Annexon is back with final Huntington's data confirming hypothesis—and no new safety issues to declare

Investors were troubled by the dropout rate for patients in a phase 2 trial for Annexon’s Huntington’s disease med earlier this year. But now, the biotech is back with the finalized data from that study, with no new discontinuations to report and a solution to mitigate risk.

Annexon shared final data from the phase 2 open-label clinical trial for ANX005 in patients with or at risk for Huntington’s disease, a devastating inherited disorder that causes a progressive breakdown of nerve cells in the brain. The 28 patients were dosed for six months and followed for three more. The goal of the study was safety and tolerability.

The company is taking a precision medicine approach to treating the disease by targeting the C1q complex, which is the start of the complement pathway that plays a key role in triggering inflammation and the defense against pathogens as part of innate immunity. The biotech has hypothesized that by stopping the complement cascade before it starts, diseases like Huntington’s can be prevented.

Specifically, C1q inappropriately recognizes and tags functioning synapses that are critical to normal brain health and sparks a chain reaction of neuroinflammation, synapse damage and ultimately synapse loss. The hope is that ANX005 will block C1q and the complement pathway to preserve functioning synapses and slow or halt neurodegeneration.

And that’s what Annexon says has happened in the midstage trial. ANX005 demonstrated full and durable C1q target inhibition as measured by two biomarkers.

Annexon also got a look at efficacy, with results showing a stabilization of disease progression in the overall population for the entire nine months of the study. This was assessed using a common rating scale that measures disease progression in early to moderate Huntington’s. Patients with the disease typically degenerate over this length of time.

What’s most exciting for Annexon, however, is that the data seem to confirm the precision medicine approach, which has been the plan all along. Patients who had higher baseline complement activity at the start of the study experienced rapid clinical benefit during the nine-month study period, beginning about six weeks after dosing.

“Annexon has followed this hypothesis of patients responding uniquely to our approach based on their elevated classical complement levels in multiple complement-mediated autoimmune conditions, and this HD trial is the first such clinical assessment in complement-mediated neurodegenerative diseases,” President and CEO Douglas Love told Fierce Biotech in an email.

Data from the subset of patients with elevated levels of C4a, which is a measurement of complement activation, "support our hypothesis that these patients might have a stronger and more durable response to C1q inhibition than those with lower complement activity.”

That means that Annexon can take the precision medicine approach forward and target patients with higher complement activity in future trials.

About that safety data

But that was not the only lesson, Love noted. When the interim results were released back in January, investors balked at the news that five patients dropped out of the trial—two were deemed unrelated (including a case of COVID) and three were potentially linked to the treatment. The adverse events experienced by the three patients included a case of systemic lupus and idiopathic pneumonitis, a type of noninfectious pneumonia. But no serious cases of infection or death were reported.

The case of lupus resolved after treatment stopped, while the idiopathic pneumonitis event "improved" once dosing ceased, according to the final data release. The third patient experienced hemolytic anemia, which was asymptomatic and also resolved with the end of treatment. 

Overall, the safety data have not changed, and no new treatment-related events were recorded, Love stressed. And the company now has an idea of what happened with the three patients.

“There has been no change in safety profile from the interim results we released in January of this year,” he said.

Annexon found that all three patients had elevated antinuclear antibody titers at the start of the study, which is an indication of an underlying autoimmune condition. No patients who had normal levels of this biomarker discontinued the study.

The company has therefore enhanced screening for this biomarker and added some additional layers of monitoring to reduce the risk of encountering adverse events like this in the future. But patients who do have elevated antinuclear antibody titers may still have a chance to participate, as Love said the therapy can be administered with less frequent dosing to reduce risks from a chronic dosing protocol. ANX005 has now been given to more than 170 people, “with a consistently favorable benefit-risk profile,” according to Love.

Annexon plans to talk with regulators in the U.S. and the EU to discuss the design of a well-controlled confirmatory trial, according to Love. This will use the precision medicine approach, but the exact protocol will be finalized with input from the regulators. 

But first, Annexon will host a conference call to discuss the ANX005 results, starting at 8 a.m. ET today, when Love and his fellow execs will find out whether the new lessons about the safety data are enough to smooth over investor concerns.

ANX005 is also being tested in amyotrophic lateral sclerosis, Guillain Barré syndrome and warm autoimmune hemolytic anemia.