This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This ...study was a single‐center, randomized, open, single‐dose, parallel‐controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17‐day observation period after administration, and a 7‐day safety follow‐up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration‐time curve from zero time to the estimated infinite time (AUC0–∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0–∞ geometric mean ratios were 102.9%–122.0% and 97.1%–116.9%, respectively, which were both within the range of 80.00%–125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.
Background and Objective
The combination of rosuvastatin and ezetimibe has promising clinical benefits with a significant safety and tolerability profile. However, there is a lack of clinical data ...supporting the drug–drug interaction (DDI) in Chinese population. Thus, the aim of this study is to assess the potential pharmacokinetic DDI between rosuvastatin and ezetimibe in a Chinese population.
Methods
In this randomized, open-label, phase 1 study, 12 healthy volunteers were randomized to three treatment groups: 10 mg rosuvastatin plus 10 mg ezetimibe, 10 mg rosuvastatin alone, and 10 mg ezetimibe alone under fasting conditions. The plasma concentrations of rosuvastatin and ezetimibe were determined, and the pharmacokinetic parameters were calculated. Primary endpoints were peak plasma concentration (
C
max
), area under the curve from zero to last measurement (AUC
0–t
), and area under the curve from zero to infinity (AUC
0–∞
) that were log-transformed, and co-administration was compared with monotherapy to evaluate the DDI.
Results
The geometric mean ratios (GMRs) of rosuvastatin with 90% confidence intervals (CIs) were 0.94 (0.80–1.12) for
C
max
, 0.96 (0.85–1.08) for AUC
0–t
, and 0.96 (0.86–1.07) for AUC
0–∞
when administered in combination with ezetimibe versus administered alone. The GMRs of unconjugated ezetimibe and total ezetimibe with 90% CIs were 1.15 (1.00–1.32) and 0.93 (0.80–1.07) for
C
max
, 0.96 (0.84–1.10) and 0.95 (0.83–1.08) for AUC
0–t
, and 1.06 (0.96–1.18) and 0.94 (0.80–1.11) for AUC
0–∞
, respectively, when administered in combination with rosuvastatin versus administered alone.
Conclusion
Co-administration of rosuvastatin and ezetimibe showed no clinically significant pharmacokinetic interactions in a healthy Chinese population.
•Sonrotoclax is a potent and selective BCL2 inhibitor that is also effective in venetoclax-resistant BCL2 mutants both in vitro and in vivo.•The crystal structure of BCL2 G101V:sonrotoclax elucidates ...the molecular basis of overcoming G101V–induced venetoclax resistance.
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Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation–induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.
The first-in-class selective BCL2 inhibitor (BCL2i), venetoclax, has improved outcomes for patients with chronic lymphocytic leukemia and acute myeloid leukemia. Liu and colleagues reveal the structure and preclinical characterization of a new BCL2i, sonrotoclax, which binds with higher affinity to BCL2 than venetoclax and induces apoptosis in models of venetoclax-induced BCL2 mutations. These data suggest that sonrotoclax could find clinical applications in BCL2-dependent malignancies and underpin ongoing early-phase clinical trials with the drug.
