are obligated to pay Stanford a low double-digit percentage of certain consideration we receive as a result of granting sublicenses to the licensed patents and, in connection with our acquisition of Combangio, Stanford became eligible to receive a one-time change of control fee of $100,000.
+Added: Additionally, we are required to pay Stanford a low double-digit percentage of certain consideration we receive as a result of granting sublicenses to the licensed patents.
+Added: In connection with our acquisition of Combangio, we paid Stanford a one-time change of control fee of $100,000.
Stanford retains the right, on behalf of itself, Stanford Health Care, Lucile Packard Children’s Hospital at Stanford, and all other non-profit research institutions, to practice the licensed patents for any non-profit purpose.
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Stanford may terminate the agreement if we breach certain provisions of the agreement and fail to remedy such breach within 60 days after written notice of such breach by Stanford.
+Added: Combangio Merger Agreement
+Added: In connection with the acquisition of Combangio on November 15, 2021, we entered into an Agreement and Plan of Merger, or the Merger Agreement, with Combangio.
+Added: In connection with the closing, we made an upfront payment of an aggregate of $5.0 million in cash to former Combangio stockholders and other equityholders, or the Combangio Equityholders, subject to customary adjustments, and agreed to issue an aggregate of 155,664 shares, or the Deferred Purchase Consideration, of our common stock to the Combangio Equityholders with an aggregate value of approximately $16.1 million, consisting of (i) an aggregate of 136,314 shares of common stock which were issued on January 3, 2022 and (ii) an aggregate of 19,350 shares of common stock that were initially held back as partial security for the satisfaction of indemnification obligations and other payment obligations of the Combangio Equityholders and that will be issued in March 2023 upon escrow release.
+Added: In addition, pursuant to the Merger Agreement, the Combangio Equityholders are entitled to receive from us up to $105.0 million in payments that are contingent upon the achievement of specified development, regulatory and commercialization milestones, or the Contingent Consideration, and are payable in cash and shares of our common stock, subject to the Share Cap (as defined below), of which $4.9 million will be paid in March 2023.
+Added: If the issuance of the Deferred Purchase Consideration or any contingent consideration payable in shares of our common stock, or the Contingent Stock Consideration, would result in the aggregate number of shares of our common stock issued under the Merger Agreement equaling or exceeding 19.9% of the total number of shares of our common stock issued and outstanding immediately prior to the closing, or the Share Cap, then we will be required to pay the portion of such consideration in excess of the Share Cap in cash.
+Added: The portion of any payment of Contingent Consideration payable in cash is referred to as “Contingent Cash Consideration”.
+Added: Upon dosing of the first patient in our CHASE Phase 2b clinical trial of KPI-012 for PCED in the United States in February 2023, or the Dosing Milestone, in March 2023 we will pay to the former Combangio Equityholders an aggregate of $2.5 million in cash and $2.4 million in shares of our common stock (representing an aggregate of 105,039 shares of our common stock).
+Added: The remaining amount of $0.1 million will be paid in January 2024.
+Added: Upon payment of the Dosing Milestone, we reached the Share Cap and any Contingent Consideration payable under the Merger Agreement in the future will be paid only in cash.
+Added: Subject to the terms and conditions of the Merger Agreement, the former Combangio Equityholders are entitled to receive from us the following remaining Contingent Consideration in cash:
+Added: ● (i) $5.0 million payable upon the first patient dosed with any product candidate whose active ingredient comprises one or more biological factors secreted by MSCs or their progenitors, including KPI-012, or the Product Candidate, in a pivotal clinical trial, (ii) $12.5 million payable upon regulatory approval by the FDA of marketing and sale of a Product Candidate in the United States, subject to certain specified reductions;
+Added: (iii) $17.5 million payable upon the first commercial sale of a Product Candidate in the United States, subject to certain specified reductions and (iv) an aggregate of up to $65.0 million payable upon the achievement of specified sales milestones;
+Added: ● tiered cash royalties at percentage rates in the mid-to-high single digits payable on annual net sales of all Product Candidates;
+Added: ● a cash payment at a percentage rate in the high single digits of all income, including earnout payments, received by us or any of our affiliates from a product license granted by us to a third party to sell or otherwise commercialize the Product Candidate in countries where neither we nor our affiliates conduct sales of such Product Candidate, subject to certain exceptions set forth in the Merger Agreement.
+Added: If the aggregate amount of Contingent Cash Consideration payable in any calendar year (after giving effect to the Share Cap) exceeds $2,500,000, or the Excess Cash Cap, such excess portion, or the Carry Forward Contingent Cash Consideration, will be carried forward and, subject to application of the Excess Cash Cap in the following calendar year, become payable on the first business day of the following calendar year.
+Added: Any Carry Forward Contingent Cash Consideration outstanding on June 1, 2026 is payable in full on June 1, 2026.
+Added: Securities Purchase Agreement for Private Placement
+Added: On November 28, 2022, we entered into a Securities Purchase Agreement, or the Securities Purchase Agreement, with certain institutional investors named therein, or the Purchasers, pursuant to which we agreed to issue and sell, in a private placement priced at-the-market under Nasdaq rules, shares of our common stock and shares of our Series E Convertible Non-Redeemable Preferred Stock, or Series E Preferred Stock, in two tranches for aggregate gross proceeds of up to $31.0 million, which we refer to collectively as the Private Placement.
+Added: Pursuant to the Securities Purchase Agreement, if at any time during the four-year period following the date of the first tranche closing, or the Participation Period, we propose to offer and sell new equity securities in an offering that is conducted pursuant to an exemption from registration under the Securities Act of 1933, as amended, or the Securities Act, or in an offering that is registered under the Securities Act that is not conducted as a firm-commitment underwritten offering, then, subject to compliance with securities laws and regulations, we have agreed to offer each Purchaser the right to purchase its pro rata share of the total amount of the new equity securities, subject to certain conditions and limitations.
+Added: In addition, if during the Participation Period, we propose to offer and sell new equity securities in a firm-commitment underwritten offering registered under the Securities Act, then subject to compliance with securities laws and regulations, we have agreed to use our commercially reasonable efforts to cause the managing underwriters of such offering to contact the Purchasers about potentially participating in such offering and to provide to each Purchaser the opportunity to purchase its pro rata share of such new equity securities, subject to certain conditions and limitations.
+Added: The participation rights will terminate if the Purchasers are offered the opportunity to participate in an offering pursuant to the participation rights and do not purchase at least 50% of their aggregate pro rata share of the new equity securities offered for sale in such offering.
+Added: Pursuant to the Securities Purchase Agreement, the Purchasers have the right to have up to two non-voting observers attend and participate in all Board and committee meetings and, subject to the Purchasers owning directly specified minimum amounts of our common stock, the right to have the Board nominate and recommend for election by the stockholders up to three Purchaser designees to the Board (one designee at 9.9%, two designees at 15.0% and three designees at 25.0%) designated by the Purchasers, provided that at such time as the Purchasers have designated three Board designees, at least one such designee must qualify as an “independent” director under Nasdaq rules and be acceptable to the members of the Board who are not Purchaser designees.
