BTK Inhibitor Orelabrutinib Shows Promising Efficacy in Phase 2 Study of Relapsing-Remitting Multiple Sclerosis

Xiangyang Chen

New data from a phase 2 double-blind, placebo-controlled trial (NCT04711148) demonstrated that treatment with investigational orelabrutinib (InnoCare Pharma) was highly effective in reducing new/enlarging gadolinium-enhancing lesions (Gd+) lesions in patients with relapsing-remitting multiple sclerosis (RRMS) over a 24-week period. Overall, the 80 mg once daily (QD) dosage of the Bruton tyrosine kinase (BTK) inhibitor was the most effective and thus will be selected for phase 3 progressive MS studies.¹

The study featured 158 patients who were randomly assigned 1:1:1:1 to either placebo, orelabrutinib 50 mg QD, orelabrutinib 80 mg QD, and orelabrutinib 50 mg twice daily (BID) for a 24-week period. After 12 weeks of treatment, all 3 active treatment groups revealed statistically significant reductions in the cumulative number of new Gd+ T1 brain lesions, the primary end point (n = 115), in comparison with placebo (P <.05). Notably, the 80 mg QD and 50 mg BID groups continued to show statistically significant reductions throughout 24 weeks relative to the placebo and 50 mg QD groups (P <.05).

These data were presented as a poster at the 2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1, in West Palm Beach, Florida, by Xiangyang Chen, chief technology officer at InnoCare. In the latest data, the 80 mg QD group showcased the highest Gd+ reductions at week 12 (90.4%; 95% CI, 58.2-97.8) compared with placebo and at week 24 (92.3%; 95% CI, 56.5-98.6) compared with the placebo/50 mg QD group. Importantly, the lesion control observed in each orelabrutinib group was observed at the earliest assessment of 4 weeks and sustained through the 24-week period.

In terms of safety, investigators recorded a similar incidence of treatment-emergent adverse events (TEAEs) across all 3 orelabrutinib group, which were slightly higher than that in the placebo group at week 12. Overall, there were no serious TEAEs recorded in the 80 mg QD group, considered the most efficacious. Notably, this group had the lowest liver-related AEs compared with placebo. In December 2022, the FDA placed this trial on partial hold because of a small number of participants who experienced liver injury.

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Orelabrutinib, a covalent BTK inhibitor with high selectivity, is designed to cross the blood brain barrier, thus inhibiting B cell and myeloid cell effector functions in the central nervous system. By addressing the progressive biology of the disease, the belief is that orelabrutinib has the potential to slow disease progression and provide meaningful benefit in all forms of MS. The agent is currently approved in China for certain hematologic cancers, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), and is also undergoing clinical trials for other cancers and autoimmune conditions.

In September 2024, InnoCare announced the completion of a successful End of Phase 2 Meeting with the FDA regarding the clinical development of orelabrutinib for the treatment of MS. At the conclusion of the hearing, the parties reached an agreement on the initiation of a phase 3 trial in patients with primary progressive MS. In addition, InnoCare was encouraged by the agency to conduct a second phase 3 clinical trial of orelabrutinib in patients with progressive MS and secondary progressive MS.²

More recently, the company received approval from the China National Medical Products Administration (NMPA) for a phase 3 registrational trial testing the effects of its B-cell lymphoma inhibitor ICP-248 in combination with orelabrutinib as a first like therapy for patients with CLL/small lymphocytic lymphoma. ICP-248, a novel, orally bioavailable BCL2 selective inhibitor, previously demonstrated promising efficacy and safety in combination with orelabrutinib in a phase 2 trial of treatment-naïve patients with CLL/SLL. The belief is that this combination of treatments would provide deeper remission for this patient population without drug-resistant mutations.³

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REFERENCES
1. Xu Y, Chen X, Tang W. P094. Positive Phase 2 Results of Orelabrutinib in Patients with Relapsing-Remitting Multiple Sclerosis. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT P094.
2. InnoCare Announces End-of-Phase 2 Meeting with FDA and Agreement to Initiate a Phase III clinical trial of orelabrutinib for the treatment of PPMS. News release. InnoCare. September 7, 2024. Accessed February 27, 2025. https://www.innocarepharma.com/en/news/activity/en020240908-Phase-III-trial-of-orelabrutinib-for-the-treatment-of-PPMS
3. InnoCare Announces the Approval of Registrational Phase III Study of BCL2 Inhibitor ICP-248 in Combination with Orelabrutinib as First-Line Therapy for Treatment of CLL/SLL Patients in China. News release. InnoCare Pharma. February 17, 2025. Accessed February 27, 2025. https://www.businesswire.com/news/home/20250217973889/en/InnoCare-Announces-the-Approval-of-Registrational-Phase-III-Study-of-BCL2-Inhibitor-ICP-248-in-Combination-with-Orelabrutinib-as-First-Line-Therapy-for-Treatment-of-CLLSLL-Patients-in-China