Ozempic, Wegovy have become the pharmaceutical drugs of the moment thanks to their powerful weight loss effects.

Nearly half of Americans have said they would take one of these so-called GLP-1 agonists, which are part of a market projected to be worth as much as $100 billion by 2030.

However, these in-demand drugs still have drawbacks, from unpleasant side effects to high price tags. They can also cause loss of lean tissue as well as fat, said Peter Ackerman, head of clinical development at Biohaven.

The Connecticut-based drugmaker sold its portfolio of migraine medicines to Pfizer for $11.6 billion and spun out its remaining research into standalone company. Along with clinical-stage candidates for epilepsy and OCD, Biohaven is investigating a weight loss drug that works differently than GLP-1s.

“There are concerns not about the amount of weight loss that's being generated, but the quality of the weight loss,” said Ackerman.

Up to 40% of the weight people lose when taking GLP-1 agonists might come from lean mass loss, which includes muscle. This could affect functional ability, and emerging data has linked low lean mass with higher overall mortality and poorer metabolic health — worrying challenges for drugs now recommended as a long-term therapy, Ackerman said.

Biohaven thinks it may have an option that could strike a better balance between weight loss and muscle preservation. A myostatin inhibitor called taldefgrobep alfa, the experimental drug was licensed from Bristol Myers Squibb in 2022. In preclinical animal testing, the candidate led to weight loss and increased lean tissue.

“We believe with our ability to reduce fat mass, which is the primary pathologic tissue in the disease of obesity, as well as increase lean mass and improve those metabolic parameters that are associated with obesity, taldefgrobep can provide meaningful change or benefit,” he said.

Muscles matter

Myostatin is a muscle-regulating protein that keeps muscles from growing too large. Laboratory mice without a myostatin gene had their muscle mass double, sparking interest in developing myostatin inhibitors that block the protein to treat muscle-wasting disorders.

Several companies are developing these drugs for that use, including Biohaven. Taldefgrobep alfa is also in Phase 3 testing for spinal muscular atrophy, a rare, often fatal condition that affects young children, leading to the loss of motor neurons.

Now some are giving the approach a closer look for obesity, too.

“There are a lot of anti-myostatin drugs being developed out there, some of them being explored in the obesity space,” Ackerman said. “We’re excited about our mechanism without judging anyone else’s.”

Among their competitors is Boston-based Versanis Bio, which is testing bimagrumab, an activin receptor type 2B antagonist, now in Phase 2b. An earlier Phase 2 trial that enrolled people who were overweight or obese and had Type 2 diabetes found bimagrumab decreased total body fat mass by 20.5% and lean mass increase by 3.6%. In July, Eli Lilly, which makes the GLP-1 drugs Mounjaro and Zepbound, agreed to acquire Versanis for as much as $1.9 billion.

Scholar Rock is in preclinical stages with a myostatin inhibitor candidate called SRK-439 and moving into Phase 2 with another drug, apitegromab, that researchers will test in combination with a GLP-1 drug.

A new mechanism of action

“[Taldefgrobep alfa] is markedly different from the current and new obesity medications that are out there,” said Ackerman. “Body mass depends on the intake and the output of energy, the balance — anti-obesity medications work on the former, which is the energy intake piece.”

These drugs make people feel full, so they eat less, and “as a result, you lose tissue stores, including fat and lean muscle mass,” he said.

Taldefgrobep works on the energy expenditure side, spurring the body to burn more calories.

Because taldefgrobep already has a known safety profile, Biohaven can jump to a Phase 2 trial, planned for the first half of 2024, Ackerman said. The company may measure the drug’s effects differently than other obesity drugs.

“Historically, regulators in the field assess the quality or the efficacy of obesity medicines based on change in total body weight,” Ackerman said. But because the drug generates an increase in lean tissue, the company is exploring the idea of using a different measure such as reduction in waist circumference or waist-to-hip ratio.

“We need more sensitive measures for the quality of the weight loss that's occurring or in the quality of the body composition change that's occurring,” he said.

It’s not clear how taldefgrobep might compare to GLP-1 inhibitors when it comes to side effects. GLP-1 inhibitors can bring unpleasant gastrointestinal symptoms and have been linked to a potentially serious condition called gastroparesis, which is stomach paralysis that impedes digestion, as well as pancreatitis, or inflammation of the pancreas.

In testing, taldefgrobep alfa, administered as a once weekly injection, most commonly led to side effects such as injection site reactions, headache, stomach upset and pain, Ackerman said.

Moving forward, Akcermain said Biohaven will need to answer an important question: Can people who lose weight using the company’s drug keep it off?

“What's the role of a drug like ours? That's a critical question in front of the field right now,” Ackerman said.