Acanthamoeba spp are microbial protozoa with a life cycle consisting of two main stages: trophozoite and cyst. Whilst the former is sensitive to most available chemotherapeutic agents, the latter is a dormant form that can survive in extreme adverse environmental conditions. People wearing contact lenses are particularly concerned with this threat: they make up 85 % of AK cases and often present increased infection levels.
Yet there is hope. In 2007, SIFI (Società Industria Farmaceutica Italiana) received an orphan drug designation for PHMB, an antimicrobial polymer, to treat AK. Whilst drug development was delayed due to a cost/benefit analysis that made preclinical and clinical research activities difficult to sustain, EC funding under the ODAK (Orphan Drug for Acanthamoeba Keratitis) project has allowed the company and five other organisations from across Europe to invest in clinical trials.
What is ODAK about?
Antonino Asero: ODAK is a project led by SIFI, mobilising the critical mass of industrial and academic expertise needed to develop and optimise a therapeutic approach using PHMB to alleviate the severe negative impacts of AK on the health and quality of life of patients.
What is PHMB and how can it cure this disease?
Polyhexamethylene biguanide hydrochloride (PHMB) has been used for over 60 years as an antimicrobial agent. Commercially, it is used as a general disinfectant and antiseptic in swimming pools, in the cosmetics industry, in contact lens and eye drop solutions, in surgical and non-surgical wound dressings and in the food industry, due to its broad spectrum of antimicrobial activity.
PHMB works by binding to the cell membrane, causing complex reactions to alter the integrity of the wall. This interaction with the cytoplasmic membrane results in loss of cellular components and inhibition of respiratory enzymes. This allows entry of the PHMB, reducing wall strength and, hence, death of the organism.
In the early 1990s, Moorfields Eye Hospital and the Institute of Ophthalmology conducted a groundbreaking study on the use of PHMB to treat AK. It has since been used worldwide, off label, in the treatment of AK. Data suggest that PHMB used as monotherapy has a good risk-to-benefit ratio and is a valid candidate for a new drug licensing application.
What were the main challenges you faced in moving this project forward and how did you overcome them?
We have encountered several technical obstacles during the project development path. The most critical ones have been a constant and continuous supply of PHMB. Additionally, developing an appropriate analytical method to investigate PHMB pharmacokinetics in biological matrices was a difficult barrier to overcome.
However, negotiation with the manufacturer was the key to resolving the PHMB supply issue. The pharmacokinetics were approached through different analytical studies. A recent scientific publication has been very helpful in demonstrating the intrinsic difficulties in the PHMB molecule being detected at low doses in animal tissues.
What would you say have been the most notable results of the project so far? Did it meet your initial expectations?
After resolving the main technical issues, the positive results of preclinical work allowed us to initiate and successfully complete a Phase I clinical study with three dose levels (0.04 %, 0.06 % and 0.08 %) of PHMB ophthalmic solution.
The double-masked, placebo-controlled, parallel-group multi-centre Phase I study was performed in 90 healthy volunteers. The study concluded that 0.08 % PHMB eye drops are safe and could be investigated in a Phase III study in patients with AK. These results met our expectations of selecting a safe PHMB concentration to be used in humans.
What do you still need to achieve before the end of the project?
The Phase 3 clinical study started in August 2017 at the first clinical trial site in Moorfields Eye Hospital – London. This study will evaluate the efficacy, safety and tolerability of a 0.08 % PHMB ophthalmic solution in 130 subjects affected by AK. Additional UK sites in Manchester and Southampton are expected to follow shortly and trial sites in Italy (Milan and Venice) and Poland (Katowice) are expected to open for recruitment in September 2017. Following the completion of the study, SIFI will apply to the EMA for marketing authorisation and once granted bring the drug to market. The project is also providing guidelines and information on the prevention, diagnosis and treatment of the disease. Currently, AK is easily misdiagnosed in contact lens wearers, but early diagnosis is crucial to ensure the correct treatment. Often, topical corticosteroids are initiated following misdiagnosis of AK as herpetic keratitis. Unfortunately, this can make the symptoms worse and treatment more difficult.
If all goes according to plan, when do you expect the new treatment to be commercialised?
Overall, our ambition is to improve clinical resolution rates through early, accurate diagnosis and an effective drug regimen. We want to achieve this as quickly as possible.
The current timelines suggest that the Marketing Authorisation Application dossier will be ready for submission in Q1 2020 and commercialisation will rapidly follow once approval is received. In the short term, our approaches to providing guidelines on disease diagnosis and prevention will be completed in the coming months.
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