Assessment of Multiple-Dose Pharmacokinetics and Safety of the Co-administration of Galicaftor, Navocaftor and ABBV-576 and Potential of ABBV-576 for CYP3A Induction in Healthy Volunteers

Start Date20 Sep 2022

Sponsor / Collaborator

AbbVie, Inc.

NCT04853368 / TerminatedPhase 2

A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

Cystic Fibrosis (CF) is a rare, life-threatening, genetic disease that affects the lungs and digestive system, significantly impairing the quality of life, with those affected having a median age of death at 40. The main objective of this study is to assess how safe and effective is the combination therapy of galicaftor/navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 in adult participants with CF who are homozygous or heterozygous for the F508del mutation in each arm.
Galicaftor/Navocaftor/ABBV-119 combination therapy and Galicaftor/Navocaftor/ABBV-576 is being developed as an investigational drug for the treatment of CF. Study doctors place participants in 1 of the 4 groups, called treatment arms. Each group receives a different treatment. Around 90 adult participants with a diagnosis of CF will be enrolled in the study around approximately 35 sites worldwide.
Participants in arm 1 will receive oral capsules of galicaftor/navocaftor dual combination for 28 days followed by galicaftor/navocaftor/ABBV-119 triple combination for 28 days. Participants in arms 2 and 3 will receive the galicaftor/navocaftor/ABBV-119 triple combination or placebo for 28 days. Participants in arm 4 will receive galicaftor/navocaftor/ABBV-576 triple combination therapy for 28 days. For all study arms, ABBV-576, galicaftor, navocaftor, will be given once daily and ABBV-119 twice a day.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Start Date20 Sep 2021

Sponsor / Collaborator

AbbVie, Inc.

100 Clinical Results associated with Galicaftor

100 Translational Medicine associated with Galicaftor

100 Patents (Medical) associated with Galicaftor

Literatures (Medical) associated with Galicaftor

15 Aug 2023·Biochemistry

Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs.

Article

Author: Mitchell, Alexis ; Johnson, Quentin R ; Girard, Christian ; Henager, Marissa E ; Ramsdell, Havanna ; Lester, Anna ; Dixon, Brandon ; Poulos, Jack ; Evans, Claudia N ; Reber, Callista ; Spinney, Allison ; Herring, Caitlin ; Sandman, Madeline ; Turlington, Mark

Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The recent development of a class of drugs called "correctors", which repair the structure and function of mutant CFTR, has greatly enhanced the life expectancy of CF patients. These correctors target the most common disease causing CFTR mutant F508del and are exemplified by the FDA-approved VX-809. While one binding site of VX-809 to CFTR was recently elucidated by cryo-electron microscopy, four additional binding sites have been proposed in the literature and it has been theorized that VX-809 and structurally similar correctors may engage multiple CFTR binding sites. 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. For wild-type CFTR, we find that only one site, located in membrane spanning domain 1 (MSD1), binds favorably to our ligand library. While this MSD1 site also binds our ligand library for F508del-CFTR, the F508del mutation also opens a binding site in nucleotide binding domain 1 (NBD1), which enables strong binding of our ligand library to this site. This NBD1 site in F508del-CFTR exhibits the strongest overall binding affinity for our library of corrector drugs. 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.

01 May 2021·American journal of respiratory cell and molecular biology

Novel Correctors and Potentiators Enhance Translational Readthrough in CFTR Nonsense Mutations

Article

Author: Conrath, Katja ; Peng, Ning ; Mutyam, Venkateshwar ; Li, Yao ; Singh, Ashvani K. ; Tang, Li Ping ; Sharma, Jyoti ; Chen, Jianguo ; Falk Libby, Emily ; Rowe, Steven M.

Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) result in nonfunctional CFTR protein and are the proximate cause of ∼11% of CF-causing alleles, for which no treatments exist. The CFTR corrector lumacaftor and the potentiator ivacaftor improve CFTR function with terminal PTC mutations and enhance the effect of readthrough agents. Novel correctors GLPG2222 (corrector 1 [C1]), GLPG3221 (corrector 2 [C2]), and potentiator GLPG1837 compare favorably with lumacaftor and ivacaftor in vitro. Here, we evaluated the effect of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in combination with the readthrough compound G418 on CFTR function using heterologous Fischer rat thyroid (FRT) cells, the genetically engineered human bronchial epithelial (HBE) 16HBE14o^- cell lines, and primary human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded those from ivacaftor in FRT-W1282X and FRT-R1162X cells. A three-mechanism strategy consisting of G418, GLPG1837, and two correctors (C1a + C2a) yielded the greatest functional improvements in FRT and 16HBE14o^- PTC variants, noting that correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X cells. GLPG1837 + C1a + C2a restored substantial function in G542X/F508del HBE cells and restored even more function for W1282X/F508del cells, largely because of the corrector/potentiator effect, with no additional benefit from G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin-induced swelling was observed with G418 + GLPG1837 + C1a + C2a, although GLPG1837 + C1a + C2a alone was sufficient to improve forskolin-induced swelling in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators, and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR.

