Pharmacodynamic Profile Research Articles

Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Proline Henagliflozin in Chinese Subjects with Varying Degrees of Liver Dysfunction.

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (UCr) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population.

The Class I Histone Deacetylase Inhibitor as a Potent Therapeutic Target for Treating Glioblastoma and Mocetinostat as a Novel Inhibitor in the Induction Death of Cancer Cells

Epigenetic abnormality is one of the hallmarks of glioblastoma cancer cells. Histone deacetylase (HDAC) modification has a crucial role in epigenetic abnormality, which results in the initiation and progression of glioblastoma cancer cells. The selective HDAC inhibitors are well-known epigenetic regulators and promising anti-cancer agents that target specific HDAC enzymes and inhibit the proliferation of many cancer cells. Selective HDAC inhibitors isoform provides a high efficacy as chemotherapy in inhibiting cancer confirmation compared to non-selective HDAC inhibitors. Additionally, selective HDAC inhibitors suppress Class -I HDAC1, HDAC2, HDAC3, and HDAC11. HDAC class I inhibitors induce apoptosis, differentiation, autophagic death cells, and reactive oxygen species (ROS)- induced cell death, inhibit cell migration, invasion, and angiogenesis in cancer cells, while the normal cells showed more resistance to HDAC class I inhibitors. Mocetinostat (MGCD0103), a benzamide histone deacetylase, is a potent anti-cancer therapy for the treatment of several cancer cell lines and induction of autophagy. It has been approved by The Food and Drug Administration (FDA) for the treatment of Hodgkin lymphoma (HL) cell lines. MGCD0103 is a synthesized and selective HDAC inhibitor that has vigorous inhibitory activity against Class-I and IV HDAC. MGCD0103 is well tolerated and has favorable pharmacokinetic properties, pharmacodynamic profile, and fast absorption within 1 hour after oral administration, long elimination half-life, and sustained HDAC inhibition. Therefore, MGCD0103 is expected to be a promising anti-cancer drug for treating several types of human cancer cells. Keywords: MGCD0103; Apoptosis; Differentiation; Gliblastoma; HDAC; inhibitors.

Study on genotype and phenotype of novel CYP2D6 variants using pharmacokinetic and pharmacodynamic models with metoprolol as a substrate drug.

To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug.

The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium-glucose cotransporter-2 inhibitor, in type 2 diabetes.

To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.

Characterization of structural, biochemical, pharmacokinetic, and pharmacodynamic properties of the LSD1 inhibitor bomedemstat in preclinical models.

Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes. Bomedemstat was characterized via crystallization, flavine adenine dinucleotide spectrophotometry, and enzyme kinetics. On-target effects were assessed in relevant prostate cancer cell models by measuring proliferation and H3K4 methylation using western blot analysis. In vivo, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of bomedemstat are also described. Structural, biochemical, and PK/PD properties of bomedemstat, an irreversible, orally-bioavailable inhibitor of LSD1 are reported. Our data demonstrate bomedemstat has >2500-fold greater specificity for LSD1 over monoamine oxidase (MAO)-A and -B. Bomedemstat also demonstrates activity against several models of advanced CRPC, including NEPC patient-derived xenografts. Significant intra-tumoral accumulation of orally-administered bomedemstat is measured with micromolar levels achieved in vivo (1.2 ± 0.45 µM at the 7.5 mg/kg dose and 3.76 ± 0.43 µM at the 15 mg/kg dose). Daily oral dosing of bomedemstat at 40 mg/kg/day is well-tolerated, with on-target thrombocytopenia observed that is rapidly reversible following treatment cessation. Bomedemstat provides enhanced specificity against LSD1, as revealed by structural and biochemical data. PK/PD data display an overall safety profile with manageable side effects resulting from LSD1 inhibition using bomedemstat in preclinical models. Altogether, our results support clinical testing of bomedemstat in the setting of mCRPC.

Abstract CT183: Initial results from a phase 1a/1b study of STK-012, a first-in-class α/β IL-2 receptor biased partial agonist in advanced solid tumors (NCT05098132)

