Data supports ANX007 as the first complement therapy to preserve visual acuity, achieving statistically significant protection, but reduction in rate of geographic atrophy lesion growth did not reach statistical significance.
Annexon, Inc., announced topline results from its ARCHER Phase 2 trial of ANX007 in patients with geographic atrophy (GA), demonstrating a statistically significant, dose-dependent preservation of visual function. However, reduction in rate of geographic atrophy lesion growth did not reach statistical significance. The company plans to engage with regulatory agencies to determine optimal path forward for ANX007.
Results from the 12-month treatment period of ARCHER showed that patients treated monthly and every-other-month with ANX007 were protected against vision loss as measured by changes from baseline in the widely accepted functional endpoint of best corrected visual acuity (BCVA). Patients in the monthly treatment group showed a 72% reduction in risk of 15-letter loss (n=89, p=0.006), and patients in the every-other-month treatment group showed a 48% reduction in risk of 15-letter loss (n=92, p=0.064). Patients in the pooled treatment group showed a 59% reduction in risk of >15-letter loss (n=181, p=0.008). These data represent the first demonstration of a complement-based therapy to protect against vision loss in a prospective 12-month clinical trial and support the differentiated mechanism of action of ANX007, which is designed to target and preserve photoreceptor cells, synapses and function.
The primary endpoint of mean rate of change (slope) in GA lesion area compared to sham at 12 months did not reach statistical significance. A 6.2% reduction in lesion growth was observed in monthly treatment group (p=0.526), a 1.3% reduction was observed in the every-other-month treatment group (p-value=0.896) and a 3.7% reduction was observed in the pooled patient population (p-value=0.673). ANX007 was generally well tolerated as both a monthly and every-other-month treatment.
“The chronic, progressive nature of GA means a steady and inevitable loss of vision, which profoundly impacts the life of the millions of people with GA,” said Jeffrey S. Heier, M.D., Director of the Retina Service and Retina Research, Ophthalmic Consultants of Boston, and an investigator in ARCHER. “The ultimate goal for any physician is to preserve vision for our patients for as long as possible. The totality of the data on ANX007 from the ARCHER trial are promising, with the demonstrated preservation of functional vision in GA patients, regardless of their lesion location or size. I am encouraged with the overall profile of ANX007 and look forward to its continued development.”
GA is a disease of vision loss driven by the loss of photoreceptor cells, a type of neuron. Based on Annexon’s founding discovery, C1q, the initiator of the classical complement pathway, drives the elimination of functional synapses in disease, essentially driving the loss of photoreceptor cells and their function. Preclinical models have demonstrated that inhibition of C1q protects photoreceptor cell synapses, and importantly, photoreceptor cell function. Lesion growth is measured by fundus autofluorescence (FAF). FAF measures retinal pigment epithelial (RPE) cells under photoreceptors, not photoreceptor cells themselves or their function. While downstream complement inhibition protects the RPE on the edge of a growing lesion (demonstrated by FAF), a functional impact on photoreceptor cells has not been clearly demonstrated. Annexon’s mechanism is distinct and designed to target functional photoreceptors throughout the macula to protect synapses and function. C1q inhibition appears to have less impact on the clearance of RPE cells on the edge of the lesion, which may be driven by downstream complement pathways.
“GA is a devastating disease of aging that greatly limits a person’s ability to read, perform activities of daily living and even see the faces of their loved ones. Based on the totality of the topline data from the ARCHER trial, we believe that ANX007 has the potential to be a new and distinct treatment option for patients with GA, marking an important step toward achieving our mission of delivering game-changing therapies to patients living with complement-mediated diseases,” said Douglas Love, chief executive officer of Annexon. “Protecting against vision loss for patients with GA is the ultimate clinical goal. We are grateful to the many patients, caregivers and physicians who have enabled the development of ANX007 and are encouraged by the opportunity ANX007 may have in meaningfully enhancing their lives. Based on the ARCHER trial results, we plan to engage with regulators to determine the optimal path forward to bring ANX007 to patients as expeditiously as possible.”
ARCHER is a randomized, multi-center, double-masked, sham-controlled Phase 2 clinical trial comparing the safety and efficacy of ANX007 in patients with GA secondary to AMD. The study enrolled a total of 270 patients, stratified by GA lesion size, location and choroidal neovascularization (CNV) in the fellow eye at the time of enrollment. Patients were nearly equally split between foveal (49.4% to 57.3%) and non-foveal groups, had an average age of 80 years and were balanced between female and male. Ninety-six percent of patients enrolled were from the United States.
Patients were randomized to receive an intravitreal dose of 5mg ANX007 monthly (n=89), 5mg ANX007 every other month (n=92) or sham monthly or every other month (pooled n=89) for a treatment period of 12 months, followed by a six-month off-treatment period.
The primary outcome measure of the study was the rate of change in GA lesion growth (slope) from baseline as measured by fundus autofluorescence (FAF) through 12 months for the study eye. The study included multiple pre-specified visual function measures to assess the effects of ANX007 on vision:
ANX007 represents the first complement therapeutic candidate to preserve visual acuity, demonstrating a statistically significant reduction of vision loss in both foveal and non-foveal patients at 12 months.
When assessing the BCVA treatment effect by lesion location, the combined analysis, stratified by foveal and non-foveal patients, demonstrated an overall statistically significant difference between ANX007 and sham:
When assessing the BCVA treatment effect by retinal health, the combined analysis, stratified by healthier and less healthy retina, demonstrated an overall statistically significant difference between ANX007 and sham. This effect supports the potential use as an early treatment for GA:
Low-luminance visual acuity: LLVA is BCVA assessed in low light conditions. ANX007 demonstrated a non-significant trend in slowing the progression of LLVA loss in the monthly, every-other-month and pooled treatment groups, which Annexon believes supports the ANX007 mechanism of action:
Low-luminance visual deficit: LLVD is the difference between BCVA and LLVA. When assessing the LLVD treatment effect by baseline visual acuity, the combined analysis stratified by baseline vision demonstrated an overall statistically significant difference between ANX007 and sham:
Treatment with ANX007 was generally well-tolerated in the 181 GA patients treated either monthly or every other month. There was a limited incidence of choroidal neovascularization (CNV) conversion across all three groups, with 3.4% in the sham group vs. 4.5% and 4.3% in the ANX007 monthly and every-other-month groups, respectively. Among the patients treated with ANX007, three serious adverse events (SAEs) of endophthalmitis were observed, which were determined to be related to intravitreal injection procedure and not related to treatment. There were three SAEs of intraocular inflammation, suspected of being treatment-related, which were not associated with retinal vasculitis. One SAE of retinal artery occlusion was reported, suspected of being treatment-related, which was also not associated with retinal vasculitis.