GDC-0334 / Roche - LARVOL DELTA

Beyond single-dose human mass balance study: minimizing subject confinement and enabling true steady-state assessment with a novel multiple-dose design proposal. (PubMed, Drug Metab Dispos) - "To address these challenges, a novel study design implementing multiple fractional [14C]-microtracer doses was proposed and evaluated in a rat proof-of-concept study using [14C]GDC-0334...SIGNIFICANCE STATEMENT: This study validates a novel multiple-dose mass balance design that overcomes the limitations of traditional single-dose methods by enabling evaluation at true steady state. This new approach offers a more reliable and efficient framework for human mass balance studies, with significant benefits including reduced subject confinement, simpler logistics, and more robust sample analysis and data interpretation, ultimately improving the assessment of drug metabolism and clearance."

Journal

Investigating the Effects of Formulation Variables on the Disintegration of Spray Dried Amorphous Solid Dispersion Tablets. (PubMed, J Pharm Sci) - "GDC-0334: copovidone (PVPVA) 60: 40 ASD prepared by spray drying was selected as the model ASD system...Water uptake experiments were performed on selected tablets and the results demonstrated a positive correlation with tablet disintegration time, indicating water penetration is a major contributing step for the disintegration of our ASD tablets. Overall, this work provides a rationale for excipient selection and insights into building a platform formulation approach for developing immediate-release ASD tablets."

Journal

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

Membrane-facilitated access and binding of TRPA1 antagonists to a transmembrane site: Chameleonic efficiency of ligands affects their pharmacology (ACS-Fall 2024) - "Moreover, association and dissociation simulations revealed a unique flipping motion of the sulfonamide group of GDC-0334 in facilitating the entry into the receptor, determining the ligand’s affinity. The novel insights from this study highlight the importance of optimal lipid interactions in facilitating the favorable access and high-affinity binding of ligands and warrant the inclusion of structural features such as the trifluoromethyl group during lead optimization while targeting transmembrane lipid-facing sites."

Asthma • Immunology • Inflammation • Neuralgia • Pain • Respiratory Diseases

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies. (PubMed, Mol Pharm) - "Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities."

Journal

Impact of Surfactant Selection and Incorporation on in situ Nanoparticle Formation from Amorphous Solid Dispersions. (PubMed, Int J Pharm) - "The ASD nanoparticles produced by the Genentech developmental compound, GDC-0334, were highly stable and retained their original particle size and amorphous feature for at least 18 hours under biorelevant conditions. The high degree of nanoparticle formation from spray dried GDC-0334 containing Tween 80 combined with the superior physical stability of the nanoparticles also translated to enhanced in vivo performance in a rat pharmacokinetics study."

Journal

Translational and pharmacokinetic-pharmacodynamic application for the clinical development of GDC-0334, a novel TRPA1 inhibitor. (PubMed, Clin Transl Sci) - "HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The models developed based on TRPA1 agonist-induced dermal blood flow inhibition data can be used to predict PK-PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1."

Clinical • Journal • PK/PD data • Respiratory Diseases

A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment. (PubMed, J Exp Med) - "In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma."

Journal • Asthma • Immunology • Inflammation • Pain • Respiratory Diseases

Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015-2019). (PubMed, Expert Opin Ther Pat) - "During this period, three new molecules entered the clinic (ODM-108, HX-100, and GDC-0334) bringing the total number of TRPA1 antagonists to reach clinical trials to five (including two earlier molecules, CB-625 and GRC 17536); however, to our knowledge, development of all five molecules have been discontinued. Further clinical trials of recent TRPA1 antagonists with good pharmacokinetics would be needed to help understand TRPA1 involvement in human diseases and its potential as a therapeutic target."

Journal • Asthma • Pain • Respiratory Diseases

A Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of Single and Multiple Ascending Doses of GDC-0334 and the Effect of Food on the Pharmacokinetics of GDC-0334 in Healthy Adult Participants (clinicaltrials.gov) - P1; N=66; Terminated; Sponsor: Genentech, Inc.; N=120 ➔ 66; Recruiting ➔ Terminated; Molecule development was terminated

Clinical • Enrollment change • Trial termination