114. Hemoglobinopathies, Excluding Thalassemia—Clinical:Novel Treatments for Sickle Cell Disease

Alexis A. Thompson, Mark C. Walters, Markus Y Mapara, et al. 

Authors Conclusion from the Abstract: LentiGlobin for SCD GT results in near pancellular βA-T87Q expression and reduced HbS expression, which impacts the pathophysiology of SCD as demonstrated by reduced RBC sickling and hemolysis and increased total Hb. Complete resolution of VOC/ACS was observed in almost all patients, with 99.5% mean reduction in the annualized VOC+ACS rate post-treatment. In addition, patients overall reported an improved pain intensity score. The safety profile post-LentiGlobin remains generally consistent with myeloablative single-agent busulfan conditioning and underlying SCD. Longer follow-up and additional patients will be presented.

Carlton D. Dampier, Marilyn J. Telen, Ted Wun, et al. 

Authors Conclusion from the Abstract: Rivipansel administered early in VOC results in clinically meaningful benefit for adults and children with SCD, shortening IV opioid use and hospital stay. Biomarker data confirm on-target effect, suggesting that the diminishing effect of later rivipansel treatment results from downstream pathophysiology. These findings suggest the utility of early treatment to shorten or interrupt acute VOCs, analogous to thrombolysis for heart attack or stroke. This could change the VOC treatment paradigm from deferral of hospitalization to one of early intervention to reduce length of hospitalization and IV opioid requirement, relieve VOC symptoms, and possibly mitigate end-organ damage from tissue ischemia.

R. Clark Brown, Kimberly Cruz, Theodosia A. Kalfa, et al.

Authors Conclusion from the Abstract: FT-4202 has a favorable safety profile in pts with SCD receiving a single dose or up to 14 days of dosing. A single dose of FT-4202 led to decreased 2,3-DPG and increased ATP, resulting in increased O2 affinity, decreased PoS, improved RBC deformability, and improved RBC membrane function. Initial blinded results of daily dosing with 300 mg FT-4202/placebo over 14 days show improvement in both hematologic and hemolytic parameters in 2 of 3 pts with SCD, along with improved RBC functional studies, suggesting the pharmacodynamic consequences of PKR activation may be of clinical benefit in SCD. Multiple-dose cohorts are ongoing to further evaluate the safety, PK/PD, and biological activity of FT-4202 following daily administration in pts with SCD; updated data will be presented.

Michael Grimley, Monika Asnani, Archana Shrestha, et al.

Authors Conclusion from the Abstract: We show that engraftment of ARU-1801 and amelioration of disease is possible with RIC using IV melphalan, with persistent stable ASG expression and meaningful improvement in VOEs in P1 and P2. P1 shows stable HbFG16D and high ASG despite low, albeit stable VCN. P2 had lower HSCP engraftment, which we hypothesize was due to below target melphalan exposure. Nevertheless, significant clinical benefit was observed in P2 due to stable ASG of 22% at mo 30. It is likely that the presence of this amount of HbFG16D has provided enough ASG to prevent sickling/ineffective erythropoiesis, resulting in the preferential survival of HbF+HbFG16D-expressing RBC. Process II DP in P3 resulted in 2-4X higher engraftment of transduced HSCPs at 6 mo. Additional process enhancements are under development for future treated patients. ARU-1801, administered with RIC, holds significant promise for achieving durable responses with a favorable safety profile in patients with severe SCD.

Julia Z. Xu, Anna Conrey, Ingrid Frey, et al.

Authors Conclusion from the Abstract: Mitapivat demonstrated an acceptable safety profile across the tested dose levels in 8 subjects with SCD. Analyses of data show promising evidence of efficacy in terms of Hb increase from baseline with concomitant decreases in hemolytic markers. The accompanying changes in metabolites and sickling studies are consistent with the proposed mechanism of the drug. The study is ongoing with a planned sample size of 15 subjects completing 6-8 weeks of treatment. Additional data including PK will be presented