Topical rVA576 for Treatment of Atopic Keratoconjunctivitis

Recombinant rVA576 is a small protein (16.7kDa) which has two independent actions. It inhibits the activation and cleavage of complement C5 and it binds and inactivates leukotriene B4 (LTB4). It acts on the complement system by preventing the cleavage of C5 by C5 convertase into C5a and C5b and so is effective in inhibiting terminal complement activity irrespective of the activating pathway.

Atopic keratoconjunctivitis (AKC) is a type of allergic conjunctivitis which involves mast cell activation due to the predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines (Mishra et al. 2011).

Recombinant rVA576 eye drops solution is the investigational medicinal product. It is intended for ophthalmic use by topical administration to the eye.

Recombinant rVA576 is a compact small protein molecule with a lipocalin-like structure consisting of alpha helices and a beta barrel. There is a surface-active site which binds to the complement C5 molecule with a high affinity (KD 1.85 x 10-8 M) and an internalised active site which binds the small eicosinoid molecule leukotriene B4 (Hepburn et al. 2007).

• rVA576 (Drug), also known as Nomacopan: Part 1: The first 3 patients selected for the study will be treated with the active drug in open-label.
• Placebo (Other): Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial.
• rVA576 (Drug), also known as Nomacopan: Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial.

Primary outcomes

• Incidence of Ocular TEAE [56 days]: Incidence of ocular treatment-emergent adverse events (TEAE) during the treatment period which have occurred during the 56 days following randomisation.

Secondary outcomes

• Post-instillation Comfort [Day 1 to 56]: Graded on patient diary cards at the intervals Day 1-14, 15-28, 29-42 and 43-56. Eye comfort scoring: 0 - Perfectly comfortable 1. \- Slight discomfort. Some burning, itching or stinging for up to half a minute after using the eye drop, solution but the discomfort improves without treatment. 2. \- Moderate discomfort. Burning, itching or stinging lasts for 0.5 minute or longer but improves without treatment. 3. \- Severe discomfort. Burning, itching or stinging last for at least 0.5 minute and requires washing the eyes to relieve it. 4. \- Unbearable burning itching or stinging. So severe that you cannot continue treatment. The 14 day average score for each interval have been calculated for each patient (possible range of 0 to 40). Classifications were assigned using the average total score at each two week period as follows: < 10 = Comfortable/Acceptable, 10 - 19 = Moderately Uncomfortable, 20 - 29 = Very Uncomfortable, >= 30 = Severely/Unacceptably Uncomfortable.
• Visual Acuity [Day 1 to 56]: Visual acuity for the worst eye over time by Early Treatment Diabetic Retinopathy Study (ETDRS) charts comparison from Day 1 to Day 56 In ETDRS charts, zero indicates standard vision, positive values indicates poor vision, and negative values indicates good vision.
• Clinical Scores [Day 1 to 56]: Change from Day 1 in composite clinical scores at Day 14, 28, 42 and 56, for the eye judged as worst affected at each visit. Score calculated from symptom and sign sub-components. AKC/VKC: symptom sub-component consisted of itch, tearing, discomfort, discharge, and photophobia, and the sign component consisted of bulbar conjunctival hyperaemia, tarsal conjunctival papillary hypertrophy, punctate keratitis, neovascularization of cornea, cicatrizing conjunctivitis, blepharitis. SAC/PAC: symptom sub-component consisted itch, tearing, discomfort, and photophobia, and the sign sub-component consisted of upper tarsal conjunctival hyperaemia, upper bulbar conjunctival hyperaemia, chemosis, upper tarsal conjunctival papillae, blepharitis. For each sign/symptom a score of 0 - 3 is awarded (0=absence of a sign/symptom; an increase in score indicates increase in severity). These scores are summed at the end of the exam to give the composite score. Range:0 to 33 (AKC/VKC) or 27 (SAC/PAC).
• MMP-9 Positive [Day 1 to 56]: Percentage of patients with Matrix metalloprotease 9 (MMP-9) positive levels at Days 1, 28, and 56. MMP-9 is a is a nonspecific inflammatory marker. Detection was made using the Inflammadry® device. This device gives a binary (positive/negative) result.
• Tear Film Break up Time [Change from Day 1 at Day 14, 28, 42 and 56]: Change from Day 1 in Tear film break up time (TBUT) at Day 14, 28, 42 and 56. TBUT data was available for one eye only. Tear breakup time (TBUT) is a clinical test used to assess for evaporative dry eye disease. To measure TBUT, fluorescein is instilled into the patient's tear film and the patient is asked not to blink while the tear film is observed under a broad beam of cobalt blue illumination. The TBUT is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film. A TBUT under 10 seconds is considered abnormal.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Aged 18 and above
2. Diagnosis of moderate to severe AKC, VKC, or severe allergic conjunctivitis (seasonal or perennial). Defined as:

