RG6341 / Roche - LARVOL DELTA

Efficient Single and Dual Iridium-Catalyzed Stereoselective Hydrogenations to Access trans-Butane-1,2,4-triols. (PubMed, J Am Chem Soc) - "Herein, we report a synthetic methodology for the asymmetric hydrogenation of 4-(4-chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester to (2R,4R)-4-(4-chlorophenyl)-butane-1,2,4-triol ((R,R)-7a), a key GDC-6599 trans-triol building block, in a one-pot, consecutive reaction sequence...Finally, the engagement of novel LCs bearing new, easily accessible PNN ligands based on MeOBIPHAN and BINAN motifs furnished (R,R)-7a in comparable quality, the highest yield (81%), and the lowest possible cost. To the best of our knowledge, such a dual catalytic system was utilized for the first time in the stereoselective synthesis of a pharmaceutical intermediate."

Journal

Data science-driven evolution of the manufacturing process to TRPA1 inhibitor GDC-6599 (ACS-Fall 2025) - "The endgame sequence was amended where a late-stage O-acylation set the stage for API via oxadiazole formation and crystallization. Overall, this second-generation synthesis reduced the step count from 13 to 8, significantly increased the process mass intensity, and improved the overall manufacturability of GDC-6599."

Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases • TRPA1

Solid-State Evaluation of a Newly Emerged Polymorph for Early-Stage Pharmaceutical Development. (PubMed, Mol Pharm) - "This work presents the solid-state evaluation of a new polymorph (Form M) discovered during the early-stage pharmaceutical development of a new chemical entity GDC-6599...Accordingly, Form M was recommended for future API manufacturing and solid dosage form development. Meanwhile, Form A was confirmed to be physically stable in a suspension formulation for extemporaneous preparation and was recommended to support the early cohorts of Phase I clinical studies."

Journal

Characterization of Cough Phenotypes and Mannitol Evoked Coughs in Refractory and Unexplained Chronic Cough (ATS 2025) - P2 | "This study aims to characterize the baseline demographics and clinical profiles of RCC/UCC patients and investigate their responses to mannitol-evoked cough and airway hyper-responsiveness (AHR). Patients diagnosed with RCC (≥1-year duration) with demonstrated hypersensitivity to inhaled mannitol (cough dose ratio [CDR] ≥ 12 participated in this Phase 2a study assessing a novel TRPA-1 antagonist (GDC6599, NCT05660850)... Spontaneous cough is an independent neuro-phenotype in patients with RCC/UCC. Results should be interpreted cautiously due to the small sample size, but suggest airway and cough hypersensitivity to mannitol are modestly correlated and may contribute to increased cough burden in patients with CC."

Asthma • Chronic Cough • Cough • Gastroenterology • Gastroesophageal Reflux Disease • Immunology • Inflammation • Renal Cell Carcinoma • Respiratory Diseases

A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough (clinicaltrials.gov) - P2 | N=80 | Completed | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Completed

Trial completion • Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases

A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough (clinicaltrials.gov) - P2 | N=80 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases

Optimization of TRPA1 antagonists at the cell membrane interface: A tale of two binding sites (ACS-Fall 2024) - "Herein we present the discovery of two development candidates, GDC-0334 and GDC-6599, and describe how their distinct binding sites and location relative to the cell membrane influenced compound optimization and physiochemical profiles. Extension of this work through academic collaborations will also be described."

Asthma • Immunology • Pain • Respiratory Diseases • TRPA1

Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease. (PubMed, J Med Chem) - "Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications."

Journal • Preclinical • Neuralgia • Pain • Respiratory Diseases • TRPA1

Development of an extemporaneous preparation formulation using a simple and non-solubilizing matrix for first in human clinical study. (PubMed, Int J Pharm) - "The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies."

Journal • P1 data • Gastrointestinal Disorder

A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Genentech, Inc. | Phase classification: P2a ➔ P2

Phase classification • Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases

Discovery of TRPA1 antagonist GDC-6599: How mechanistic investigation of pre-clinical toxicity led to a potential first-in-class therapy for respiratory disease (ACS-Fall 2023) - "Based on a thorough mechanistic investigation, anticoagulation effects in vivo are hypothesized to be a result of the formation of a significant amount of an aldehyde oxidase (AO) metabolite, possessing the same pharmacophore as known anti-coagulants (i.e. coumarins, indandiones). Further optimization of the series blocked this AO-mediated metabolism, ameliorating coagulation effects in vivo and resulted in the discovery and advancement of clinical candidate, GDC-6599, currently in Phase II clinical trials for respiratory indications."

Preclinical • Neuralgia • Pain • Respiratory Diseases • TRPA1

A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough (clinicaltrials.gov) - P2a | N=80 | Recruiting | Sponsor: Genentech, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases

A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough (clinicaltrials.gov) - P2a | N=80 | Not yet recruiting | Sponsor: Genentech, Inc.

New P2a trial • Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases