Therapeutics

ANX005

Tools

Back to the Top

Overview

Name: ANX005
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2)
Company: Annexon, Inc.

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.

Last Updated: 12 May 2023

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. C1q Shows Promise as Therapeutic Target to Stop Synapse Loss

Paper Citations

  1. . Effect of Combined Intravenous Immunoglobulin and Classical Complement Inhibitor ANX005 in Guillain-Barré Syndrome (S25.002). Neurology, First published May 3, 2022
  2. . Nonclinical Development of ANX005: A Humanized Anti-C1q Antibody for Treatment of Autoimmune and Neurodegenerative Diseases. Int J Toxicol. 2017 Nov/Dec;36(6):449-462. Epub 2017 Dec 4 PubMed.
  3. . Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.
  4. . Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies. Neuron. 2018 Dec 19;100(6):1322-1336.e7. Epub 2018 Nov 1 PubMed.
  5. . Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury. Science. 2021 Sep 10;373(6560):eabj2685. PubMed.
  6. . Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis. 2011 Jun;42(3):211-20. PubMed.
  7. . Complement activation at the motor end-plates in amyotrophic lateral sclerosis. J Neuroinflammation. 2016 Apr 7;13(1):72. PubMed.

External Citations

  1. presentation slides #11-13
  2. press release
  3. clinicaltrials.gov

Further Reading

Papers

  1. . Correlation of the expression level of C1q mRNA and the number of C1q-positive plaques in the Alzheimer Disease temporal cortex. analysis of C1q mrna and its protein using adjacent or nearby sections. Dement Geriatr Cogn Disord. 2001 Jul-Aug;12(4):237-42. PubMed.
  2. . Traumatic Brain Injury in Aged Mice Induces Chronic Microglia Activation, Synapse Loss, and Complement-Dependent Memory Deficits. Int J Mol Sci. 2018 Nov 26;19(12) PubMed.
  3. . The Classical Complement Pathway Mediates Microglia-Dependent Remodeling of Spinal Motor Circuits during Development and in SMA. Cell Rep. 2019 Dec 3;29(10):3087-3100.e7. PubMed.
  4. . Rise of the planet of rare anemias: An update on emerging treatment strategies. Front Med (Lausanne). 2022;9:1097426. Epub 2023 Jan 9 PubMed.
  5. . Immunoglobulin and Monoclonal Antibody Therapies in Guillain-Barré Syndrome. Neurotherapeutics. 2022 Apr;19(3):885-896. Epub 2022 Jun 1 PubMed.