Abstract Background: STK-012 is a first-in-class α/β-IL-2R biased partial agonist designed to drive antitumor activity by selectively stimulating CD25+ antigen activated T cells, while avoiding hallmark IL-2 toxicities by sparing pleotropic activation of lymphocytes including NK cells. Methods: STK-012-101 is a Phase 1a/b study of STK-012 administered subcutaneously in subjects with advanced, relapsed/refractory (r/r) solid tumors. During Phase 1a, subjects are enrolled in a 3+3 dose escalation to STK-012 as monotherapy (QW or Q3W) or STK-012 + pembrolizumab (Q3W) followed by Phase 1b expansions. Results: Phase 1a and preliminary Phase 1b data are being presented for STK-012 monotherapy. As of Oct 23rd, 2023, 45 subjects were treated at 7 dose levels (DL) across 2 schedules (QW at 0.375 mg and 0.75mg; Q3W at 0.75mg-3mg). The most common tumors were NSCLC (35.6%) and RCC (20%). The most common treatment related AEs (TRAEs) were maculo-papular rash (38%), injection site reactions (28.9%), fatigue (28.9%), and nausea (24.4%). Grade 3 TRAEs occurred in 12 subjects (26.6%) and included maculo-papular rash (4), vomiting (2), nausea (1), diarrhea (1), enterocolitis (1), arthralgia (1), urticaria (1), periorbital edema (1), blood creatinine increase (1) and leukocytosis (1). One subject had a Grade 4 TRAE of anaphylaxis in Cycle 9 after the data extract date. TRAEs were reversible, and no subjects had Grade 5 TRAEs. No subjects had capillary leak syndrome and &amp;lt;5% experienced other IL-2 hallmark TRAEs (hypotension [4.4%], AST/ALT increase [0%], pyrexia [4.4%], peripheral edema [4.4%]). No DLTs were observed. The maximum administered dose of STK-012 was 3mg Q3W. A DL of 2.25mg Q3W was advanced into Phase 1b based on safety, pharmacokinetic (PK) and pharmacodynamic (PD) data. Peripheral PD data showed STAT5 phosphorylation in CD25+ T cells and a dose dependent increase in activated T cells (Ki-67+CD38+CD8+) and serum IFNγ. Expansion of NK cells and Tregs was limited. STK-012 has a half-life of 4 days. Of 38 efficacy evaluable subjects, 3 had a partial response (PR) and 17 had stable disease as best overall response by RECIST V1.1. The PRs included 2 confirmed (anti-PD-1 r/r NSCLC and RCC) and 1 unconfirmed (anti-PD-1 r/r SCCHN) with the RCC subject in response for over 9 months with treatment ongoing. After the data extract date, a fourth subject achieved a PR (confirmed) with 80% reduction in target lesions (anti-PD-1/CTLA-4 and TKI r/r RCC) with treatment ongoing. Monotherapy Phase 1b dose expansions in r/r NSCLC and r/r RCC are ongoing. Conclusions: In our ongoing Phase 1a/b trial, STK-012 demonstrated a favorable safety, PK, and PD profile which is distinct from that of aldesleukin and non-α IL-2 analogues. Peripheral PD and PK data support selectivity for IL-2R α/β. Preliminary monotherapy efficacy in subjects who are r/r to prior immunotherapy warrants further development. Citation Format: Benjamin Izar, Dmitriy Zamarin, David R. Spigel, Christopher J. Hoimes, David F. McDermott, Kartik Sehgal, Yana G. Najjar, Adam J. Schoenfeld, Edward B. Garon, Ryan J. Sullivan, Brian S. Henick, Ticiana A. Leal, Michael E. Hurwitz, Rana R. McKay, Natalie Busby, Anita Mehta-Damani, Alex Azrilevich, Tony Tran, Naiyer Rizvi, Martin Oft, Alexander I. Spira. Initial results from a phase 1a/1b study of STK-012, a first-in-class α/β IL-2 receptor biased partial agonist in advanced solid tumors (NCT05098132) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT183.

Abstract CT069: Targeting EpCAM via CAR T-cells is an effective treatment for gastric cancer patients and subsequent toll-like receptor signaling activation in CD36+ monocyte underlies the resulting cytokine release syndrome

