Agios Launches Phase 2/3 Trial, RISE UP, for Mitapivat

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A half-full bottle of a liquid prescription medicine bears a label reading

Agios Pharmaceuticals has launched a Phase 2/3 trial called RISE UP to test its investigational therapy mitapivat (AG-348) in people with sickle cell disease (SCD).

The trial (NCT05031780), which is not yet recruiting, aims to enroll about 237 people with SCD, ages 16 and older. To be eligible, prospective participants must have hemoglobin levels between 5.5 and 10.5 grams per deciliter (g/dL) and have had two to 10 sickle cell pain crises in the previous year.

Mitapivat is an oral small molecule designed to activate the enzyme pyruvate kinase-R (PKR). This enzyme is important for glycolisis — the process of generating cellular energy by breaking down sugar molecules.

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When PKR is active, it uses up 2,3-diphosphoglycerate (2,3-DPG). In SCD, 2,3-DPG is thought to accumulate in red blood cells and cause them to become misshapen by prompting hemoglobin molecules to clump together in a process known as polymerization. By activating PKR, mitapivat is expected to lower the 2,3-DPG accumulation and thereby lessen hemoglobin polymerization and red blood cell sickling.

Agios announced positive data from a proof-of-concept Phase 1 trial (NCT04000165) last year, which indicated mitapivat was able to increase hemoglobin levels and lower markers of red blood cell damage.

At the recent American Society of Hematology Annual Meeting and Exposition, held in December virtually and in Atlanta, researchers presented findings from two investigator-sponsored studies of mitapivat.

“Results reported from these investigator-led studies provide additional efficacy, safety and translational data that continue to support the clinical development of mitapivat in people with sickle cell disease, a lifelong, debilitating condition with few treatment options,” Sarah Gheuens, MD, PhD, Agios’ chief medical officer, said in a press release.

In the presentation “Safety and Efficacy of Mitapivat (AG-348), an Oral Activator of Pyruvate Kinase-R, in Patients with Sickle Cell Disease: A Phase 2, Open-Label Study (ESTIMATE),” scientists at UMC Utrecht in the Netherlands shared data on six people with SCD who were treated with the investigational therapy.

During an eight-week dose-finding period, participants were given increasing doses of the medicine, starting at 20 milligrams (mg) twice daily. All six participants were escalated up to a maximum dose of 100 mg twice daily.

No serious adverse events (side effects) were reported, and adverse events that did occur were generally mild and resolved with time. The most common ones included headache, high levels of liver enzymes, and digestive problems like diarrhea or abdominal pain. One patient had a vaso-occlusive crisis (VOC), which did not require hospitalization or treatment discontinuation.

Analyses of the patients’ blood suggested their red blood cells were more resistant to sickling at low oxygen levels after treatment. Additionally, all but one patient had an increase in hemoglobin levels of at least 1 g/dL, and 2,3-DPG levels decreased following treatment.

These data “show promising efficacy,” the researchers wrote, adding that “mitapivat demonstrated an adequate safety profile.”

In another presentation, “Mitapivat (AG-348) Demonstrates Safety, Tolerability, and Improvements in Anemia, Hemolysis, Oxygen Affinity, and Hemoglobin S Polymerization Kinetics in Adults with Sickle Cell Disease: A Phase 1 Dose Escalation Study,” scientists at the National Institutes of Health (NIH) presented data from 16 SCD patients treated with mitapivat at doses of up to 50 or 100 mg, given twice daily for two weeks.

Results showed that the medication was generally well-tolerated. The most common adverse events linked to treatment included insomnia, joint pain, and high blood pressure. There were two VOCs potentially linked to mitapivat, both of which occurred during a roughly two-week taper after the initial treatment period.

Blood analyses also suggested treatment reduced sickling. Hemoglobin levels rose by a mean of 1.2 g/dL in patients given mitapivat at a dose of 50 mg twice daily. More than half (56.3%) of participants experienced an increase in hemoglobin levels of at least 1 g/dL. These patients are continuing to be followed in an extension study (NCT04610866).

“We’d like to thank our collaborators at the NIH and UMC Utrecht and look forward to building upon their contributions through our recently initiated Phase 2/3 RISE UP trial,” Gheuens said.

In the Phase 2 portion of RISE UP, participants will be given mitapivat at a dose of 50 or 100 mg twice daily, or a placebo, for 12 weeks. Based on data from that phase, one of the doses will be selected for use in Phase 3, which will evaluate the effects of mitapivat against a placebo for 52 weeks (about a year).

The trial’s main goal is to assess mitapivat’s effect on hemoglobin levels and sickle cell pain crises.

“We designed this trial to have a broad global reach, reduce barriers to participation and understand how mitapivat can impact the aspects of the disease that patients indicated were of greatest importance to them,” Gheuens said.