On June 7, Annexon, that is a clinical-stage biopharmaceutical company developing a new class of medicines for patients with classical complement-mediated autoimmune, neurodegenerative and ophthalmic disorders, today announced promising, final data from its open-label Phase 2 clinical trial of ANX005 in patients with Huntington’s disease (HD).

“Huntington’s disease is a devastating condition, with no cure or approved disease-modifying treatments available,” said Edward Wild, FRCP, Ph.D., professor of neurology at University College London, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London’s Queen Square, and associate director of UCL Huntington’s Disease Centre. “The apparent continued stabilization of clinical function over nine months is notable, and generally not expected in a progressive disease like HD. Moreover, the evidence of sustained improvement observed in patients with elevated baseline complement activity coupled with the benefit-risk profile demonstrated by ANX005 through the nine-month study underscore the potential of complement inhibition as a promising therapeutic mechanism for this difficult disease.”

ANX005 Phase 2 Target Engagement, Efficacy and Biomarker Results
The Phase 2 multi-center, open-label clinical trial evaluated ANX005 administered intravenously for a six-month dosing period in patients with, or at risk for, early manifest HD, followed by a three-month follow-up period. The primary outcome measures of the study were the safety and tolerability of ANX005; the pharmacokinetics (PK) of ANX005, as measured by serum and CSF concentrations; and pharmacodynamics (PD) effects, as measured by C1q, C4a and NfL serum and CSF concentrations. The study enrolled a total of 28 patients, of whom 23 completed both six-months of treatment and subsequent three-month follow-up period. The Phase 2 results reported today include efficacy data as measured by Composite Unified Huntington’s Disease Rating Scale (cUHDRS) and Total Functional Capacity (TFC), PK and PD data and NfL for those 23 patients, and safety data for all 28 patients enrolled.

Final data showed:

  • Treatment with ANX005 led to complete and durable target engagement of C1q in both serum and CSF throughout the treatment period and well into the follow-up period
  • Disease progression was stabilized in the overall HD patient population for the entire nine months of the study, as assessed by both cUHDRS and TFC, the two primary clinical measurement scales for HD
    • In contrast, published natural history data show that HD patients are expected to experience decline over nine months as their disease progresses
  • HD patients with higher baseline complement activity, as measured by elevated levels of C4a in CSF, demonstrated a rapid clinical benefit, as assessed by both cUHDRS and TFC, that was sustained over the entire nine months of the study
    • Improvement in cUHDRS and TFC in HD patients with higher baseline complement was evident six weeks after dosing initiation and was maintained over nine months through the on-treatment and follow-up periods
  • Plasma and CSF NfL levels remained generally consistent through the nine-month study, and were comparable to NfL levels described in published natural history data for HD patients1
    • Published data suggest that in slowly progressive neurodegenerative diseases like HD, synapse loss is associated with progressive functional decline, and precedes the loss of neurons2 and increase in NfL, a biomarker of neuronal loss3 

ANX005 Phase 2 Safety Results
ANX005 was generally well-tolerated throughout the trial, with no change in safety results from the interim findings previously reported. To date, ANX005 has been evaluated and generally well-tolerated in trials that have enrolled more than 170 patients across multiple indications.

Findings from the Phase 2 clinical trial in HD showed (n=28):

  • Transient first dose-associated infusion-related reactions were the most common adverse events (AEs) reported
  • No cases of serious infection were observed, and there were no deaths during study
  • Five patients discontinued ANX005 treatment, two of which were unrelated to treatment. Three discontinuations were determined to be potentially drug-related, and all three cases improved or resolved after ANX005 treatment was discontinued:
    • A total of two drug-related SAEs were reported: one event of systemic lupus erythematosus, which completely resolved with dosing cessation, and one event of idiopathic pneumonitis (noninfectious), which improved after dosing cessation
    • One patient experienced an AE of hemolytic anemia that remained asymptomatic and completely resolved after dosing cessation
    • All three cases were observed in patients with elevated antinuclear antibody (ANA) titers at baseline. No patient with normal ANA titers at baseline developed a SAE, experienced autoimmune-associated complications or discontinued the study

“We are very encouraged by these final data with ANX005, which provide significant insights into our mechanism of action for a chronic neurodegenerative disease where the role of classical complement has been well-characterized,” remarked Douglas Love, Esq., president and chief executive officer of Annexon. “The totality of the data, including robust and sustained C1q inhibition, clear impact on clinical outcomes, and favorable safety results observed, strongly support the potential for ANX005 to treat patients with HD. We are particularly encouraged that patients with higher complement activity may be more likely to respond to anti-C1q therapy. Based on these results, we look forward to engaging with regulatory authorities to assess the opportunity for a well-controlled trial in HD leveraging a mechanistically compelling precision medicine approach. Our mission is to deliver game-changing treatments to patients, and these data bring us an important step closer to achieving our objective.”

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