Cystic fibrosis, a promising molecule in the last phase of development (which is a prelude to clinical trials) – WWN

There cystic fibrosis a serious rare degenerative genetic disease. To this day they know each other approximately two thousand mutations affecting the CFTR protein (acronym for Cystic Fibrosis Transmembrane Regulator). At present there are treatments to alleviate the numerous disorders caused by the genetic deficiency but There is no definitive cure yet , even if research continues to identify increasingly effective therapies. Among the ongoing projects is Task Force for Cystic Fibrosis (TFCF) developed by the Cystic Fibrosis Research Foundation in collaboration with IRCCS Istituto Giannina Gaslini and the Italian Institute of Technology of Genoa. Thanks to this project, a promising corrector of the CFTR protein, ARN23765, was developed and is now exclusively licensed by the American company Sionna Therapeutics.

Towards the final stage of development

In these years of study and, starting from the results achieved by Task Force for Cystic Fibrosis
on ARN23765, the company further developed the compound obtaining a derivative with good pharmacological activity and favorable characteristics. Dr. Carlo Castellani, scientific director of FFC Ricerca and head of the Cystic Fibrosis Center of the Giannina Gaslini Institute in Genoa, comments: The courage to believe in a large project like that of the Task Force, aware of the opportunities but also of the risks of failure of a similar research investment receives deserved recognition today. A new promising molecule originated from the compound developed by the Foundation. The company that holds the patent now has the opportunity to continue the process the last phase of development which is a prelude to clinical trials.

The TFCF project

The project Task Force for Cystic Fibrosissupported by the Foundation, born in 2014 with the aim of identifying new correctors of the CFTR protein – more effective than those that existed at the time – from the collaboration between the Medical Genetics Laboratory of the Giannina Gaslini Institute of Genoa – historically expert in the pharmacology of CFTR and in the’high throughput screening with Professor Luis Galietta and Dr. Nicoletta Pedemonte – and the Italian Institute of Technology of Genoa – at the forefront in the field of innovative drug discovery, with Dr. Tiziano Bandiera.
In the first phase of the projectlasting 3 and a half years, were sift through thousands of molecules to identify compounds active on CFTR. The first phase was coordinated by Luis Galietta (currently at Tigem in Pozzuoli, Naples), who comments on this achievement: news that gives great satisfaction to all those who have been involved in this undertaking, in particular to the Foundation and its supporters who they believed in such an ambitious project.

The first stages

Since 2017, after having identified a family of compounds particularly effective in vitro on the mutated CFTR protein, the coordination of the project passed to Tiziano Bandiera in collaboration with the person responsible for the tests on primary cultures carried out at the Giannina Gaslini Institute, Nicoletta Pedemonte, current deputy director of the Foundation, which comments as follows: Among the most relevant characteristics of the family of compounds identified during the TFCF, in particular of ARN23765, is their high power (i.e. they work at very low doses) and one particular effectiveness in recovering the maturation defect
caused not only from F508del but also from many other mutations that are still orphaned of therapy to date. This was the added value of these compounds.
Arrived to the preclinical evaluation phase, under the coordination of Tiziano Bandiera and with the involvement of a preclinical development services company, the project generated important data on the safety of the compound ARN23765. These data allowed us to begin discussions with pharmaceutical companies to complete its development.

Towards experimentation

After 7 years of studies, Task Force for Cystic Fibrosis has achieved the hoped-for and long-awaited objective of laying the foundations for the development of a particularly powerful compound in recovering the functionality of mutated CFTR.
In 2021, after a negotiation phase, ARN23765 was licensed by Sionna Therapeutics with the aim of continuing preclinical studies and evaluating whether it possessed all the characteristics to be able to start the experimentation in humans, also in combination with other modulatory drugs. The fact that a pharmaceutical company has licensed ARN23765 – underlines Tiziano Bandiera – testifies to the quality of the work that the team Task Force for Cystic Fibrosis has accomplished both in the discovery phase of the molecule and in that of the initial preclinical development studies.

Network of researchers

Task Force for Cystic Fibrosis It was a project strongly supported by Professor Gianni Mastella, co-founder and scientific director of FFC Ricerca until his death – recalls Matteo Marzotto, president of FFC Ricerca –. We owe him the intuition of the need to combine network projects with some important strategic projects, the construction of an authoritative network of researchers. But our thanks also go to the companies and volunteers who have placed their trust in us and have been able to accept this challenge, contributing, through local initiatives and support groups, to an overall investment of over 2.5 million euros over the years, which allowed us to reach this hoped-for, but by no means guaranteed, goal.
Carlo Castellani concludes: Other strategic projects I am active or leaving soon always with the aim of identifying new therapeutic strategies
for the treatment of cystic fibrosistrusting to follow the path marked by the TFCF.