Mitapivat for SCD seen to increase hemoglobin for nearly half in trial

2 dose groups meet efficacy goal in Phase 2 part of RISE UP study

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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For nearly half of people with sickle cell disease who took part in the Phase 2 part of a clinical trial called RISE UP, treatment with the oral medication mitapivat brought about a significant increase in levels of hemoglobin — the oxygen-carrying protein in red blood cells — new data show.

This means that the study’s primary efficacy endpoint, which was to see if the medication could increase hemoglobin levels by at least one gram per deciliter (g/dL), was achieved for both mitapivat dose groups, according to its developer, Agios Pharmaceuticals.

In fact, higher hemoglobin levels were seen in up to 50% of patients in the 100 mg dosage group, and in nearly as many given the 50 mg dose.

“We are pleased with the results of the Phase 2 portion of the RISE UP pivotal study in sickle cell disease, which bring us closer to our goal of providing a novel oral therapy that may improve anemia, reduce sickle cell pain crises and improve how patients feel and function,” Sarah Gheuens, MD, PhD, chief medical officer and head of research and development at Agios, said in a company press release.

“We are grateful to all of the patients who participated in our trial, our collaborators, study investigators and advisors in the patient and clinical communities for their partnership in achieving this milestone,” Gheuens said.

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Mitapivat may help reduce vaso-occlusive crises

The medication’s side effects seen here were similar to what had been reported in previous studies involving people with sickle cell disease and other types of hemolytic anemia caused by the excessive breakdown of red blood cells.

But there also were improvements found in markers related to the breakdown of red blood cells — destruction known as hemolysis — and to the production of new ones, called erythropoiesis. A trend also was seen toward fewer episodes of acute pain episodes known as vaso-occlusive crises.

While still in the process of deciding which of the two doses works best, the company is moving ahead with its plans to launch the study’s Phase 3 portion in the last quarter of this year. If all goes well, the company expects to have data in about two years’ time, and a potential U.S. approval by 2026, according to Agios.

“The sickle cell community is in dire need of effective disease-modifying therapies — particularly novel oral therapies — to address … unmet needs,” said Modupe Idowu, MD, associate professor at The University of Texas Health Science Center at Houston, one of the study’s locations.

Red blood cells normally are round and flexible, which allows them to fit through blood vessels and carry oxygen to body tissues. In SCD, however, red blood cells become stiff and take on the sickle-like shape that gives the disease its name. This makes them more sticky and prone to getting stuck in blood vessels.

When this happens, blood flow can become obstructed, causing pain and organ damage. These episodes are known as vaso-occlusive crises and can set the stage for future complications. Other symptoms include fatigue, anemia, or having too few red blood cells, and frequent infections.

Mitapivat is the active substance in Pyrukynd, an approved medication used to treat adults with pyruvate kinase deficiency. Pyruvate kinase is an enzyme that helps cells convert glucose, or blood sugar, into energy. When this enzyme does not work well, it causes red blood cells to break down faster than normal.

The medication works by attaching to and activating pyruvate kinase, causing it to work more effectively. This is expected to prevent excessive hemolysis. In sickle cell disease, it also may prevent red blood cell sickling.

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RISE UP testing safety, efficacy of mitapivat

RISE UP (NCT05031780), launched in January 2022, is testing how safe mitapivat is and how well it works in people with sickle cell disease. The study comprises two portions, each with different participants — an estimated 267 patients in all.

Participants in the study are ages 16 and older and had experienced 2-10 vaso-occlusive crises in the year prior to the trial’s start (baseline).

The Phase 2 portion involved 79 individuals who were randomly assigned to receive either of two doses of mitapivat — 50 mg or 100 mg, taken twice daily — or a placebo for 12 weeks, or about three months.

After 10-12 weeks, the proportion of participants who saw their hemoglobin level increase by at least 1 g/dL was higher in the mitapivat groups — by 46.2% in the 50 mg group and by 50% in the 100 mg group — than in the placebo group. Those taking the placebo saw a 3.7% increase.

“Treatment with mitapivat demonstrated a statistically significant increase in hemoglobin response rate compared to placebo,” the researchers wrote in a presentation to a webcast hosted by Agios in late June.

The annualized rate of vaso-occlusive crises, which refers to the number of pain episodes divided by the number of months of the study and multiplied by 12, was more than halved in the mitapivat groups compared with the placebo group. That rate was 0.83 in the 100 mg group and 0.51 for those taking the 50 mg dose versus 1.71 for the participants in the placebo group.

Treatment with mitapivat demonstrated a statistically significant increase in hemoglobin response rate compared to placebo.

There were no side effects leading to treatment discontinuation over the course of the study, and nearly all participants — 73 or 92.4% — started or continued taking mitapivat as they rolled over into an open-label extension period.

The Phase 3 portion of RISE UP is expected to enroll 198 participants, who will be randomly assigned to receive either the selected dose of mitapivat based on Phase 2 data or a placebo for 52 weeks, or about one year. These patients also will have the option to move into a 216-week (just longer than four years) open-label extension period.

“Mitapivat has a high potential to address aspects of the disease of greatest concern to patients,” Idowu said, adding, “I look forward to continuing the Phase 3 RISE UP study and am hopeful this will deliver a potential new treatment option for sickle cell warriors.”