The FDA’s approach to approvals has been all over the map, from declining to review Moderna’s mRNA flu vaccine application and then abruptly reversing course, to delaying decisions for various candidates — even those with priority vouchers.
Moves like these, along with the agency’s swift and often politicized overhaul of staff, expert panels and review processes, have made its decisions and actions more difficult to predict.
But three recent FDA rejections may offer insights into how these changes are reshaping the agency’s future.
They could also provide clues to what pharma and biotech companies can expect moving forward.
Disc Medicine’s bitopertin
The takeaway: The Commissioner’s National Priority Voucher isn’t a golden ticket.
Disc Medicine nabbed one of the FDA’s prized Commissioner’s National Priority Vouchers in October for bitopertin, a drug candidate for the rare hematologic disease erythropoietic protoporphyria.
The program promised to evaluate new medicines that address U.S. “national interests” in just one to two months. But that promise didn’t pan out for Disc. Not only did the FDA not review bitopertin within that accelerated timeframe, but it rejected the drug altogether.
The rebuff casts doubt on the effectiveness and value of the voucher program, with analysts at BMO Capital Markets stating in an investor note that the selection must not guarantee faster reviews or approval. It added that since the FDA had already agreed to Disc’s data, “the larger issue we’re seeing is inconsistency from FDA.”
The agency’s complete response letter said its ongoing study “could serve as evidence to support traditional approval,” down the road according to Disc. But the rejection also raises questions about how the FDA will treat upcoming decisions for other drugs that received a CNPV. Several have already had decision dates pushed back, including Eli Lilly's weight loss pill orforglipron, according to Reuters.
Boehringer Ingelheim's lung cancer drug zongertinib, another CNPV drug the FDA delayed, got the accelerated approval nod last week.
Regenxbio’s RGX-121
The takeaway: Despite promising additional flexibility for rare diseases, the FDA might insist on placebo controls and push back on previously approved trial design.
RGX-121, Regenxbio’s gene therapy for the ultra-rare neurodegenerative condition Hunter syndrome, was one of the year’s most anticipated FDA approvals. But it wasn’t to be. The FDA recently rejected RGX-121, citing a lack of a placebo-controlled arm, despite agreeing to the study protocol “in principle,” according to the company.
Several hot button issues and mixed messages are at play in this rejection, specifically around hope for greater FDA flexibility for rare disease approvals.
For instance, the FDA called on Regenxbio to conduct another study that treats additional patients and uses a placebo-controlled arm. However, Regenxbio noted that “would be challenging in an ultra-rare disease population,” which is why the company used natural history data in the first place. Hunter syndrome has a patient population of just 2,000 boys worldwide.
The FDA’s decision also runs counter to its new stated approach to rare disease reviews.
Just weeks after the agency rejected RGX-121, the FDA released new draft guidance to allow for more flexibility in trial design for individualized therapies in ultra-rare diseases when randomized controlled trials are not feasible due to small patient populations.
The draft guidance specifies “therapies that target a specific genetic, cellular or molecular abnormality and are designed to correct or modify the underlying cause of disease” and trials that rely on “well-characterized natural history data in untreated patients.” Both of those factors were at play for RGX-121.
Moreover, Regenxbio said it conducted “active discussions” with the FDA during the application process and submitted “additional data and responses to numerous information requests.” RGX-121 also had orphan drug, rare pediatric disease, fast track and regenerative medicine advanced therapy designations from the FDA.
Placebo study arms have been a sticking point in other therapeutic areas too, with agency leaders aiming to require them for new vaccine approvals.
Additionally, the FDA also seemed to renege on a previously approved study design when it declined to review Moderna’s biologics license application for its mRNA seasonal flu vaccine, a decision it reversed eight days later.
Corcept Therapeutics’ relacorilant
The takeaway: The FDA’s publication of complete response letters can land companies in hot water.
When Corcept Therapeutics’ Cushing’s syndrome drug relacorilant was hit with an FDA rejection in December, the company’s CEO said it was “surprised and disappointed” by the outcome. But an updated complete response letter published by the FDA a few weeks later told a different story.
“During the pre-submission meetings, we informed you on several occasions of our concerns about the adequacy of the clinical development program … and to expect significant review issues if you were to submit your application,” the letter said. The agency also “concluded that relacorilant is associated with drug induced liver injury.”
Corcept has since been hit with a class action lawsuit from shareholders who claim the company misrepresented its new drug application for relacorilant.
The FDA aimed for this kind of increased transparency when it announced in July it would start publishing CRLs for the first time.
“Because the FDA has historically refrained from publishing CRLs for pending applications, sponsors often misrepresent the rationale behind FDA’s decision to their stakeholders and the public,” the agency said in its announcement.
Because of the new FDA policy, legal experts advised caution among industry leaders, with one law firm warning life sciences companies to “carefully assess and re-evaluate their existing disclosures.”
