UPDATE: Agenus withdraws cervical cancer application, and a behind the scenes David vs. Big Pharma regulatory battle is revealed

Agenus’ cervical cancer drug balstilimab seemed on its way to FDA approval, but the biotech is now pulling the application after the agency granted full approval to Merck’s Keytruda in the same indication.

The biotech said in a statement released today that a filing for the approval of balstilimab is being voluntarily withdrawn, but according to a source with knowledge of the decision, the FDA pushed Agenus into a corner and recommended that the request be retracted.

Agenus Chairman and CEO Garo Armen, Ph.D., has urged the FDA’s Richard Pazdur, M.D., to intervene and allow the company’s therapy to be reviewed under the accelerated pathway, according to a document seen by Fierce Biotech.

This one gets into the weeds a bit, so stay with me here: Keytruda was granted accelerated approval in second line cervical cancer back in 2018. Earlier this month, the drug was moved up to the first-line setting as well. At that time, the FDA also confirmed that the accelerated approval in the second-line setting had been converted to a full approval. Merck submitted data from the first-line setting to support the second-line decision.

RELATED: Merck bags imperfect immunotherapy first with Keytruda cervical cancer approval

This is standard practice in the industry. New drugs often start out as later-line therapies before moving up to the first-line setting, and data from the earlier-line treatment can be used to support the later-line settings.

If you’re still with me, Agenus’ complaint is this: once the full approval was granted to Keytruda in the second-line setting, “the window for accelerated approval of balstilimab closed,” according to a company press release. The agency acted four months ahead of the goal date for Merck’s application. Had the FDA stuck with that goal, Agenus would have had a shot at securing the coveted accelerated approval.

Agenus found out about the Merck approval the same day it met with the FDA in a late-cycle meeting, a regulatory meeting that happens towards the end of the FDA's consideration of an application. 

"This seemingly quick approval of pembrolizumab (Keytruda) hours before Agenus’s late-cycle meeting suggests that FDA may have afforded special consideration to Merck, the sponsor of the pembrolizumab application," Armen wrote to Pazdur, who serves as director of the Oncology Center of Excellence for the Center for Drug Evaluation and Research. "The fact that pembrolizumab’s approval blocked Agenus’s chances of accelerated approval further implies that FDA was not intending to afford balstilimab the full and fair review that it deserves."

In an interview following a conference call with investors Friday morning, Armen said the FDA issued the release about the Keytruda approval before the meeting.

"The first thing they did was cite the fact that Merck had been approved, and the window for us for accelerated approval was no longer available," he said. "They didn't discuss any substance, nothing about the product efficacy or anything like that. So as far as we're concerned, this is a technicality and the agency's entitled to do whatever they need to do."

Armen asked Pazdur in the letter to step in to ensure the agency is fostering an environment that supports innovation and competition to "offset a monopolistic environment by large companies."

David vs. Big Pharma

Accelerated approvals have become a flashpoint for the FDA since the approval of Biogen’s Aduhelm under this pathway. The agency can approve drugs this way when they address “a serious or life-threatening disease or condition,” when a drug has an effect on a surrogate endpoint that is “reasonably likely to predict clinical benefit,” or when a clinical endpoint suggests an effect on “irreversible morbidity or mortality.” The guidelines also take into account the availability or lack of alternative treatments.

RELATED: Biogen's aducanumab crosses FDA finish line just in time to save its business

According to Armen, these criteria still fit the balstilimab application to a T, and Keytruda’s approval should have no bearing on Agenus’ application under the law.

“FDA’s own precedent recognizes the clinical value in making multiple therapies available to meet the diverse needs of patients in a single disease setting,” he wrote.

The FDA apparently advised Agenus that any therapy coming after must show improvement over existing ones and that the balstilimab application had not shown it could improve upon Keytruda's performance. Accelerated approvals are reserved for therapies that can fill an unmet medical need, according to the agency. So if Merck has filled that need, Agenus now has a higher bar to meet. 

Agenus also argues that Merck didn’t have to submit any extra data to support the second-line full approval. Accelerated approvals are granted on the basis that the company must conduct a confirmatory trial, so Armen believes that Merck was given special treatment. Merck submitted data from the KEYNOTE-826 trial based on patients who had not received prior treatment with chemotherapy. 

The chief executive said that Agenus’ therapy has a better safety profile and could provide treatment for a wider range of cervical cancer patients than Keytruda. 