+Added: The Purchasers’ participation rights, observer rights and Board designation rights also will terminate at such time as the Purchasers and their affiliates cease to own, in the aggregate, specified minimum amounts of the shares purchased in the Private Placement.
+Added: Pursuant to the Securities Purchase Agreement, we agreed that we will not without the prior approval of the requisite Purchasers (i) issue or authorize the issuance of any equity security that is senior or pari passu to the Series E Preferred Stock with respect to liquidation preference, (ii) incur any additional indebtedness for borrowed money in excess of $1,000,000, in the aggregate, outside the ordinary course of business, subject to specified exceptions, including the refinancing of our existing indebtedness or (iii) pay or declare any dividend or make any distribution on, any shares of our capital stock, subject to specified exceptions.
+Added: In connection with the Private Placement, we have also entered into a registration rights agreement with the Purchasers, pursuant to which the Purchasers are entitled to certain resale registration rights with respect to the shares of common stock acquired in the Private Placement and the shares of common stock issuable upon conversion of the shares of Series E Preferred Stock acquired in the Private Placement.
Government Regulation and Product Approvals
−Removed: Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, pricing, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of biopharmaceutical products.
+Added: Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, pricing, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of biopharmaceutical
The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions, along with compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.
Government Regulation of Drugs and Biological Products
−Removed: In the United States, the FDA approves and regulates human drugs under the Federal Food, Drug, and Cosmetic Act, or the FDCA.
−Removed: Biological products, or biologics, are licensed for marketing under the Public Health Service Act, or the PHSA, and regulated under the FDCA.
−Removed: The failure of an applicant to comply with applicable U.S.
−Removed: requirements may result in FDA delays or refusal to approve pending NDAs or BLAs, and may subject an applicant to administrative or judicial sanctions, such as issuance of warning letters, or the imposition of fines, civil penalties, product recalls, product seizures, total or partial suspension of production or distribution, injunctions and/or civil or criminal prosecution brought by the FDA and the U.S.
−Removed: Department of Justice or other governmental entities.
−Removed: The FDA must approve our product candidates for therapeutic indications before they may be marketed in the United States.
−Removed: For drug products, the FDA must approve an NDA.
−Removed: For biologic products, the FDA must approve a BLA.
−Removed: An applicant seeking approval to market and distribute a new drug or biologic in the United States must satisfactorily complete each of the following steps:
+Added: In the United States, biological products, or biologics, are licensed for marketing by the FDA under the Public Health Service Act, or the PHSA, and regulated by the FDA under the Food, Drug and Cosmetic Act, or FDCA.
+Added: A company, institution, or organization which takes responsibility for the initiation and management of a clinical development program for such products, and for their regulatory approval, is typically referred to as a sponsor.
+Added: A sponsor seeking approval to market and distribute a new biologic in the United States must satisfactorily complete each of the following steps:
● completion of preclinical laboratory tests, animal studies and formulation studies according to good laboratory practices, or GLP, regulations or other applicable regulations;
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● performance of adequate and well-controlled human clinical trials in accordance with applicable IND regulations, good clinical practices, or GCPs, and other clinical-trial related regulations to evaluate the safety and efficacy of the investigational product for each proposed indication;
−Removed: ● preparation and submission to the FDA of an NDA or BLA requesting marketing approval for one or more proposed indications, including payment of application user fees;
−Removed: ● review of the NDA or BLA by an FDA advisory committee, where applicable;
−Removed: ● satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the drug or biologic is produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;
−Removed: ● satisfactory completion of any FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data submitted in support of the NDA or BLA;
−Removed: ● FDA review and approval of the NDA or BLA, which may be subject to additional post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy, or REMS, and any post-approval studies required by the FDA.
+Added: ● preparation and submission to the FDA of a BLA requesting marketing approval for one or more proposed indications, including payment of application user fees;
+Added: ● review of the BLA by an FDA advisory committee, where applicable;
+Added: ● satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the biologic is produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;
+Added: ● satisfactory completion of any FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data submitted in support of the BLA;
+Added: ● FDA review and approval of the BLA, which may be subject to additional post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy, or REMS, and any post-approval studies required by the FDA.
Preclinical Studies
−Removed: Before an applicant begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.
+Added: Before a sponsor begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.
Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as other studies to evaluate, among other things, the toxicity of the product candidate.
+Added: These studies are typically referred to as IND-enabling studies.
The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP regulations and standards and the United States Department of Agriculture’s Animal Welfare Act, if applicable.
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An IND is an exemption from the FDCA that allows an unapproved product candidate to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer such investigational product to humans.
−Removed: Such authorization must be secured prior to interstate shipment and administration of any product candidate that is not the subject of an approved NDA.
−Removed: In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.
+Added: Such authorization must be secured prior to interstate shipment and administration of any product candidate that is not the subject of an approved BLA.
+Added: In support of a request for an IND, sponsors must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.
In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, must be submitted to the FDA as part of an IND.
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In particular, information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial.
−Removed: Although sponsors are also obligated to disclose the results of their clinical trials after completion, disclosure of the results can be delayed in some cases for up to two years after the date of completion of the trial.
+Added: Although sponsors are also obligated to disclose the results of their clinical trials after completion, disclosure of the results can be delayed in some cases for up to two years after the date of
+Added: completion of the trial.
The NIH’s final rule on registration and reporting requirements for clinical trials became effective in 2017, and both NIH and the FDA have recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors.
3 unchanged sentences
In addition to civil monetary penalties, violations may also result in other regulatory action, such as injunction and/or criminal prosecution or disqualification from federal grants.
−Removed: Although the FDA has historically not enforced these reporting requirements due to the Department of Health and Human Services, or HHS’s, long delay in issuing final implementing regulations, those regulations have now been issued and the FDA did issue its first Notice of Noncompliance to a manufacturer in April 2021.
+Added: Although the FDA has historically not enforced these reporting requirements due to the Department of Health and Human Services, or HHS’s, long delay in issuing final implementing regulations, those regulations have now been issued and the FDA has issued several Notices of Noncompliance to manufacturers since April 2021.
Expanded Access to an Investigational Drug for Treatment Use
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There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.
−Removed: Human Clinical Trials in Support of an NDA or BLA
+Added: Human Clinical Trials in Support of a BLA
Clinical trials involve the administration of the investigational product candidate to human subjects under the supervision of a qualified investigator in accordance with GCP requirements which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial.
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Phase 1 clinical trials are initially conducted in a limited population to test the product candidate for safety, including adverse effects, dose tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics in healthy humans or in patients.
−Removed: During Phase 1 clinical trials, information about the investigational drug product’s pharmacokinetics and pharmacological effects may be obtained to permit the design of well-controlled and scientifically valid Phase 2 clinical trials.
+Added: During Phase 1 clinical trials, information about the investigational product’s pharmacokinetics and pharmacological effects may be obtained to permit the design of well-controlled and scientifically valid Phase 2 clinical trials.
Phase 2 clinical trials are generally conducted in a limited patient population to identify possible adverse effects and safety risks, evaluate the efficacy of the product candidate for specific targeted indications and determine dose tolerance and optimal dosage.
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such Phase 3 studies are referred to as “pivotal.”
