−Removed: We are a clinical-stage biopharmaceutical company focused on discovering, acquiring, developing and commercializing therapeutics in the disease areas of immunology, inflammation and oncology.
−Removed: Our goal is to be an industry
−Removed: leader in each of these therapeutic areas and to enhance and extend the lives of patients suffering from such diseases.
−Removed: To accomplish this goal, we have assembled a deeply experienced and highly skilled group of industry veterans, scientists, clinicians and key opinion leaders from leading biotechnology and pharmaceutical companies, as well as leading academic centers from around the world.
−Removed: Our collective immunology and translational discovery and development expertise serves as the foundation of our company.
+Added: We are a clinical-stage biopharmaceutical company focused on the development and commercialization of seralutinib for the treatment of pulmonary arterial hypertension, or PAH.
+Added: Our goal is to be an industry leader in, and to enhance the lives of patients living with, pulmonary hypertension, or PH.
+Added: To accomplish this goal, we have assembled a deeply
+Added: experienced and highly skilled group of industry veterans, scientists, clinicians and key opinion leaders from leading biotechnology and pharmaceutical companies, as well as leading academic centers from around the world.
We intend to maintain a scientifically rigorous and inclusive corporate culture where employees strive to bring improved therapeutic options to patients.
−Removed: We are pursuing product candidates with strong scientific rationale to address indications where there is both a high unmet need and an opportunity to develop best-in-class or first-in-class therapeutics.
−Removed: We currently have two clinical-stage product candidates, in addition to one late-stage preclinical product candidate.
−Removed: The following table summarizes our current programs:
−Removed: Seralutinib (PDGFR, CSF1R and c-KIT Inhibitor)
−Removed: Seralutinib, also known as GB002, is an inhaled, small molecule, platelet-derived growth factor receptor, or PDGFR, colony-stimulating factor 1 receptor, or CSF1R, and c-KIT inhibitor in development for the treatment of pulmonary arterial hypertension, or PAH.
−Removed: In contrast to the three classes of marketed vasodilatory therapies for PAH, we believe that seralutinib has the potential to reverse pathological remodeling by addressing mechanisms that underlie PAH.
−Removed: Inhaled seralutinib, which is designed to act on both isoforms of the PDGFR, α and β, as well as the CSF1R and c-KIT pathways, inhibited and reversed cellular overgrowth in lung blood vessels in multiple animal PAH models.
−Removed: In December 2022, we announced positive topline results from the 24-week Phase 2 TORREY trial in 86 PAH patients.
−Removed: In this well-treated patient population, the seralutinib arm demonstrated a statistically significant improvement of 14.3% against the placebo arm in its primary efficacy endpoint, pulmonary vascular resistance, or PVR.
−Removed: Seralutinib has been generally well tolerated in all completed clinical trials.
−Removed: Upon completion of the 24-week blinded portion of the Phase 2 TORREY Study, patients were able to enroll into an open-label extension trial.
−Removed: We anticipate reporting results from this ongoing open-label extension trial in the middle of 2023.
−Removed: We expect to commence a registrational Phase 3 clinical trial in PAH in the second half of 2023.
−Removed: We in-licensed seralutinib from Pulmokine, Inc.
−Removed: in 2017 and retain worldwide rights.
−Removed: The United States Food and Drug Administration, or FDA, and the European Commission, or EC, have granted seralutinib orphan drug designation for the treatment of patients with PAH.
−Removed: GB5121 (CNS-Penetrant BTK Inhibitor)
−Removed: GB5121 is an oral, irreversible, covalent, small molecule inhibitor of Bruton’s Tyrosine Kinase, or BTK, in clinical development for the treatment of primary central nervous system lymphoma, or PCNSL.
−Removed: GB5121 was selected based on its central nervous system, or CNS, penetration and kinase selectivity.
−Removed: BTK is expressed in several immune cells including B cells and myeloid cells, where it mediates signaling downstream of multiple receptors.
−Removed: Inhibition of BTK results in the immediate blockade and down-regulation of several cellular activities that drive autoimmunity and inflammation.
−Removed: signaling is also present in many B cell malignancies.
−Removed: BTK inhibitors are approved in the United States to treat oncology indications.
−Removed: In preclinical mouse models, GB5121 has demonstrated superior CNS penetration at studied doses when compared to selected BTK inhibitors.
−Removed: We believe the CNS penetration observed in these preclinical studies supports the development of GB5121 as a potential therapy for the treatment of hematologic malignancies in the CNS, including PCNSL.
−Removed: GB5121 is currently being evaluated in the Phase 1b/2 STAR CNS Study in relapsed / refractory PCNSL and other rare CNS malignancies.
−Removed: Based upon the benefit / risk profile observed to date and a prioritization of resources to support the seralutinib program, we have decided to pause enrollment in the Phase 1b/2 STAR CNS study.
−Removed: We plan to discuss available data with the study’s Data Review Committee to determine next steps.
−Removed: We expect to report data from this ongoing, open-label clinical trial at relevant medical conferences.
−Removed: GB5121 was internally developed and is wholly owned.
−Removed: GB7208 (CNS-Penetrant BTK Inhibitor)
−Removed: GB7208 is an oral, small molecule, BTK inhibitor in preclinical development for the treatment of multiple sclerosis, or MS.
−Removed: Like GB5121, GB7208 was selected based on its CNS penetration and kinase selectivity.
−Removed: Immune cells are believed to play an important role in the pathology of MS, and BTK inhibitors are in late-stage clinical development for the treatment of autoimmune indications, such as MS.
−Removed: In preclinical mouse models, GB7208 has demonstrated superior CNS penetration at studied doses, when compared to selected BTK inhibitors in development for autoimmune indications, including MS.
−Removed: GB7208 is currently undergoing preclinical testing.
−Removed: GB7208 was internally developed and is wholly owned.
−Removed: Our Research Capabilities and Preclinical Programs
−Removed: Including GB7208, we have multiple programs in preclinical development, with a focus on the therapeutic areas of immunology, inflammation and oncology, and we are currently evaluating the continued development of our multiple programs in preclinical development.
Our founders and management team have held senior positions at leading biopharmaceutical companies and possess substantial experience and expertise across the spectrum of drug discovery, development and commercialization.
6 unchanged sentences
Previously, Mr.
−Removed: Hasnain was the President and Chief Executive Officer and a director of Facet Biotech Corporation, a biology-driven antibody company with a focus in MS and oncology.
+Added: Hasnain was the President and Chief Executive Officer and a director of Facet Biotech Corporation, a biology-driven antibody company with a focus in multiple sclerosis and oncology.
He held that position from December 2008 until the company's acquisition by Abbott Laboratories in April 2010.
1 unchanged sentence
Richard Aranda, M.D., our Chief Medical Officer, is an experienced clinician and drug developer with previous experience at Bristol Myers Squibb Company, Novo-Nordisk, Inc., Receptos and Celegene Corporation.
−Removed: Laura Carter, Ph.D., our Chief Scientific Officer, has over 20 years of industry experience spanning target identification and validation activities through Phase 2 clinical trials in multiple therapeutic areas having previously held positions at Lycera Corporation, Medimmune, Array Biopharma and Wyeth.
−Removed: Christian Waage, our Executive Vice President, Technical Operations & Administration, has meaningful management biotechnology experience, having previously held various positions at Receptos, most recently as Managing Director after its acquisition by Celgene, and served at Ardea Biosciences, Inc.
+Added: Bob Smith, our Chief Commercial Officer, has over 30 years of experience in pharmaceuticals, with a strong focus on PAH and rare disease.
+Added: Prior to Gossamer, Mr.
+Added: Smith was the National Sales Lead in charge of preparing for the potential launch of sotatercept for the treatment of PAH in the US at Merck & Co., or Merck.
+Added: Previously until 2018, Mr.
+Added: Smith was the Senior Vice President of Sales and an Executive Leadership Team member at Actelion Pharmaceuticals US, Inc., where he spearheaded two successful PAH drug launches, Opsumit (macitentan) and Uptravi (selexipag).
+Added: Christian Waage, our Executive Vice President, Technical Operations & Administration, has meaningful management biotechnology experience, having previously held various positions at Receptos, most recently as Managing Director after its acquisition by Celgene, and at Ardea Biosciences, Inc.
as Vice President, General Counsel.
Caryn Peterson, our Executive Vice President, Regulatory Affairs, has considerable experience and regulatory expertise as a Managing Director of Development & Strategic Consulting Associates, as well as management positions leading regulatory affairs at Syndax Pharmaceuticals and FeRx Incorporated.
