Highlights
- •Disease-modifying drug therapies for sickle cell disease are rapidly emerging.
- •Three new drugs have been approved by the FDA in addition to hydroxyurea.
- •Over 30 clinical trials are ongoing to test new drugs or drug indications.
Abstract
Sickle cell disease is an inherited blood disorder afflicting an estimated 100,000
individuals in the United States and over 20 million people worldwide. The disease
is heralded as the first molecular disease. However, despite its genetic simplicity,
the pathophysiologic processes leading to its clinical sequelae are complex, heterogeneous
and interrelated, making drug development to treat the disease challenging. For over
two decades only one drug, hydroxyurea, had been used as disease-modifying therapy.
New pharmacologic agents are rapidly evolving with three new drugs, with different
mechanisms of action, approved by the United States Food and Drug Administration in
recent years (L-glutamine, crizanlizumab and voxelotor). Several therapeutic approaches targeting
different pathways in the disease pathophysiology are being investigated. These include
inhibition of hemoglobin S polymerization such as by fetal hemoglobin induction or
by increasing hemoglobin oxygen affinity, as well as intervention of downstream pathways
including inhibiting cellular adhesion, reducing inflammation and oxidant stress,
modulating platelet activation and coagulation abnormalities, and targeting nitric
oxide signaling. This review will provide an overview of these therapeutic strategies,
discuss the four currently approved drugs in detail, and summarize ongoing clinical
trials of new drugs or drug indications for the treatment of sickle cell disease in
different phases of development excluding those related to cellular therapies.
Keywords
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Published online: August 28, 2022
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