Agios Announces Clinical Proof-of-Concept Has Been Established in Phase 1 Study

Agios Pharmaceuticals, Inc. recently announced that clinical proof-of-concept has been established based on a preliminary analysis in the Phase 1 trial of mitapivat (AG-348) in patients with sickle cell disease. The study is being conducted in collaboration with the National Institutes of Health (NIH) as part of a cooperative research and development agreement. Mitapivat is an investigational, first-in-class, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase-R (PKR) enzymes. Mitapivat has been shown to decrease 2,3-diphosphoglycerate (2,3-DPG) and increase adenosine triphosphate (ATP), and through this mechanism, it may reduce hemoglobin (Hb) S polymerization and red blood cell sickling.

The ongoing Phase 1 study has enrolled nine patients to date. Eight patients have completed all planned dose levels, and one patient discontinued within the first week due to a pre-existing condition and was subsequently lost to follow-up. Six patients were treated with three ascending dose levels of mitapivat (5 mg BID, 20 mg BID, 50 mg BID) for 2 weeks duration, respectively, followed by 9- or 12-day drug taper, and two patients received an additional ascending dose of 100 mg BID for 2 weeks before initiating the drug taper. Adverse events (AEs) reported during the study were generally consistent with those previously reported in pyruvate kinase (PK) deficiency or are to be expected in the context of sickle cell disease. One severe AE, a vaso-occlusive crisis, occurred during drug taper and was attributed as possibly related to the drug.

Seven of eight (88%) patients who completed all planned dose levels of mitapivat experienced an Hb increase, with five of eight patients (63%) achieving a hemoglobin increase of ≥1.0 g/dL from baseline (range 1.0-2.7 g/dL). All five patients who achieved a hemoglobin increase of ≥1.0 g/dL did so at doses of 50 mg BID or lower. Treatment with mitapivat was associated with decreases in hemolytic markers such as bilirubin, lactic acid dehydrogenase, and reticulocytes. As expected, decreases in 2,3-DPG and increases in ATP levels were observed, consistent with the proposed mechanism of action and comparable to that observed in healthy volunteer studies with mitapivat. Evaluation of sickling curves (t50) and oxygen dissociation curves (p50) were consistent with decreases in both sickling and HbS polymerization, further supporting the proposed mechanism of action.

“The interim results from the Phase 1 study of mitapivat demonstrate for the first time that PKR activation has the potential to address chronic hemolytic anemia and impact markers of sickling in sickle cell disease patients as hypothesized based on the mechanism of action,” said Swee Lay Thein, MBBS, FRCP, FRCPath, DSc, Chief of the Sickle Cell Branch of the National Heart, Lung, and Blood Institute, NIH, and the principal investigator of the study. “The safety profile of mitapivat continues to be consistent with prior studies in both mutated and wildtype PKR, and hemoglobin responses were seen in 63% of patients. We are excited about these preliminary results, and I look forward to continuing to collaborate with Agios to advance this treatment for sickle cell disease patients.”

“First, I would like to thank the NIH and Dr. Thein for the incredible collaboration on this study. These data build on our 6 years of clinical experience with this mechanism and establish proof-of-concept for mitapivat as a potential novel approach for the treatment of sickle cell disease, a chronic lifelong condition with few treatment options,” said Chris Bowden, MD, Chief Medical Officer at Agios. “Looking ahead, we are focused on advancing mitapivat to pivotal development, with the goal of initiating a pivotal study next year.”

The ongoing Phase 1 study, which can enroll up to 25 patients, is evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of treatment with mitapivat in adults with sickle cell disease. Six patients received three ascending dose levels of mitapivat (5 mg BID, 20 mg BID, 50 mg BID) for 2 weeks duration, respectively, followed by 9- or 12-day drug taper. The two patients most recently enrolled and all subsequent patients receive an additional ascending dose of 100 mg BID for 2 weeks before initiating the drug taper in order to further explore dose-response relationship. The primary endpoint of the study is safety and tolerability as assessed by frequency and severity of adverse events and laboratory parameters. Secondary endpoints included changes in hemoglobin, markers of hemolysis, 2,3-DPG and ATP levels and HbS polymerization.

Agios has two ongoing global, pivotal trials in adults with PK deficiency that are fully enrolled.

-ACTIVATE: A placebo-controlled trial with a 1:1 randomization evaluating patients who do not receive regular transfusions. The primary endpoint of the trial is the proportion of patients who achieve a sustained hemoglobin increase of ≥1.5 g/dL.

-ACTIVATE-T: A single arm trial of regularly transfused patients with a primary endpoint of reduction in transfusion burden over 6 months compared to individual historical transfusion burden over prior 12 months.

In addition, mitapivat is being studied in an ongoing Phase 2 study in adults with non-transfusion-dependent β- and α-thalassemia. Interim results from the study were reported today in an oral presentation at the 25th European Hematology Association Annual Congress (EHA).

Mitapivat is not approved for use by any regulatory authority.

Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has two approved oncology precision medicines and multiple first-in-class investigational therapies in clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging our knowledge of metabolism, biology, and genomics. For more information, visit www.agios.com.