FDA Grants Priority Review to Novartis’ Application for Crizanlizumab

The U.S. Food and Drug Administration (FDA) accepted Novartis’ Biologics License Application (BLA) seeking marketing permission for crizanlizumab (SEG101), a potential treatment for vaso-occlusive crises (VOCs) in people with sickle cell disease (SCD). The agency granted the file priority review, to accelerate the product’s evaluation.

“The FDA’s decision to give crizanlizumab priority review reflects the impact that this medicine could have for the many thousands of US sickle cell adult patients who experience painful vaso-occlusive crises,” John Tsai, MD, Novartis’ head of global drug development and chief medical officer, said in a press release.

“We are looking forward to the opportunity, if crizanlizumab is approved, to reimagine medicine in sickle cell disease for patients who live with this condition every day of their lives,” Tsai said.

Under priority status, the FDA will review and take action within a shorter period (six months) compared to standard review time (10 months). The designation is granted to therapies with potential to bring significant improvements in the safety or effectiveness in treatment, diagnosis, or prevention of serious conditions.

VOCs, also called pain crises, are unpredictable, acute episodes of severe pain that can lead to serious life-threatening complications and death in people with sickle cell disease. They are the primary reason why these patients seek medical care at emergency departments and need hospital admissions.

Novartis’ submission is supported by the promising results obtained in the Phase 2 SUSTAIN study (NCT01895361), which demonstrated that crizanlizumab lowered the number of pain crises regardless of patients’ genetic mutations or hydroxyurea use.

The study evaluated crizanlizumab’s safety and effectiveness in 198 patients with SCD and a history of two to 10 pain crises in the previous year.

Patients received either a low dose (2.5 mg per kilogram of body weight), or a high dose of crizanlizumab (5 mg/kg), or placebo, given as an injection into the vein, 14 times over a period of 52 weeks (generally, every four weeks).

At the highest dose tested (5 mg/kg), the agent reduced by 45.3% the median annual rate of VOCs leading to health care visits, compared to a placebo, whether patients were treated or not with hydroxyurea.

Crizanlizumab also increased by more than two-fold the number of patients who never experienced VOCs over the course of the study relative to placebo (36% vs. 17%). In the high-dose group, time until the first crisis was 2.9 times longer (4.07 vs 1.38 months), and patients had lower annual rates of days hospitalized, compared to placebo (4.00 vs 6.87).

The most frequent adverse side effects associated with high-dose crizanlizumab were back pain, nausea, fever, and joint pain. Most reactions were mild-to-moderate.

SUSTAIN is part of a total of seven trials comprising the SENTRY clinical trial program, designed to obtain additional information on the effects of crizanlizumab on SCD management. Active trials include SOLACE-adults studying crizanlizumab in patients 16 and older (NCT03264989), SOLACE-kids in pediatric patients (NCT03474965), STAND in patients 12 and older (NCT03814746), and SUCCESSOR, a retrospective study among adult patients in the U.S.

Crizanlizumab (SEG101) is a lab-made monoclonal antibody that binds to and inhibits P-selectin, an adhesion protein found on the surface platelets and endothelial cells (cells lining the inner walls of blood vessels). In people with SCD, P-selectin promotes blood vessels getting stuck with sickle cells — the more rigid and sickle-shaped red blood cells that are a hallmark of the disease. This causes inflammation and pain crisis.

Blocking, or inhibiting, P-selectin with crizanlizumab might prevent the process that leads to blood vessel occlusion and help to maintain normal blood flow. Crizanlizumab was designated a breakthrough therapy by the FDA in December 2018, as a potential therapy for VOCs prevention.

If approved, the biologic will be the first antibody targeting P-selectin mediated multi-cellular adhesion for SCD, according to Novartis.