First-in-human Research Articles

MA16.07 A First in Human (FIH), Phase 1 Open Label, Dose Escalation and Expansion Study of CTM103, a LNP MRNA Encoding an IL2Rß? Selective Il-2v, As Monotherapy and in Combination with Pembrolizumab, in Patients with Advanced Solid Tumors

MA16.07 A First in Human (FIH), Phase 1 Open Label, Dose Escalation and Expansion Study of CTM103, a LNP MRNA Encoding an IL2Rß? Selective Il-2v, As Monotherapy and in Combination with Pembrolizumab, in Patients with Advanced Solid Tumors

Reevaluating safety pharmacology respiratory studies within the ICH S7A core battery: A multi-company evaluation of preclinical utility and clinical translation

Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings. A large database of novel molecules included all relevant data from standard S7A respiratory (n = 459) and FIH studies (n = 309). The data were analyzed with respect to the progression of these molecules, clinical adverse event reporting of these same molecules, and achieved exposures. These S7A respiratory assay findings had no impact on compound progression, and only 12 of 309 drug candidates were ‘positive’ preclinically and reported a respiratory-related AE in clinical trials (i.e. cough, dyspnea, etc.), an overall incidence rate of 3.9%. Contingency tables/statistics support a lack of concordance of these preclinical assays. Overall, our extensive analysis clearly indicated that the preclinical respiratory assay fails to provide any prognostic value for detecting clinically relevant respiratory adverse events.

Abstract CT132: A Phase I/IIa clinical trial (TranStar101) to evaluate the safety, tolerability and pharmacokinetics of OSEMITAMAB administered as monotherapy or in combination with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors

Abstract Introduction: TST001/osemitamab is a novel, recombinant humanized IgG1 mAb with improved CLDN18.2 binding affinity and enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) and can result in more efficient cytotoxicity of tumors expressing human CLDN18.2 across a broad range of levels including low to medium expression. Methods: This is an open-label, multi-center phase I/IIa first in human (FIH) study of osemitamab administered as monotherapy or in combination with nivolumab or standard of care for patients with locally advanced or metastatic solid tumors. The study includes two parts: Part A (completed), a dose escalation of osemitamab as a monotherapy in solid tumors, osemitamab intravenous infusion at dose from 1mg/kg to 10mg/kg and once every two weeks (Q2W) or once every three weeks (Q3W) were evaluated; Part B (ongoing) includes expansion cohorts of osemitamab in combination with other therapies (cohort A and B). Cohort A includes combination of osemitamab, nivolumab, and mFOLFOX6 as the 1st line treatment for G/GEJ cancer. Cohort B includes osemitamab in combination with nivolumab in advanced pre-treated G/GEJ cancer. Results: As of Nov. 30, 2023, 68 patients have been treated: 38 patients were enrolled in the Part A dose escalation,13 in Part B Cohort A, and 17 in Part B Cohort B. The population (N=68) consisted of 59% males, median age 62 years and 50% with G/GEJ cancer. Doses evaluated are 3 to 10mg/kg Q3W and 1 to 6 mg/kg Q2W in part A. One dose limiting toxicity of Grade 3 infusion related reaction was reported at the 1mg/kg dose Q2W. The MTD was not reached. The recommended phase 2 dose was determined as 6mg/kg Q3W or 4mg/kg Q2W based on the totality of available safety, efficacy, PK/PD data including information from another phase I/II study (TranStar102). The most common TRAEs (occurred in ≥ 20% subjects) were nausea (73.5%), vomiting (48.5%), fatigue (30.9%). TRAE of Grade ≥ 3 across all tested doses (3-10 mg/kg) that occurred in ≥3% of patients included nausea, vomiting, hypoalbuminemia, hypertension, infusion related reaction, and lymphocyte count increased. Within the dose ranges studied, PK exposures increased as dose increased. The mean CLss value of osemitamab ranged from 9.4 to 13.7 mL/day/kg across different dose levels, without a clear dose relationship. Mild accumulation was observed following Q2W and Q3W dosing. Conclusion: Osemitamab as monotherapy or in combination with nivolumab or mFOLFOX plus nivolumab is well tolerated and safe with a PK profile consistent with other studies (TranStar 102 study -NCT04495296). TranStar 101 is currently ongoing. More information will be shared. Clinical trial information: NCT04396821. Study Sponsor: Suzhou Transcenta Therapeutics Co., Ltd. Citation Format: Yelena Janjigian, Anthony Tolcher, Rutika Mehta, Michael Cecchini, Brian Van Tine, Madappa Kundranda, Alese Olatunji, Manish R. Patel, Jordan Berlin, Caio Max Sao Pedro Rocha-Lima, Dulabh Monga, Ben George, Aaron Scott, Zhenzhong Xia, Mohamed Elsafy, Erikca Jones, Zhenling Yao, Chuan Qi, Caroline Germa, Nash Gabrail. A Phase I/IIa clinical trial (TranStar101) to evaluate the safety, tolerability and pharmacokinetics of OSEMITAMAB administered as monotherapy or in combination with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors [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 CT132.

