Annexon Reports Positive Phase 2 Results in Huntington’s Disease
June 7, 2022
Annexon reported promising, final data from its open-label phase 2 clinical trial of ANX005 in patients with Huntington’s disease, a rare, fatal, progressive movement disorder that affects approximately 80,000 people globally, with about 300,000 people who are at-risk of inheriting the disease-causing gene.
Annexon’s approach to tackle Huntington’s (HD) targets C1q, the initiating molecule of the classical complement pathway, to slow or halt classical complement diseases. In neurodegenerative diseases like HD, C1q inappropriately recognizes and tags functioning synapses necessary for normal brain health by activating and amplifying complement components that cause neuroinflammation, synapse damage, and ultimately synapse loss. ANX005 is designed to fully block C1q and the entire classical complement pathway with the aim of preserving functioning synapses to slow or halt neurodegeneration.
“Huntington’s disease is a devastating condition, with no cure or approved disease-modifying treatments available,” said Edward Wild, 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.”
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 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 that 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, which 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 patients, which suggest that in slowly progressive neurodegenerative diseases like HD, synapse loss is associated with progressive functional decline, and precedes the loss of neurons and increase in NfL, a biomarker of neuronal loss.
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.
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.
“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,” said Douglas Love, president and CEO of Annexon. “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.”
Author: Rare Daily Staff
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