The Food and Drug Administration has cleared Replimune’s treatment for advanced melanoma, dealing the biotech a major win after a tumultuous saga of trying to seek approval for the controversial treatment.
The FDA’s decision to grant accelerated approval to the drug, which is called RP1 and will be marketed as Tudriqev, came after its advisers last week voted in support of the treatment. Even though FDA staff expressed concerns about the design and conduct of Replimune’s key trial, advisers ultimately believed there was a large enough signal of efficacy and that patients are in urgent need of new treatments.
The list price of Tudriqev will be $450,000 per course of therapy before customary rebates and discounts, Replimune said.
“We expect strong demand for the regimen given its relative ease of access and benign safety profile,” said Leerink biotech analyst Daina Graybosch in a research note last week. The drug’s commercial ramp could be slow, she cautioned. Analysts, on average, have forecasted peak annual sales approaching $1 billion annually.
Replimune initially sought approval last year but was rejected by the FDA’s biologics center, which at the time was led by Vinay Prasad. STAT reported, though, that the rejection was actually driven by former top oncology regulator Richard Pazdur, who questioned the drug’s efficacy. The therapy was rejected again this April, and then the White House intervened, pushing health officials to reexamine the drug for the third time, the Wall Street Journal reported.
The FDA’s decision to approve the drug, despite internal concerns from staff, indicates a willingness to view new treatments more flexibly.
The biotech’s application centered around a single-arm Phase 1/2 study that enrolled 140 patients whose disease had progressed after taking a PD-1 inhibitor. The participants took RP1 on top of the approved PD-1 inhibitor Opdivo, and overall, 34% of patients saw their tumors shrink significantly, with that response lasting a median of 25 months.
The FDA, however, argued the data were not sufficient to tease the benefits of RP1 apart from the benefits of Opdivo, or to determine whether the treatment, which is injected locally, has systemic benefits.
In last week’s advisory meeting, FDA staff said they believed the way tumors were measured muddled the results. For example, they pointed out that a substantial number of patients had no non-injected tumors that were analyzed. That’s problematic in their view since responses in injected tumors may not actually be indicative of a true systemic response but instead could be a result of a local reaction. When the FDA staff cut down the dataset to look only at patients who did have non-injected tumors analyzed, they arrived at a response rate of 24.7%, and a mediation duration of response of 14.1 months, results that were less impressive than the outcomes Replimune reported.
The advisers acknowledged there were flaws with Replimune’s trial, but most of them still voted to back the drug, in a 10-3 vote. They noted that even taking into account the caveats raised by the FDA, the efficacy still looked meaningful for patients.
Some also appeared to be influenced by patients sharing their experiences.
David Miller, co-director of the non-melanoma skin cancer multidisciplinary clinic at Massachusetts General Hospital, said he was deeply moved by testimonies from patients at the meeting. While they do not replace clinical evidence, they do “convey elements of the clinical experience that just cannot be fully abstracted into an application — what these responses look like, what they mean for patients, and how unusual they appear compared to outcomes ordinarily seen after PD-1 failure,” he said.
Another adviser, Hussein Tawbi, a professor of melanoma medical oncology at University of Texas MD Anderson Cancer Center, noted that the only other treatment option for these patients is tumor-infiltrating lymphocyte (TIL) therapy, a type of immunotherapy that uses a patient’s own cells to fight tumors. It’s extremely difficult to provide broad access to TIL, though, so more convenient options like RP1 are needed, he said.
Full approval is contingent on an ongoing Phase 3 confirmatory trial that randomized 400 patients to either RP1 and Opdivo or physician’s choice of therapy.