Abstract 4068: In vitro masked effect, in vivo anti-tumor activity and toxicology study of KGX101, an interleukin-12 prodrug, in monotherapy or in combination with anti-PD-L1 antibody

Abstract Interleukin-12 (IL-12) has long been limited in its clinical use due to its short half-life (t1/2) and dose-related toxicity, despite its remarkable ability to activate effector functions in T cells and natural killer (NK) cells. To address these challenges, we engineered an IL-12 prodrug called KGX101. In KGX101, the C-terminus of IL-12 is fused with ADCC-impaired IgG1 Fc to extend its half-life. Meanwhile, the N-terminus is concealed with its corresponding receptor soluble domains, IL-12Rβ1 and IL-12Rβ2, using tumor-specific protease cleavable linkers. This innovative design prevents systemic immune system overactivation. Once the linker is cleaved by tumor microenvironment (TME)-specific proteases, KGX101 functions like IL-12, effectively stimulating T cells and NK cells, reshaping the TME, and displaying significant potential in cancer therapy. To confirm KGX101's masking effect, we conducted IFNγ induction efficacy tests using peripheral blood mononuclear cells (PBMCs) from three donors. KGX101 demonstrated a 300 to 2500-fold reduction in activity compared to unmasked IL-12-Fc. Importantly, the masking effect of KGX101 was nearly abolished after protease digestion, affirming its mechanism of action. To further establish KGX101's effectiveness, we conducted in vivo antitumor studies in hPBMC xenograft mouse models using human colorectal cancer HCT116 and PD-L1-overexpressed human malignant melanoma A375. Mice were subcutaneously implanted with a specific mixture of cancer cells and hPBMCs, and then intravenously injected with PBS or KGX101 at various dose levels twice a week for 4-5 cycles. Compared to the PBS control group, KGX101 demonstrated up to a 42% tumor growth inhibition (TGI) in the HCT116 model at 0.18 mg/kg and a 76% TGI in the hPD-L1-A375 model at 0.06 mg/kg. Analysis of tumor-infiltrating lymphocytes (TILs) revealed that KGX101 increased the percentage of T cells in the tumor environment in a dose-dependent manner. We also evaluated the combination of KGX101 with an anti-PD-L1 antibody in an HCT116/hPBMC xenograft mouse model, which showed limited response to anti-PD-L1 monotherapy. The TGI% for KGX101 at 0.06 mg/kg, anti-PD-L1 antibody at 1 mg/kg, and their combination were 36.56%, 6.93%, and 66.22%, respectively, demonstrating a promising antitumor synergy. In terms of pharmacokinetics, a single dose of KGX101 at 0.06 mg/kg and 0.18 mg/kg in the HCT116/hPBMC xenograft mouse model resulted in a serum half-life ranging from 52.75 to 64.87 hours, while the t1/2 in Cynomolgus monkeys was approximately 3 days. In a 4-week repeat dose toxicity study in Cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) of KGX101 was determined to be 0.1 mg/kg. The results from nonclinical toxicology studies support the potential of KGX101 as a well-tolerated therapy for the First-in-Human (FIH) clinical trial. Citation Format: Shumin Yang, Nuo Li, Jing Wang, Li Ma, Yi Zhao, Hui Chen, Haixiang Wu, Weidong Jiang. In vitro masked effect, in vivo anti-tumor activity and toxicology study of KGX101, an interleukin-12 prodrug, in monotherapy or in combination with anti-PD-L1 antibody [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 4068.

