ANX005 Showing Potential for Early Huntington’s in Phase 2 Trial

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by Patricia Inacio PhD |

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Annexon’s investigational therapy ANX005 is showing tolerability and a potential to treat people in the earlier stages of Huntington’s disease or at genetic risk of the disorder, according to interim data from an ongoing Phase 2 trial.

ANX005, an antibody designed to inhibit the activation of the complement cascade — a key pathway involved in early Huntington’s, was well tolerated across a six-month dosing period.

Data also showed that ANX005 led to improvements in several clinical outcomes, particularly among patients with excessive complement activity. It had full target engagement in both the blood and cerebrospinal fluid (CSF, the fluid surrounding the brain and spinal cord).

The Phase 2 trial is underway in the U.S. and complete results are expected by late June. If findings are positive, Annexon will considerate moving ANX005 into a larger, Phase 3 trial in Huntington’s patients.

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“We are quite encouraged by the interim data generated with ANX005 in HD [Huntington’s disease]. 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,” Douglas Love, president and chief executive officer of Annexon, said in a press release.

ANX005 is a monoclonal antibody to specifically block C1q, a molecule that regulates the complement cascade — an important component of the immune system that functions primarily as a first-line defense against infections.

Abnormal activation of the C1q protein plays a key role in neurodegeneration by causing the loss of synapses —  the junction between two nerve cells that allows them to communicate — and chronic neuroinflammation, eventually killing nerve cells. ANX005 aims to halt complement system activation to prevent synaptic loss in several neurodegenerative diseases, including Huntington’s.

The open-label Phase 2 ANX005-HD-01 study (NCT04514367), which dosed its first patient in November 2020, is evaluating the safety, tolerability, pharmacokinetics (the movement of a medicine into, through, and out of the body) and pharmacodynamics (the effects of a compound on the body) of ANX005, delivered intravenously (into-the-vein), in 28 adults either with early Huntington’s or at risk of the disease. After the treatment period of 24 weeks (roughly six months) patients will be followed for an additional three months.

Efficacy measures include changes at six months in the mean composite unified Huntington’s disease rating scale (cUHDRS) relative to scores at the study’s start (baseline). The cUHDRS is a composite score that takes into account two tests of cognition, a measure of motor function, and a test of functional capacity (a person’s ability to function independently and successfully day-to-day).

Alterations in neurofilament light chain (NfL) levels in the blood and CSF and additional complement biomarkers, specifically the complement component C4a (C4a), are also analyzed.

NfL is a protein proposed as a biomarker of nerve cell damage in people with Huntington’s and other neurodegenerative disorders. C4a is released once the complement pathway is activated, and has been shown to correlate with disease progression and multiple clinical endpoints in Huntington’s.

By the cut-off date of Dec. 14, 2021, 23 patients who had completed the 24-week treatment period were evaluated for changes in cUHDRS.

While previous natural history studies showed that Huntington’s patients typically experience a decline of 0.5 points in cUHDRS over six months, interim trial results showed no decline in clinical function in these treated patients.

A majority (56%) were reported to show improvements in cUHDRS and several of its subdomains over the six-month treatment period. Gains here were particularly notable in patients with abnormally high C4a activity at baseline, with 75% of them showing improvements as assessed by the cUHDRS over the six months, compared to 36% of patients with low C4a activity.

“Elevated C4a is an objective measurement of excess complement activity in CSF that has been found to correlate with disease progression and multiple clinical endpoints in HD,” Annexon reported in its release. “These findings suggest that patients with excess complement activity may be more likely to respond to anti-C1q therapy in future clinical trials,” including the proposed Phase 3 trial.

These findings “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,” Love said.

NfL levels were measured in 16 patients after the treatment period. The analysis found generally stable NfL levels in the blood and CSF, with levels comparable to those described in previous natural history studies of Huntington’s patients.

Since the earlier studies showed that NfL changes occur late in slowly progressive neurodegenerative diseases like Huntington’s, the findings support the need for longer treatment periods — beyond six-months — to detected changes. Annexon will continue to monitor NfL levels in patients over its planned three months of follow-up.

Safety data from all patients obtained by the cut-off date of Oct. 17, 2021, found ANX005 to be generally well-tolerated, with infusion-related reactions after the first dose, including a transient skin rash, the most common side effect.

Five patients stopped ANX005, with three of them due to a therapy-related adverse events. Two patients experienced a treatment-related serious adverse event: one case of idiopathic pneumonitis, inflammation of the lungs of immediate unknown cause, which stabilized after the therapy was discontinued. The other was a case of systemic lupus erythematosus, which resolved after treatment discontinuation. No cases of serious infection and no deaths were reported.

Data from 13 patients showed that ANX005 achieved full target engagement of C1q in both blood and CSF.

“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, PhD, professor of neurology at the Neurodegenerative Diseases UCL Queen Square Institute of Neurology in London, and an associate director of 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,” he added.