RELATED: Agenus, with FDA approval in sight, showcases anti-PD-1 data

Armen argued to Pazdur that the FDA was looking at the objective response rate (ORR) for the trial overall, which hit 14%, and not the PD-L1-positive subgroup, which got to 20% compared to Keytruda’s 14.3% from its KEYNOTE-158 trial, which won Merck the accelerated approval for patients whose tumors express the PD-L1 protein. He also believes the PD-L1-negative population remains an unmet need. There, balstilimab achieved a 9% response rate compared to 0% with Keytruda.

The CEO said in the interview that the FDA would not consider the negative population for a narrowed indication. 

"We've tried to argue that point but their pushback has been the numbers are small," Armen said. 

While Armen did not state what Keytruda's ORR was for the entire trial, not broken down by subpopulation, a study published in August in Gynecologic Oncology of Agenus' data suggests that number was 12%. So 14% for balstilimab would represent a modest but not earth shattering improvement.

Armen said the study achieved the "prespecified accelerated approval-eligible endpoint" of overall response rate. Armen also noted the study's larger size of 125 women treated with balstilimab, compared to 77 for Keytruda. KEYNOTE-158 included an additional 21 Keytruda-treated patients who were PD-L1 negative. 

“Agenus believes that the reviewers are overlooking the fact that balstilimab had demonstrated efficacy and safety in a much larger trial than pembrolizumab and has met or exceeded accelerated approval endpoints agreed upon by Agenus and FDA,” the CEO wrote. “We stand by our assertion that balstilimab’s phase 2 trial has demonstrated robust efficacy.”

RELATED: Merck's Keytruda snags I-O's first cervical cancer nod to back up HPV fighter Gardasil

The company touted the response rates from the phase 2 trial of balstilimab at the American Society of Clinical Oncology annual meeting earlier this year. The results suggested that Agenus could carve out a niche versus other checkpoint inhibitors in the PD-L1-negative population even thought it would be hitting the market much later. 

So what now?

After the FDA’s recommendation to withdraw, Agenus sought out the advice of a former deputy commissioner who worked at the agency in the 90s, according to the source. That person told Agenus that the FDA’s decision was “negligent and unjust.” The former official recommended that Agenus not withdraw but try to keep pushing the application, but the biotech ultimately decided not to move forward. 

Armen would not speak to the suggestion that Merck got special treatment, but did say the agency's decision "results in a monopoly and lack of access by patients."

"We have a safe product and patients should be allowed to have that choice. And I think what the FDA did was block that choice, unfortunately. And this allows larger companies to continue to monopolize the market at their price point," he said.

In another twist to the story, Armen said in his letter dated Oct. 18 that Agenus expects the overall survival benefit to be confirmed in a phase 3 confirmatory trial. But in the statement issued this morning, the company said that study, called BRAVA, will be discontinued. 

The cancellation of the trial will save $100 million in R&D expenses for Agenus.

The biotech will, however, plow on with combination trials pairing the therapy with the anti-CTLA-4 antibody AGEN1181 in multiple tumor types.

RELATED: ESMO: Merck details Keytruda's 'practice-changing' cervical cancer survival win

Agenus will make balstilimab available to patients with cervical cancer through an expanded access program for the time being, with priority given to the patients who were lined up for the BRAVA trial. 

The loss of the indication is going to have a profound effect on Agenus, which calls balstilimab one of its lead programs.

“Balstilimab has demonstrated meaningful clinical activity and an excellent safety profile in second-line cervical cancer, including in PD-L1 negative patients, who are ineligible to receive standard of care anti-PD-1 therapy, which makes the decision to withdraw so difficult for us,” said Agenus Chief Medical Officer Steven O’Day, M.D., in the statement.

Speaking to investors on a conference call this morning, Armen said the company has a quarter of a billion in cash on hand to "bridge any process into a major corporate development transaction." Asked later about what could be coming next, Armen said he has been conducting "a number of discussions" about the company's pipeline. He expects one or more transactions will be announced in the next three to five months. 

One of those transactions could involve Agenus' next generation CTLA-4 therapy and "could be a very, very substantial infusion of cash," Armen said. That treatment is currently in a phase 2 trial. 

Armen said the FDA's move has provided some lessons for the company as they look at the rest of the pipeline. He now knows his team can clear inspections and other regulatory hurdles to get a drug close to approval: "the fact that the line has been moved in a race doesn't mean that we didn't run the race properly."

Agenus shares were trading down 27% around 10:43 a.m. ET Friday at $3.73, compared to a prior close of $5.13.

Editor's note: This story was updated at 10:45 a.m. ET on Oct. 22 to include additional commentary from Agenus CEO Garo Armen, Ph.D.