−Removed: In some cases, the FDA may approve an NDA or BLA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after approval.
+Added: In some cases, the FDA may approve a BLA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after approval.
Such post-approval trials are typically referred to as Phase 4 clinical trials.
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Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials could result in withdrawal of approval for products.
−Removed: In response to the COVID-19 pandemic, FDA issued guidance on March 18, 2020, and has updated it periodically since that time to address the conduct of clinical trials during the pandemic.
−Removed: The guidance sets out a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical study report (or as a separate document) contingency measures implemented to manage the study, and any disruption of the study as a result of COVID-19;
−Removed: a list of all study participants affected by COVID-19-related study disruptions by a unique subject identifier and by investigational site, and a description of how the individual’s participation was altered;
−Removed: and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study, among other
−Removed: The FDA has indicated that it will continue to provide any necessary guidance to sponsors, clinical investigators, and research institutions as the public health emergency evolves.
+Added: In December 2022, with the passage of Food and Drug Omnibus Reform Act, or FDORA, Congress required sponsors to develop and submit a diversity action plan for each phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.
+Added: These plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinical trials of FDA-regulated products.
+Added: Specifically, actions plans must include the sponsor’s goals for enrollment, the underlying rationale for those goals, and an explanation of how the sponsor intends to meet them.
+Added: In addition to these requirements, the legislation directs the FDA to issue new guidance on diversity action plans.
Interactions with FDA During the Clinical Development Program
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In addition, sponsors are given opportunities to meet with the FDA at certain points in the clinical development program.
−Removed: Specifically, sponsors may meet with the FDA prior to the submission of an IND (Pre-IND meeting), at the end of Phase 2 clinical trial (EOP2 meeting) and before an NDA or BLA is submitted (Pre-NDA or Pre-BLA meeting).
+Added: Specifically, sponsors may meet with the FDA prior to the submission of an IND (Pre-IND meeting), at the end of Phase 2 clinical trial (EOP2 meeting) and before a BLA is submitted (Pre-BLA meeting).
Meetings at other times may also be requested.
−Removed: There are three types of meetings that occur between sponsors and the FDA.
+Added: There are four types of meetings that occur between sponsors and the FDA.
Type A meetings are those that are necessary for an otherwise stalled product development program to proceed or to address an important safety issue.
−Removed: Type B meetings include pre-IND and pre-NDA/pre-BLA meetings, as well as end of phase meetings such as EOP2 meetings.
−Removed: A Type C meeting is any meeting other than a Type A or Type B meeting regarding the development and review of a product, including for example meetings to facilitate early consultations on the use of a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval in the proposed context of use.
+Added: Type B meetings include pre-IND and pre-BLA meetings, as well as end of phase meetings such as EOP2 meetings.
+Added: A Type C meeting is any meeting other than a Type A or Type B meeting regarding the development and
+Added: review of a product, including for example meetings to facilitate early consultations on the use of a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval in the proposed context of use.
+Added: Finally, a type D meeting is focused on a narrow set of issues (should be limited to no more than two focused topics) and should not require input from more than three disciplines or divisions.
These meetings provide an opportunity for the sponsor to share information about the data gathered to date with the FDA and for the FDA to provide advice on the next phase of development.
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The cGMP regulations include requirements relating to organization of personnel, buildings and facilities, equipment, control of components and product containers and closures, production and process controls, packaging and labeling controls, holding and distribution, laboratory controls, records and reports and returned or salvaged products.
−Removed: Manufacturers and other entities involved in the manufacture and distribution of approved pharmaceuticals are required to register their establishments with the FDA and some state agencies, and they are subject to periodic unannounced inspections by the FDA for compliance with cGMPs and other requirements.
+Added: Manufacturers and other entities involved in the manufacture and distribution of approved pharmaceuticals are required to register their establishments with the FDA and some state agencies.
+Added: The PREVENT Pandemics Act, which was enacted in December 2022, clarifies that foreign drug manufacturing establishments are subject to registration and listing requirements even if a drug or biologic undergoes further manufacture, preparation, propagation, compounding or processing at a separate establishment outside the United States prior to being imported or offered for import into the United States.
+Added: Manufacturing facilities are subject to periodic unannounced inspections by the FDA for compliance with cGMPs and other requirements.
Inspections must follow a “risk-based schedule” that may result in certain establishments being inspected more frequently.
Manufacturers may also have to provide, on request, electronic or physical records regarding their establishments.
−Removed: Delaying, denying, limiting, or refusing inspection by the FDA may lead to a product being deemed to
−Removed: be adulterated.
+Added: Delaying, denying, limiting, or refusing inspection by the FDA may lead to a product being deemed to be adulterated.
Changes to the manufacturing process, specifications or container closure system for an approved product are strictly regulated and often require prior FDA approval before being implemented.
1 unchanged sentence
Pediatric Studies
−Removed: Under the Pediatric Research Equity Act of 2003, an application or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
+Added: Under the Pediatric Research Equity Act of 2003, or PREA, an application or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
Sponsors must also submit pediatric study plans prior to the assessment data.
−Removed: Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests and other information required by regulation.
−Removed: The applicant, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other and agree upon a final plan.
−Removed: The FDA or the applicant may request an amendment to the plan at any time.
−Removed: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
+Added: Those plans must contain an outline of the proposed pediatric study or studies the sponsor plans to conduct, including study objectives and design, any deferral or waiver requests and other information required by regulation.
+Added: The sponsor, the
+Added: FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other and agree upon a final plan.
+Added: The FDA or the sponsor may request an amendment to the plan at any time.
+Added: The FDA may, on its own initiative or at the request of the sponsor, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults before pediatric trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin.
+Added: The law now requires the FDA to send a PREA Non-Compliance letter to sponsors who have failed to submit their pediatric assessments required under PREA, have failed to seek or obtain a deferral or deferral extension or have failed to request approval for a required pediatric formulation.
+Added: It further requires the FDA to publicly post the PREA Non-Compliance letter and sponsor’s response.
Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although FDA has recently taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.
2 unchanged sentences
The FDA is authorized to expedite the review of applications in several ways.
−Removed: Under the Fast Track program, the sponsor of a product candidate may request the FDA to designate the product for a specific indication as a Fast Track product concurrent with or after the filing of the IND.
−Removed: Candidate 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.
+Added: None of these expedited programs, however, changes the standards for approval but they may help expedite the development or approval process of product candidates.
+Added: ● Fast Track designation :
+Added: Product candidates 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.
Fast Track designation applies to the combination of the product candidate and the specific indication for which it is being studied.
In addition to other benefits, such as the ability to have greater interactions with the FDA, the FDA may initiate review of sections of a Fast Track application before the application is complete, a process known as rolling review.
−Removed: Any product candidate submitted to the FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as breakthrough therapy designation, priority review and accelerated approval.
● Breakthrough therapy designation.
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Drug or biologic products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval.
−Removed: Accelerated approval means that a product candidate may
−Removed: be approved on the basis of adequate and well controlled clinical trials establishing that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity and prevalence of the condition and the availability or lack of alternative treatments.
+Added: Accelerated approval means that a product candidate may be approved on the basis of adequate and well controlled clinical trials establishing that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity and prevalence of the condition and the availability or lack of alternative treatments.