−Removed: We are a clinical-stage biopharmaceutical company focused on discovering, acquiring, developing and commercializing therapeutics in the disease areas of immunology, inflammation and oncology.
−Removed: Our goal is to be an industry leader in these therapeutic areas and to enhance and extend the lives of patients suffering from such diseases.
+Added: We are a clinical-stage biopharmaceutical company focused on the development and commercialization of seralutinib for the treatment of PAH.
+Added: Our goal is to be an industry leader in, and to enhance the lives of patients living with, PH.
Critical components of our business strategy include:
• Leverage the clinical development and commercialization expertise of our world-class team.
−Removed: Our executive management team and key scientific leaders have successfully discovered, developed and commercialized small molecule and biologic agents at both large and small biopharmaceutical companies.
−Removed: We plan to utilize this deep, broad set of expertise and experiences as we execute on our in-house discovery and development strategies, including our planned registrational Phase 3 clinical trial of seralutinib in PAH.
−Removed: • Increase the impact of our product candidates by expanding development across multiple indications.
−Removed: We aim to focus our development efforts on product candidates that have the potential to treat multiple diseases and plan to develop them in additional indications where warranted.
−Removed: For example, we plan to develop seralutinib in both WHO Group 1 and WHO Group 3 pulmonary hypertension.
−Removed: We also continue to evaluate potential neurological conditions for our CNS-penetrant BTK inhibitors, GB5121 and GB7208.
+Added: Our executive management team and key scientific leaders have successfully discovered, developed and commercialized pharmaceuticals at both large and small biopharmaceutical companies.
+Added: Additionally, we have built experienced PH development and commercialization teams, with key team members selected from the leadership of such companies as Actelion, Johnson & Johnson, Merck and United Therapeutics.
+Added: • Increase the impact of seralutinib by expanding development into PH indications of high unmet need, beyond PAH.
+Added: We believe that not only does seralutinib offer potential as a therapeutic option for the treatment of PAH but also for the treatment of other rare PH indications of high unmet need, including pulmonary hypertension associated with interstitial lung disease, or PH-ILD.
+Added: We are actively pursuing clinical development plans for seralutinib in PH-ILD.
+Added: • Build our operational capabilities to successfully commercialize seralutinib for PH, if approved.
+Added: If we obtain regulatory approvals for seralutinib, we intend to build in-house sales and marketing capabilities to commercialize seralutinib in the United States and/or geographies for which we maintain seralutinib commercialization rights.
+Added: Both PAH and PH-ILD patients are often treated by cardiologists and pulmonologists at national or regional centers of excellence.
+Added: concentrations of patients could allow us to commercialize seralutinib with a relatively small commercial footprint, if approved.
• Engage in partnerships, collaborations, licensing deals or other transactions.
−Removed: Gossamer may seek to enter transactions to gain access to additional financial, clinical or commercial resources to support the development and commercialization of its product candidates.
−Removed: Our Product Candidates
+Added: Gossamer may seek to enter into strategic or financial transactions to gain access to additional financial, clinical or commercial resources to support the development and commercialization of seralutinib for PH.
Seralutinib (PDGFR, CSF1R and c-KIT Inhibitor)
−Removed: Seralutinib, also known as GB002, is an inhaled, small molecule, PDGFR, CSF1R, and c-KIT inhibitor in development for the treatment of PAH.
+Added: Seralutinib, also known as GB002, is an investigational inhaled, small molecule, platelet-derived growth factor receptor, or PDGFR, colony-stimulating factor 1 receptor, or CSF1R, and c-KIT inhibitor, currently being evaluated in a Phase 3 clinical trial for the treatment of PAH.
In contrast to the three classes of marketed vasodilatory therapies for PAH, we believe that seralutinib has the potential to reverse pathological remodeling by addressing mechanisms that underlie PAH.
1 unchanged sentence
In December 2022, we announced positive topline results from the 24-week Phase 2 TORREY trial in 86 PAH patients.
−Removed: In this well-treated patient population, the seralutinib arm demonstrated a statistically significant improvement against the placebo arm in its primary efficacy endpoint, pulmonary vascular resistance, or PVR.
−Removed: Improvements in PVR favored the seralutinib arm across all pre-specified patient sub-groups.
+Added: In this well-treated patient population, the seralutinib arm demonstrated a statistically significant, placebo-adjusted improvement of 14.3% in its primary efficacy endpoint, pulmonary vascular resistance, or PVR.
Seralutinib has been generally well tolerated in all completed clinical trials.
−Removed: Upon completion of the 24-week blinded portion of the Phase 2 TORREY Study, patients were able to enroll into an open-label extension trial.
−Removed: We anticipate reporting results from this ongoing open-label extension trial in the middle of 2023.
−Removed: We expect to commence a registrational Phase 3 clinical trial in PAH in the second half of 2023.
+Added: We dosed the first patient in our registrational Phase 3 PROSERA Study in PAH in the fourth quarter of 2023.
+Added: We expect to report topline data from the PROSERA study in the fourth quarter of 2025.
+Added: In addition to PAH, we believe that seralutinib holds potential as a therapeutic option for the treatment of PH-ILD.
+Added: We are actively pursuing clinical development plans for seralutinib in PH-ILD.
We in-licensed seralutinib from Pulmokine, Inc.
in 2017 and retain worldwide rights.
−Removed: The FDA and the EC have granted seralutinib orphan drug designation for the treatment of patients with PAH.
−Removed: Mechanism of Action
+Added: The United States Food and Drug Administration, or FDA, and the European Medicines Agency, or EMA, have granted seralutinib orphan drug designation for the treatment of patients with PAH.
+Added: The following table summarizes the current development plan for seralutinib in PH:
+Added: Mechanism of Action in PAH
PAH is driven by abnormal cellular proliferation within and around the small blood vessels of the lung that carry blood from the right side of the heart to the lungs.
8 unchanged sentences
Upregulated PDGFR signaling results in endothelial cell and fibroblast dysfunction and the proliferation and migration of smooth muscle cells.
−Removed: This effect results in the overgrowth and occlusion of blood vessels in the lung.
+Added: This effect results in the overgrowth and occlusion of
+Added: blood vessels in the lung.
Kinase inhibitors with activity against the PDGFR pathway have shown the ability to reverse PAH in animal models.
3 unchanged sentences
Inhibiting PDGFRα may help reduce the abnormal cell proliferation of PAVSMCs that results in blood vessel thickening.
−Removed: PDGFRβ is more highly
−Removed: expressed in fibroblasts and myofibroblasts that are involved with the abnormal cell proliferation within the blood vessel that leads to the obstruction of the pulmonary arterioles.
+Added: PDGFRβ is more highly expressed in fibroblasts and myofibroblasts that are involved with the abnormal cell proliferation within the blood vessel that leads to the obstruction of the pulmonary arterioles.
We believe inhibiting PDGFRβ is therefore important in decreasing the abnormal cell proliferation of these cell types.
14 unchanged sentences
Imatinib has known activity against multiple tyrosine kinases, including the PDGFR, c-KIT receptors and Abelson murine leukemia viral oncogene homolog 1, or c-ABL.
−Removed: 202 patients were enrolled in the IMPRES trial, of which 41% were being treated with prostanoids, oral phosphodiesterase type 5, or PDE5, inhibitors and oral endothelin receptor agonists, or ERAs.
−Removed: The trial met its primary endpoint, improvement in 6-minute walk distance, or 6MWD, versus placebo at week 24 from baseline, with statistical significance (p = 0.002).
−Removed: The p-value is the probability that the difference between two data sets was due to chance.
−Removed: The smaller the p-value, the more likely the differences are not due to chance alone.
−Removed: In general, if the p-value is less than or equal to 0.05, the outcome is considered statistically significant.
−Removed: Patients on imatinib also demonstrated statistically significant improvements in measures of hemodynamics, including pulmonary vascular resistance, or PVR, a standard measurement in the evaluation of patients with PAH.
+Added: The trial met its primary endpoint, improvement in 6-minute walk distance, or 6MWD, versus placebo at week 24.
However, systemic adverse events such as bleeding and poor tolerability and frequent drug discontinuation led to a high drop-out rate within the active arm of the trial.
6 unchanged sentences
The progressive nature of this disease causes the right side of the heart to work much harder and eventually weaken or fail.
−Removed: Patients are often evaluated by functional class, which categorizes patients by their ability to carry out physical activity and symptom severity.
