A Single-dose, Open-label, Randomized, 4-way Crossover Study to Assess the Relative Bioavailability And Food Effect of a Tablet Formulation of GDC-0276 in Healthy Subjects

This open-label, randomized, 4-way crossover study in healthy participants will determine the relative bioavailability of the tablet formulation relative to the capsule formulation and the effect of a high-fat and low-fat meal on the relative bioavailability of the tablet formulation.

Start Date01 Jun 2016

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with RG-7893

100 Translational Medicine associated with RG-7893

100 Patents (Medical) associated with RG-7893

Literatures (Medical) associated with RG-7893

25 Mar 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Acyl-sulfonamide Na_v1.7 Inhibitors GDC-0276 and GDC-0310

Q1 · MEDICINE

Article

Author: Johnson, J.P. ; Chen, Chien-An ; DiPasquale, Antonio ; Ortwine, Daniel F. ; White, Andrew D. ; Hackos, David H. ; Jia, Qi ; Bankar, Girish ; Chang, Jae H. ; Cohen, Charles J. ; Chang, Elaine ; Mezeyova, Janette ; Shields, Shannon D. ; Focken, Thilo ; Nelkenbrecher, Karen ; Hemeon, Ivan ; Waldbrook, Matthew ; Li, Jun ; Zabka, Tanja S. ; Zenova, Alla Y. ; Andrez, Jean-Christophe ; Sojo, Luis ; Wilson, Michael S. ; McKerrall, Steven J. ; Xie, Zhiwei ; Safina, Brian S. ; Kwan, Rainbow ; Robinette, C. Lee ; Maher, Jonathan ; Kim, Amy ; Sutherlin, Daniel P. ; Sheng, Tao ; Dean, Richard ; Lindgren, Andrea ; Young, Clint ; Chowdhury, Sultan ; Verschoof, Henry ; Sun, Shaoyi ; Bergeron, Philippe ; Decker, Shannon M. ; Reese, Rebecca ; Chen, Jun ; Lin, Sophia ; Khakh, Kuldip ; Pang, Jodie ; Misner, Dinah ; Dehnhardt, Christoph M.

Na_v1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Na_v1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Na_v1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Na_v selectivity and pharmacokinetic profile over 1.

04 Jan 2021·Molecular PharmaceuticsQ2 · MEDICINE

Isothermal Crystallization Monitoring and Time–Temperature-Transformation of Amorphous GDC-0276: Differential Scanning Calorimetric and Rheological Measurements

Q2 · MEDICINE

Article

Author: Nagapudi, Karthik ; Cheng, Sixue ; McKenna, Gregory B. ; Chakravarty, Paroma

Cold crystallization of amorphous pharmaceuticals is an important aspect in the search to stabilize amorphous or glassy compounds used as amorphous pharmaceutical ingredients (APIs). In the present work, we report results for the isothermal crystallization of the compound GDC-0276 based on differential scanning calorimetric and rheometric measurements. The kinetics of isothermal crystallization from the induction time to the completion of crystallization can be described by the classic Johnson-Mehl-Avrami (JMA) equation. The time-temperature-transformation (TTT) diagrams were constructed for two time points-that of induction and that of completion of crystallization. The results show that the rheological measurement for GDC-0276 has a better overall sensitivity in detection of the early stage nucleation and, consequently, detects the onset of crystallization sooner than does the differential scanning calorimetry. Rheological measurements were also used to obtain the temperature dependence of the viscosity of GDC-0276 and the relevant parameters were used in a modified form of the JMA model to describe the temperature dependence of the crystal induction and completion times, that is, the TTT diagram for the material. In the modification, we assumed that the kinetics followed the viscosity to the 0.75 power as suggested by the recent work of Huang et al. (Huang, C., et al., J. Chem. Phys.2018,149, 054503). The relationship and the possible impact on crystallization kinetics of the break-down of the Stokes-Einstein relation in glass-forming liquids are discussed. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σ_SL was obtained for GDC-0276 and was compared with that obtained from the melting point depression measurements of the material confined in nanoporous glasses. The differences between the values from the two methods are discussed.

01 Sep 2019·Clinical Drug InvestigationQ4 · MEDICINE

Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers

Q4 · MEDICINE

Article

Author: Tagen, Michael ; Rothenberg, Michael E ; Chang, Jae H ; Hackos, David H ; Boyce-Rustay, Janel ; Hains, Avis ; Ward, Michael ; Sutherlin, Dan ; Friesenhahn, Michel ; Cho, William

BACKGROUND AND OBJECTIVECurrent pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that Na_V1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel Na_V1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects.METHODSThis phase I, randomized, double-blind, placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined.RESULTSThree stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred.CONCLUSIONGDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.

100 Deals associated with RG-7893

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Indication	Highest Phase	Country/Location	Organization	Date
Pain	Phase 1	-	F. Hoffmann-La Roche Ltd.	-
Pain	Phase 1	-	Xenon Pharmaceuticals, Inc.	-
Pain	Discovery	CA	-	-

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