BGB-16673 Has Low Risk of CYP3A-Mediated Drug-Drug Interactions in Healthy Volunteers in Phase 1 Studies

The investigational BTK degrader BGB-16673 demonstrated a low risk of clinically relevant CYP3A-mediated drug-drug interactions, supporting greater dosing flexibility than is typical for currently available BTK inhibitors, according to data from 2 phase 1 studies conducted in healthy participants that were presented at the 2026 EHA Congress.¹

In the human absorption, metabolism, and excretion (AME) BGB-16673-106 study (NCT06776679), fecal excretion was the predominant route of elimination, accounting for 88.5% of administered radioactivity, with only 0.07% of radioactivity recovered in urine. In the fixed-sequence drug-drug interaction BGB-16673-105 study (NCT06906809), coadministration with the strong CYP3A inducer phenytoin (Dilantin) or the strong CYP3A inhibitor itraconazole (Sporanox) produced changes in BGB-16673 exposure that remained close to unity, with no clinically meaningful effect.

“The combined [BGB-16673-105] and [BGB-16673-106] findings indicate that human systemic disposition is not meaningfully driven by CYP3A-mediated oxidative clearance, despite an in vitro CYP3A metabolism signal,” lead study author Bilal Tariq, of BeOne Medicines, and coauthors, wrote in the poster presentation.

Why was BGB-16673’s drug-drug interaction profile evaluated?

BGB-16673 is a potential first-in-class oral BTK degrader that targets BTK for degradation through the proteasome pathway, which can initiate tumor regression. Real-world studies have shown that CYP3A inhibitors are often used in the treatment of patients with B-cell malignancies, including those with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, many antifungal medications, such as azoles, strongly inhibit CYP3A. The BTK inhibitors that re currently available for clinical use are primarily metabolized by CYP3A and require the use of caution or dose modification when co-administered with CYP3A modulators because of exposure changes.

Questions regarding drug-drug interactions in the context of BTK inhibitors are central to the evolving CLL treatment paradigm, where covalent BTK inhibitors remain a first-line standard and BTK degraders are emerging as a distinct class. At EHA 2026, the first-in-class BTK degrader tacabrutideg produced an overall response rate of 94.1% at the recommended phase 2 dose in patients with relapsed/refractory CLL/SLL,² whereas a separate real-world analysis characterized first-line treatment discontinuation patterns with covalent BTK inhibitors in patients with CLL.³

How were the absorption/metabolism/excretion and drug-drug interaction studies with BGB-16673 designed?

BGB-16673-106 was an open-label, radiolabeled absorption, metabolism, and excretion study in 8 healthy male participants (mean age, 33.8 years) who received a single oral 200-mg dose of [¹⁴C]-BGB-16673 containing approximately 200 µCi.¹ The study collected urine and feces for mass balance, excretion, and metabolite profiling, with intensive serial pharmacokinetic (PK) sampling in the fed state.

BGB-16673-105 was an open-label, fixed-sequence crossover study evaluating the effect of strong CYP3A induction and inhibition on BGB-16673 PK. Part A evaluated phenytoin as a strong CYP3A inducer; participants (n = 19; mean age, 41.4 years) received a single 200-mg dose of BGB-16673 alone and in combination with phenytoin at 100 mg 3 times daily. Part B evaluated itraconazole as a strong CYP3A inhibitor; participants (n = 18; mean age, 38.9 years) received a single 50-mg dose of BGB-16673 alone and in combination with itraconazole at 200 mg.

What did the studies reveal about BGB-16673 elimination and CYP3A modulation?

In the absorption, metabolism, and excretion study, the overall mean combined rate of recovery of total radioactivity in urine and feces was 88.6% through 816 hours post-dose, with most administered radioactivity recovered in feces between 0 and 72 hours. Unchanged parent BGB-16673 was the predominant component in feces, with minor hepatic metabolites observed. Parent BGB-16673 was the dominant circulating component in plasma, accounting for approximately 82.3% of total radioactivity, with a geometric mean plasma terminal half-life of approximately 82.4 hours. These findings supported the identification of the predominant elimination method of unchanged parent drug to be through intestinal or biliary secretion, with limited oxidative hepatic metabolism and negligible renal contribution.

In the dose-dose interaction study, co-administration with phenytoin increased the area under the curve (AUC) from time 0 to the last quantifiable concentration (AUC_₀-last) by approximately 9% and the increased maximum concentration (C_max) by approximately 22%, with geometric least-squares mean (GLSM) ratios of 1.09 (90% CI, 0.84-1.42) for AUC₀-last and 1.22 (90% CI, 0.95-1.56) for C_max. Co-administration with itraconazole resulted in generally comparable AUC_₀-last (GLSM ratio, 1.05; 90% CI, 0.84-1.33) and an approximately 23% lower C_max (GLSM ratio, 0.77; 90% CI, 0.58-1.02). Variability within the participant groups was high across these analyses, and the findings of post hoc sensitivity analyses were directionally consistent with the primary results.

What was the safety profile of BGB-16673 in healthy volunteers?

In part A of BGB-16673-105, 89.5% of participants experienced at least 1 treatment-emergent adverse effect (TEAE), as did 94.4% of participants in part B; no grade 3 or higher TEAEs, serious AEs, or deaths were reported in either part. Most TEAEs were grade 1, and petechiae was the most frequently reported AE in both parts. In part A, 1 participant discontinued because of grade 1 hematuria considered related to study intervention, with a normal follow-up urinalysis after drug withdrawal. In study BGB-16673-106, the only reported TEAE was grade 1 diarrhea that resolved and was not considered treatment related, with no serious AEs, deaths, or AE-related discontinuations. No clinically meaningful treatment-related trends or abnormalities were observed in laboratory tests, vital signs, electrocardiograms, or physical examinations across either study.

“These findings collectively indicate a low risk of clinically relevant CYP3A-mediated drug-drug interactions and support greater dosing flexibility for BGB-11673 than is typical for currently available BTK inhibitors,” the authors concluded.

References

1. Tariq B, Zhang H, Takai M, et al. BGB-16673, a Bruton tyrosine kinase degrader, has low risk of CYP3A-mediated drug-drug interaction: phase 1 absorption, metabolism, and excretion and drug-drug interaction study results. Presented at: 2026 EHA Congress. June 11-14, 2026; Stockholm, Sweden. Abstract 1711.
2. OncLive Staff. Tacabrutideg drives responses in heavily pretreated CLL/SLL. OncLive.com. June 14, 2026. Accessed June 18, 2026. https://www.onclive.com/view/tacabrutideg-drives-responses-in-heavily-pretreated-cll-sll
3. Ryan C. Real-world analysis sheds light on treatment discontinuation with covalent BTK inhibitors first-line CLL. OncLive.com. June 18, 2026. Accessed June 18, 2026. https://www.onclive.com/view/real-world-analysis-sheds-light-on-treatment-discontinuation-with-covalent-btk-inhibitors-first-line-cll