Allogene ditches enhanced lymphodepletion

Allogene has reported a patient death in the pivotal Alpha-3 trial of its allogeneic CD19 Car-T project cemacabtagene ansegedleucel in front-line DLBCL consolidation – but reckons this wasn’t related to cema-cel itself. Instead, Allogene is blaming a supposedly enhanced lymphodepletion regimen using its anti-CD52 antibody ALLO-647.

Alpha-3 will continue, minus a cohort testing cema-cel alongside fludarabine, cyclophosphamide and ALLO-647 lymphodepletion. The new focus will be on cema-cel plus standard flu-cy lymphodepletion, with an interim futility analysis set for the first half of 2026, as before.

Allogene tried to put a brave face on the move, saying that flu-cy lymphodepletion was simpler and already well accepted by physicians. However, shares in the company closed down 12% on Friday.

One reason could be lingering doubts over whether ALLO-647, rather than cema-cel itself, really was to blame for the death, which was caused by an adenoviral infection that led to “rapid and severe” liver inflammation. During an investor call Allogene’s chief medical officer, Zachary Roberts, noted that such infections were usually mild, but could be serious in people with low T-cell counts – something brought about by ALLO-647, which was designed to boost Car-T expansion and persistence.

Furthermore, by the time the patient’s symptoms were seen, around seven weeks after therapy, cema-cel had disappeared, according to Allogene’s chief executive officer, David Chang.

He added that, based on FDA interactions, he wasn’t concerned about Alpha-3 being put on formal clinical hold by the agency. But any further delay would be bad news for the company, as Alpha-3 has already been pushed back. The futility analysis had once been expected in mid-2025, with event-free survival data in 2026, and a BLA filing in 2027.

As of May 2025, Allogene had $335m in the bank, enough to get it into the second half of 2027. With no update on submission timelines, investors could be nervous about the group running out of cash before cema-cel makes it to regulators – not to mention the daunting prospect of a solo launch, given the difficulties other cell therapy specialists have run into.

Futility analysis

The reason Allogene was developing ALLO-647 dates back to Cellectis, the originator of Allogene's Car-T pipeline. Cellectis originally designed its protocols to include lymphodepletion with alemtuzumab, the anti-CD52 MAb used in Campath (as well as the multiple sclerosis drug Lemtrada), which apparently was preferred by European doctors over flu-cy. A subsequent shortage of Campath prompted Allogene to design its own anti-CD52 MAb, which became ALLO-647.

Alpha-3 will continue as a two-arm trial, comparing cema-cel plus standard flu-cy lymphodepletion, versus observation. The study is in DLBCL patients still in response to front-line R-Chop therapy, but with minimum residual disease (MRD).

The futility analysis will compare MRD conversion between these arms. Chang noted that the company hadn’t specified the bar for futility, but added that Allogene is looking for an improvement in MRD clearance in the experimental arm compared with the observation arm. He noted that “virtually none” of the observation patients would be expected to spontaneously clear MRD.

The primary endpoint of the trial itself is event-free survival, and Allogene plans to give an update on the timing of this readout, plus potential regulatory filings, when it discloses results from the futility analysis.

Alpha-3 itself heralded a switch in strategy: Allogene had previously been studying cema-cel in third-line DLBCL, but dropped these efforts last year, likely influenced by the changing lymphoma landscape.

The company’s latest setback sees its stock now sitting at a near all-time low. The discontinuation of ALLO-647 might not be a huge deal, but Allogene will have to hope that its problems don’t spread to cema-cel itself.

Cema-cel’s DLBCL trials

Note: *also included CLL/SLL cohort. Source: OncologyPipeline.