Annexon Calls Interim Huntington’s Data Promising, but Stock Falls as Three Patients Have Drug-Related Adverse Events

Annexon reported what it characterized as “promising” interim data from its ongoing, open-label phase 2 clinical trial of ANX005 in patients with Huntington’s disease who completed the 24-week treatment period, but its stock fell more than 35 percent as five of 28 patients discontinued treatment, three of whom did so due to drug-related adverse events.

Photo: Douglas Love, president and CEO of Annexon

Huntington’s disease (HD) is a fatal, progressive movement disorder involving the activation of the classical complement pathway. C1q, the initiator of the classical pathway, is recognized as a major driver of a destructive immune response that leads to synapse loss and neurodegeneration. ANX005 is designed to disrupt the disease course, stopping the start of damaging complement activation by blocking C1q and the entire classical complement pathway.

Interim data from the ongoing phase 2 trial show that treatment with ANX005 has been generally well-tolerated, with full target engagement of C1q in both serum and cerebrospinal fluid (CSF) observed in evaluable patients through the dosing period. Evaluable patients maintained clinical function, as measured by changes in mean Composite Unified Huntington’s Disease Rating Scale (cUHDRS), relative to baseline after six months of treatment, and improvement in cUHDRS was observed in more than half of all evaluable patients and in 75 percent of evaluable patients who showed excess complement activity at baseline.

Neurofilament light protein (NfL) levels observed after six months of treatment remained generally consistent and were comparable to NfL levels described in published natural history data for HD patients. NfL levels are a biomarker in blood that has been used to predict regional atrophy in HD. The company said overall, these interim findings appear to build on the scientific hypothesis that blocking C1q protects synaptic loss and can lead to rapid functional impact on clinical outcomes in neurodegenerative diseases.

“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, consultant neurologist, NHNN Queen Square and associate director, UCL Huntington’s Disease Centre. “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.”

The phase 2 multi-center, open-label trial is evaluating ANX005 administered intravenously for a 24-week (six-month) dosing period in patients with, or at risk for, early manifest HD. The study enrolled a total of 28 patients in May of 2021, and 23 patients completed the 24-week treatment period. The interim data reported today include safety data for all 28 patients enrolled, efficacy data as measured by UHDRS in all 23 evaluable patients, pharmacokinetics (PK) and pharmacodynamics (PD) data for the first 13 patients, and NfL for the first 16 patients who completed the 24-week treatment period based on cutoff dates required to obtain data for this interim analysis.

ANX005 has been generally well-tolerated in the study. As of the data cutoff date of October 17, 2021, the most common adverse events (AEs) reported were first dose-associated infusion-related reactions, including transient skin rash, consistent with the experience observed in the company’s phase 1b trial of ANX005 in patients with Guillain-Barré Syndrome (GBS).

In the HD trial, five patients discontinued ANX005 treatment, three of whom discontinued due to a drug-related AE. Two patients experienced a drug-related serious adverse event, including one event of systemic lupus erythematosus (mucocutaneous), whose symptoms resolved post-study drug discontinuation, and one event of idiopathic pneumonitis, which stabilized post-study drug discontinuation. Of note, no cases of serious infection were identified, and no deaths were reported.

Interim data show that treatment with ANX005 has led to full target engagement of C1q in both serum and CSF through the dosing period in the 13 patients who were evaluable as of the cutoff date of October 17, 2021.  

“We are quite encouraged by the interim data generated with ANX005 in HD. We are particularly excited to see a heightened clinical response in patients with excess baseline complement activity, suggesting that the classical complement pathway plays a key role in the neurodegenerative disease process and that ANX005 has the potential to provide meaningful benefit to HD patients,” remarked Douglas Love, president and CEO of Annexon. “These early data in HD patients, coupled with prior proof-of-concept data in GBS, provide a growing body of evidence for the potential role of anti-C1q in treating complement mediated neurodegenerative and autoimmune diseases, and we look forward to continuing to assess the full potential of our approach in several ongoing trials in diseases of high unmet need.”

Author: Rare Daily Staff