麻豆传媒

SAN DIEGO -- An experimental monoclonal antibody almost halved the rate of painful crises in people with sickle cell disease, a researcher said here.

Over a year of treatment, patients given crizanlizumab had a 45.3% lower rate of crises than patients getting a placebo, according to , of the University of North Carolina at Chapel Hill.

The drug also markedly slowed the time to the first crisis after starting therapy and the time to the second crisis over the year of treatment, Ataga reported at the American Society of Hematology (ASH) annual meeting.

Details of the phase II SUSTAIN study were in the New England Journal of Medicine.

The findings are exciting for several reasons, commented , of the Children's Hospital of Philadelphia, who was not part of the study but who moderated an ASH media briefing.

In the first place, the drug appears to work in all genotypes of sickle cell disease, she told 麻豆传媒, adding that "even though sickle cell disease is a single disease, it's really a syndrome. The fact that they have included [all] genotypes is very promising."

It's also exciting that the drug targets a new target, she added, as most attempts to treat sickle cell disease -- including the only approved drug hydroxyurea -- have focused on using fetal hemoglobin. This study opens the possibility of using multiple drugs for therapy.

"We can actually look at combining hydroxyurea with this type of agent," Smith-Whitley said.

Sickle cell disease is characterized by the presence of sickle hemoglobin (HbS) in red blood cells, which changes their shape and make it difficult for them to move through blood vessels, causing recurrent pain crises (also called vaso-occlusive crises).

Hydroxyurea is the only drug shown to have a beneficial effect on sickle cell disease, but even with such treatment many patients continue to have pain crises, Ataga's group noted.

The change in cell shape is the key factor in pain crises but the "pathogenesis of vaso-occlusion is complex," the authors stated. In particular, the process by which sickled cells adhere to the walls of blood vessels appears to be initiated by a protein called P-selectin.

In transgenic mice with sickle cell disease, a deficiency of P-selectin meant they were protected from vaso-occlusion, so Ataga's group hypothesized that they would see a similar benefit if the molecule could be blocked in humans. Crizanlizumab binds to P-selectin.

The authors enrolled 198 patients and gave them one of two doses of the drug (2.5 or 5.0 mg/kg body weight) or placebo, administered intravenously 14 times over 52 weeks.

The primary endpoint of the study was the difference between the high-dose arm and placebo in the number of pain crises over course of the study, although the researchers also examined other endpoints, including safety, the times to first and second crises, and annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism).

The researchers found that patients getting high-dose crizanlizumab had a median of 1.63 crises a year, compared with 2.98 among those given placebo. Those numbers indicated a 45.3% lower rate with high-dose crizanlizumab (P=0.01).

The number of patients who had no crises at all during the year was more than doubled with crizanlizumab compared with placebo at 24 versus 11.

The authors also found that:

• The median time to the first crisis with high-dose crizanlizumab was 4.07 months versus 1.38 months for placebo.
• The median time to the second crisis was 10.32 and 5.09, respectively.
• The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab versus 2.91 with placebo, indicating 62.9% lower rate with the drug.

For the main endpoints, the low dose of crizanlizumab did not have a significant difference from placebo.

Patients were stratified by their frequency of crises in the previous year and by whether they were also taking hydroxyurea. Ataga told 麻豆传媒 that neither factor affected the efficacy of crizanlizumab.

The rates of adverse events and serious adverse events were similar among the arms. Adverse events that were seen in 10% or more of the patients in either active-treatment group and were at least twice as common as among placebo patients and included arthralgia, diarrhea, pruritus, vomiting, and chest pain.

The authors noted that longer follow-up and monitoring are needed to ensure that late neutralizing antibodies don't emerge that might limit the ability to administer the study drug long-term.

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