As a condition of approval, the FDA may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well controlled post-marketing clinical trials.
In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials.
+Added: With passage of the Food and Drug Omnibus Reform Act, or FDORA, in December 2022, Congress modified certain provisions governing accelerated approval of drug and biologic products.
+Added: Specifically, the new legislation authorized the FDA to:
+Added: require a sponsor to have its confirmatory clinical trial underway before accelerated approval is awarded, require a sponsor of a product granted accelerated approval to submit progress reports on its
+Added: post-approval studies to FDA every six months (until the study is completed;
+Added: and use expedited procedures to withdraw accelerated approval of a BLA after the confirmatory trial fails to verify the product’s clinical benefit.
+Added: Further, FDORA requires the agency to publish on its website “the rationale for why a post-approval study is not appropriate or necessary” whenever it decides not to require such a study upon granting accelerated approval.
● Regenerative advanced therapy.
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The benefits of a regenerative advanced therapy designation include early interactions with the FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints.
−Removed: None of these expedited programs change the standards for approval but they may help expedite the development or approval process of product candidates.
−Removed: Acceptance and Review of NDAs and BLAs
+Added: Acceptance and Review of BLAs
Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials, along with information relating to the product’s chemistry, manufacturing, controls, safety updates, patent information, abuse information and proposed labeling, are submitted to the FDA as part of an application requesting approval to market the product candidate for one or more indications.
−Removed: Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators.
−Removed: To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of a drug product and the safety, potency and purity of the biological product to the satisfaction of the FDA.
+Added: Data may come from company-sponsored clinical trials or from a number of alternative sources, including studies initiated by investigators.
+Added: To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety, potency and purity of the biological product to the satisfaction of the FDA.
The fee required for the submission and review of an application under the Prescription Drug User Fee Act, or PDUFA, is substantial (for example, for fiscal year 2023 this application fee is approximately $3.25 million), and the sponsor of an approved application is also subject to an annual program fee, currently more than $394,000 per eligible prescription product.
−Removed: These fees are typically adjusted annually, and exemptions and waivers may be available under certain circumstances, such as where a waiver is necessary to protect the public health, where the fee would present a significant barrier to innovation, or where the applicant is a small business submitting its first human therapeutic application for review.
+Added: These fees are typically adjusted annually, and exemptions and waivers may be available under certain circumstances, such as where a waiver is necessary to protect the public health, where the fee would present a significant barrier to innovation, or where the sponsor is a small business submitting its first human therapeutic application for review.
The FDA conducts a preliminary review of all applications within 60 calendar days of receipt and must inform the sponsor at that time or before whether an application is sufficiently complete to permit substantive review.
In pertinent part, FDA’s regulations state that an application “shall not be considered as filed until all pertinent information and data have been received” by the FDA.
−Removed: In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File, or RTF, determination to the applicant.
+Added: In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File, or RTF, determination to the sponsor.
Typically, an RTF will be based on administrative incompleteness, such as clear omission of information or sections of required information;
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Under the goals and policies agreed to by the FDA under PDUFA, the FDA has ten months from the filing date in which to complete its initial review of a standard application that is a new molecular entity, and six months from the filing date for an application with “priority review”.
−Removed: The review process may be extended by the FDA for three additional months to consider new information or in
−Removed: the case of a clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.
+Added: The review process may be extended by the FDA for three additional months to consider new information or in the case of a clarification provided by the sponsor to address an outstanding deficiency identified by the FDA following the original submission.
Despite these review goals, it is not uncommon for FDA review of an application to extend beyond the PDUFA goal date.
−Removed: In connection with its review of an application, the FDA will typically submit information requests to the applicant and set deadlines for responses thereto.
+Added: In connection with its review of an application, the FDA will typically submit information requests to the sponsor and set deadlines for responses thereto.
The FDA will also conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether the manufacturing processes and facilities comply with cGMPs.
1 unchanged sentence
The FDA also may inspect the sponsor and one or more clinical trial sites to assure compliance with IND and GCP requirements and the integrity of the clinical data submitted to the FDA.
−Removed: To ensure cGMP and GCP compliance by its employees and third-party contractors, an applicant may incur significant expenditure of time, money and effort in the areas of training, record keeping, production and quality control.
+Added: With passage of FDORA, Congress clarified FDA’s authority to conduct inspections by expressly permitting inspection of facilities involved in the preparation, conduct, or analysis of clinical and non-clinical studies submitted to FDA as well as other persons holding study records or involved in the study process.
+Added: To ensure cGMP and GCP compliance by its employees and third-party contractors, a sponsor may incur significant expenditure of time, money and effort in the areas of training, record keeping, production and quality control.
Additionally, the FDA may refer an application, including applications for novel product candidates which present difficult questions of safety or efficacy, to an advisory committee for review, evaluation and recommendation as to whether the application should be approved and under what conditions.
2 unchanged sentences
Data from clinical trials are not always conclusive, and the FDA or its advisory committee may interpret data differently than the sponsor interprets the same data.
−Removed: The FDA may also re-analyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process.
+Added: The FDA may also re-analyze the clinical trial data, which could result in extensive discussions between the FDA and the sponsor during the review process.
The FDA also may require submission of a REMS, if it determines that a REMS is necessary to ensure that the benefits of the product outweigh its risks and to assure the safe use of the product.
2 unchanged sentences
If the FDA concludes a REMS is needed, the sponsor of the application must submit a proposed REMS and the FDA will not approve the application without a REMS.
−Removed: Decisions on NDAs and BLAs
−Removed: The FDA reviews an applicant to determine, among other things, whether the product is safe and whether it is effective for its intended use(s), with the latter determination being made on the basis of substantial evidence.
+Added: Decisions on BLAs
+Added: The FDA reviews a BLA to determine, among other things, whether the product is safe and whether it is effective for its intended use(s), with the latter determination being made on the basis of substantial evidence.
The term “substantial evidence” is defined under the FDCA as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the product involved, on the basis of which it could fairly and responsibly be concluded by such experts that the product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”
4 unchanged sentences
It has not yet finalized that guidance.
−Removed: After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial sites, the FDA will issue
−Removed: either a Complete Response Letter, or CRL, or an approval letter.
−Removed: To reach this determination, the FDA must determine that the drug is effective and that its expected benefits outweigh its potential risks to patients.
−Removed: This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and efficacy in the NDA or BLA.
+Added: After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial sites, the FDA will issue either a Complete Response Letter, or CRL, or an approval letter.
+Added: To reach this determination, the FDA must determine that the investigational product is effective and that its expected benefits outweigh its potential risks to patients.
+Added: This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and efficacy in the BLA.
This assessment is also informed by other factors, including:
7 unchanged sentences
The CRL may require additional clinical or other data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing.
−Removed: If a CRL is issued, the applicant will have one year to respond to the deficiencies identified by the FDA, at which time the FDA can deem the application withdrawn or, in its discretion, grant the applicant an additional six month extension to respond.
+Added: If a CRL is issued, the sponsor will have one year to respond to the deficiencies identified by the FDA, at which time the FDA can deem the application withdrawn or, in its discretion, grant the sponsor an additional six month extension to respond.
The FDA has committed to reviewing resubmissions in response to an issued CRL in either two or six months depending on the type of information included.
14 unchanged sentences
A product may also be subject to official lot release, meaning that the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.
−Removed: If the product is subject to official release, the manufacturer must submit samples of each lot, together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot, to the FDA.
−Removed: in addition perform certain confirmatory tests on lots of some products before releasing the lots for distribution.
+Added: If the product is subject to official release, the
+Added: manufacturer must submit samples of each lot, together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot, to the FDA.
+Added: The FDA may in addition perform certain confirmatory tests on lots of some products before releasing the lots for distribution.
Finally, the FDA will conduct laboratory research related to the safety, purity, potency and effectiveness of pharmaceutical products.
13 unchanged sentences
After approval, a product generally may not be promoted for uses that are not approved by the FDA, as reflected in the product’s prescribing information.
−Removed: In September 2021, the FDA published final regulations which describe the types of evidence that the FDA will consider in determining the intended use of a drug or biologic.
+Added: In September 2021, the FDA published final regulations which describe the types of evidence that the FDA will consider in determining the intended use of a biologic.
In the United States, health care professionals are generally permitted to prescribe products for such uses not described in the labeling, known as off-label uses, because the FDA does not regulate the practice of medicine.
−Removed: However, FDA regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of off-label uses.
−Removed: It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information.
+Added: It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information , such as distributing scientific or medical journal information.
+Added: Further, with passage of the Pre-Approval Information Exchange Act, or PIE Act, in December 2022, sponsors of products that have not been approved may proactively communicate to payors certain information about products in development to help expedite patient access upon product approval.
+Added: Previously, such communications were permitted under FDA guidance but the new legislation explicitly provides protection to sponsors who convey certain information about products in development to payors, including unapproved uses of approved products.
If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.
1 unchanged sentence
The federal government has levied large civil and criminal fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
−Removed: In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act, or DSCA, which regulate the distribution and tracing of prescription drug samples at the federal level, and set minimum standards for the regulation of distributors by the states.
+Added: In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act, or DSCA, which regulate the distribution and tracing of prescription drug samples at the federal level, and set minimum standards
+Added: for the regulation of distributors by the states.
The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.
−Removed: Section 505(b)(2) NDAs
−Removed: NDAs for most new drug products are based on two full clinical studies which must contain substantial evidence of the safety and efficacy of the proposed new product for the proposed use.
−Removed: These applications are submitted under Section 505(b)(1) of the FDCA.
−Removed: The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA.
−Removed: This type of application allows the applicant to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar product, or published literature.
−Removed: Specifically, Section 505(b)(2) applies to NDAs for a drug for which the investigations made to show whether or not the drug is safe for use and effective in use and relied upon by the applicant for approval of the application “were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”
−Removed: Section 505(b)(2) authorizes the FDA to approve an NDA based on safety and effectiveness data that were not developed by the applicant.
−Removed: NDAs filed under Section 505(b)(2) may provide an alternate and potentially more expeditious pathway to FDA approval for new or improved formulations or new uses of previously approved products.
−Removed: If the 505(b)(2) applicant can establish that reliance on the FDA’s previous approval is scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical or clinical studies of the new product.
−Removed: The FDA may also require companies to perform additional studies or measurements to support the change from the approved product.
−Removed: The FDA may then approve the new drug candidate for all or some of the label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant.
−Removed: Generic Drugs and Regulatory Exclusivity
−Removed: In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress established an abbreviated regulatory scheme authorizing the FDA to approve generic drugs that are shown to contain the same active ingredients as, and to be bioequivalent to, drugs previously approved by the FDA pursuant to NDAs and it also enacted Section 505(b)(2).
−Removed: To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the FDA.
−Removed: An ANDA is a comprehensive submission that contains, among other things, data and information pertaining to the active pharmaceutical ingredient, bioequivalence, drug product formulation, specifications and stability of the generic drug, as well as analytical methods, manufacturing process validation data and quality control procedures.
−Removed: ANDAs are “abbreviated” because they generally do not include preclinical and clinical data to demonstrate safety and effectiveness.
−Removed: Instead, in support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference listed drug, or RLD.
−Removed: Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, the strength of the drug and the conditions of use of the drug.
−Removed: At the same time, the FDA must also determine that the generic drug is “bioequivalent” to the innovator drug.
−Removed: Under the statute, a generic drug is bioequivalent to a RLD if “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug.” Upon approval of an ANDA, the FDA indicates whether the generic product is “therapeutically equivalent” to the RLD in its publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” also referred to as the “Orange Book.” Physicians and pharmacists consider a therapeutic equivalent generic drug to be fully substitutable for the RLD.
−Removed: Under the Hatch-Waxman Act, the FDA may not approve an ANDA or 505(b)(2) application until any applicable period of non-patent exclusivity for the RLD has expired.
−Removed: The FDCA provides a period of five years of non-patent data exclusivity for a new drug containing a new chemical entity, or NCE.
−Removed: For the purposes of this provision, FDA has consistently taken the position that an NCE is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA.
−Removed: This interpretation was confirmed with enactment of the Ensuring Innovation Act in April 2021.
−Removed: An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance.
−Removed: In cases where such NCE exclusivity has been granted, a generic or follow-on drug application may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.
−Removed: The FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the
−Removed: applicant and are essential to the approval of the application.
−Removed: This three-year exclusivity period often protects changes to a previously approved drug product, such as new indications, dosage forms, route of administration or combination of ingredients.
−Removed: Three-year exclusivity would be available for a drug product that contains a previously approved active moiety, provided the statutory requirement for a new clinical investigation is satisfied.
−Removed: Unlike five-year NCE exclusivity, an award of three-year exclusivity does not block the FDA from accepting ANDAs or 505(b)(2) NDAs seeking approval for generic versions of the drug as of the date of approval of the original drug product;
−Removed: rather, this three-year exclusivity covers only the conditions of use associated with the new clinical investigations and, as a general matter, does not prohibit the FDA from approving follow-on applications for drugs containing the original active ingredient.
−Removed: Five-year and three-year exclusivity also will not delay the submission or approval of a traditional NDA filed under Section 505(b)(1) of the FDCA;
−Removed: however, an applicant submitting a traditional NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
−Removed: As part of the submission of an NDA or certain supplemental applications, NDA sponsors are required to list with the FDA each patent with claims that cover the applicant’s product or an approved method of using the product.
−Removed: Upon approval of a new product, each of the patents listed in the application for the product is then published in the Orange Book.
−Removed: The FDA’s regulations governing patient listings were largely codified into law with enactment of the Orange Book Modernization Act in January 2021.
−Removed: When an ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book.
−Removed: Specifically, the ANDA applicant must certify that:
−Removed: (i) the required patent information has not been filed;
−Removed: (ii) the listed patent has expired;
−Removed: (iii) the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration;
−Removed: or (iv) the listed patent is invalid or will not be infringed by the new product.
−Removed: Moreover, to the extent that the Section 505(b)(2) NDA applicant is relying on studies conducted for an already approved product, the applicant is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would.
