Conditional approval of Adakveo for SCD revoked in Europe by EC
Therapy fails to meet goal of reducing crises in confirmatory trial
The European Commission has decided to revoke its conditional approval of Adakveo (crizanlizumab) for sickle cell disease (SCD) — meaning its developer, Novartis, will have to remove the antibody-based therapy from the market in all 27 countries that are part of the European Union.
The decision came after a failed confirmatory trial in which Adakveo did not meet its primary goal of reducing the occurrence of vaso-occlusive crises (VOCs) in SCD patients. VOCs are a hallmark feature of SCD, and are characterized by severe pain due to blocked blood vessels; the therapy was designed to reduce their frequency.
The Committee for Medicinal Products for Human Use (CHMP), an arm of the European Medicines Agency, had recommended in June that the approval be revoked, concluding after a review of the trial data that Adakveo’s potential benefits did not outweigh its risks.
Now, per the regulatory agency’s “legally binding decision,” Novartis must pull Adakveo in all of the EU countries, as well as Iceland, Norway, Liechtenstein, and Northern Ireland, the company announced in a press release.
“Patients who are currently on treatment with [Adakveo] should speak with their healthcare professionals to discuss alternative treatment options,” Novartis stated in the release.
Therapy remains available for SCD patients in US
Adakveo is a lab-made antibody designed to block P-selectin, a protein found on the surface of blood vessel cells that contributes to the clumping of sickled red blood cells and their adhesion to blood vessel walls.
By blocking this protein, the antibody — administered intravenously, or by infusion into the bloodstream — stops the cells from sticking to each other and to blood vessel walls, thus allowing for better blood flow and less pain.
The therapy was conditionally approved in Europe in 2020 to reduce the risk of VOCs in adults and adolescents, ages 16 and older, with sickle cell disease. A similar approval was handed down in the U.S. in 2019.
Both approvals were based on data from the SUSTAIN Phase 2 trial (NCT01895361), which enrolled 198 patients with a history of frequent VOCs. The results suggested that the therapy could reduce the risk of such crises, with patients given Adakveo for one year experiencing 45% fewer episodes requiring treatment per year than those on a placebo.
The medication also lowered the length of hospital stays due to VOCs and extended the time to a first pain crisis.
However, because the data were limited and questions regarding Adakveo’s efficacy were still pending, the EMA requested further testing by Novartis as part of the conditional approval.
Thus, the company launched the STAND Phase 3 trial (NCT03814746) to test Adakveo at its approved 5 mg/kg dose, as well as at a higher 7.5 mg/kg dose. A total of 254 SCD patients, ages 12 and older, were randomly assigned to one of the two doses of Adakveo or a placebo for one year.
However, preliminary data have failed to recapitulate earlier results, with neither dose of Adakveo significantly outperforming a placebo at lowering the annual rates of VOCs requiring a healthcare visit. No new safety issues linked with Adakveo were identified in the trial, Novartis noted.
These findings prompted the CHMP to conduct its own review of the available clinical trial data, along with other studies and real-world data on Adakveo. Based on its findings, the CHMP concluded the potential benefits of Adakveo do not outweigh its risks and recommended the therapy’s conditional approval be revoked.
In the U.S., the therapy remains approved for the treatment of VOCs in adults and pediatric patients, ages 16 and older. Novartis is discussing STAND results with the FDA and other health authorities. Patients in the EU nations who were taking Adakveo now will have to explore other treatment options.
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