Background/Purpose: Lupus nephritis (LN) is an autoantibody-mediated disease involving glomerular deposition of immune complexes containing pathogenic anti-C1q antibodies, leading to C1q binding and activation of the classical complement pathway. ANX009 is a subcutaneously administered antigen-binding fragment of a humanized antibody that inhibits C1q interaction with immune complexes. Plasma measures of classical complement activation (C4d/C4 ratio) strongly correlate with disease activity in LN patients, suggesting that these patients may benefit from anti-C1q therapy.

Methods: LN-01 is an ongoing, single-arm, phase 1b study evaluating safety and tolerability of ANX009 in patients (N≤8) with class III or IV LN and a diagnosis of systemic lupus erythematosus according to EULAR/ACR 2019 criteria. Patients also exhibited high plasma C4d/C4 ratio and urine protein creatinine ratio >0.5 g/g at study enrollment. Patients undergo an 8-week screening period, a 3-week treatment period, and an 11-week off-treatment follow-up period. Primary and secondary endpoints are the percentage of patients with treatment-emergent adverse events (TEAEs) and change in complement biomarkers, respectively.

Results: To date, 4 patients completed treatment, one patient discontinued treatment, and screening is ongoing. Among 3/5 patients, 29 TEAEs occurred. All AEs were non-serious, except fever of unknown diagnosis in one patient. Injection site reactions arose in 3/5 patients—mild, mostly erythema. C4d/C4 ratio decreased with treatment in all 5 patients and returned to baseline after treatment cessation. Inhibition of C1q also resulted in normalization of downstream complement markers of activation and consumption for the entire pathway.

Conclusion: In this interim analysis, ANX009 administered subcutaneously was well tolerated and demonstrated C1q target engagement and complement inhibition in 5/5 patients. Normalization of all downstream activation markers and primary components, notably C3 and C5b-9, suggests the classical pathway, not the alternative pathway, is a key driver of complement activation in these LN patients. These interim results support further study of anti-C1q therapy in LN patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/results-of-single-arm-phase-1b-study-of-anti-c1q-treatment-anx009-show-that-the-classical-pathway-is-a-key-driver-of-complement-activation-and-consumption-in-patients-with-active-lupus-nephritis/