RARE Daily

Annexon Reports Positive Results from Phase 3 Trial of ANX005 in Guillain-Barré Syndrome

June 4, 2024

Rare Daily Staff

Annexon reported positive topline results from its randomized placebo-controlled pivotal phase 3 trial in patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a severe disease resulting from an acute autoantibody attack on peripheral nerves that generally occurs post-infection in otherwise healthy persons following activation of C1q and the classical complement cascade. It is a rapid and acute neurological disease with a narrow therapeutic window that results in hospitalization of more than 22,000 people annually in the U.S. and Europe. The peripheral nerve damage progresses rapidly, causing acute neuromuscular paralysis, and may lead to significant morbidity, disability and mortality. Currently, there are no approved treatments for GBS in the United States.

Annexon’s phase 3 trial met its primary endpoint, with ANX005 30 mg/kg achieving a highly statistically significant 2.4-fold improvement on the GBS-disability scale (GBS-DS) at week 8. ANX005 30 mg/kg treatment also demonstrated improvements versus placebo on key secondary endpoints, including early gains in muscle strength by Medical Research Council (MRC) sum score at day 8 and at week 8, and a median of 28 fewer days on artificial ventilation through week 26. Additionally, ANX005 30 mg/kg demonstrated a 31-day reduction in the median time to walk independently versus placebo in a prespecified analysis. ANX005 30 mg/kg treated patients got better sooner on each of these assessments, presenting important clinical care outcomes for patients and the healthcare community. ANX005 also provided an early reduction in the prespecified analysis of serum levels of neurofilament light chain (NfL), a biomarker of nerve damage (11.2 percent reduction relative to placebo between weeks 2–4).

“These data represent an important moment for the GBS community and Annexon,” said Douglas Love, president and CEO of Annexon. “With the potential to be the first targeted treatment for GBS in the U.S., ANX005 demonstrated consistent improvement and functional benefits on key primary and secondary endpoints. Additionally, we observed in our phase 3 trial that early treatment with ANX005 resulted in rapid neuroprotection that stopped the advancement of disease and helped GBS patients get better sooner. These results reinforce Annexon’s founding thesis that C1q inhibition is a powerful mechanism of action to stop the progression of neuroinflammation and underscore the potential of ANX005 and our classical complement platform to treat GBS and a host of other diseases of the body, brain and eye.”

The randomized, placebo-controlled phase 3 trial enrolled 241 subjects in Bangladesh and the Philippines and evaluated two doses of ANX005, 30 mg/kg and 75 mg/kg, which both delivered rapid and complete suppression of complement activity but differed in duration of C1q inhibition. The 30 mg/kg dose suppression lasted one week and the 75 mg/kg dose suppression lasted two to three weeks. ANX005 75 mg/kg outperformed placebo on multiple endpoints, however, it was not statistically significant on the primary endpoint of GBS-DS at week 8. The two dose levels were evaluated based on findings in the earlier phase 1b proof-of-concept study, which showed efficacy in pooled analysis of both shorter and longer duration of ANX005 C1q inhibition. Because classical complement drives tissue damage in the early phase of disease, while facilitating nerve repair after acute nerve injury, the strong positive phase 3 results with the 30 mg/kg dose resulting in one week of C1q inhibition appeared to define the optimal treatment window.

The clinical safety and tolerability findings of ANX005 at both doses in the phase 3 study support a generally well-tolerated profile with no new safety signals. The majority of adverse events were mild Grade 1 to moderate Grade 2 events. The most common treatment-related adverse events were infusion related reactions (30.4 percent) that were mostly mild transient rashes. There were no autoimmune related adverse events, and no drug-related deaths or serious infections were observed.

The GBS phase 3 study was conducted in Bangladesh and Philippines due to the high prevalence of GBS and limited access to standard of care intravenous immunoglobulin. Based on feedback from the U.S. Food and Drug Administration, Annexon has initiated a real-world evidence (RWE) protocol with International Guillain-Barré Syndrome Outcomes Study (IGOS) to establish comparability between phase 3 participants and Western patients. IGOS is a global, prospective, observational, multicenter cohort study that has enrolled 2,000 patients who were followed for one to three years. Approximately 50 percent of all Western IGOS patients met the entry criteria for the Annexon GBS phase 3 trial and, importantly, ANX005 30 mg/kg achieved a robust treatment effect on GBS-DS at week 8 in patients with Western characteristics and milder GBS. In a prespecified subgroup analysis of patients with baseline MRC sum score ≥20, ANX005 30 mg/kg treated patients were three times more likely to be in a better state of health compared to placebo on GBS-DS at week 8.

RWE data and BLA submission are expected in the first half of 2025. Annexon plans to present phase 3 data at the 2024 Peripheral Nerve Society Annual Meeting on June 25, 2024.

ANX005 has been granted Fast Track and Orphan Drug designations from the FDA, and Orphan Drug designation by the European Medicines Agency.

Photo: Douglas Love, president and CEO of Annexon

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