First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL

Byrd, John C.; Smith, Stephen D.; Wagner‐Johnston, Nina D.; Sharman, Jeff P.; Chen, Andy I.; Advani, Ranjana H.; Augustson, Bradley; Marlton, Paula; Commerford, S. Renee; Okrah, Kwame; Liu, Lichuan; Murray, Elaine R.; Penuel, Elicia; Ward, Ashley F.; Flinn, Ian W.

doi:10.18632/oncotarget.24310

Cited by 73 publications

(64 citation statements)

References 39 publications

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“…Fenebrutinib (GDC-0853, RG7845) is an orally administered BTK inhibitor that is highly selective and noncovalent, leading to reversible binding, intended to block B cell proliferation and the resulting excessive immune response seen in autoimmune disorders (21). Fenebrutinib has previously been evaluated in healthy subjects (22) and patients with resistant B cell lymphoma or chronic lymphocytic leukemia (23).…”

Section: Bruton's Tyrosine Kinase (Btk) and Fenebrutinibmentioning

confidence: 99%

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Chan¹,

Yu²,

Chinn³

et al. 2020

Pharm Res

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Purpose Fenebrutinib (GDC-0853), a Bruton's tyrosine kinase (BTK) inhibitor was investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis (RA). Our aim was to apply a model-informed drug development (MIDD) approach to examine the totality of available clinical efficacy data. Methods Population pharmacokinetics (popPK) modeling, exposure-response (E-R) analysis, and model-based metaanalysis (MBMA) of fenebrutinib were performed based on the Phase 2 data. Results PopPK of fenebrutinib after oral administration was described using a 3-compartment model with linear elimination and a flexible absorption transit compartment model. Healthy subjects had a 52% higher apparent clearance than patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28 (CRP) data modeled fenebrutinib effect with an E max function, and an efficacy plateau was achieved within the exposure range obtained in the Phase 2 clinical trial. Based on literature data, a summary-level clinical efficacy database was constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the placebo and adalimumab arms of the Phase 2 clinical trial were found to be consistent with historical data for these treatments. Conclusions Our multi-pronged approach applied MIDD to maximize knowledge extraction of efficacy data and enabled robust interpretation from a Phase 2 clinical trial. KEY WORDS Bruton's tyrosine kinase (BTK) inhibitor. exposure-response. model-based meta-analysis. population pharmacokinetics. rheumatoid arthritis ABBREVIATIONS AUC Area under the concentration-time curve BTK Bruton's tyrosine kinase CL/F Apparent clearance C max Maximum concentration C min Trough concentration CRP C-reactive protein DAS28 Disease Activity Score with 28-joint counts EBE Empirical Bayes estimates E-R Exposure-response F1 Relative extent of absorption FOCE-I First order conditional estimation with interaction MBMA Model-based meta-analysis MIDD Model-informed drug development MTT Mean transit time MTX Methotrexate NLME Non-linear mixed effects NTR Number of transit compartments pcVPC Prediction-corrected visual predictive check PD Pharmacodynamic The original version of this article was revised: The article was published with an incomplete title. The complete title is "Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis".

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Section: Bruton's Tyrosine Kinase (Btk) and Fenebrutinibmentioning

confidence: 99%

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Chan¹,

Yu²,

Chinn³

et al. 2020

Pharm Res

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“…Fenebrutinib appears unique due to its high selectivity (for BTK versus nontarget kinases) relative to other BTK inhibitors as well as its noncovalent binding mode (15). Phase I clinical studies have shown fenebrutinib to be well-tolerated with no safety signals precluding further clinical development (16,17).…”

Section: Introductionmentioning

confidence: 99%

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

Tuckwell¹,

Katsumoto

Zhao³

et al. 2020

Arthritis & Rheumatology

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Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

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“…GDC-0853 suppresses downstream BCR signaling, resulting in downregulation of the NF-κB pathway and inhibition of cell proliferation [112,113]. In a phase I study, GDC-0853 was indicated in 24 patients with relapsed or refractory non-Hodgkin lymphoma (10 patients) or CLL (14 patients) [114]. Six patients were positive for C481S mutation.…”

Section: Gdc-0853mentioning

confidence: 99%

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia

Puła

Gołoś

Górniak

et al. 2019

Cancers

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Ibrutinib is the first Bruton's tyrosine kinase (BTK) inhibitor, which showed significant clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients regardless of cytogenetic risk factors. Recent results of phase III clinical trials in treatment-naïve CLL patients shift the importance of the agent to frontline therapy. Nevertheless, beside its clinical efficacy, ibrutinib possesses some off-target activity resulting in ibrutinib-characteristic adverse events including bleeding diathesis and arrhythmias. Furthermore, acquired and primary resistance to the drug have been described. As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors' resistance and discuss the post-ibrutinib treatment options.

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First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL

Cited by 73 publications

References 39 publications

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia

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