Abstract EpCAM is highly expressed in various cancer types of the gastrointestinal system and at metastatic sites. It serves as a promising prognostic marker and therapeutic target. We conducted a first-in-human, open-label, single-arm, multicenter, phase 1 clinical trial following the classical "3+3" dose escalation design. The endpoints of this clinical trial are to assess the safety, efficacy, and pharmacokinetic (PK)/pharmacodynamic (PD) profile of EpCAM CAR-T. The trial is still ongoing, and our interim analysis results revealed a favorable safety profile of EpCAM CAR-T. No treatment-related deaths were observed within the 4-week follow-up period after infusion. 2 (12.5%) patients in high dose group (3*106) experienced dose-limiting toxicity (DLT) and 8 (50%) patients experienced grade 1-3 CRS. EpCAM CAR-T showed promising efficacy in gastric cancer. In gastric cancer group, the overall response rate (ORR) and disease control rate (DCR) reached 20.0% and 90.0%, respectively. However, the efficacy of EpCAM CAR-T in treating colorectal cancer was suboptimal, with an objective response rate (ORR) of 0% and disease control rate (DCR) of 50%. In our study, we observed that patients in gastric cancer (GC) group who developed cytokine release syndrome (CRS) had a weak response to CAR-T cell therapy, which is consistent with previous observations in animal models. We employed single-cell RNA sequencing (scRNA-seq) to analyze peripheral blood mononuclear cells (PBMCs) from GC group patients receiving EpCAM CAR-T treatment to explore the potential antagonism between CRS and treatment efficacy. Our findings underscore the significant role of monocytes in the regulation of CRS and treatment response. Specifically, we identified an increased abundance of Toll-like receptor (TLR)-dependent CD36+ monocytes in non-responders experiencing CRS. In a mouse model, we demonstrated that blocking TLR signaling in monocytes attenuated CRS induced by EpCAM CAR-T cells. Conversely, CD16+ monocytes were enriched in responders, displaying upregulated antigen presentation pathways and enhanced tumor infiltration capacity. In vivo, experiments revealed that blocking the antigen presentation pathway or inhibiting tumor infiltration of CD16+ monocytes resulted in reduced anti-tumor response of EpCAM CAR-T cells. Our findings highlight the critical role of intrinsic monocyte subpopulations as determinants of CAR-T efficacy and CRS. These insights may provide valuable strategies for predicting and enhancing the safety and efficacy of CAR-T cell therapy for solid tumors. Citation Format: TIanhang Luo, Zhengmao Lu, Zhongen Wu, Yuxuan Dong, Yuanyuan Zhu, Mei Feng, Shenglin Mei, Weijia Fang, Di Zhu. Targeting EpCAM via CAR T-cells is an effective treatment for gastric cancer patients and subsequent toll-like receptor signaling activation in CD36+ monocyte underlies the resulting cytokine release syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT069.

Abstract CT110: A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in solid tumor cohorts

Abstract Background: Aberrant splicing contributes to the progression of cancer but lacks targeted drugs. CTX-712 is a potent oral CDC2-like kinase (CLK) inhibitor affecting RNA splicing, CTX-712 demonstrated potent inhibition of proliferation in human tumor cell lines and elicited robust anti-tumor activity in xenograft models. This study aimed to evaluate CTX-712’s maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK)/pharmacodynamics (PD) profiles, and preliminary efficacy in patients with advanced solid tumors. Methods: This study consisted of a dose escalation cohort (A) and three dose expansion cohorts (C, D and E) for solid tumors. The dose escalation cohort (A) was initiated with accelerated titration and then switched to a 3+3 design (10, 20, 40, 70, 105, 140 and 175 mg twice a week [TW]). The dosing regimens for dose expansion cohorts were 105 mg TW (C), 70 mg TW (D), and 105 mg once a week (QW) (E). Results: As of November 20, 2023, a total of 46 patients with solid tumors were enrolled in the dose escalation cohort (16 patients) and dose expansion cohorts (30 patients total). In the dose escalation cohort, CTX-712 was administered at a dose of 10/20/40/70 mg TW (n=1 each), 105/175 mg TW (n=3 each) and 140 mg TW (n=6). DLTs were observed in 2 patients (140 mg TW [platelet count decreased, hypokalemia], 175 mg TW [dehydration]) and MTD was determined to be 140 mg TW. Among the safety analysis population (n=46), median treatment duration was 77 days (Range 1-413+ days); 1 patient is ongoing, and 45 patients discontinued. The common any-grade related adverse events (AEs) (≥30%) were nausea (93.5%), vomiting (65.2%), diarrhea (54.3%), decreased appetite (45.7%) and blood creatinine increase (32.6%). The most common related Grade 3 or higher AE was platelet count decrease (6.5%). Among all the patients (n=46), partial responses were observed in 4 (8.7%) patients (40 (n=1)/70 (n=2)/105 (n=1) mg TW cohorts), who were all patients with ovarian cancer; the median treatment duration of ovarian cancer (n=14) was 84 days (Range 1-413+ days). In PK analysis, a dose-dependent increase in systemic exposure of CTX-712 was observed. PD response was assessed in RNA extracted from peripheral blood cells. Dose-dependent increases of exon skipping in two marker RNAs (S6K and THAP9-AS1) demonstrated mRNA splicing modification induced by CTX-712. Conclusions: CTX-712 demonstrated an acceptable safety profile in patients with solid tumors. Additionally, CTX-712 demonstrated favorable clinical efficacy for patients with ovarian cancer and further investigation is warranted. Clinical trial information: jRCT2080224127 Citation Format: Noboru Yamamoto, Takafumi Koyama, Yuki Katsuya, Jun Sato, Toshio Shimizu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert W. Oda, Hiroshi Miyake, Kan Yonemori. A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in solid tumor cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT110.

