First Patient Enrolled in Phase 3 SMA Trial of Taldefgrobep Alfa

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by Marta Figueiredo, PhD |

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A Phase 3 clinical trial evaluating Biohaven Pharmaceuticals’ taldefgrobep alfa as an add-on therapy in children and young adults with spinal muscular atrophy (SMA) has enrolled its first patient.

The trial, dubbed RESILIENT (NCT05337553), expects to recruit up to 180 SMA patients already on disease-modifying therapies (DMTs), and is currently enrolling at Rare Disease Research, in Atlanta, Georgia. More locations are expected to open.

“This is an important milestone for the taldefgrobep program and for people living with SMA,” Irfan Qureshi, MD, Biohaven’s senior vice president of neurology, said in a company press release.

“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,” Qureshi added.

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“Additional research is needed to help improve the quality of life for people living with SMA,” and “we are happy to see progress being made with additional novel therapies focused on neuromuscular health,” said Han Phan, MD, the director of clinical research at Rare Disease Research.

“We are thankful for the SMA community that has welcomed and worked with us to develop this patient-focused study,” Qureshi said.

Originally developed by Bristol Myers Squibb and licensed to Biohaven early this year, taldefgrobep alfa (also known as BMS-986089) was designed to specifically bind to and block myostatin, a muscle protein that suppresses the growth of muscles involved in voluntary movement.

In preclinical studies and clinical trials, myostatin suppression resulted in a significant increase in muscle mass, supporting the approach’s potential to increase muscle strength and function in people with neuromuscular diseases such as SMA.

Taldefgrobep alfa, administered through under-the-skin injections, is an adnectin, a new family of therapeutic proteins derived from fibronectin, a protein found at high levels in blood, that works in a similar way to antibodies.

Specifically, adnectins form a stronger connection with their target and show higher specificity than standard antibodies, in addition to being highly stable, lingering in the body for long periods of time and potentially allowing less-frequent dosing.

As such, taldefgrobep alfa is expected to further improve motor function in SMA patients already on DMTs. Currently, three such therapies are available —  Biogen’s Spinraza (nusinersen), Novartis’ Zolgensma, and Roche’s Evrysdi (risdiplam). All work to increase the levels of SMN, the missing protein in people with SMA.

The experimental therapy was tested previously in several trials involving people with Duchenne muscular dystrophy, another neuromuscular disease. It was found to be safe generally, but signs of lack of effectiveness led to the discontinuation of its development by Roche, which had acquired licensing rights for DMD.

The Phase 3 RESILIENT trial now will evaluate the safety and effectiveness of taldefgrobep alpha as an adjunctive therapy for SMA patients ages 4–21 who  already are taking a stable dose of Spinraza or Evrysdi, or were treated with the one-time gene therapy Zolgensma.

The study is open to patients with all types of SMA, irrespective of their ability to walk.

Eligible participants must weigh at least 15 kgs (about 33 pounds), and must not have previously received anti-myostatin therapies, undergone spinal fusion surgery, or need invasive or non-invasive ventilation while awake.

Participants will be assigned randomly to receive an under-the-skin injection of either one of two weight-based doses of the experimental therapy (35 or 50 mg) or a matching placebo, once a week for 48 weeks (about 11 months).

Taldefgrobep alpha’s efficacy over a placebo will be assessed through changes in the validated Motor Function Measure-32 scale, which measures motor skills across a range of patients with neuromuscular diseases.

After completing the 48-week period, participants may choose to enter in the study’s extension phase, in which all will receive taldefgrobep alpha for a longer period.