With Phase III trial results looming in the second quarter of 2024, Annexon Biosciences aims to transform treatment for Guillain-Barre syndrome with its investigational antibody, ANX005. The candidate is also being trialed in Huntington disease and ALS.
This quarter, Annexon Biosciences expects to release Phase III trial results from its flagship program for Guillain-Barre syndrome. At the same time, the company is looking beyond GBS and investigating the possibility of fighting other inflammation-driven diseases with the antibody, ANX005.
Historically, GBS has been difficult to treat and understand due to a relative lack of understanding around the cause of the disease. With causative associations ranging from viral infections to surgeries, GBS is a rare autoimmune disease affecting approximately 12,000 people in the U.S. and Europe each year. It can debilitate patients by paralyzing peripheral nerves in the limbs.
There is currently no curative or long-term treatment for GBS, although intravenous immunoglobulin (IVIg, available as a generic from multiple companies) and plasmapheresis are used for acute bouts of the disease.
As a pooled antibody from human blood sources, IVIg does not lead to better outcomes in subsequent administrations for GBS after the first dose due to poor prognosis, a 2021 randomized controlled study found. The study found that compared with placebo, patients who received a second IVIg dose had more serious adverse events such as thromboembolic events.
By contrast, plasmapheresis is a procedure that uses a machine to separate plasma from blood cells, then replaces the patient’s plasma before returning the blood to the body. In doing so, plasmapheresis removes antibodies in the plasma, easing the inflammation characteristic of GBS. But the procedure requires access to a central line via catheters and carries a risk of bleeding and infections.
ANX005’s mechanism is different: it inhibits a protein complex called C1q that is part of the classical complement pathway, which is in turn a component of the innate immune system. ANX005 thus targets the classical complement pathway upstream while—unlike IVIg—leaving the lectin pathway and the alternative complement pathway intact. In other words, patients treated with ANX005 will still be able to activate C3 via the lectin pathway and the alternative complement pathway, but not the classical complement pathway. This mechanism likely leads to less immunosuppression than does IVIg, enabling the body to continue defending itself against pathogens.
In Phase Ib trials, ANX005 was administered along with IVIg in an open-label treatment arm to GBS patients. But in Phase III trials, Annexon is betting on comparing two different ANX005 doses compared to placebo. As this trial’s primary endpoints measure the GBS Disability Score at eight weeks and look at the number of patients with adverse effects for six months, there is much at stake in terms of safety and efficacy.
By targeting GBS from a new angle, ANX005 is offering hope in a therapeutic area where corticosteroids and interferon-beta 1a have failed in the past.
Beyond GBS
While Annexon continues to assemble data on its Phase III GBS trial for upcoming release, it is also moving toward testing C1q inhibition in other inflammatory diseases, and these trials provide additional information about its safety profile.
Huntington’s disease, a progressive movement disorder, is also driven by the activation of the classical complement pathway. Based on Phase IIa safety data from its Huntington’s disease trial with ANX005, ANX005’s adverse effect profile is limited to mainly infusion-site reactions that appear only upon the first dose, making it safer than IVIg for these patients.
By contrast, with various side effects that appear even with the first dose such as chills, fever, flushing, flu-like muscle pains or joint pains, fatigue, nausea, vomiting, and rash, IVIg is only used when necessary to boost immune responses due to systemic adverse effects.
With ANX005 also being investigated for use in amyotrophic lateral sclerosis (ALS), where the drugmaker aims to reduce disease progression, there are certainly exciting developments ahead for Annexon in the coming months.
Jia Jie Chen writes analyses focusing on drug development in the biotech and pharma industries for BioSpace. He has a doctorate degree in pharmacy and experiences ranging from biotech equity research to business intelligence analysis. Follow him on LinkedIn.
