Adakveo (crizanlizumab) is an anti-P-selectin antibody that was developed by Novartis and has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for painful vaso-occlusive crisis events caused by sickle cell disease in patients 16 and older.
What is sickle cell disease?
Sickle cell disease is a rare genetic disorder that affects red blood cells. Normal red blood cells have a flexible disk-like shape that allows them to move easily through the smallest blood vessels. In sickle cell disease, the red blood cells assume a sickle-shaped appearance, and clump or aggregate. The aggregates are unable to flow through small blood vessels, preventing oxygen from reaching tissues. These aggregates cause inflammation and episodes of pain called vaso-occlusive pain crises.
How does Adakveo work?
Adakveo contains a monoclonal antibody, a molecule made in the laboratory to bind P-selectin, a protein that is found on the surface of endothelial cells (the cells that line the inner walls of blood vessels) and in platelets (blood cells that are involved in clotting).
P-selectin normally works to control the flow of white blood cells through blood vessels and how they adhere to blood vessel walls during periods of inflammation and tissue repair, such as after an injury. In sickle cell disease, P-selectin contributes to the adhesion of sickle red blood cells (cells with an abnormal crescent shape) to blood vessels, preventing blood flow through smaller vessels. This causes inflammation and vaso-occlusive pain crises.
By blocking or inhibiting P-selectin, Adakveo prevents this adhesion molecule from starting the process that leads to blood vessel occlusion, inflammation, and pain, and helps to maintain normal blood flow.
After two initial doses given two weeks apart in the first month, the treatment must then be administered once per month at 5 mg per kg of body weight by infusion into the bloodstream.
Adakveo in clinical trials
A Phase 2 clinical trial (NCT01895361), called SUSTAIN, evaluated the safety and effectiveness of Adakveo in 198 patients with sickle cell disease and a history of two to 10 vaso-occlusive pain crises in the previous year. Patients received either a low dose of Adakveo (2.5 mg per kg of body weight), a high dose (5 mg per kg of body weight), or a placebo, given as an injection into the bloodstream 14 times over a period of 52 weeks (generally, every four weeks). Patients using hydroxyurea, a common treatment for sickle cell disease, at a stable dose could continue that treatment.
Trial results were presented at the 2016 American Society of Hematology annual meeting, in San Diego, California, and published in The New England Journal of Medicine in early 2017.
They showed that the high dose of Adakveo significantly reduced the frequency of vaso-occlusive pain crises by 45.3% compared with the placebo, while the low dose reduced these episodes by 32.6%, regardless of whether or not patients used hydroxyurea. The time until the first pain crisis was also 2.9 times longer in the high-dose group than in placebo-treated patients, and time to a second crisis was twice as long.
The most frequent adverse effects associated with the use of Adakveo were joint pain, diarrhea, itching, vomiting, and chest pain.
New findings from the SUSTAIN trial presented at the 2017 ASH annual meeting in Atlanta further confirmed Adakveo’s efficacy at the high dose in patients with sickle cell disease.
The Phase 2 SOLACE-adults trial (NCT03264989) is evaluating Adakveo at a dose of 5 mg/kg in sickle cell disease patients, 16 to 70 years old, with vaso-occlusive pain crises. The trial aims to investigate the way Adakveo is absorbed, distributed, and eliminated by the body (pharmacokinetics), as well as its effects on the body (pharmacodynamics). The safety and effectiveness of the treatment will also be evaluated. The study continues but is no longer recruiting.
Once the target number of 45 patients were enrolled, the study recruited 10 more patients to evaluate Adakveo at a higher dose of 7.5 mg/kg. The study is estimated to be completed in February of 2021.
An open-label Phase 2 clinical trial, called SOLACE-kids (NCT03474965) is recruiting up to 100 patients, 6 months to 17 years old, with sickle cell disease who have had at least one vaso-occlusive crisis in the past year. The study is designed to establish the appropriate dose of Adakveo for this younger patient population and is recruiting at sites around the world. The study is estimated to be completed in 2023.
A Phase 3 clinical trial, called STAND, (NCT03814746) will evaluate the efficacy and safety of 2 doses of Adakveo versus placebo in up to 240 sickle cell disease participants ages 12 and up. Patients will be given either 5 mg/kg, 7.5 mg/kg, or placebo and the number of vaso-occlusive crises will be recorded for 1 year. The study is estimated to be completed in 2027.
A Phase 2, open-label randomized trial, called STEADFAST, (NCT04053764) will compare renal function between participants receiving Adakveo and those receiving standard of care treatment. The study is recruiting up to 170 patients ages 16 and up with chronic kidney disease due to sickle cell nephropathy. The study is estimated to be completed in September of 2022.
Another Phase 2, open-label trial, called SPARTAN, (NCT03938454) will investigate the effect of Adakveo on the rate of priapism, or painful unwanted erections, in up to 56 men with sickle cell disease. After an initial set of infusions, patients will receive an injection every 4 weeks for 52 weeks total. The rate and change of priapic events will be self-reported and collected throughout the 52-week study. The study is estimated to be completed in March 2022.
Novartis initiated a Managed Access Program (NCT03720626) to allow access to Adakveo in regions of the world where it is not yet approved. Novartis has partnered with the country of Ghana to provide hydroxyurea to patients with sickle cell disease. They are also working to create a clinical trial to test the drug in the country as well.
Last updated: Dec. 14, 2019
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