nesolicaftor (PTI-428) / FAIR Therapeutics, TuHURA Bio - LARVOL DELTA

CHOICES: Clinical Trial to Evaluate the Efficacy and Safety of Dirocaftor/Posenacaftor/Nesolicaftor in Adults With CF (clinicaltrials.gov) - P2 | N=41 | Completed | Sponsor: Kors van der Ent | Recruiting ➔ Completed

Trial completion • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Therapeutic strategies to reverse cigarette smoke-induced ion channel and mucociliary dysfunction in COPD airway epithelial cells. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Similar to nesolicaftor, the angiotensin receptor blocker (ARB) losartan rescued TGF-β1-mediated decreases in PCBP1 binding to LRRC26 mRNA. In addition, the ARB telmisartan restored PCBP1 binding to CFTR and LRRC26 mRNAs to rescue CFTR and BK function in CS-exposed COPD-HBEC. Thus, nesolicaftor and ARBs act on the same target and were therefore neither additive nor synergistic in their actions. These data demonstrate that nesolicaftor and ARBs may provide benefits in COPD by improving ion channel function important for mucus hydration."

Journal • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR • MUC5AC • TGFB1

Fair Therapeutics Completes Enrollment in Phase IIb CHOICES Trial of Novel CFTR Modulator for Ultra-Rare Variants of Cystic Fibrosis (PRWeb) - "Fair Therapeutics...announced the full enrollment of its Phase IIb clinical trial, CHOICES (NCT06468527). The trial aims to assess the efficacy and safety of Fair TX's novel Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) triple modulator therapy-Diponecaftor (Dirocaftor/Posenacaftor/Nesolicaftor)-in adults with ultra-rare CF variants who currently cannot benefit from any disease-modifying treatment. The CHOICES trial is a pivotal step in the company's mission to address the high unmet needs of people with cystic fibrosis (PwCF). Results of the trial are expected mid-2025. The trial, a double-blinded cross-over trial, began in June 2024, and has enrolled 40 adult patients (18+) from 10 European countries."

Enrollment closed • P2b data • Cystic Fibrosis

CHOICES: Clinical Trial to Evaluate the Efficacy and Safety of Dirocaftor/Posenacaftor/Nesolicaftor in Adults With CF (clinicaltrials.gov) - P2 | N=52 | Recruiting | Sponsor: Kors van der Ent

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

The CFTR Amplifier Nesolicaftor Rescues TGF-β1 Inhibition of Modulator-Corrected F508del CFTR Function. (PubMed, Int J Mol Sci) - "CFBE cells homozygous for F508del were treated with the combination of elexacaftor/tezacaftor/ivacaftor (ETI) and TGF-β1 in the presence and absence of nesolicaftor. Finally, nesolicaftor augmented the F508del CFTR response to ETI in CFBE cells overexpressing miR-145, a negative regulator of CFTR expression. Thus, CFTR amplifiers, but only when used with highly effective modulators, may provide benefit in an inflamed environment."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CFTR • CXCL8 • IL6 • MIR145 • TGFB1

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene. (PubMed, Int J Mol Sci) - "We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation."

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

[VIRTUAL] CFTR MODULATOR THERAPY FOR CYSTIC FIBROSIS CAUSED BY THE RARE C.3700A>G MUTATION (NACFC 2020) - "However, I1234del-CFTR showed much reduced activity, with modest activation seen with potentiators VX-770 and GLPG1837, correctors VX-809, VX-661 and VX-445, or low-temperature incubation...In primary cultures of human airway epithelial cells from nasal brushings on one homozygous c.3700A G subject, however, little CFTR current was seen without or with multiple correctors and potentiators/co-potentiators, including the combination VX-661/VX-445, with or without the CFTR amplifier PTI-428. To further clarify the potential utility of CFTR modulators, two limited N-of-1 studies were done, testing the efficacy of elexacaftor/tezacaftor/ivacaftor (ETI) in homozygous c.3700A G subjects. One subject showed a 30 mM decrease in sweat chloride and symptomatic improvement on ETI. These results suggest the potential benefit of CFTR modulators, including co-potentiators, for CF caused by the c.3700A G mutation."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

