Genentech’s Fenebrutinib Shows Unprecedented Positive Phase III Results as the Potential First and Only BTK Inhibitor in Both Relapsing and Primary Progressive Multiple Sclerosis

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that the first Phase III (FENhance 2) of two pivotal, similarly-designed Phase III studies (FENhance 1 and 2) in patients with relapsing multiple sclerosis (RMS) met its primary endpoint. Fenebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, significantly reduced the annualized relapse rate (ARR) compared to teriflunomide over a period of at least 96 weeks of treatment.

Additionally, the Phase III FENtrepid pivotal study evaluating fenebrutinib, compared with Ocrevus® (ocrelizumab) in patients with primary progressive multiple sclerosis (PPMS), met its primary endpoint. The results showed that fenebrutinib was non-inferior compared to ocrelizumab, the only approved therapy in PPMS, as measured by a delay in the onset of composite confirmed disability progression over a period of at least 120 weeks of treatment. A numerical benefit for fenebrutinib compared to ocrelizumab was seen as early as week 24, and lasted throughout the observation period.

“Fenebrutinib substantially reduced the number of relapses in RMS and slowed disability progression in PPMS. These unprecedented results suggest that fenebrutinib could potentially become a best-in-disease medicine as the first high-efficacy, oral treatment for people with RMS or PPMS,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. "Therefore, these pivotal results for fenebrutinib may offer new hope for people living with MS, and they reaffirm our enduring commitment to the MS community.”

Liver safety was consistent with previous fenebrutinib studies. Additional safety data is being further evaluated. The results of the second RMS Phase III trial (FENhance 1) are expected by the first half of 2026.

Fenebrutinib targets cells in the immune system known as B cells and microglia. Targeting B cells helps control the acute inflammation that causes relapses, while targeting microglia inside the brain addresses the chronic damage that is thought to drive long-term disability progression. Fenebrutinib, a non-covalent BTKi, is designed to have high potency, selectivity and reversibility. This design allows it to act throughout the body, and also to cross the blood-brain barrier into the central nervous system (CNS) targeting chronic inflammation.

About the FENhance 1 and 2 studies

FENhance 1 and 2 are similarly designed Phase III multicenter, randomized, double-blind, double-dummy, parallel-group studies to evaluate the efficacy and safety of investigational fenebrutinib compared with teriflunomide in a total of 1,497 adult patients with RMS. Eligible participants were randomized 1:1 to receive treatment with either oral fenebrutinib twice a day (and placebo matched to oral teriflunomide once a day) or oral teriflunomide once a day (and placebo matched to oral fenebrutinib twice a day) for at least 96 weeks.

The primary endpoint is annualized relapse rate (ARR). Key secondary endpoints include the time to onset of composite 24-week confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24).

Following the double-blind treatment period, patients have the option to enter an open-label extension (OLE) phase, in which all patients receive treatment with fenebrutinib.

About the FENtrepid study

FENtrepid is a Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of fenebrutinib compared with Ocrevus in 985 adult patients with PPMS. Eligible participants were randomized 1:1 to receive treatment with either daily oral fenebrutinib (and placebo matched to intravenous [IV] Ocrevus) or IV Ocrevus (and placebo matched to oral fenebrutinib) for at least 120 weeks.

The primary endpoint is the time to onset of 12-week composite confirmed disability progression (cCDP12). The cCDP incorporates three measures of disability – total functional disability measured by the Expanded Disability Status Scale (EDSS), walking speed measured by the timed 25-foot walk (T25FW), and upper limb function measured by the nine-hole peg test (9HPT). This comprehensive composite endpoint offers greater sensitivity than the EDSS alone, capturing additional aspects of disability and often earlier. Key secondary endpoints include the time to onset of 24-week composite confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24).