Abstract CT115: A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort

Abstract Background: Mutations in genes encoding RNA splicing factors such as SF3B1, SRSF2, U2AF1, and ZRSR2, are common genetic aberrations in many forms of myeloid neoplasms. CTX-712 is a first-in-class, orally available, highly potent, and selective small molecule inhibitor of CDC2-like kinase (CLK), a key regulator of RNA splicing. Preclinical data show that CTX-712 demonstrated anti-proliferative activity in in-vitro and in-vivo models derived from hematologic malignancies. A phase I study of CTX-712 was conducted to evaluate the safety and the preliminary efficacy of CTX-712 in patients with relapsed or refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS). Methods: The objectives of this cohort were to evaluate the dose-limiting toxicity (DLT), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profiles, and preliminary efficacy of CTX-712 in patients with hematologic malignancies. A 3+3 design was used in two dose levels (70 mg and 105 mg twice a week (TW)) based on the safety data from the previous dose escalation cohort in patients with solid tumors. Results: As of data cutoff on November 20, 2023, a total of 14 patients (12 AML and 2 MDS) were enrolled in 70 mg TW (n=8) and 105 mg TW dose levels (n=6). DLT of Grade 4 pneumonia was observed in 1 of 3 DLT-evaluable patients in the 105 mg TW group. In the 70 mg TW group, no DLT was observed in 6 DLT-evaluable patients. Among the safety analysis population (n=14), median treatment duration was 76 days (Range 15-974 days). At data cutoff, treatment was ongoing in 1 patient and discontinued in 13 patients. The common any-grade adverse events (AEs) (≥30%) were diarrhea (57.1%) and nausea (42.9%). The most common Grade 3 or higher AE were white blood cell count decreased and tumor lysis syndrome (14.3%). In AML patients (n=12), complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery (CRi) was observed in 1 patient (8.3%). The median time to remission was 67 days (Range 29-113 days), and the median duration of response was 281 days (Range 56-924 days). In MDS patients (n=2), CR was observed in 1 patient (50.0%). PK/PD profiles of the hematologic malignancies dose escalation cohort were comparable with those of the solid tumor cohort at the same dosage. Conclusions: CTX-712 demonstrated a manageable and tolerable safety profile and showed anti-tumor efficacy in patients with hematologic malignancies. Currently, a Phase I/II Study of CTX-712 in relapsed/refractory AML and higher risk MDS is ongoing using a new tablet formulation in the United States. Clinical trial information: jRCT2080224127 Citation Format: Hisayuki Yokoyama, Noriko Fukuhara, Koji Ando, Hiroatsu Iida, Takahiro Yamauchi, Suguru Fukuhara, Koji Izutsu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert W. Oda, Hiroshi Miyake, Noboru Yamamoto. A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT115.

Unified Methodology for the Primary Preclinical In Vivo Screening of New Anticoagulant Pharmaceutical Agents from Hematophagous Organisms.

The development of novel anticoagulants requires a comprehensive investigational approach that is capable of characterizing different aspects of antithrombotic activity. The necessary experiments include both in vitro assays and studies on animal models. The required in vivo approaches include the assessment of pharmacokinetic and pharmacodynamic profiles and studies of hemorrhagic and antithrombotic effects. Comparison of anticoagulants with different mechanisms of action and administration types requires unification of the experiment scheme and its adaptation to existing laboratory conditions. The rodent thrombosis models in combination with the assessment of hemostasis parameters and hematological analysis are the classic methods for conducting preclinical studies. We report an approach for the comparative study of the activity of different anticoagulants in vivo, including the investigation of pharmacodynamics and the assessment of hemorrhagic effects (tail-cut bleeding model) and pathological thrombus formation (inferior vena cava stenosis model of venous thrombosis). The reproducibility and uniformity of our set of experiments were illustrated on unfractionated heparin and dabigatran etexilate (the most common pharmaceuticals in antithrombic therapy) as comparator drugs and an experimental drug variegin from the tick Amblyomma variegatum. Variegin is notorious since it is a potential analogue of bivalirudin (Angiomax, Novartis AG, Basel, Switzerland), which is now being actively introduced into antithrombotic therapy.

Pharmacokinetics, pharmacodynamics, and safety of fesomersen, a novel antisense inhibitor of factor XI, in healthy Chinese, Japanese, and Caucasian volunteers.

