Biohaven announced this week that its phase 3 trial of taldefgrobep alfa, a recombinant protein targeting myostatin, had failed to meet its primary endpoint in patients with spinal muscular atrophy.
Spinal muscular atrophy (SMA) is a rare neurodegenerative disorder causing loss of motor neurons as well as muscle wasting. It is caused by mutations in the SMN1 gene and there are about five different types of SMA that are characterized by severity and age of onset, with the majority of cases showing symptoms in early childhood.
There are now a few treatments available for SMA, including the gene therapy Zolgensma and the antisense oligonucleotide therapy (ASO) Spinraza, but these are focused on treating the neurological symptoms of the condition and not the muscle wasting.
Recently, the potential of inhibiting myostatin activity has been recognized as having potential for improving muscle function in people with conditions like SMA. Myostatin is a natural limiter of muscle growth so inhibiting its action allows muscles to become bigger and stronger than they would otherwise be, which could help people with muscle weakness.
There have also been some successes in SMA patients, for example, Scholar Rock announced positive phase 3 results for its myostatin inhibitor earlier this year.
Biohaven’s RESILIENT SMA study tested taldefgrobep in addition to standard SMA care versus placebo and standard SMA care in a population of just over 200 patients. Although some improvement in motor function was seen in the treatment group, it was not significantly greater than that seen in the placebo group.
The company stated that people of Caucasian ancestry and those with measurable myostatin at enrollment had better motor function results than other study participants.
“SMA is a devastating rare disease and although we are disappointed that taldefgrobep did not achieve a statistically significant difference in the broad study population… we are encouraged that a majority subgroup did show a treatment benefit compared to the placebo arm,” said Cliff Bechtold, Taldefgrobep Development Lead and President of Biohaven Ireland, in a press statement.
“The observed treatment effect on motor function, which had a similar magnitude on the Motor Function Measurement-32 scale after 1 year of treatment as approved therapies (i.e., risdiplam), along with the strong biomarker evidence of target engagement, suggests that taldefgrobep may play a potentially beneficial role in a majority subgroup population of SMA patients.”
Exploring a second indication
Although the results for taldefgrobep are disappointing for SMA, the company is also testing the drug for treatment of obesity. This development program is at an earlier stage (phase 1/2) but according to the company, the results from the SMA trial support this second indication.
In the trial, patients treated with taldefgrobep had a significant reduction in total fat mass and increase in lean muscle mass and bone density compared with the placebo group at the end of the study.
The metabolic effects of taldefgrobep could give it an edge against other anti-obesity drugs such as GLP-1 receptor analogs like Novo Nordisk’s Wegovy (semaglutide) and Eli Lilly’s Zepbound (tirzepatide), as while they are effective at inducing weight loss they trigger the loss of both fat mass and muscle mass.
It is undoubtedly a competitive market, however, as both Roche and Eli Lilly are exploring anti-obesity candidates that will help protect muscle and Scholar Rock is also testing its SMA candidate in obesity as well. Whether Biohaven can compete with other players in this area remains to be seen.