Following the double-blind treatment period, patients have the option to enter an open-label extension (OLE) phase, in which all patients receive treatment with fenebrutinib.

https://en.wikipedia.org/wiki/Fenebrutinib

Genentech’s Fenebrutinib Shows Unprecedented Positive Phase III Results as the Potential First and Only BTK Inhibitor in Both Relapsing and Primary Progressive Multiple Sclerosis - Drugs.com MedNews

FDA Approves Ekterly (sebetralstat) the First and Only Oral On-demand Treatment for Hereditary Angioedema (HAE)

KalVista Pharmaceuticals, Inc.  announced  the U.S. Food and Drug Administration (FDA) approval of Ekterly (sebetralstat), a novel plasma kallikrein inhibitor, for the treatment of acute attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older. Ekterly is the first and only oral on-demand treatment for HAE.

“The FDA approval of Ekterly is a defining moment for people living with HAE,” said Ben Palleiko, CEO of KalVista. “Ekterly enables people to treat attacks the moment symptoms begin, wherever they are. This approval affirms the strength of our science and deep commitment to the HAE community. I am profoundly grateful to the KalVista team for their dedication and perseverance, and to the patients and healthcare providers, as well as the HAEA and HAEi, for making this possible. Ekterly has the potential to become the foundational treatment for HAE, and our focus now is on delivering it to the people who need it.”

“As the first orally administered on-demand therapy for HAE attacks, Ekterly provides patients and physicians with an important and welcome advance in HAE treatment options,” said Anthony J. Castaldo, chief executive officer of the U.S. Hereditary Angioedema Association.

Prior to Ekterly’s approval, all on-demand HAE treatment options approved in the U.S. required intravenous or subcutaneous administration, which carries a significant treatment burden.1 Even with the use of long-term prophylaxis as a preventative therapy, most people living with HAE continue to have unpredictable attacks and require ready access to on-demand medication.1

“This is an important moment for patients, giving people living with HAE a treatment option that could provide greater independence and control over managing their condition,” said Marc A. Riedl, MD, Professor of Medicine and Clinical Director, U.S. Hereditary Angioedema Association Center at the University of California, San Diego, and an investigator for the KONFIDENT phase 3 trial. "Until now, on-demand treatment relied on injectable subcutaneous or intravenous administration, often resulting in delayed intervention. Having an oral option empowers patients to treat attacks early, which aligns with treatment guidelines and advances our goal as physicians to reduce the overall burden of disease.”

The efficacy and safety of Ekterly was established by the results from KalVista’s phase 3 KONFIDENT clinical trial, which was the largest clinical trial program ever conducted in HAE. Data from KONFIDENT was published in the New England Journal of Medicine in May 2024, showing that Ekterly achieved significantly faster symptom relief, reduction in attack severity, and attack resolution than placebo, and was well-tolerated with a safety profile similar to placebo.2 The trial randomized 136 HAE patients from 66 clinical sites across 20 countries. These results were further supported by the more real-world KONFIDENT-S open-label extension trial, which as of September 2024, showed that EKTERLY enabled patients to treat attacks in a median of 10 minutes following onset. The most recent data from KONFIDENT-S shows that beginning of symptom relief occurred in a median of 1.3 hours among attacks involving the larynx, the abdomen, and for breakthrough attacks among patients receiving long-term prophylaxis. The safety profile of EKTERLY 600 mg in KONFIDENT-S, in a much larger number of attacks (>1700), was consistent with that observed in KONFIDENT.

KalVista will launch Ekterly in the U.S. immediately, and physicians can begin writing prescriptions today. As part of the Company’s commitment to supporting patients, KalVista has established KalVista Cares™, a comprehensive patient support program that offers personalized services and resources for eligible individuals. This includes assistance with navigating insurance coverage, access support, and ongoing help throughout the treatment journey.

REF: https://en.wikipedia.org/wiki/Sebetralstat

FDA Approves Ekterly (sebetralstat) the First and Only Oral On-demand Treatment for Hereditary Angioedema (HAE)