Design of the TRANSCENDING Study: A Phase 2 Study of the Safety of Anumigilimab in Adults with Sickle Cell Disease
Santosh L Saraf, Bart J Biemond, Paul M Shore, Nicole Avalos, Sean Gill, Annemieke Hatzmann, William McKeand, Yuanyuan Wang, Gregory J Kato, Fuad El RassiAbstract
Background
Sickle cell disease (SCD) is a chronic, multisystem genetic disorder affecting hemoglobin, leading to chronic anemia and multi-organ dysfunction with associated morbidity and mortality. Unpredictable episodes of severe pain known as vaso-occlusive crises (VOCs) are a key feature of SCD, leading to impaired quality of life, increased healthcare costs, and reduced lifespan. Pharmacological treatments to prevent VOC and other complications of SCD have not been entirely successful; thus, remains a high unmet need to develop effective therapies. Neutrophils, activated by chronic hemolysis and episodes of ischemia-reperfusion injury, are thought to play a key role in the pathophysiology of SCD. Activated neutrophils express cellular adhesion proteins and can initiate NETosis, inducing the multicellular aggregates that cause the microvessel occlusion that underlies VOC. Anumigilimab is a fully human monoclonal antibody targeting and competitively inhibiting the human granulocyte colony-stimulating factor (G-CSF) receptor. Anumigilimab decreases G-CSF-mediated abundance, activation, enhanced migration, and survival of neutrophils. VR81 (the mouse analog of anumigilimab) showed dose-dependent prophylactic efficacy in SCD mouse models of VOC. VR81 prevented experimentally triggered vaso-occlusion up to 1 week after administration and prevented long-term organ injury with chronic administration, likely by reducing NETs (Neutrophil Extracellular Traps) and adhesion molecule expression. Although treatment with VR81 reduced neutrophil count in some studies in wild-type mice, neutrophil count remained stable or increased slightly with both acute and chronic treatment in SCD mice. Anumigilimab is anticipated to prevent neutrophil-induced consequences such as VOCs in patients with SCD and is being developed as a prophylactic treatment in SCD. Four phase 1 studies have been completed with anumigilimab in healthy volunteers (HVs) and in patients with neutrophilic dermatoses. Transient, dose-dependent neutropenia was observed in all studies; no other safety concerns were observed, and no severe, related infections occurred. The TRANSCENDING study (CSL324_2002, NCT07224360) seeks to evaluate the safety of anumigilimab in adults with SCD.
Methods
TRANSCENDING is a phase 2a, global, multicenter, randomized, double-blind, placebo-controlled study. Up to 63 adults with SCD of any genotype who experienced between 1 and 12 VOCs in the 12 months before screening will be randomized (2:1) to receive anumigilimab or placebo, stratified by hydroxyurea (HU) use. Subjects on HU must be on a stable regimen for > = 30 days and HU will be continued throughout the study. Subjects with an absolute neutrophil count (ANC) < 2.5 × 10^9 cells/L, with insufficient vaccination status, receiving chronic immunomodulatory medications, or with a severe infection will be excluded. Dosage of anumigilimab will be escalated over 12 weeks to each subject’s maximum tolerated dose (MTD), guided by ANC and safety concerns (eg, fever, serious infection), then MTD will be maintained for 52 weeks. An independent data monitoring committee will oversee study conduct and safety.
Results
The primary endpoint of this study is the safety of anumigilimab, assessed via treatment-emergent adverse events (TEAEs) and clinically relevant changes from baseline in laboratory assessments and vital signs. Neutropenia (moderate or severe), severe infection and neutropenic fever are AEs of special interest (AESIs). Secondary endpoints include PK and efficacy, assessed by the annualized rate of VOC treated at a medical facility during the 52-week Maintenance Period. Safety (ANC) and PK assessments are more frequent during the Dose Escalation Period to confirm that exposure to multiple doses of anumigilimab is as predicted and to recommend adjustments to the dosage regimens, if necessary. Safety and PK assessments will be less frequent during the Maintenance Period to reduce subject burden.
Conclusions
The TRANSCENDING study of anumigilimab will provide data that may support a subsequent clinical trial assessing the efficacy of anumigilimab in SCD. Anumigilimab has potential to prevent VOC with a novel mechanism targeting the central role of neutrophils. The effect on the safety parameter of ANC is of particular interest – since neutrophil count is not reduced in SCD mice as it is in wild-type mice, the effect of anumigilimab on people living with SCD may be different from that seen in HVs or patients with neutrophilic dermatoses.