Akari Therapeutcis (AKTX) Presesnts Positive Results from Two Preclinical Development Programs of Long-Acting PAS-Nomacopan
Akari Therapeutics, plc (Nasdaq: AKTX) presented positive results from two preclinical studies of its lead asset, investigational nomacopan, in diseases of the eye at the Association of Research in Vision and Ophthalmology (ARVO) 2022 Annual Meeting. The two presentations are available at www.investor.akaritx.com/news-and-events/presentations.
“There is significant unmet need in ophthalmology, and we are encouraged by the results of our work so far in the development of long-acting PAS-nomacopan for geographic atrophy,” said Rachelle Jacques, President and CEO of Akari Therapeutics. “This will be an area of focus and investment for Akari as we drive this program forward.”
Development of long-acting PASylated-nomacopan for treatment of GA and other retinal diseases
Geographic atrophy (GA) is a chronic progressive degeneration of the macula, which occurs during late-stage dry age-related macular degeneration (dAMD). Over time, GA can lead to permanent vision loss. It is estimated that more than 8 million people worldwide are affected by GA in AMD and currently there are no approved treatments.
Studies have indicated that while certain complement inhibitors slow the progression of GA, they may also promote choroidal neovascularisation (CNV), which can harm the macula, damage vision,1,2 and require VEGF rescue therapy.
Leukotriene B4 (LTB4) is a potent leukotactic agent that can increase retinal vascular endothelial growth factor (VEGF) a key driver of CNV. Inhibition of LTB4 may decrease the risk of CNV.3 Akari has conducted pre-clinical studies that explore the importance of the LTB4-VEGF axis and the potential role of nomacopan’s bispecific inhibition of both C5 and LTB4 in treating GA/dAMD. In a non-infectious allergic uveitis animal model, PAS-nomacopan reduced VEGF by more than 50% compared to saline control, equivalent to the inhibition caused by an anti-VEGF antibody. In addition, PAS-nomacopan was significantly more effective in reducing retinal inflammation than the anti-VEGF antibody.
One of the pre-clinical studies presented at ARVO 2022 used an industry standard model of laser-induced CNV. Intravitreal (IVT) PAS-nomacopan injected once during a 16-day treatment period was compared to a U.S. Food and Drug Administration-approved VEGF inhibitor for impact on neo-vascularization. The IVT single dose of PAS-nomacopan significantly reduced CNV (p=0.022) as compared to saline and was as effective as multiple IVT injections of the VEGF inhibitor (p=0.019.) Single IVT injection of PAS-nomacopan showed a trend towards reduced leakage on Day 14 (p = 0.097).
Currently approved therapies for retinal diseases injected directly into the vitreous cavity are typically administered monthly. Studies have shown that due to adverse effects (such as an increase in intraocular pressure [IOP]), discomfort and anxiety, IVT injection presents a heavy burden on patients. PASylation of nomacopan has the potential to make it long-lasting in the back of the eye and may provide a dosing interval that is more attractive to patients.
Akari is continuing PK and PD work to optimize PAS-nomacopan with the aim of achieving safety and efficacy in GA, and meeting patient preferences for less frequent injections
Comparison of topical nomacopan, a dual complement and LTB4 inhibitor with dexamethasone in downregulating experimental immune-mediated conjunctival disease (EIC)
Steroid-resistant allergic conjunctivitis, including atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC), is difficult to treat and can lead to corneal scarring and vision loss. Topical or systemic dexamethasone and/or cyclosporin A (CsA) is often required, however dexamethasone may be associated with adverse reactions, including increased IOP.
Topical administration of nomacopan, a therapeutic protein, was recently shown to be effective at attenuating inflammation in a model of experimental immune-mediated conjunctivitis (EIC). The aim of the study presented at ARVO 2022 was to compare the anti-inflammatory effects of nomacopan with topical dexamethasone.
IL-9 expressing mast cells and CD4+T cells are upregulated during ovalbumin (OVA)-induced EIC.
In the preclinical study presented at ARVO 2022, nomacopan preferentially downregulated conjunctival Th2 IL9 producing, Th2 and Th9 CD4+T-cells and nomacopan, dexamethasone and cyclosporinA all effectively decreased Th2 and Th9 cells in draining lymphnodes (dLNs). These findings support use of topical nomacopan to treat allergic eye diseases including VKC and AKC.
References:
Liao DS, et al. Ophthalmology. 2020 Feb;127(2)
Jaffe GJ et al. Ophthalmology. 2021 Apr;128(4)
Sasaki F et al. JCI Insight. 2018 Sep 20;3(18)
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