posenacaftor (PTI-801) / Kineta - LARVOL DELTA

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

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

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] 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

Initial results evaluating the add-on effect of the novel CFTR corrector PTI-801 in cystic fibrosis subjects (ECFS 2019) - "PTI-801 is being studied in clinical trials designed to determine safety, tolerability and effect in subjects with CF currently receiving ORKAMBI® (lumacaftor+ivacaftor) as background therapy. PTI-801 represents a novel third generation CFTR corrector in clinical development."

Clinical

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

Proteostasis Therapeutics announces broad new dataset from proprietary combination and add-on CFTR modulator studies in cystic fibrosis patients (PRNewswire) - “Proteostasis Therapeutics…announced results from Phase 1 clinical studies of its proprietary cystic fibrosis transmembrane conductance regulator (CFTR) modulators: PTI-801, a third-generation CFTR corrector; PTI-808, a novel CFTR potentiator; and PTI-428, a novel CFTR amplifier….Based on the totality of data, the Company will be launching three new Phase 2, 28-day studies in CF subjects with at least one F508del mutation….These studies will position the Company to complete Phase 2 enrollment in 2019 and initiate Phase 3 studies in mid-2020, as previously guided.”

Enrollment status • New P2 trial • P1 data • Trial initiation date

Proteostasis plunges on weak data from cystic fibrosis study (Zacks) - “Shares of Proteostasis Therapeutics…plunged 67.8% on Mar 25, after it announced data from a dose-selecting phase I study evaluating its triple combination candidate in patients with cystic fibrosis….Shares of Proteostasis have decreased 59.6% so far this year against the industry’s 8.1% growth.“

Stock price

Proteostasis down 48% premarket on disappointing data on CF candidates (SeekingAlpha) - “Proteostasis Therapeutics…slumps 48% premarket on increased volume on the heels of its announcement of Phase 1 data on cystic fibrosis (CF) triplet therapy of PTI-801 (CFTR corrector), PTI-808 (CFTR potentiator) and PTI-428 (CFTR amplifier) and separate studies of PTI-801 and PTI-428 as add-on therapies to background tezacaftor/ivacaftor [Vertex Pharmaceuticals'”

Stock price

Proteostasis selected to join European Consortium to pioneer personalized medicine in cystic fibrosis (PRNewswire) - “PTI-428, PTI-801 and PTI-808 Testing Underway in Organoids from CF Patients, with Potential for Clinical Data in 2020...Proteostasis Therapeutics…announced it has been invited to join the HIT-CF Europe, a pan European strategic initiative which seeks to validate a personalized therapy approach for CF patients with extremely rare genetic mutations….patients may be invited to participate in clinical trials with the investigational drugs to validate the ability of the in vitro response to predict clinical benefit. This project is fully funded by a €6.7M award from the Horizon 2020 EU funding program.”

Clinical data • Financing • Licensing / partnership

Phase update (clinicaltrials.gov) - P1➔P2, Cystic Fibrosis

Phase shift