GSK Receives FDA Fast Track Designation for Bepirovirsen in Chronic Hepatitis B

GSK plc has revealed that the US Food and Drug Administration (FDA) has awarded Fast Track status to bepirovirsen, an experimental antisense oligonucleotide (ASO) designed to treat chronic hepatitis B (CHB). Fast Track designation aims to streamline the drug development process and accelerate the review of medications targeting severe conditions with unmet medical requirements.

The request for designation was made due to the promising potential of bepirovirsen in tackling an urgent medical necessity for CHB, a severe and potentially fatal condition. Evidence from the B-Clear and B-Sure phase IIb trials, assessing the effectiveness, safety, and lasting impact of bepirovirsen in CHB patients, was provided to support the application. Additionally, a confirmatory phase III program, B-Well, is currently underway.

CHB impacts approximately 300 million individuals globally, and existing treatment options provide a functional cure rate of less than 2-8%, which lacks clinical significance. As per DelveInsight analysis, The total prevalent cases of Chronic Hepatitis B in the 7MM and China comprised approximately 81 million cases in 2022 and are projected to decrease by 2032. A functional cure denotes a state where hepatitis B virus DNA and viral proteins are at sufficiently low levels to be undetectable in the bloodstream and can be managed by the immune system without medication. Presently, oral antiviral therapies known as nucleoside/nucleotide analogs (NAs) merely suppress the virus and do not directly reduce hepatitis B surface antigen (HBsAg), a crucial factor for achieving a functional cure.

Bepirovirsen stands out as the sole single agent currently in phase III development with the potential to achieve a significant functional cure response, particularly when paired with oral nucleoside/nucleotide analogs (NAs). This potential was highlighted through positive outcomes observed in the B-Clear and B-Sure clinical trials. The B-Clear trial specifically identified that patients with initially low levels of hepatitis B surface antigen are most likely to benefit from bepirovirsen treatment. Additionally, bepirovirsen is being explored as a potential foundational therapy in forthcoming sequential treatment regimens aimed at pursuing functional cures in a wider range of patients with chronic hepatitis B.

Gilead Sciences Expands Liver Portfolio With Acquisition of CymaBay Therapeutics

Gilead Sciences, Inc. and CymaBay Therapeutics, Inc. have declared a firm agreement wherein Gilead will purchase CymaBay for $32.50 per share in cash, totaling an equity value of $4.3 billion. This acquisition includes CymaBay’s main product under investigation, seladelpar, intended for treating primary biliary cholangitis (PBC), including pruritus. This addition complements Gilead’s existing range of liver-related treatments and aligns with its ongoing dedication to delivering groundbreaking medications to patients.

“We eagerly anticipate progressing seladelpar with the benefit of Gilead’s extensive experience in managing and curing liver ailments,” stated Daniel O’Day, Gilead Sciences’ Chairman and Chief Executive Officer. “By capitalizing on the solid research and development efforts of the CymaBay team thus far, we have the opportunity to fulfill a substantial gap in care for individuals with PBC and enhance our already diverse array of groundbreaking treatments.”

Primary Biliary Cholangitis is a rare, persistent liver condition characterized by impaired bile flow, predominantly observed in women (approximately 1 in 1,000 women aged 40 and above, totaling around 130,000 individuals in the United States). This condition detrimentally affects liver function and diminishes the overall quality of life. As per DelveInsight, in 2021, the total diagnosed prevalent cases of Primary Biliary Cholangitis were more than 1 million in the 7MM + China.

Seladelpar is a potential oral medication that selectively activates the peroxisome proliferator-activated receptor delta (PPARδ). It has demonstrated its ability to manage important metabolic and liver disease pathways. The FDA has finished reviewing the application for this drug and has approved it for further evaluation, giving it priority status. The target action date under the Prescription Drug User Fee Act is set for August 14, 2024.

CSL Announces Top-line Results from the Phase III AEGIS-II Trial Evaluating the Efficacy and Safety of CSL112

CSL, a prominent player in biotechnology globally, has disclosed initial findings from the Phase III AEGIS-II trial. This study assessed the effectiveness and safety of CSL112 (apolipoprotein A-I [human]) compared to a placebo in lessening the likelihood of major adverse cardiovascular events (MACE) among patients who had experienced an acute myocardial infarction (AMI). Regrettably, the trial did not achieve its primary goal of reducing MACE within 90 days. Consequently, there are no immediate intentions to submit for regulatory approval. Notably, no significant concerns were observed regarding the safety or tolerability of CSL112 during the trial.

