A phase 3 trial of Biohaven’s taldefgrobep alfa in spinal muscular atrophy (SMA) has missed its primary endpoint. The biotech plans to talk to the FDA about the next steps in SMA and is stepping up its interest in obesity on the strength of the data.
Taldefgrobep is designed to inhibit myostatin and activin receptor signaling. Because myostatin inhibits muscle growth, Biohaven and other companies have identified the protein as a target of interest in rare diseases such as SMA. More recently, Eli Lilly, Roche and Scholar Rock have latched on to the potential for the mechanism to help people lose weight while retaining muscle mass.
Scholar Rock produced evidence that the approach can work in SMA in October, when positive phase 3 data on apitegromab sent its stock through the roof. Taldefgrobep’s effect on activin sets it apart from apitegromab but Biohaven has argued its molecule’s dual mechanism is a positive for its prospects.
Yet, Biohaven failed where Scholar Rock succeeded. After 48 weeks, SMA patients on taldefgrobep fared no better than their peers on placebo and standard of care on the MFM-32 measure of motor function, causing the trial to miss its primary goal. Biohaven said it saw clinically meaningful improvements in motor function at all timepoints.
The biotech identified a higher-than-expected placebo response in non-Caucasian subjects as a potential factor in the failure. According to Biohaven, enrichment of known, common genetic polymorphisms in non-Caucasian subjects may explain the “ethnic separation of responsiveness to therapy.” The situation offers “a potentially facile biomarker” for identifying patients who are likely to respond, Biohaven said.
Biohaven plans to talk to the FDA about the next steps. William Blair analysts said in a note to investors that the failure is “not a complete surprise” given significant differences between the Biohaven and Scholar Rock trials. Variability in the patient population “was a notable concern heading into the data,” the analysts said.
The analysts “have questions on the path forward in SMA” and cut their probability of success from 45% to 10%. That setback was softened somewhat by the data behind Biohaven’s pivot to weight loss. The analysts said they are encouraged by “observations of improved body composition” and see the obesity program as an interesting approach to potentially differentiate from current treatments.
Biohaven tracked a significant reduction in the change in total body fat mass in the taldefgrobep cohort compared to the control group. That improvement was accompanied by numerically larger increases in lean muscle mass and bone density on the study drug.
The results provide evidence that taldefgrobep can help counter a limitation of GLP-1 receptor agonists. Patients taking GLP-1 drugs such as Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound lose weight but the loss is driven by reductions in both muscle and fat. Muscle loss is undesirable, especially in older people.
Biohaven is preparing to study the ability of taldefgrobep on the loss of muscle and fat when used with a GLP-1 drug. The trial will also assess how taking the study drug as a monotherapy after the cessation of GLP-1 therapy influences weight regain. Scholar Rock is running a phase 2 trial of its drug candidate in obesity. Roche has a rival myostatin agent and Lilly picked up an activin inhibitor in its Versanis buyout.
Biohaven’s stock fell almost 7% to $42.60 in early trading Monday but had regained its losses by 10 am ET.