Today, Replimune announced that it had received a complete response letter (CRL) in relation to the regulatory application filed for RP1 (vusolimogene oderparepvec) in combination with OPDIVO (nivolumab) for the treatment of patients with advanced melanoma. The stock price closed lower by 77% at $2.81 per share because of this FDA rejection. A major reason for the rejection is because this U.S. agency noted that it didn’t accept the IGNYTE trial as being a well-controlled clinical study to prove that the drug indeed is capable of treating these patients. The company itself is not just using this biologic to target all advanced melanoma patients. The criteria are that these are sick patients who progress in disease, despite taking both an anti-PD-1 and anti-CTLA-4 therapy.
This CRL is very shocking indeed because the company had been generating substantial clinical data to date, showing that the RP1 + OPDIVO combination is indeed effective in treating this specific subpopulation of advanced melanoma patients. More recently, it released two poster presentations at the 2025 American Society of Clinical Oncology (ASCO) meeting back on June 1st of 2025. While there were two posters presented, one of them highlighted data from the registrational cohort of the IGNYTE study targeting patients who had failed with anti-PD-1 therapies. It was revealed that the objective response rate (ORR) for the group of 140 patients was 32.9% using RECIST 1.1 criteria.
The therapy even went beyond only showing that patients could respond to therapy, providing credibility that it could also extend survival for many of these advanced melanoma patients. Most notably, even after 3 years, there was a 54.8% survival rate laid out. Another cause laid out by the FDA was that there was a huge deviation in the type of patients recruited. In essence, the heterogeneity of these patients. What this means is that even though they had the same disease, there were differences remaining to set them apart, and thus this is another item that the FDA didn’t like about the IGNYTE trial. It is quite possible that the FDA changed course on accelerated approvals.
That’s because this CRL was a huge surprise beyond the fact of what was highlighted in terms of the IGNYTE trial. Consider that the FDA had not only accepted the Biologics License Application (BLA) of RP1 + OPDIVO but also granted it Breakthrough Therapy Designation (BTD). In addition, what is also concerning is that the company had mid- and late-stage cycle reviews with the FDA, and none of these issues raised in the CRL were even brought up at any of such time points. Although this is really bad for the patients who needed a new treatment option, the company is not giving up hope. It expects to request an FDA Type A meeting and that such a move could be granted within 30 days.
Such a meeting will be crucial to lay out what the company can do moving forward to accelerate the pathway to regulatory approval. Typically, in this situation where a CRL is given, the company would use the ongoing confirmatory study as another way to eventually file for potential marketing approval of a therapy candidate. However, another issue raised in the CRL by the FDA was that there were some problems with the way that the confirmatory study it has, known as IGNYTE-3. The bottom line now is that the FDA Type A meeting needs to spell out exactly what Replimune must do in order to be in a position to re-file for regulatory approval of RP1 + OPDIVO for the treatment of these patients with advanced melanoma.
From what I gather, it doesn’t seem like Accelerated Approval is on deck based on the remarks laid out by the FDA itself. Thus, the fallback option is the confirmatory trial. However, if this can be used to eventually resubmit the BLA of RP1 remains to be seen, and if the company can resolve the deficiency of it cited by the FDA itself. The company is now in limbo, and what path it is to take next largely depends on what the possible outcome of a Type A meeting ends up establishing.
The hope is that the situation with RP1 for the targeting of advanced melanoma patients can be rectified, and that is because it is the primary focus of its entire pipeline. For instance, RP1 consists of an engineered HSV backbone, GM-CSF, and GALV-GP R, and the only difference between it and its other candidate RP2, would be that it would be the same as RP1 but with the addition of an anti-CTLA-4 component. The point being is that if the RP1 situation can’t be handled in terms of fixing regulatory issues, then there may not exist much hope for RP2. This other therapy candidate is being evaluated to treat patients with metastatic uveal melanoma (mUM) and hepatocellular carcinoma (HCC), or liver cancer.
The science of RP1 is to deploy an engineered herpes simplex virus (HSV) whereby attachment of a fusogenic protein known as GALV-GP-R and GM-CSF are put in place to increase tumor-killing potency. Specifically, RP1 is an oncolytic virus that has been developed to selectively only target and kill cancer cells. While this happens, the PD-1 inhibitor given alongside it is used to block PD-1 protein on the surface of cancer cells [removing brakes on the immune system], allowing the immune system to recognize and kill cancer cells. This mechanism of action (MOA) of this method was established in the IGNYTE trial, where a good number of patients responded (32.9% ORR) and a landmark 3-year overall survival (OS) rate of 54.8% was achieved.