The inhibition of coagulation factor XI (FXI) presents an attractive approach for anticoagulation as it is not expected to increase the risk of clinically relevant bleeding and is anticipated to be at least as effective as currently available anticoagulants. Fesomersen is a conjugated antisense oligonucleotide that selectively inhibits the expression of FXI. The article describes three clinical studies that investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of fesomersen after subcutaneous (s.c.) injection to healthy participants. The studies included participants from diverse ethnic backgrounds (Caucasian, Japanese, and Chinese). Fesomersen demonstrated good safety and tolerability in all three studies. No major bleeding events were observed. After single-dose s.c. injection, fesomersen was rapidly absorbed into the systemic circulation, with maximum fesomersen-equivalent (fesomersen-eq) concentrations (Cmax) in plasma observed within a few hours. After reaching Cmax, plasma fesomersen-eq concentrations declined in a biphasic fashion. The PD analyses showed that the injection of fesomersen led to dose-dependent reductions in FXI activity and increases in activated partial thromboplastin time (aPTT). The maximum observed PD effects were reached between Day 15 and 30, and FXI activity and aPTT returned to near-baseline levels by Day 90 after a single dose. The PK/PD profiles after a single injection were similar among the various ethnic groups. Collectively, the study results suggest that fesomersen has a favorable safety profile and predictable and similar PK and PD profiles across Chinese, Japanese, and Caucasian participants.

Pharmacodynamic characteristics, safety profile, and interactions of CDK4/6 inhibitors (CDK4/6i) in HR+/HER2– advanced/metastatic breast cancer

Abstract Targeted therapies such as cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) have improved the prognosis of hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+)/(HER2–) advanced/metastatic breast cancer (a/mBC) by combating the resistance observed with traditional endocrine therapy. Currently, palbociclib, ribociclib, and abemaciclib are the three medicinal products authorized by the European Medicines Agency and the Food and Drug Administration. In addition to their overall similarities, related to their primary molecular mechanism of action through CDK4/6 inhibition, they also exhibit significant pharmacodynamic differences that affect their efficacy and safety profile, which may, through further research, help in understanding predicted toxicity, safety, and interactions and assist in adjusting dosing regimens in daily clinical practice. This review article will examine the pharmacodynamic profile of CDK4/6 inhibitors, their efficacy and safety in the treatment of HR+/HER2– a/mBC.

Analgesic Peptides: From Natural Diversity to Rational Design.

Pain affects one-third of the global population and is a significant public health issue. The use of opioid drugs, which are the strongest painkillers, is associated with several side effects, such as tolerance, addiction, overdose, and even death. An increasing demand for novel, safer analgesic agents is a driving force for exploring natural sources of bioactive peptides with antinociceptive activity. Since the G protein-coupled receptors (GPCRs) play a crucial role in pain modulation, the discovery of new peptide ligands for GPCRs is a significant challenge for novel drug development. The aim of this review is to present peptides of human and animal origin with antinociceptive potential and to show the possibilities of their modification, as well as the design of novel structures. The study presents the current knowledge on structure-activity relationship in the design of peptide-based biomimetic compounds, the modification strategies directed at increasing the antinociceptive activity, and improvement of metabolic stability and pharmacodynamic profile. The procedures employed in prolonged drug delivery of emerging compounds are also discussed. The work summarizes the conditions leading to the development of potential morphine replacements.

In vitro activity, pharmacodynamic profile and dose optimization of biapenem against NDM and OXA-48-like carbapenemase-producing Klebsiella pneumoniae: A multicentre study in Thailand

Biapenem (BIPM) exhibited a less efficient substrate for various metallo-β-lactamase (MBL) than other carbapenems. We aimed to evaluate in vitro susceptibility data of BIPM and optimal dose based on Monte Carlo simulation to extend treatment options. We collected 192 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients among multicentres in Thailand, from June 2019 to March 2023. BIPM disk diffusion and broth-microdilution testing were performed to obtain minimum inhibitory concentration (MIC). Each BIPM regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). The most common genotypes among 192 CRKP isolates were blaOXA-48 (62.3%), blaOXA-48+blaNDM (22.6%) and blaNDM (15.1%). BIPM showed 22.4 and 28.6% susceptible rate when interpreted at clinical breakpoints of 1 and 2 mg/L. The MIC50 and MIC90 of BIPM against CRKP were 8 and 32 mg/L. The BIPM dosing regimens of 300 mg q 6 h infused 6 h and 600 mg q 8 h infused 8 h met the PTA target of %fTime >MIC at 50%, 75% and 100% against isolates MICs of ≤2 mg/L. Based on CFR ≥90%, no BIPM regimens were effective against all the studied CRKP isolates. BIPM exhibited a partially susceptible rate among the CRKP isolates in Thailand. The current suggested dose of BIPM with prolonged infusion appears appropriate regimen against CRKP MICs of ≤2 mg/L. However, the empirical use of BIPM for severe CRE infection is not recommended unless the susceptibility has been confirmed.

