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REgeneration of inner ear hair cells with GAmma-secretase INhibitors to regain hearing in patients with sensorineural hearing loss

Periodic Reporting for period 4 - REGAIN (REgeneration of inner ear hair cells with GAmma-secretase INhibitors to regain hearing in patients with sensorineural hearing loss)

Reporting period: 2018-11-01 to 2019-10-31

"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"" (SNHL) is a major cause of acquired hearing loss. Since hair cells do not regenerate spontaneously, the dogma has been that SNHL is irreversible. No pharmacological treatment for SNHL 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 REGAIN 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 gamma-secretase inhibitor (GSI) as a treatment of SNHL.

The objective of the REGAIN project is to establish the efficacy of a locally administered GSI in terms of improving hearing through regeneration of inner ear hair cells. The project involves 1) upscaling of GMP production of the clinical GSI candidate, 2) generation of preclinical data on GSI dosing and local safety, 3) ethics approval for the clinical trial l and 4) demonstration of proof of concept for the GSI for the treatment of patients with adult onset SNHL. Small molecule drugs targeting the underlying biological causes of hearing loss in a safe way are expected to meet an urgent clinical need for millions of patients, who currently rely on the limited benefits provided by hearing aids and cochlear implants.

The REGAIN Consortium is uniquely skilled and placed to advance this proof of concept to and through clinical studies, and brings together eight dedicated partners, coordinated by Audion Therapeutics BV and including University College London Ear Institute, University College London Hospitals, University of Tübingen, The National and Kapodistrian University of Athens, Eli Lilly, Nordic Biosciences and ttopstart BV). These Consortium partners represent the current state of the art in regenerative hearing loss research in the EU and bring together expertise in hearing loss biology and GSI’s with a deep understanding of preclinical and clinical drug development. The REGAIN project is funded by the European Commission in the Horizon 2020 - research and innovation framework programme."
The REGAIN project contains five Work Packages:

WP1: Chemistry, Manufacturing and Controls (CMC) data package
WP1 focused on the development of a dosage form for transtympanic administration of the drug product. We have selected the proposed candidate compound and worked extensively on product formulation development, resulting in a target product profile that will allow local transtympanic application of the candidate compound into the middle ear and onto the round window membrane (RWM). Furthermore, we have developed analytical procedures to support the GMP manufacture and release of drug product for clinical trials in humans.

WP2: Non-clinical data package
We have finalised the work set out in WP, that is we generated a non-clinical data package that enabled submission of a Clinical Trial Application.

WP3: Regulatory approval and ethics
WP3 entailed the preparation and submission of the complete Clinical Trial Application Dossier in order to obtain regulatory approval for the clinical studies. We have finalized this work and were awarded ethical and regulatory approval in the UK, Greece and Germany.

WP4: Clinical proof of concept study
WP4 focused on establishing the safety, tolerability and efficacy of the locally applied GSI in a clinical proof of concept study in patients with SNHL. Both the phase I and phase IIa clinical trials have been delivered successfully. In part A (phase I trial) of the study we have established that the highest dose of our drug product is safe to use, no Serious Adverse Events were observed. In part B (phase IIa trial) of the study the efficacy of our drug product in terms of improving hearing has been studied. Primary efficacy endpoints were not met across the entire patient population. However, the safety and efficacy results observed in a number of patients across sites merit further evaluation of the product in additional clinical studies.

WP5: Consortium management, dissemination and exploitation
Within WP5 we focused on efficient and professional management of the Consortium and dissemination of the project’s progress and results. To this end, we have disseminated press releases about the grant and phase I trial results and have opened a project website with key information for professionals, patients and the public. Along the course of the project we have disseminated progress and results at relevant scientific congresses and public events, hearing charity websites, and have given interviews for the radio and newspapers and lay and professional journals.
REGAIN aims to provide the first clinical validation of a pharmaceutical intervention strategy in SNHL.

So far, 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 GSI.
2. First PK studies with GSI 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.
5. Successful completion pf phase I of the clinical trial (safety)
6. Successful completion of the 12-week follow-up period of a phase IIa of the clinical trial (efficacy).

After a successful long-term follow-up of the Phase IIa study, REGAIN is expected to deliver an innovatory therapeutic strategy to improve hearing in patients with SNHL, through regeneration of inner ear hair cells. The successful clinical trials are already a breakthrough themselves in the field of hearing loss, since clinical trials in this field are relatively new, but the potential impact of REGAIN lies beyond the clinical trial results. Throughout REGAIN the challenges that were encountered and overcome have resulted in valuable lessons learnt for the field. REGAIN has set the clinical trial standard and the team have presented challenges, results and best practices to the scientific community and other relevant stakeholders through international conference presentations and publication.