First-in-human feasibility study of the aXess graft (aXess-FIH): 6-Month results.

The creation of an arteriovenous fistula (AVF) is considered the most effective hemodialysis (HD) vascular access. For patients who are not suitable for AVF, arteriovenous grafts (AVGs) are the best access option for chronic HD. However, conventional AVGs are prone to intimal hyperplasia, stenosis, thrombosis, and infection. Xeltis has developed an AVG as a potential alternative to currently available AVGs based on the concept of endogenous tissue restoration. The results of the first 6-month follow-up are presented here. The aXess first-in-human (FIH) study [NCT04898153] is a prospective, single-arm, multicenter feasibility study that evaluates the early safety and performance of the aXess Hemodialysis Graft. A total of 20 patients with end-stage renal disease were enrolled across six European investigational sites. At 6-months follow-up, all grafts were patent with primary and secondary patency rates were 80% and 100%, respectively. Three patients required a re-intervention to maintain graft patency, while one re-intervention was required to restore patency. One graft thrombosis and zero infections were reported. The expected advantages of the novel aXess Hemodialysis Graft over conventional AVGs would be evaluated by the analysis on long-term safety and effectiveness during the 5-year follow-up of the currently ongoing trial.

Abstract PR008: MYTHIC: First-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with CCNE1 amplification or deleterious alterations in FBXW7 or PPP2R1A

Abstract Background: Lunre (RP-6306), a first-in-class membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) inhibitor, disrupts G2/M checkpoint causing DNA damage in cells with synthetic lethal alterations. Lunre plus the ATR inhibitor cam (RP-3500) promotes premature mitosis via CHK1/Cdc25 regulation and tumor regression. The FIH phase 1 MYTHIC trial assessed lunre alone or in combo with cam (lunre + cam) (NCT04855656). Methods: Pts >12yrs with advanced solid tumors and CCNE1 amplification, or deleterious FBXW7 or PPP2R1A mutations received oral lunre alone (QD or BID) or lunre (QD or BID) + cam (QD) continuously or intermittently using BOIN design. Endpoints: safety, tolerability, RP2D, preliminary efficacy (RECIST v1.1, GCIG CA-125), clinical benefit rate (CBR; RECIST/GCIG CA-125 or therapy duration ≥16w), ctDNA molecular response, PK and PD. Results: As of June 1, 2023, 108 pts were treated; n=66 lunre alone; n=42 lunre + cam. Tumors: uterine (31.5%), colorectal (20.4%), ovarian (16.7%), others (31.5%); median 3 prior therapies. 39.8% had CCNE1, 36.1% FBXW7, 19.4% PPP2R1A, and 4.6% had 2 or no alterations. Treatment-related AEs for lunre alone vs lunre + cam: nausea/vomiting (31.8% vs 64.3%; G3 1.5% vs 0%), anemia (21.2% vs 64.3%; G3 7.6% vs 38.1%), rash (34.8% vs 31%; G3 7.6% vs 2.4%), fatigue (22.7% vs 38.1%; G3 1.5% vs 0%). Lunre DLTs included G2/3 rash reversible with drug holds +/- supportive care. Preliminary RP2Ds: (1) lunre alone 100mg BID 5 days (d) on/2d off or 240mg QD continuous; (2) lunre 80mg BID + cam 80mg QD, both 3d on/4d off. Lunre exhibited linear PK up to daily doses ~240mg with ~9h half-life. No lunre + cam drug-drug interaction was observed. Target engagement (CDK1-Thr14 IHC) was confirmed in paired tumor biopsies treated with lunre alone (p=0.001; n=17) and with cam (p=0.039; n=11). DNA damage induction (gH2AX) was observed across both treatment groups (p=0.013; n=36). ctDNA molecular responses were achieved in 10/18 pts (55.6%) on lunre + cam. For lunre alone, 1 pt with uterine carcinosarcoma/PPP2R1A & FBXW7 had RECIST PR. For lunre + cam, among evaluable pts, 8 had either RECIST response (confirmed or unconfirmed; n=6: bile duct/CCNE1, breast/FBXW7, CRC/FBXW7, endometrial/FBXW7, PPP2R1A & CCNE1, or PPP2R1A & FBXW7) or CA-125 response (n=2: ovarian/CCNE1), including 5/15 pts (33.3%) with endometrial/ovarian cancers; CBR was 43.2% in all pts, and 66.7% in pts with endometrial/ovarian cancers. Conclusion: Lunre is safe and well-tolerated with robust PK/PD proof-of-mechanism. Antitumor responses or durable clinical benefit was observed in tumors with CCNE1, FBXW7, and PPP2R1A alterations at biologically active doses of lunre + cam, especially in gynecological cancers. These data provide the first clinical proof-of-concept for synthetic lethal targeting of PKMYT1 in cancer medicine. Dose optimization and efficacy expansions are ongoing. Trial registration number: NCT04855656 Citation Format: Timothy A Yap, Alison Schram, Elizabeth K Lee, Fiona Simpkins, Mia C Weiss, Patricia LoRusso, Martin Højgaard, Benedito A Carneiro, Ryan H Moy, Ignacio Garrido-Laguna, Maria Koehler, Thaddeus J Unger, Emeline Bacque, Elia Aguado-Fraile, Sunantha Sethuraman, Snehal Dhake, Yajun Liu, Adrian J Fretland, Xizi Sun, Yi Xu, Nathan Hawkey, Jen Truong, Stephanie Lheureux. MYTHIC: First-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with CCNE1 amplification or deleterious alterations in FBXW7 or PPP2R1A [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR008.

