Novartis’ P-Selectin Inhibitor Adakveo Receives Positive CHMP Opinion for Sickle Cell Disease, Now Approved in Eight Countries

July 25, 2020 News /Bio ValleyBIOON/ --Novartis(Novartis) recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion, recommending conditional approval of Adakveo (crizanlizumab) for the prevention of recurrent vaso-occlusive crises (VOCs) or pain crises in adult and pediatric patients aged 16 years and older 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 unsuitable or who have an inadequate response to HU/HC.

The CHMP’s positive opinion will now be reviewed by the European Commission (EC), which typically issues its final decision within two months. If approved, Adakveo will become the first targeted therapy available in Europe for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). VOCs are sudden and unpredictable events associated with an increased risk of organ damage and mortality. Clinical data demonstrate that Adakveo significantly reduces the incidence of VOCs and markedly decreases the number of hospitalization days compared with placebo, both when used in combination with and without hydroxyurea (HU/HC) therapy.

Adakveo received the world’s first approval in the United States in November 2019. The drug has been approved in the United States and seven other countries to reduce the frequency of vaso-occlusive crises (VOCs) or pain crises in adult and pediatric patients aged 16 years and older with sickle cell disease (SCD). Notably, Adakveo is the first and only approved targeted biologic agent that exerts its therapeutic effect by binding to P-selectin. In the United States,FDAAdakveo had previously been granted Breakthrough Therapy designation and Priority Review. P-selectin is a cell adhesion protein that plays a central role in the multicellular interactions leading to vaso-occlusion.

The approval and market launch of Adakveo mark a new era in the treatment of sickle cell disease (SCD). Sickle cell disease (SCD) refers to a group ofHereditySickle cell disease (SCD) is named for the characteristic “C”-shaped or “sickle” appearance of red blood cells. Patients with SCD are prone to vaso-occlusive crises (VOC), particularly vaso-occlusive pain crises, which represent the primary reason for healthcare utilization among these patients; however, currently available strategies for VOC prevention are very limited. VOC is triggered by multi-cellular adhesion or cellular aggregates that obstruct blood flow and is associated with increased morbidity and mortality. By targeting P-selectin, Adakveo effectively reduces multi-cellular adhesion.

The CHMP’s positive opinion is based on the favorable 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 concomitant hydroxyurea therapy, in preventing vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD).

The results showed that, whether or not used in combination with hydroxyurea therapy, Adakveo (5 mg/kg) significantly reduced the median annual incidence rate of VOC 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 in the Adakveo (5 mg/kg) treatment group who experienced no VOC during the treatment period was more than twice that of the placebo group (36% vs. 17%, p=0.010); the median time to first VOC was three times longer than that of 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).

In terms of safety, the most common adverse reactions (incidence ≥10%) in patients treated with 5 mg/kg Adakveo (n=111) included back pain, nausea, fever, and arthralgia. Most adverse reactions were mild to moderate (Grade 1 or 2). Severe (Grade 3) arthralgia and fever each occurred in 0.9% (1 case) of patients. 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 adverse events of overall infection (53.0% vs 53.2%) or neutropenia (3.1% vs 6.5%) reported in the Adakveo treatment group.

Vaso-occlusive crisis (VOC), also known as sickle cell pain crisis (SCPC), refers to a category of unpredictable and excruciatingly painful events that can lead to severe acute and chronic life-threatening complications and death. VOC also results in substantial healthcare utilization; it is the most common cause of 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 aggregate and adhere to the vascular endothelium, 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, leading to the blockade of P-selectin and inhibiting interactions among endothelial cells, platelets, red blood cells, sickled red blood cells, and white blood cells. P-selectin is one of the major drivers of vaso-occlusive crises (VOC), 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 includes multiple clinical studies aimed at generating comprehensive data on the use of crizanlizumab in the clinical management of SCD (Bioon.com).

Original Source:Novartis Adakveo® receives positive CHMP opinion for the prevention of recurrent vaso-occlusive crises in patients with sickle cell disease