In an open letter, 22 experts who designed and ran Replimmune’s Phase III IGNYTE trial answered the FDA’s issues, as outlined in the complete response letter for the melanoma candidate RP1.
On July 23, the FDA rejected Replimmune’s oncolytic immunotherapy RP1 for advanced melanoma. The researchers who designed and ran Replimmune’s Phase III IGNYTE study assessing the drug have urged the FDA to “re-review” the company’s application.
In an open letter sent on Friday—the full text of which was posted Monday on LinkedIn by the writers—22 experts responded to several issues outlined by the FDA in its complete response letter, leading to its refusal to approve RP1. The letter was spearheaded and organized by Michael Wong, physician in chief at the Roswell Park Cancer Institute and co-first author of the IGNYTE trial. Eric Whitman, who posted the letter and is a signatory, is the director of the Atlantic Melanoma Center. Twenty other melanoma and cancer experts have attached their names to the open letter.
In rejecting RP1, the FDA cited the “heterogeneity” of the IGYNTE patient population, flagging marked differences in participants’ prior exposure to therapies and severity of disease at baseline. But what the FDA sees as a methodological shortcoming, the experts consider representative of the real-world scenario. Current treatment guidelines, they argued, “show multiple treatment pathways in both the adjuvant and advanced disease setting funneling to the point of IGNYTE eligibility.”
“This means that this real-world population will be, by necessity, heterogeneous,” the open letter reads.
The FDA also raised questions about RP1’s efficacy, noting that given IGNYTE’s design—RP1 was tested in combination with Bristol Myers Squibb’s PD-1 blocker Opdivo (nivolumab)—it is difficult to establish RP1’s contribution to the documented response rate.
To address this concern, the experts argued, Replimmune would have to run a control arm with Opdivo monotherapy. But IGNYTE’s enrollment is already “rigorous,” they added, with patients receiving at least eight weeks of continuous anti-PD-1 therapy. Participants also need to stay on PD-1 treatment throughout the trial and have experienced disease progression on two occasions at least a month apart.
“A nivolumab monotherapy control arm would be impractical, unacceptable and borders on the unethical,” the researchers write.
In light of these clarifications, the experts “believe that reassessment” of IGNYTE is in order “to do right by our constituents and our patients.”
RP1, also known as vusolimogene oderparepvec, is composed of a proprietary and engineered strain of the herpes simplex virus carrying a fusion protein, according to Replimmune’s website. This construct attacks cancer cells and destroys them, while simultaneously altering the tumor’s microenvironment, in turn stimulating and activating the body’s anti-cancer immune response.
In IGNYTE, the combination of RP1 with Opdivo resulted in a 32.9% overall response rate in patients with melanoma who had previously failed anti-PD-1 therapy. Complete response rate was 15% and overall survival hit 54.8% at 3 years.