+Added: Patients are often evaluated by functional class, which categorizes patients by their ability to carry out physical activity and their symptom severity.
Worsening symptoms, and thus higher numbered functional classes, are associated with higher mortality.
14 unchanged sentences
Discomfort is increased by any physical activity.
−Removed: Additionally, recent medical society guidelines have identified intermediate and high-risk categories of PAH based on several variables including signs of right heart failure, rate of symptom progression, functional class, 6MWD, maximum oxygen consumption, NT-proBNP, which is a biomarker for heart failure and measures of right heart function.
+Added: Additionally, recent medical society guidelines have identified intermediate and high-risk categories of PAH based on several variables including signs of right heart failure, rate of symptom progression, functional class, 6MWD, maximum oxygen consumption and NT-proBNP, which is a biomarker for heart failure and measures of right heart function.
One of these risk categorization tools, the REVEAL 2.0 Risk Score, was utilized in the completed Phase 2 TORREY Study.
4 unchanged sentences
The true incidence and prevalence of PAH are unknown.
−Removed: The American Lung Association estimates that between 500 and 1,000 new cases are diagnosed each year in the US.
−Removed: PAH has an estimated prevalence of 70,000 patients in the US and Europe.
+Added: The estimated PAH patient population in the US is over 50,000 patients, and the estimated patient population in the EU is over 70,000 patients.
The number of diagnosed PAH patients continues to increase, and we believe this increase is likely due to enhanced awareness and diagnosis of the disease.
9 unchanged sentences
We believe an agent with the ability to safely reverse pathological remodeling could provide utility across functional classes and risk categories.
−Removed: New investigational therapies, such as sotatercept (Merck & Co., Inc.), may impact the PAH treatment paradigm, if approved.
+Added: New investigational therapies, such as sotatercept (Merck), may impact the PAH treatment paradigm, if approved.
Sotatercept, a subcutaneously administered activin receptor type IIA-Fc fusion protein, is an investigational drug candidate that has been evaluated in a completed Phase 3 PAH clinical trial.
−Removed: Seralutinib Product Differentiation
+Added: Marketing authorization for sotatercept for the treatment of PAH has been filed in both the US and the EU.
+Added: Seralutinib Product Differentiation in PAH
Seralutinib is an inhaled kinase inhibitor designed to build on the evidence of efficacy seen in trials of imatinib while overcoming imatinib’s observed systemic safety and tolerability issues and improving on imatinib's kinase inhibitory profile.
Seralutinib is designed to have a differentiated selectivity profile as compared to imatinib with increased potency against the PDGFRα isoform, ten-fold higher potency against the PDGFRβ isoform and c-KIT, and no activity against c-ABL or the tyrosine kinase, LCK.
−Removed: Additionally, seralutinib is multiple orders more potent against CSF1R, as compared to imatinib.
−Removed: We believe seralutinib has the potential to be a PAH therapeutic that may provide a:
+Added: Additionally, seralutinib is multiple orders of magnitude more potent against CSF1R, as compared to imatinib.
+Added: We believe seralutinib has the potential to be a therapeutic option for PAH that may provide a:
• differentiated, anti-proliferative mechanism that addresses the underlying mechanisms of PAH;
• more tolerable safety profile than systemic imatinib;
−Removed: • convenient, simple and portable inhalation methodology and delivery system.
−Removed: Clinical Development History of Seralutinib
−Removed: Summary of Preclinical Program
+Added: • convenient, simple and portable inhalation delivery system.
+Added: Summary of Preclinical Program in PAH
Seralutinib inhibits both PGDFR α and β, and it inhibited and reversed cell overgrowth in lung blood vessels in a PAH rat model, which replicates many features of human PAH, including the abnormal cell proliferation that can block the small vessels of the lung.
1 unchanged sentence
Additionally, seralutinib demonstrated a statistically significant reduction in right ventricular systolic pressure as compared to placebo.
−Removed: In a separate rat model of PAH, the SU5416 hypoxia model, seralutinib demonstrated a statistically significant reduction in circulating plasma NT-proBNP compared to placebo, while the difference between imatinib and placebo was not significant for this PAH biomarker.
+Added: In a separate rat model of PAH, the SU5416 hypoxia model, seralutinib demonstrated a statistically significant reduction in circulating plasma NT-proBNP as compared to placebo, while the difference between imatinib and placebo was not significant for this PAH biomarker.
Seralutinib also restored rat lung BMPR2 expression to healthy levels, which was a statistically significant improvement as compared to placebo and imatinib.
Irregularities in BMPR2 expression have been linked to PAH.
−Removed: In a separate rat model of PAH, the SU5416 hypoxia model, seralutinib demonstrated a statistically significant reduction in circulating plasma NT-proBNP compared to placebo, while the difference between imatinib and placebo was not significant for this PAH biomarker.
+Added: In a separate rat model of PAH, the SU5416 hypoxia model, seralutinib demonstrated a statistically significant reduction in circulating plasma NT-proBNP as compared to placebo, while the difference between imatinib and placebo was not significant for this PAH biomarker.
Seralutinib also restored rat lung BMPR2 expression to healthy levels, which was a statistically significant improvement as compared to placebo and imatinib.
Irregularities in BMPR2 expression have been linked to PAH.
+Added: Clinical Development History of Seralutinib
Summary of Completed Phase 1a Studies
27 unchanged sentences
Seralutinib demonstrated a statistically significant improvement on the primary endpoint, change from baseline in PVR over a 24-week treatment period.
−Removed: A mean improvement in PVR between the placebo and seralutinib arms of
−Removed: 96.1 dynes (p = 0.0310), equating to a placebo-corrected improvement of 14.3%, was observed in the study.
+Added: A mean improvement in PVR between the placebo and seralutinib arms of 96.1 dynes × seconds/cm 5 (p = 0.0310), equating to a placebo-adjusted improvement of 14.3%, was observed in the study.
+Added: The p-value is the probability that the difference between two data sets was due to chance.
+Added: The smaller the p-value, the more likely the differences are not due to chance alone.
+Added: In general, if the p-value is less than or equal to 0.05, the outcome is considered statistically significant.
Improvements in PVR favored the seralutinib arm across all pre-specified patient sub-groups.
4 unchanged sentences
Enhanced effects for both PVR and 6MWD were observed in patients with more severe baseline disease, as defined by WHO Functional Class, or FC, and REVEAL 2.0 Risk Scores.
−Removed: In FC III patients, a 21% reduction in PVR (p = 0.0427) and 37-meter improvement in 6MWD (p = 0.0476) were observed for the seralutinib arm vs.
−Removed: In patients with a baseline REVEAL 2.0 Risk Score of 6 or greater, a 23% reduction in PVR (p = 0.0134) and 22-meter improvement in 6MWD (p = 0.2482) were observed for the seralutinib arm vs.
−Removed: Seralutinib treatment resulted in a statistically significant reduction in NT-proBNP, a biomarker of right heart stress, as early as 12 weeks, increasing to a 408.3 ng/L mean difference from placebo at Week 24 (p = 0.0012).
+Added: In FC III patients, a 21% placebo-adjusted reduction in PVR (p = 0.0427) and 37-meter placebo-adjusted improvement in 6MWD (p = 0.0476) were observed for the seralutinib arm.
+Added: In patients with a baseline REVEAL 2.0 Risk Score of 6 or greater, seralutinib demonstrated a 23% placebo-adjusted reduction in PVR (p = 0.0134) and a placebo-adjusted 22-meter improvement in 6MWD (p = 0.2482).
+Added: Seralutinib treatment resulted in a statistically significant reduction in NT-proBNP, a biomarker of right heart stress, as early as 12 weeks, increasing to a placebo-adjusted 408.3 ng/L mean difference at Week 24 (p = 0.0012).
This biomarker change was accompanied by clinically relevant and statistically significant changes for seralutinib vs.
7 unchanged sentences
No cases of subdural hematoma were reported in the study.
−Removed: Upon completion of the 24-week blinded portion of the Phase 2 TORREY Study, patients were able to enroll into an open-label extension trial.
−Removed: We anticipate reporting results from this ongoing open-label extension trial in the middle of 2023.
−Removed: Summary of Planned Phase 3 PAH Clinical Trial
−Removed: We expect to commence a Phase 3 PAH clinical trial in the second half of 2023.
−Removed: The planned Phase 3 clinical trial will be a randomized, double-blind, placebo-controlled, global clinical trial in PAH patients.
−Removed: Patients will be randomized to receive either seralutinib or placebo, in addition to their background PAH therapies.