“We look forward to sharing our scientific learnings regarding cholesterol efflux and recurrent cardiovascular events,” said C. Michael Gibson, M.S., M.D., Baim Institute for Clinical Research, Harvard Medical School.We will continue to analyze the findings and share the full results in the coming months.”

Additional examination of AEGIS-II is currently in progress, and initial findings will be showcased at the American College of Cardiology Scientific Sessions on April 6, 2024, and subsequently published in a peer-reviewed journal.

Dr. Bill Mezzanotte, Executive Vice President and Head of R&D at CSL, acknowledged that there is still significant work required to thoroughly analyze and comprehend the entire dataset before determining the future course for this asset. He expressed gratitude to all the patients, families, caregivers, and investigators involved in the AEGIS program for their support and participation.” “Highlighting the importance of AEGIS-II, Dr. Mezzanotte described it as the most ambitious study in CSL’s history. He expressed pride in the study’s quality and the enhanced capabilities developed to conduct it. CSL intends to leverage these capabilities and its plasma protein platform to address unmet medical needs in cardiovascular and metabolic conditions, as well as other strategic therapeutic areas in the future.”

Ruxoprubart (NM8074) Scores FDA Orphan Drug Designation for Paroxysmal Nocturnal Hemoglobinuria Treatment

NovelMed made a significant announcement on February 12, 2024, revealing that the US Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to its therapy, Ruxoprubart. This breakthrough alternative pathway (AP) blocker anti-Bb antibody has been recognized for its potential in treating Paroxysmal Nocturnal Hemoglobinuria (PNH), a condition affecting many individuals. The FDA’s designation underscores the vital role Ruxoprubart could play in addressing the unmet needs of those afflicted by Paroxysmal Nocturnal Hemoglobinuria, marking a pivotal step forward in healthcare innovation.

Setting itself apart from Iptacopan (Fabhalta) by lacking affinity for Factor B, Ruxoprubart specifically targets protein Bb within the alternative pathway. This humanized anti-Bb monoclonal antibody functions as a robust inhibitor of the Alternative Pathway.

After successfully completing the phase I trial with anticipated outcomes among healthy volunteers, Ruxoprubart has advanced to a phase II trial, focusing on treatment-naïve Paroxysmal Nocturnal Hemoglobinuria patients in a multi-dose regimen. Notably, the Anti-Bb molecule represents a pioneering biologic undergoing evaluation in treatment-naïve Paroxysmal Nocturnal Hemoglobinuria patients. The FDA has also greenlit the commencement of Phase II trials for various indications, including C3 Glomerulopathy (C3G), Atypical Hemolytic Uremic Syndrome (aHUS), and ANCA vasculitis (AAV), with trials scheduled to take place in the United States. Overseas regulatory approvals encompass trials for Paroxysmal Nocturnal Hemoglobinuria among the adult population and aHUS, extending to both adult and pediatric populations.

“We are delighted by the FDA’s decision to grant orphan drug designation to Ruxoprubart, underscoring the pressing need for innovative therapeutic solutions for patients with PNH,” says Robert Bard, VP Regulatory Affairs. This ODD approval marks a significant advancement in the therapeutic landscape with Ruxoprubart ‘s unique ability to selectively block the alternative pathway (AP) while preserving the classical pathway required for clearing infections in Paroxysmal Nocturnal Hemoglobinuria patients.

The dysregulation of the Alternative Pathway (AP) is widely acknowledged as a critical determinant influencing the progression of Paroxysmal Nocturnal Hemoglobinuria disease. Recognized as an orphan disease, the available treatment options for Paroxysmal Nocturnal Hemoglobinuria are still limited and imperfect. Presently sanctioned treatments either impede infection clearance or provoke hyperlipidemia. PNH is characterized by various clinical manifestations such as low PNH-RBC clone size, hemolysis, hemoglobinuria, diminished hemoglobin levels, elevated LDH, and a plethora of other symptoms that can result in chronic complications, including premature mortality if left unaddressed. Chronic symptoms and multi-organ damage are also prevalent among Paroxysmal Nocturnal Hemoglobinuria patients, underscoring the complex nature and profound impact of the disease on affected individuals. It’s imperative to explore and develop novel therapeutic interventions that specifically target the dysregulated Alternative Pathway to improve outcomes and enhance the quality of life for Paroxysmal Nocturnal Hemoglobinuria patients.

