Crizanlizumab Lowers Pain Crises in At-risk Sickle Cell Patients, Ad-hoc Trial Data Show

Novartis’ investigational therapy for sickle cell disease (SCD), crizanlizumab (SEG101), was seen to reduce the number of patients reporting a pain crisis — including in those with a recent history of multiple crises — a post-hoc analysis of the SUSTAIN Phase 2 study reports.

More patients (35.8%) treated with crizanlizumab — among a study subgroup who had between two and 10 vaso-occlusive crises (VOCs) in the year prior to entering the trial — had no such crises post-treatment, compared to those given placebo (16.9%), its researchers reported.

These findings were reported in the study, “Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis,” published in the American Journal of Hematology.

Crizanlizumab is a monoclonal antibody targeting P-selectin, a molecule existing on the surface of endothelial cells (which line the inner surface of blood vessels), and platelets (cell fragments involved in clotting).

P-selectins are responsible for multi-cell adhesion, a process key in the development of VOCs. Vaso-occlusive crises can lead to organ damage or failure, and stroke. Current treatments are limited.

Crizanlizumab is designed to prevent several cells in the bloodstream from sticking together and blocking blood vessels, reducing the occurrence and severity of VOCs, a common painful complication in SCD.

“The unpredictable, intense painful crises that patients with sickle cell disease experience are the hallmark of the disease and the primary cause of hospitalization in this patient population,” Abdullah Kutlar, MD, director of the Sickle Cell Center at the Medical College of Georgia, Augusta University, and primary study author, said in a press release.

“I am encouraged that results from this post hoc analysis of SUSTAIN study data found that crizanlizumab could substantially delay or prevent these crises, which also may mean less organ damage in the long run,” Kutlar added.

The Phase 2 SUSTAIN study (NCT01895361) investigated the safety and efficacy of crizanlizumab at two doses, 2.5 mg/kg, and 5 mg/kg, given intravenously with or without hydroxyurea therapy, in preventing or reducing the occurrence of pain crises in SCD patients. A total of 198 patients were enrolled in the roughly one-year study

Primary results, published in the New England Journal of Medicine in 2017, showed that crizanlizumab reduced the median annual rate of pain crises by 45.3% compared to placebo, in treated patients whether or not they also used hydroxyurea therapy.

Crizanlizumab was well-tolerated, with a low observed rate of acute chest syndrome incidence and other treatment-related adverse events at both doses.

Kutlar and his team now carried out a post-hoc trial analysis of results. Here, total of 132 patients were analyzed, including 67 treated with crizanlizumab 5 mg/kg and 65 who received placebo.

All had a history of at least two VOCs in the year prior to the study, with 62.9% experiencing two to four crises events and 37.1% between five and 10 events.

The analysis found that crizanlizumab at high dose helped to prevent VOCs in both groups of these at-risk patients. Among those with two-to-four prior VOCs, no recurrence was experienced by 40.5% of treated patients compared to 24.4% of those given placebo. In the five-to-10 group, no recurrence was reported in 28.0% of treated patients compared to 4.2% of those on placebo.

The same trend was seen in a specific subgroup with the most common genetic profile in SCD, homozygous hemoglobin S (HbSS).

Crizanlizumab at 5 mg/kg  was able to suppress the occurrence of VOCs in a higher extent than placebo, either with or without hydroxyurea therapy .

Importantly, no new safety concerns were observed in this analysis with treatment-related adverse events similar among the studied groups.

“The insights gained from this analysis and others from the SUSTAIN study, strengthen our belief that crizanlizumab may become an important new therapeutic option for sickle cell patients who continue to need step changes in medical innovation,” Samit Hirawat, MD head of Novartis Oncology Global Drug Development, said in the release.