An improvement in cUHDRS was observed in more than half of all evaluable patients and was specifically seen in 75% of the evaluable population who showed excess complement activity at baseline.
Late Tuesday, Annexon Biosciences announced interim data from an ongoing Phase II clinical trial of its monoclonal antibody candidate in patients with Huntington’s disease (HD) after a 24-week treatment period.
Annexon has been a pioneer in the development and clinical evaluation of therapeutic candidates to treat complement-mediated autoimmune disorders in the neurology and ophthalmology spaces. The drug in question here is ANX005, which is in development for a range of complement-mediated disorders, including HD.
ANX005 has been undergoing evaluation in a Phase II multi-center, open-label trial of 28 patients since May 2021. It was administered intravenously for a 24-week (six-month) dosing period in patients with, or at risk for, early manifest HD. Of the 28 patients enrolled, 23 completed the 24-week treatment period. The interim analysis included safety data for all 28 participants and efficacy data as measured by the cUHDRS (Composite Unified Huntington’s Disease Rating Scale) in all 23 evaluable patients. The analysis also included pharmacokinetics and pharmacodynamics data for the first 13 patients and NfL levels for the first 16 patients who completed the 24-week treatment period.
HD is a rare, inherited neurodegenerative disorder that causes progressive degeneration of nerve cells in the brain, impacting movement, cognitive functions and emotions. The damage is caused by overactivation of the classical complement pathway. C1q, the initiator of the classical pathway, is an otherwise neuroprotective molecule and is responsible for controlling immune pathways against pathogens. The same C1q in HD, however, causes the release of abnormally excessive pro-inflammatory cytokines, driving a destructive immune response that leads to synapse loss and neurodegeneration. ANX005 is designed to disrupt the disease course, inhibiting the destructive complement activation by blocking C1q and the entire classical complement pathway.
The interim results showed that treatment with ANX005 was generally well-tolerated, with full target engagement of C1q in both serum and cerebrospinal fluid (CSF) observed in evaluable patients through the 24-week treatment period. These patients maintained clinical function, as per the cUHDRS scale, relative to baseline. An improvement in cUHDRS was observed in more than half of all evaluable patients and was specifically seen in 75% of the evaluable population who showed excess complement activity at baseline. NfL levels remained consistent throughout the treatment period and were comparable to NfL levels described in published natural history data for HD patients.
“People with HD face a devastating condition, with no cure or approved disease-modifying treatments available. I believe the interim data from this open-label trial of ANX005 are encouraging, showing complete CSF target engagement and that ANX005 has been generally well-tolerated, with no concern regarding the NfL levels seen in this early readout,” said Edward Wild, FRCP, Ph.D., consultant neurologist at NHNN Queen Square and associate director of the UCL Huntington’s Disease Centre.
The most common adverse events reported were first dose-associated infusion-related reactions, including transient skin rash.
Wild added, “The apparent stabilization of cUHDRS observed relative to normal disease progression, together with the potential improvement seen in patients with elevated baseline C4a, supports the hypothesis that protecting synapses via C1q inhibition could produce meaningful functional benefit in HD, and justifies the continued development of ANX005 for this indication.”
