UPDATE: Agenus Withdraws His Application to Join Cervical Cancer, and Behind-the-Scenes Regulatory Battle between David and Big Pharma Revealed

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Agenus’ cervical cancer drug balstilimab appeared on track for FDA approval, but biotech now withdraws application after agency grants full approval to Merck’s Keytruda in the same indication.

Biotech said in a statement released today that an approval dossier for balstilimab was being voluntarily withdrawn, but according to a source familiar with the decision, the FDA pushed Agenus into a corner and recommended that the application be withdrawn. .

Agenus Chief Executive Officer Garo Armen, Ph.D. urged FDA’s Richard Pazdur, MD, to step in and enable business therapy to be reviewed under the fast track, according to a document seen by Fierce Biotech.

This one is getting into the weeds a bit, so stay with me here: Keytruda got fast-track approval for second-line cervical cancer in 2018. Earlier this month, the drug was also released. moved to the first line parameter. At that time, the FDA also confirmed that the expedited second-line approval had been converted to full approval. Merck submitted the first line parameter data to support the second line decision.

RELATED: Merck Puts Imperfect Immunotherapy First With Keytruda Approval For Cervical Cancer

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

If you’re still with me, Agenus’ complaint is this: Once Keytruda was given full approval under the second line, “the balstilimab expedited approval window closed,” according to one. company press release. The agency acted four months ahead of the deadline for Merck’s candidacy. Had the FDA stuck to this goal, Agenus would have stood a chance of securing the coveted expedited approval.

Agenus found out about Merck’s approval the same day he met with the FDA at an end-of-cycle meeting, a regulatory meeting that takes place near the end of the FDA’s review of an application.

“This apparently rapid approval of pembrolizumab (Keytruda) a few hours before Agenus’ end-of-cycle meeting suggests that the FDA may have given special attention to Merck, the sponsor of the pembrolizumab application,” Armen wrote to Pazdur, who is director of the Oncology Center of Excellence for the Center for Drug Evaluation and Research. “The fact that the approval of pembrolizumab blocked the chances of Agenus’ expedited approval further implies that the FDA did not intend to give balstilimab the full and fair consideration it deserves.”

In an interview following an investor conference call on Friday morning, Armen said the FDA released the press release regarding Keytruda’s approval ahead of the meeting.

“The first thing they did was quote the fact that Merck had been approved and the window for us for expedited approval was no longer available,” he said. “They haven’t discussed any substance, nothing about the efficacy of the product or anything like that. So as far as we’re concerned it’s a technical detail and the agency has the right to do whatever she has to do. “

Armen asked Pazdur in the letter to intervene to ensure that the agency fosters an environment that supports innovation and competition to “compensate for a monopoly environment by big business.”

David vs. Big Pharma

Expedited approvals have become a flashpoint for the FDA since Biogen’s Aduhelm approval in this path. The agency can approve drugs in this way when they treat “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 parameter suggests an effect on “irreversible morbidity or mortality”. The guidelines also take into account the availability or absence of alternative treatments.

RELATED: Biogen’s Aducanumab Crosses FDA Finish Line Just in Time to Save Its Business

According to Armen, those criteria still match balstilimab’s request to a T, and Keytruda’s approval should not impact Agenus’ request under the law.

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

The FDA has apparently notified Agenus that any therapy coming after should show an improvement over the existing ones and that the application of balstilimab had not shown that it could improve the performance of Keytruda. Expedited approvals are reserved for therapies that may address an unmet medical need, according to the agency. So if Merck has met that need, Agenus now has a higher bar to meet.

Agenus also maintains that Merck did not have to submit additional data to support full second-line approval. Expedited approvals are granted on the basis that the company has to conduct a confirmatory trial, so Armen believes Merck has received special treatment. Merck submitted data from the KEYNOTE-826 trial based on patients who had not received prior chemotherapy treatment.

The CEO said Agenus’ therapy has a better safety profile and could provide treatment to a wider range of cervical cancer patients than Keytruda.

