dirocaftor (PTI-808) / 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

Mode of action of the FAIR therapeutics CFTR modulators nesolicaftor, posenacaftor and dirocaftor in in vitro and in vivo preclinical studies (ECFS 2025) - "The metabolism of NES, POS, and DIR showed high recovery and prolonged half-lives (1525 hours). NES is primarily excreted in urine, while POS and DIR are mainly excreted in feces."

Preclinical • CFTR

Safety assessment of the FAIR therapeutics CFTR modulators nesolicaftor, posenacaftor and dirocaftor in CF patients (ECFS 2025) - "Subjects either received background treatment with lumacaftor/ivacaftor or tezacaftor/ivacaftor or no CFTR modulator. The compounds were generally well-tolerated, with NES administered at up to 100 mg daily for 14 days, POS at up to 400 mg daily for 14 days, and DIR at up to 300 mg daily for 7 days. The DIR/POS/NES combination therapy was well tolerated with mostly mild-to-moderate, reversible AEs, and no SAEs attributed to the drugs."

Clinical • Cough • Diabetes • Gastrointestinal Disorder • Infectious Disease • Pain • Respiratory Diseases

14C recovery of the FAIR Therapeutics CFTR modulators Nesolicaftor, Posenacaftor and Dirocaftor in Sprague Dawley rats (ECFS 2025) - "The distribution analysis of the DIR/POS/NES therapy indicates excretion via urine and/or feces. DIR and POS are primarily metabolized by the liver, while NES is metabolized by the kidneys. Total recovery exceeded 90% for each compound over the study period."

Preclinical • Cholangiocarcinoma • Solid Tumor

Metabolic and excretion profiles of the FAIR therapeutics CFTR modulators nesolicaftor, posenacaftor and dirocaftor in humans (healthy volunteers) (ECFS 2025) - "The metabolism of NES, POS, and DIR showed high recovery and prolonged half-lives (1525 hours). NES is mainly excreted via urine, while POS and DIR are excreted through feces."

Clinical • CFTR

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

Subject selection plan for CHOICES clinical trial aiming to assess efficacy of new CFTR modulators and to validate the intestinal organoid model (ECFS 2024) - "Objective : The CHOICES trial, an investigator-initiated study arising from HIT CF Europe project, aims to evaluate the effectiveness of FAIR Therapeutic’s new CFTR modulators dirocaftor/posenacaftor/nesolicaftor (DIR/POS/NES)...Conclusion : This approach enables an unbiased treatment evaluation and by comparing clinical data of this study with organoid response, it enables the validation of the organoid model. This model could provide an accessible and affordable means to make drugs available for patients with cystic fibrosis carrying rare mutations."

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

Identification of organoid responders to CFTR modulators in the HIT-CF Europe project -Underlying the need for new treatment strategies for people with ultra-rare mutations (NACFC 2022) - "Intestinal organoids of PwCF withultra-rare mutations were screened with compounds that had alreadypassed phase I and II clinical trials (dirocaftor (DIR)/posenacaftor (POS)/nesolicaftor (NES) and ELX-02)...In the DIR/POS/NES screen, PDOs were incubated for 24 hours withDIR/POS using a PDO from a F508del/F508del donor incubated for 24 hourswith tezacaftor/ivacaftor as the positive control...Based on organoid responsiveness to ELX-02 and DIR/POS, upto 78% of PwCF that carry ultra-rare mutations could benefit fromupcoming CFTR modulating therapies. Although we have taken a greatstep forward in personalized medicine for PwCF, there is still a large unmetneed for those who haveCFTRclass VII (unrescuable) mutations or variantsthat cannot be restored by the tested CFTR modulating therapies."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • TCF19

Comparison of cystic fibrosis transmembrane conductance regulator rescue in intestinal organoids with Fair Therapeutics triple combination with elexacaftor/tezacaftor/ivacaftor (NACFC 2022) - "One of thesealternatives includes the triple modulator combination by FairTherapeutics (FT) consisting of a CFTR corrector (posenacaftor), potentiator(dirocaftor) and messenger ribonucleic acid amplifier (nesolicaftor). This project is in progress, but preliminary data showpromising results for the FT triple-combination treatment.643 Delivery of gp64-pseudotyped lentivirus carrying codon-optimizedcystic fibrosis transmembrane conductance regulator provides betterfunctional restoration in human cystic fibrosis airway epithelialcultures"

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

[VIRTUAL] First results of the HIT-CF ex vivo organoid study show rescue of CFTR with ultra-rare mutations by a novel triple combination of CFTR modulators (ECFS 2021) - "Here, we report on the efficacy of a novel triple therapy consisting of potentiator dirocaftor (DIR, PTI-808), corrector posenacaftor (POS, PTI-801) and amplifier nesolicaftor (NES, PTI-428) to rescue CFTR function in intestinal organoids... Based on organoid results, 26 individuals will be invited to participate in a clinical trial to confirm clinical efficacy of the investigational triple combo DIR/POS/NES. This is a unique opportunity for these individuals with ultra-rare mutations to benefit from novel drugs. The clinical trial could also validate the organoid-based personalised medicine approach."

Preclinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • TCF19

[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 Assessing the Safety, Tolerability, Pharmacokinetics, Food Effect, and Drug-Drug Interactions of PTI-801 in Healthy Volunteers, and Safety, Tolerability, and Pharmacokinetics of PTI-801 in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P1; N=171; Completed; Sponsor: Proteostasis Therapeutics, Inc.; Recruiting ➔ Completed

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

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 the Safety, Tolerability, Pharmacokinetics, Food Effect, and Drug-Drug Interactions of PTI-801 in Healthy Volunteers, and Safety, Tolerability, and Pharmacokinetics of PTI-801 in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P1; N=180; Recruiting; Sponsor: Proteostasis Therapeutics, Inc.; Trial completion date: Dec 2019 ➔ Mar 2020; Trial primary completion date: Dec 2019 ➔ Mar 2020

Clinical • Trial completion date • Trial primary completion date

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

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 Assessing the Safety, Tolerability, Pharmacokinetics, Food Effect, and Drug-Drug Interactions of PTI-801 in Healthy Volunteers, and Safety, Tolerability, and Pharmacokinetics of PTI-801 in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P1; N=180; Recruiting; Sponsor: Proteostasis Therapeutics, Inc.; Trial completion date: Jun 2019 ➔ Dec 2019; Trial primary completion date: Jun 2019 ➔ Dec 2019

Clinical • Trial completion date • Trial primary completion date

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