FDA Accepts BLA, Grants Priority Review for Crizanlizumab

Novartis announced the US Food and Drug Administration (FDA) accepted the company's Biologics License Application (BLA) and has granted Priority Review for its investigational sickle cell medicine crizanlizumab (SEG101). If FDA-approved, crizanlizumab is expected to represent the first monoclonal antibody targeting the P-selectin mediated multi-cellular adhesion in sickle cell disease.

Novartis submitted the application for crizanlizumab for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) and was granted Breakthrough Therapy designation in December 2018. VOCs are unpredictable and extremely painful events that can lead to serious acute and chronic life-threatening complications and death. VOCs also lead to significant health care utilization. They are the most common cause of emergency room visits and hospital admissions for SCD patients, with total medical costs exceeding $1.1 billion annually in the United States.

Priority Review is granted to therapies that the FDA determines have the potential to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The designation is intended to shorten the FDA review period to six months from the standard ten months.

"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," said John Tsai, MD, Head of Global Drug Development and Chief Medical Officer, Novartis. "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."

The FDA submission is supported by Phase II results from the SUSTAIN study, which showed that crizanlizumab (5 mg/kg) reduced the median annual rate of VOCs leading to health care visits by 45.3% compared with placebo (1.63 vs 2.98, P=0.010) in patients with or without hydroxyurea. Clinically significant reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype or hydroxyurea use.

The study also demonstrated that crizanlizumab (5 mg/kg) showed:

A greater than two-fold increase in the percentage of patients who did not experience any VOCs vs placebo (36% vs 17%, P=0.010)

A three-fold longer median time to first VOC vs placebo (4.07 vs 1.38 months, P< 0.001)

A 42% reduction in median annual rate of days hospitalized vs placebo (4.00 vs 6.87 P=0.45)

The most frequently reported adverse reactions (≥10%) in patients (N=111) treated with 5 mg/kg crizanlizumab were back pain, nausea, pyrexia, and arthralgia. The majority of adverse reactions were mild to moderate (Grade 1 or 2). Severe (Grade 3) events were observed for arthralgia and pyrexia 0.9% [1 case] each. No patients discontinued treatment due to adverse reactions based on the analysis. In the SUSTAIN trial, there were no apparent increases in reported overall infections (53.0% vs 53.2%) or neutropenia (3.1% vs 6.5%) adverse events with crizanlizumab treatment compared to placebo.

Sickle cell disease is a debilitating inherited genetic blood disorder that affects the shape of the red blood cells and can make blood cells and blood vessels stickier than usual. When blood cells stick to one another, they can form multicellular adhesion clusters in the bloodstream. These clusters can reduce and block the flow of blood and oxygen, which can cause damage to the blood vessels and lead to acute and chronic complications. These blockages also can lead to painful crises called VOCs, which are considered the clinical hallmark of the disease and the main reason why patients seek medical care in hospitals4. The average sickle cell patient in the United States is estimated to face nearly $1 million in total lifetime health care costs.

Crizanlizumab (SEG101) is an investigational humanized monoclonal antibody blocking P-selectin mediated multicellular adhesion that is in late-stage development for the prevention of vaso-occlusive crises (VOCs), also known as pain crises, in patients with sickle cell disease (SCD). Crizanlizumab binds to a molecule called P-selectin on the surface of platelets and endothelium in the blood vessels, and has been shown to inhibit interactions between endothelial cells, platelets, red blood cells, sickled red blood cells, and leukocytes. P-selectin is one of the major drivers of the vaso-occlusive process. Our goal is to deepen understanding of the true impact of VOCs on patients' bodies and lives and to explore how crizanlizumab can help to achieve more pain-crisis-free days for patients with SCD.

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