Background: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States, caused by polymerization of a mutated form of hemoglobin (HbS). HbS can form long polymers inside red blood cells (RBCs) that affect RBC shape and adhesion, resulting in RBC destruction, acute and chronic pain, inflammation and cumulative organ damage. SCD-101 is a botanical drug with in vitro and in vivo anti-sickling activity. The mechanism by which SCD-101 inhibits sickling is unknown; however, it does not bind directly to Hb or change the affinity of Hb for oxygen. We recently completed a dose-escalation clinical study of SCD-101 in adults with sickle cell disease in steady state, and other clinical studies are on-going.
Methods: The initial prospective, open-label, Phase 1B dose-escalation study enrolled homozygous (SS) sickle cell patients and S/beta0 thalassemia patients ages 18-55 with baseline Hb levels 6.0-9.0 g/dL and hemoglobin F ≤10%. Admission within 30 days, transfusion within 90 days, and hydroxyurea within 6 months were exclusions. SCD-101 was dosed orally for 28-days with a 14-day follow-up visit. Doses administered during the dose escalation study were 550 mg, 1100 mg, 2200 mg and 4400 mg BID. The primary endpoint was safety, and the secondary endpoints were mean change in Hb, Hct, percent reticulocytes, LDH, indirect bilirubin, CRP, PROMIS fatigue questionnaire score, and percent circulating partially oxygenated sickle cells (POSCs) in venous whole blood fixed in 2% glutaraldehyde without exposure to air. A repeat cohort study is ongoing with dose adjusted to 2750 mg TID, a 6-minute walk test added as a functional endpoint and measurement of inflammatory cytokines by ELISA to explore the effect of SCD-101 on inflammation.
Results: As of August 4, 2016, 26 patients with sickle cell disease have been enrolled, 20 patients have completed the 28-day dose-escalation study and 3 were discontinued before receiving their first dose of SCD-101. Three patients are enrolled in the 28-day repeat cohort study. There have been no dose reductions or interruptions due to drug-related effects. SCD-101 was generally well-tolerated with mild-moderate bloating and flatulence at the highest dose on a BID schedule in the dose-escalation study, which were not observed with a TID schedule in the repeat cohort study. There were no significant changes in safety laboratory tests and no significant changes in hemoglobin, hematocrit, LDH, unconjugated bilirubin, or reticulocytes. No significant changes were observed in renal, hepatic or other safety chemistries or electrocardiograms. SCD-101 participants treated at higher doses reported a decrease in chronic pain and fatigue after 7-14 days, which returned post-treatment when measured on the 14-day follow-up visit. Participants at the two highest doses reported an increase in exercise capacity and an improvement in sleep. Two participants with ankle ulcers, enrolled at the two highest doses, showed improved healing. Analysis of peripheral blood smears revealed an improvement in the shape of circulating RBCs. There was no change in inflammatory cytokines in the first 7 days in the repeat cohort study, though the Day 28 data may show a different result.
Conclusions: SCD-101 is a promising new drug for the treatment of sickle cell disease, based on the results from the studies reported here. SCD-101 was well tolerated over an 8-fold dose range, and dose-dependent anti-sickling effects on RBC were observed, though without significant changes in hemolysis. Clinical benefits included reduced chronic pain and fatigue, improved sleep and improved ulcer healing. While the identity of the active substance(s) in SCD-101 and the mechanism(s) of action are unknown, SCD-101 has a direct anti-sickling effect on RBCs, compatible with an intracellular or membrane effect on RBCs. We hypothesize that the observed effects could be explained by increased vascular flow or increased oxygen delivery or a reduction in inflammation. A placebo-controlled crossover study will be completed in 2016 including a 6-minute walk test as a primary clinical endpoint, and a multi-site Phase 2 study is planned for 2017. As a botanical drug, SCD-101 may be a useful treatment for sickle cell disease worldwide.
Swift:Global Blood Therapeutics: Equity Ownership; Mast Therapeutics: Equity Ownership; SCD Development: Employment, Equity Ownership.
Asterisk with author names denotes non-ASH members.