This Phase 2 trial was a worldwide, randomized experiment in which parallel groups of individuals with IPF and PPF received 30 mg or 60 mg of BMS-986278 or matching placebo orally twice daily for 26 weeks. Antifibrotics with a stable background use in the IPF cohort and/or select immunosuppressives in the PPF group were permitted. The primary endpoint of the trial was the rate of change in ppFVC in the IPF cohort from baseline to Week 26. A key secondary objective of the trial was the rate of change in ppFVC from baseline to 26 weeks in the PPF group, which was measured using two prespecified estimands (treatment policy estimand and while-on-treatment estimand).
Alnylam Reports Positive Topline Results from KARDIA-1 Phase 2 Dose-Ranging Study of Zilebesiran
Alnylam Pharmaceuticals, Inc., the world’s leading RNAi therapeutics company, announced that the KARDIA-1 Phase 2 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension, met the primary endpoint of a dose-dependent, clinically significant reduction in 24-hour mean systolic blood pressure (SBP) measured by ambulatory blood pressure monitoring (ABPM) at Month 3, achieving a placebo-subtracted reduction greater than 15 mmHg (p less than 0.0001) with both 300 mg and 600 mg doses.
The trial also met crucial secondary objectives, including a substantial change in 24-hour mean SBP as determined by ABPM at Month 6 and a significant change in office SBP at Month 3 and Month 6 for all zilebesiran arms when compared to placebo. According to the findings of the study, zilebesiran was related with a dose-dependent, significant, and long-lasting reduction in serum AGT levels through Month 6. Zilebesiran also showed a favorable safety and tolerability profile, which the company feels will support further development. These findings of robust and tonic blood pressure regulation will aid in determining the best zilebesiran dose and regimen for future trials.
Hypertension is a growing global health crisis that accounts for approximately 10 million deaths worldwide each year.” Despite the availability of several classes of oral anti-hypertensive treatments, up to 80% of people worldwide remain uncontrolled, putting them at risk of cardiovascular, cerebrovascular, and renal disease, which is exacerbated by blood pressure variability, a lack of nighttime blood pressure control, and poor adherence,” said Professor George L. Bakris, M.D., Board-Certified Hypertension Specialist and Director of the American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine. “As a physician, I believe that these KARDIA-1 results, which show clinically significant reductions in systolic blood pressure of more than 15 mmHg, as well as the ability to achieve durable tonic blood pressure control, give us hope that we will one day have access to a novel therapy with the potential to address the significant unmet needs of patients with uncontrolled hypertension who are at high risk of future cardiovascular events.
Zilebesiran had a promising safety and tolerability profile. One fatality from cardiopulmonary arrest in a zilebesiran-treated patient was ruled unconnected to the trial medication. In 3.6% of zilebesiran-treated patients and 6.7% of placebo-treated individuals, serious adverse events were reported. The KARDIA-1 Phase 2 trial is a multi-center global dose-ranging randomized, double-blind (DB), placebo-controlled research aimed to assess the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. In June 2023, recruitment in the KARDIA-2 Phase 2 research of zilebesiran in conjunction with one of three mainstream classes of antihypertensive medicines was completed. The topline results are anticipated in early 2024.
FDA Approval Sought for Tovorafenib in Relapsed or Progressive Pediatric Low-Grade Glioma
Day One Biopharmaceuticals has announced the successful submission of a rolling New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tovorafenib as a standalone treatment for relapsed or progressive pediatric low-grade glioma (pLGG). The company expects the FDA to officially accept this rolling NDA by mid-November 2023.
Pediatric low-grade glioma is the most frequently diagnosed brain tumor in children, causing significant health challenges and treatment-related complications that can affect a child’s long-term well-being. In the relapsed scenario, there is currently no established standard of care or approved therapies available for most patients.
Jeremy Bender, Ph.D., the CEO of Day One, expressed optimism about the potential impact of tovorafenib if it receives FDA approval. He views the NDA submission for tovorafenib as a major milestone for the company, representing a crucial step toward providing a targeted therapy option for children with brain cancer.
The NDA submission process began in May 2023, leveraging data from the FIREFLY-1 trial, with data collected until December 22, 2022. An updated Clinical Study Report (CSR) was submitted to the FDA, including an additional six months of safety and efficacy data up to June 5, 2023.
The FIREFLY-1 trial, an open-label Phase 2 study, involved 137 patients across two study arms. Arm 1 investigated the use of tovorafenib as a weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG. The trial’s primary endpoint was the Objective Response Rate (ORR) as assessed by Response Assessment for Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria. Secondary endpoints included ORR by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG), progression-free survival (PFS), duration of response (DOR), time to response, clinical benefit rate, and safety. The NDA submission also included an exploratory analysis of ORR using Response Assessment for Neuro-Oncology Low-Grade Glioma (RANO-LGG). An Independent Review Committee (IRC) evaluated all the data in a blinded manner.