Although FDA-approved anti-C3, C5, and Factor B drugs are available for Paroxysmal Nocturnal Hemoglobinuria treatment, offering potential symptom management, they are often associated with significant side effects. The pressing need for additional treatment options for Paroxysmal Nocturnal Hemoglobinuria, which are not only effective but also well-tolerated, remains widely acknowledged. The development of such treatments holds promise for improving the overall outcome of the disease and enhancing the quality of life for patients living with Paroxysmal Nocturnal Hemoglobinuria.

However, the current treatment options, while providing some relief, often come with limitations and potential side effects, leaving patients and healthcare providers in search of more effective therapies. Pharmaceutical companies such as NovelMed and others are actively addressing this unmet medical need by investing in research and development efforts aimed at advancing novel treatments for Paroxysmal Nocturnal Hemoglobinuria. These endeavors hold promise for improving disease management, reducing symptom burden, and ultimately enhancing the overall well-being and prognosis of individuals.

CymaBay Announces FDA Acceptance of NDA and Priority Review for Seladelpar for the Treatment of Primary Biliary Cholangitis

On February 12, 2024, CymaBay Therapeutics, Inc. (NASDAQ: CBAY) disclosed that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) concerning seladelpar. Seladelpar is being investigated as a treatment for managing Primary Biliary Cholangitis (PBC), including pruritus, in adults who do not have cirrhosis or have compensated cirrhosis (Child Pugh A) and who have shown inadequate response or intolerance to ursodeoxycholic acid. The FDA has given priority review status to this application and established a Prescription Drug User Fee Act (PDUFA) target action date of August 14, 2024. Additionally, the company has been informed by the FDA that there are no current plans to convene an advisory committee meeting to discuss the application.

Seladelpar is a promising, selective, orally active agonist of PPARδ, under investigation as a potential treatment for Primary Biliary Cholangitis. It stands out as the sole investigational compound to exhibit a statistically notable enhancement in biochemical indicators of disease advancement and predefined assessments of PBC-associated itching in a Phase 3 trial. In the pivotal Phase 3 RESPONSE study, the safety evaluation of seladelpar, as determined by the incidence of adverse events, was comparable between the groups receiving seladelpar and those given a placebo.

The New Drug Application (NDA) encompasses information gathered from the entirety of the seladelpar clinical development program, involving over 500 individuals diagnosed with Primary Biliary Cholangitis. This data includes findings from placebo-controlled Phase 3 RESPONSE and ENHANCE studies, the long-term open-label ASSURE study, as well as previous Phase 2 trials. The FDA had previously granted seladelpar Breakthrough Therapy Designation (BTD), facilitating the early submission of selected non-clinical data through a rolling review process, which was made possible by seladelpar’s BTD status. In October 2023, the FDA updated the Breakthrough Therapy Designation for seladelpar, acknowledging clinical evidence suggesting that seladelpar may offer significant improvements over existing therapies, as indicated by reductions in alkaline phosphatase (ALP) levels and enhancements in pruritus among patients without cirrhosis or with compensated cirrhosis.

“Acceptance of the seladelpar NDA for the treatment of PBC, is an important step forward in our ongoing mission to make this potential, novel, targeted treatment option available for people living with PBC,” said Klara Dickinson, Chief Regulatory and Compliance Officer, CymaBay Therapeutics. “We are encouraged by the agency’s decision to grant priority review for seladelpar, and its recognition of the significant need for new treatment options for people living with PBC. If approved, we believe seladelpar has the potential to raise the bar in second-line treatment of PBC by reducing markers of disease progression and improving pruritus, so we look forward to continued discussion with the agency throughout its review.”

Primary Biliary Cholangitis is a rare, chronic inflammatory liver ailment predominantly afflicting women, with an estimated incidence of 1 in 1,000 women aged 40 or older, equating to approximately 130,000 individuals in the United States alone. This condition is hallmarked by compromised bile flow, medically termed cholestasis, and the buildup of harmful bile acids within the liver. Consequently, inflammation ensues, leading to the degeneration of bile ducts within the liver and resulting in elevated levels of liver enzymes such as ALP, ALT, and GGT, along with total bilirubin. These enzymes are predominantly found in the liver and their heightened levels are indicative of liver damage. Among the initial symptoms experienced by individuals with Primary Biliary Cholangitis, pruritus (itching) and fatigue are most prevalent, and for some patients, these symptoms can severely impact their quality of life. As Primary Biliary Cholangitis progresses, there is a heightened risk of liver-related mortality, underlining the severity and significance of the condition.

Current treatment options often fall short in effectively managing the disease, leaving patients with limited options and the looming threat of complications. However, pharmaceutical companies such as CymaBay and others are actively addressing this pressing need by developing innovative therapies aimed at improving the treatment outlook for Primary Biliary Cholangitis patients. These efforts include the development of novel drugs targeting key pathways involved in the disease process, offering renewed hope for better disease management, symptom control, and ultimately, improved outcomes for those affected by Primary Biliary Cholangitis.

