Positive topline results from pivotal phase III trial for first in class C1Q blocking antibody ANX 005 in Guillain- Barre Syndrome

The Phase III trial met its primary endpoint, with ANX 005 30 mg/kg achieving a highly statistically significant 2.4-fold improvement on the GBS-disability scale (GBS-DS) at week 8 (proportional odds analysis, p = 0.0058).

ANX 005 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 (p <0.0001) and at week 8 (p="0.0351)," and a median of 28 fewer days on artificial ventilation through week 26 (p="0.0356" ). additionally, anx 005 30 mg kg demonstrated a 31-day reduction in the median time to walk independently versus placebo (p="0.0211" ) in a prespecified analysis. anx 005 30 mg kg treated patients got better sooner on each of these assessments, presenting important clinical care outcomes for patients and the healthcare community. anx 005 also provided an early reduction in the prespecified analysis of serum levels of neurofilament light chain (nfl), a biomarker of nerve damage (11.2% reduction relative to placebo between weeks 2–4, p="0.03)."

Guillain-Barré Syndrome (GBS) is a rapid and acute neurological disease with a narrow therapeutic window that results in the hospitalization of over 22,000 people annually in the U.S. and Europe. The significant and long-term disease burden associated with GBS on patients, caregivers, hospitals and payers has led to a multi-billion-dollar annual economic cost to the U.S. healthcare system. Currently, there are no approved treatments for GBS by the FDA.

The randomized, placebo-controlled Phase III trial which enrolled 241 subjects in Bangladesh and the Philippines evaluated two doses of ANX 005, 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. ANX 005 75 mg/kg outperformed placebo on multiple endpoints, however, it was not statistically significant on the primary endpoint of GBS-DS at week 8 (p = 0.5548). 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 ANX 005 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 III results with the 30 mg/kg dose resulting in one week of C1q inhibition appeared to define the optimal treatment window.

Hugh Willison, MBBS, PhD, Professor Emeritus of Neurology, University of Glasgow said, “In the first placebo-controlled pivotal study in GBS in approximately 40 years, ANX 005 demonstrated robust and immediate neuroprotection by inhibiting C1q and suppressing downstream complement components with a single dose during the critical progressive phase of the disease. By directly targeting complement-mediated inflammation, AN X005 has the potential to act early to prevent nerve damage in this acute neurological emergency. The outcomes of this study represent an important breakthrough in effectively tackling GBS and support the potential of ANX 005 to address the significant unmet need in this vulnerable patient population.”

The clinical safety and tolerability findings of ANX 005 at both doses in the Phase III 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%) 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 III study was conducted in Bangladesh and Philippines due to the high prevalence of GBS and limited access to standard of care intravenous immunoglobulin (IVIg). Based on feedback from the FDA, Annexon has initiated a real-world evidence (RWE) protocol with International Guillain-Barré Syndrome Outcomes Study (IGOS) to establish comparability between Phase III 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% of all Western IGOS patients met the entry criteria for the Annexon GBS Phase III trial and, importantly, ANX 005 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 greater than 20, ANX 005 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 (p = 0.0102).

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