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Nose to Brain Delivery of Antibodies via the Olfactory Region for the Treatment of Multiple Sclerosis Using Novel Multi-functional Biomaterials Combined with a Medical Device

Periodic Reporting for period 2 - N2B-patch (Nose to Brain Delivery of antibodies via the Olfactory Region for the Treatment of Multiple Sclerosis Using Novel Multi-functional Biomaterials Combined with a Medical Device)

Reporting period: 2018-07-01 to 2019-12-31

N2B-patch stands for Nose-to-Brain-patch. We aim to develop an innovative technology for multiple sclerosis (MS) treatment by developing a ‘nose to brain’ (N2B) delivery system which will avoid the need for injections and oral medicine. The long-term objective is to improve treatment of MS patients.
The therapy of central nervous system (CNS) diseases like MS is still an unmet medical need due to the low CNS bioavailability of innovative drugs like antibodies. On the other hand, the N2B transport of substances is scientifically well-known and a recently clinically proven alternative route of administration as the so-administered substances can bypass the blood-brain barrier (BBB). Nevertheless until now, highly efficient technologies for olfactory uptake and direct brain delivery are missing.
We aim to develop an innovative N2B drug delivery technology for the treatment of MS based on the synthesis of a biomaterial-based innovative galenic formulation, a novel class of hydrogel matrix-patch and a medical applicator device system. The N2B route of administration provides a minimally invasive method of bypassing the BBB. Moreover, the innovative multifunctional galenic formulation of N2B-patch aims to shield sensitive drugs and maintain the drug’s bioactivity.
The direct transport route from the nasal cavity to the brain, bypassing the BBB, could potentially offer an exciting method for CNS drug delivery. It may be used not only for demyelinating disorders such as MS but also for other neurological and neurodegenerative indications or tumours.
N2B-patch aims at the following scientific and technological objectives during a 4-year period:

1. Development of a multifunctional hydrogel matrix with different mechanical and viscoelastic characteristics to achieve the required properties.
2. Development of multifunctional particles.
3. Proof-of-concept, pharmacokinetics (PK) and efficacy of the API, N2B drug transport.
4. Design of the application process.
5. Design and manufacturing of the Container Closure System (CCS).
6. Implementation of scale-up processes related to the galenic formulation.
7. Assessment of regulations and ethics in order to deliver proof of concept and PK data in vivo.
8. Full exploitation of project results along the whole value-chain.
9. Communication and Dissemination activities.

The N2B-patch team will deliver a proof-of-concept of N2B drug delivery therapeutic potential. Science, industry and patients’ representatives work hand in hand in order to achieve the project objectives and maximise impact for patients and their relatives, health professionals and European industries. They are guided by regulatory and business exploitation experts.
The project addresses the development of a biomaterial-based galenic formulation in combination with a medical device for the treatment of MS.

The development of the formulation including an ensemble composed of particles and hydrogel started with the beginning of the project. Various particles had been manufactured for screening. The lead matrix was selected and for the final formulation the particle development started. Novel techniques to evaluate adhesion and spreading of the formulation at the olfactory region were set-up further one. The technology transfer of the galenic formulation was demonstrated by using previously prepared batch production documentation at pilot scales.
The validity of the end product is a very important step. Therefore, the setting of the user-requirement specifications (URS) started where the product quality related attributes and their specifications are defined for safe and high quality medicinal product development. The evaluation of the safety of the applicator via cytotoxicity assays in accordance with ISO requirements has been achieved and those pertaining to the particles and the hydrogel are on-going. The experimental work on the application process will be supported by using 3D casts.

Preparatory work for exploitation of project results along the whole value-chain was performed. A targeted survey for patients was prepared and translated in different languages. It was distributed through the national MS patient’s platforms in different EU countries. The survey results revealed that MS patients would be open to consider the change of their current drug administration modes.
Besides general communication activities, N2B-patch is present in Social Media (youtube and LinkedIn). Feedback of the project partner EMSP regarding patients view was considered for project material and an easy-to-read Q&A section was added to the website. More patient oriented activities, e.g. interviews and an article were performed in RP2.
The consortium attended relevant scientific conferences, held presentations or presented posters related to N2B-patch, which included patient-related events. The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) congress provided the opportunity to record video interviews with MS patient representatives. They expect the innovative technology to be safe, increase efficacy of treatments, reduce side effects, minimise hospital visit frequency, improve their quality of life, and hope that this technology is soon available on the market to be accessible to MS patients.
Our project is a brand new approach that aims to develop a delivery technology based on the synthesis of a biomaterial-based innovative galenic formulation, a novel class of hydrogel matrix-patch and a medical applicator device system. Moreover, the innovative multifunctional galenic formulation aims to shield sensitive drugs and maintain the drug’s bioactivity.
The N2B-patch project aims to deliver the following three outputs (for illustration see figure enclosed):
A: An Ensemble composed of biomaterial-based drug particles and an innovative API (biomolecules) for MS treatment.
B: The hydrogel formulation as a minimally-invasive carrier.
C: The applicator device as integral part of the functional and minimally-invasive system.

The N2B-patch project aims to have considerable impacts on society as a whole, on markets and research. The information coming from the patients’ community is assured through coordinated actions. An evaluation report with a patient-oriented risk/benefit analysis supported a preliminary market report to estimate the patient`s acceptance potential towards “nose-to-brain” application. The data for the analysis is retrieved principally through surveys (online and at selected events) and bilateral contacts of the project partner EMSP. The N2B-patch project addresses these issues by delivering the following impacts:
• Innovative biomaterials for the treatment of patients with demyelinating disorders of the CNS.
• Reduced direct and indirect costs linked to these diseases and their treatment.
• Enhance competitiveness of the biomaterials and biomedical industries in the EU.
• Dissemination of results.
• The N2B-patch Business case - N2B-patch platform technology.
• Improving the innovation capacity and the integration of new knowledge.
• Strengthening competitiveness and growth by meeting the needs of European and global markets.
• N2B-patch will improve patients’ quality of life due to minimally invasive action and longer duration of implants and devices
• N2B-patch also impacts sustainability and holds an environmental benefit.

N2B-patch perfectly matches market and user needs in a cost effective and thus competitive manner.
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