   * AKC, VKC - a composite symptom/sign score from one eye of ≥ 18 out of 33
   * Severe allergic conjunctivitis (SAC or PAC) - a composite symptom/sign score from one eye of ≥ 15 out of 27
3. Will have had received some topical therapy during the last 3 months without improvement but will not currently be receiving systemic immunotherapy. Topical therapy may be topical calcineurin inhibitors, antihistamines or corticosteroids alone or in combination. Lubricants or artificial tears will not a count as topical therapy for these purposes.
4. Will have had at least 7 days without topical ocular corticosteroids prior to entry
5. Willing to give informed consent
6. Willing to use highly effective contraceptive precautions for the duration of the study and for 90 days after the last dose of IMP
7. Willing to avoid prohibited medications for duration of study (see list of prohibited medications)

Exclusion Criteria:

1. Eye surface disease other than AKC, VKC or severe allergic conjunctivitis (SAC or PAC)
2. Contact lens use during the study
3. Complete or partial tarsorrhaphy. If such a procedure becomes necessary during the course of the trial patients may remain in the trial providing that at least 50% of the eye surface remains visible to slit lamp examination
4. Ankyloblepharon of any degree at entry to the trial
5. Known or suspected ocular malignancy
6. Active ocular infection at entry to the trial. Patients with eye surface bacterial, viral, fungal or protozoal infection may enter the trial after elimination of the infection as confirmed by eye swabs
7. Known or suspected uveitis
8. Participation in any other clinical trial within 1 month of enrolment
9. Use of any of the following prohibited medications:

   * Eculizumab
   * Any other investigational complement inhibitor whether systemic or topical (e.g. RA101495)
   * Montelukast
   * Zafirlukast
   * Pranlukast
   * Zileuton
   * Hypericum perforatum (St John's wort)
10. Corneal perforation
11. Uncontrolled glaucoma (increase in dose of glaucoma medication or surgical intervention for glaucoma within 3 months prior to entry)
12. Pregnancy (females)
13. Breast feeding (females)
14. Known allergy to ticks or severe reaction to arthropod venom (e.g. bee or wasp venom)
15. Use of topical ocular steroids within 7 days of the Screening visit
16. Failure to satisfy the PI of suitability to participate for any other reason

Participant flow

Outcome results

• Incidence of Ocular TEAE (Primary), Count of participants, Participants: rVA576, Open-label Period 3; rVA576, Double-blind Period 2; Placebo 3
• Post-instillation Comfort (Secondary), Count of participants, Participants: rVA576, Open-label Period 3; rVA576, Double-blind Period 1; Placebo 4
• Visual Acuity (Secondary), Mean, Number of ETDRS letters: rVA576, Open-label Period 56.7 +/- 49.1; rVA576, Double-blind Period 66.0 +/- 19.8; Placebo 82.7 +/- 8.778
• Clinical Scores (Secondary), Mean, score on a scale: rVA576, Open-label Period 23.2 +/- 1.53; rVA576, Double-blind Period 20.7 +/- 2.31; Placebo (AKC/VKC) 21.3 +/- 1.26; Placebo (SAC/PAC) 19.5 +/- 3.54
• MMP-9 Positive (Secondary), Count of participants, Participants: rVA576, Open-label Period 2; rVA576, Double-blind Period 2; Placebo 4
• Tear Film Break up Time (Secondary), Mean, seconds: rVA576, Open-label Period 5.0 +/- 5.57; rVA576, Double-blind Period 3.0 +/- 1.00; Placebo 3.5 +/- 1.05

Adverse events

Time frame: From day 1 to day 56.

Other adverse events by term

Limitations and caveats: 1. Early termination due to the Covid-19 pandemic. 2. Uneven distribution of patients between rVA576 and placebo in Part 2, due to incorrect storage and impossibility of manufacturing a new batch, leading to replacement by the only available randomized and labelled product and resulting in patients being allocated to placebo. With a 6 to 3 distribution of completed patients it is difficult to draw meaningful statistical conclusions or detect trends. The safety data were not compromised.

• Study Protocol (PDF, 2020-02-10)
• Statistical Analysis Plan (PDF, 2021-07-12)

• Sajjad Ahmad, Principal investigator, Moorfields Eye Hospital NHS Foundation Trust