RELATED: Agenus, With FDA Approval In Sight, Shows Anti-PD-1 Data

Armen argued to Pazdur that the FDA was looking at the objective response rate (ORR) for the overall trial, which reached 14%, and not the PD-L1 positive subgroup, which rose to 20% from the 14.3% of Keytruda from its KEYNOTE -158, which has earned Merck fast track approval for patients whose tumors express the PD-L1 protein. He also believes that the PD-L1-negative population remains an unmet need. There, balstilimab obtained a response rate of 9% against 0% with Keytruda.

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

“We’ve tried to discuss this point, but their hindsight has been that the numbers are low,” Armen said.

Although Armen did not indicate 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 by 12%. So 14% for balstilimab would represent a modest improvement, but not overwhelming.

Armen said the study met the “pre-specified accelerated endpoint eligible for approval” of the overall response rate. Armen also noted the larger study size of 125 women treated with balstilimab, compared to 77 for Keytruda. KEYNOTE-158 included 21 other patients treated with Keytruda who were negative for PD-L1.

“Agenus believes the reviewers are overlooking the fact that balstilimab has been shown to be effective and safe in a much larger trial than pembrolizumab and has met or exceeded the expedited approval criteria agreed upon by Agenus and the FDA,” wrote the CEO. “We stand by our claim that the phase 2 trial of balstilimab has demonstrated strong efficacy. “

RELATED: Merck’s Keytruda Nods First IO Nod for Cervical Cancer to Support HPV Fighter Gardasil

The company touted response rates from the phase 2 trial of balstilimab at the American Society of Clinical Oncology annual meeting earlier this year. The results suggest that Agenus could carve a niche relative to other checkpoint inhibitors in the PD-L1 negative population, even assuming it would hit the market much later.

And now ?

After the FDA’s recommendation to step down, Agenus sought the advice of a former deputy commissioner who worked at the agency in the ’90s, according to the source. This person told Agenus that the FDA’s decision was “negligent and unfair.” The former official advised Agenus not to step aside but to try to keep pushing demand, but biotech ultimately decided not to go ahead.

Armen declined to talk about the suggestion that Merck received special treatment, but said the agency’s decision “results in a monopoly and lack of access for patients.”

“We have a safe product and patients should have this choice. And I think the FDA has unfortunately blocked that choice. And that allows the big companies to continue to monopolize the market at their cost,” he said.

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

Canceling the trial will save Agenus $ 100 million in R&D expenses.

Biotechnology will, however, pursue combined trials combining therapy with the anti-CTLA-4 antibody AGEN1181 in several types of tumors.

RELATED: ESMO: Merck Details Keytruda’s Victory Over Cervical Cancer Survival

Agenus will make balstilimab available to patients with cervical cancer through an expanded access program at this time, with priority given to patients enrolled in the BRAVA trial.

The loss of the indication will have a profound effect on Agenus, who calls balstilimab one of its flagship programs.

“Balstilimab has demonstrated clinically significant activity and an excellent safety profile in second-line cervical cancer, including in PD-L1 negative patients, who are not eligible for anti- Standard PD-1, which makes the decision to opt out so difficult for us, ”Agenus chief medical officer Steven O’Day, MD, said in the statement.

Speaking to investors on a conference call this morning, Armen said the company has a quarter of a billion dollars in cash to “bridge any process to a major business development transaction.” When asked what might happen next, Armen said he had “a number of discussions” about the company’s pipeline. He expects one or more deals to be announced in the next three to five months.

One of those deals could involve Agenus’ next-generation CTLA-4 therapy and “could be a very, very substantial injection of money,” Armen said. This treatment is currently in a phase 2 trial.

Armen said the FDA decision provided lessons for the company as it reviews the rest of the pipeline. He now knows his team can overcome inspections and other regulatory hurdles to get a drug close to approval: “Just because the line was moved in a race doesn’t mean we didn’t run the race properly. “

Agenus shares were trading down 27% around 10:43 am ET on Friday at $ 3.73, from a previous close of $ 5.13.

Editor’s Note: This story was updated at 10:45 a.m. ET on October 22 to include additional comments from Agenus CEO Garo Armen, Ph.D.


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