−Removed: We are engaging with global regulatory authorities in the first half of 2023 and expect that these interactions will inform the final design of the Phase 3 clinical trial.
−Removed: Based on FDA feedback, we expect to test a single dose of 90 mg twice daily, and we expect the primary endpoint of the trial to be change in 6MWD from baseline;
−Removed: provided, however, the final trial design is subject to further feedback from global regulatory authorities.
−Removed: In addition to secondary and exploratory endpoints, safety and tolerability will also be evaluated in the Phase 3 clinical trial.
−Removed: Clinical Development Plan in Additional Indications
−Removed: We believe that seralutinib has potential for use as a therapeutic treatment for pulmonary hypertension associated with interstitial lung disease, or PH-ILD.
−Removed: A subgroup of WHO Group 3 Pulmonary Hypertension, PH-ILD is a collection of progressive and often fatal forms of pulmonary hypertension that affect the small airways of the lungs.
+Added: Summary of Ongoing TORREY Open-Label Extension Clinical Trial in PAH
+Added: Upon completion of the 24-week blinded portion of the Phase 2 TORREY Study, 73 of the 80 (91%) completing patients elected to rollover into an ongoing open-label extension trial.
+Added: In December 2023, we reported out interim results, including PVR results at Week 72.
+Added: The 27 seralutinib-continued patients who reported Week 72 PVR data showed a median PVR improvement from TORREY baseline of 146 dynes × seconds/cm 5 at Week 72, as compared to a median improvement of 89 dynes × seconds/cm 5 at Week 24.
+Added: 18 of the 25 (72%) placebo-crossover patients who reached Week 72 (48 weeks on seralutinib) showed improvement in PVR at Week 72 as compared to TORREY baseline.
+Added: Additionally, further improvements in 6MWD, as compared to TORREY baseline, were observed, with greater improvements seen in patients with an elevated risk score.
+Added: Consistent with completed clinical trials, seralutinib has been generally well tolerated in the ongoing label extension study.
+Added: Summary of Ongoing PROSERA Phase 3 PAH Clinical Trial
+Added: In the fourth quarter of 2023, we commenced the registrational Phase 3 PROSERA Study, a randomized, double-blind, placebo-controlled, global clinical trial in PAH patients, after receiving input from global regulatory authorities, including the FDA and EMA.
+Added: We are enrolling approximately 350 Functional Class II and III PAH patients on stable background therapy.
+Added: Patients will be randomized in a 1:1 fashion to 90 mg twice daily seralutinib and placebo, and patients will receive blinded therapy for up to 48 weeks.
+Added: Patients will remain on their background PAH therapies throughout the trial.
+Added: The primary endpoint of the PROSERA trial is change from baseline in 6MWD at Week 24.
+Added: A key secondary endpoint is time to first clinical worsening while on blinded therapy, up to 48 weeks.
+Added: In addition to secondary and exploratory endpoints, safety and tolerability will also be evaluated in the Phase 3 PROSERA Study.
+Added: We expect to report topline data from the PROSERA in the fourth quarter of 2025.
+Added: Plans for Future Development in PH-ILD
+Added: We believe that seralutinib has potential for development as a therapeutic treatment for PH-ILD.
+Added: A subgroup of WHO Group 3 Pulmonary Hypertension, PH-ILD is a collection of progressive and often fatal forms of pulmonary
+Added: hypertension that affect the small airways of the lungs.
+Added: PH-ILD includes PH related to idiopathic pulmonary fibrosis and PH related connective tissue disease-associated interstitial lung disease.
These diseases are characterized by pulmonary vascular pathology associated with pulmonary hypertension, in addition to thickening and scarring of the lung interstitium from interstitial lung disease.
−Removed: There is only one FDA-approved treatment for PH-ILD, and there are no approved therapies in the EU.
We believe that seralutinib has the potential to improve the quality of life for PH-ILD patients.
−Removed: We expect to commence clinical development in PH-ILD in the second half of 2023 or the first half of 2024.
−Removed: GB5121 (CNS-Penetrant BTK Inhibitor)
−Removed: GB5121 is an oral, irreversible, covalent, small molecule inhibitor of BTK, in clinical development for the treatment of PCNSL.
−Removed: GB5121 was selected based on its CNS penetration and kinase selectivity.
−Removed: BTK is expressed in several immune cells including B cells and myeloid cells, where it mediates signaling downstream of multiple receptors.
−Removed: Inhibition of BTK results in the immediate blockade and down-regulation of several cellular activities that drive autoimmunity and inflammation.
−Removed: Active BTK signaling is also present in many B cell malignancies.
−Removed: BTK inhibitors are approved in the United States to treat oncology indications.
−Removed: In preclinical mouse models, GB5121 has demonstrated superior CNS penetration at studied doses when compared to selected BTK inhibitors.
−Removed: We believe the CNS penetration observed in these preclinical studies
−Removed: supports the development of GB5121 as a potential therapy for the treatment of hematologic malignancies in the CNS, including PCNSL.
−Removed: GB5121 is currently being evaluated in the Phase 1b/2 STAR CNS Study in relapsed / refractory PCNSL and other rare CNS malignancies.
−Removed: Based upon the benefit / risk profile observed to date and a prioritization of resources to support the seralutinib program, we have decided to pause enrollment in the Phase 1b/2 STAR CNS study.
−Removed: We plan to discuss available data with the study’s Data Review Committee to determine next steps.
−Removed: We expect to report data from this ongoing, open-label clinical trial at relevant medical conferences.
−Removed: GB5121 was internally developed and is wholly owned.
−Removed: Mechanism of Action
−Removed: BTK plays a critical and multifaceted role within the immune system.
−Removed: BTK is a non-receptor protein-tyrosine kinase that belongs to the TEC family of kinases.
−Removed: It is present in hematopoietic cells such as B cells, macrophages, neutrophils and mast cells.
−Removed: BTK is a critical mediator of B cell receptor, or BCR, signaling and the adaptive immune response.
−Removed: Upon stimulation of BCR, the BTK pathway results in an increased level of intracellular calcium and activation of transcription factors involved in B cell proliferation, differentiation and survival.
−Removed: The pathway is also key for the proliferation, migration and survival of malignant B cells, and inhibition of this pathway has been effective in treating several hematological malignancies.
−Removed: BTK inhibitors are approved by the FDA for the treatment of multiple B cell lymphomas.
−Removed: While BTK inhibitors provide a valuable treatment option for patients with hematologic malignancies, existing treatments may be suboptimal for the treatment of CNS disease.
−Removed: The blood brain barrier, or BBB, is comprised of endothelial cells that serve as a highly discriminatory boundary, separating the systemic circulation and the extracellular fluid of the CNS.
−Removed: The BBB effectively protects the brain from circulating pathogens, but it also restricts the ability of pharmaceutical agents from crossing from the systemic circulation into the CNS, including most BTK inhibitors.
−Removed: GB5121 demonstrated superior CNS penetration at studied doses in preclinical mouse models, when compared to other BTK inhibitors targeting oncological conditions.
−Removed: Treatment with BTK inhibitors is associated with on-target and off-target AEs, such as rash, diarrhea, infection, bleeding, cytopenias and cardiovascular AEs, including atrial fibrillation.
−Removed: Liver enzyme elevations have also been observed in patients receiving BTK inhibitors.
−Removed: Molecules with modest selectivity may incur increased off-target AEs through unintended interaction with off-target kinases.
−Removed: Later generation BTK inhibitors have focused on minimizing off-target toxicities with increased selectivity, but limited CNS penetration makes these molecules potentially suboptimal for the treatment of CNS disease.
−Removed: In pre-clinical assays, GB5121 has been observed to be highly selective for BTK, and we believe that higher selectivity has the potential to limit the adverse events associated with modestly selective BTK inhibitors.
−Removed: Overview of Primary CNS Lymphoma
−Removed: PCNSL is a rare, aggressive form of non-Hodgkin lymphoma that originates from the brain, eyes and cerebrospinal fluid without evidence of systemic involvement.
−Removed: Standard lymphoma therapies are inadequate due to poor penetration of the BBB.
−Removed: First-line PCNSL treatment typically includes polychemotherapy on backbone high-dose methotrexate, followed by consolidative whole brain radiotherapy.
−Removed: Despite this treatment option, durable remission is achieved in only 50% of patients.
−Removed: Treatment is associated with significant neurotoxicity, and for those patients who cannot tolerate methotrexate or for those whose cancer progresses, there is no FDA approved treatment.
