Obefazimod

Since launching eight years ago, Causeway Therapeutics has quietly developed a synthetic microRNA molecule it hopes will heal tendon injuries and tested the novel drug in a pair of clinical trials on a slender budget of $26 million. The company shared the results of its Phase 2 study for the first time in an exclusive interview with Endpoints News and hopes to raise more funding despite the trial missing its main goal. In 120 patients with tennis elbow — or lateral epicondylitis — the drug failed to meet its primary endpoint of pain reduction. But Causeway said a quarter of patients were improperly injected, and when they were excluded, the drug had a statistically significant reduction in pain and improvement in elbow function. The Glasgow-based company is gearing up for a Phase 3 trial of the drug in tennis elbow and a Phase 2 study in rotator cuff tendinopathy. Causeway has begun reaching out to investors and hopes to raise a Series A round “in the order of $150 million-plus” to complete those bigger studies, CEO Declan Doogan told Endpoints. “We believe this drug has the potential to be a tendon disease modifier,” Doogan said. “Our belief is that one dose of this agent is sufficient to catalyze a repair mechanism within the tendon, and that will continue on after the end of the study.” If the company can raise the money needed for its bigger studies, it could be one of the first times a drug based on synthetic microRNA reaches a Phase 3 trial. Regulus Therapeutics, which was acquired by Novartis this year, was planning a Phase 3 study of its oligonucleotide drug farabursen, which inhibits a microRNA involved in kidney disease. And this summer, Abivax announced a success in a Phase 3 study of its small molecule obefazimod, which boosts a microRNA to combat ulcerative colitis. MicroRNAs are important for controlling how whole swaths of related genes are turned on and off. Since they were discovered more than 30 years ago, scientists have linked the abundance or deficiency of numerous microRNAs to many diseases. Two scientists who discovered microRNAs were awarded the Nobel Prize in Physiology or Medicine in 2024. But the development of new therapies based on the molecules has been slow, in part because the complex functions of microRNAs make them more challenging to study than their simpler cousins, siRNAs, which can be programmed to knock down the expression of a single gene. Causeway has been working on the problem since 2017, when it was founded by orthopedic surgeon Neal Millar, the startup’s chief medical officer, and molecular biologist Derek Gilchrist, who serves as chief scientific officer. The company was based on the observation that a particular microRNA known as miR-29a decreases in tendons when the tissue fails to heal after injury — of which Causeway’s drug is a synthetic mimic. Low levels of miR-29a are associated with inflammation and the formation of weaker tendons made of collagen type III. Higher levels of the microRNA lead to stronger tendons made of collagen type I. “Collagen III is an imperfect response to tendon injury,” Doogan said. “What we can do is suppress it and allow the natural change in collagen I lead to the restoration of proper fiber alignment.” The randomized, double-blind Phase 2 study tested a single dose of 200 µg or 500 µg injected into the injured tendon. One-third of the participants got a subdermal saline injection as a placebo. The study hasn’t been publicly presented or published yet, but in a company presentation that Causeway shared with Endpoints, there was no difference in pain reduction or measures of limb and elbow function among the three groups after 90 days. Doogan said that an independent radiologist who reviewed the injections found that 27% of patients didn’t receive the microRNA drug in the correct part of the tendon. Causeway started the trial in “expert centers,” but later expanded it to commercial and generalist clinics that proved more likely to inject the drug improperly, he said. Doogan remains optimistic about the subanalysis of patients who got the proper injections and said the company isn’t “foraging around in the data to see a signal.” He also pointed to Causeway’s analysis of ultrasound images, which suggests that patients on the drug continued to have lower tendinopathy scores, falling from severe to mild disease over the 90-day study. People who got the sham injection plateaued with moderate disease. Doogan believes that difference “will continue to be amplified” over time.