[VIRTUAL] EVALUATION OF COMBINATIONS OF THE CFTR POTENTIATOR DIROCAFTOR, CORRECTOR POSENACAFTOR AND AMPLIFIER NESOLICAFTOR IN CF SUBJECTS WITH TWO COPIES OF THE F508DEL MUTATION (NACFC 2020) - "In vitro, in human bronchial epithelial cells from F508del homozygous donors, the combination of DIR/POS/ NES increased CFTR chloride transport activity to levels comparable to that elicited by the elexacaftor/tezacaftor/ivacaftor combination... Dirocaftor, posenacaftor and nesolicaftor represent novel CFTR modulators in clinical development."

Clinical • CFTR

Initial evaluation of the ex vivo response to the CFTR potentiator dirocaftor, corrector posenacaftor and amplifier nesolicaftor in organoids derived from cystic fibrosis subjects with ultra-rare mutations (ECFS 2020) - "Based on their response in the organoid test assay a subset of subjects will be invited to participate in a study to confirm clinical efficacy."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Evaluation of combinations of the CFTR potentiator dirocaftor, corrector posenacaftor and amplifier nesolicaftor in cystic fibrosis subjects with two copies of the F508del mutation (ECFS 2020) - "In vitro, in human bronchial epithelial cells from F508del homozygous donors, the combination of DIR/ POS/NES increased CFTR chloride transport activity to levels comparable to that elicited by the elexacaftor/tezacaftor/ivacaftor combination... Dirocaftor, posenacaftor and nesolicaftor represent novel CFTR modulators in clinical development."

Clinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Study Designed to Assess the Safety, Tolerability, PK and Food Effect of PTI-808 in Healthy Volunteers (clinicaltrials.gov) - P1; N=70; Active, not recruiting; Sponsor: Proteostasis Therapeutics, Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Biosimilar • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology

Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis (clinicaltrials.gov) - P1; N=135; Recruiting; Sponsor: Proteostasis Therapeutics, Inc.; Active, not recruiting ➔ Recruiting

Enrollment open • Biosimilar • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology

Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis (clinicaltrials.gov) - P1/2; N=179; Completed; Sponsor: Proteostasis Therapeutics, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Study Assessing PTI-428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis on KALYDECO® as Background Therapy (clinicaltrials.gov) - P1; N=15; Completed; Sponsor: Proteostasis Therapeutics, Inc.; Recruiting ➔ Completed

Trial completion

Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis (clinicaltrials.gov) - P1/2; N=180; Active, not recruiting; Sponsor: Proteostasis Therapeutics, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

INITIAL RESULTS EVALUATING THE FIRST-IN-CLASS CFTR AMPLIFIER, PTI-428, IN SUBJECTS WITH CF ON BACKGROUND TREATMENT WITH TEZACAFTOR/ IVACAFTOR (NACFC 2019) - "PTI-428 is the only known CFTR modulator in clinical development that is genotype agnostic. Treatment with PTI-428 led to an increase in CFTR protein production of approximately 50% in subjects with CF on background treatment with tezacaftor/ivacaftor, similar to that seen with PTI-428 plus lumacaftor/ivacaftor. Subject selection may explain the differential impact of PTI-428 on ppFEV1 on backgrounds of lumacaftor/ivacaftor versus tezacaftor/ivacaftor, and thus provides an important example of possible selection bias in the current era of the availability of multiple CFTR modulators."

Clinical

INITIAL RESULTS EVALUATING THE FIRST-IN-CLASS CFTR AMPLIFIER, PTI-428, IN SUBJECTS WITH CF ON BACKGROUND TREATMENT WITH TEZACAFTOR/ IVACAFTOR (NACFC 2019) - "PTI-428 is the only known CFTR modulator in clinical development that is genotype agnostic. Treatment with PTI-428 led to an increase in CFTR protein production of approximately 50% in subjects with CF on background treatment with tezacaftor/ivacaftor, similar to that seen with PTI-428 plus lumacaftor/ivacaftor. Subject selection may explain the differential impact of PTI-428 on ppFEV1 on backgrounds of lumacaftor/ivacaftor versus tezacaftor/ivacaftor, and thus provides an important example of possible selection bias in the current era of the availability of multiple CFTR modulators."