Biogen Received European Commission Approval for SKYCLARYS® (omaveloxolone), the First Therapy to Treat Friedreich’s Ataxia

Biogen Inc. declared on February 12, 2024, that the European Commission (EC) has granted authorization for SKYCLARYS® (omaveloxolone) to treat Friedreich’s Ataxia (FA) in adults and adolescents aged 16 years and above. This marks SKYCLARYS as the inaugural treatment sanctioned within the European Union for this rare, genetic, and progressive neurodegenerative disorder. 

Friedreich’s Ataxia imposes a significant burden on individuals affected by its debilitating symptoms, robbing them of mobility, independence, and ultimately, shortening their lifespan. The approval of SKYCLARYS® (omaveloxolone) by the European Commission represents a beacon of hope for those battling Friedreich’s Ataxia. This groundbreaking medication offers a promising avenue for improved treatment outcomes, potentially alleviating symptoms, slowing disease progression, and enhancing the quality of life for patients and their families affected by this devastating condition.

The EC’s approval of SKYCLARYS is grounded on the efficacy and safety findings from the placebo-controlled MOXIe Part 2 trial. At the conclusion of the 48-week study, participants administered SKYCLARYS demonstrated significantly enhanced modified Friedreich Ataxia Rating Scale (mFARS) scores in comparison to those on placebo. Every aspect of the mFARS evaluation, encompassing bulbar function, upper and lower limb coordination, and upright stability, showed a preference for SKYCLARYS over placebo. 

Supplementary exploratory data was derived from a post hoc, propensity-matched analysis, indicating that patients treated with SKYCLARYS in MOXIe (Extension) exhibited lower mFARS scores at the 3-year mark compared to a matched natural history group. The most frequently encountered side effects include elevated liver enzymes, reduced weight and appetite, nausea, vomiting, diarrhea, headaches, fatigue, oropharyngeal and back pain, muscle spasms, and influenza.

SKYCLARYS has been granted Orphan Drug, Fast Track, and Rare Pediatric Disease Designations by the U.S. Food and Drug Administration. Additionally, the European Commission has designated SKYCLARYS as an Orphan Drug for Friedreich’s Ataxia treatment in Europe.

“In my clinical practice, I have seen the devastating impact that Friedreich’s Ataxia has on patients and their families,” said Sylvia Boesch, M.D., MSc, Principal Investigator of the MOXIe study and Head of the Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Austria. “Friedreich’s Ataxia patients treated with SKYCLARYS in the clinical trial experienced important and clinically meaningful improvements for their daily lives. With this approval, there is optimism within the community that SKYCLARYS has the potential to usher in a new era in the management of Friedreich’s Ataxia.”

“Biogen is proud to add SKYCLARYS to our portfolio of medicines and address a significant unmet need by bringing the first treatment to people living with Friedreich’s Ataxia in Europe,” said Priya Singhal, M.D., M.P.H., Head of Development at Biogen. “Our team is committed to engaging with the medical community and local authorities as we work to urgently secure access for patients. We sincerely thank the Friedreich’s Ataxia community for their contributions that enabled the development of SKYCLARYS and made today’s approval possible.”

Friedreich’s Ataxia stands as a rare, genetic, and progressively degenerative neuromuscular disorder, characterized by a life-shortening and debilitating impact on affected individuals. Serving as the most prevalent inherited ataxia, Friedreich’s Ataxia manifests with early symptoms such as a gradual loss of coordination, muscle weakness, and fatigue, typically emerging during childhood. These initial signs often present challenges in diagnosis as they can resemble symptoms of other conditions. Within a span of 10 to 20 years from the onset of symptoms, most individuals with Friedreich’s Ataxia will require wheelchair assistance due to the progression of the disease. Regrettably, the average reported age of mortality among Friedreich’s Ataxia patients stands alarmingly low at 37 years old. 

However, with tailored and targeted medical care, individuals affected by Friedreich’s Ataxia may extend their lifespan significantly even after reliance on a wheelchair for mobility. This underscores the critical importance of early diagnosis, comprehensive management, and ongoing support for those living with Friedreich’s Ataxia. Biogen’s European Commission approval of SKYCLARYS® (omaveloxolone) heralds a promising advancement in Friedreich’s Ataxia treatment. This innovative medication holds the potential to mitigate symptoms, delay disease progression, and offer newfound hope to individuals grappling with this challenging condition.