Biohaven Commences Phase 3 Study of Taldefgrobep Alfa in Spinal Muscular Atrophy

Irfan Qureshi, MD

According to an announcement, Biohaven has enrolled its first patient in a new phase 3 study—the RESILIENT trial (NCT05337553)—which will evaluate the efficacy and safety of taldefgrobep alfa, an investigational, muscle-targeted recombinant protein, in patients with spinal muscular atrophy (SMA).¹

The placebo-controlled, double-blind trial is expected to enroll approximately 180 patients with SMA who are already taking a stable dose of nusinersen (Spinraza; Biogen) or risdiplam (Evrysdi; Genentech) or have a history of treatment with onasemnogene abeparvovec-xioi (Zolgensma; Novartis). Additionally, the study is not restricted nor limited to patients based on ambulatory status or classification of SMA.

Previously known as BMS-986089, taldefgrobep alfa is a fully human antimyostatin recombinant protein that lowers free myostatin and acts an activin 2b receptor antagonist with the myostatin-taldefgrobep complex. Originally developed by Bristol Myers Squibb, Biohaven acquired the worldwide rights to the phase 3 neuromuscular program in February 2022, while allowing Bristol Myers Squibb to benefit off potential regulatory approval milestone payments and tiered, sales-based royalties as part of the agreement.²

"This is an important milestone for the taldefgrobep program and for people living with SMA. There have been great strides in advancing therapeutics in this challenging disease. Yet, there remains a significant unmet need to address the residual weakness and functional impairments, such as difficulty walking, that are caused by the disease," Irfan Qureshi, MD, senior vice president, Neurology, Biohaven, said in a statement.¹ "We are thankful for the SMA community that has welcomed and worked with us to develop this patient-focused study."

READ MORE: Gene Therapy SRP-9001 Performs Well in Duchenne Muscular Dystrophy, Multiple Findings Show

Patients cannot enter the study if they’ve previously taken antimyostatin therapies or if they’ve had a history of spinal fusion. Furthermore, other exclusion criteria include presence of an implanted shunt for the drainage of cerebrospinal fluid or an implanted central nervous system catheter.

Before it was renamed taldefgrobep alfa, the therapeutic was assessed in several studies involving patients with other neuromuscular disorders, such as Duchenne muscular dystrophy (DMD). In one pivotal phase 1b/2 study (NCT02515669) treatment with the agent in a cohort of 43 ambulatory boys with DMD resulted in a dose-dependent reduction (77% to 97%) in free myostatin after 24 weeks. The drug also demonstrated a safe profile, with the most common adverse events being mild-to-moderate site reactions, which were resolved without change to study treatment.³

An additional phase 2/3 study called SPITFIRE (NCT03039686) further assessed the tolerability of BMS-986089 in 166 ambulatory boys with DMD over a 48-week treatment period. Analysis of the preliminary results indicated that the study was not likely to meet its primary end point of changes in North Star Ambulatory Assessment score, prompting Roche, who also entered a separate agreement with Bristol Myers Squibb in 2017 for the rights of BMS-986089 (also known as RG6206 at the time), to discontinue the trial.⁴

Han Phan, PhD, director, Clinical Research, Rare Disease Research, and associate professor of pediatrics, University of Alabama at Birmingham, said in a statement, "we are happy to see progress being made with additional novel therapies focused on neuromuscular health. Despite current therapies, a high unmet need for safe and effective supportive treatments for SMA remains, as many patients still experience significant weakness and reduced levels of functioning. Additional research is needed to help improve the quality of life for people living with SMA."¹

REFERENCES
1. Biohaven enrolls first patient in phase 3 trial of taldefgrobep alfa in spinal muscular atrophy (SMA). News release. Biohaven Pharmaceuticals. July 7, 2022. Accessed July 8, 2022. https://www.prnewswire.com/news-releases/biohaven-enrolls-first-patient-in-phase-3-trial-of-taldefgrobep-alfa-in-spinal-muscle-atrophy-sma-301581909.html
2. Biohaven licenses taldefgrobep alfa, a phase 3-ready anti-myostatin adenectin for spinal muscular atrophy (SMA), from Bristol Myers Squibb. News release. Biohaven Pharmaceuticals. February 25, 2022. Accessed July 7, 2022. https://www.biohavenpharma.com/investors/news-events/press-releases/02-25-2022
3. Wagner KR, Wong BL, Byrne BJ, et al. A phase 1b/2 study of the anti-myostatin adnectin RG6206 (BMS-986089) in ambulatory boys with Duchenne muscular dystrophy: a 72-week treatment update. Neurology. 2019;92(15 Supplement).
4. Roche Genentech releases letter to DMD community announcing discontinuation of clinical trials program for DMD. News release. November 6, 2019. Accessed July 6, 2022. https://strongly.mda.org/roche-genentech-releases-letter-to-dmd-community-announcing-discontinuation-of-clinical-trials-program-for-dmd/