Clinical

CURRENT STATUS OF THE PROTEOSTASIS THERAPEUTICS CFTR MODULATOR DEVELOPMENT PROGRAM (NACFC 2019) - P1/2; "The dual combination of PTI 801 with PTI 808 has shown greater measures of CFTR activity than the marketed dual combinations of lumacaftor/ ivacaftor and tezacaftor/ivacaftor in homozygous and heterozygous F508del cell cultures. Similarly, in vitro CFTR activity of the triple combination of PTI 801 and PTI 808 with the PTI 428 amplifier is superior to that seen with tezacaftor/ivacaftor in combination with VX-659 (corrector) in homozygous and heterozygous F508del cell cultures (data to be presented)...A phase 2 study is currently ongoing to evaluate the effects of PTI 808 in combination with PTI 801, with or without PTI 428, over a 28-day treatment period in CF subjects who are either homozygous or heterozygous for the F508del CFTR genotype. The goal is to initiate a phase 3 study in 2020."

EVALUATION OF NOVEL CFTR MODULATOR COMBINATIONS OF THE CORRECTOR PTI-801, POTENTIATOR PTI-808, AND AMPLIFIER PTI-428 IN CF SUBJECTS (NACFC 2019) - "In vitro, in human bronchial epithelial cells from F508del homozygous donors, the combinations of PTI-801+PTI-808 and PTI-801+PTI-808+PTI-428 increased CFTR chloride transport activity by 193% and 369%, compared to that of tezacaftor+ivacaftor, respectively, suggesting a superior in vitro response to a currently approved modulator combination. PTI-801, PTI-808 and PTI-428 represent novel CFTR modulators in clinical development."

Clinical

Safety, Tolerability, and Pharmacokinetics of PTI-808, PTI-801, and PTI-428 Combination Therapy in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P1/2; N=12; Completed; Sponsor: Proteostasis Therapeutics, Inc.; Recruiting ➔ Completed; N=32 ➔ 12

Clinical • Combination therapy • Enrollment change • Trial completion

Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis (clinicaltrials.gov) - P1/2; N=180; Recruiting; Sponsor: Proteostasis Therapeutics, Inc.; Phase classification: P1 ➔ P1/2; N=135 ➔ 180; Trial completion date: Jun 2019 ➔ Jan 2020; Trial primary completion date: Jun 2019 ➔ Jan 2020

Clinical • Enrollment change • Phase classification • Trial completion date • Trial primary completion date

Initial results evaluating combinations of the novel CFTR corrector PTI-801, potentiator PTI-808, and amplifier PTI-428 in cystic fibrosis subjects (ECFS 2019) - "In vitro , in human bronchial epithelial cells from F508del homozygous donors, the combination of PTI-801+PTI-808 increased CFTR chloride transport activity by 170 and 193%, compared to that of lumacaftor+ivacaftor and tezacaftor+ivacaftor, respectively, suggesting a superior in vitro response to currently approved modulator combinations. PTI-801, PTI-808 and PTI-428 represent novel CFTR modulators in clinical development."

Clinical

Initial results evaluating the novel CFTR corrector PTI-801, potentiator PTI-808, and amplifier PTI-428 in F508del homozygous CF subjects (ECFS 2019) - No abstract available.

Clinical • Late-breaking abstract

"$PTI Receives Orphan Drug Designation in the EU for PTI-428 for the Treatment of Cystic Fibrosis" (@BioStocks)

Orphan drug

Study Assessing PTI-428 Safety, Tolerability, Pharmacokinetics and Effect in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P2; N=40; Completed; Sponsor: Proteostasis Therapeutics, Inc.; Recruiting ➔ Completed

Clinical • Trial completion