Abstract C063: OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies

Abstract Background: Anti-PD-1 antibodies have shown significant clinical activity with favorable safety. Bispecific anti-PD-1 antibodies are being developed. OSE279 is a humanized S228P-immunoglobulin (Ig)G4 monoclonal bivalent antibody directed against PD-1 which will be further used as the anti-PD-1 backbone component of a bifunctional checkpoint inhibitor BiCKI® platform. Methods: We performed preclinical assessments of OSE279 that support development in humans. A FIH study investigating OSE279 is ongoing, evaluating 2 Dose Levels (DLs) of 100 and 300 mg given q3w and 1 DL of 600 mg q6w, according to BOIN design, in subjects with refractory malignancies, with no standard treatments, for which anti-PD1/PDL1 have shown efficacy but are not locally available, or rare tumors with reported activity of anti-PD1, or PDL1 positive tumors. Primary objective is to determine the MTD and/or Recommended Phase 2 Doses (RP2D). Secondary objectives are efficacy, safety, PK and PD profiles. DLT period is 21 days. Results: Preclinical investigations showed that OSE279 has antagonist activity against PD1, blocking the binding of PD1 ligands (IC50 308 ± 170 ng/mL). OSE279 blocked PDL1-induced SHP1 phosphorylation in a cell-based assay (IC50=14.19 ng/mL) and promoted reactivation of primary T cell effector functions leading to interleukin 2 and Interferon γ secretion in MLR assay. OSE279 showed potent antitumor activity in syngeneic models of colon cancer, hepatocarcinoma and mesothelioma implanted in immunocompetent Human PD1 Knock-in mice, with long-term response and survival. OSE279 showed good affinity to hFcRn receptor predicting good half-life in humans. Simulations showed that trough Receptor Occupancy (RO) would be 94.1±36.9% and 98.3±36.8% at 100 mg and 300 mg, respectively. NOAEL was determined in monkey at 100 mg/kg for 1 month. In the FIH study as of June 2023, 9 subjects were treated, with 8 tumor types. Median age was 60y (range 43-70), 6/9 patients (67%) were female, median number of prior metastatic lines was 2 (range 1-6). 300 mg was declared RP2D for a q3w regimen; a new cohort is exploring 600 mg q6w. One (with HCC) of seven patients in DL2 (300 mg) had a DLT of gr3 hepatitis. Treatment-Related Adverse Events (TRAEs) occurred in 8 patients (88.9%). Serious TRAEs (pneumonitis gr2, hepatitis gr3) occurred in 2 patients (22.2%). A confirmed PR was observed in HCC after one dose of OSE279 300mg. SD was reported in 3 patients. PK profile showed good exposure and dose-proportionality. RO was maintained and within the boundaries of simulation. Conclusions: OSE279 preclinical data showed comparable efficacy and safety profiles to the EMA/FDA approved anti-PD1 antibodies. In FIH study, OSE279 showed a manageable safety profile with preliminary signs of efficacy in the first 9 patients treated. A RP2D of 300 mg q3w was selected. 600 mg q6w is being evaluated (data available by October 2023). PK and PD profiles were according to modelling. Expansion cohorts are planned. Clinical trial information: NCT 05751798. Research Sponsor: OSE Immunotherapeutics. Citation Format: Philippe Cassier, Carlos Gomez-Roca, Nuria Kotecki, Christophe Massard, Sophie Postel-Vinay, Aurore Morello, Mylène Déramé, Caroline Chevalier, Laurie Cordonnier, Constant Josse, Silvia Comis, Nicolas Poirier, Marie Robert. OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C063.

