Pyruvate Kinase Deficiency of Red Cells

– Topline Data from 52-week Phase 3 Study Expected in Late 2025 – CAMBRIDGE, Mass., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, today announced that enrollment is complete for the Phase 3 RISE UP study. This global, double-blind, randomized, placebo-controlled trial is evaluating the efficacy and safety of mitapivat, an oral, small molecule PK activator, in sickle cell disease patients who are 16 years of age or older. Agios expects to report topline results from this 52-week Phase 3 study in late 2025. Sickle cell disease is an inherited, lifelong blood disorder caused by mutations in hemoglobin, the major protein that carries oxygen in red blood cells. In sickle cell disease, red blood cells are sickle-shaped due to a gene mutation that affects the hemoglobin molecule. When red blood cells sickle, they do not bend or move easily and can block blood flow to the rest of the body, resulting in chronic hemolytic anemia, pain, poor quality of life, organ damage and early mortality. In sickle cell disease there is an increased energy demand of adenosine triphosphate (ATP) to support red blood cell function and increased 2,3-diphosphoglycerate (2,3-DPG) concentrations that increase the likelihood of red blood cell sickling. Mitapivat is designed to optimize the glycolytic pathway, which has a dual effect of increasing ATP levels and decreasing 2,3-DPG concentrations in red blood cells. “There is a critical need for novel regimens that elevate the standard of care for patients suffering from sickle cell disease, a burdensome and debilitating disease,” said Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios. “We sincerely thank the patients, study investigators and patient advocates for their instrumental support and partnership in helping us complete enrollment of the Phase 3 RISE UP study. With enrollment now complete, we look forward to completing the trial and sharing topline results with the community in late 2025.” The Phase 3 RISE UP study enrolled more than 200 patients worldwide. The trial’s primary endpoints are hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 24 through Week 52 compared with baseline, and annualized rate of sickle cell pain crises. These are important clinical endpoints in sickle cell disease because anemia and pain episodes are the hallmark symptoms of the disease that severely impact a patient’s quality of life. The positive results from the double-blind period of the RISE UP Phase 2 study, which were presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2023, supported Agios’ further exploration of mitapivat’s risk-benefit profile in sickle cell disease in the Phase 3 study. About Phase 2/3 RISE UP StudyThe RISE UP Phase 2 and 3 studies are evaluating the efficacy and safety of mitapivat in sickle cell disease patients who are 16 years of age or older, have had between two and 10 sickle cell pain crises in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 g/dL during screening. The Phase 2 and Phase 3 studies are conducted under a single operationally seamless Phase 2/3 protocol. The two studies enrolled different participants and achieved operational efficiency through leveraging the same sites, vendors and other resources. The Phase 2 study included a 12-week randomized, placebo-controlled period in which participants were randomized in a 1:1:1 ratio to receive 50 mg mitapivat twice daily, 100 mg mitapivat twice daily or matched placebo. The primary endpoints were hemoglobin response, defined as ≥1.0 g/dL increase in average hemoglobin concentration from Week 10 through Week 12 compared to baseline, and safety. The Phase 3 study includes a 52-week randomized, placebo-controlled period in which participants will be randomized in a 2:1 ratio to receive 100 mg of mitapivat twice daily or matched placebo. The primary endpoints are hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 24 through Week 52 compared with baseline, and annualized rate of sickle cell pain crises. Participants who complete the double-blind period of the Phase 2 or Phase 3 studies will have the option to move into a 216-week open-label extension period to receive mitapivat. About PYRUKYND® (mitapivat)PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States, and for the treatment of PK deficiency in adult patients in the European Union. IMPORTANT SAFETY INFORMATIONAcute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath. Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. Drug Interactions: Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage.Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index.UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment. Please see full Prescribing Information and Summary of Product Characteristics for PYRUKYND. About AgiosAgios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency, myelodysplastic syndrome (MDS)-associated anemia and phenylketonuria (PKU). In addition to its clinical pipeline, Agios is advancing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. For more information, please visit the company’s website at www.agios.