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ABSTRACT
Introduction: Sickle cell disease (SCD) is an inherited disease with lifelong morbidity, whose complications include frequent acute painful vaso-occlusive episodes (VOEs) that often require hospitalization. The only pharmacotherapy currently in regular use for SCD management is hydroxyurea (hydroxycarbamide).
Areas covered: We review recent advances in pharmacotherapy for SCD and summarize promising synthetic agents that are in late-stage development (phase 3) for SCD.
Expert opinion: Emerging SCD therapies have been developed to target specific pathophysiological mechanisms of the disease, as either preventative or abortive approaches to VOEs. Continuous-use pharmacotherapeutics in late-phase development for VOE prevention include voxelotor (GBT440), which elevates hemoglobin oxygenation, and prasugrel, a platelet activation inhibitor. However, at least in the near future, it is probable that biological molecules will play a primary role in SCD preventative therapy; in combination with hydroxyurea, crizanlizumab, an anti-P-selectin monoclonal antibody, appears to reduce VOE frequency, while L-glutamine was the first substance licensed by the FDA for use in SCD in 20 years. Synthetic drugs, however, may represent key approaches for the management of individuals upon hospitalization for VOE, a major challenge for SCD. For example, rivipansel (GMI-1070), a pan-selectin inhibitor, has shown encouraging effects on hospitalization time and opioid use.
Article Highlights
SCD constitutes a group of inherited disorders, where the production of atypical hemoglobin S results in RBC alterations. The disease affects up to 300,000 newborns worldwide and generally incurs lifelong morbidity, with manifestations that include recurrent painful VOEs.
Aside regular blood transfusions and hematopoietic stem cell transplant, hydroxyurea, which exerts a number of benefits on the clinical course of SCD, is the only drug in frequent use for treating the disease in higher-income countries.
Of drugs in late-phase evaluation for the prevention/reduction of VOEs and acute SCD complications, prasugrel failed to demonstrate convincing efficacy, while preliminary data for voxelotor have been encouraging.
In the foreseeable near future, biological drugs (rather than synthetic drugs) may be important for continuous preventative therapy in SCD, in combination with hydroxyurea; crizanlizumab significantly reduced SCD painful crisis frequency in a recent multicenter trial, while the amino acid, L-glutamine, was the first substance in 20 years to be licensed by the FDA for use in SCD due to its ability to modestly reduce VOE frequency.
A key challenge for SCD pharmacotherapy continues to be the management of the acute VOEs experienced by the majority of patients, as the current approach is limited to hydration and analgesia. In early trials, rivipansel presented clinically meaningful benefits for SCD patients hospitalized for VOEs, and results for the ongoing phase 3 study are awaited.
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Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One referee declares that they have acted as a Site Principal Investigator for clinical trials by Novartis, Bluebird Bio, Pfizer and Global Blood Therapeutics. They have also served on advisory committees for Novartis, Bluebird Bio and Global Blood Therapeutics.