Crovalimab for sickle cell disease

Last updated July 16, 2024, by Andrea Lobo, PhD
Fact-checked by Inês Martins, PhD

What is crovalimab for sickle cell disease?

Crovalimab is an antibody-based therapy that is being investigated in people with sickle cell disease (SCD) as an adjunctive, or add-on, therapy for treating and preventing the acute pain events called vaso-occlusive crises (VOCs).

Developed by the Roche subsidiary Genentech, it is being tested as an initial intravenous (into-the-vein) infusion followed by routine injections under the skin, or subcutaneous injections.

Crovalimab also is being developed as a potential treatment for other disorders, including atypical hemolytic uremic syndrome (aHUS) lupus nephritis, a common complication of lupus. It’s already approved in the U.S., under the brand name PiaSky, to reduce the destruction of red blood cells in people with paroxysmal nocturnal hemoglobinuria (PNH).

Therapy snapshot

How does crovalimab work in sickle cell disease?

Sickle cell disease is caused by mutations in the HBB gene that result in the production of hemoglobin S, a faulty version of hemoglobin. Hemoglobin is the protein in red blood cells responsible for transporting oxygen.

Hemoglobin S tends to clump inside red blood cells, causing them to acquire a sickle-like shape that makes them more prone to die prematurely, a process called hemolysis. Sickled cells also are stiffer and tend to stick together, leading to frequent blockages in blood flow that cause painful episodes known as VOCs.

Accumulating evidence suggests that the abnormal regulation of the complement system, a part of the immune system, plays a vital role in SCD, including in the anemia and painful crises that mark the condition.

Crovalimab is a new antibody-based therapy designed to specifically bind to a complement protein called C5, which ultimately blocks the complement system. By doing so, the treatment is expected to reduce hemolysis and ease the frequency and severity of VOCs.

How will crovalimab be administered in sickle cell disease?

In SCD clinical trials, crovalimab has been dosed differently depending on whether it is used to manage an acute severe VOC, or to prevent those painful crises from happening.

When given to sickle cell patients experiencing an acute VOC that required hospitalization, the therapy is being administered as a single intravenous infusion, at a dose of 1,000 or 1,500 mg depending on a patient’s body weight.

When used for the prevention of VOCs, the treatment is being given as an initial intravenous loading dose (1,000 or 1,500 mg depending on weight), followed by subcutaneous injections. These include four weekly injections at a 340 mg dose, followed by monthly injections at a dose of 680 mg or 1,020 mg depending on body weight.

However, crovalimab is in the early stages of development for SCD. It’s too soon to know if these will be the drug’s doses and regimens should it receive regulatory approval as a disease treatment.

Crovalimab in sickle cell disease clinical trials

Crovalimab initially was tested in healthy volunteers and PNH patients in the Phase 1/2 COMPOSER clinical trial (NCT03157635), which supported its approval for that disease in the U.S. and elsewhere. The therapy was found to be well tolerated, with no serious adverse events reported.

Genentech is sponsoring two ongoing and global clinical trials into the safety, pharmacological properties, and efficacy of crovalimab in people with SCD. Both trials are enrolling patients ages 12 to 55 and weighing at least 40 kg (88 lbs), who will be randomly assigned to crovalimab or a placebo.

CROSSWALK-a Phase 1b trial

The CROSSWALK-a Phase 1b trial (NCT04912869) aims to include 30 adults and adolescents who are experiencing a vaso-occlusive crisis that requires hospitalization and treatment with injectable opioids.

Patients randomized to crovalimab are being given a single 1,000 mg dose if they weigh from 40 up to 100 kg (about 88-220 lbs), or a 1,500 mg dose if they weigh 100 kg or more. All enrolled, including those in the placebo group, also are receiving pain management and other supportive care for their VOC, and patients may continue with their standard SCD medications.

The study’s main goal is to assess the treatment’s safety, including infusion-related or allergic reactions. As secondary goals, researchers will examine whether crovalimab outperforms a placebo in various efficacy measures, including the time to VOC improvement, changes in pain levels, need for medications to manage pain, and time to hospital discharge.

The trial is expected to finish in July 2025.

CROSSWALK-c Phase 2a trial

The CROSSWALK-c Phase 2a trial (NCT05075824) is testing crovalimab’s safety and efficacy when given as an adjunct therapy to prevent vaso-occlusive crises. The trial is expected to enroll 90 children and adults with SCD, ages 12 to 55, who experienced two to 10 VOCs in the year before enrollment.

Those randomly assigned to crovalimab initially are being given an intravenous infusion at a 1,000 mg dose if they weigh from 40 up to 100 kg, or at a 1,500 mg dose if they weigh 100 kg or more. They then continue with the medication at a weekly 340 mg dose (given by subcutaneous injection) for four weeks, followed by monthly injections at a dose of 680 mg for those in the lower weight group, or 1,020 mg injections for those in the higher weight group for a total 48 weeks (almost one year) of treatment.

Patients on stable doses of other SCD therapies may continue with those doses during the trial.

CROSSWALK-c’s main goal is to determine whether crovalimab can reduce the annual rate of VOCs requiring admission to a medical facility. Secondary goals include changes in the frequency of VOCs at home, the number of days hospitalized due to VOCs, patient-reported fatigue, and the rate of acute chest syndrome events — a serious lung condition marked by fever, chest pain, and breathing difficulties.

Changes in measures of kidney and heart function, and overall safety also are being evaluated. The trial is expected to conclude in January 2025.

Common side effects of crovalimab

Because clinical trials of crovalimab in sickle cell disease are still in early stages, its safety profile in this population is not yet known.

Trials in people with the blood disorder paroxysmal nocturnal hemoglobinuria, however, suggest that crovalimab’s most common side effects could include infusion-related and allergic reactions, respiratory tract infections, and viral infections.

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