−Removed: In human trials, ibrutinib, a non-selective BTK inhibitor with limited ability to cross the BBB, has demonstrated efficacy at high doses in recurrent or refractory PCSNL patients.
−Removed: We believe the high dose necessary to reach therapeutic levels in the CNS, as well as an affinity for other kinases, including EGFR, JAK3 and HER2, are likely responsible for some of the toxicities associated with ibrutinib therapy.
−Removed: We believe that the high specificity for BTK and high CNS penetration observed in preclinical models could potentially allow GB5121 to achieve the clinical efficacy seen with ibrutinib at lower systemic doses, which could improve tolerability.
−Removed: We selected GB5121 to move forward into human clinical trials based on the potency, specificity and high brain penetration observed in preclinical models.
−Removed: Clinical Development History of GB5121
−Removed: Summary of Ongoing Phase 1 Clinical Study
−Removed: In the fourth quarter of 2021, we commenced a dose-escalating Phase 1 study in healthy human volunteers to evaluate the safety, tolerability, PK and PD of GB5121 in humans.
−Removed: The study includes both SAD and MAD portions as well as clinical pharmacology assessments.
−Removed: Summary of Ongoing STAR CNS Phase 1b/2 Clinical Trial in PCNSL
−Removed: In the second quarter of 2022, we commenced the Phase 1b portion of a global Phase 1b/2 clinical trial.
−Removed: The Phase 1b portion of the trial enrolled patients with recurrent or refractory primary or secondary CNS lymphoma or with recurrent or refractory primary vitreoretinal lymphoma.
−Removed: The primary endpoint of the Phase 1b is safety and tolerability, and the secondary endpoints include overall response rate, or ORR, and duration of response.
−Removed: Phase 2 dose selection will be informed by the results from the Phase 1b.
−Removed: Based upon the benefit / risk profile observed to date and a prioritization of resources to support the seralutinib program, we have decided to pause enrollment in the Phase 1b/2 STAR CNS study.
−Removed: We plan to discuss available data with the study’s Data Review Committee to determine next steps.
−Removed: GB7208 (CNS-Penetrant BTK Inhibitor)
−Removed: GB7208 is an oral, small molecule, BTK inhibitor in preclinical development for the treatment of MS.
−Removed: Like GB5121, GB7208 was selected based on its CNS penetration and kinase selectivity.
−Removed: Immune cells are believed to play an important role in the pathology of MS, and BTK inhibitors are in late-stage clinical development for the treatment of autoimmune indications, such as MS.
−Removed: In preclinical mouse models, GB7208 has demonstrated superior CNS penetration at studied doses, when compared to selected BTK inhibitors in development for autoimmune indications, including MS.
−Removed: GB7208 is currently undergoing preclinical testing.
−Removed: GB7208 was internally developed and is wholly owned.
−Removed: Our Research Capabilities and Preclinical Programs
−Removed: Including GB7208, we have multiple programs in preclinical development, with a focus on the therapeutic areas of immunology, inflammation and oncology, and we are currently evaluating the continued development of these programs.
+Added: There is only one FDA-approved treatment for PH-ILD, and there are no approved therapies in the EU.
+Added: We are actively pursuing clinical development plans for seralutinib in PH-ILD.
The biotechnology and pharmaceutical industries are characterized by rapid technological advancement, significant competition and an emphasis on intellectual property.
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We believe that the key competitive factors affecting the success of any of our product candidates will include efficacy, safety profile, convenience, cost, level of promotional activity devoted to them and intellectual property protection.
−Removed: We expect to face competition from existing products and products in development for each of our product candidates.
−Removed: Seralutinib is a PDGFR, CSF1R and c-KIT inhibitor initially targeted for PAH patients.
−Removed: We expect competition in this patient set will include prostanoids / prostacyclin receptor agonists, including Orenitram (United Therapeutics Corporation, or United Therapeutics), Uptravi (Janssen), Tyvaso (United Therapeutics), and Remodulin (United Therapeutics).
+Added: We expect to face competition for seralutinib from existing products and products in development.
+Added: Seralutinib is a PDGFR, CSF1R and c-KIT inhibitor initially targeted for PAH and PH-ILD patients.
+Added: We expect competition within the PAH indication will include prostanoids / prostacyclin receptor agonists, including Orenitram (United Therapeutics), Uptravi (Janssen), Tyvaso (United Therapeutics), and Remodulin (United Therapeutics).
We also may face some competition from products used in class I and II patients, such as the oral PDE5 inhibitors, including Revatio (Pfizer Inc.) and Adcirca (United Therapeutics);
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We believe that, if approved, seralutinib could be used alongside all three classes of approved therapies.
−Removed: PAH is also an active indication for investigational drugs, and we may face competition in the future from ralinepag (Pfizer and United Therapeutics), sotatercept (Merck & Co., Inc.), rodatristat ethyl (Enzyyant Therapeutics GmbH) and MK-5475 (Merck).
−Removed: Additionally, although not approved for the treatment of PAH, we may face competition from formulations of imatinib, including those from Tenax Therapeutics, Aerovate Therapeutics and Aerami Therapeutics / Vectura Group.
−Removed: GB5121 and GB7208 are BTK inhibitors for the treatment of oncological and immunological indications, including PCNSL and MS.
−Removed: There are no FDA or EC approved therapies for refractory or recurrent PCNSL.
−Removed: If approved in MS, GB7208 may face competition from existing approved and investigational therapies.
−Removed: While no BTK inhibitors are FDA or EC approved for the treatment of either PCNSL or MS, we believe that if approved, GB5121 and / or GB7208 may face competition from currently FDA and / or EC approved BTK inhibitors Imbruvica (AbbVie Inc.
−Removed: / Janssen), Calquence (AstraZeneca plc), Brukinsa (BeiGene, Ltd.) and / or Jaypirca (Eli Lilly and Company).
−Removed: Our BTK inhibitors may also face competition from BTK inhibitor Velexbru (Ono Pharmaceutical Co., Ltd.), which is approved in Japan, South Korea and
−Removed: Taiwan for the treatment of recurrent or refractory primary central nervous system lymphoma.
−Removed: We may also face competition from early and late-stage investigational BTK inhibitors, including, but not limited to, evobrutinib, tolebrutinib, fenebrutinib, orelabrutinib, rilzabrutinib and remibrutinib.
−Removed: There may be other earlier stage clinical programs that, if approved, would compete with our product candidates.
+Added: PAH is also an active indication for investigational drugs, and we may face competition in the future from CS1 (Cereno Scientific), KER-012 (Keros Therapeutics, Inc.), L606 (Pharmosa Biopharm Inc.), MK-5475 (Merck & Co., Inc.), ralinepag (Pfizer and United Therapeutics) and sotatercept (Merck).
+Added: Additionally, although not approved for the treatment of PAH, we may face competition from formulations of imatinib in development for the treatment of PAH, including those from Aerami Therapeutics, Aerovate Therapeutics and Tenax Therapeutics.
+Added: We expect to face competition from Tyvaso (United Therapeutics) within the PH-ILD indication, as it is the only approved therapy for PH-ILD in the US.
+Added: There are no approved therapies for PH-ILD in the EU.
+Added: PH-ILD is also an active indication for investigational drugs, and we may face competition in the future from L606 (Pharmosa Biopharm Inc.), MD-711 (Mochida Pharmaceutical Co., Ltd.), sirolimus (OrphAI Therapeutics) and treprostinil palmitil (Insmed, Inc.).
+Added: Additionally, although not approved for the treatment of PH-ILD, we may face competition from formulations of imatinib, including those from Aerami Therapeutics, Aerovate Therapeutics and Tenax Therapeutics.
+Added: There may be other earlier stage clinical programs that, if approved, would compete with seralutinib.
Many of our competitors have substantially greater financial, technical and human resources than we have.
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We are required to use commercially reasonable efforts to develop and commercialize at least one licensed product in the United States and in at least two countries in the European Union.
−Removed: Under the terms of the Pulmokine Agreement, we made an upfront payment of $5.5 million and a milestone payment of $5.0 million to Pulmokine and are obligated to make future development and regulatory milestone payments of up to $58 million, commercial milestone payments of up to $45 million, and sales milestone payments of up to $190 million.
−Removed: In 2023, we anticipate incurring a development milestone payment of $10.0 million upon initiation of seralutinib in a Phase 3 clinical trial.
