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

Purpose To evaluate the safety and preliminary efficacy of topical rVA576, a dual inhibitor of complement component 5 (C5) and leukotriene B4 (LTB4), in patients with recalcitrant atopic keratoconjunctivitis (AKC) in the open label phase 1 TRACKER clinical trial. Methods Three patients diagnosed with moderate or severe AKC who had been on maximal topical treatment (antihistamines and ciclosporin) for at least three months prior to entry, and showed persistent symptoms and signs of inflammation, were recruited into the trial. Patients received rVA576 eye drops twice a day for 8 weeks. Patients were seen at baseline and weeks 1, 2, 4, 6 and 8. Safety data was recorded and a composite sum score of symptoms and signs was obtained. This score comprised symptoms such as itching, mucous discharge and photophobia, and conjunctival and corneal signs such as hyperemia, tarsal papillae, punctate keratitis and corneal neovascularization, all rated individually from 0 to 3 for a maximum score of 33. Results Two of the three patients completed the initial open label phase of the trial. The third patient was unable to attend appointments and terminated the study early at day 14. Topical rVA576 was well tolerated with no serious adverse events reported. There was an average improvement in overall 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. Conclusions In this open label phase 1 TRACKER trial, rVA576 eye drops were well tolerated and showed a response across signs and symptoms of active inflammation. This study is exploratory but supports topical rVA576 safety and shows promising efficacy for recalcitrant AKC. A phase 2 randomised control trial is currently underway. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-01890-6.


Introduction
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 Open Access *Correspondence: s.t.sara.g@gmail.com 1 Moorfields Eye Hospital, 51 North Block, 5 Chicheley Street, London SE1 7PJ, UK Full list of author information is available at the end of the article 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.

Inclusion/exclusion criteria and follow up
This study was an open label phase 1 clinical trial of topical rVA576 eye drops in patients with moderate to severe AKC with a treatment period of 8 weeks and a further follow-up of 4 weeks beyond rVA576 therapy. It is to be followed up by a randomized, double blinded, placebocontrolled phase 2 clinical trial (ongoing at present).
Patients included were aged 18 and above who had been on maximal topical therapy for at least three months without improvement but were not receiving systemic immunotherapy. A full list of inclusion and exclusion criteria has been provided in Table 1. Topical rVA576 2.5 mg/mL eye drops were administered to both eyes twice daily for 56 days (8 weeks) with a further follow-up of 4 weeks after rVA576 treatment cessation. Patients continued on the topical medication they were using before entering the trial. Rescue medication in the form of topical steroids was allowable if considered clinically necessary and was documented.

Data acquisition and analysis
The primary trial objective was to demonstrate the safety and tolerability of rVA576 when given by topical ocular administration to patients with AKC. Tolerability of the study drug was assessed by patient diary cards. The diary cards measured the comfort profile by asking the patient to describe in one word how comfortable or not they felt immediately after the instillation of the study drug and after 1, 2, 3 and 5 min. Safety data was assessed by review of adverse event reporting.
Safety data was recorded and a composite sum score of signs and symptoms was obtained. This scoring system is described in Table 2, adapted from Akpek et al. [5]. The data comprises symptoms such as itching, mucous discharge and photophobia, and conjunctival and corneal signs such as hyperemia, tarsal papillae, punctate keratitis and corneal neovascularization, rated individually from 0 to 3 for a maximum score of 33. The score was recorded at baseline, at follow-up visits and at the end of the treatment period.
The secondary objective was to evaluate efficacy. Efficacy was assessed in the eye judged to be worst affected by the patient, or if equally affected, in the right eye.

Results
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.

Discussion
TRACKER (Topical rVA576 for TReatment of Atopic KERatoconjunctivitis) is the first clinical trial to evaluate rVA576 as a treatment for any ocular disease (first-ineye 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.