Sanofi cans late-stage study for rare autoimmune disease on underwhelming efficacy

Sanofi Halts Phase 3 Riliprubart Trial for CIDP

Sanofi has decided to discontinue its Phase 3 MOBILIZE study for the investigational complement inhibitor riliprubart in chronic inflammatory demyelinating polyneuropathy (CIDP). This decision follows an interim data analysis by an independent data board, which concluded that the trial was "unlikely to provide sufficient efficacy." The study, launched in 2024, was comparing riliprubart against placebo in approximately 140 CIDP patients. While the news is seen as a setback for the complement inhibitor class in CIDP, Sanofi does not anticipate significant financial costs from the wind-down of MOBILIZE.

• Sanofi's decision to halt the Phase 3 MOBILIZE trial for riliprubart in CIDP was prompted by an interim analysis from an independent data board. The board concluded that the study was "unlikely to provide sufficient efficacy," leading to the discontinuation of the trial which had been comparing riliprubart against placebo in approximately 140 CIDP patients since its launch in 2024.
• The discontinuation of Sanofi's riliprubart trial is viewed by analysts at William Blair as a "disappointing blow" to the broader complement inhibitor class for CIDP, potentially causing "volatility" for other companies like argenx. Sanofi is still evaluating the future of its other riliprubart programs, including the Phase 3 VITALIZE trial, which features intravenous immunoglobulin as a comparator arm.
• Despite the MOBILIZE trial's outcome, riliprubart had previously shown promising results in open-label Phase 2 data, where 87% of patients improved or remained stable after switching from standard of care, and 72% were relapse-free after about a year. This context highlights the challenge of translating early-phase success to late-stage efficacy in CIDP, a condition where argenx's FDA-approved Vyvgart Hytrulo received approval in June 2024.

Sanofi Halts Riliprubart's MOBILIZE Trial in CIDP

The most recent CIDP trials demonstrate sophisticated study designs targeting emerging therapeutic mechanisms. The SAR445088 Phase 2 study (NCT04658472) employs a comprehensive three-cohort approach evaluating this complement C1s inhibitor across 90 patients stratified by treatment history: standard-of-care treated, refractory, and treatment-naïve groups. The trial features a 24-week primary treatment period followed by an optional 52-week extension, with primary endpoints measuring relapse rates in the treated group and response rates in refractory and naïve cohorts. Data analysis utilizes Bayesian statistics with predefined efficacy thresholds. Concurrently, real-world efgartigimod studies in 12 CIDP patients demonstrate robust methodology with standardized assessments using MRC muscle strength scales, I-RODS disability measures, and INCAT scoring, achieving 91.7% clinical improvement rates by week five.

Established immunoglobulin trials have refined maintenance therapy protocols through rigorous placebo-controlled designs. The ProCID Phase III study systematically compares three IVIg doses (0.5, 1.0, and 2.0 g/kg) administered every three weeks over 24 weeks, with treatment response defined as ≥1-point improvement in adjusted inflammatory neuropathy cause and treatment disability scores. The study incorporates a structured washout phase followed by loading doses and maintenance therapy, with predetermined rescue medication protocols for patients in lower-dose groups experiencing deterioration. The PATH study similarly evaluates subcutaneous immunoglobulin maintenance with primary endpoints measuring relapse rates defined by 1-point INCAT disability score deterioration or withdrawal within 24 weeks.

Combination therapy trials represent advanced therapeutic strategies with sophisticated endpoint hierarchies. The international randomized trial comparing IVIg plus methylprednisolone versus IVIg plus placebo employs a primary endpoint of sustained remission at one year, defined as disability improvement maintained between weeks 18-52 without additional treatment. This design addresses the critical clinical need for treatment-free remission rather than mere symptom control. Secondary endpoints encompass comprehensive assessments including disability progression, pain, fatigue, quality of life measures, and healthcare utilization costs, reflecting the multidimensional impact of CIDP on patient outcomes and healthcare systems.

The Persistent Unmet Needs in CIDP Treatment

Despite advances in CIDP management, significant treatment challenges persist that impact patient outcomes and healthcare utilization. The heterogeneous nature of the disease and variable treatment responses create substantial clinical complexity requiring individualized therapeutic approaches.

