On Tuesday, 1/7/2025, the FDA shared updated draft guidance regarding weight reduction drugs and biological products.
In addition, Metsera published Phase 2 clinical data for its treatment of obesity (MET-079i).
Demand for GLP-1s continues to grow, with sales to the Type 2 diabetes and obesity markets predicted to reach more than $125B by 2033. However, one of the emerging side effects of drastic weight loss using GLP-1s is muscle loss, which can account for as much as 50% of the total weight lost. This is likely due to the caloric restriction and decrease in protein intake while patients are on GLP-1s. Also, it is likely because GLP-1s slow digestion and stimulate insulin production - decreasing appetite and reducing caloric intake.
This is an excellent mechanism for weight loss, but it also starves the body of the building blocks for muscle. It is important to preserve lean muscle mass for metabolic benefits, long-term weight management, and overall better health outcomes. Myostatin inhibitors may be useful in preventing the muscle loss associated with GLP-1 use. Fat loss and muscle gain generally point to a potential role for myostatin inhibitors in the treatment of obesity. Some studies are already advancing trials of myostatin inhibitor and GLP-1 combinations, the first data for which are expected as early as Q2 2025.
We’re mindful that the obesity landscape is evolving rapidly and that myostatin inhibitors are still in the early stages of research in that patient population. Future studies will need to show clinical benefit—likely in addition to GLP-1s—to be approved for use in obesity. Studies may show the effectiveness of myostatin inhibitors in treating other conditions of muscle wasting such as additional genetic conditions, cachexia, and aging.
With more than 25,000 people starting Wegovy each week and 42% of the adult U.S. population being obese, the opportunity for myostatin inhibition in combination with weight loss medications is growing. In patients over 50, age-related muscle loss has already begun in 10% of patients. Past this age, adults typically lose muscle mass each year. Combining a weight loss agent with an existing case of age-related muscle loss may spell worse outcomes and quality of life for these older patients who make up 45% of the treatable population, or roughly 50 million people.
While some large pharma players are developing myostatin inhibitors expressly for use in combination with weight-loss offerings, we believe greater opportunities may exist in the handful of small cap companies developing myostatin inhibitors indications in addition to obesity, like the rare neuromuscular disease SMA.
These smaller indications confer several advantages, including:
Expedited FDA review if data are positive
Rare disease price dynamics
Seven-year market exclusivity thanks to Orphan Drug Designation, also assigned by the FDA to treatments that address rare and high unmet need indications
The rare muscular dystrophy market is smaller than obesity (in the U.S., estimated at 250,000 people versus 105 million, respectively). Although this may be viewed as a disadvantage, it potentially enables small companies to launch drugs independently and thus realize the full return on investment versus needing to partner with a larger company in exchange for a percentage of sales.
Within muscular dystrophies, a disease-modifying therapy might expect 40% market share or more, whereas an obesity candidate competes against 20 other drugs and may capture just 5% of the market. Further, once a drug candidate has positive data in a rare disease, a larger company may feel the asset is sufficiently de-risked to allow for a commercialization partnership in a large indication like obesity. Among small cap companies developing myostatin inhibitors, their approaches differ in several ways:
The specificity of their molecule to mature myostatin over a latent precursor or other growth factors
The resulting tolerability profile
The associated change in muscle mass and strength
Their approaches may also differ in route of administration (i.e., injectable or infused) and frequency of dosing (i.e., weekly or quarterly). We believe safety will be paramount, as these inhibitors are intended for chronic use in a broad population that can be afflicted with comorbidities. The balance of safety and efficacy, as well as convenience of dosing, will determine which company takes the most share in rare disease and larger markets.
In conclusion, as we contemplate the number and strength of our muscle fibers during gym sessions, we remain optimistic about near-term data points and long-term indication expansion opportunities for this treatment modality.
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