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of PYRUKYND® (mitapivat); Agios’ plans, strategies and expectations for its preclinical, clinical and commercial advancement of its drug development, including PYRUKYND®; Agios’ strategic vision and goals, including its key milestones for 2024 and 2025; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to establish and maintain key collaborations; uncertainty regarding any milestone or royalty payments related to the sale of its oncology business or its in-licensing of TMPRSS6 siRNA, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios’ cash and cash equivalents; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Contacts: Investor ContactChris Taylor, VP, Investor Relations and Corporate CommunicationsAgios PharmaceuticalsIR@agios.com Media ContactEamonn Nolan, Senior Director, Corporate CommunicationsAgios PharmaceuticalsMedia@agios.com

iStock/ YuLi4ka In the wake of Pfizer’s voluntary market withdrawal of the popular sickle cell disease therapy, BioSpace looks at five investigational drugs currently making their way through the pipeline. A recent fumble has left the sickle cell disease community reeling . Last month, Pfizer abruptly pulled Oxbryta from all global markets after new data showed a higher risk of deaths and complications in treated patients. “[Oxbryta] was one of four medications which we would describe as disease-modifying,” Clifford Takemoto, director of clinical hematology at St. Jude Children’s Research Hospital, told BioSpace . Since the approval of Bristol Myers Squibb’s hydroxyurea for sickle cell disease (SCD) in 1998, only three disease-modifying medications have entered the market, he said. Oxbryta, which won FDA accelerated approval in November 2019, was one of these. Another, Novartis’ Adakveo, has also been called into question after failing to reduce vaso-occlusive crises (VOC) in people with SCD in a Phase III trial last year. EU regulators formally revoked Adakveo’s approval in August 2023, but it remains available in the U.S. “We were optimistic that things were changing,” Takemoto said. “People had hoped that these medications would make a difference.” SCD affects more than 100,000 people in the U.S. and 8 million worldwide. With so few treatment options, it remains a seriously underserved population . Takemoto said the Oxbryta withdrawal has left some patients a “bit angry” and distrustful of new medications, and the question for the community remains: “What’s next?” For Takemoto, the ultimate hope for SCD treatment lies in next-gen transplantation and gene therapy. With the approval of bluebird bio’s Lyfgenia and Vertex and CRISPR Therapeutics’ Casgevy, the potential for gene therapies in SCD is there, even if the rollout is slow and for most, not very accessible, he said. St. Jude is developing its own gene therapy, which the research hospital hopes to move into clinical trials sometime next year. Takemoto also pointed to work being done in bone marrow transplantation intended to reduce toxicity and improve success rates. St. Jude is working on a process that will utilize a “half match,” where a parent’s bone marrow can be used instead of a sibling. These treatments could be transformative, Takemoto said. Here, BioSpace looks at five investigational therapies making their way through the SCD pipeline. Pfizer’s Inclacumab and Osivelotor Oxbryta is not the only SCD asset Pfizer brought onboard with its 2022 acquisition of Global Blood Therapeutics . Two other investigational therapies, inclacumab and osivelotor, were also part of the deal. Inclacumab, a P-selectin inhibitor, is currently being assessed in a Phase III trial to determine its safety and efficacy in reducing VOC. The drug works by binding to P-selectin, a cell adhesion molecule found on platelets. According to Pfizer, this prevents platelets from aggregating, which in turn, is expected to help maintain normal blood flow. Like Oxbryta, osivelotor is a sickle hemoglobin polymerization inhibitor, but with a next-generation design. The asset is currently being studied in a Phase II/III study slated for completion in 2028. While Pfizer has not stated whether the recent findings related to Oxbryta will impact the development of osivelotor, Leerink Partners noted that a Phase II study raised safety concerns, with treatment-emergent adverse events seen in 8 out of 35 patients. Agios Pharmaceuticals’ Mitapivat Agios Pharmaceuticals is developing mitapivat, a pyruvate kinase (PK) activator that is already approved for the treatment of hemolytic anemia in adults with PK deficiency, for