According to a news release, Akari is targeting an Investigational New Drug application submission to the FDA in the first half of 2024
Akari Therapeutics Plc this week announced updates on progress in the pre-clinical development program for long-acting PAS-nomacopan as a potential treatment for geographic atrophy (GA) secondary to dry age-related macular degeneration (dAMD).
Rachelle Jacques, president and CEO of Akari, noted in a news release that the company has maintained its focus on the development.
“Our pre-clinical development work has been focused on engineering, evaluating and selecting the version of long-acting PAS-nomacopan that will achieve the maximum dose interval, while not sacrificing manufacturability, as well as securing our intellectual property,” Jacques said in a news release. “We have made significant development progress and I am pleased we are on track for an IND application submission next year to enable clinical trials for this potentially important treatment option for patients with geographic atrophy.”
According to the company’s news release, long-acting PAS-nomacopan is in pre-clinical development as a treatment for GA that addresses areas of significant unmet patient need including a long dose interval and reduction in the risk of choroidal neovascularization (CNV).
The company noted that PASylation (PAS) technology is a biological alternative to the chemical conjugate polyethylene glycol (PEGylation) in the development of extended half-life recombinant protein therapeutics. The dual mechanism of long-acting PAS-nomacopan inhibits both complement C5 and leukotriene B4 (LTB4). Complement overactivation is a validated target and an important aspect in the pathophysiology of GA, while LTB4 may contribute to overexpression of VEGF-A, a key driver of CNV. Increased incidence of CNV is associated with late-stage complement-only inhibitors.1
Elias Reichel, MD, professor and vice chairman of the Department of Ophthalmology at Tufts University School of Medicine, pointed out in the news release that it can be a long path for patients diagnosed with chronic retinal diseases.
“Patients being treated for chronic retinal diseases face a long treatment journey and experience significant burdens from frequent, repeated intravitreal injections into the eye, including high levels of anxiety and risks of serious clinical complications like infections, which can lead to discontinuation of the treatment they need, Reichel said.
Reichel added that a longer dose interval with fewer injections into the eye is an area of significant unmet need for patients and the retinal specialists who treat them.
“Patients who have geographic atrophy also are at risk of developing an additional sight-threatening condition known as choroidal neovascularization or CNV, which presents more hurdles in the fight to preserve sigh,” Reichel pointed out. “A dual mechanism treatment that inhibits both complement C5 and LTB4 simultaneously is a promising approach to address key drivers of both geographic atrophy lesions and CNV.”
The new PAS-nomacopan versions are fully active, with binding kinetics to complement C5 equivalent to the parent drug nomacopan and earlier PAS-nomacopan versions. New versions show high expression levels in recombinant protein manufacturing.
According to the news release, development of PAS-nomacopan has progressed from lab scale to pre-GMP optimization. With these advances, Akari is on track to select the version that will advance to GMP manufacturing and non-clinical safety studies in preparation for an investigational new drug application (IND) and the start of clinical trials in GA. Importantly, the new versions of PAS-nomacopan have significantly increased hydrodynamic radii compared to previous versions, increasing the PAS-nomacopan target dosing interval beyond 3 months with the potential for only 3 or 4 intravitreal injections a year.
Intravitreal injections into the eye for the treatment of conditions like GA and choroidal neovascularization (CNV) are sources of significant anxiety, discontinuation of treatment, and clinical complications for patients.2-3 Patients report depression, impacts on relationships and daily activities, financial and physical burdens. Long-term exposure to IVIs can have clinical complications, including eye infections and inflammation. A Medicare claims review of anti-VEGF IVIs used to treat conditions like CNV found a 4% overall risk per injection of severe complications. For anti-VEGF CNV IVI treatments, up to one third of patients may discontinue or not adhere to treatment.3
An overdevelopment of blood vessels in the retina,4 CNV is a sight-threatening condition that has been associated with late-stage complement-only inhibitors. CNV starts with inflammation in the choroid, which is part of the vascular layer of the eye. The inflammation damages an epithelial layer of the retina, which leads to the release of leukotrienes, including LTB4.5,6 LTB4 can upregulate the production of VEGF-A, which is responsible for the proliferation and migration of endothelial cells that form the inner layer of blood vessels. VEGF-A is a key driver of CNV. Inhibiting the action of excess LTB4 can lead to VEGF-A overexpression is a rational strategy in the reduction of CNV risk.
In pre-clinical studies presented at ARVO 2022, an earlier version of PAS-nomacopan injected once during a 16-day treatment period was compared to an FDA-approved VEGF inhibitor for impact on neovascularization. The single dose of PAS-nomacopan significantly reduced CNV as compared to saline (p=0.022) and was as effective as multiple injections of the VEGF inhibitor (p=0.019 compared to saline). Single IVT injection of PAS-nomacopan showed a trend towards reduced leakage on Day 14 (p = 0.097).