galicaftor (SION-2222) / AbbVie, Galapagos, Sionna Therap - LARVOL DELTA

Partial rescue of p.Phe08del-CFTR trafficking and stability defects by dual and triple corrector combinations (NACFC 2024) - "The additive correction of PTI-801 to type I (ABBV-2222, FDL-169, VX-661, VX-809), type II (Corr-4a), and type III (VX-445) correctors was also assessed. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue p.Phe508del-CFTR. Nevertheless, despite the higher level of functional rescue by dual- and triple-corrector combinations, p.Phe508del-CFTR still presents instability and accelerated degradation."

CFTR

Sionna Therapeutics Expands Pipeline with Multiple Clinical Stage Cystic Fibrosis Compounds Through a License Agreement with AbbVie (PRNewswire) - "Sionna Therapeutics...announced that it has obtained exclusive worldwide rights to develop and commercialize multiple clinical-stage compounds through a license agreement with AbbVie. Under the terms of the agreement, Sionna will assume all development responsibilities for galicaftor (ABBV-2222), a transmembrane domain 1 (TMD1)-directed cystic fibrosis transmembrane conductance regulator (CFTR) corrector, and navocaftor (ABBV-3067), a CFTR potentiator, both of which have completed Phase 2 studies, and a Phase 1 TMD1-directed corrector, ABBV-2851. Sionna will prioritize advancing one of the AbbVie compounds and SION-109 as potential dual combination options with a first nucleotide binding domain (NBD1) stabilizer. AbbVie will receive an upfront payment, an equity investment in Sionna and will be eligible to receive late-stage development and commercial milestones and royalties."

Licensing / partnership • Cystic Fibrosis

Partial Rescue of p.Phe08del-CFTR Trafficking and Stability Defects by Dual and Triple Corrector Combinations (ECFS 2024) - "The additive correction of PTI-801 to type I (ABBV-2222, FDL-169, VX-661, VX-809), type II (Corr-4a) and type III (VX-445) was also assessed. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue p.Phe508del-CFTR. Nevertheless, despite the higher level of functional rescue by dual and triple corrector combinations, p.Phe508del-CFTR still presents instability and accelerated degradation."

CFTR

PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR. (PubMed, Eur J Pharmacol) - "Despite the high efficacy of PTI-801 in combination with ABBV-2222, FDL-169, VX-661, or VX-809, these dual corrector combinations only partially restored p.Phe508del-CFTR conformational stability, as shown by the lower half-life of the mutant protein compared to that of WT-CFTR. In summary, PTI-801 likely shares a common MoA with VX-445 in rescuing p.Phe508del-CFTR, thus being a feasible alternative for the development of novel corrector combinations with greater capacity to rescue mutant CFTR folding and stability."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Allosteric pathways of CFTR activation reveal mechanistic insights into modulator-resistant variants (NACFC 2023) - "Finally, I507del folding (mature band C) was unresponsive to correctors C18 and C4a at 37°C or with galicaftor or FDL-169 at 27°C...Likewise, I507del single-channel activity was observed in 10 of 71 (14%) membrane patches but only after low-temperature incubation (27°C for >25 days) when combined with elexacaftor-tezacaftor-ivacaftor (1–3 days)... Structural and functional analyses suggest that a subset of variants that are poorly responsive to current modulators disrupt a key allosteric hub that coordinates CFTR activity. Attaining clinically relevant levels of function for CFTR I507del and others in this region will require a new series of correctors, possibly compounds that stabilize NBD1 folding directly."

Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs. (PubMed, Biochemistry) - "To explore these five binding sites, ensemble docking was performed on wild-type CFTR and the F508del mutant using a large library of structurally similar corrector drugs, including VX-809 (lumacaftor), VX-661 (tezacaftor), ABBV-2222 (galicaftor), and a host of other structurally related molecules. This data may serve to better understand the structural changes induced by mutation of CFTR and how correctors bind to the protein. Additionally, it may aid in the design of new, more effective CFTR corrector drugs."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Partial correction of F508del-CFTR trafficking and stability defects by the combination of PTI-801 with ABBV-2222 or FDL-169 (ECFS 2023) - "To shed light on the MoA of PTI-801, its additive effects to correctors (VX-445, VX-661, ABBV-2222, FLD-169, and Corr-4a), genetic revertants of F508del-CFTR (G550E, R1070W, and 4RK) and the traffic-null variant DD/AA were assessed. The maximal rescue of F508del-CFTR processing and function by PTI-801 was achieved at 3 µM concentration. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue F508del-CFTR."

CFTR

M23-492 FE: A Study to Assess How Food Affects the Safety and Pharmacokinetics of Galicaftor and Navocaftor (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed | Trial completion date: Mar 2023 ➔ Dec 2022 | Trial primary completion date: Mar 2023 ➔ Dec 2022

Trial completion • Trial completion date • Trial primary completion date

M23-492 FE: A Study to Assess How Food Affects the Safety and Pharmacokinetics of Galicaftor and Navocaftor (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Enrollment closed

M23-492 FE: A Study to Assess How Food Affects the Safety and Pharmacokinetics of Galicaftor and Navocaftor (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: AbbVie | Not yet recruiting ➔ Recruiting

Enrollment open

M23-492 FE: A Study to Assess How Food Affects the Safety and Pharmacokinetics of Galicaftor and Navocaftor (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: AbbVie

New P1 trial

Characterisation of F508del-CFTR rescue by corrector PTI-801 (ECFS 2022) - "PTI-801 demonstrated additivity to the genetic revertants G550E, R1070W and 4RK, but was unable to rescue DD/AA trafficking. In summary, these preliminary findings suggest that PTI-801 acts as a pharmacological chaperone and may have different binding sites compared to other correctors, namely VX-661, VX-809, ABBV-2222 and FDL-169."