SCD. Red blood cells require the PK enzyme for energy, Takemoto explained. In December 2023, the company presented positive data from the Phase II portion of its pivotal RISE UP study. The annualized rate of sickle cell pain crises for patients in the higher dose treatment arm was 0.51 compared to 1.71 for participants in the placebo arm. Takemoto said the oral medication seems to benefit red blood cell health in general and noted that the data look favorable for patients with SCD and other hemolytic anemias. But not everyone is as convinced. Leerink Partners analysts wrote last month of concerns that similar physiological effects could be seen with both Oxbryta and mitapivat. A Phase III readout is expected next year, and the company is targeting a label expansion in 2026. Novo Nordisk’s Etavopivat In 2022, Novo Nordisk paid $1.1 billion to acquire Forma Therapeutics, gaining a lead SCD asset, etavopivat, in the deal. Like mitapivat, etavopivat is also a PK activator, but Novo’s candidate comes with a potential advantage —once daily dosing, versus mitapivat’s twice daily regimen. Etavopivat is currently being studied in a Phase III trial slated for completion in 2026. Phase I data presented by Forma at the American Society of Hematology’s annual meeting in 2021 showed a “sustained increase in hemoglobin and improvement in biomarkers of hemolysis and red blood cell health.” The results, from 15 patients dosed for up to 12 weeks, also showed a trend toward decreasing VOC compared to the 12 months prior to their entering the trial. Takemoto said the candidate “looks very promising” so far but acknowledged that “there are things we don’t know about it. We may learn new side effects as it’s used.” St. Jude will serve as a site for the Phase III trial. Fulcrum Therapeutics’ Pociredir Fulcrum Therapeutics ’ pociredir, a polycomb repressive complex 2 (PRC2) inhibitor, is designed to induce expression of fetal hemoglobin to compensate for the mutated hemoglobin that occurs in SCD. The development path for pociredir has not been without bumps. In February 2023, the FDA slapped Fulcrum with a clinical hold based on previously submitted preclinical data and non-clinical and clinical evidence of hematological malignancies observed with other PRC2 inhibitors. The hold was released six months later. The small molecule, which is currently being studied in a Phase Ib trial, has been well-tolerated in people with SCD with no treatment-related adverse events reported after up to three months exposure, according to a press release announcing the lifted clinical hold.

Novo Nordisk has ended one of the multiple trials testing the lead oral drug from its $1.1 billion Forma Therapeutics buyout , according to an update to the US federal trials database this week. The Danish drug giant terminated a Phase 2 trial of etavopivat for anemia in adults with various forms of myelodysplastic syndromes, or MDS, according to an update to the US clinical trials site on Thursday. In patients with MDS, red blood cells don’t mature or become healthy ones, and the cancer can progress into leukemia. The drug is still being tested in mid – and late-stage trials for patients with sickle cell disease and thalassemia. Novo made the decision after a “futility assessment concluded low likelihood of the trial showing meaningful patient benefit,” according to an update to the Fortitude trial registry. “This decision was not taken lightly and reflects a judgement of low likelihood that the Fortitude trial would generate benefit for patients with MDS,” a Novo spokesperson said in an emailed statement to Endpoints News . MDS wasn’t highlighted in Novo’s deal announcement in fall 2022, but it was nonetheless another patient population that the pharmaceutical company had hoped to treat with the selective pyruvate kinase-R activator. Patients with sickle cell disease and thalassemia are the main populations for which Novo is developing the once-daily medicine. “We remain confident in etavopivat’s promise and are committed to its continued development in sickle cell disease (SCD) and thalassemia,” the spokesperson said. “The termination of the Fortitude trial does not diminish our belief in etavopivat’s potential to make a significant impact on patients’ lives.” Novo highlighted the asset’s potential in MDS in its annual report in January. Agios Pharmaceuticals is also testing a PK activator, dubbed tebapivat, for MDS-associated anemia. Agios’ more advanced PK activator, mitapivat, is approved for adult PK deficiency and marketed as Pyrukynd. Bristol Myers Squibb’s Reblozyl is indicated for MDS-related anemia. Since the acquisition, Novo has offloaded some of the pipeline at Forma, a drug developer that had touted “ the science of giving a damn. ” It sold a preclinical cancer candidate to Debiopharm and a Phase 1 prostate cancer drug to Pathos AI .