– 37 Percent of Patients Treated with Mitapivat Achieved ≥33% Reduction in Transfusion Burden Compared to Individual Historical Transfusion Burden Standardized to 24 Weeks (1-Sided p=0.0002) –

– 22 Percent of Patients Treated with Mitapivat Were Transfusion-Free During the 24-Week Fixed Dose Period –

– Safety Profile Consistent with Previously Reported Data –

– Company Expects to File for Regulatory Approval for Mitapivat for the Treatment of Adults with Pyruvate Kinase (PK) Deficiency in the U.S. in Q2 2021 and in the EU in Mid-2021 –

CAMBRIDGE, MA, USA I January 26, 2021 I Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and genetically defined diseases, today announced that the global, open-label Phase 3 ACTIVATE-T trial of mitapivat in regularly transfused adults with PK deficiency demonstrated a statistically significant and clinically meaningful reduction in transfusion burden. All 27 patients enrolled in the study were treated with mitapivat. In the 24-week fixed dose period, 37 percent (n = 10) achieved a ≥33% reduction in transfusion burden compared to individual historical transfusion burden standardized to 24 weeks (1-sided p=0.0002). In addition, 22 percent (n = 6) were transfusion-free during the 24-week fixed dose period. Mitapivat is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated PKR enzymes.

Agios recently reported that its global, randomized, double-blind, placebo-controlled Phase 3 ACTIVATE trial of mitapivat in adults with PK deficiency who do not receive regular transfusions met its primary endpoint, with 40 percent of patients randomized to mitapivat achieving a hemoglobin response, defined as a ≥1.5 g/dL sustained increase in hemoglobin concentration from baseline, compared to 0 patients randomized to placebo (2-sided p<0.0001). Agios anticipates filing for regulatory approval based on data from ACTIVATE and ACTIVATE-T in the U.S. in Q2 2021 and in the EU in mid-2021, with a potential 2022 commercial launch in both geographies.

“Based on results from both the ACTIVATE and ACTIVATE-T Phase 3 trials, we believe mitapivat has the potential to make a meaningful difference for people living with pyruvate kinase deficiency, a debilitating, lifelong hemolytic anemia characterized by serious complications regardless of patients’ transfusion status. The ACTIVATE-T study represents our first study of mitapivat in regularly transfused patients, and when taken together with the ACTIVATE results, demonstrates mitapivat’s potential clinical benefit for patients regardless of transfusion burden,” said Chris Bowden, M.D., chief medical officer at Agios. “We look forward to working with regulatory authorities in both the U.S. and EU to rapidly bring mitapivat to patients as the first potentially disease-modifying therapy for this community that currently has limited treatment options.”

Results from the ACTIVATE-T trial were as follows:

  • 37 percent of patients dosed with mitapivat (n = 10 of 27) achieved a ≥33% reduction in transfusion burden in the 24-week fixed dose period compared with individual historical transfusion burden standardized to 24 weeks (1-sided p=0.0002).
  • 22 percent of patients dosed with mitapivat (n = 6 of 27) were transfusion-free during the 24-week fixed dose period.
  • Treatment with mitapivat showed a reduction in the annualized total number of red blood cell units transfused during the study compared with the historical transfusion burden.
  • The safety profile observed in the study was consistent with previously reported data.

Agios is conducting a full analysis of the ACTIVATE-T results and expects to submit the complete results of the trial for presentation at the European Hematology Association (EHA) Virtual Congress, which is being held June 9-17, 2021.

ACTIVATE-T Trial Design
ACTIVATE-T is a global, multicenter, open-label study to evaluate the efficacy and safety of mitapivat in adult patients with PK deficiency who are regularly transfused, defined as receiving six or more transfusions in the past 52 weeks. The trial enrolled 27 patients across North America, Europe and Asia.

The study was designed with two parts. Part 1 was a dose escalation period in which patients started at 5 mg twice daily of mitapivat, with two potential dose increases to 20 mg twice daily and 50 mg twice daily for up to 16 weeks. After the dose escalation period, patients received a fixed dose for an additional 24 weeks in Part 2.

The primary endpoint of the study was reduction in transfusion burden, defined as a reduction of ≥33 percent in the number of red blood cell units transfused during the 24-week fixed dose period compared with the historical transfusion burden standardized to 24 weeks. Participants who discontinued the study before completing at least 12 weeks of treatment in the fixed dose period were considered non-responders. The p-value is based on the binomial exact test of H0: transfusion reduction response rate≤10% vs. H1: transfusion reduction response rate>10% at a 1-sided α=0.025.

Mitapivat Clinical Development
ACTIVATE-T is one of two studies intended to support a marketing application for mitapivat in patients with PK deficiency. In addition to the ACTIVATE-T trial, Agios recently reported topline results from the global Phase 3 ACTIVATE trial of mitapivat in adults with PK deficiency who do not receive regular transfusions. A full analysis of the data – including patient-reported outcomes (PRO) – is expected to be submitted for presentation at the EHA Virtual Congress. Agios is also conducting an extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T, which is designed to evaluate the long-term safety, tolerability and efficacy of treatment with mitapivat.

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 α- or β-thalassemia. The trial is fully enrolled, and the primary endpoint is hemoglobin response, defined as a ≥1.0 g/dL increase in Hb concentration from baseline at one or more assessments between Week 4 and Week 12. Results from the study are expected to be submitted for presentation at the EHA Virtual Congress. Agios expects to initiate two Phase 3 studies of mitapivat, ENERGIZE and ENERGIZE-T, in not regularly transfused and regularly transfused adults with thalassemia in the second half of 2021.

In addition, 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. 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 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, and updated data were presented at the American Society of Hematology (ASH) Annual Meeting in December 2020. Agios expects to disclose its pivotal program in sickle cell disease in the first half of 2021 and initiate the study by year-end 2021.

Mitapivat has been granted orphan drug designation for the treatment of PK deficiency by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. Additionally, mitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and sickle cell disease.

Mitapivat is not approved for use by any regulatory authority.

About PK Deficiency
Pyruvate kinase (PK) deficiency is a rare, inherited disease that presents as chronic hemolytic anemia, which is the accelerated destruction of red blood cells. The inherited mutations in PKR genes cause a deficit in cellular energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate (ATP) levels and a build-up of upstream metabolites, including 2,3-DPG (2,3-diphosphoglycerate).

PK deficiency is associated with serious complications, including gallstones, pulmonary hypertension, extramedullary hematopoiesis, osteoporosis and iron overload and its sequelae, which can occur regardless of the degree of anemia or transfusion burden. PK deficiency can also cause quality of life problems, including challenges with work and school activities, social life and emotional health. Current management strategies for PK deficiency, including red blood cell transfusions and splenectomy, are associated with both short- and long-term risks. There are no currently approved therapies for PK deficiency. For more information, please visit www.knowpkdeficiency.com.

Agios, in partnership with PerkinElmer Genomics, launched the Anemia ID program to offer no-cost genetic testing to eligible patients in the U.S with suspected hereditary anemias, including PK deficiency. The program was created in response to feedback from patients, advocates and physicians about the need for improved diagnosis to inform disease management decisions. To learn more, please visit www.AnemiaID.com.

About Agios
Agios is focused on discovering and developing novel investigational medicines to treat malignant hematology, solid tumors and genetically defined diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across these three therapeutic areas, Agios has two approved oncology precision medicines and multiple first-in-class investigational therapies in clinical and/or preclinical development. For more information, please visit the company’s website at www.agios.com.

SOURCE: Agios Pharmaceuticals