- Adverum Biotechnologies will stop testing an experimental gene therapy in patients with diabetic macular edema after multiple clinical trial participants who received a high dose of the treatment developed a serious side effect.
- The biotech unmasked the Phase 2 study in April when one treated participant experienced inflammation, vision loss and decrease in eye pressure. On Thursday, the biotech said four more experienced similar side effects. None responded to steroids and three required surgery to repressurize the treated eye.
- Adverum still hopes to advance a lower dose of the gene therapy that hasn't been associated with those side effects in age-related macular degeneration. But U.S. regulators will have to sign off on plans for a newly designed trial and analysts are skeptical whether the gene therapy, known as ADVM-022, has a future.
There are already several effective therapies for diabetic macular edema and age-related macular degeneration, two leading causes of vision loss. Though those drugs, like Eylea and Lucentis, require frequent injections, they're considered safe. That makes the bar for gene therapy, which is aimed at eliminating the need for chronic treatment, much higher.
Adverum was already on thin ice after the first report of inflammation and deflation in an eye of a trial participant. Disclosure of four new, similar cases in DME patients — events Adverum described in a statement as "not seen before in ocular gene therapy" — lengthens already long odds for the program's success.
Adverum suggested that underlying conditions DME patients can have, such as vascular disease, may make them more susceptible to the severe inflammation researchers observed. No such side effects were observed in DME patients treated with a lower dose or in participants with AMD in a separate trial, some of whom have been monitored for more than two years.
Adverum claims ADVM-022 still has a future in AMD if patients get a lower dose than previously planned along with a different regimen of protective drugs.
The data "shows that disease matters, and dose matters," said CEO Laurent Fischer, on a conference call. The company scrapped plans to start two Phase 3 trials in AMD later this year. But it aims to start a new mid-stage study in 2021, after completing an investigation of the adverse events and discussing the findings with regulators.
"Gene therapy is a relatively new field, we're pushing boundaries," Fischer added.
Analysts, however, are unsure Adverum can rebound. The company still doesn't know why the side effects occurred, making it difficult to gauge the risk AMD patients face. While DME patients "may be at higher risk", wrote RBC Capital Markets analyst Luca Issi, AMD will be challenging for Adverum as well, as "the risk is difficult to mitigate given the etiology is unknown."
Additionally, Adverum has fallen further behind competitor RegenXBio, which is developing a similar gene therapy for AMD and began two Phase 3 studies earlier this year.
"With no mechanistic explanation for the toxicity, and a multi-year delay in development, we struggle to see any viable path forward" in AMD, added Mani Foroohar, an analyst at SVB Leerink. At less than $3 apiece, shares are trading below cash, implying a negative value for the program, he wrote in a note to clients.
Foroohar suggested Adverum attempt a reverse merger, a way for struggling biotechs to bring in new assets by combining with a privately held company seeking fast access to public markets. Such a deal would be familiar territory for Adverum. The biotech was formed through a 2016 reverse merger between Annapurna Therapeutics and Avalanche Biotechnologies, after an Avalanche gene therapy for AMD disappointed.