Project No. F/090033/01/X36

CUP - B68I20000140005

Project co-financed by the European Union, European Regional Development Fund - National Operational Programme Enterprise and Competitiveness 2014-2020

AXIS I Investment Priority 1b Action 1.1.3

Grant decree: no. 2895 of 29/07/2020

Duration: 36 months from 01/11/2017 to 31/10/2020

Extension: 12 months from 01/11/2020 to 31/10/2021

Project carried out jointly by:

• Dompé farmaceutici S.p.A.

• Axxam S.p.A

• Takis s.r.l.

Total project cost: € 7.280.463,13

Total funding granted: € 4.861.433,21

Project cost related to Dompé farmaceutici: € 4.530.537,50

Funding to Dompé farmaceutici: €. 2.723.144,19

The general objective of the project

The general objective of the project is to create an integrated platform dedicated to the research and development of new drugs for the treatment of rare diseases and diseases with a high unmet need for treatment to improve the health and well-being of the population and to generate new candidates for clinical development validated by a pharmacological-toxicological characterization directed at the specific therapeutic indication. The objective will be pursued by integrating particular industry expertise in pharmaceutical research in medicinal chemistry, molecular and cellular biology. Within the general aim of the project, the areas of the specific knowledge of each participating entity have been identified, which will be developed and will contribute to the selection, characterization, and development of new molecules, both synthetic and protein and/or antibody-based, potentially useful for the treatment of diseases that still lack treatment strategies. Among the studied disorders are diseases with a high social and welfare impact, such as severe metabolic diseases currently without effective treatments, ophthalmic conditions of the anterior segment of the eye, and infectious diseases caused by fungi such as invasive Aspergillosis. In addition, studies on new molecular mechanisms will be carried out in parallel to understand better the metabolic pathways responsible for the onset and progression of the diseases under investigation. To this end, high-performance screening technology platforms (HTS) will be developed to substantially accelerate the research process of identifying, characterizing, and developing new drugs. The project also aims to go beyond rare diseases: in fact, another relevant objective is to extend studies on new molecular targets for the development of drugs to treat diseases with a high unmet need for treatment that shares the same molecular determinants.

Research activities will be planned and carried out to identify new pharmacological agents directed, with innovative mechanisms of action, against molecular targets whose physiopathological role is well known and linked to the onset and/or progression of rare forms of metabolic, ophthalmic infectious diseases. The objective will be pursued using mechanism-of-action studies to gain a better understanding of the biological mechanisms underlying the conditions under investigation.

The companies involved in the project have shared and promoted a focused drug discovery program, which sees a complete integration of industrial expertise related to pharmaceutical research processes and specific scientific skills in synthesis, molecular/cellular biology, and pharmacology, the strong point of the whole project.

The project is organized around the classic "drug discovery" pathway. It is oriented towards the identification of new treatments for rare diseases or diseases with a high unmet need for treatment, with a focus on metabolic-inflammatory and ophthalmic illnesses that will be treated with innovative pharmacological approaches. Based on the results, preclinical studies will be launched to characterize the most active molecules.

The research follows the guidelines defined based on the methodological approach applied. A broadly structured approach in industrial pharmaceutical research based on rational design of modulators will be adopted, but at the same time, it will go beyond rare diseases. The highest objective of the project will be the development of a technology platform for the development of innovative molecules that are candidates for clinical development with therapeutic potential for the treatment of rare diseases and/or high unmet medical needs.

Innovation will be ensured by selecting preclinical and clinical candidates, active with novel mechanisms of action on molecular targets responsible for the onset and/or progression of the chosen disease.

Dompé farmaceutici's objectives within the project

Dompé's main objectives within the project concern the identification, through the technology platform, and the development of new active chemical entities with an innovative mechanism of action for the treatment of metabolic diseases such as NASH, IBD, potentially extendable to other types of fibrosis. New synthetic molecules active as agonists or antagonists of 7-domain membrane receptors such as GPR120 and chemokine receptors will be identified and characterized. The best molecules from the in vitro potency and selectivity assays will be forwarded to the in vivo pharmacological characterization phases and, if successful, to the preclinical development phases.

A further objective of Dompé in the ophthalmology area will be the identification of a clinical candidate belonging to the neurotrophin family through its validation in relevant models of corneal hyperesthesia for the subsequent initiation of clinical trials; in addition, the knowledge acquired on the biological mechanisms and structure-activity relationships will be transferred to new areas of therapeutic interest, such as inner ear diseases characterized by progressive loss of function of the hair cells.

A further important objective of Dompé in the field of Experimental Development will be to complete the toxicological profile of a clinical candidate to support clinical trials in early-onset severe Type 1 diabetes.

The activities planned to achieve the program's objectives will enable the company, particularly its Research and Development area, to increase its scientific knowledge, expertise and visibility at an international level while also increasing the interest of potential partners in the activation of new collaborations.

Results achieved by Dompé farmaceutici

At the date of the last update, and even though the project is still in progress, an initial assessment of the results achieved can only be considered positive.

The Industrial Research activities were carried out according to schedule and, for the most part, were concluded on schedule, thanks also to the granting of a 12-month extension to the project. The extension was essential to complete some preclinical activities that required more time frames for execution due to experimental difficulties encountered in the early stages of research.

The selection of molecules belonging to a chemical library for virtual screening towards the targets of interest led to the identification of new chemical classes and understanding the mechanisms of action underlying their biological activity.

Synthetic processes were studied for the best-selected molecules directed against the main molecular targets selected to obtain quantities suitable for subsequent preclinical studies and analytical characterization. As a result, about 20 promising new molecules were selected for one target and another 30 for a second target, ion channel. The chosen molecules were then characterized in relevant preclinical models. At the same time, formulation studies were started in parallel with possible clinical development in humans, aimed at optimizing the reaching of target tissues with pharmacological doses of the active ingredient. These activities led to the selection of two ideal candidates for the next steps.

Studies in the field of neurosensory pathologies have enabled the characterization of the therapeutic potential of neurotrophins in diseases of the anterior segment of the eye and ear diseases.

The activities planned as Experimental Development allowed the characterization of the toxicological profile of the clinical candidate for development in the indication of severe onset type 1 diabetes. At present, no issues have arisen due to the toxic effects of the candidate, so the toxicology study program continues regularly in parallel with the initiation of clinical studies.