Improving Outcomes for Acanthamoeba Keratitis

Phase 3 study supports PHMB monotherapy and an empirical evidence-based delivery protocol. Cheryl Guttman Krader reports

Polyhexamethylene biguanide (PHMB) 0.08% monotherapy is equivalent to dual therapy with PHMB 0.02% + propamidine 0.1% for achieving medical cure suggest results from the phase 3 study Orphan Drug for Acanthamoeba Keratitis (ODAK).

In addition, a comparison of the results with findings from a retrospective study of Acanthamoeba keratitis (AK) therapy demonstrates that use of a detailed empirical protocol for treatment delivery improves outcomes compared to individual physician standard of care. The aim of the ODAK programme was to develop a licensed PHMB treatment for AK, said John K G Dart MD, principal investigator of the study.

“Acanthamoeba keratitis is the worst form of keratitis and often a life-changing disease. Treatment is delayed for many patients with AK due to unavailability of medication. If we had a licensed therapy, we could be [more confident] that it would be safe and more readily available,” said Dr Dart.

“Monotherapy is always preferable to dual therapy, and we hope to obtain licensing for PHMB 0.08% as monotherapy for AK on similar grounds of non-inferiority that supported the ciprofloxacin license for bacterial keratitis. The application is with the European Medicines Agency (EMA), an application will be going to the US Food and Drug Administration soon, and we hope to get an answer from the EMA next summer.”

Sponsored by the SIFI pharmaceutical company, the doubleblind phase 3 study was conducted at six European centres and randomised 135 subjects to PHMB 0.08% or PHMB 0.02% + propamidine 0.1%. Inclusion criteria required diagnostic confirmation of AK with in vivo confocal microscopy. To make the study as pragmatic as possible, the team set other eligibility criteria so the participants would be representative of a clinic population.

“Patients could be on steroids and have bacterial keratitis. We only excluded patients with active herpetic or fungal keratitis,” Dr Dart said.

The treatment protocol defined regimens for intensive and continuation therapy and included guidelines for antiinflammatory drug use, managing infection relapse, managing exacerbated inflammation, and treatment discontinuation.

The full analysis subset for the phase 3 study involved 127 patients. Medical cure at 12 months—the primary outcome—was achieved by identical proportions of patients in the monotherapy and dual therapy arms (about 87% in a covariate-adjusted analysis). In both groups, 80% of eyes achieved medical cure within 200 days.

“80% of eyes achieved medical cure within 200 days.”

There were also no differences between study groups in analyses of BCVA outcomes, corneal scarring rates, adverse events, blood chemistry values, cataract, and anti-inflammatory drug use after baseline. Median BCVA was 20/20, and BCVA was less than 20/20 in only 25% of eyes.

“These are exceptional visual outcomes that I think are replicable in clinical practice if treatment is delivered the way we described in the study,” Dr Dart said.

Comparing the medical cure and BCVA results achieved in the phase 3 study with those reported in the retrospective study in which treatment delivery was according to individual physician standard of carei, Dr Dart reported the empirical evidence-based protocol was associated with “huge improvements”. In the phase 3 study, the rate of medical cure at 12 months was 1.5-fold higher than in the retrospective study, the proportion of eyes achieving BCVA better than 20/25 was two-fold higher, and the proportion of eyes with BCVA worse than 20/60 was almost 50% lower.

Dr Dart delivered the Jones-Smolin Lecture at the AAO 2022 annual meeting in Chicago, US.

i Papa et al. British Journal of Ophthalmology, 2020; 104(4): 575–581.

John K G Dart MD is principal investigator ODAK phase 3 programme and consultant ophthalmologist, Moorfields Eye Hospital, London, UK. j.dart@ucl.ac.uk