Annexon Biosciences Inc.’s handsome $250 million IPO this summer verified the mounting interest in its two front-running C1q inhibitors: ANX-005, which has turned up promising phase Ib data in Guillain-Barre syndrome (GBS), with a phase II/III effort planned for next year, and ANX-007, due to enter a phase II experiment in geographic atrophy (GA) during 2021 as well.
The South San Francisco-based firm sold about 14.7 million shares at $17 each. Though the stock didn’t go gangbusters immediately, by mid-August the price (NASDAQ:ANNX) had reached upward of $28. The trend has since moderated somewhat but shares stayed well above the IPO level.
C1q sits at the top of the classical complement pathway. When functioning normally, it clears pathogens, damaged cells, and unwanted cellular components. In the brain, it helps to carve neuronal pathways during development by weeding out weaker synapses, shifting them away from neurons to reinforce stronger ones so that appropriate neuronal connections can form. Aberrant activation of C1q, though, means pretty much the opposite: tissue destruction and disease.
Annexon is focused on two processes where C1q goes awry. In antibody-mediated autoimmune disease, C1q amplifies the activity of self-reactive antibodies to cause tissue damage. In neurodegenerative disorders, C1q drives the loss of synapses in the central nervous system, leading to progressive neuronal damage. Classical complement components are linked to neurodegeneration in the brain as well as the eye, the company notes, and blocking C1q is believed to leave the other complement pathways (lectin, alternative) intact for normal immune function.
GBS is caused by pathogenic antibody binding to peripheral nerves, which flips the switch on the classical complement pathway, sometimes causing acute paralytic neuropathy that can mean permanent disability or death. Top-line data from Annexon’s trial are expected in the first half of 2023. Lately, GBS has shared the spotlight with COVID-19. A paper in the European Journal of Neurology cited “published cases of GBS associated with COVID-19 [that] report a sensorimotor, predominantly demyelinating GBS with a typical clinical presentation,” observing that the features and disease course “seem similar to those observed in GBS related to other etiologies,” while adding that the “results should be interpreted with caution since only 18 cases have been heterogeneously reported so far.”
According to the NIH, in GBS “unexplained sensations often occur first, such as tingling in the feet or hands, or even pain (especially in children), often starting in the legs or back. Children will also show symptoms with difficulty walking and may refuse to walk. These sensations tend to disappear before the major, longer-term symptoms appear.” As problematic as those are, about 70% of people with GBS eventually recover, the NIH says. “With careful intensive care and successful treatment of infection, autonomic dysfunction and other medical complications, even those individuals with respiratory failure usually survive.” But that leaves a significant number who don’t.
GA, targeted by Annexon’s ANX-007, appears in some patients with age-related macular degeneration (AMD). Certain cells waste away in certain regions of the retina, resulting in blind spots; the affected areas may resemble a map to the physician, hence GA’s name. The disease can develop in one or both eyes, and a patient with GA in one eye is more likely to develop it in the other, according to the Brightfocus Foundation, a nonprofit that backs scientific research. Patients may manifest GA – which strikes about 1 million people in the U.S. – before, during, or after they are diagnosed with wet AMD. In phase Ib glaucoma study, ANX-007 inhibited C1q in the eye.
Annexon is hardly alone in GA. Waltham, Mass.-based Apellis Pharmaceuticals Inc., in July said it has completed enrollment in two phase III trials called Derby and Oaks, testing intravitreal pegcetacoplan, a C3 therapy also known as APL-2, in a combined total of 1,259 patients. Although the company has more in the pipeline, “interestingly, based on investor inbounds, our sense is that focus is shifting” to the GA studies, from which results are expected in the third quarter of 2021, J.P. Morgan analyst Anupam Rama wrote in an August 25 report.
Lineage Cell Therapeutics, of Carlsbad, Calif., also had news in GA this summer. The company said restoration of retinal tissue was observed in a patient with the condition who was enrolled in a phase I/IIa study with lead candidate OpRegen, a retinal pigment epithelium cell transplant therapy for dry AMD. Wainwright analyst Joseph Pantginis called the finding “unprecedented, suggesting for the first time that OpRegen could not only halt the progression of the disease but it could replace or rescue retinal cells.” GA can surface in people with wet or dry AMD.
Big pharma is among the others to pursue GA, though not every bid has not gone especially well. Basel, Switzerland-based Roche Holding AG terminated a phase III study called Spectri with lampalizumab because the complement factor D inhibitor missed its primary endpoint. Another phase III experiment, called Chroma, also fizzled.
Cowen analyst Phil Nadeau likes Annexon, pointing in an August 18 report to ANX-007’s unique ability to knock down multiple mediators of complement-induced damage while preserving the destruction of pathogens by the alternative and lectin pathways. He pegged peak sales at potentially more than $900 million in peak sales. Nadeau foresaw good things for ANX-005 in GBS, too, saying his firm’s consultants are optimistic based on early data. He projected a launch in 2025, with sales ramping to $775 million at maximum.