Abstract C162: Assessment of the potential for QTc prolongation by the investigational ATR inhibitor tuvusertib in patients with advanced solid tumors using integrated nonclinical and clinical assessments

Abstract Background: Tuvusertib (M1774) is a potent, selective, orally administered inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR) with demonstrated antitumor activity in preclinical models. Tuvusertib is currently being evaluated in phase I and II trials as monotherapy and in combination with other DNA damage response inhibitors and immune checkpoint inhibitors. Assessment of an investigational agent’s potential to cause delayed ventricular repolarization (QTc prolongation) is essential in drug development. QTc prolongation is assessed using nonclinical studies and concentration-QTc (c-QTC) analysis of phase I clinical data across a wide dose range and/or a thorough QT/QTc (TQT) clinical study. Here, we assess tuvusertib’s potential to cause QTc prolongation by integrating nonclinical evaluations and clinical c-QTc analyses. Methods: Nonclinical evaluations included in vitro binding of tuvusertib to the ether-a-go-go-related gene (hERG) channel and telemetry of tuvusertib in male beagle dogs and minipigs. Pharmacokinetics-time-matched triplicate electrocardiograms were collected in patients with advanced solid tumors from the first-in-human (FIH) trial (NCT04170153) for tuvusertib 5−270 mg QD along with intermittent dosing regimens. Based on exploratory analyses, a linear mixed-effect model (Garnett C, et al. J Pharmacokinet Pharmacodyn 2018;45:383–97) was chosen to describe the relationship between tuvusertib plasma concentrations and selected heart rate (HR)-corrected QT using the Fridericia correction (QTcF). Results: In vitro hERG channel binding potency for tuvusertib 0.3–10.0 µM was calculated with a half-maximal inhibitory concentration (IC50) of 2.8 µM. Nonclinical telemetry studies showed no treatment effect on QT/QTc prolongation at doses of up to 3 mg/kg in male beagle dogs and minipigs. c-QTc analyses in 55 patients from the FIH trial revealed a small positive slope of drug effect (slope estimate [95% CI] = 0.00244 [0.000708, 0.00417] ms/(ng/mL)). This increase in model-predicted QTcF from baseline was not considered to be clinically meaningful (<20 ms threshold) at steady-state maximum concentration (Cmax) achieved with the recommended dose for expansion (RDE) of 180 mg QD 2w on/1w off (mean [upper bound of 95% CI] = 3.4 [5.5] ms) and up to 3 times the RDE (10.3 [16.5] ms). Concentration-HR modeling found no relationship between tuvusertib concentration and HR, suggesting the absence of an effect. Conclusions: Integrating nonclinical and clinical assessments revealed no clinically meaningful effect of tuvusertib on QTc at concentrations achieved with the RDE and up to 3-times higher concentrations. Citation Format: Jatinder Kaur Mukker, Timothy A. Yap, Anthony W. Tolcher, Johann S. de Bono, Ruth Plummer, Rohan Kulkarni, Han Witjes, Paul Matthias Diderichsen, Axel Krebs-Brown, Rainer Strotmann, Zoltan Szucs, Ioannis Gounaris, Karthik Venkatakrishnan. Assessment of the potential for QTc prolongation by the investigational ATR inhibitor tuvusertib in patients with advanced solid tumors using integrated nonclinical and clinical assessments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C162.