+Added: Under the terms of the Pulmokine Agreement, we made an upfront payment of $5.5 million and milestone payments of $5.0 million and $10.0 million to Pulmokine and are obligated to make future development and regulatory milestone payments of up to $48 million, commercial milestone payments of up to $45 million, and sales milestone payments of up to $190 million.
+Added: In January 2024, the Company made a payment of $10.0 million in connection with the initiation of the Phase 3 clinical trial of seralutinib.
We are also obligated to pay tiered royalties on sales for each licensed product, at percentages ranging from the mid-single digits to the high single-digits.
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Manufacturing
−Removed: We currently rely on multiple third-party manufacturers for the manufacture of our product candidates for preclinical and clinical testing.
−Removed: We intend to rely on third-party contract manufacturers for commercial manufacturing if our product candidates receive marketing approval.
−Removed: Typically, there are multiple sources for all of the materials required for the manufacture of our product candidates.
−Removed: Our manufacturing strategy enables us to more efficiently direct financial resources to the research, development and commercialization of product candidates rather than diverting resources to internally develop manufacturing facilities.
−Removed: As our product candidates advance through development, we expect to enter into longer-term commercial supply agreements with key suppliers and manufacturers to fulfill and secure our production needs.
+Added: We currently rely on multiple third-party manufacturers for the manufacture of seralutinib for preclinical and clinical testing.
+Added: We intend to rely on third-party contract manufacturers for commercial manufacturing if seralutinib receives marketing approval.
+Added: Typically, there are multiple sources for all of the materials required for the manufacture of seralutinib.
+Added: Our manufacturing strategy enables us to more efficiently direct financial resources to the research, development and commercialization of seralutinib rather than diverting resources to internally develop manufacturing facilities.
+Added: As seralutinib advances through development, we expect to enter into longer-term commercial supply agreements with key suppliers and manufacturers to fulfill and secure our production needs.
Intellectual Property
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to preserve the confidentiality of our trade secrets;
−Removed: to defend and enforce our proprietary rights, including any patents that we may own in the future;
+Added: to defend and enforce our proprietary rights, including any patents that we may
+Added: own in the future;
and to operate without infringing on the valid and enforceable patents and other proprietary rights of third parties.
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These patents and patent applications are directed to method of use claims.
−Removed: We also have exclusively licensed four issued U.S.
+Added: We have also exclusively licensed four issued U.S.
patents co-owned by Pulmokine and Gilead Sciences, Inc., which are not due to expire before 2034, excluding any additional term for patent term extension;
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These patents and patent applications are directed to seralutinib compound, formulation and method of use claims.
−Removed: We also own one pending patent application, which, if issued, is not due to expire before 2041, directed to forms of seralutinib.
−Removed: As of December 31, 2022, with respect to GB5121, we owned one pending U.S.
−Removed: patent application, ten corresponding foreign patent applications, and one international application directed to GB5121 compound, formulation and method of use claims, which, if issued, is not due to expire before 2041, excluding any additional term for patent term extension.
−Removed: As of December 31, 2022, with respect to GB7208, we owned one pending U.S.
−Removed: patent application, and a corresponding international patent application, directed to GB7208 compound, formulation and method of use claims, which, if issued, is not due to expire before 2042, excluding any additional term for patent term extension.
+Added: We also own a pending patent application, which, if issued, is not due to expire before 2042, directed to forms of seralutinib, and a pending application, which, if issued, is not due to expire before 2043, directed to combination treatment with seralutinib.
Government Regulation
−Removed: Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing and export and import of products such as
−Removed: those we are developing.
+Added: Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing and export and import of products such as those we are developing.
A new drug must be approved by the FDA through the new drug application, or NDA, process before it may be legally marketed in the United States.
−Removed: Certain of our product candidates are subject to regulation as combination products, which means that they are composed of both a drug product and device product.
+Added: Seralutinib is subject to regulation as a combination product, which means that it is composed of both a drug product and device product.
If marketed individually, each component would be subject to different regulatory pathways and reviewed by different centers within the FDA.
A combination product, however, is assigned to a Center that will have primary jurisdiction over its regulation based on a determination of the combination product’s primary mode of action, which is the single mode of action that provides the most important therapeutic action.
−Removed: In the case of our inhaled product candidate regulated as a combination product, the primary mode of action is attributable to the drug component of the product, which means that the FDA’s Center for Drug Evaluation and Research has primary jurisdiction over the premarket development, review and approval.
−Removed: Accordingly, we plan to investigate this product through the IND framework and seek approval through the NDA pathway.
+Added: In the case of seralutinib, the primary mode of action is attributable to the drug component of the product, which means that the FDA’s Center for Drug Evaluation and Research has primary jurisdiction over the premarket development, review and approval.
+Added: Accordingly, we plan to investigate seralutinib through the IND framework and seek approval through the NDA pathway.
We do not anticipate that the FDA will require a separate medical device authorization for the device, but this could change during the course of its review of any marketing application that we may submit.
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The process required by the FDA before a drug may be marketed in the United States generally involves the following:
−Removed: • completion of preclinical laboratory tests, animal studies and formulation studies in accordance with Good Laboratory Practice, or GLP, regulations and other applicable regulations;
+Added: • completion of certain preclinical laboratory tests, animal studies and formulation studies in accordance with Good Laboratory Practice, or GLP, regulations and other applicable regulations;
• submission to the FDA of an IND, which must become effective before human clinical trials may begin;
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• satisfactory completion of an FDA advisory committee review, if applicable;
−Removed: • satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current GMP, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity, and of selected clinical investigation sites to assess compliance with GCPs;
+Added: • satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current GMP, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity, and potential inspection of selected clinical investigation sites to assess compliance with GCPs;
• FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the United States.
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An IND sponsor must submit the results of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of the IND.
−Removed: An IND is a request for authorization from the FDA to administer an investigational drug product to humans.
−Removed: The sponsor will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the clinical trial lends itself to an
−Removed: efficacy evaluation.
+Added: An IND is a request for allowance from the FDA to administer an investigational drug product to humans.
+Added: The sponsor will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the clinical trial lends itself to an efficacy evaluation.
Some preclinical testing may continue even after the IND is submitted.
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In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.
−Removed: Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns about on-going or proposed clinical trials or non-compliance with specific FDA requirements, and the trials may not begin or continue until the FDA notifies the sponsor that the hold has been lifted.
−Removed: Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.
−Removed: All clinical trials must be conducted under the supervision of one or more qualified investigators in accordance with GCP regulations, which include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial.
−Removed: They must be conducted under protocols detailing, among other things, the objectives of the trial, dosing procedures, subject selection and exclusion criteria and the safety and effectiveness criteria to be evaluated.
+Added: Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns about on-going or proposed clinical trials or non-compliance with specific FDA requirements, and trials may not begin or continue under the IND until the FDA notifies the sponsor that the hold has been lifted.
+Added: Submission of an IND therefore may or may not result in FDA allowance to begin a clinical trial.
+Added: All clinical trials must be conducted under the supervision of one or more qualified investigators in accordance with GCP regulations, which among other things, include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial.
+Added: Clinical Trials must be conducted under protocols detailing, among other things, the objectives of the trial, dosing procedures, subject selection and exclusion criteria and the safety and effectiveness criteria to be evaluated.
Each protocol must be submitted to the FDA as part of the IND as well as any subsequent protocol amendments.
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Information related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the clinical trial is then made public as part of the registration.
−Removed: Sponsors are also obligated to disclose the results of their clinical trials after completion.
+Added: Sponsors are also obligated to
+Added: disclose the results of their clinical trials after completion.
Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved.
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In the case of some products for severe or life-threatening diseases, such as cancer, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.
−Removed: This phase involves clinical trials in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and appropriate dosage.
−Removed: Clinical trials are undertaken to further evaluate dosage, clinical efficacy and safety in an expanded patient population, generally at geographically dispersed clinical study sites.
+Added: The product candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and appropriate dosage.
+Added: The product candidate is further evaluated for dosage, clinical efficacy and safety in an expanded patient population, generally at geographically dispersed clinical study sites.
These clinical trials are intended to establish the overall risk-benefit ratio of the product candidate and provide an adequate basis for product labeling.
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Meetings at other times may be requested.
−Removed: These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach agreement on the next phase of development.
−Removed: Sponsors typically use the meetings at the end of the Phase 2 trial to discuss Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the new drug.
+Added: These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and/or for the sponsor and the FDA to reach agreement on the next phase of development.
Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.
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NDA Review and Approval Process
−Removed: The results of product development, preclinical and other non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.
