Adakveo Fails to Reduce VOCs in Latest Phase 3 Trial, Novartis Says
Data do not match results of study that led to therapy's approval
Treatment with Adakveo (crizanlizumab) did not reduce the yearly occurrence of painful vaso-occlusive crises (VOCs) leading to a medical visit, as compared with a placebo, in people with sickle cell disease (SCD), according to preliminary data from an ongoing Phase 3 trial.
The study, called STAND (NCT03814746), is testing Novartis’ Adakveo at its approved 5.0 mg/kg dose, as well as at a higher 7.5 mg/kg dose, in 254 SCD patients, ages 12 and older.
So far, neither dose has outperformed a placebo at lowering the annual rates of VOCs requiring a healthcare visit — a finding that is inconsistent with previous results from the SUSTAIN trial (NCT01895361) that supported Adakveo’s approval in the U.S. in 2019.
That Phase 2 trial had demonstrated the therapy’s superiority — when given at a dose of 5.0 mg/kg — over a placebo at reducing the frequency of yearly VOCs in 198 patients, ages 16 and older.
The company noted in a press release that these findings do not suggest any new safety concerns with Adakveo, and that its safety profile remains consistent with the commercially available 5.0 mg/kg dose.
EU regulators now reviewing therapy’s conditional approval
Vaso-occlusive crises, known as VOCs, are a common SCD complication that occur when sickled red blood cells block blood flow and deprive tissues of oxygen. These crises result in substantial pain, most commonly in the back, chest, or extremities.
P-selectin, a protein found on the surface of cells that line blood vessels, promotes the clumping of sickled red blood cells and their adhesion to blood vessel walls.
Adakveo, administered by infusion into the bloodstream (intravenously), is a lab-made antibody designed to block P-selectin. It works to stop sickled blood cells from sticking to each other and blood vessel walls, thus allowing for better blood flow and less pain.
The therapy was approved by the U.S. Food and Drug Administration (FDA) in November 2019 as a treatment for VOCs in SCD patients ages 16 and older. Almost a year later, the European Medicines Agency (EMA) granted Adakveo conditional approval in Europe for the same patient population.
Based on these new Phase 3 data, the EMA’s Committee for Medicinal Products for Human Use (CHMP) has requested STAND data and launched a review of Adakveo. According to Novartis, CHMP is evaluating how these new results affect the treatment’s current authorization in the EU.
While further assessment of the trial data is ongoing, physicians should consider the individual benefit and risks when making therapeutic decisions regarding the use of [Adakveo].
Novartis also has initiated a review of the full STAND dataset, and assured it will work with regulators worldwide — including the EMA and the FDA, as well as trial investigators — to determine how to proceed.
Meanwhile, the company has recommended that, “while further assessment of the trial data is ongoing, physicians should consider the individual benefit and risks when making therapeutic decisions regarding the use of [Adakveo].”
In addition to STAND, several other clinical trials are now testing Adakveo’s effects in different patient groups.
SOLACE-adults (NCT03264989) is a Phase 2 trial evaluating Adakveo at doses of 5 and 7.5 mg/kg in 57 SCD patients, ages 16 to 70, with VOCs. SOLACE-kids (NCT03474965), also Phase 2 study, is recruiting up to about 120 SCD patients, ages 6 months to 17 years, to confirm the appropriate dose of Adakveo to use in younger patients. This study is open label, meaning both participants and researchers know the medication and dosage being given to each patient.
SPARTAN (NCT03938454) is a Phase 2 study also now enrolling participants. It is seeking up to 56 SCD men across 19 U.S. study sites to investigate the effect of Adakveo on painful, unwanted erections due to trapped blood.
The Phase 2 STEADFAST trial (NCT04053764) is testing Adakveo plus standard care, against standard care alone, in 58 people with SCD-related chronic kidney disease, ages 16 and older. This trial is slated for completion in 2023.
STAND is expected to be completed in December 2026.
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