A Phase 3 trial is testing a higher dose of Adakveo (crizanlizumab), the first approved targeted treatment for sickle cell disease, to explore if that dose might be more effective — while still safe — in easing the painful vaso-occlusive crises (VOCs) patients can have each year, according to its developer, Novartis.
It is one of five ongoing studies looking at Adakveo in a variety of people with sickle cell disease (SCD), part of Novartis’ SENTRY trial program.
The double-blind and placebo-controlled study, called STAND (NCT03814746), is testing Adakveo at a 7.5 mg/kg dose, as well as at its approved 5.0 mg/kg dose. That dose was shown to lower the frequency of annual VOCs in SCD patients in the company’s Phase 2 SUSTAIN (NCT01895361) trial.
Adakveo, a man-made antibody, works to block the activity of P-selectin, an adhesion protein that makes sickled blood cells more sticky and more likely to clog blood vessels, causing inflammation and pain crises.
“In SUSTAIN, the 5.0 mg/kg dose was found to be safe, effective and well tolerated. We also learned that P-selectin inhibition is dose-dependent, suggesting that a higher dose may potentially result in even better inhibition/efficacy,” Novartis said in an email response to questions.
“The 7.5 mg/kg dose is now being studied to evaluate if we can see even greater P-selectin inhibition with a higher dose.”
STAND is expected to enroll up to 240 SCD patients, ages 12 and older, who had at least two VOCs in the previous year and may be using hydroxyurea to treat these crises. It is now enrolling at sites in the U.S., across Europe, and in Brazil and Lebanon.
Patients will be randomly assigned 1:1:1 to either Adakveo, given as an intravenous injected, at its approved dose or the higher dose, or to a placebo.
The trial is set to run for five years, but people on placebo may move to treatment after a crucial first year of data collection.
“The primary analysis will occur once all patients have completed at least one year of treatment,” Novartis said, “after which placebo patients will be allowed to switch to the investigational treatment.”
STAND’s main goal is to evaluate the treatment’s impact, versus placebo, on the frequency of VOCs requiring a visit to a medical facility over the study’s first year.
Additional trial goals include assessing, after one or five years of treatment, the medication’s pharmacokinetic profile (its movement in, through, and out of the body), as well as changes in hemoglobin, and VOC emergency room visits, hospitalizations, or those handled at home.
Adakveo was approved by the U.S. Food and Drug Administration (FDA) to treat VOCs in people with sickle cell disease (SCD) ages 16 and older on Nov. 15. The medication is a monoclonal antibody that works by inhibiting P-selectin’s activity. This adhesion protein is found on the surface of endothelial cells (which line blood vessels) and platelets.
In SCD, P-selectin promotes the sticking of sickle-shaped red blood cells to each other and to the walls of blood vessels, obstructing the vessels and increasing the risk of VOCs. By blocking its activity, Adakveo helps to stop red blood cells from adhering to blood vessel walls, allowing for better blood flow and reducing the risks of VOCs.
In addition to STAND, four other ongoing clinical trials testing the Adakveo’s effects in different patient groups.
An open-label Phase 2 study, called SOLACE-kids (NCT03474965), is a safety and dose-confirming study in up to 100 young SCD patients, 6 months to 17 years old, who had at least one VOC in the previous year and may or may not be using hydroxyurea.
All in this trial will be given Adakveo, as an intravenous injection, at its 5 mg/kg dose for up to two years.
The study is currently recruiting at 41 sites across the U.S., and in Canada, Europe, and elsewhere, and its findings may support a request for Adakveo’s approval in pediatric patients.
Like STAND, SOLACE-adults is testing Adakveo at a higher dose (7.5 mg/kg), but only in about 10 this trial’s roughly 55 participants. Others are being given the treatment at 5 mg/kg, and emphasis is on the treatment’s pharmacokinetic profile. This study is set to end in February 2021, and is fully enrolled.