Safety, Pharmacokinetics and Immunogenicity of Single and Multiple Ascending Doses of the Anti‐Tau Therapeutic Antibody E2814: A Phase 1, First‐In‐Human (FIH) Study in Healthy Subjects

AbstractBackgroundE2814 is an anti‐tau therapeutic monoclonal antibody (mAb) which is being developed as a potential disease‐modifying therapy for Alzheimer’s disease (AD). E2814 inhibits the propagation of pathological tau species by binding to the microtubule binding region (MTBR). This study evaluated safety, pharmacokinetics (PK), and immunogenicity of single and multiple doses of E2814.MethodsThis randomized, placebo‐controlled study evaluated 5 single ascending doses (SAD) and 4 multiple ascending doses (MAD) in healthy subjects. Subjects (n = 8/cohort) received single or multiple (every 4 weeks) 1‐hour IV infusions of E2814 (or placebo). Safety was evaluated through a review of adverse events (AE), clinical laboratory test results, physical examination, electrocardiogram results, and vital signs. Serial blood and CSF samples for measurement of serum and CSF E2814 concentrations by a validated electrochemiluminescence (ECL) assay were obtained at prespecified time‐points. The serum PK parameters were estimated using non‐compartmental analysis. Anti‐drug antibodies (ADA) in serum were measured by a validated ECL assay.ResultsE2814 has an adequate single and multiple dose safety profile. No treatment‐emergent serious AEs, severe AEs, infusion‐related reactions, or dose limiting events were observed. There was a dose‐related increase in serum and CSF E2814 exposures. The median time to maximum E2814 concentrations in serum was 1.5 to 2 h. The half‐life of E2814 was 23 days which is typical of mAb. In SAD, serum AUC and Cmax were approximately dose proportional at lower doses and greater than dose‐proportional at higher doses. In MAD, accumulation based on Cmax and AUC was ∼1.2 and 1.3‐fold, respectively by the third dose in all dose group. The serum‐to‐CSF concentration ratio ranged between 0.1 to 0.3%. The immunogenicity to E2814 was low. In SAD, 5 subjects had transient low level ADA titers by last study day. In MAD, 1 subject had a confirmatory positive ADA at baseline prior to dose on Day 1. PK in the ADA positive subjects was comparable to that of ADA negative subjects.ConclusionE2814 presented an adequate safety and immunogenicity profile in healthy adults. E2814 PK was comparable to that with other mAbs. These results support further development of E2814 as a potential disease‐modifying therapy for AD.

Predictability of human exposure by human-CYP3A4-transgenic mouse models: A meta-analysis.