• Treatment refractoriness and partial response: A significant proportion of CIDP patients remains refractory to standard-of-care treatments or achieves only partial response, with limited evidence available on the disease burden affecting this patient population

• High treatment switching rates: Approximately one-third (31%) of patients switched to second-line treatment within 2 years of initiating first-line therapy, with a median time to switch of 5.6 months, indicating suboptimal initial treatment selection or efficacy

• Limited first-line therapy efficacy: Treatment switching patterns suggest limited efficacy of first-line therapies, while the observed decrease in treatment duration after initial therapy may indicate diminishing utility of subsequent therapeutic options

• Increased healthcare burden: Patients requiring treatment switches demonstrated significantly higher healthcare utilization compared to those maintaining initial therapy (45.3 vs. 35.3 visits/year), with 92% requiring outpatient visits and 40% experiencing hospitalization within 2 years of treatment initiation

• Severe cases requiring intensive interventions: Among ICU-treated patients, 95% required mechanical ventilation with severe tetraparesis, 62% needed escalation beyond first-line immunotherapy, and 24% remained treatment-refractory requiring advanced therapies including daratumumab, efgartigimod, or autologous stem cell transplantation

• Poor outcomes in critical cases: ICU-treated patients experienced 29% mortality, with survivors demonstrating significantly worse long-term outcomes compared to non-ICU patients (adjusted cumulative OR: mRS 7.1, INCAT 6.4), highlighting the severity of refractory disease

• Diagnostic challenges and delays: Frequent misdiagnosis occurs due to complex clinical presentations, particularly with conditions like POEMS syndrome, leading to delays in appropriate therapeutic interventions and suboptimal patient outcomes

• Predictive biomarker limitations: Patients with early-stage typical CIDP and elevated zNFL >2 presented with severe manifestations unresponsive to first-line treatments, indicating current difficulties in predicting treatment response and optimizing initial therapeutic selection

The Future of Complement Inhibitors in CIDP

Based on the available literature, no other drugs are currently identified as being trialled for cold agglutinin disease using the same anti-C1s mechanism of action as riliprubart. While the literature references "novel anti-C1s monoclonal antibodies such as riliprubart," no other specific anti-C1s inhibitors are named or described in clinical development for this indication.

Riliprubart's CIDP Setback: Rethinking Complement in Neurological Autoimmunity

The recent decision by Sanofi to discontinue its Phase 3 MOBILIZE study for riliprubart in chronic inflammatory demyelinating polyneuropathy (CIDP) marks a notable moment for the complement inhibitor landscape. Riliprubart, an anti-C1s humanized monoclonal antibody, was designed to specifically inhibit the activated form of the C1s component of the classical complement pathway. While earlier studies demonstrated favorable pharmacokinetic and pharmacodynamic profiles, along with a good safety and tolerability record in healthy individuals, these attributes did not translate into sufficient efficacy in the CIDP trial.

This outcome carries several implications for Sanofi and the broader field. For the company, it necessitates a strategic pivot, likely intensifying focus on other indications where riliprubart has shown more promise, such as cold agglutinin disease (CAD). In CAD, model-informed drug development has predicted high efficacy and safety for a quarterly dosing regimen, suggesting that the drug's mechanism of action may be more directly relevant and impactful in that specific autoimmune condition. This re-prioritization of resources is a common, albeit challenging, aspect of pharmaceutical development.

However, the discontinuation also raises important questions about the role of the classical complement pathway in CIDP. The lack of efficacy suggests that C1s inhibition may not be a primary or sufficiently dominant therapeutic strategy for this complex neurological disorder. This could imply that other complement components or alternative pathways are more critical to CIDP's pathology, or that the disease's mechanisms are more heterogeneous than initially understood. This challenge in translating mechanistic understanding into clinical efficacy across different disease indications, even within the same complement-mediated class, is a persistent risk in drug development. Future research may need to delve deeper into the precise drivers of CIDP to identify more effective therapeutic targets. The event underscores the continuous learning curve in developing treatments for complex autoimmune diseases and the need for robust clinical validation, even for well-characterized molecular targets.