Abstract 6588: Discovery of ASTX295, a potent, next-generation small molecule antagonist of MDM2 with differentiated pharmacokinetic profile

Abstract In response to cellular stress, the tumor suppressor p53 is activated to modulate cell cycle progression, DNA repair, and apoptosis. Inhibition of the MDM2-p53 interaction in tumors carrying wild-type p53 prevents its degradation and can reactivate p53 to elicit an anti-cancer effect. Targeting the p53-MDM2 interaction therefore remains a promising strategy for cancer therapy. However, development of first generation MDM2 antagonists has been challenged by dose-limiting, on-target bone marrow toxicities. Understanding of differential effects of p53 pathway activation in normal hematopoietic versus cancer cells (to be presented in a separate abstract) together with our expertise in structure-based drug design have led to the discovery of ASTX295, a potent MDM2 antagonist with differentiated pharmacokinetic profile aimed at sparing bone marrow toxicities and increasing the therapeutic index. Here, we present the first disclosure of the structure and pre-clinical characterisation of ASTX295. ASTX295 exhibits potent activity (IC50&amp;lt;1 nM) against MDM2 in an ELISA-based in vitro assay and induces significant growth reduction in p53 wild-type, MDM2-amplified SJSA-1 cells (GI50=27 nM). Antiproliferative activity of ASTX295 was further demonstrated in a panel of 219 p53 wild-type cell lines, with 143 cell lines showing GI50 values less than 1 μM and 50 showing values less than 0.1 μM. Effects of ASTX295 are shown in cell lines carrying functional p53 as confirmed in three p53 wild-type and mutant cell line pairs (SJSA1 and SN40R2, A2780 and A2780CP, HCT116 and HCT116 p53−/−). In addition to inhibiting cell cycle progression and cell proliferation, ASTX295 also potently induces apoptosis following 24-48 hour treatment. Further in vitro analyses of ASTX295 demonstrated an increase in the levels of p53 (EC50=10 nM after 2 hours) and its transcriptional targets such as p21 and MDM2. In vivo, ASTX295 shows robust induction of p53 and its target genes at 3 and 6 hours after oral administration together with dose-dependent inhibition of tumour growth in the SJSA-1 xenograft model. Importantly, ASTX295 exhibits optimised pharmacokinetic and pharmacodynamic profiles with relatively short duration of pathway modulation and a desired predicted human half-life of 2-8 hours. Based on our pre-clinical hypothesis on differential time-dependent sensitivities of normal versus cancer cells to p53 activation, achieving such a profile while maintaining potency may increase the therapeutic index. These data highlight the therapeutic potential of ASTX295, which is currently being tested in a Phase 1/2 clinical trial in advanced solid tumors with wild-type p53 (NCT03975387). We plan to present preliminary clinical data in a separate abstract at this meeting. Citation Format: Maria Ahn, Luke Bevan, Ildiko Buck, Celine Cano, Juan Castro, Ben Cons, Jane Endicott, Lynsey Fazal, Nicola Ferrari, Ian Hardcastle, Keisha Hearn, Rhian Holvey, Steven Howard, Chris Johnson, Claire Jennings, Justyna Kucia-Tran, Suzanne Kyle, John Lunec, John Lyons, Duncan Miller, David Rees, Martin Noble, David R. Newell, Judith Reeks, Harpreet Saini, Jeffrey St. Denis, Emiliano Tamanini, Huw Thomas, Neil Thompson, Mladen Vinkovic, George Ward, Nicola Wallis, Hugh Walton, Stephen Wedge, Pamela Williams, Elaine Willmore, Nicola Wilshire, Yan Zhao, Gianni Chessari. Discovery of ASTX295, a potent, next-generation small molecule antagonist of MDM2 with differentiated pharmacokinetic profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6588.

Abstract 1943: Discovery and characterization of potential drivers of resistance to the KRAS G12D inhibitor, MRTX1133, in cancer cell line models

Abstract Introduction: KRASG12D is the most common KRAS mutation and is present in approximately 34% of pancreatic cancer, 10-12% of colorectal cancer, 4% of lung adenocarcinoma and in a number of other cancer types. We previously identified MRTX1133, a potent, selective, and non-covalent KRASG12D inhibitor. The advancement of MRTX1133 to clinical trials warrants continued study of the role of the KRASG12D mutation in cancer pathogenesis and progression. Methods: Previous pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant models identified mechanisms implicated in limiting the anti-tumor response including signaling pathways that induce feedback reactivation and/or bypass KRAS dependence. Thus, cell lines (GP2D and SNU-1033, colorectal cancer; HPAC and AsPC-1, pancreatic cancer) were utilized to study acquired resistance to MRTX1133 following continuous treatment at increasing concentrations over time. These cell lines were confirmed to be stably resistant as determined by evaluation of response to MRTX1133 in vitro and in vivo. These cell lines were extensively profiled to determine underlying mechanisms of resistance utilizing molecular profiling strategies as well as drug combination screens to interrogate pathways that could circumvent resistance. Results: In one of the four generated cell lines with acquired resistance, evidence of secondary KRAS mutations Y96N and H95Q were confirmed by RNAseq and are likely drivers of resistance in this cell line and are consistent with known mechanisms of KRASG12C inhibitor resistance. The three other MRTX1133 resistant cell lines did not show evidence of secondary KRAS mutations and were further evaluated for mechanisms that bypass KRAS dependence. Combinations of MRTX1133 with therapies that target pathways including upstream RTK signaling, mTOR, or AKT broadly enhanced the anti-tumor activity of MRTX1133 in both in vitro cell viability and in vivo efficacy studies in the resistant cell lines. Conclusion: Collectively, these data provide early insight onto potential mechanisms of resistance to selective KRASG12D inhibitors and demonstrate the importance of developing rational combination strategies designed to address drug resistance. In addition, these studies provide a catalogue of potentially druggable vulnerabilities that complement KRAS blockade. Citation Format: Xousaen M. Helu, Ellie Griffiths, Andrew Calinisan, Allan Hebbert, Larry Yan, Natalie Hoffman, David Trinh, Laura Hover, Julio Fernandez-Banet, David M. Briere, Ella Lifset, Peter Olson, James G. Christensen, Jill Hallin. Discovery and characterization of potential drivers of resistance to the KRAS G12D inhibitor, MRTX1133, in cancer cell line models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1943.

A Systematic Review: Safety and Efficacy of Anticoagulation therapy for Atrial fibrillation and venous thromboembolism

For the prevention and treatment of thrombosis, anticoagulants continue to be the principal approach. Since direct thrombin inhibitors are usually saved for patients who need intervention or who have complications, unfractionated heparin, low molecular weight heparin, and warfarin have all been thoroughly studied and used.As a result of their improved pharmacodynamic profiles and ease of use, novel oral anticoagulants are predicted to supplant older ones once they emerge from clinical development. Of all the side effects of anticoagulants, bleeding is the most worrying. Anticoagulant pharmacology, dosage, and toxicity are widely used, so clinicians must be well-versed in these areas. Traditionally, heparin was given to patients who needed parenteral anticoagulation, while warfarin was given to patients who needed oral anticoagulation. There has been a push to create newer, more potent anticoagulants because of warfarin's limited therapeutic index and the requirement for regular laboratory monitoring.

Abstract 3732: Peripheral pharmacodynamic activity of epcoritamab as monotherapy and in combination with rituximab + lenalidomide in patients with follicular lymphoma

Abstract Introduction: Epcoritamab (DuoBody®-CD3xCD20) is a subcutaneous IgG1 bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells to mediate killing of target lymphoma cells. Epcoritamab is approved in the US for the treatment of adults with relapsed/refractory (R/R) diffuse and high-grade large B-cell lymphoma after ≥2 lines of systemic therapy (also approved in Europe, the UK, Japan, and Canada). Here we present the pharmacodynamic effects of epcoritamab as monotherapy (EPCORE NHL-1: NCT03625037) or in combination with rituximab + lenalidomide (R2) (EPCORE NHL-2: NCT04663347) in peripheral blood of patients with follicular lymphoma (FL), a heterogeneous disease for which many patients have an unmet medical need for efficacious, well-tolerated, off-the-shelf therapies. Methods: In EPCORE NHL-1 expansion phase, adults with R/R FL received epcoritamab monotherapy; in EPCORE NHL-2, adults with R/R (arm 2) or newly diagnosed (ND) (arm 6) FL received epcoritamab combined with R2. B-cell markers and T-cell proliferation and activation markers in whole blood were assessed using validated flow cytometry assays. Cytokines in plasma were measured using a validated multiplex immunoassay. Results: Epcoritamab as monotherapy and in combination with R2 induced rapid depletion of circulating peripheral B cells (CD19+) in patients with detectable peripheral B cells at baseline. Additionally, within the first 2 cycles, epcoritamab monotherapy induced a transient elevation of peripheral CD8+ and CD4+ T cells expressing proliferation (Ki67+%) and activation (HLA-DR+% and PD-1+%) markers. R/R and ND patient groups treated with epcoritamab + R2 showed a trend for greater induction of proliferating and activated peripheral T cells. Likewise, elevation in T-cell absolute counts was observed from cycle 2 onward, with a trend of higher levels with epcoritamab + R2 vs epcoritamab monotherapy. In addition, a moderate but transient elevation of circulating cytokines including IFNγ, IL-6, and IL-10 during cycle 1 was observed with epcoritamab monotherapy and epcoritamab + R2. Importantly, IL-6 and IL-10 returned to approximate baseline levels prior to the subsequent dose. Compared with epcoritamab monotherapy, patients treated with epcoritamab + R2 showed a trend for lower median levels of IL-6 peaks 24 hours after the first full dose. Conclusion: The pharmacodynamic activity of epcoritamab combined with R2 in R/R and ND FL was consistent with epcoritamab’s mechanism of action as monotherapy. Epcoritamab + R2 showed a favorable pharmacodynamic profile with a trend toward increased T-cell activation and T-cell elevation, and lower IL-6 levels. These data support the ongoing phase 3 trial of epcoritamab + R2 compared with R2 alone in patients with R/R FL (EPCORE FL-1: NCT05409066). Citation Format: Han Si, Jimin Zhang, Monica Wielgos-Bonvallet, Lorenzo Falchi, Kim Linton, Wojciech Jurczak, David Belada, Işıl Altıntaş, Mariana Sacchi, Elena Favaro, Ali Rana, Daniela Hoehn, David Soong, Christopher W. Chiu, Maria Jure-Kunkel. Peripheral pharmacodynamic activity of epcoritamab as monotherapy and in combination with rituximab + lenalidomide in patients with follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3732.

Abstract 7177: Development and validation of clinical pharmacodynamic biomarkers to assess treatment response to HPK1 inhibition and guide dosing decisions

Abstract Checkpoint inhibitors represent promising cancer therapeutics as they have the potential to reignite T cell activity and reverse T cell exhaustion, which is a critical mechanism of immune evasion by tumors. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell signaling that has recently emerged as a novel target for cancer immunotherapy. Inhibition of HPK1 can restore T cell function and anti-tumor immune responses, and several HPK1 inhibitors are currently under pre-clinical development, or clinical evaluation. Identifying clinically useful pharmacodynamic (PD) biomarkers in response to HPK1 inhibition is critical to characterize exposure-response relationship in early-phase trials and inform dose selection for later-phase studies. However, development and implementation of clinical PD assays are challenging because high sensitivity and specificity are required. Here, we developed a multi-biomarker strategy that combines a proximal biomarker (SLP-76 (Ser376) phosphorylation, a specific substrate of HPK1) and distal biomarkers (cytokine production) to evaluate target engagement (TE) and establish proof of mechanism (POM) of HPK1 inhibitors to determine their comprehensive PD profile. These PD biomarker assays were developed using peripheral blood as a surrogate tissue to assess HPK1 inhibition-induced pSLP-76 level decrease and cytokine levels increase, thus reflecting drug inhibitory effects and T-cell activity recovery. However, the lack of basal levels of these biomarkers presented a challenge for clinical workflow, as ex-vivo T-cell receptor stimulation of the clinical specimen is required after collection. Phosphoflow cytometry was prioritized over several technology platforms evaluated for quantifying blood pSLP-76 levels because of superior assay performance and signal stability under the developed clinical workflow. Blood cytokines upregulated upon HPK1 inhibition were first identified using targeted proteomics. IFNγ, IL2, TNFα, and IL17A were next confirmed and validated using quantitative immunoassays. Both pSLP-76 and whole blood cytokine workflows were thoroughly optimized for every step of sample handling from specimen processing at clinical sites to sample analysis at testing lab to ensure standardized, precise, and robust assay performance for clinical application. In addition, consistent HPK1 inhibition potency values were achieved using blood from cancer patients, demonstrating that the established PD biomarker assays apply to the clinical target population. In conclusion, robust peripheral TE and POM biomarkers were successfully developed to support future phase I/II studies with HPK1 inhibitors. These are expected to enable characterization of the exposure-response relationships and help define the therapeutic window and optimal dose. Citation Format: Lin Jia, Yasmin Marikar-Coplin, Jeff Chen, Kevin Xu, Deanna A. Mele, Nadia Luheshi, Sonia Iyer, Anton I. Rosenbaum, Sonia Terrillon. Development and validation of clinical pharmacodynamic biomarkers to assess treatment response to HPK1 inhibition and guide dosing decisions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7177.

Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: A multidisciplinary review.

To review the pharmacokinetic (PK)-pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and to provide a multidisciplinary perspective on treatment selection and educational needs relating to HMA use. Clinical and real-world data for parenteral decitabine and azacitidine and two oral HMAs: decitabine-cedazuridine (DEC-C) for MDS and azacitidine (CC-486) for AML maintenance therapy. Differences in the PK-PD profiles of oral and parenteral HMA formulations have implications for their potential toxicities and planned use. Oral DEC-C (decitabine 35 mg and cedazuridine 100 mg) has demonstrated equivalent systemic area under the concentration-time curve (AUC) exposure to a 5-day regimen of intravenous (IV) decitabine 20 mg/m2 and showed no significant difference in PD. The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle). Oral azacitidine has a distinct PK-PD profile versus IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures. Clinical trials are ongoing to evaluate oral HMA combinations and novel oral HMAs, such as NTX-301 and ASTX030. Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML.