Inclacumab

Agios' Pyrukynd missed one of its two primary endpoints in a phase 3 sickle cell disease trial, but the company is still plotting an FDA bid next year. In its mission to grow the reach of its pyruvate kinase (PK) activator Pyrukynd (mitapivat), Agios Pharmaceuticals has come up short of producing an unequivocal win in the key indication of sickle cell disease (SCD).Attempting to capture a “broad assessment” of the potential benefits of the drug across “multiple aspects of the disease,” the company ran the 52-week Rise Up study, with primary endpoints assessing hemoglobin responses and the annualized rate of sickle cell pain crises (SCPCs) compared to placebo. The study further examined five secondary endpoints, including other biomarker responses, patient fatigue and the annualized rate of hospitalizations for SCPCs.Rise Up met one primary endpoint by demonstrating an improved hemoglobin response, Agios said on Wednesday, with 40.6% of patients on the drug meeting hemoglobin response criteria, versus 2.9% on placebo. On the other primary measure, however, Pyrukynd showed a “reduction” in SCPCs but did not ultimately achieve statistical significance.On secondary endpoints, the drug showed certain improved biomarker outcomes but failed to show an average change from baseline on a patient-reported fatigue scoring system. Two other secondary measures couldn't be determined, Agios said.Agios plans to “engage with the FDA to discuss these findings and our goal of bringing this innovative medicine to patients with sickle cell disease,” Sarah Gheuens, M.D., Ph.D., chief medical officer, said in the company’s release.“The RISE UP Phase 3 results further support mitapivat’s strong anti-hemolytic profile, as demonstrated in other rare blood disease trials,” Gheuens said. “These effects can help address debilitating features of sickle cell disease that can profoundly worsen quality of life and lead to early mortality.”The company aims to submit its bid for Pyrukynd in SCD after a meeting with the FDA in the first quarter of 2026, the company said.It's tough to get a sense of the drug's outlook in SCD in the wake of the readout, but investors aren't thrilled. The company’s stock price crashed by more than 49% on Wednesday morning, reaching $22.91 by midday, down from its previous close of $45.49.For another indication of how the company is digesting the news, Agios said it's planning to take "proactive steps to reduce operating expenses" to support its financial position and support another potential launch. Pyrukynd won approval in 2022 as the first therapy indicated for hemolytic anemia in adults with PK deficiency. The company’s ambitions to grow beyond its existing patient population have so far faced ups and downs, with last year’s study of Pyrukynd in children with PK deficiency who receive regular transfusions missing its prespecified statistical criterion.Meanwhile, an FDA approval decision in another potential area of expansion, thalassemia, is expected next month after the agency extended its review by three months.Troubles in SCD trialsSickle cell disease challenges aren’t unique to Agios. Besides the 2023 FDA approvals of multimillion-dollar genetic medicines from Genetix Biotherapeutics (formerly known as bluebird bio), Vertex Pharmaceuticals and CRISPR Therapeutics, the field has seen several setbacks lately.Pfizer, for one, last year cut one of its two phase 3 studies evaluating its sickle cell asset, inclacumab and ultimately reported that the remaining study missed its primary vaso-occlusive crises (VOCs) endpoint in August. That setback came after another major stumble for Pfizer’s SCD portfolio—and the oral SCD treatment market as a whole—with the withdrawal of its oral Oxbryta.Oxbryta formed the centerpiece of Pfizer’s $5.4 billion acquisition of Global Blood Therapeutics in 2022, from which the company also got inclacumab. Upon its accelerated FDA approval in 2019, Oxbryta was touted as the first medicine to target the root cause of sickle cell disease. However, that approval was based on a phase 3 study that, like Agios', used a measure of hemoglobin response as its primary efficacy indicator.Years later, when Pfizer pulled the drug from global markets, it cited “the totality of clinical data that now indicates the overall benefit of Oxbryta no longer outweighs the risk” in SCD patients, pointing to data that suggested an “imbalance in vaso-occlusive crises and fatal events.”A February article published in the journal HemaSphere explored the drug development hurdles in SCD. According to the authors, the Oxbryta situation exemplified that although “laboratory endpoints, such as increased hemoglobin levels, are easier to achieve, it is still important to demonstrate some meaningful clinical benefit, such as reduced episodes of pain or improved quality of life.”