The strategic project Task Force for Cystic Fibrosis (TFCF), initiated and funded by FFC Ricerca, began in 2014 (Phase 1 – Phase 2 – Phase 3) with the aim of identifying new CFTR modulators that are more effective than those available at the time. The discovery phase produced a very potent corrector, ARN23765, a candidate for development into a drug. After conducting a series of in vitro experimental assays, which did not reveal any particular safety concerns regarding the compound, we proceeded to a subsequent derisking phase, a series of activities aimed at identifying any potential issues that could compromise the compound’s development as a drug. The derisking activities were entrusted to Aptuit, a Contract Research Organisation (CRO) specialised in the sector, which optimised large-scale synthesis, conducted formulation studies and carried out an initial series of animal studies to assess the compound’s potential toxicity, as required for any molecule intended to progress to clinical trials. This initial derisking phase was completed at the end of July 2020 and revealed no toxicity issues in animals.

In the meantime, the search for a partner to complete the development of the compound has begun. CF research has clearly shown that, in order to achieve adequate restoration of the function of the mutated CFTR, a combination of two different correctors is required, possibly in conjunction with an enhancer.

In fact, a combination of this type, known as Trikafta (Kaftrio in Europe), has recently been approved; it has demonstrated significant clinical efficacy even in people with CF with a single copy of the F508del mutation. This represents a major step forward in treatments for the underlying CF defect. Nevertheless, there is a recognised need for patients to have access to other drug combinations that are equally effective or potentially superior to the existing one. This option would also help reduce the cost of treatment, thereby increasing its accessibility for people with CF.

The TFCF strategic plan has therefore changed from its original intentions, as it is necessary to incorporate ARN23765 – which has the advantage of being highly potent – into a dual or triple combination of CFTR modulators. The aim is to identify a combination that demonstrates an effect comparable to or superior to that of Trikafta.

The TFCF strategic project has also generated intellectual property jointly owned by IIT, the Giannina Gaslini Institute (IGG) and FFC Ricerca. Two patents have been granted in the United States, the references for which are given below.

In the final months of 2020, the team initiated contact with a potential partner who has developed correctors with a mechanism of action complementary to that of ARN23765. A confidentiality agreement was first signed with this partner, followed by an exchange of information and data on their respective compounds.

In the final months of 2021, the US company Sionna Therapeutics acquired the licence to use ARN23765 (read the news here). This significant transfer has enabled the continuation of preclinical studies on the compound, which are necessary to potentially start human trials.

The results achieved by TFCF are very promising and, thanks to the recent agreement for the future development of the molecule, could lead to a new and more effective drug for cystic fibrosis.

Publications

• Capurro V, Tomati V, Sondo E, Renda M, Borrelli A, Pastorino C, Guidone D, Venturini A, Giraudo A, Mandrup Bertozzi S, Musante I, Bertozzi F, Bandiera T, Zara F, Galietta LJV, Pedemonte N. Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment. Int J Mol Sci. 2021 May 17;22(10):5262. doi: 10.3390/ijms22105262. PMID: 34067708; PMCID: PMC8156943.
• Brindani N, Gianotti A, Giovani S, Giacomina F, Di Fruscia P, Sorana F, Bertozzi SM, Ottonello G, Goldoni L, Penna I, Russo D, Summa M, Bertorelli R, Ferrera L, Pesce E, Sondo E, Galietta LJV, Bandiera T, Pedemonte N, Bertozzi F. Identification, Structure−Activity Relationship, and Biological Characterization of 2,3,4,5-Tetrahydro‑1H‑pyrido[4,3‑b]indoles as a Novel Class of CFTR Potentiators. J Med Chem. 2020 Oct 8;63(19):11169-11194. doi: 10.1021/acs.jmedchem.0c01050. Epub 2020 Sep 18. PMID: 32946228; PMCID: PMC8011931.
• Armirotti A, Tomati V, Matthes E, Veit G, Cholon DM, Phuan PW, Braccia C, Guidone D, Gentzsch M, Lukacs GL, Verkman AS, Galietta LJV, Hanrahan JW, Pedemonte N. Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity. Sci Rep. 2019 Jul 16;9(1):10310. doi: 10.1038/s41598-019-46639-1. PMID: 31311979; PMCID: PMC6635361.
• Pedemonte N, Bertozzi F, Caci E, Sorana F, Di Fruscia P, Tomati V, Ferrera L, Rodríguez-Gimeno A, Berti F, Pesce E, Sondo E, Gianotti A, Scudieri P, Bandiera T, Galietta LJV. Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel. Sci Adv. 2020 Feb 21;6(8):eaay9669. doi: 10.1126/sciadv.aay9669. PMID: 32128418; PMCID: PMC7034990.
• Liessi N, Pesce E, Braccia C, Bertozzi SM, Giraudo A, Bandiera T, Pedemonte N, Armirotti A. Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta. JCI Insight. 2020 Aug 20;5(16):e138722. doi: 10.1172/jci.insight.138722. PMID: 32673287; PMCID: PMC7455125.

Patents

• Method for the preparation of pyrazole derivatives as modulators of CFTR protein

Inventors: Bandiera Tiziano, Bertozzi Fabio, Berti Francesco, Rodriguez-Gimeno Alejandra, Sorana Federico, Romoli Filippo, Calogero Francesco

Holders: Fondazione Istituto Italiano Tecnologia (IIT), FFC Ricerca.

• Compounds and composition for the treatment of cystic fibrosis

Inventors: Bandiera Tiziano, Bertozzi Fabio, Zaetta Giorgia, Sorana Federico, Caci Emanuela, Ferrera Loretta, Pedemonte Nicoletta, Galietta Luis Juan Vicente

Holders: Fondazione Istituto Italiano Tecnologia (IIT), Istituto Giannina Gaslin, FFC Ricerca

• Compounds and composition for the treatment of cystic fibrosis

Inventors: Bandiera Tiziano, Bertozzi Fabio, Giacomina Francesca, Giovani Simone, Sorana Federico, Caci Emanuela, Ferrera Loretta, Pedemonte Nicoletta, Galietta Luis Juan Vicente

Holders: Fondazione Istituto Italiano Tecnologia (IIT), Istituto Giannina Gaslin, FFC Ricerca

• Pyrazole derivatives for the treatment of cystic fibrosis

Inventors: Bandiera Tiziano, Bertozzi Fabio, Di Fruscia Paolo, Sorana Federico, Caci Emanuela, Ferrera Loretta, Pedemonte Nicoletta, Galietta Luis Juan Vicente

Holders: Fondazione Istituto Italiano Tecnologia (IIT), Istituto Giannina Gaslin, FFC Ricerca

• Heterocyclic derivatives for the treatment of cystic fibrosis

Inventors: Bandiera Tiziano, Bertozzi Fabio, Di Fruscia Paolo, Rodriguez-Gimeno Alejandra, Sorana Federico, Berti Francesco, Caci Emanuela, Ferrera Loretta, Pedemonte Nicoletta, Galietta Luis Juan Vicente

Holders: Fondazione Istituto Italiano Tecnologia (IIT), Istituto Giannina Gaslin, FFC Ricerca