+Added: The results of product development, including results from preclinical and other non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.
The submission of an NDA is subject to the payment of substantial user fees;
a waiver of such fees may be obtained under certain limited circumstances.
+Added: The FDA conducts a preliminary review of an NDA within the first 60 days after submission, before accepting the application for filing, to determine whether it is sufficiently complete to permit substantive review.
+Added: The FDA may request additional information rather than accept an NDA for filing.
+Added: In this event, the NDA must be resubmitted with the additional information.
+Added: The resubmitted application also is subject to review before the FDA accepts it for filing.
Once filed, the FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity.
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This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted.
−Removed: The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review The FDA may request additional information rather than accept an NDA for filing.
−Removed: In this event, the NDA must be resubmitted with the additional information.
−Removed: The resubmitted application also is subject to review before the FDA accepts it for filing.
The FDA may refer an application for a novel drug to an advisory committee.
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The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
−Removed: Before approving an NDA, the FDA will inspect the facility or facilities where the product is manufactured.
+Added: Before approving an NDA, the FDA will typically inspect the facility or facilities where the product is manufactured.
The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
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A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.
−Removed: A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data, such as an additional clinical trial or other significant and time consuming requirements related to clinical trials, nonclinical studies or manufacturing.
+Added: A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data or other significant and time consuming requirements related to clinical trials, nonclinical studies or manufacturing.
If a Complete Response Letter is issued, the sponsor must resubmit the NDA or, addressing all of the deficiencies identified in the letter, or withdraw the application.
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If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product.
−Removed: In addition, the FDA may require a sponsor to conduct Phase 4 testing, which involves clinical trials designed to further assess a drug’s safety and effectiveness after NDA approval, and may require testing and surveillance programs to monitor the safety of approved products which have been commercialized.
+Added: In addition, the FDA may require a sponsor to conduct additional clinical or non-clinical testing, including Phase 4 testing, to further assess a drug’s safety and effectiveness after NDA approval, and may require additional testing and surveillance programs to monitor the safety of approved products.
The FDA may also place other conditions on approval including the requirement for a risk evaluation and mitigation strategy, or REMS, to assure the safe use of the drug.
−Removed: If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS.
−Removed: The FDA will not approve the NDA without an approved REMS, if required.
+Added: If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS, and the FDA will not approve the application without an approved REMS.
A REMS could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.
Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products.
−Removed: Marketing approval may be withdrawn for non-compliance with regulatory requirements or if problems occur following initial marketing.
In addition, the Pediatric Research Equity Act, or PREA, requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.
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Orphan Drug Designation
−Removed: Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects
−Removed: more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product.
+Added: Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product.
Orphan designation must be requested before submitting an NDA.
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However, competitors, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.
−Removed: In addition, if an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.
+Added: In addition, if an orphan designated product receives marketing approval for a disease or condition broader than what is designated, it may not be entitled to orphan exclusivity.
In addition, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if the second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.
Expedited Development and Review Programs
−Removed: A sponsor may seek approval of its product candidate under programs designed to accelerate FDA’s review and approval of new drugs and biological products that meet certain criteria.
+Added: A sponsor may seek approval of its product candidate under programs designed to expedite FDA’s review and approval of new drugs and biological products that meet certain criteria.
For example, the FDA has a fast track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria.
−Removed: Specifically, a product candidate is eligible for fast track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.
+Added: Specifically, a product candidate is eligible for fast track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address unmet medical needs for the disease or condition.
Fast track designation applies to the combination of the product candidate and the specific indication for which it is being studied.
The sponsor of a fast track product candidate has opportunities for more frequent interactions with the applicable FDA review team during development.
−Removed: With regard to a fast track product, the FDA may also consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.
+Added: With regard to a fast track product, the FDA may also consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA,
+Added: the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.
A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review.
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The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.
−Removed: Any NDA for a product candidate submitted to the FDA for approval, including for a product candidate with a fast track designation or breakthrough designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.
+Added: Any NDA for a product candidate submitted to the FDA for approval, including for a product candidate with a fast track designation or breakthrough designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review.
An NDA is eligible for priority review if the product candidate is designed to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available alternatives for such disease or condition.
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The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.
−Removed: In addition, a product candidate may be eligible for accelerated approval.
+Added: In addition, depending on the design of the applicable clinical trials, a product candidate may be eligible for accelerated approval.
Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
−Removed: As a condition of approval, the FDA will generally require that a sponsor of a drug receiving
−Removed: accelerated approval perform adequate and well-controlled confirmatory clinical trials.
+Added: As a condition of approval, the FDA will generally require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled confirmatory clinical trials and may require that such confirmatory trials be underway prior to granting accelerated approval.
In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.
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Any drug products manufactured or distributed pursuant to FDA approvals will be subject to pervasive and continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the drug, providing the FDA with updated safety and efficacy information, drug sampling and distribution requirements, complying with certain electronic records and signature requirements, and complying with FDA promotion and advertising requirements.
−Removed: The FDA strictly regulates labeling, advertising, promotion and other types of information on products that are placed on the market and imposes requirements and restrictions on drug manufacturers, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the internet.
+Added: The FDA strictly regulates labeling, advertising, promotion and other types of information on products that are placed on the market and imposes requirements and restrictions on drug manufacturers, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described
+Added: in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the internet.
Discovery of previously unknown problems or the failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions.
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However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.
−Removed: The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or
−Removed: strengths of an existing drug.
+Added: The FDCA alternatively provides three years of non-patent exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug.
This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use.
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Pediatric exclusivity is another type of marketing exclusivity available in the United States.
−Removed: Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA.
+Added: Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to an existing period of regulatory exclusivity or patent term if a sponsor conducts clinical trials in children in response to a written request from the FDA.
The issuance of a written request does not require the sponsor to undertake the described clinical trials.
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Sales in the United States will depend, in part, on the availability of sufficient coverage and adequate reimbursement from third-party payors, which include government health programs such as Medicare, Medicaid, TRICARE and the Veterans Administration, as well as managed care organizations and private health insurers.
−Removed: Prices at which we or our customers seek reimbursement for our product candidates can be subject to challenge, reduction or denial by third-party payors.
+Added: Prices at which we or our customers seek reimbursement for seralutinib can be subject to challenge, reduction or denial by third-party payors.
The process for determining whether a third-party payor will provide coverage for a product is typically separate from the process for setting the reimbursement rate that the payor will pay for the product.
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In order to obtain coverage and reimbursement for any product that might be approved for marketing, we may need to conduct expensive studies in order to demonstrate the medical necessity and cost-effectiveness of any products, which would be in addition to the costs expended to obtain regulatory approvals.
−Removed: Third-party payors may not consider our product candidates to be medically necessary or cost-effective compared to other available therapies, or the rebate percentages required to secure favorable coverage may not yield an adequate margin over cost or may not enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development.
+Added: Third-party payors may not consider seralutinib to be medically necessary or cost-effective compared to other available therapies, or the rebate percentages required to secure favorable coverage may not yield an adequate margin over cost or may not enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development.
Healthcare Reform
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(5) expanded the eligibility criteria for Medicaid programs;
−Removed: (6) created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such
+Added: (6) created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;
(7) created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (which was increased to 70% commencing January 1, 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
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Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.
−Removed: Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.
−Removed: The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.
Other legislative changes have been proposed and adopted since the ACA was enacted.
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The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
+Added: In August 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal
For that and other reasons, it is currently unclear how the IRA will be effectuated.
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The federal civil and criminal false claims laws, including the civil False Claims Act, prohibit, among other things, any individual or entity from knowingly presenting, or causing to be presented, a false claim for payment to the federal government or knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.
−Removed: In addition, the government may assert that a claim including items or services
−Removed: resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act and the civil monetary penalties statute.
+Added: In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act and the civil monetary penalties statute.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created additional federal civil and criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit program.
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Additionally, there has been a recent trend of increased regulation of payments and transfers of value provided to healthcare professionals or entities and many EU member states have adopted national “Sunshine Acts” which impose reporting and transparency requirements (often on an annual basis), similar to the requirements in the United States, on pharmaceutical companies.
−Removed: Certain countries also mandate implementation of commercial compliance programs, or require disclosure of marketing expenditures and pricing information.
+Added: countries also mandate implementation of commercial compliance programs, or require disclosure of marketing expenditures and pricing information.
Efforts to ensure compliance with applicable healthcare laws and regulations can involve substantial costs.
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These GLP standards reflect the Organization for Economic Co-operation and Development requirements.
−Removed: Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.
