Agenus is shelving immediate plans for a confirmatory Phase 3 study for its lead immunotherapy program after the FDA “discouraged” it from filing for accelerated approval and asked for a “definitive survival study,” the company said Thursday morning.
The biotech’s executives called the feedback from the FDA “disappointing” given that its program — which combines a CTLA-4 antibody with a PD-1 antibody — has shown promise in a cancer type that’s proven particularly challenging and where essentially “nothing works,” they said. While Agenus will keep trying to persuade the FDA to reconsider as it collects more Phase 2 data, it is also talking to European regulators and focusing on other cancer types that could lead to accelerated approvals.
Garo Armen“We cannot justify, without near-term commercialization revenue coming in, funding a full-fledged Phase 3 trial that will yield commercialization in three or four years in the absence of an accelerated approval pathway,” CEO Garo Armen told Endpoints News in an interview. The company is also exploring deals that would fund the Phase 3.
Agenus shares $AGEN plummeted 62% to $6.7 in premarket trading Thursday.
This is the second time the FDA has blocked Agenus’ plans for an accelerated approval. In 2021, it pulled a BLA for its PD-1 inhibitor, balstilimab, in cervical cancer at regulators’ request after Merck’s Keytruda was granted full approval in the same indication.
The company then switched its focus to developing balstilimab together with the anti-CTLA-4 drug botensilimab, first in relapsed/refractory non-MSI-H-colorectal cancer. Over the past few years, it’s collected Phase 1 and 2 data from about 350 patients, with a response rate “in the 20% range.” Among patients who have been treated the longest on the open-label Phase 1, median overall survival is 21.2 months — which Agenus said is almost double the 10 to 12 months from historical data.
Steven O’DayBut the FDA noted that in this specific type of cancer, response rates “have not always predicted survival,” said Steven O’Day, Agenus’ chief medical officer. The agency wanted to see a definitive survival study.
While a small fraction of patients with colorectal cancer have microsatellite instability-high (MSI-H) tumors that can be treated with Keytruda, Bristol Myers Squibb’s Opdivo or GSK’s Jemperli, the overwhelming majority have microsatellite stable colorectal cancer that are considered immunologically “cold,” meaning they don’t typically respond to immunotherapy treatment. Agenus believes its CTLA-4 antibody, which is engineered to be extra “sticky,” can better prime the immune system to attack the tumor when paired with a PD-1.
Agenus is not completely giving up on seeking accelerated approval in the US — it continues to track response and survival data from a Phase 2 randomized study that could beef up the package — although Armen admitted it is a “low probability.” Given about 1,000 inquiries for compassionate use, he said the company feels a “moral responsibility” to keep making its case.
Jennifer BuellDespite the setback, he added, Agenus and the FDA did agree on a Phase 3 design during their end-of-Phase-2 meeting. The biotech has been talking to potential partners, and can now bring more “clarity” to those discussions, said Jennifer Buell, who chairs Agenus’ executive council.
With about $90 million in cash and some expected milestone payments, the company’s runway stretches to the middle of next year. It will need to be more prudent with expenditures and may cut external consultants and advisors, according to Armen, but doesn’t expect layoffs at the moment.
“We did trim pretty much as much as possible” in a revamp late last year to focus on the botensilimab/balstilimab combo, Buell said, leaving about 300 employees in the team.
Agenus will also continue to invest in other trials testing the drugs’ potential, including sarcoma, melanoma, pancreatic cancer, lung cancer and the neoadjuvant setting for colorectal cancer, with some data expected later this year.
Editor’s note: This story has been updated to include stock reaction.