−Removed: If the generic drug or follow-on drug applicant does not challenge the innovator’s listed patents, FDA will not approve the ANDA or 505(b)(2) application until all the listed patents claiming the referenced product have expired.
−Removed: A certification that the new generic product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification.
−Removed: If the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA owner and patent holders once the ANDA has been accepted for filing by the FDA.
−Removed: The NDA owner and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification.
−Removed: The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earliest of 30 months after the receipt of the Paragraph IV notice, expiration of the patent and a decision in the infringement case that is favorable to the ANDA or 505(b)(2) NDA applicant.
Regulatory Exclusivity Governing Biologics
4 unchanged sentences
The FDA has also issued numerous guidance documents outlining its approach to reviewing and licensing biosimilars and interchangeable biosimilars under the PHSA, including a draft guidance issued in November 2020 that seeks to provide additional clarity to manufacturers of interchangeable biosimilars.
−Removed: Under the BPCIA, a manufacturer may submit an application for a product that is “biosimilar to” a previously approved biological product, which the statute refers to as a “reference product.” In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and the
−Removed: proposed biosimilar product in terms of safety, purity and potency.
−Removed: The biosimilar applicant may demonstrate that its product is biosimilar to the reference product on the basis of data from analytical studies, animal studies and one or more clinical studies to demonstrate safety, purity and potency in one or more appropriate conditions of use for which the reference product is approved.
−Removed: In addition, the applicant must show that the biosimilar and reference products have the same mechanism of action for the conditions of use on the label, route of administration, dosage and strength, and the production facility must meet standards designed to assure product safety, purity and potency.
+Added: Under the BPCIA, a manufacturer may submit an application for a product that is “biosimilar to” a previously approved biological product, which the statute refers to as a “reference product.” In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and the proposed biosimilar product in terms of safety, purity and potency.
+Added: The biosimilar sponsor may demonstrate that its product is biosimilar to the reference product on the basis of data from analytical studies, animal studies and one or more clinical studies to demonstrate safety, purity and potency in one or more appropriate conditions of use for which the reference product is approved.
+Added: In addition, the sponsor must show that the biosimilar and reference products have the same mechanism of action for the conditions of use on the label, route of administration, dosage and strength, and the production facility must meet standards designed to assure product safety, purity and potency.
For the FDA to approve a biosimilar product as interchangeable with a reference product, the FDA must find not only that the product is biosimilar to the reference product but also that it can be expected to produce the same clinical results as the reference product such that the two products may be switched without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
1 unchanged sentence
Following approval of the interchangeable biosimilar product, the FDA may not grant interchangeability status for any second biosimilar until one year after the first commercial marketing of the first interchangeable biosimilar product.
+Added: In December 2022, Congress clarified through FDORA that FDA may approve multiple first interchangeable biosimilar biological products so long as the products are all approved on the first day on which such a product is approved as interchangeable with the reference product.
A reference biological product is granted 12 years of exclusivity from the time of first licensure of the product, and the FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product.
4 unchanged sentences
Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of exclusivity.
−Removed: For drug products, the six month exclusivity may be attached to the term of any existing patent or regulatory exclusivity, including the orphan exclusivity and regulatory exclusivities available under the Hatch-Waxman provisions of the FDCA.
For biologic products, the six month period may be attached to any existing regulatory exclusivities but not to any patent terms.
−Removed: The conditions for pediatric exclusivity include the FDA’s determination that information relating to the use of a new product in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric clinical trials, and the applicant agreeing to perform, and reporting on, the requested clinical trials within the statutory timeframe.
−Removed: This six-month exclusivity may be granted if an NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.
+Added: The conditions for pediatric exclusivity include the FDA’s determination that information relating to the use of a new product in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric clinical trials, and the sponsor agreeing to perform, and reporting on, the requested clinical trials within the statutory timeframe.
+Added: This six-month
+Added: exclusivity may be granted if a sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.
The data do not need to show the product to be effective in the pediatric population studied;
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An application for designation as an orphan product can be made any time prior to the filing of an application for approval to market the product.
−Removed: A product becomes an orphan when it receives orphan drug designation from the Office of Orphan Products Development at the FDA based on
−Removed: acceptable confidential requests.
+Added: A product becomes an orphan when it receives orphan drug designation from the Office of Orphan Products Development at the FDA based on acceptable confidential requests.
The product must then go through the review and approval process like any other product.
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Under Omnibus legislation passed in December 2020, the requirement for a product to show clinical superiority applies to drug products that received orphan drug designation before enactment of amendments to the FDCA in 2017 but have not yet been approved by FDA.
−Removed: In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” It is unclear how this court decision will be implemented by the FDA.
+Added: In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” Although there have been legislative proposals to overrule this decision, they have not been enacted into law.
+Added: On January 23, 2023, FDA announced that, in matters beyond the scope of that court order, FDA will continue to apply its existing regulations tying orphan-drug exclusivity to the uses or indications for which the orphan drug was approved.
Patent Term Restoration and Extension
In the United States, a patent claiming a new product, its method of use or its method of manufacture may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent extension of up to five years for patent term lost during product development and FDA regulatory review.
−Removed: Assuming grant of the patent for which the extension is sought, the restoration period for a patent covering a product is typically one-half the time between the effective date of the IND involving human beings is begun and the submission date of the NDA or BLA, plus the time between the submission date of the application and the ultimate approval date.
+Added: Assuming grant of the patent for which the extension is sought, the restoration period for a patent covering a product is typically one-half the time between the effective date of the IND involving human beings is begun and the submission date of the BLA, plus the time between the submission date of the application and the ultimate approval date.
Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date in the United States.
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The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, can take several years or longer.
−Removed: It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.
+Added: It involves a rigorous premarket review during which the sponsor must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.
PMA applications are subject to an application fee.
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officials for the purpose of obtaining or retaining business or otherwise seeking favorable treatment;
−Removed: ● the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, or the Affordable Care Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the United States Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers and their immediate family members;
+Added: ● the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, or the Affordable Care Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the United States Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;
● analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to health care items or services that are reimbursed by non-government third-party payors, including private insurers.
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In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.
−Removed: A Joint Select
−Removed: Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.
+Added: A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.
These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2031.
−Removed: Pursuant to the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, and subsequent legislation, these Medicare sequester reductions have been suspended through the end of March 2022.
−Removed: From April 2022 through June 2022 a 1% sequester cut will be in effect, with the full 2% cut resuming thereafter.
+Added: Pursuant to the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, and subsequent legislation, these Medicare sequester reductions were suspended and reduced through the end of June 2022, with the full 2% cut resuming thereafter.
Since enactment of the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law.
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District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.
−Removed: Supreme Court heard this case on November 10, 2020 and, on June 17, 2021, dismissed this action after finding that the plaintiffs do not have standing to challenge the constitutionality of the ACA.
+Added: Supreme Court dismissed this action after finding that the plaintiffs do not have standing to challenge the constitutionality of the ACA.
Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.
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The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.
−Removed: The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023.
+Added: The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which has been delayed until January 1, 2026 by the Infrastructure Investment and Jobs Act.
On July 9, 2021, President Biden signed Executive Order 14063, which focuses on, among other things, the price of pharmaceuticals.
