Dual inhibition of complement component 5 and leukotriene B4 by topical rVA576 in atopic keratoconjunctivis: TRACKER phase 1 clinical trial results

The recombinant protein rVA576 (commercially known as Nomacopan; Akari Therapeutics, New York, USA) is derived from a protein discovered in the saliva of the Ornithodoros moubata tick, also known as OMCI [1], where it counteracts the host inflammatory response and allows the parasite to obtain repeated blood meals. For this reason, the molecule needs to be well-tolerated and needs to maintain its inhibitory effect in the host repeatedly exposed to the same molecule. Nomacopan binds to the complement C5 molecule, thereby interfering with the interaction between C5 and the C5 convertases and thus preventing its cleavage to C5a and C5b. This generates a total blockade of the terminal complement system and prevents the formation of the membrane attack complex (MAC) [1]. Nomacopan has a second independent action: it binds and inactivates leukotriene B4 (LTB4), a potent white blood cell chemotactant, at a separate, internalised binding site. This is a high-affinity binding that outcompetes the natural receptors, BLT1 and BLT2 and results in an effectively irreversibly bound complex. Both C5 and leukotriene B4 have been implicated in ocular surface inflammation [2, 3].

Atopic keratoconjunctivitis (AKC) is a severe chronic allergic eye disease that primarily affects the adult population. Compared to other forms of allergy, AKC is characterised by a more chronic and insidious course, with recurrent episodes of inflammation that can lead to corneal scarring and neovascularisation, and ultimately vision loss. AKC involves mast cell activation secondary to the predominance of inflammatory mediators such as eosinophils and Th2-type cytokines [4]. Management consists of a stepladder approach of topical treatment in the first instance, including lubricants, antihistamines, immunomodulators (e.g. ciclosporin A) and intermittent short-term courses of topical steroids. However, systemic immunosuppression can become necessary in unresponsive patients or those requiring recurrent or long-term topical steroid treatment. There is a requirement for alternative topical anti-inflammatory agents as an intermediate or alternative treatment step prior to systemic therapy. This open label study presents safety and efficacy data of rVA576 as a novel topical treatment for AKC which fills this therapeutic space in the stepladder of management.

Three patients were enrolled in the study. Two of them completed 56 days (8 weeks) of treatment and one completed 14 days and then withdrew for reasons unrelated to the study treatment. The two patients who completed the study continued a further 4-week follow-up after cessation of rVA576 use. The drops were found to be comfortable and well-tolerated throughout the trial for all three patients. Post-instillation comfort was reported by patients as excellent with high levels of acceptance of eye drops, which were described as comfortable. Tolerability in ocular surface inflammatory disease is important to ensure long-term compliance of therapy. There were no serious adverse events (SAE) reported in this trial.

All patients saw a reduction in average sign and symptom scores by day seven of treatment (Figs. 1, 2, Additional file 1: Table S3 for complete scores). Improvement from baseline was maintained until the end of the treatment period (day 56) and persisted after discontinuation of treatment (day 84). There was an overall improvement in clinical score of 53% composed of an improvement in symptoms of 65% [63.64–66.67%] and signs of 40% [40–40.12%] by Day 56 (Fig. 3). By day 84 the average clinical score improvement was of 45%, composed of an improvement in symptoms of 71% and signs of 29%, again compared to baseline scores. Patient 1 received a rescue course of topical steroids (unpreserved dexamethasone 0.1% four times a day for one week, then three times a day for one week, then twice a day for one week, then once a day for one week) to both eyes at day 50 because of a flare-up of his AKC symptoms.

TRACKER (Topical rVA576 for TReatment of Atopic KERatoconjunctivitis) is the first clinical trial to evaluate rVA576 as a treatment for any ocular disease (first-in-eye study). It was administered topically to patients with recalcitrant atopic keratoconjunctivitis. Systemic rVA576 has already been studied for the treatment of non-ocular disease. Paroxysmal nocturnal haemoglobinuria (PNH) is one such disease where subcutaneous injections of rVA576 have been used with success [6]. PNH is a life threatening disease that results in complement-induced haemolysis. Treatment with rVA576 achieved significant reduction of haemolytic complement to less than 8 U Eq/ml (the lower limit of quantification) while symptoms and laboratory markers of haemolysis improved. A phase IIa open label single arm study of rVA576 in adult mild to moderate bullous pemphigoid has just been completed.

The data from this study suggests rVA576 is safe and well tolerated as an eye drop medication. In terms of efficacy, albeit in a small number of patients, the results of this first-in-eye open label clinical trial of topical rVA576 showed clinically relevant reduction across signs and symptoms of active inflammation in a group of patients with recalcitrant disease. It is therefore a promising new topical treatment for atopic keratoconjunctivitis filling a stepladder space of clinical need. Limitations of this trial include a small number of participants and lack of placebo comparison. However, part 2 of the TRACKER clinical trial is underway with a control arm to the study.

Overall the results of this first-in-eye open label trial are novel and important, showing a potentially relevant role for rVA576 eye drops in the treatment of atopic keratoconjunctivitis. This work also highlights the need for further investigation of the role of complement in inflammatory ocular surface disease.