Conditional approval of Adakveo for SCD now revoked in UK

Novartis last year recalled therapy in EU after approval there was revoked

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Novartis is recalling its sickle cell disease (SCD) treatment Adakveo (crizanlizumab) in the U.K., after the nation’s drug regulatory agency revoked the conditional approval it had previously granted to the antibody-based therapy.

The U.K. Medicines & Healthcare products Regulatory Agency (MHRA) made its decision based on Adakveo’s failure to reduce the annual rates of vaso-occlusive crises (VOCs) in SCD patients participating in a Phase 3 clinical trial. VOCs are episodes of acute pain that occur due to blood vessel blockage, and are considered a hallmark of SCD.

With that failure, the therapy did not meet the main goal of the STAND trial (NCT03814746), which had been launched to confirm the drug’s effectiveness as part of the full approval process in the U.K.

“The benefit-risk balance of Adakveo [is] no longer being considered favourable by the MHRA. This is because the Phase III study (STAND) of Adakveo in sickle cell disease patients with vaso-occlusive crises did not confirm its clinical benefit,” the agency stated in a recall announcement.

While Novartis is now in the process of removing the therapy from the market, the MHRA noted that patients should also not stop taking Adakveo without first talking to the healthcare professional who prescribed it to them. The agency also noted clinicians should inform patients who had been started on Adakveo of the decision and discuss alternative treatment options with them. No new patients should be started on Adakveo in the U.K., the notice also stated.

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Adakveo failed to reduce the rate of VOCs in a Phase 3 trial

Based on the same trial data, the European Commission last year also decided to revoke Adakveo’s conditional approval in the European Union. That led Novartis to remove the therapy from the markets in all 27 EU countries.

Adakveo remains fully approved in the U.S. for treating SCD patients ages 16 and older. It was granted that approval by the U.S. Food and Drug Administration (FDA) in November 2019 to reduce the frequency of VOCs in individuals with sickle cell disease. The therapy had been conditionally approved in Europe in November 2020 and in the U.K. in October 2021 for similar indications.

SCD is caused by mutations in the beta-globin (HBB) gene that lead to the production of a faulty version of hemoglobin — the protein that helps red blood cells transport oxygen throughout the body. This causes red blood cells to acquire a sickle-like shape and clump up, making them more prone to obstruct blood vessels, which can lead to VOCs and other complications.

Adakveo is a lab-made antibody that’s designed to block P-selectin, a protein found on blood vessel cells that contributes to the clumping of sickled red blood cells and their adhesion to blood vessel walls. In blocking that protein, the treatment is expected to improve blood flow and reduce the frequency of VOCs.

The therapy’s initial approvals were based on data from a Phase 2 trial called SUSTAIN (NCT01895361) that enrolled 198 SCD patients with a history of frequent VOCs. The results showed that Adakveo could reduce the risk of VOCs, as well as the length of hospital stays due to such crises.

In the STAND trial, more than 200 SCD patients, ages 12 and older, were randomly assigned to receive either 5 or 7.5 mg/kg of Adakveo, or a placebo, for one year. However, neither dose was shown to significantly reduce the annual rates of VOCs leading to a healthcare visit compared with the placebo.

The benefit-risk balance of Adakveo [is] no longer being considered favourable by the MHRA [U.K. regulatory agency].

According to the MHRA’s review of the data, patients treated with Adakveo also experienced more severe side effects than those given a placebo, even though no new safety concerns were identified.

Based on the fact that Adakveo’s clinical benefit could not be confirmed in STAND, the MHRA concluded that the benefit-risk profile of Adakveo was unfavorable and that the therapy’s conditional approval in the country should be revoked.