Akari Therapeutics Announces Expanded Ophthalmology Program Based on Positive Emerging Data on LTB4-C5 Dual Action in Surface and Back of the Eye Diseases
- In an experimental back of the eye, autoimmune uveitis (EAU) model to be reported in a poster presentation at ARVO 2019, nomacopan (Coversin) and its long acting variants administered intravitreally, reported:
○ Significant improvement in clinical scoring versus control
○ Co-localization of LTB4 and C5a receptors in retinal inflammatory cells seen for the first time
○ Significant downregulation of pro-inflammatory T-helper 17 cells and the inflammatory cytokine IL-17
○ Efficacy of LTB4 and C5 inhibition, supporting its potential as a novel, non-steroidal therapy across a range of severe ‘back-of-eye’ diseases
- In a “first in eye” Phase I/II study in atopic keratoconjunctivitis (AKC) initial surface of the eye data from the first two patients, treated topically, nomacopan (Coversin) demonstrated:
○ No serious drug related adverse events and good tolerability
○ Rapid improvement in mean comfort and composite efficacy endpoint scores compared to baseline on cyclosporin
○ In allergic conjunctivitis, an eye surface disease, elevated levels of LTB4 were observed
“This positive initial data from our ophthalmology program supports the potential efficacy of LTB4 and C5 inhibition in eye surface and back-of-the-eye diseases. Nomacopan as a dual action inhibitor of LTB4 and C5 has the potential to be a novel eye therapy in multiple ophthalmic indications,” said
Poster Presentation at ARVO 2019
Title: Targeting the leukotriene B4 pathway and/or complement C5 via dual-functional recombinant coversin (nomacopan) in Experimental Autoimmune Uveitis (EAU)
In a poster to be presented at the
Uveitis is an inflammation of the uvea, the pigmented part of the eye, which is caused by infection, autoimmunity, trauma, and certain drugs or is secondary to other diseases. The prevalence of uveitis is between 17 and 61 per 100,000 of the population and autoimmune uveitis accounts for approximately 60% of all cases. It is considered to be the major cause of preventable blindness in the world.
In this experimental (EAU) model, long-acting variants of nomacopan administered intravitreally demonstrated significant improvement in clinical scoring versus control. This improvement persisted until the end of the experiment (four days after the last intravitreal injection) and was approximately equivalent to that of intravitreally injected dexamethasone, a potent corticosteroid. The long acting variants of nomacopan are PASylated (using a technology licensed from XL-protein) and have the potential to have longer residence time in the back of the eye to provide the extended treatment time required for intravitreal injection.
Using confocal microscopy, C5a as well as LTB4 (BLT1) receptors were reported in mouse retinal inflammatory cells for the first time. In some cases these were co-located on the same cell types. Long-acting intravitreal nomacopan, which inhibits both LTB4 and C5, demonstrated significant downregulation of T-helper 17 cells and IL-17A. T-helper 17 is an important inflammatory cell associated with the release of inflammatory cytokines, in particular IL-17, and is related to the progression of uveitis and other back of the eye diseases.
Importantly, topical administration of nomacopan also demonstrated mitigation of retinal disease as determined by clinical scoring, and this initial signal will be investigated further given the potential patient benefits.
These preclinical results highlight an opportunity to develop nomacopan variants for intravitreal and topical use in uveitis and other posterior inflammatory eye diseases such as AMD and diabetic retinopathy. The novel dual inhibitory mechanism of action may provide an alternative to corticosteroids, the current standard of care for uveitis and avoid the adverse side effects that limit their usefulness. Akari is now planning to evaluate the role of topical and injected nomacopan in proliferative retinal diseases.
A copy of the poster will be made available on the Company’s website at www.akaritx.com following the presentation.
Phase I/II Clinical Trial in Patients with Atopic Keratoconjunctivitis (AKC)
(AKC) is a serious orphan inflammatory disease of the eye surface which, if inadequately treated, may lead to scarring of the cornea and loss of vision. In at least 70% of cases it is associated with severe dry eye disease (DED) which may lead to further corneal damage and chronic discomfort. Current treatment, if associated with DED, includes topical immunosuppressants including cyclosporin A or lifitegrast, but in many cases systemic immunosuppression becomes necessary. Furthermore, 15% to 30% of patients experience post-instillation stinging and burning which may lead to poor compliance.*
The ongoing open label Phase I/II clinical trial of nomacopan in patients with moderate to severe AKC is enrolling patients at
Encouraging interim data from the first two patients in Part A showed no serious drug related adverse events and the patients also reported that eye drops were well tolerated post installation, which may reflect the iso-osmolarity and neutral pH of the formulation.
The two patients demonstrated improvements in the primary efficacy endpoint, a composite of 11 symptoms and signs with a >35% improvement in composite efficacy score at day 14 of treatment compared to baseline treatment on maximal cyclosporin. In the first patient, who continues in the study, a change of the primary efficacy endpoint toward baseline values was observed at day 42 and is being assessed.
In both patients, there was a marked therapeutic improvement in symptom discomfort from a mean of 2.5 at baseline on cyclosporin to 0.25 by Day 14 (where 0 is no discomfort and 3 is intolerable discomfort).
Ex-vivo study in allergic conjunctivitis patients
Severe allergic conjunctivitis and severe AKC are both associated with dry eye. Preclinical and ex-vivo studies commissioned by Akari at the
*Refs: Holland E J et al. Ocul Surf. 2019
Akari is a biopharmaceutical company focused on developing inhibitors of acute and chronic inflammation, specifically for the treatment of rare and orphan diseases, in particular those where the complement (C5) or leukotriene (LTB4) systems, or both complement and leukotrienes together, play a primary role in disease progression. Akari's lead drug candidate, nomacopan (Coversin), is a C5 complement inhibitor that also independently and specifically inhibits leukotriene B4 (LTB4) activity. Nomacopan (Coversin) is currently being clinically evaluated in four indications: bullous pemphigoid (BP), atopic keratoconjunctivitis (AKC), thrombotic microangiopathy (TMA), and paroxysmal nocturnal hemoglobinuria (PNH). Akari believes that the dual action of nomacopan (Coversin) on both C5 and LTB4 may be beneficial in AKC and BP. Akari is also developing other tick derived proteins, including longer acting versions.
Cautionary Note Regarding Forward-Looking Statements
Certain statements in this press release constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control. Such risks and uncertainties for our company include, but are not limited to: needs for additional capital to fund our operations, our ability to continue as a going concern; uncertainties of cash flows and inability to meet working capital needs; an inability or delay in obtaining required regulatory approvals for nomacopan (Coversin) and any other product candidates, which may result in unexpected cost expenditures; our ability to obtain orphan drug designation in additional indications; risks inherent in drug development in general; uncertainties in obtaining successful clinical results for nomacopan (Coversin) and any other product candidates and unexpected costs that may result therefrom; difficulties enrolling patients in our clinical trials; failure to realize any value of nomacopan (Coversin) and any other product candidates developed and being developed in light of inherent risks and difficulties involved in successfully bringing product candidates to market; inability to develop new product candidates and support existing product candidates; the approval by the
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Source: Akari Therapeutics Plc