Jul 09, 2025
At European Academy of Neurology (EAN) 2025, data from the Phase II ARDA study (NCT05225675) provided compelling proof-of-concept evidence for empasiprubart, a novel C2 complement inhibitor, in treating multifocal motor neuropathy (MMN). MMN is a chronic, immune-mediated neuropathy characterized by asymmetric limb weakness and axonal degeneration, with complement activation via the classical and lectin pathways playing a central role in its pathogenesis. By targeting complement component C2, empasiprubart interrupts this cascade at an upstream point, offering a potentially disease-modifying approach.
The ARDA study enrolled 27 adults with definite or probable MMN who were IVIg-dependent and on stable IVIg regimens. Participants were randomized 2:1 to receive empasiprubart or placebo within two cohorts. Cohort 2 included older patients with longer disease duration and prior IVIg exposure. The primary efficacy endpoint was time to first IVIg retreatment during the Double-blind Treatment Period (DBTP), along with secondary endpoints including grip strength, Patient Global Impression of Change (PGIC), and serum neurofilament light chain (NfL chain levels).
Empasiprubart demonstrated a favorable safety profile, with adverse events mostly mild or moderate in severity. Importantly, it significantly delayed the need for IVIg retreatment. In Cohort 1, the hazard ratio (HR for retreatment was 0.09 (95% CI: 0.02, 0.44), while in Cohort 2 it was 0.17 (95% CI: 0.02, 1.60), both favoring empasiprubart over placebo. This suggests a meaningful reduction in relapse risk and supports the potential to reduce IVIg dependence.
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Patient-reported outcomes also favored empasiprubart. In Cohort 1, 56% of patients treated with empasiprubart reported being “very much” or “much improved” vs. 11% in the placebo group. In Cohort 2, 66.6% of empasiprubart-treated patients reported similar improvement vs. 22.2% with placebo. Notably, more patients on the placebo reported deterioration in their condition.
An objective functional benefit was also observed. In Cohort 1, the median change in grip strength was +11.28 kPa (Q1–Q3: 0.00–28.78) with empasiprubart, compared to only +0.89 kPa (–0.67 to 9.00) with placebo. In Cohort 2, grip strength improvement reached +19.89 kPa (3.33–38.89) vs. +0.78 kPa (–2.22 to 7.89), further demonstrating treatment-related gains in motor function. Additionally, serum NfL levels decreased in both cohorts following empasiprubart treatment, suggesting preservation of axonal integrity and reinforcing its neuroprotective mechanism of action.
KOL View
Empasiprubart, which remains in development for other conditions like delayed graft function, dermatomyositis, and chronic inflammatory demyelinating polyneuropathy, is designed to be a humanized sweeping antibody that binds specifically to C2 in a pH– and Ca2+ dependent manner. By blocking complement activity, the belief is that this therapy may reduce tissue inflammation and the adaptive immune response. Notably, the agent is engineered for a long half-life through increased affinity to FcRn at acidic pH. – Expert Opinion
Conclusion
The ARDA study marks a pivotal advance in MMN treatment, positioning empasiprubart as a safe and potentially disease-modifying therapy. By selectively inhibiting complement C2, it led to meaningful improvements in grip strength, reduced IVIg dependence, and signs of axonal preservation, validating complement activation as a key driver of disease. Empasiprubart may address a critical unmet need in MMN where no approved disease-modifying therapies currently exist. These results support empasiprubart not as an adjunct, but as a targeted, biomarker-driven therapy that could redefine MMN care. With a Phase III trial already underway, further validation in a broader population will be key to confirming its long-term efficacy and establishing a new standard of care.
Article in PDF
Jul 09, 2025
At European Academy of Neurology (EAN) 2025, data from the Phase II ARDA study (NCT05225675) provided compelling proof-of-concept evidence for empasiprubart, a novel C2 complement inhibitor, in treating multifocal motor neuropathy (MMN). MMN is a chronic, immune-mediated neuropathy characterized by asymmetric limb weakness and axonal degeneration, with complement activation via the classical and lectin pathways playing a central role in its pathogenesis. By targeting complement component C2, empasiprubart interrupts this cascade at an upstream point, offering a potentially disease-modifying approach.
The ARDA study enrolled 27 adults with definite or probable MMN who were IVIg-dependent and on stable IVIg regimens. Participants were randomized 2:1 to receive empasiprubart or placebo within two cohorts. Cohort 2 included older patients with longer disease duration and prior IVIg exposure. The primary efficacy endpoint was time to first IVIg retreatment during the Double-blind Treatment Period (DBTP), along with secondary endpoints including grip strength, Patient Global Impression of Change (PGIC), and serum neurofilament light chain (NfL chain levels).
Empasiprubart demonstrated a favorable safety profile, with adverse events mostly mild or moderate in severity. Importantly, it significantly delayed the need for IVIg retreatment. In Cohort 1, the hazard ratio (HR for retreatment was 0.09 (95% CI: 0.02, 0.44), while in Cohort 2 it was 0.17 (95% CI: 0.02, 1.60), both favoring empasiprubart over placebo. This suggests a meaningful reduction in relapse risk and supports the potential to reduce IVIg dependence.
Patient-reported outcomes also favored empasiprubart. In Cohort 1, 56% of patients treated with empasiprubart reported being “very much” or “much improved” vs. 11% in the placebo group. In Cohort 2, 66.6% of empasiprubart-treated patients reported similar improvement vs. 22.2% with placebo. Notably, more patients on the placebo reported deterioration in their condition.
An objective functional benefit was also observed. In Cohort 1, the median change in grip strength was +11.28 kPa (Q1–Q3: 0.00–28.78) with empasiprubart, compared to only +0.89 kPa (–0.67 to 9.00) with placebo. In Cohort 2, grip strength improvement reached +19.89 kPa (3.33–38.89) vs. +0.78 kPa (–2.22 to 7.89), further demonstrating treatment-related gains in motor function. Additionally, serum NfL levels decreased in both cohorts following empasiprubart treatment, suggesting preservation of axonal integrity and reinforcing its neuroprotective mechanism of action.
KOL View
Empasiprubart, which remains in development for other conditions like delayed graft function, dermatomyositis, and chronic inflammatory demyelinating polyneuropathy, is designed to be a humanized sweeping antibody that binds specifically to C2 in a pH– and Ca2+ dependent manner. By blocking complement activity, the belief is that this therapy may reduce tissue inflammation and the adaptive immune response. Notably, the agent is engineered for a long half-life through increased affinity to FcRn at acidic pH. – Expert Opinion
Conclusion
The ARDA study marks a pivotal advance in MMN treatment, positioning empasiprubart as a safe and potentially disease-modifying therapy. By selectively inhibiting complement C2, it led to meaningful improvements in grip strength, reduced IVIg dependence, and signs of axonal preservation, validating complement activation as a key driver of disease. Empasiprubart may address a critical unmet need in MMN where no approved disease-modifying therapies currently exist. These results support empasiprubart not as an adjunct, but as a targeted, biomarker-driven therapy that could redefine MMN care. With a Phase III trial already underway, further validation in a broader population will be key to confirming its long-term efficacy and establishing a new standard of care.
