At the American Academy of Neurology (AAN) 2024 Annual Meeting, Biohaven presented its Phase III RESILIENT trial (NCT05337553), which investigates the efficacy and safety of taldefgrobep alfa in patients with spinal muscular atrophy (SMA).

Taldefgrobep alfa is a myostatin inhibitor in development as an adjunctive therapy alongside marketed therapies to offer symptomatic relief to patients with type I-IV SMA.

SMA is characterised by the loss of lower motor neurons in the spinal cord, resulting in progressive muscle weakness, muscle wasting (atrophy), and low muscle tone (hypotonia), more commonly observed in the proximal muscles such as the shoulders, hips, and back.

However, neurons controlling most voluntary muscles such as those involved in feeding, swallowing, and breathing can also be affected.

SMA patients have reduced levels of survival motor neuron (SMN) proteins due to SMN1 gene mutations or deletions.

The availability of disease-modifying therapies, Biogen’s Spinraza and Roche’s Evrysdi, and curative gene therapy Novartis’ Zolgensma, which increase the amount of SMN produced in the body, have greatly improved disease prognosis, allowing patients to reach normal childhood development milestones.

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However, presenters at AAN 2024 and key opinion leaders previously interviewed by leading data and analytics company GlobalData highlighted that while these SMN-dependent therapies have revolutionised SMA treatment and advanced the care of patients with SMA, many SMA patients continue to have chronic motor impairments and functional deficits.

As such, there is a need for additional treatment options for patients with SMA.

Currently in clinical development are pipeline assets with novel mechanisms of action that are suggested to improve muscle function independent of SMN production.

Such therapies, if proven to be safe and effective, are expected to play a significant role in improving the quality of life of SMA patients.

Biohaven’s AAN 2024 poster presentation reported the design of the RESILIENT trial, a 48-week randomised, double-blind, placebo-controlled study of taldefgrobep alfa in SMA patients.

Taldefgrobep alfa is a bivalent, humanised, anti-myostatin adnectin modified with a human IgG1 Fc tail.

It is proposed to both block active myostatin and inhibit activin receptor type IIB signalling in skeletal muscle and increase muscle mass.

The trial has completed enrolment of 269 patients from across nine countries, including the US, Germany, Italy, Spain, and the UK.

In the presentation, Biohaven highlighted that the RESILIENT trial enrolment includes both ambulant and non-ambulant patients aged 4-21 years with any SMA type on stable treatment of Spinraza or Evrysdi, and/or have a history of treatment with Zolgensma.

Biohaven notes that the double-blind phase of the RESILIENT trial will conclude in the second half of 2024, and eligible participants can enrol in an open-label extension, in which they will receive taldefgrobep for 48 weeks before being assessed for an additional eight weeks in a safety follow-up period.

According to GlobalData’s Drug Database, there are two other myostatin inhibitors in Phase III development as adjunctive treatments for SMA: Scholar Rock’s apitegromab (TOPAZ [NCT03921528); SAPPHIRE [NCT05156320]; ONYX [NCT05626855]) and Roche’s RG-6237/GYM329 (MANATEE [NCT05115110]).

Apitegromab and RG-6237 are monoclonal antibodies against myostatin that are intended to be administered once per month via intravenous infusion and subcutaneous injection, respectively.

The lower dosing frequency of apitegromab and RG-6237 could be convenient to patients and their caregivers, offering an advantage against taldefgrobep alfa’s once-weekly subcutaneous injection.

However, the clinical trials for apitegromab and RG-6237 are restricted to specific SMA patient populations.

Currently apitegromab is being investigated in patients with SMA type II and type III on a stable treatment of Spinraza or Evrysdi, and/or with a history of treatment with Zolgensma, and the MANATEE trial is investigating RG-6237 in patients on a stable dose of Evrysdi and/or with a history of treatment with Zolgensma.

As such, there is an opportunity for Scholar Rock to expand the eligible population for apitegromab by investigating its efficacy in patients with SMA type I and type IV.

In addition, Roche may wish to consider investigating the efficacy of RG-6237 in patients on a stable treatment of Spinraza.

While the first-to-market myostatin inhibitor will have its own accolades, the size of the target patient population, strong efficacy data, and long-term safety data could provide a competitive edge for the myostatin inhibitors, should they receive regulatory approval.