Table 2.

Emerging therapies for management of sickle cell disease

Medication		Mechanism	Clinical Trial Information
Pyruvate Kinase Activator	Etavopivat	RBC pyruvate kinase-R (PKR) activator. Decreases 2,3-DPG in RBCs to increase Hb oxygen affinity. Increase ATP	Phase 2/3: NCT04624659 HIBISCUS Age 12-65 years Endpoints: • Increase in hemoglobin • Rate of VOEs.
	Mitapivat	RBC pyruvate kinase-R (PKR) activator. Decreases 2,3-DPG in RBCs to increase hemoglobin oxygen affinity. -Increase ATP	Phase 2 /3 NCT05031780 Age ≥ 16 years Endpoints: • % with a hemoglobin response by 12 weeks • % with treatment-emergent adverse events and treatment-emergent serious adverse events • % with a hemoglobin response by week 52 • Phase 3: Annual rate of sickle cell pain crises
Anti-sickling	GBT021601	Second generation HbS polymerization inhibitor. Binds to hemoglobin and shifts O2 dissociation curve toward normal (i.e., leftward), thus reducing O2 tension at which hemoglobin deoxygenates, thereby reducing sickling	Phase 2/3 NCT05431088 6 Months to 65 Years Endpoints: • Number of adults with change from baseline in hemoglobin through week 12 • Proportion of participants with an increase from baseline of >1 g/dL in hemoglobin at week 48 • Pharmacokinetics, while observing maximum concentration after a single dose. • Pharmacokinetics, at minimum concentration and maximum concentration after multiple dose administration
Anti-adhesion therapies	Inclacumab	IgG4 monoclonal antibody that selectively targets P-selectin	Phase 3 NCT04935879 Age ≥ 12 Endpoints: • Rate of VOEs during the 48-week treatment period Phase 3 NCT04927247 Age ≥ 12 years Endpoints: • Re-admission for a VOE within 90 days of randomization
Antioxidant/Anti-inflammatory	Crovalimab	C-5 (complement) inhibitor to downregulate complement contribution to acute VOE	Phase 2 CROSSWALK-c (NCT05075824) Aged 12 - 55 years Endpoints: • Annual rate of medical facility VOEs
	Rifaximin	Oral antibiotic for intestinal microbial modulation (gut decontamination) to reduce translocation of intestinal bacteria and activated neutrophils	Phase 2 (NCT03719729) Median age 29 years (range 24-56). Endpoints: • Toxicity profile (incidence of nausea, vomiting, diarrhea, abdominal discomfort, worsening anemia)

DPG, diphosphoglycerate. RBC, red blood cell, ATP, adenosine triphosphate. VOE, vaso-occlusive events