Capricor Therapeutics has been performing a balancing act with its lead drug for more than a year. After the cell therapy posted positive mid-stage data in May 2020 for the rare disease Duchenne muscular dystrophy, the company began shopping the asset to potential partners. Along the way, the biotech spoke with the FDA multiple times, trying to find a path to file for accelerated approval based on the preliminary Phase 2 results.

So far, no pharma partner has signed on, perhaps because no company wants to take on the therapy, CAP-1002, without knowing for sure what the next regulatory steps will be. The FDA urged Capricor to conduct a Phase 3 test, and the biotech is now preparing to do so. But the partnering search continues, and Capricor has a fresh analysis of the full Phase 2 data so suitors will have a better look at what they could be getting (and what more the FDA wants to see). Beverly Hills, California-based Capricor presented those results Friday at the World Muscle Society Virtual Congress.

Duchenne is an inherited disorder in which patients are unable to produce a key muscle protein, causing them to develop progressive weakening of skeletal and cardiac muscle. The disease leads to death by the late teens or early 20s. There is no cure, but drugs have been developed and approved to treat the condition. The first, an antisense oligonucleotide from Sarepta Therapeutics, is designed to get cells to produce a version of the key muscle protein that Duchenne patients lack.

Capricor’s CAP-1002 is derived from cells that come from donated heart muscle. The cell therapy does not engraft into the host’s tissue. It works by secreting exosomes, tiny vesicles carrying lipids, proteins, and nucleic acids. That cargo is delivered into target cells. Capricor scientists believe that this approach decreases inflammation and slows muscle degeneration, and perhaps even sparks muscle regeneration.

The Phase 2 test of CAP-1002 was a placebo-controlled study enrolling 20 boys and young men with Duchenne, all of them already receiving corticosteroids that can slow muscle damage and weakness. About 80% of the study participants were unable to walk. All of the patients were randomly assigned to groups given either an infusion of the cell therapy or a placebo every three months for one year. The main goal was to assess patients according to Performance of the Upper Limb (PUL), a rating scale designed to assess shoulder, elbow, and wrist and hand function.

In the study, eight patients received the treatment while 12 were given a placebo. Craig McDonald, chair of the Department of Physical Medicine and Rehabilitation at the University of California, Davis, and the lead investigator for the clinical trial, said on a conference call Friday that the results showed that the patients treated with CAP-1002 had statistically significant changes in both skeletal and cardiac function. The therapy was well tolerated by patients. Two patients experienced hypersensitivity reactions early in the study, which were mitigated with a pre-medication regiment. No serious safety signals were reported.

Beyond showing statistically significant changes according to PUL, McDonald said that the results translated into improvements in the daily lives of patients. He explained that PUL is highly predictive of the loss of hand-to-mouth function, and patient advocacy groups say that the measure is clinically meaningful.

“The complete loss of hand-to-mouth function makes someone totally depending on others for feeding, scratching their nose, scratching their scalp or getting their hand to the scalp to be able to comb their hair, or even be able to brush their teeth independently,” he said.

The first FDA-approved Duchenne therapy, Sarepta’s Exondys 51, addresses a subset of patients who have a particular genetic mutation. The approval was based on a small, open-label study whose results, measured by a walking test, were unclear about how well the treatment worked. The Cambridge, Massachusetts-based biotech has since won approvals for two more Duchenne therapies. Last summer, the FDA approved yet another Duchenne treatment, NS Pharma drug Viltepso.

The Sarapeta and NS Pharma drugs reached the market under accelerated approval decisions. Each of those therapies addresses subsets of Duchenne patients with rare genetic mutations. Capricor’s experimental treatment does not address any particular genetic subset of patients, and that could be one reason why the FDA wants to see more data from a larger group. Capricor CEO Linda Marbán said the FDA recognizes the strength of CAP-1002’s data, as well as the potential clinical significance. However, the agency told the company that the sample size was too small to grant accelerated approval, and therefore asked the company to conduct a larger Phase 3 clinical trial.

The Phase 3 test of CAP-1002 will enroll 65 to 75 patients at up to 20 U.S. sites, Marbán said. In addition to being larger, this study will also include patients who are younger and still have the ability to walk. Based on the FDA’s feedback, the main goal will be to assess PUL. Meanwhile, Capricor is still looking for a larger company that can partner on the development and potential commercialization of the drug.

Capricor previously had a partner for CAP-1002. The cell therapy was first tested in cardiovascular applications. In 2014, Johnson & Johnson’s Janssen Biotech subsidiary struck up an alliance, paying $12.5 million up front to gain an option to develop the therapy. Janssen returned the rights to the experimental treatment in 2017 after Phase 2 results showed the drug was unlikely to be successful in reducing scar tissue caused by a heart attack. That failure led the company to shift its focus to developing CAP-1002 for Duchenne.

Marbán said Capricor is in “active discussions” with several potential partners. The company aims to secure a partnership before clinical trial enrollment begins.

Public domain image by Flickr user Berkshire Community College Bioscience Image Library