Updated: FDA clears first CD20xCD3 bispecific, giving Genentech leg up in a crowded lymphoma R&D field

The first CD20xCD3 bispecific antibody will soon become available in the US following an FDA approval disclosed Thursday night, Dec. 22.

Roche and Genentech’s mosunetuzumab was greenlit as a third-line treatment for adults with relapsed or refractory follicular lymphoma. FDA’s accelerated approval of the therapy now branded as Lunsumio comes seven days early and follows suit behind the European Union, which cleared the drug on June 3, 2022.

The “estimated cost for a fixed course of treatment,” a Genentech spokesperson told Endpoints News via email, is “approximately $180,000 for 8 cycles.” Per the accelerated nod, the FDA said 8 cycles — 21 days each — is the recommended administration. If patients completely respond at that point, they should discontinue Lunsumio. If they experience just a partial response or stable disease, they should undergo up to nine more cycles, “unless they experience progressive disease or unacceptable toxicity.”

The FDA attached a boxed warning to the drug for “serious or life-threatening cytokine release syndrome,” in which the immune system goes into overdrive. The reaction, which has been documented in multiple trials of bispecific antibodies, was reported in 39% of patients in a clinical trial of Lunsumio, with Grade 3 and 4 levels in 2.3% and 0.5% of patients, respectively. All events were resolved, Genentech said. In its approval statement, FDA noted “warnings and precautions” of: neurologic toxicity, infections, cytopenias, and tumor flare.

By crossing the finish line, Lunsumio kick-starts a race to market for competitors, including Genmab and AbbVie’s epcoritamab, which has a May 21, 2023 PDUFA date for third-line R/R large B-cell lymphoma. Meanwhile, Regeneron plans on filing with odronextamab next year, and Johnson & Johnson is further behind with its partner Xencor.

Genmab’s bispecific is subcutaneous, whereas Genentech’s first approval is an intravenous infusion that can be given in an outpatient setting. Genentech is also testing a subcutaneous version, which would shift the administration paradigm from two hours to as little as a few minutes, according to trial investigator and City of Hope associate professor Elizabeth Lihua Budde.

Elizabeth Lihua Budde

“We are already planning to think about how to make it more convenient, how to further reduce the cytokine release incidents and further improve the efficacy, so we’re doing this subcutaneous administration,” Budde told Endpoints in advance of the approval during the American Society of Hematology medical congress in December. The lymphoma and leukemia researcher said she’d heard from some of her own patients who were awaiting the approval because they didn’t meet inclusion criteria for clinical trials.

The FDA reviewed data from a Phase II pivotal study, in which 60% of patients (54/90) had a complete response at a median follow-up of 28.3 months. Another 18 patients had a partial response to the treatment. At the two-year mark, Genentech said 48.3% of patients had not seen their disease progress, according to an update at this year’s ASH conference.

The ongoing pivotal study is testing the drug alone and in combination with Tecentriq, also marketed by Roche. The trial also includes patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Ginna Laport

“This is a bispecific antibody. It’s not conventional chemotherapy,” Ginna Laport, VP and global head of lymphoma clinical development at Genentech, told Endpoints on the sidelines of ASH, in advance of the approval. “It’s fairly well-tolerated. Again, it’s outpatient.”

Laport noted that Lunsumio was tested as a fixed duration rather than a continued-until-progression treatment regimen that Genentech’s competitors have used in clinical investigation.

“What we’re trying to show or emphasize, is for the patients who reach a complete remission, even when treatment is done, the chance of them progressing is very low,” the pharma VP explained.

A confirmatory trial is already more than halfway accrued, with a readout slated for late-2024, Laport said, noting that study is expected to move the treatment up to second-line.

In recent weeks, Genentech also submitted approval paperwork for its other CD20xCD3 bispecific, known as glofitamab. Whereas Lunsumio has one arm to bind to CD20 on B cells and one arm targeting CD3 on T cells, the second-gen asset has two arms to latch onto CD20.

That makes glofitamab more potent, Laport said, which translates to the pharma positioning that drug for more aggressive lymphomas. A marketing application was also submitted to the European Medicines Agency last spring for diffuse large B-cell lymphoma, she said, and a confirmatory trial is also underway.

Both drugs were developed in-house, with Lunsumio coming out of Genentech and first dosed in 2015, and glofitamab out of Roche and first given to patients in 2017, Laport said.

As part of their 27-year tie-up on CD20, Biogen opted into co-commercialization on Lunsumio earlier this year. And earlier this month, the partners penned a royalty deal on glofitamab.

Editor’s note: This story was updated to include the estimated cost of Lunsumio and that an additional 18 patients had a partial response in the data package supporting approval, not 14. Information from the FDA was also added.

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