Benzinga | Dec 7, 2020 04:33PM EST

Agios Reports Updated Data From Phase 1 Study Of Mitapivat In Sickle Cell Disease

Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, today reported updated data from a Phase 1 trial of mitapivat, the company's first-in-class pyruvate kinase R (PKR) activator, 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. Data from the study were featured in an oral presentation at the American Society of Hematology (ASH) Annual Meeting, which is being held virtually. Mitapivat is an investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated PKR enzymes.

As of the October 6, 2020 data cut-off, six of 11 efficacy evaluable patients (55%) achieved a hemoglobin increase of ?1.0 g/dL from baseline. The mean maximal hemoglobin increase among all efficacy evaluable patients was 1.3 g/dL, and the mean maximal hemoglobin increase among responders was 1.9 g/dL. Treatment with mitapivat was associated with decreases in hemolytic markers such as bilirubin, lactate dehydrogenase (LDH) and reticulocytes. As expected, dose-dependent decreases in 2,3-diphosphoglycerate (2,3-DPG) and increases in adenosine triphosphate (ATP) levels were observed, consistent with the proposed mechanism of action. Adverse events (AEs) reported during the study were generally consistent with those previously reported in pyruvate kinase (PK) deficiency and thalassemia studies.

"The hemoglobin improvement, in conjunction with improvements in markers of hemolysis, induced by mitapivat in sickle cell disease patients is highly encouraging, particularly given the short duration patients are on treatment at the higher dose levels," said Swee Lay Thein, M.B.B.S., F.R.C.P., F.R.C.Path., D.Sc., chief of the Sickle Cell Branch of the National Heart, Lung, and Blood Institute, NIH, and the principal investigator of the study. "I believe mitapivat may be a promising sickle cell disease treatment option with a well-tolerated safety profile and convenient oral administration. I look forward to further investigating the long-term effects of mitapivat in an ongoing sickle cell disease extension study and to working with Agios to continue to advance mitapivat on behalf of this patient community, a historically under-served population in tremendous need of new treatment options."

"We are pleased to continue collaborating with Dr. Thein and her colleagues at the NIH to further elucidate mitapivat's potential to improve red blood cell health, energy and longevity for people living with sickle cell disease, a debilitating, inherited, lifelong red blood cell disorder," said Chris Bowden, M.D., chief medical officer at Agios. "We are excited by the updated results of this study and plan to build on our findings by initiating a pivotal study of mitapivat in adults with sickle cell disease next year."

Updated Data from the Mitapivat Phase 1 Trial in Sickle Cell Disease

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. As of the data cut-off, 12 patients were dosed and 11 were evaluable for efficacy. One patient discontinued within the first week due to a pre-existing condition and was subsequently lost to follow-up, one patient discontinued prior to completing the 100 mg BID dose level, one patient is ongoing and nine had completed all planned dose levels. All 11 efficacy evaluable patients have received three ascending dose levels of mitapivat (5 mg BID, 20 mg BID, 50 mg BID) for two weeks' duration, respectively, and of these, three patients have received an additional ascending dose of 100 mg BID for two weeks. All underwent a 12- or 15-day drug taper after completing the dosing.

Safety Data

A safety analysis conducted for all 12 patients as of the data cut-off demonstrated:

* The majority of treatment-related AEs were Grade 1-2 and generally consistent with previous studies in PK deficiency and thalassemia. The most common AEs of all grades were pain and hyperglycemia.

* As previously reported, one vaso-occlusive crisis (VOC) occurred during drug taper and was attributed as possibly related to the drug. Two other VOCs occurred during the 28-day safety follow-up post drug exposure and were not attributed to mitapivat. No VOCs were observed during dose escalation.

* One patient had hip pain at baseline, not attributed to study drug, that led to discontinuation prior to completing the 100 mg BID dose.

* One patient with a pre-existing pulmonary embolism was withdrawn from the study shortly after initiation.

Efficacy and Pharmacodynamic Data

An efficacy analysis conducted for 11 patients as of the data cut-off demonstrated:

* Six of 11 efficacy evaluable patients (55%) achieved a hemoglobin increase of ?1.0 g/dL from baseline, all at doses of 50 mg or less.

* The mean maximal hemoglobin increase among all efficacy evaluable patients was 1.3 g/dL.

* The mean maximal hemoglobin increase among responders was 1.9 g/dL.

* Dose-dependent increases in ATP and decreases in 2,3-DPG were observed.

* Decreases in total bilirubin, LDH and absolute reticulocyte count were also observed.

Mitapivat Clinical Development

Mitapivat is being evaluated as a potential treatment for sickle cell disease under a Cooperative Research and Development Agreement (CRADA) with the U.S. National Institutes of Health (NIH). Mitapivat has been shown to decrease 2,3-DPG and increase ATP, and through this mechanism, it may reduce hemoglobin S polymerization and red blood cell sickling. Preliminary clinical data establishing proof-of-concept for mitapivat in sickle cell disease were disclosed in June 2020. The NIH is also running an extension study for individuals with sickle cell disease who participated in the Phase 1 trial. Agios expects to initiate a Phase 3, global, pivotal study of mitapivat in sickle cell disease in 2021.

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

* ACTIVATE: A placebo-controlled trial with a 1:1 randomization evaluating mitapivat in patients who do not receive regular transfusions. The primary endpoint of the trial, defined as a sustained hemoglobin increase of ?1.5 g/dL from baseline, was met, as reported last week. Full results from the study will be presented at a medical meeting in 2021.

* ACTIVATE-T: A single arm trial evaluating mitapivat in patients who receive regular transfusions. The primary endpoint of the trial is the proportion of patients who achieve a reduction in transfusion burden compared to individual historical transfusion burden standardized to 24 weeks. Agios anticipates reporting topline ACTIVATE-T data in Q1 2021.

Agios is also conducting a Phase 2 study evaluating the efficacy, safety, pharmacokinetics and pharmacodynamics of treatment with mitapivat in adults with non-transfusion-dependent ?- or ?-thalassemia. The trial is fully enrolled with 20 patients, and the primary endpoint is hemoglobin response, defined as a ?1.0 g/dL increase in Hb concentration from baseline. Agios expects to report the final results from this Phase 2 trial at a medical meeting in 2021. The company also expects to initiate a Phase 3 pivotal program evaluating mitapivat in thalassemia, including both ?-and ?-thalassemia, as well as transfusion dependent and non-transfusion dependent patient populations, in 2021.

Mitapivat has not received marketing authorization from any regulatory authority.