First-in-human dose predictions are primarily based on no-observed-adverse-effect levels in animal studies. Predictions from these animal models are only as effective as their ability to predict human results. To narrow the gap between human and animals, researchers have, among other things, focused on the replacement of animal cytochrome P450 (CYP) enzymes with their human counterparts (called humanization), especially in mice. Whereas research in humanized mice is extensive, the emphasis has been particularly on qualitative rather than quantitative predictions. Because the CYP3A4 enzyme is most involved in the metabolism of clinically used drugs, most benefit was expected from CYP3A4 models. There are several applications of these mouse models regarding invivo CYP3A4 functionality, one of which might be their capacity to help improve first-in-human (FIH) dose predictions for CYP3A4-metabolized drugs. To evaluate whether human-CYP3A4-transgenic mouse models are better predictors of human exposure compared to the wild-type mouse model, we performed a meta-analysis comparing both mouse models in their ability to accurately predict human exposure of small-molecule drugs metabolized by CYP3A4. Results showed that, in general, the human-CYP3A4-transgenic mouse model had similar accuracy in the prediction of human exposure compared to the wild-type mouse model, suggesting that there is limited added value in humanization of the mouse Cyp3a enzymes if the primary aim is to acquire more accurate FIH dose predictions. Despite the results of this meta-analysis, corrections for interspecies differences through extension of human-CYP3A4-transgenic mouse models with pharmacokinetic modeling approaches seems a promising contribution to more accurate quantitative predictions of human pharmacokinetics.

Abstract PR006: Initial results from first-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in biomarker-selected solid tumors

Abstract Background: AMG 193 is a second-generation protein arginine methyltransferase 5 (PRMT5) inhibitor that targets the MTA-bound state of PRMT5 in methylthioadenosine phosphorylase (MTAP)-null tumors. PRMT5 is responsible for methylation and gene silencing of cell-essential proteins dysregulated in cancer and is partially inhibited in tumors harboring MTAP deletion, which occurs in ~15% of solid tumors. First generation PRMT5 inhibitors were intolerable due to indiscriminate inhibition of PRMT5 leading to dose-limiting myelosuppression. In preclinical studies, AMG 193 demonstrated selective antitumor activity in MTAP-null models by further suppressing PRMT5 function while sparing normal function, thereby improving upon first generation molecules. We report the initial clinical results from dose-escalation in the ongoing first-in-human (FIH) study. Methods: AMG193 was orally administered in continuous 28-day cycles to patients (pts) with advanced MTAP-null solid tumors. Dose escalation proceeded via a BLRM method. The primary objectives include safety, tolerability, and identification of the maximum tolerated dose (MTD). Secondary objectives include preliminary antitumor activity by investigator-assessed RECIST, pharmacokinetics (PK) and pharmacodynamic (PD) effects. Results: As of August 8, 2023, 47 pts with MTAP-null cancer (PDAC n = 10; NSCLC n = 6; CCA = 5; MESO n = 3; others n = 23) were enrolled in seven escalating cohorts. Five pts had DLTs, and exploration continues per protocol to identify the MTD. The most common TRAEs were nausea (45%), fatigue (26%), decreased appetite (17%), and vomiting (17%). Preliminary PK analyses showed dose-proportional systemic exposure with a half-life of 7–11 hrs. Among 31 pts who had at least one postbaseline scan, there were 5 with confirmed PRs [PDAC (–100%), ovarian Sertoli-Leydig (–59%), RCC (–58%), esophageal (–46%), and gallbladder cancer (–63%), 1 each], 14 with stable disease (including 9 with some degree of tumor shrinkage), and 12 with disease progression. All PRs were ongoing at the data cutoff with treatment durations of 140–275 days. PD effects demonstrated dose-dependent reduction in serum total SDMA levels and complete PRMT5 inhibition was confirmed in five pts with on-treatment biopsies spanning multiple dose levels. Exploratory analysis of changes in variant allele frequency by ctDNA demonstrated rapid treatment effects that was predictive and correlated with response. Conclusion: AMG 193 is an MTA-cooperative PRMT5 inhibitor designed to induce synthetic lethality in MTAP-null solid tumors while sparing hematologic toxicity. The initial results of the FIH study demonstrate proof-of-concept with encouraging signs of preliminary clinical activity without evidence of myelosuppression. Dose escalation continues to proceed to establish the MTD. AMG 193 has demonstrated promise as a potential new therapeutic for pts with tumors that have MTAP loss. Citation Format: Jordi Rodon, Noboru Yamamoto, Toshihiko Doi, François Ghiringhelli, Maria-Elisabeth Goebeler, Yutaka Fujuwara, Miguel Villalona-Calero, Nicolas Penel, Amita Patnaik, Jean-Pascal Machiels, Alfredo Addeo, James Abbruzzese, Sophie Postel-Vinay, Sylvie Rottey, Chunxu Liu, Chen-Hua Chuang, William Kormany, Paul Hughes, Kiana Keyvanjah, Bert O'Neil. Initial results from first-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in biomarker-selected solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR006.

