Novartis’ P-Selectin Inhibitor Adakveo Approved in EU for Prevention of Vaso-Occlusive Crises in Sickle Cell Disease

October 31, 2020 News /Bio ValleyBIOON/ --NovartisNovartis recently announced that the European Commission (EC) has approved Adakveo (crizanlizumab) for the prevention of recurrent vaso-occlusive crises (VOCs) or pain crises in adult and pediatric patients aged ≥16 years with sickle cell disease (SCD). Adakveo may be used as an add-on therapy to hydroxyurea (HU/HC) or as monotherapy in patients for whom HU/HC is inappropriate or who have an inadequate response to HU/HC.

Adakveo received its first global approval in the United States in November 2019 and has since been approved in 36 countries, including the United States and European Union member states.This drug is the first targeted therapy approved for the prevention of vaso-occlusive crises (VOC) in patients with sickle cell disease (SCD), and it is also the first and only approved targeted biologic agent that exerts its therapeutic effect by binding to P-selectin.P-selectin is a cell adhesion protein that plays a central role in multicellular interactions leading to vascular occlusion. By binding to P-selectin on the surface of activated endothelial cells and platelets, Adakveo blocks interactions among endothelial cells, platelets, red blood cells, and white blood cells.

Sickle Cell Disease (SCD) refers to a group ofHereditySickle cell disease, named for the characteristic "C" or "sickle" shape of red blood cells. Patients with sickle cell disease (SCD) are prone to vaso-occlusive crises (VOC), particularly vaso-occlusive pain crises, which represent the primary reason SCD patients seek medical care; however, currently available strategies for preventing VOC are very limited. VOC is triggered by multi-cellular adhesion or cellular aggregates that obstruct blood flow, is sudden and unpredictable, and is associated with an increased risk of organ damage and mortality.

The approval of Adakveo marks a new era in the treatment of sickle cell disease (SCD). By targeting P-selectin, Adakveo effectively reduces multi-cellular adhesion. Clinical data demonstrate that, whether used in combination with or without hydroxyurea (HU/HC) therapy, Adakveo significantly reduces the incidence of vaso-occlusive crises (VOCs) and significantly decreases the number of hospitalization days compared to placebo.

This approval is based on positive data from the Phase II SUSTAIN clinical study. This was a multicenter, multinational, randomized, placebo-controlled, double-blind, 12-month study designed to evaluate the efficacy and safety of Adakveo, with or without hydroxyurea therapy, in preventing vaso-occlusive crises (VOC) in patients with sickle cell disease (SCD).

The results showed that, whether used in combination with hydroxyurea therapy or not, Adakveo (5 mg/kg) significantly reduced the median annual incidence rate of VOCs by 45.3% compared to placebo (1.63 vs. 2.98, p=0.010). A clinically significant reduction in VOC frequency was observed regardless of SCD genotype or hydroxyurea use. Furthermore, the study demonstrated that the proportion of patients who did not experience any VOCs during the treatment period was more than twice as high in the Adakveo (5 mg/kg) group as in the placebo group (36% vs. 17%, p=0.010); the median time to first VOC was three times longer than that in the placebo group (4.07 months vs. 1.38 months, p<0.001); and the median annual number of hospitalization days was reduced by 42% (4.00 days vs. 6.87 days, p=0.45).

Regarding safety, the most common adverse reactions (incidence ≥10%) in patients treated with Adakveo at 5 mg/kg (n=111) included back pain, nausea, pyrexia, and arthralgia. Most adverse reactions were mild to moderate (Grade 1 or 2). Severe (Grade 3) arthralgia and pyrexia each occurred in 0.9% of patients (1 case each). According to the analysis, no patients discontinued treatment due toAdverse Reactionsand treatment was discontinued. In the SUSTAIN study, compared with the placebo group, there was no significant increase in overall infections (53.0% vs 53.2%) or neutropenia (3.1% vs 6.5%) adverse events reported in the Adakveo treatment group.

Vaso-occlusive crises (VOC), also known as sickle cell pain crises (SCPC), are unpredictable, excruciating events that can lead to severe acute and chronic life-threatening complications and death. VOC also results in significant healthcare utilization; it is the most common reason for emergency department visits and hospitalizations among patients with sickle cell disease (SCD). The average lifetime medical cost per patient is approximately $1 million, with total annual medical expenditures in the United States exceeding $1.1 billion. In patients with SCD, VOC occurs when multiple blood cells adhere to one another and attach to the vessel walls, causing obstruction. Reducing the adhesiveness of blood cells and blood vessels may help decrease the number of days patients experience VOC.

The active pharmaceutical ingredient of Adakveo is crizanlizumab, a monoclonal antibody against P-selectin that selectively binds to P-selectin on the surface of endothelial cells and platelets in blood vessels, resulting in the blockade of P-selectin and inhibiting interactions among endothelial cells, platelets, red blood cells, diseased red blood cells, and white blood cells. P-selectin is one of the main drivers of vaso-occlusive crises (VOCs), which cause vascular obstruction and are a painful complication of sickle cell disease (SCD).

Currently, Adakveo is being developed for the prevention of vaso-occlusive crises (VOC) in patients with sickle cell disease (SCD). SUSTAIN is part of the SENTRY clinical research program, which comprises multiple clinical studies aimed at generating comprehensive data on the use of crizanlizumab in the clinical management of SCD (Bioon.com).

Original Source: Novartis Sickle Cell Medicine Adakveo®approved in Europe to prevent recurrent vaso-occlusive crises