This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, group-sequential study (Part A), followed by an open-label long-term extension (LTE) period (Part B). This study will investigate the efficacy and safety of rilzabrutinib 400 mg, administered twice daily (BID), in participants with sickle-cell disease (homozygous [HbSS] and HbS/β0 thalassemia). The study will enroll male and female pediatric participants aged 10 to <18 years of age, and adults aged 18 to 65 years who have had 2 to 10 episodes of documented acute clinical vaso-occlusive crisis (VOC) within 1 year of the screening visit.

One non-binding futility interim analysis (IA) will be conducted when 50% of the total number of planned participants (96 adults) have been exposed for at least 12 weeks or have discontinued treatment early. Enrollment will be paused during the IA period. The purpose is to stop studying for futility or continue studying. Enrollment of pediatric participants starts only after the interim analysis has been completed and deemed appropriate by the independent DMC

Study EFC17872 is a randomized, double-blind, parallel-group, multicenter, group-sequential, placebo-controlled study with a double-blind treatment period of 52 weeks followed by an open- label, LTE period (Part B). Only the participants who complete the double-blind treatment period (Part A) are eligible to continue to the LTE period. The duration of the LTE period (Part B) will be from the first participant-in (FPI)-LTE (Part B) until the last participant who enters the LTE has completed 52 weeks. The total duration of the LTE period (Part B) will be 106 weeks (including the 2-week follow-up) at a minimum (for the LPI-LTE period). The study will evaluate the efficacy and safety of oral rilzabrutinib in participants with SCD (HbSS and hemoglobin S/β°-thalassemia [HbS/b°-thalassemia]) who have had at least 2 but no more than 10 episodes of documented acute clinical VOC within 1 year before the Screening Visit.

Although HbS polymerization is central to the pathophysiology of the disease, recent advances in SCD research confirm a more complex process. Instability of HbS induces impairments in erythrocyte membrane structure, elasticity, viscosity, and biochemical properties. In addition, plasma of patients with SCD contains excess cell-free Hb and heme, together with other damage-associated molecular patterns (DAMPs). Heme can drive sterile inflammation sufficiently severely to cause tissue damage and promote acute organ failure in SCD. Oxidative stress, inflammation, activation and enhanced adhesiveness of neutrophils, release of NETosis products into the blood, and hypercoagulability are increasingly recognized to play a primary role in vaso- occlusion, tissue ischemia, and organ damage. It has been increasingly recognized that innate immune cells, including monocytes, neutrophils, invariant natural killer T cells, platelets, and mast cells, have a role in promoting inflammation, adhesion, and pain in SCD. Activated and adherent leukocytes and endothelium are the likely drivers of vaso-occlusion in collecting venules, whereas sickle erythrocytes may contribute to the occlusion of smaller vessels.

Studies conducted over the past decade have identified inflammasome pathways as key regulators of sterile inflammation. Nucleotide-binding domain and leucine-rich repeat receptors (NLRs) or absent melanoma 2 (AIM2)-like receptors (ALRs) are major components of the inflammasome complex. Inflammasomes are multimeric cytoplasmic pattern recognition receptor complexes that are activated by cell-and tissue-derived DAMPs, ROS, TLR4 activation, double- stranded DNA, NET fragments, and several unknown cell- or tissue-derived danger signals. Following activation, inflammasomes process and release activated IL-1β and IL-18. Once released, IL-1β binds to IL-1 receptor (IL-1R) on leukocytes and vascular cells, promoting a cascade of downstream events that lead to activation of neutrophils and platelets and upregulation of E-selectin, P-selectin, VCAM-1, ICAM-1, and chemokines such as IL-8 in endothelial cells, all of which promote vaso-occlusion.

Bruton’s tyrosine kinase (BTK) is an essential signaling element and activation of the B-cell, basophils, mast cells (FcεR signaling), macrophages, and neutrophils. Platelets express BTK; alternative signaling pathways exist that bypass BTK signaling to retain normal platelet functions and thrombus formation. BTK is not expressed in T cells, natural killer cells, and plasma cells. Growing evidence suggests multiple roles of BTK in innate immunity, especially as a regulator of key innate inflammatory machinery, the NLRP3 inflammasome, heme and TLR4-mediated inflammasome activation, adhesion molecule expression, and neutrophil trap formation (NET). Studies have shown that inhibition of BTK reduces selectin- mediated LFA-1-dependent slow leukocyte rolling, markedly diminishes NET, downregulates oxidative stress in neutrophils, suppresses adenosine triphosphate secretion and P-selectin expression in platelets, and prevents thrombo-inflammation. Interestingly, treatment with NLRP3 inhibitor (MCC950) or irreversible BTKi (ibrutinib) administered for 4 weeks decreases platelet caspase 1 activity in SCD mice but not in control mice, suggesting a treatment-by-genotype interaction. Moreover, platelet aggregation and in vitro thrombus formation were upregulated in SCD mice and were inhibited when mice were subjected to pharmacological inhibition of NLRP3 and BTK.

Rilzabrutinib (SAR444671, PRN1008) is a high-affinity inhibitor of BTK. We hypothesize that treating patients with SCD with rilzabrutinib may result in a reduction of chronic inflammatory state, blood cells adhesion, oxidative stress that can ultimately prevent VOC and hemolysis. It has been shown in Townes HbSS mice (10 to 14 weeks old) after treatment with rilzabrutinib(40 mg/kg BID, generating exposure comparable to that in humans dosed at 400 mg BID) for 2 weeks and challenged with H/R or Hb Challenge, treatment with rilzabrutinib significantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygenation or hemoglobin compared to Townes HbSS mice. In addition, treatment with rilzabrutinib significantly reduced spleen size, white blood cell counts, liver NF-κB activation, P-selectin and vWF mobilization in lung tissue, suggesting amelioration in the inflammatory state and reduction in cells adhesion. In the liver of SCD mice from the Hb model, treatment with rilzabrutinib resulted in downregulation of inflammasome-related genes (BTK, caspase-1, NRLP3, IL1b, IL-18). In both H/R and Hb models, other markers of inflammation, markers of adhesion (P-selectin, E-selectin/C62L), complement, NETosis, and thrombosis. There were no significant differences among HbSS treatment groups for any red blood cell indices.

In human neutrophils after fMLP activation, treatment with rilzabrutinib attenuated ROS production (N = 5 donors) and activated CD11b (N = 11 donors). In addition, in human eosinophils, pretreatment with rilzabrutinib significantly inhibited the response across all doses tested (p<0.001 ROS production; p<0.05 CD11b activation). These results show that BTK plays a novel role in the reduction of oxidative stress.

Hypercoagulopathy and thrombo-inflammation play an important role in the pathophysiology of SCD. Moreover, platelet aggregation and in vitro thrombus formation were upregulated in SCD mice and were inhibited when mice were subjected to pharmacological inhibition of NLRP3 and BTK (35). Interestingly, studies have shown that rilzabrutinib could have an anti-thrombotic effect without increasing the risk of bleeding through inhibition of human platelet C-typelectin-like receptor 2 (CLEC-2), together with the lack of off-target inhibition of Src family kinase (SFK). Therefore, rilzabrutinib is uniquely positioned to prevent VOC via multiple mechanisms of action (MOA) that include reduction of oxidative stress, inflammation, blood cell adhesion, and thrombo-inflammation.

Rilzabrutinib 400 mg BID is being studied in children (≥10 years) and adults with immune thrombocytopenia (ITP) in Phase 3 and warm autoimmune hemolytic anemia (wAIHA) in Phase 2, and the final study results provide robust evidence of sustained efficacy and a favorable safety profile. This dose was shown in earlier studies to generate rapidly strong BTK occupancy with durable occupancy throughout the dosing interval (12 hours). Therefore, based on the observed multipronged MOA of rilzabrutinib, the positive preclinical findings in the sickle cell mouse model, and the observed beneficial therapeutic effects on ITP and wAIHA diseases, treatment with rilzabrutinib 400 mg BID could be an efficacious treatment for patients with SCD.