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Treatment Hope for Sickle Cell Disease

A new drug shows clinical efficacy and safety in preventing sickle cell crises

by Vitria Adisetiyo

sickle cell illustration

A new drug, crizanlizumab, may soon be an approved treatment option for sickle cell disease (SCD), the most common inherited blood disorder in the U.S.

Patients with this lifelong disorder experience recurrent pain episodes called vaso-occlusive episodes (VOE) or sickle cell crises that increase the risk of death due to tissue and organ damage. These crises are the primary cause of frequent health care visits and the source of substantial financial burden.

“Sickle cell disease is one of the most costly medical conditions next to congestive heart failure,” says Julie Kanter, M.D., associate professor of pediatrics and director of sickle cell disease research at MUSC.

Moreover, there are few treatments for the disorder and only one medication (hydroxyurea) has been previously approved to reduce VOE, until now. Findings from a phase 2 clinical trial published in the February 2, 2017 issue of the New England Journal of Medicine show that crizanlizumab (Novartis, Basel, Switzerland) significantly reduces VOE in those with SCD. Kanter, who is a co-author on the article, recruited patients into the trial and served on the publication committee.

“The goal is to prevent these episodes because this will contribute to decreased chronic pain and improved quality of life,” says Kanter.

The pathology of VOE is inflammatory based. Abnormal sickle-shaped red blood cells adhere to the inner lining of blood vessels, blocking microcirculation and leading to inflammation and pain. This adhesion requires a cell adhesion molecule called P-selectin. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin.

“Crizanlizumab prevents pain episodes by inhibiting the stickiness of the blood cells to the inside of blood vessels,” explains Kanter.

In this double-blind, randomized, placebo-controlled study, 198 patients aged 16 to 65 years who were experiencing VOE were randomized to receive low-dose crizanlizumab, high-does crizanlizumab or placebo. Treatment was administered intravenously 14 times over 52 weeks, followed by a six-week evaluation phase.

The annual rate of VOE in the high-dose group was 43.3 percent lower than placebo. Additionally, the median time to the first and second crises was significantly delayed with high-dose crizanlizumab compared to placebo (4.07 vs. 1.38 months; 10.32 vs. 5.09 months, respectively), and the annual rate of uncomplicated VOE in the high-dose group was 62.9 percent lower than placebo. Low-dose outcomes did not differ from placebo.

Only minor adverse effects were associated with crizanlizumab (i.e., joint pain, diarrhea, itchy skin, vomiting, chest pain), and no group differences were noted in total adverse effects. No problems with wound healing were reported, suggesting that temporary blockage of P-selectin does not disrupt blood clotting. No antibodies against crizanlizumab were detected, suggesting that an immune response limiting long-term administration of crizanlizumab is unlikely.

Lastly, the efficacy of crizanlizumab was demonstrated in adults with all types of sickle cell disease, as findings were observed in a representative patient sample that included all common sickle cell genotypes and in patients receiving concomitant hydroxyurea therapy and/or long-term opioid therapy.

Given the comprehensive study design and robust clinical outcomes, the drug manufacturer is applying for FDA approval based on these published results. Meanwhile, plans for a pediatric clinical trial of crizanlizumab are underway. Kanter will serve on the advisory committee designing the study, and MUSC will once again serve as a leading recruitment site.