Allogene Therapeutics has reported a patient death tied to its anti-CD52 monoclonal antibody used for lymphodepletion in its key CAR-T cell therapy trial for large B-cell lymphoma (LBCL).
The male patient was enrolled in ALPHA3, an all-important Allogene pivotal study evaluating cemacabtagene ansegedleucel (cema-cel), an allogeneic anti-CD19 CAR-T, for patients with first-line consolidation LBCL. The fatality was not related to cema-cel, according to an Aug. 1 release.
The grade 5 adverse event occurred on Day 54 after infusion of cema-cel, ALLO-647 and the standard lymphodepletion regimen of fludarabine and cyclophosphamide (FC). The death has been attributed to the antibody ALLO-647.
The death was caused by liver failure thought to be the result of disseminated adenovirus infection—a severe condition in which a common virus spreads to several organs other than the respiratory or gastrointestinal tract—while in a state of immunosuppression induced by the antibody.
ALLO-647 is designed to prolong and deepen the lymphodepletion process, Allogene President, CEO and cofounder David Chang, M.D., Ph.D., told Fierce Biotech.
Given the patient's death, the company is dropping the asset completely, a move that won’t impact any other trial, Chang said.
“Frankly, ALPHA3 was the only study still using ALLO-647,” he said, adding that Allogene had been slowly transitioning away from the asset in favor of the biotech’s next-gen platform, dubbed Dagger.
Now, instead of a three-arm trial, Allogene will use the standard FC approach in the newly converted two-arm study. Previously, ALPHA3 included a group of patients receiving ALLO-647 and FC as the lymphodepletion regimen before cema-cel treatment; another arm for patients receiving only FC and cema-cel; and an observation arm.
The statistical design of the trial and the prespecified study conduct are still the same, Chang confirmed. The next milestone will be a futility analysis expected to happen sometime in the first half of 2026, an event that the biotech had originally planned on using to determine which lymphodepletion strategy it wanted to move forward.
Instead, the patient's death triggered an unplanned review and accelerated that decision.
“Today’s update is prompted by this unfortunate circumstance but marks a clear and confident step forward,” Chang said, adding that “retiring ALLO-647 simplifies the trial.”
Administering cema-cel after FC lymphodepletion in an outpatient setting will speed up enrollment while streamlining any potential regulatory review, Chang added. The study is still recruiting patients for the two arms.
The decision to discontinue ALLO-647 was made in conjunction with a data and safety monitoring board and steering committee as well as in consultation with the FDA. Chang said the federal agency was “very prompt” in its discussions with Allogene.
While Chang said he couldn’t share specifics from ALPHA3’s safety data as it is still early in the trial, the CEO did say the limited safety analysis from ALPHA3 showed that FC alone was “better without question” than FC and ALLO-647 together.
According to Chang, no other deaths related to ALLO-647 have occurred in this trial or any other that haven’t been publicly disclosed already.
Allogene made the bold move to vault cema-cel development into the first-line setting in early 2024 with the hope that it can leapfrog the crowded late-line LBCL treatment space.
In 2020, Allogene reported a patient death in a phase 1 trial of the biotech’s anti-BCMA CAR-T treatment, ALLO-715, in relapsed or refractory multiple myeloma. Of the two patients receiving ALLO-715, one died from an infection—a suspected case of fungal pneumonia.
The infection was diagnosed the day after the patient received ALLO-715, and the investigator said the death was likely due to the cancer worsening and the conditioning regimen.
Chang said Allogene has deprioritized studies in the relapsed or refractory setting, adding that the benefit-risk profile in a first-line setting is much different than at the advanced setting.
“[In] any clinical trial, patient safety is the most important part,” the CEO said, but, for a first-line study like ALPHA3 where the goal is to “improve the cure rate,” he emphasized the focus on safety.
Allogene will instead pin its hopes on Dagger, the biotech’s novel platform technology made to reduce reliance on standard lymphodepletion. The science is designed to resist the host cell’s rejection of allogeneic CAR-T cells and is used in Allogene’s clinical CD70 program called ALLO-316 in advanced renal cell carcinoma, plus for another asset called ALLO-329 in autoimmune diseases.
The dagger technology “brings precision to how we deplete T-cells,” Chang said, adding that the science is “state-of-the-art” for allogeneic therapies.
And, while the biotech underwent a 28% staff reduction in May, Chang doesn’t foresee layoffs being necessary due to the discontinuation of ALLO-647.
“If anything, we may have to hire more people,” he said, citing the potentially accelerated enrollment process.