Osivelotor for sickle cell disease

Last updated May 29, 2024, by Lindsey Shapiro, PhD
Fact-checked by Joana Carvalho, PhD

What is osivelotor for sickle cell disease?

Osivelotor, previously known as PF-07940367, GBT601, or GBT021601, is an investigational oral therapy being evaluated as a possible treatment for sickle cell disease (SCD).

It’s being developed by Pfizer, which acquired osivelotor’s original developer, Global Blood Therapeutics, in a 2022 deal.

Osivelotor has been granted orphan drug, rare pediatric disease, and fast track designations in the U.S., all of which are intended to facilitate its clinical development and hasten its regulatory review.

Therapy snapshot

How does osivelotor work in sickle cell disease?

In SCD, genetic mutations lead to the production of an abnormal version of hemoglobin, called hemoglobin S, or HbS. Hemoglobin is the protein that helps red blood cells carry oxygen through the body. HbS molecules are prone to clumping together, or polymerizing, into rigid fibers that distort red blood cells into a sickle-like shape, ultimately driving the painful symptoms of SCD and giving the disease its name.

Osivelotor is what’s known as an HbS polymerization inhibitor. Essentially, it aims to prevent HbS from aggregating or clumping together into the rigid fibers that cause red blood cells to lose their rounded, healthy shape.

HbS polymerization only happens when hemoglobin is deoxygenated, meaning it is not fully bound to oxygen molecules. Osivelotor binds directly to hemoglobin and works to increase its affinity for oxygen and stabilize it in its oxygenated state. The idea is that if HbS is fully oxygenated, it won’t polymerize, thereby preventing red blood cell sickling and easing SCD symptoms.

This is the same mechanism as Pfizer’s Oxbryta (voxelotor), which has been conditionally approved in the U.S. for treating SCD since 2019. Osivelotor is being developed as a possible next-generation successor to Oxbryta that may yield greater therapeutic efficacy at lower doses.

How will osivelotor be administered in sickle cell disease?

In clinical trials involving SCD patients, osivelotor has been administered as oral tablets at daily doses ranging from 50 mg to 150 mg.

Osivelotor in sickle cell disease clinical trials

A Pfizer-sponsored Phase 1 trial (NCT04983264) was conducted to establish the safety of single and multiple doses of osivelotor in six adults with SCD.

The results showed that the therapy was well tolerated and increased hemoglobin’s affinity for oxygen, as intended. 

Ongoing trials

An ongoing Phase 2/3 clinical trial (NCT05431088) is now evaluating osivelotor’s safety and efficacy in approximately 517 adults and children with SCD, ages 6 months to 65 years.

The trial is being conducted in three parts. Its first part is a dose-optimization stage, in which adult participants receive twice-daily loading doses of osivelotor (100 or 150 mg), followed by once-daily maintenance dosing through week 12, or for about three months.

Results from that part have indicated that the treatment led to improvements in several red blood cell parameters. Specifically, data showed an increase in hemoglobin levels and red blood cell counts, decreases in red blood cell sickling, and better flexibility (deformability), which enables cells to more easily pass through blood vessels. The treatment also was well tolerated, with no increases in pain episodes reported.

Part 2 involves adult and adolescent patients, ages 12 to 65, who experienced 2-10 painful vaso-occlusive crises (VOCs) in the year leading up to screening. These participants will be randomly assigned to receive osivelotor or a placebo for 48 weeks, or nearly a year. The main goals are to evaluate changes in hemoglobin levels and the rate of VOCs through week 48.

Finally, the open-label part 3 is designed to evaluate the safety and pharmacological properties of osivelotor in pediatric SCD patients through six weeks of treatment.

After the Phase 2/3 trial, eligible participants will be able to enter into a long-term extension study (NCT05632354), in which osivelotor’s safety and efficacy will be assessed for up to four years.

Common side effects of osivelotor

As clinical trials of osivelotor in SCD are still in the early stages, its side effect profile in this patient population is not fully known.

Side effects reported in clinical trials of SCD so far include:

• headache
• diarrhea.

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