FDA Plays Cynical Political Games to Keep Effective Cancer Drug from Patients

Under the current FDA, patients don't tire of losing. This time, the FDA re-rejected a drug which, when given together with anti-PD1 therapy, achieved a 32.9% overall response rate (ORR) in the IGNYTE trial in patients with unresectable advanced cutaneous melanoma who had progressed on anti-PD1 therapy. This is a far cry from the 6–7% expected ORR in this patient population with anti-PD1 monotherapy rechallenge (Ribas et al. 2018).

The FDA's Real Objections

In fact, it was not the question of whether oncolytic virus RP-1 had anticancer activity at all that the FDA took issue with. Instead, it was the academic questions of how much RP-1 contributed to the efficacy and how much of it was due to generating a systemic antitumor immune response beyond the oncolytic activity at the injected tumors.

Another issue that was raised was that the patient population in the trial was heterogeneous and whether certain subjects would have been better served receiving another existing treatment option. This partly accuses trial investigators of not having the best interest of their patients in mind, and is a question better suited for the melanoma societies to flesh out in the post-marketing setting. The more evidence for early treatment the sponsor, Replimune, provides, the more it would obviously be utilized.

Arguing Science Is a Waste of Time

But arguing the case for approving RP-1 based on science is a big waste of time. The FDA set Replimune up for a CRL from the moment it allowed it to resubmit its BLA. To achieve this, it replaced the primary review staff that until last summer wanted to approve RP-1, before a late-stage intervention from Pazdur and controlled-trial absolutist Prasad. Whereas Pazdur has already left the FDA, Prasad will leave it by the end of this month and has played a big part in reshaping it, degrading its quality of regulatory science — his handwriting is all over this CRL.

"Maintaining Objectivity" Is Evil Cynicism

So the claim that, to "maintain objectivity," the FDA replaced the review staff that had been in favor of RP-1 is just evil cynicism.  For example, in a since deleted Linkedin comment, Dr Peter Bross, former Chief of Oncology Branch 1 who had been involved in the first BLA review stated:

 He has subsequently been purged by CBER Chief Prasad.

Also, accusing the company of injecting all accessible tumors with RP-1 — which supposedly made it difficult to divine the systemic activity to be gained from adding RP-1 to anti-PD1 — is confusing actual patients with guinea pigs. Is the FDA requesting that patients be left undertreated and exposed unnecessarily to disease progression, just for the sake of scientific curiosity? Seriously?

Similarly, running a trial with three cohorts that would be required to figure out "contribution of components" (cohort 1: RP-1 mono; cohort 2: anti-PD1 mono; cohort 3: combo) is clearly unethical, and may be something you would possibly expect from ICER — the self-anointed body for determining the value of drugs to society and which is receiving substantial funding by ex-Enron trader John Arnold.

Mischaracterizing the FDA–Replimune Relationship

The "maintain objectivity" framing is also meant to mischaracterize the FDA–Replimune relationship as having been adversarial from the outset. While the agency would have preferred a different trial design in 2021 — that is, before this Trump FDA came to power — it did go along with the 6–7% ORR null hypothesis, granted RP-1 breakthrough therapy designation upon initial review of the data in November 2024, and until the very last minute wanted to approve RP-1 following the first BLA submission.

The Cherry on Top

The cherry on top of the cynicism came when the CRL explained why Replimune was allowed to submit the BLA in the first place despite the single-arm study design being unacceptable to the FDA. They claim to have only noticed the design issue "on review" of the BLA: 

Hey, you geniuses at the FDA, how about consulting ClinicalTrials.gov next time? And while you newcomers are at it, maybe align with your colleagues and get some coaching about SEC compliance — dropping the CRL online was the second time in a row that an FDA rejection was made public before a trading halt was instituted (see also the uniQure–Makary CNBC interview).

Bottom Line

Desperately ill patients are once again denied access to a clearly efficacious drug because the study design did not please aesthetically. This is all in fact a pretext to save money from being spent on expensive medicines for small patient populations — a key objective of the John Arnold Foundation, which has been a main financial influencer of the current FDA leadership.

To keep face and keep hopes of melanoma patients and treating physicians alive, a promptly scheduled Advisory Committee meeting to hear testimony from the melanoma expert und patient community, perhaps following the announcement of the new CBER Chief, could be a solution.  Absent signs of a potential reversal by the FDA, Replimune will be forced to kill RP-1 once and for all for financial reasons in yet another blog to the US biotech ecosystem.