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and (3) foster scientific innovation to promote better healthcare and improve health by supporting public and private research and making sure that market incentives promote discovery of valuable and accessible new treatments.
+Added: More recently, on August 16, 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law by President Biden.
+Added: The new legislation has implications for Medicare Part D, which is a program available to individuals who are entitled to Medicare Part A or enrolled in Medicare Part B to give them the option of paying a monthly premium for outpatient prescription drug coverage.
+Added: Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;
+Added: imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023);
+Added: and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).
+Added: The IRA permits the Secretary of the Department of Health and Human Services to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
+Added: Specifically, with respect to price negotiations, Congress authorized Medicare to negotiate lower prices for certain costly single-source drug and biologic products that do not have competing generics or biosimilars and are reimbursed under Medicare Part B and Part D.
+Added: CMS may negotiate prices for ten high-cost drugs paid for by Medicare Part D starting in 2026, followed by 15 Part D drugs in 2027, 15 Part B or Part D drugs in 2028 and 20 Part B or Part D drugs in 2029 and beyond.
+Added: This provision applies to drug products that have been approved for at least 9 years and biologics that have been licensed for 13 years, but it does not apply to drugs and biologics that have been approved for a single rare disease or condition.
+Added: Further, the legislation subjects drug manufacturers to civil monetary penalties and a
+Added: potential excise tax for failing to comply with the legislation by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law or for taking price increases that exceed inflation.
+Added: The legislation also requires manufacturers to pay rebates for drugs in Medicare Part D whose price increases exceed inflation.
+Added: The new law also caps Medicare out-of-pocket drug costs at an estimated $4,000 a year in 2024 and, thereafter beginning in 2025, at 2,000 a year.
At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
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New laws and regulations governing privacy and security may be adopted in the future as well.
−Removed: At the state level, California has enacted legislation that has been dubbed the first “GDPR-like” law in the United States.
−Removed: Known as the California Consumer Privacy Act, or CCPA, it creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.
−Removed: The CCPA went into effect on January 1, 2020 and requires covered companies to provide new disclosures to California consumers, provide such consumers new ways to opt-out of certain sales of personal information, and allow for a new cause of action for data breaches.
−Removed: Additionally, effective starting on January 1, 2023, the California Privacy Rights Act, or CPRA, will significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information.
−Removed: The CPRA also creates a new state agency that will be vested with authority to implement and enforce the CCPA and the CPRA.
−Removed: The CCPA and CPRA could impact our business activities depending on how it is interpreted and exemplifies the vulnerability of our business
−Removed: to not only cyber threats but also the evolving regulatory environment related to personal data and individually identifiable health information.
−Removed: These provisions may apply to some of our business activities.
−Removed: In addition, other states, including Virginia and Colorado, already have passed state privacy laws and other states will likely be considering similar laws in the near future.
+Added: In 2018, California passed into law the California Consumer Privacy Act, or CCPA, which took effect on January 1, 2020 and imposed many requirements on businesses that process the personal information of California residents.
+Added: Many of the CCPA’s requirements are similar to those found in the General Data Protection Regulation, or GDPR, in Europe, including requiring businesses to provide notice to data subjects regarding the information collected about them and how such information is used and shared, and providing data subjects the right to request access to such personal information and, in certain cases, request the erasure of such personal information.
+Added: The CCPA also affords California residents the right to opt-out of “sales” of their personal information.
+Added: The CCPA contains significant penalties for companies that violate its requirements.
+Added: In November 2020, California voters passed a ballot initiative for the California Privacy Rights Act, or CPRA, which went into effect on January 1, 2023 and significantly expanded the CCPA to incorporate additional GDPR-like provisions including requiring that the use, retention and sharing of personal information of California residents be reasonably necessary and proportionate to the purposes of collection or processing, granting additional protections for sensitive personal information, and requiring greater disclosures related to notice to residents regarding retention of information.
+Added: The CPRA also created a new enforcement agency – the California Privacy Protection Agency – whose sole responsibility is to enforce the CPRA, which will further increase compliance risk.
+Added: The provisions in the CPRA may apply to some of our business activities.
+Added: In addition, other states, including Virginia, Colorado, Utah and Connecticut already have passed state privacy laws.
+Added: Virginia’s privacy law also
+Added: went into effect on January 1, 2023, and the laws in the other three states will go into effect later in the year.
+Added: Other states will be considering these laws in the future, and Congress has also been debating passing a federal privacy law.
+Added: These laws may impact our business activities, including our identification of research subjects, relationships with business partners and ultimately the marketing and distribution of our products.
Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available under such laws, it is possible that some of our current or future business activities, including certain clinical research, sales and marketing practices and the provision of certain items and services to our customers, could be subject to challenge under one or more of such privacy and data security laws.
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In order to market any product outside of the United States, a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of products.
−Removed: Whether or not it obtains FDA approval for a product, an applicant will need to obtain the necessary approvals by the comparable non-U.S.
+Added: Whether or not it obtains FDA approval for a product, a sponsor will need to obtain the necessary approvals by the comparable non-U.S.
regulatory authorities before it can commence clinical trials or marketing of the product in those countries or jurisdictions.
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The submission will be made through the Clinical Trials Information System, a new clinical trials portal overseen by the EMA and available to clinical trial sponsors, competent authorities of the EU Member States and the public.
+Added: The main characteristics of the new Clinical Trials Regulation include:
+Added: a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;
+Added: and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.
+Added: Part I is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned).
+Added: Part II is assessed separately by each Member State concerned.
+Added: Strict deadlines have been established for the assessment of clinical trial applications.
+Added: The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State.
+Added: However, overall related timelines will be defined by the Clinical Trials Regulation.
The new regulation did not change the preexisting requirement that a sponsor must obtain prior approval from the competent national authority of the EU Member State in which the clinical trial is to be conducted.
−Removed: If the clinical trial is conducted in different EU Member States, the competent authorities in each of these EU Member States must provide their approval for the conduct of the clinical trial.
+Added: If the clinical trial
+Added: is conducted in different EU Member States, the competent authorities in each of these EU Member States must provide their approval for the conduct of the clinical trial.
Furthermore, the sponsor may only start a clinical trial at a specific study site after the applicable ethics committee has issued a favorable opinion.
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The centralized procedure is optional for products that represent a significant therapeutic, scientific or technical innovation, or whose authorization would be in the interest of public health.
−Removed: Under the centralized procedure, the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the Committee for Medicinal Products for Human Use, or the CHMP.
+Added: Under the centralized procedure, the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the sponsor in response to questions asked by the Committee for Medicinal Products for Human Use, or the CHMP.
Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation.
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● Decentralized procedure .
−Removed: Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized procedure.
−Removed: The applicant may choose a member state as the reference member State to lead the scientific evaluation of the application.
+Added: Using the decentralized procedure, a sponsor may apply for simultaneous authorization in more than one EU country of medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized procedure.
+Added: The sponsor may choose a member state as the reference member State to lead the scientific evaluation of the application.
● Mutual recognition procedure .
−Removed: In the mutual recognition procedure, a medicine is first authorized in one EU Member State (which acts as the reference member state), in accordance with the national procedures of that
+Added: In the mutual recognition procedure, a medicine is first authorized in one EU Member State (which acts as the reference member state), in accordance with the national procedures of that country.
