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Periodic Report Summary 2 - ODAK (Orphan Drug for Acanthamoeba Keratitis)

Project Context and Objectives:
The ODAK project is undertaking research and technology development activities on the Orphan Drug Polihexanide (PHMB) towards providing the first approved therapeutic ophthalmic treatment for Acanthamoeba keratitis (AK), a rare ocular disease. This infectious disease is caused by a free living protozoan which, in the absence of an effective therapy, can result in catastrophic consequences such as severe pain, visual loss and eye enucleation. Currently, there is no approved drug to treat this disease. The main objective of the ODAK project is to develop a safe and effective drug for the treatment of Acanthamoeba keratitis tested according to the international regulatory standards of the medicinal products. ODAK is a project that mobilises the critical mass from industrial as well as academic field. This complementary expertise is needed to develop and optimise the use of PHMB as a therapeutic approach to alleviate the severe negative impacts of AK on the health and quality of life of patients. An orphan designation for polihexanide (PHMB) (EU/3/07/498) was granted by the European Commission to SIFI for the treatment of Acanthamoeba keratitis. Soon after, SIFI received a preliminary Protocol Assistance from the European Medicines Agency (EMA) on the drug development plan of PHMB. The ODAK project design incorporates the EMA advice by including non-clinical as well as Phase I/Phase III clinical studies. The project objectives are to demonstrate experimental scientific evidence on the quality, safety and efficacy of PHMB and to prepare the basis for a Marketing Authorisation application before the end of 2017. In addition, the project intends to provide recommendations to improve clinical practices in the management of AK, in particular, through the identification of the optimal PHMB eye drops formulation, and to become the first rationale reference in providing the best therapeutic dosage regimen for Acanthamoeba keratitis. This project directly contributes to reaching the International Rare Diseases Research Consortium (IRDiRC) ambitious goal to deliver 200 new therapies for rare diseases by 2020. Although there are no agents approved for the treatment of AK, in recent years combinations of anti-amoebic agents such as biguanides and diamidines have greatly improved the treatment outcome of this rare ocular disease. However, even if these drugs have shown some efficacy in the treatment regimens, the concentrations of the active agents are essentially based on empirical safety and efficacy data.
Project Results:
The work programme has seven Work Packages (WPs) designed to efficiently address the project objectives through non-clinical and clinical studies advancing the state of the art. WPs 1-4 describe research and technology development. WP5 collates regulatory information whereas WPs 6-7 refer to Management, Engagement and Dissemination activities.
WP1- Pharmaceutical Technology, Pre-formulation studies and validation of analytical methods are completed. This information has been utilised for sample preparation and batch release of PHMB for the investigative non-clinical studies.
WP2 has completed a range of non-clinical studies including in vitro PHMB efficacy, in vitro cytotoxicity, and ocular tolerance and toxicity. Investigative pharmacokinetic studies are ongoing.
WP3 – Manufacturing of product, PHMB batches for non-clinical GLP studies have been produced. Batches for Phase I clinical trial have been produced. Stability batches for ICH stability studies are under production.
WP4- Clinical Studies, the retrospective evaluation of the clinical management of patients affected by AK was completed. Phase I clinical study to assess safety is underway in two EU countries. The Phase III clinical trial design comparing PHMB as monotherapy to a comparator combination therapy (PHMB and propamidine) is currently being finalised.
WP5- Regulatory Affairs, meetings with the EMA requesting protocol assistance and scientific advice for the development of PHMB eye drops for the treatment of AK have been productive in obtaining scientific advice for the design of the Phase I trial. Further scientific advice will be sought from the EMA for the Phase III trial.
WP6 – Project management. The project has regular meetings and teleconferences to ensure constant communication of project progress. An amendment to the grant agreement was completed in November 2015 to address required changes to specific tasks, deliverables and milestones.
WP7- Dissemination, has successfully engaged with a range of stakeholders including patient groups, clinicians and payers, to raising awareness of the project and disseminate available results. The project website has been developed to establish a reliable source of information relating to this rare disease, provide information on current treatments and diagnosis, and provide up to date information on the progress of the project. Facebook and twitter sites have been established and a range of international conferences have been attended and presentations on the ODAK project delivered.

Potential Impact:
The ODAK project aims to develop and license the most effective PHMB eye drop formulation. The bioavailability of PHMB to the ocular surface will be improved as well as its therapeutic index by minimizing the potential side effects of the current empirical treatment. The final selected formulation will guarantee the appropriate presence in the cornea in an amount sufficient for obtaining the desired therapeutic effect. The final result will be a safer and more effective licensed treatment which will improve patient care and reduce the need for hospitalization and surgery. This will benefit payers as well as patients and their families.
The project will raise awareness of the disease to ‘at risk’ groups (contact lens wearers), ophthalmologists and clinicians. Making contact lens wearers aware of the risk factors will reduce incidence of the disease as they will be less likely to continue high risk activities and potentially seek earlier treatment. Ophthalmologists are responsible for dispensing contact lenses and eye health care so raising awareness of the risk factors and symptoms of the disease should help reduce incidence of this infectious disease. Clinicians play an important role in identifying AK as early diagnosis has been proven to benefit treatment outcomes. Currently AK is often misdiagnosed in the early stages of the disease. All these activities will improve treatment outcomes for patients or reduce incidence of the disease.
By establishing stakeholder networks, AK sufferers will receive advice and support. The website and social media sites will connect patients and be used to share information and experiences. Currently this rare disease does not have an established patient group and obtaining information on treatments and diagnostic techniques is dependent on the clinician, hospital and country. The project unites patients, clinicians, researchers, and pharmaceutical companies utilizing the knowledge and experiences of these stakeholders to improve the management of this rare infectious disease.

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