−Removed: Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Conference on Harmonization, or ICH, guidelines on GCP as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
+Added: Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application, or CTA, much like the IND prior to the commencement of human clinical trials.
+Added: Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, or ICH, guidelines on GCP as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
If the sponsor of the clinical trial is not established within the EU, it must appoint an EU entity to act as its legal representative.
−Removed: The sponsor must take out a clinical trial insurance policy, and in most EU countries, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.
+Added: must take out a clinical trial insurance policy, and in most EU countries, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.
The regulatory landscape related to clinical trials in the EU has been subject to recent changes.
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The CTR notably harmonizes the assessment and supervision processes for clinical trials throughout the EU via a Clinical Trials Information System, which contains a centralized EU portal and database.
−Removed: While the Clinical Trials Directive required a separate clinical trial application, or CTA, to be submitted in each member state in which the clinical trial takes place, to both the competent national health authority and an independent ethics committee, much like the FDA and IRB respectively, the CTR introduces a centralized process and only requires the submission of a single application for multi-center trials.
+Added: While the EU Clinical Trials Directive required a separate CTA to be submitted in each member state in which the clinical trial takes place, to both the competent national health authority and an independent ethics committee, much like the FDA and IRB respectively, the CTR introduces a centralized process and only requires the submission of a single application for multi-center trials.
The CTR allows sponsors to make a single submission to both the competent authority and an ethics committee in each member state, leading to a single decision per member state.
5 unchanged sentences
The extent to which ongoing and new clinical trials will be governed by the CTR varies.
−Removed: Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the
−Removed: application of the EU Clinical Trials Directive remain governed by said Directive until January 31, 2025.
+Added: Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the EU Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the EU Clinical Trials Directive remain governed by said Directive until January 31, 2025.
After this date, all clinical trials (including those which are ongoing) will become subject to the provisions of the CTR.
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There are two types of MAs:
−Removed: • ”Centralized MAs” are is issued by the EC through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, and are valid throughout the EU.
+Added: • “Centralized MAs” are issued by the EC through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, and are valid throughout the EU.
The centralized procedure is mandatory for certain types of products, such as:
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Furthermore, MA may also be granted “under exceptional circumstances” when the applicant can show that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced.
−Removed: may arise in particular when the intended indications are very rare and, in the present state of scientific knowledge, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles.
+Added: This may arise in particular when the intended indications are very rare and, in the present state of scientific knowledge, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles.
This MA is close to the conditional MA as it is reserved to medicinal products to be approved for severe diseases or unmet medical needs and the applicant does not hold the complete data set legally required for the grant of a MA.
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Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data is not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients.
−Removed: Once the MA is obtained in all EU member states and study results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension (if any is in effect at the time of approval) or, in the case of orphan pharmaceutical products, a two year extension of the orphan market exclusivity is granted.
+Added: Once the MA is obtained in all EU member states and study results are included in the product
+Added: information, even when negative, the product is eligible for six months’ supplementary protection certificate extension (if any is in effect at the time of approval) or, in the case of orphan pharmaceutical products, a two year extension of the orphan market exclusivity is granted.
Orphan drug designation
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The aforementioned EU rules are generally applicable in the European Economic Area, or EEA, which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.
−Removed: Failure to comply with EU and member state laws that apply to the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of the MA, manufacturing of pharmaceutical products, statutory health insurance, bribery and anti-corruption or with other applicable regulatory requirements may result in administrative, civil or criminal penalties.
+Added: Failure to comply with EU and member state laws that apply to the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of the MA, manufacturing of pharmaceutical products, statutory health insurance, bribery and anti-corruption or with other applicable regulatory
+Added: requirements may result in administrative, civil or criminal penalties.
These penalties could include delays or refusal to authorize the conduct of clinical trials, or to grant MA, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the MA, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.
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It is currently unclear to what extent the Government of the United Kingdom, or UK, will seek to align its regulations with the EU.
−Removed: The EU laws that have been transposed into UK law through secondary legislation remain applicable in Great Britain.
−Removed: However, under the Retained EU Law (Revocation and Reform) Bill 2022, which is currently before the UK parliament, any retained EU law not expressly preserved and “assimilated” into domestic law or extended by ministerial regulations (to no later than June 23, 2026) will automatically expire and be revoked by December 31, 2023.
−Removed: In addition, new legislation such as the (EU) CTR is not applicable in Great Britain.
+Added: The EU laws that have been transposed into UK law through secondary legislation remain applicable in Great Britain, however, new legislation such as the (EU) CTR is not applicable in Great Britain.
Whilst the EU-UK Trade and Cooperation Agreement, or TCA, includes the mutual recognition of GMP inspections of manufacturing facilities for medicinal products and GMP documents issued, it does not contain wholesale mutual recognition of UK and EU pharmaceutical regulations and product standards.
There may be divergent local requirements in Great Britain from the EU in the future, which may impact clinical and development activities that occur in the UK in the future.
−Removed: Similarly, clinical trial submissions in the UK will not be able to be bundled with those of EU countries within the EMA Clinical Trial Information System, or CTIS, adding further complexity, cost and potential risk to future clinical and development activity in the UK.
+Added: Similarly, clinical trial submissions in the UK will not be able to be bundled with those of EU member states within the EMA Clinical Trial Information System, or CTIS, adding further complexity, cost and potential risk to future clinical and development activity in the UK.
Significant political and economic uncertainty remains about how much the relationship between the UK and EU will differ as a result of the UK’s withdrawal.
The UK government has passed a new Medicines and Medical Devices Act 2021, which introduces delegated powers in favor of the Secretary of State or an ‘appropriate authority’ to amend or supplement existing regulations in the area of medicinal products and medical devices.
−Removed: This allows new rules to be introduced in the future by way of secondary legislation, which aims to allow flexibility in addressing regulatory gaps and future changes in the fields of human medicines, clinical trials and medical devices.
+Added: This allows new rules to be introduced in the future by way of secondary legislation,
+Added: which aims to allow flexibility in addressing regulatory gaps and future changes in the fields of human medicines, clinical trials and medical devices.
Since January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, has been the UK’s standalone medicines and medical devices regulator.
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In order to obtain a UK MA to commercialize products in the UK, an applicant must be established in the UK and must follow one of the UK national authorization procedures or one of the remaining post-Brexit international cooperation procedures to obtain an MA to commercialize products in the UK.
−Removed: The MHRA may rely on a decision taken by the EC on the approval of a new (centralized procedure) MA when determining an application for a GB authorization;
−Removed: or use the MHRA’s decentralized or mutual recognition procedures which enable MAs approved in EU member states (or Iceland, Liechtenstein, Norway) to be granted in GB.
−Removed: There will be no pre-MA orphan designation.
+Added: A new international recognition framework has been in place from January 1, 2024, whereby the MHRA will have regard to decisions on the approval of MAs made by the EMA and certain other regulators when determining an application for a new GB MA.
+Added: There is no pre-MA orphan designation.
Instead, the MHRA will review applications for orphan designation in parallel to the corresponding MA application.
2 unchanged sentences
The UK regulatory framework in relation to clinical trials is derived from existing EU legislation (as implemented into UK law, through secondary legislation).
−Removed: On January 17, 2022, the MHRA launched an eight-week consultation on reframing the UK legislation for clinical trials.
−Removed: The consultation closed on March 14, 2022 and aims to streamline clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.
−Removed: The outcome of the consultation is being closely watched and will determine whether the UK chooses to align with the (EU) CTR or diverge from it to maintain regulatory flexibility.
−Removed: Data privacy and security laws
+Added: On January 17, 2022, the MHRA launched an eight-week consultation on reframing the UK legislation for clinical trials, which aims to streamline clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.
+Added: The MHRA responded to the consultation on March 21, 2023 and confirmed that it would bring forward changes to the legislation.
+Added: The final legal texts introduced by the UK Government will ultimately determine the extent to which whether the UK clinical trials framework aligns with or diverges from with the (EU) CTR.
+Added: Foreign Data Privacy and Security Laws
We are also subject to laws and regulations in non-U.S.
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The principal purposes of our equity and cash incentive plans are to attract, retain and motivate personnel through the granting of stock-based and cash-based compensation awards, in order to align our interests and the interests of our stockholders with those of our employees and consultants.
−Removed: As of March 10, 2023, we had 178 full-time employees and no part-time employees.
+Added: As of February 27, 2024, we had 135 full-time employees and no part-time employees.
Of those 135 employees, 32, or 24%, have a Ph.D.
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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.