A Phase 2 Study of ABBV-3067 Alone and in Combination With ABBV-2222 (clinicaltrials.gov) - P2 | N=78 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed | N=189 ➔ 78

Combination therapy • Enrollment change • Trial completion • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 2 Study of ABBV-3067 Alone and in Combination With ABBV-2222 (clinicaltrials.gov) - P2 | N=189 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Study to Evaluate Adverse Events and Change in Disease Activity With Oral Capsules of Galicaftor/Navocaftor/ABBV-119 Combination Therapy in Adult Participants With Cystic Fibrosis (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Adverse events • Combination therapy • Enrollment closed • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 2 Study of ABBV-3067 Alone and in Combination With ABBV-2222 (clinicaltrials.gov) - P2 | N=189 | Recruiting | Sponsor: AbbVie | Trial primary completion date: Jan 2022 ➔ Jun 2022

Combination therapy • Trial primary completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Case Studies from the Pressure and Catalysis Group at AbbVie: Development of Selective Hydrogenation Reactions for Medicinal Chemistry Programs Targeting Cystic Fibrosis, Hepatitis C, and Parkinson’s Disease. (ACS-Sp 2022) - "Herein, we will discuss several examples of high-impact work from the PCG that assisted medicinal chemistry programs in pursuit of candidate nomination. Vignettes will highlight the development of a diastereoselective hydrogenation route toward the scale-up of clinical candidate ABBV-2222 (galicaftor) from the Cystic Fibrosis program and a late-stage hydrogenative deprotection used to prepare prodrugs of pibrentasvir (hepatitis C) and levodopa/carbidopa (Parkinson’s disease)."

Clinical • CNS Disorders • Cystic Fibrosis • Fibrosis • Genetic Disorders • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Movement Disorders • Parkinson's Disease • Pulmonary Disease • Respiratory Diseases

Study to Evaluate Adverse Events and Change in Disease Activity With Oral Capsules of Galicaftor/Navocaftor/ABBV-119 Combination Therapy in Adult Participants With Cystic Fibrosis (clinicaltrials.gov) - P2; N=90; Recruiting; Sponsor: AbbVie; Trial primary completion date: Dec 2021 ➔ Sep 2022

Adverse events • Clinical • Combination therapy • Trial primary completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Study of Galicaftor/Navocaftor/ABBV-119 Combination Therapy in Subjects with Cystic Fibrosis. (clinicaltrialsregister.eu) - P2; N=90; Ongoing; Sponsor: AbbVie Deutschland GmbH & Co. KG

Clinical • Combination therapy • New P2 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Study to Evaluate Adverse Events and Change in Disease Activity With Oral Capsules of Galicaftor/Navocaftor/ABBV-119 Combination Therapy in Adult Participants With Cystic Fibrosis (clinicaltrials.gov) - P2; N=90; Recruiting; Sponsor: AbbVie; Trial completion date: Apr 2022 ➔ Dec 2022

Adverse events • Clinical • Combination therapy • Trial completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

CFTR Rescue in Intestinal Organoids with GLPG/ABBV-2737, ABBV/GLPG-2222 and ABBV/GLPG-2451 Triple Therapy. (PubMed, Front Mol Biosci) - "The combination ABBV/GLPG-2222/ABBV-2737/ABBV/GLPG-2451 showed increased efficacy over VX-770/VX-809 for most organoids, despite considerable variation in efficacy between the different organoid cultures. These differences in CFTR restoration between organoids with comparable genotypes underline the relevance of continuing to optimize the ABBV/GLPG-Triple therapy, as well as the in vitro characterization of efficacy in clinically relevant models."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Fueling the Pipeline via Innovations in Organic Synthesis. (PubMed, ACS Med Chem Lett) - "Examples of project contributions from neuroscience, cystic fibrosis, and virology illustrate the impact of the DSG approach. In the first ten years of innovative science in pursuit of excellence in synthesis, several advanced drug candidates, including ABBV-2222 (galicaftor) for cystic fibrosis and foslevodopa/foscarbidopa for Parkinson's disease, have emerged with key contributions from COS."

Journal • CNS Disorders • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Movement Disorders • Parkinson's Disease • Pulmonary Disease • Respiratory Diseases

A Phase 2 Study of ABBV-3067 Alone and in Combination With ABBV-2222 (clinicaltrials.gov) - P2; N=189; Recruiting; Sponsor: AbbVie; Trial completion date: Jan 2022 ➔ Oct 2022

Clinical • Combination therapy • Trial completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Study to Evaluate Adverse Events and Change in Disease Activity With Oral Capsules of Galicaftor/Navocaftor/ABBV-119 Combination Therapy in Adult Participants With Cystic Fibrosis (clinicaltrials.gov) - P2; N=90; Recruiting; Sponsor: AbbVie; Not yet recruiting ➔ Recruiting

Adverse events • Clinical • Combination therapy • Enrollment open • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Study to Evaluate Adverse Events and Change in Disease Activity With Oral Capsules of Galicaftor/Navocaftor/ABBV-119 Combination Therapy in Adult Participants With Cystic Fibrosis (clinicaltrials.gov) - P2; N=90; Not yet recruiting; Sponsor: AbbVie; N=50 ➔ 90; Trial completion date: Jan 2022 ➔ Apr 2022

Adverse events • Clinical • Combination therapy • Enrollment change • Trial completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases