Background

ANX005 is a humanized IgG4 monoclonal antibody that binds with high affinity to the complement C1q protein and inhibits initiation of the classical complement cascade. Given by intravenous infusion, the antibody is in development to treat autoimmune and neurodegenerative disorders.

Besides its role in innate immunity, C1q has a function in neurodevelopment, where it marks synapses for pruning by glia. Aberrant activation of C1q in Alzheimer’s and related conditions leads to removal of healthy synapses and contributes to dementia and loss of function. Neutralizing C1q with ANX005 aims to limit complement-mediated neurodegeneration and preserve synapses.

In preclinical work, ANX-M1, the murine precursor of ANX005, inhibited the classical complement cascade in vitro with an IC50 of approximately 2.5 nM, and inhibited complement activation in blood in vivo. In rats and monkeys, ANX-005 reached CSF in concentrations sufficient to bind all C1q there. Weekly intravenous administration for one month was well tolerated in rats and monkeys. No treatment-related adverse findings were observed up to 200 mg/kg, a dose 200-fold higher than the Phase 1 starting dose in healthy volunteers (Lansita et al., 2017).

In preclinical disease models, the antibody preserved synapse function in models of Aβ and tau induced neurodegeneration, and traumatic brain injury (Hong et al., 2016; Dejanovic et al., 2018; Holden, 2021). No preclinical work is published on ALS, but complement activation has long been implicated in both peripheral and central nerve damage in this disease (e.g., see Sta et al., 2011; Bahia El Idrissi et al. 2016).

Findings

Since the start of Phase 1 in December 2016, ANX005 has accrued safety data in about 200 patients spanning the four indications of Guillain-Barré Syndrome (GBS), Huntington's disease, autoimmune hemolytic anemia, and ALS. According to the company’s website, the antibody was safe and generally well-tolerated across healthy adults and these patient populations, with some treated for up to one year. The most common adverse events were infusion-related reactions to the first dose, headache, extremity pain, and rash. There was one serious event of a lupus-like autoimmune response. There were no drug related deaths and no serious infections (March 2023 presentation slides #11-13).

The ALS trial began in January 2021. Treatment in an open-label Phase 2 in 24 people was initially set for three months, then extended to six months. Participants are to receive two induction doses of intravenous ANX005 in the first week, then maintenance doses every two weeks. To enroll, patients must be vaccinated against certain bacterial pathogens, and test negative for autoimmune antinuclear antibodies. The primary outcomes are safety, pharmacokinetics, and concentration of free C1q in blood. Other endpoints include plasma neurofilament light concentration, recordings of muscle activity, and clinical evaluation with the ALS Functional Rating Scale-Revised. The main part of the study is slated to finish in October 2023.

A January 8, 2023 investor update disclosed interim data on eight patients who completed 12 weeks of treatment. It reported a trend toward reduction in plasma NfL during the treatment period, with a rebound after three months off treatment. Two patients who completed 24 weeks of treatment stayed stable on the ALSFRS-R, while those who came off drug at 12 weeks declined in the following months (press release).

ANX005 is being evaluated in Huntington’s disease; the company reported clinical stabilization after six months of biweekly, open-label doses in 23 patients (Jun 2022 news). Participants also had reduced CSF C1q, and YKL-40, a marker of neuroinflammation, at the end of treatment.

A pivotal Phase 3 is ongoing for the lead indication of GBS, an acute autoimmune neuropathy involving aberrant C1q activation. In Phase 1, 14 Danish and Bangladeshi patients had received a single dose of 75 mg/kg ANX005 along with intravenous immunoglobulin, the standard of care for GBS. In this open-label study, all patients reportedly improved, and baseline neurofilament light concentrations in blood correlated with response to treatment (Harbo et al., 2022). In the ongoing Phase 3, 216 patients in Bangladesh and the Philippines are receiving a single administration of 30 or 75 mg/kg ANX005 alone, or placebo, with a six-month follow-up. Data is expected in 2024.

For details on ANX005 trials, see clinicaltrials.gov.