ALLO-647

iStock, Andrii Yalanskyi While the deaths occurred in patients who had been treated with Agios’ anemia treatment Pyrukynd, the biotech insisted in an SEC filing midday Monday that the drug’s risk-benefit pro unchanged. Shares of Massachusetts-based Agios Pharmaceuticals were put through the wringer on Monday after the FDA’s Adverse Event Reporting System revealed four deaths in patients who had taken its anemia drug Pyrukynd. Leerink analysts flagged a 23% dip at the stock’s lowest point, with share prices hitting $26.75 at market opening Monday before rebounding to $36.16 by the closing bell, a 3% increase from its closing price last Friday. In pre-market trading Tuesday, Agios shares have dipped 2% Agios filed an SEC document on Monday to address the four deaths, which were first made public by a securities analyst who filed a Freedom of Information Act request to the FDA’s safety database, to which Agios had reported these deaths. In its regulatory filing, Agios reassured investors that the deaths have “not altered the established benefit-risk profile” for Pyrukynd. Two of the deaths were in older patients: one in a 61-year-old man and another in a 93-year-old woman, both of whom were being treated for pyruvate kinase (PK) deficiency. Agios reported these cases to the FAERS on June 28, 2024 and July 17, 2025, respectively, according to the Leerink analysts. The last two fatalities were in much younger women, a 28-year-old and a 26-year-old, who had sickle cell disease and were being treated with Pyrukynd under compassionate use. The latter of these two cases was reported to the FDA on July 15 this year. Leerink said that these latter two deaths are “concerning given the young age of the patients.” But after following up with Agios, the analysts learned that these two younger patients were actually the same person. “The 28-year-old patient was actually a duplicate of the 26-year-old patient which was incorrectly entered into the database,” the Leerink note read, adding that this has in turn “largely offsets our concerns” that these deaths represent “a heightened mortality risk of Pyrukynd.” Despite Agios’ clarifications, “it is difficult to fully dismiss the impact of the safety concerns” on an upcoming PDUFA data for Pyrukynd, Leerink added. Agios is proposing Pyrukynd for the treatment of patients with alpha- or beta-thalassemia regardless of their dependence on transfusions. The FDA is expected to release its verdict on Sept. 7 . The drug was first approved in 2022 for adults with hemolytic anemia with PK deficiency. Patient deaths have been in the news in recent months, the most visible of which have been the three mortalities linked to Sarepta’s gene therapy portfolio: two to its Duchenne muscular dystrophy product Elevidys and one to an investigational limb-girdle muscular dystrophy candidate. Then, late last week, Allogene Therapeutics likewise reported a patient death in a Phase II study of its CAR T therapy cemacabtagene ansegedleucel, though the fatality was ultimately linked to ALLO-647, an anti-CD52 antibody used as an immunosuppressive treatment to prepare patients for the cell therapy.

iStock, Design Cells The pivotal Phase II trial is testing Allogene’s CAR T candidate cemacabtagene ansegedleucel for large B-cell lymphoma. ALLO-647 was being used as a preparative lymphodepletion therapy. A patient has died in Allogene Therapeutics’ Phase II ALPHA3 trial of cemacabtagene ansegedleucel, an investigative CAR T therapy for the treatment of large B-cell lymphoma. However, the mortality wasn’t linked with the cell therapy itself, also known as cema-cel. Instead, Allogene attributed the death to ALL-647, a monoclonal antibody that targets the CD52 protein and was being used by the biotech as a lymphodepletion therapy to prepare patients for cema-cell treatment. According to Allogene’s news release on Friday, the death was linked to liver failure, which in turn arose from “disseminated adenovirus infection in the setting of immune suppression.” The patient in question died 54 days after infusion. Severe infections such as these have been “rare” across Allogene’s trials, the biotech said, but “when present, they have been attributed to immunosuppression due in part to ALLO-647.” Writing to investors on Friday afternoon, analysts at William Blair called the patient mortality “highly unfortunate,” and agreed with the company that “available evidence supports that the event was attributed to ALLO-647-mediated prolonged T-cell suppression rather than cema-cel.” Allogene stock dropped 12% in trading Friday. Owing to the mortality, Allogene has decided to discontinue the study arm that was using ALLO-647 as part of the immunosuppressive regimen and drop the antibody from its pipeline altogether. Instead, the biotech will move forward with only using fludarabine and cyclophosphamide (FC) as lymphodepletion treatments for patients receiving cema-cel. Allogene expects a futility analysis for ALPHA3 in the first half of 2026. “We are supportive of the company’s decision to discontinue the FCA regimen in the ALPHA3 study,” William Blair wrote on Friday, however warning that “the standard lymphodepletion regimen with FC likely will not lead to as robust cema-cel expansion and persistence” as when ALLO-647 is added onto the regimen. Still, the analysts noted that patients enrolled in ALPHA3 have lower burdens of disease, “suggesting that an enhanced lymphodepletion regimen may not be required.” Moving forward with just the FC regimen could also lead to “potentially higher commercial uptake” for cema-cel, if approved, “given the lower safety risks,” William Blair contended.