The safety data, compiled from the 137 patients in both Arm 1 and Arm 2 of the FIREFLY-1 trial, indicated that monotherapy with tovorafenib was generally well-tolerated. Most adverse events were of Grade 1 or Grade 2 severity. Common side effects associated with tovorafenib included changes in hair color (76%), fatigue (44%), maculopapular rash (41%), dry skin (33%), and dermatitis acneiform (30%). The most frequently reported treatment-related lab abnormalities included CPK elevation, LDH elevation, anemia, hypophosphatemia, and AST elevation. Importantly, the majority of these lab abnormalities had no clinical impact and did not necessitate medical intervention or a change in the treatment plan.
Tovorafenib received Rare Pediatric Disease Designation for the treatment of relapsed or progressive pLGG, making it eligible for a priority review voucher if it gains FDA approval for this indication. Based on Day One’s current financial outlook, the company believes it has sufficient capital resources to sustain its operations through 2026.
Six-Year Outcomes from Phase III CheckMate -227 Trial Show Durable, Long-Term Survival with Opdivo Plus Yervoy in the First-Line Treatment of Patients with mNSCLC
Bristol-Myers Squibb Company has released findings from an analysis of survival data pooled from four clinical trials (CheckMate -017, -057, -063, and -003; involving 664 patients) involving individuals with advanced non-small cell lung cancer (NSCLC) who had previously undergone treatment with Opdivo (nivolumab). According to the combined analysis of these four studies, 14% of all patients who received Opdivo were still alive after four years. Notably, among patients with different levels of PD-L1 expression (≥1% and <1%), the four-year overall survival (OS) rates were 19% and 11%, respectively.
In a pooled analysis of two phase 3 trials, CheckMate -017 and -057, Opdivo-treated patients exhibited a four-year OS rate of 14%, while patients treated with docetaxel had a four-year OS rate of 5%. Furthermore, when exploring OS based on patient responses at six months, 58% of those who responded completely or partially to Opdivo were still alive four years later, compared to only 12% of patients treated with docetaxel. Among patients with stable disease at six months, 19% of those who received Opdivo were alive four years later, whereas only 2% of patients treated with docetaxel survived. These findings were presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting in Atlanta.
The long-term safety data for Opdivo, derived from all four studies, remained consistent with the known adverse event profile and did not reveal any new safety concerns. The rate of treatment-related adverse events (AEs) leading to discontinuation was 8.7% among patients treated with Opdivo, with fatigue being the most common treatment-related AE (reported in 21.7% of patients).
Dr. Scott Antonia, Director of the Duke Cancer Institute Center for Cancer Immunotherapy, commented on the results, highlighting the correlation between Opdivo response and prolonged survival in a substantial population of patients with previously treated advanced NSCLC. He noted that these long-term survival outcomes are particularly significant given that the historical five-year survival rate for this patient group is approximately 5%.
Dr. Sabine Maier, Development Lead for Thoracic Cancers at Bristol-Myers Squibb, emphasized the positive survival trends observed in the pooled analysis. She indicated that these findings provide a more comprehensive understanding of long-term survival outcomes compared to individual studies and underscore Opdivo’s potential value for second-line treatment of lung cancer patients. These data also underscore the company’s commitment to delivering cancer therapies that may offer lasting benefits to patients in critical need.
Lundbeck and Otsuka Announce Topline Results from Two Phase III Trials of Brexpiprazole as Combination Therapy with Sertraline for the PTSD
On September 7, 2023, Lundbeck A/S (Lundbeck) and Otsuka Pharmaceutical Co., Ltd. (Otsuka) unveiled the results from phase III clinical trials involving brexpiprazole when used in combination with sertraline for the treatment of post-traumatic stress disorder (PTSD) in adults. The initial trial (NCT04124614) was a phase III study with 416 randomized adult participants with PTSD, employing a randomized, double-blind, two-arm design to assess the effectiveness, safety, and tolerability of brexpiprazole (at doses of 2-3 mg/day) when used alongside sertraline. The second study (NCT04174170) constituted a phase III clinical trial with 553 randomized adult participants with PTSD. It followed a randomized, double-blind, three-arm design, aiming to assess the effectiveness, safety, and tolerability of brexpiprazole (administered at either 2 or 3 mg/day) when used in combination with sertraline.
The primary endpoint for both trials was the change in the Clinician-Administered PTSD Scale (CAPS-5) total score for brexpiprazole + sertraline combination therapy versus sertraline + placebo at week 10 in patients diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The first trial met its primary endpoint by demonstrating improvements from baseline on the primary endpoint of CAPS-5 for patients receiving brexpiprazole 2-3 mg/day + sertraline combination therapy being statistically significantly greater than for those receiving sertraline + placebo (p<0.05). The second phase 3 trial missed its primary endpoint (p>0.05).