Following this, further marketing authorizations can be progressively sought from other EU countries in a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization produced by the reference member state.
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In particular circumstances, E.U.
−Removed: legislation (Article 14–a Regulation (EC) No 726/2004 (as amended by Regulation (EU) 2019/5 and Regulation (EC) No 507/2006 on Conditional Marketing Authorizations for Medicinal Products for Human Use) enables applicants to obtain a “conditional marketing authorization” prior to obtaining the comprehensive clinical data required for an application for a full marketing authorization.
+Added: legislation (Article 14–a Regulation (EC) No 726/2004 (as amended by Regulation (EU) 2019/5 and Regulation (EC) No 507/2006 on Conditional Marketing Authorizations for Medicinal Products for Human Use) enables sponsors to obtain a “conditional marketing authorization” prior to obtaining the comprehensive clinical data required for an application for a full marketing authorization.
Such conditional approvals may be granted for product candidates (including medicines designated as orphan medicinal products), if (1) the product candidate is intended for the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening disease;
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(3) a marketing authorization may be granted prior to submission of comprehensive clinical data provided that the benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required;
−Removed: (4) the risk-benefit balance of the product candidate is positive, and (5) it is likely that the applicant will be in a position to provide the required comprehensive clinical trial data.
+Added: (4) the risk-benefit balance of the product candidate is positive, and (5) it is likely that the sponsor will be in a position to provide the required comprehensive clinical trial data.
A conditional marketing authorization may contain specific obligations to be fulfilled by the marketing authorization holder, including obligations with respect to the completion of ongoing or new studies, and with respect to the collection of pharmacovigilance data.
Conditional marketing authorizations are valid for one year, and may be renewed annually, if the risk-benefit balance remains positive, and after an assessment of the need for additional or modified conditions or specific obligations.
−Removed: The timelines for the centralized procedure described above also apply with respect to the review by the CHMP of applications for a conditional marketing authorization.
+Added: The timelines for the centralized procedure described above also apply with respect to the review by the CHMP of applications for a conditional marketing authorization, but sponsors can also request EMA to conduct an accelerated assessment, for instance, in cases of unmet medical needs.
Periods of Authorization and Renewals
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Once subsequently definitively renewed, the marketing authorization shall be valid for an unlimited period.
−Removed: Any authorization which is not followed by the actual placing of the medicinal product on the EU n market (in case of centralized procedure) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).
+Added: Any authorization which is not followed by the actual placing of the medicinal product on the EU n market (in
+Added: case of centralized procedure) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).
Regulatory Requirements after a Marketing Authorization has been Obtained
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● The manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice.
−Removed: These requirements include compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of
−Removed: active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU.
+Added: These requirements include compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU.
● The marketing and promotion of authorized drugs, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the EU notably under Directive 2001/83EC, as amended, and EU Member State laws.
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Regulation (EC) No 726/2004 repeats this entitlement for medicinal products authorized in accordance the centralized authorization procedure.
−Removed: Data exclusivity prevents applicants for authorization of generics of these innovative products from referencing the innovator’s data to assess a generic (abridged) application for a period of eight years.
+Added: Data exclusivity prevents sponsors for authorization of generics of these innovative products from referencing the innovator’s data to assess a generic (abridged) application for a period of eight years.
During an additional two-year period of market exclusivity, a generic marketing authorization application can be submitted and authorized, and the innovator’s data may be referenced, but no generic medicinal product can be placed on the EU market until the expiration of the market exclusivity.
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Pediatric Exclusivity
−Removed: If an applicant obtains a marketing authorization in all EU Member States, or a marketing authorization granted in the centralized procedure by the European Commission, and the study results for the pediatric population are included in the product information, even when negative, the medicine is then eligible for an additional six-month period of qualifying patent protection through extension of the term of the Supplementary Protection Certificate, or SPC, or alternatively a one year extension of the regulatory market exclusivity from ten to eleven years, as selected by the marketing authorization holder.
+Added: If a sponsor obtains a marketing authorization in all EU Member States, or a marketing authorization granted in the centralized procedure by the European Commission, and the study results for the pediatric population are included in the product information, even when negative, the medicine is then eligible for an additional six-month period of qualifying patent protection through extension of the term of the Supplementary Protection Certificate, or SPC, or alternatively a one year extension of the regulatory market exclusivity from ten to eleven years, as selected by the marketing authorization holder.
Orphan Drug Designation and Exclusivity
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847/2000 provides that a drug can be designated as an orphan drug by the European Commission if its sponsor can establish:
−Removed: that the product is intended for the diagnosis, prevention or treatment of (1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the EU when the application is made, or (2) a life-threatening, seriously debilitating or serious and chronic condition in the EU and that without incentives it is unlikely that the marketing of the drug in the EU would generate sufficient return to justify the necessary investment.
−Removed: For either of these conditions, the applicant must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the EU or, if such method exists, the drug will be of significant benefit to those affected by that condition.
+Added: that the product is intended for
+Added: the diagnosis, prevention or treatment of (1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the EU when the application is made, or (2) a life-threatening, seriously debilitating or serious and chronic condition in the EU and that without incentives it is unlikely that the marketing of the drug in the EU would generate sufficient return to justify the necessary investment.
+Added: For either of these conditions, the sponsor must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the EU or, if such method exists, the drug will be of significant benefit to those affected by that condition.
Once authorized, orphan medicinal products are entitled to 10 years of market exclusivity in all EU Member States and in addition a range of other benefits during the development and regulatory review process including scientific assistance for study protocols, authorization through the centralized marketing authorization procedure covering all member countries and a reduction or elimination of registration and marketing authorization fees.
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Marketing authorization may also be granted to a similar medicinal product with the same orphan indication if this product is safer, more effective or otherwise clinically superior to the original orphan medicinal product.
−Removed: The period of market exclusivity may,
−Removed: in addition, be reduced to six years if it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity.
+Added: The period of market exclusivity may, in addition, be reduced to six years if it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity.
Patent Term Extensions
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The GDPR also imposes strict rules on the transfer of personal data to countries outside the EEA, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.
−Removed: The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.
+Added: The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek
+Added: judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.
Compliance with the GDPR is a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.
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and includes parallel obligations to those set forth by GDPR.
+Added: Additionally, in October 2022, President Biden signed an executive order to implement the EU-U.S.
+Added: Data Privacy Framework, which would serve as a replacement to the EU-US Privacy Shield.
+Added: The European Commission initiated the process to adopt an adequacy decision for the EU-US Data Privacy Framework in December 2022.
+Added: It is unclear if and when the framework will be finalized and whether it will be challenged in court.
Human Capital
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We believe that our philosophy of providing competitive compensation, along with opportunities for career growth and development, encourages a high level of corporate employee tenure and low level of voluntary turnover.
−Removed: A large majority of our non-field based employees have obtained advanced degrees in their professions.
+Added: A large majority of our employees have obtained advanced degrees in their professions.
Our employees are supported with training and development opportunities to pursue their careers and to ensure compliance with our policies.
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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.