Community Research and Development Information Service - CORDIS

H2020

REGAIN Report Summary

Project ID: 634893
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - REGAIN (REgeneration of inner ear hair cells with GAmma-secretase INhibitors to regain hearing in patients with sensorineural hearing loss)

Reporting period: 2015-05-01 to 2016-04-30

Summary of the context and overall objectives of the project

"Hearing loss is a chronic non-communicable disease disabling over 328 million adults, and 32 million children worldwide. Untreated hearing loss currently costs Europe €213 billion each year. Hearing loss in children and youngsters hinders language learning and cognitive development, acquired hearing loss in adults impairs social integration and participation, and in the elderly, (progressive) hearing loss accelerates the progression of cognitive impairment (every 20 dB of hearing loss is associated with a loss of 7 cognitive years). The treatment of hearing loss is currently limited to the use of hearing aids or cochlear implants. These devices often perform poorly in noisy environments and can be very costly.

Damage to the hair cells in the cochlea ("sensorineural hearing loss") is a major cause of acquired hearing loss. Since hair cells do not regenerate spontaneously, the dogma has been that sensorineural hearing loss is irreversible. No pharmacological treatment for hearing loss currently exists. Studies in animal models have, however, shown that new hair cells can be generated through local treatment with a drug product and that this leads to an improvement in hearing capacity. The REGAIN (REgeneration of inner ear hair cells with GAmma-secretase INhibitors) study aims to develop a locally delivered small-molecule drug to treat hearing loss caused by the loss of sensory hair cells in the inner ear. The consortium is in the unique position to take the next crucial step in translation of these findings to the clinic, by providing clinical validation of a highly potent GSI for treatment of sensorineural hearing loss.

The objective of the REGAIN project is to demonstrate and exploit the efficacy of locally administered GS inhibitor to improve hearing through regeneration of inner ear hair cells with a lasting effect. The project will involve 1) the upscaling of GMP production of the clinical GSI candidate, 2) the generation of preclinical data on GSI dosing and local safety, 3) medical ethical clinical trial approval and 4) the demonstration of proof of concept for GSI for treatment of patients with recent onset sensorineural hearing loss. Small molecule drugs targeting the underlying biological causes of hearing loss in a safe way are expected to meet a real medical need for millions of patients, who currently rely on the limited benefits provided by hearing aids or cochlear implants.

The partners involved in REGAIN represent the current state of the art in regenerative hearing loss research in the EU. The Consortium combines expertise in hearing loss biology and gamma secretase inhibitors with preclinical and clinical drug development experts. The study is designed by and will be performed in collaboration with the leading clinicians in this field in Europe. The REGAIN project team is a unique consortium suited to advance this proof of concept to and through clinical studies. The REGAIN consortium is a collaboration between 7 highly dedicated partners, coordinated by Audion Therapeutics BV and including UCL Ear Institute, University of Tübingen, The National and Kapodistrian University of Athens, Eli Lilly, Clinquest Services and ttopstart BV (project management). This research is funded by the European Commission in the Horizon 2020 - research and innovation framework programme."

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The REGAIN project contains five Work Packages:

WP1: Chemistry, Manufacturing and Controls (CMC) data package
The aim of WP1 is to develop a dosage form for transtympanic administration. The proposed product will entail a single lot with the final drug product presentation. Before the drug substance and drug product can be manufactured under GMP conditions for human trial, pre-formulation properties of the candidate compound must be obtained. These properties will allow for assessment of synthetic and formulation parameters for both drug substance and drug product. So far, we have selected the proposed candidate compound and have obtained data on the physico-chemical properties of the candidate compound that are required for formulation, optimised the current synthetic scheme and generated drug substance for toxicology studies. We also have worked extensively on product formulation development. Hereby, we have generated a suitable target product profile that will allow local transtympanic application of the candidate compound into the middle ear on the round window membrane (RWM). Furthermore, we have initiated the development of analytical procedures to support the GMP manufacture and release of drug product for clinical trials in humans.

WP2: Non-clinical data package
WP 2 aims to generate a non-clinical data package that will enable submission of a Clinical Trial Application. Inner ear pharmacokinetic experiments with the GS inhibitor formulations in perilymph and plasma upon transtympanic dosing have determined that the candidate molecule can cross the Round Window Membrane in concentrations that exceed the requirements for local dosing. These experiments also provided initial inner ear PK and parameters to determine human dosing. These experiments were performed using rats and guinea pigs. The toxicology studies have been initiated and will characterise potential adverse effects that may occur under the conditions of the clinical trial, or the future marketed use. Given the transtympanic application of the product, ototoxicity studies are central to the safety studies. The data generated in WP2 in combination with the efficacy data of GS inhibitors that we have already generated will allow us to determine dose levels for the clinical proof of concept study.

WP3: Regulatory approval and ethics
WP3 entails the preparation and submission of the complete Investigational Medicinal Product Dossier IMPD in order to obtain regulatory approval for the clinical studies. In the first reporting period we have made a lot of progress in further developing and fine-tuning the clinical trial protocol, we have performed multiple review rounds within the consortium and obtained the expert opinion of leaders of this field.

WP4: Clinical proof of concept study
The aim of WP4 is to establish the safety, tolerability and efficacy of the locally applied GSI in clinical proof of concept study in patients presenting with recent onset sensorineural hearing loss. RWM is an attractive route to expose to the inner ear to a drug in a safe and effective manner. Drugs diffuse over the RWM to the various inner ear compartments. The product is intended to regenerate lost inner ear hair cells.

WP5: Consortium management, dissemination and exploitation
The objective of this WP is to ensure efficient and professional management of the consortium and proper dissemination of the project results. To this end, we have disseminated a press release about the grant and have installed a project website.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

REGAIN will provide the first clinical validation of a pharmaceutical intervention strategy in sensorineural hearing loss. As such, this project, if successful, will change the clinical practice of hearing loss, as it will provide the means for safe treatment and lasting effects, without the need for devices. In the current reporting period the consortium has contributed to this in the following manners:
1. GMP manufacturing including optimisation of synthetic schemes and CMC development of a new class of highly potent Gamma Secretase Inhibitors.
2. First PK studies with Gamma Secretase Inhibitor formulations in 2 different animal species
3. Development of a target product profile and a product formulation that allows local delivery through, transtympanic injections.
4. Design of a clinical protocol that takes into account the biological mechanism that we are targeting as well as the current clinical possibilities. Optimisation of endpoints and assessment schedule.

This progress is beyond the current state of the art, however, the societal impact will largely be in later reporting periods. The formulations that have been developed can potentially also be used for other applications.

Related information

Record Number: 190325 / Last updated on: 2016-11-14