In both trials, the main objective was to measure the change in the total score of the Clinician-Administered PTSD Scale (CAPS-5) after 10 weeks of treatment with brexpiprazole + sertraline combination therapy compared to sertraline + placebo in patients diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The first trial successfully achieved its primary goal, showing statistically significant improvements from the baseline in CAPS-5 scores for patients who received brexpiprazole 2-3 mg/day + sertraline combination therapy compared to those on sertraline + placebo (p<0.05). However, the second phase 3 trial did not meet its primary endpoint (p>0.05).
Full trial results are not yet available. Further prespecified and exploratory analyses of this data set will be conducted to further assess brexpiprazole as combination therapy with sertraline for the treatment of PTSD. The trial results are planned to be submitted for scientific publication.
The results from the first trial indicate that brexpiprazole in combination with sertraline provides improvement of symptoms for people living with PTSD, whereas the second trial did not meet its primary endpoint,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “We will fully analyze these results and will discuss our findings with the FDA to determine next steps.
PTSD is a serious mental health disorder with a wide range of symptoms with no new therapeutic options in more than 20 years,” Dr. Johan Luthman, executive vice president and head of Research & Development at Lundbeck. “The two trials constitute one of the largest clinical development programs ever conducted in PTSD. We will analyze the dataset to further determine the potential of brexpiprazole as combination therapy with sertraline in comprehensively addressing symptoms across the PTSD core domains.”
Post-Traumatic Stress Disorder (PTSD) can develop in individuals of any ethnicity, nationality, or cultural background, and at any stage of life. It impacts over 13 million people in the United States, with a diagnosis rate of nearly 6 out of every 100 individuals during their lifetime. As per DelveInsight, in 2022, the total 12-month Post-Traumatic Stress Disorder prevalent cases in the 7MM were 13,667,100 and the number of cases is projected to increase during the forecasted period. The total Post-Traumatic Stress Disorder market size in the 7MM was USD 1,750 million, which is expected to increase and reach ~USD 3,350 million by 2032 at a CAGR of 5.4%. In the US, antidepressants, antipsychotic drugs, and benzodiazepine will garner a market size of approximately USD 1,150 million, USD 610 million, and USD 60 million, respectively, by 2032. The launch of emerging therapies by key players such as Lundbeck and Otsuka, among others, is expected to immensely drive the PTSD market growth and treatment scenario.
European Medicines Agency Granted Orphan Drug Designation to MaaT Pharma’s MaaT033 of Hematopoietic Stem Cell Transplantation
MaaT Pharma (EURONEXT: MAAT – the “Company”) announced on September 7, 2023, that the European Medicines Agency (EMA) has granted orphan drug designation (ODD) to its therapy, MaaT033, intended to enhance overall survival in patients undergoing HSCT. The EMA recognizes the substantial potential benefit that MaaT033 could offer to this patient population. This marks the first ODD granted for MaaT033 and the third for the Company, which has previously secured ODD status for MaaT013 in both the US and Europe.
The EMA’s decision to grant orphan drug designation to MaaT033, our second clinical-stage asset and first-in-class therapeutics, recognizes the need for new treatment options for patients with liquid tumors and highlights the potential of microbiome-based drugs further strengthening the value of our clinical assets,” stated Philippe Moyen, COO of MaaT Pharma. “We look forward to continuing to collaborate closely with the regulatory agencies to accelerate the development of safe and innovative microbiome therapies.
MaaT033, an oral Microbiome Ecosystem TherapyTM rich in donor-derived microbiota, including anti-inflammatory ButycoreTM species, is in development as a supplementary treatment to enhance the overall survival of patients undergoing HSCT and similar cellular therapies. Its objective is to optimize microbiota functionality and address a broader patient group in chronic settings. The European Medicines Agency (EMA) has granted Orphan Drug Designation to MaaT033.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a medical procedure in which hematopoietic (blood-forming) stem cells are collected from a donor and transplanted into a recipient who has a hematological (blood-related) disorder, such as leukemia, lymphoma, or certain types of anemia. The goal of this transplantation is to replace the recipient’s abnormal or cancerous blood cells with healthy donor cells. As per estimate, in 2021, the European Society for Blood and Marrow Transplantation (EBMT) reported nearly 20,000 allo-HSCT procedures in Europe, and this number continues to rise.
Once the stem cells are transplanted into the recipient, they migrate to the bone marrow and begin producing new blood cells, including red blood cells, white blood cells, and platelets. This process helps to reestablish a healthy blood and immune system. Allo-HSCT is often used as a potentially curative treatment for certain blood and bone marrow disorders, but it carries significant risks and complications. Graft-versus-host disease (GVHD), in which the donor’s immune cells attack the recipient’s tissues, is a common and potentially serious complication. Close monitoring and careful management of the transplant process are essential to minimize these risks and improve the chances of a successful outcome. Globally, several major companies are actively working in the allo-HSCT market and play a crucial role in contributing to advancements in technologies, treatments, and support services.