01 Sep 2020·The Journal of pharmacology and experimental therapeutics

Correction to “Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222”

Article

Author: T. R. Neelands ; C. Tse ; B. Liu ; Y. Fan ; P. R. Kym ; H. Y. Ren ; A. K. Singh ; A. M. Manelli ; C. Balut ; X. Wang ; A. M. Swensen ; X. B. Searle ; Y. Jia ; K. Conrath ; S. Alani ; T. A. Vortherms ; W. Gao ; T. C. Hwang ; D. Cyr

News (Medical) associated with Galicaftor

24 Aug 2021

·www.pharmaceutical-technology.com

Current and future players in the cystic fibrosis market

The currently available marketed drugs for cystic fibrosis (CF) target multiple aspects of the disease. Inhaled antibiotics are used for the treatment of chronic lung infections, mucolytic agents are used for reducing the viscosity of the mucus in the lungs, pancreatic enzyme replacement therapies (PERTs) are used for the treatment of CF-related exocrine pancreatic insufficiency (EPI), and CF transmembrane conductance regulator (CFTR) modulators enhance CFTR function, targeting the underlying cause of disease. The disease-modifying nature of CFTR modulators has transformed the treatment paradigm for CF over the last decade, setting a trend that is likely to persist to 2030. More than a dozen pharmaceutical companies make up the current players in the CF market (Figure). Vertex is the clear market leader, dominating the CF space with four marketed CFTR modulators available throughout the seven major markets (7MM) (US, France, Germany, Italy, Spain, UK and Canada), including Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), Symdeko/Symkevi (tezacaftor/ivacaftor and ivacaftor), and Trikafta/Kaftrio (elexacaftor, tezacaftor, ivacaftor). Since the global approval of Kalydeco in 2012, Vertex has greatly expanded the number of CF-related mutations that are eligible for CFTR modulator treatment across all age groups. Currently, Vertex’s Trikafta/Kaftrio is the world’s first triple-combination therapy for which approximately 90% of the CF population will likely be eligible. While Vertex is currently the only company with products in the CFTR modulator drug class, other players stand out with marketed products in other drug classes. Chiesi possesses two inhaled antibiotic products, Bramitob/Bethkis (tobramycin) in the US and five major European markets (5EU) (France, Germany, Italy, Spain and the UK) and Quinsair (levofloxacin) in the 5EU, as well as the mucolytic Bronchitol (mannitol) in the US and the PERT product Pertzye (pancrelipase) in the US. Two other key companies include Viatris (formerly Mylan), which owns the most widely-used inhaled antibiotic therapies, TOBI (tobramycin) and TOBI Podhaler (tobramycin inhalation powder), and Nestlé HealthScience, which owns two PERT products, Zenpep (pancrelipase) and Viokace (pancrelipase). The rest of the pharmaceutical companies with marketed drugs used for the treatment of CF include Gilead, Teva, Genentech, AbbVie, Vivus, Horizon Therapeutics and Pharmaxis. Vertex and AbbVie are the only two companies with clear stakes in both the current and future CF market. Vertex is currently pursuing label expansion for Kalydeco to CF patients ages 0 months to less than 12 months in Canada, and Trikafta/Kaftrio to pediatric CF patients ages 2-5 years in the US and 2-11 years in the 5EU and Canada. Additionally, two new products from this company are expected to launch within the next five years: VX-561 and VX-121 + tezacaftor + VX-561. Currently, AbbVie markets Creon, the most widely used PERT by CF patients. The company has two pipeline agents, ABBV-3067, a CFTR potentiator that is being studied in late-stage Phase II trials alone and in combination with galicaftor (ABBV-2222), a CFTR corrector. If successful, AbbVie will be Vertex’s first competitor in the CFTR modulator market. Laurent Pharmaceuticals is expected to be the only new player in the CF space by 2030. It is currently developing an anti-inflammatory agent, LAU-7b (fenretinide), for reducing the levels of inflammation and the severity of pulmonary infections with Pseudomonas aeruginosa. While this pipeline agent has an innovative mechanism of action and is a first-in-class drug, the company is a novice within the CF field and has not yet brought a drug to market. Due to the limited number of pipeline agents in late-stage development, GlobalData anticipates that the current players in the CF market will likely maintain their competitive positions by 2030. Related Report Cystic Fibrosis – Global Drug Forecast and Market Analysis to 2030 Get the Report Latest report from Browse over 50,000 other reports on our store. Visit GlobalData Store

First in Class

100 Deals associated with Galicaftor

External Link

KEGG	Wiki	ATC	Drug Bank
D11724	-	-	DB14894

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 2	AU	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	BE	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	CZ	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	DE	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	IE	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	GB	Galapagos NV	01 Jan 2017

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03969888 (CTgov)	Phase 2	Cystic Fibrosis	78	Placebo ABBV-2222+ABBV-3067 (ABBV-3067 50 mg + Placebo for ABBV-2222)	qeomfopeua(hvaocsoafu) = cmugwdxpjf bsebdjiigk (ukgsqluqve, sbkcookjnv - ckyttlljka) View more	-	28 Jun 2023
				Placebo ABBV-2222+ABBV-3067 (ABBV-3067 150 mg + Placebo for ABBV-2222)	qeomfopeua(hvaocsoafu) = ewhmnmdlvq bsebdjiigk (ukgsqluqve, ddknektsst - cftgnpqbne) View more
NCT03119649 (FLAMINGO, Pubmed \| J Cyst Fibros) Manual	Phase 2	Cystic Fibrosis	59	GLPG2222	gweidjxwce(mlnnjpenfg) = rzvethwidx vockinnhuk (zljiycizev )	Negative	01 Sep 2019
NCT03119649 (FLAMINGO, CTgov)	Phase 2	Cystic Fibrosis	59	placebo+GLPG2222 100 mg (Cohort A: GLPG2222 100 mg QD)	zrgirnefki(uhoxzyivnu) = gugqmoxgvr cjjekgjlce (fzsvkeeigz, jdjfkssyig - fnorihfjnj) View more	-	16 Nov 2018
				placebo+GLPG2222 200 mg (Cohort B: GLPG2222 200 mg QD)	zrgirnefki(uhoxzyivnu) = juwwcvtugq cjjekgjlce (fzsvkeeigz, njcxxegcet - vplrkleshh) View more

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Leverages most recent intelligence information, enabling fullest potential.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis