Riliprubart Demonstrates Favorable Benefit-Risk Profile as Potential Treatment for Chronic Demyelinating Polyneuropathy

Luis Querol Gutierrez, MD, PhD

In part A of a phase 2 proof-of-concept trial (NCT04658472), treatment with riliprubart (Sanofi), a humanized monoclonal antibody targeting complement C1s, initial results showed a promising risk-to-benefit ratio profile in patients with chronic demyelinating polyneuropathy (CIDP), prompting further exploration in phase 3 studies.¹

The open-label trial evaluated the effects of riliprubart across 3 groups of patients with CIDP: currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-treated); refractory to SOC (SOC-refractory); and naïve to SOC (SOC-Naïve). Presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, patients underwent a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B).

In part A, the primary end point for the SOC-treated group was the percentage of participants with a relapse after switching from SOC to riliprubart while the primary end point for the SOC-refractory and SOC-naïve groups was the percentage of participants with a response, compared with baseline. Presented by Luis Querol Gutierrez, MD, PhD, a neurologist at the Hospital de la Santa Creu, in Barcelona, Spain, the primary end point for either groups was relapses, defined as a change of at least 1 point in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score.

Using data from a prespecified interim analysis in May 2023, Gutierrez and colleagues observed that 88% of SOC-treated participants improved or remained stable after switching from SOC to riliprubart, and 44% (11 of 25) improved. In total, 3 participants relapse (12%; 3 of 25) while 50% of SOC-refractory participants (9 of 18) responded to riliprubart. Over time, treated patients demonstrated trend-level reductions in neurofilament light chain, a biomarker of neuroaxonal damage.

Riliprubart, also known as SAR445088, targets active C1s protein, a C1 complex serine protease, responsible for activating the classical complement pathway. By selectively inhibiting the C1-complex, the agent suppresses the downstream activation of complement system signaling cascades that could block key inflammatory mechanisms underlying demyelination and axonal damage in CIDP.

Across the INCAT, Inflammatory Rasch-built Overall Disability Scale (I-RODS), Medical Research Council Sum Score (MRC-SS), and grip-strength, all outcomes of disability and impairment, clinically meaningful improvements were seen in riliprubart-treated participants. Treatment-emergent adverse events (TEAEs), which mainly included headache, fatigue, and nasopharyngitis, were reported in 60% (15 of 25) and 72% (13 of 18) of SOC-treated and SOC-refractory patients, respectively. Two deaths were reported in participants with significant comorbidities.

READ MORE: 2021 European Guidelines Improve Diagnosis and Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy Variants

The original data from part A was presented at the 2023 American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting. At baseline, mean INCAT score was 3.3 in the SOC-treated group and 5.4 in the SOC-refractory group. In addition to showing clinically meaningful improvements across primary and secondary efficacy end points, a strong (>90%) and sustained inhibition of complement activity was observed in SOC-treated and SOC-refractory groups.²

The results on the primary end point exceeded the expected placebo response rates, which were about 11% based on historical data. In total, 2 participants in the SOC-refractory group discontinued treatment because of a TEAE. The 2 deaths, both in patients with significant comorbidities, were because of factors such as a past history of pulmonary embolism, cardiovascular diseases, and immobilization due to CIDP.

Earlier this year, Sanofi registered a new phase 3 trial, dubbed VITALIZE (NCT06290141), that will assess the efficacy and safety of riliprubart vs intravenous immunoglobulin (IVIG) in patients with CIDP who are receiving IVIG as maintenance therapy. Researchers are looking to enroll approximately 160 adult participants with active, typical, motor, or multifocal CIDP or possible CIDP according to the European Academy of Neurology/Peripheral Nerve Society Task Force CIDP guidelines, second revision. The study, expected to be complete by May 2025, includes only those who’ve experienced a clinically meaningful improvement in CIDP symptoms as a result of IVIG therapy in the past 5 years.³

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REFERENCES
1. Querol L, Lewis R, Hartung HP, et al. Preliminary efficacy and safety data from the phase 2 trial of riliprubart (SAR445088), a humanized monoclonal antibody targeting complement C1s, in chronic inflammatory demyelinating polyneuropathy. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. ABSTRACT 002552
2. Querol L, Lewis RA, Hartung HP, et al. Phase 2 proof-of-concept trial evaluating riliprubart (SAR445088), a monoclonal antibody targeting complement C1s, in chronic demyelinating polyneuropathy. Presented at: 2023 AANEM. Poster 144
3. A Study to Test the Efficacy and Safety of Riliprubart Against the Usual Treatment of Intravenous Immunoglobulin (IVIg) in People With Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (VITALIZE). Clinicaltrials.gov. Accessed April 12, 2024. https://clinicaltrials.gov/study/NCT06290141