CrossFuse-XGBoost: accurate prediction of the maximum recommended daily dose through multi-feature fusion, cross-validation screening and extreme gradient boosting.

In the drug development process, approximately 30% of failures are attributed to drug safety issues. In particular, the first-in-human (FIH) trial of a new drug represents one of the highest safety risks, and initial dose selection is crucial for ensuring safety in clinical trials. With traditional dose estimation methods, which extrapolate data from animals to humans, catastrophic events have occurred during Phase I clinical trials due to interspecies differences in compound sensitivity and unknown molecular mechanisms. To address this issue, this study proposes a CrossFuse-extreme gradient boosting (XGBoost) method that can directly predict the maximum recommended daily dose of a compound based on existing human research data, providing a reference for FIH dose selection. This method not only integrates multiple features, including molecular representations, physicochemical properties and compound-protein interactions, but also improves feature selection based on cross-validation. The results demonstrate that the CrossFuse-XGBoost method not only improves prediction accuracy compared to that of existing local weighted methods [k-nearest neighbor (k-NN) and variable k-NN (v-NN)] but also solves the low prediction coverage issue of v-NN, achieving full coverage of the external validation set and enabling more reliable predictions. Furthermore, this study offers a high level of interpretability by identifying the importance of different features in model construction. The 241 features with the most significant impact on the maximum recommended daily dose were selected, providing references for optimizing the structure of new compounds and guiding experimental research. The datasets and source code are freely available at https://github.com/cqmu-lq/CrossFuse-XGBoost.

First in human study BIOMAG-I: 12 months results of the sirolimus eluting resorbable coronary magnesium scaffold system (DREAMS 3G) in the treatment of subjects with de novo coronary artery lesions

Abstract Background/Introduction Bioresorbable scaffolds have emerged as an attractive alternative to polymeric scaffolds. A 3rd generation drug-eluting resorbable magnesium scaffold (DREAMS 3G) was developed to enhance the performance of previous scaffold generations and achieve angiographic outcomes comparable to those of contemporary drug-eluting stents. Purpose The aim of the BIOMAG-I first-in-human (FIM) study was to assess the angiographic, clinical and safety performance of DREAMS 3G in patients with de novo coronary artery lesions. We assessed the 12-month safety and performance of this novel device as well intravascular imaging data at baseline, 6- and 12-month follow-up. Methods In this prospective, multicentre, non-randomized, first-in-human study 116 subjects with 117 coronary artery lesions were enrolled at 14 centers in Europe. Clinical follow-up was scheduled at 1, 6 and 12-months and annually thereafter until 5 years. Invasive imaging assessments were scheduled 6 and 12-months post-procedure. Vasomotion was assessed in a subgroup of subjects during the 12-months follow-up. The primary endpoint was in-scaffold LLL at six months. Secondary endpoints include in-segment LLL, TLF, clinically driven target lesion revascularization (TLR), cardiac death, target-vessel myocardial infarction (TV-MI) and scaffold thrombosis. Results Preliminary in-scaffold LLL (n=89 subjects) remained stable from 6 months (0.20 ± 0.28 mm) to 12 months (0.24 ± 0.35 mm). Interim intravascular ultrasound assessments and optical coherence tomography findings corroborated the QCA results with a preservation of the lumen area from 6 (IVUS: 7.0 ± 2.5 mm2; OCT: 8.1 ± 2.7 mm2) to 12 months (IVUS: 7.2 ± 2.6 mm2; OCT: 7.8 ± 2.6 mm2). Vasomotion assessment in a subgroup of subjects confirmed the motility of the scaffolded segment at 12 months follow up: after Acetylcholine administration: 12.5% ± 7.5 (n=27); after nitro administration: 10.7% ± 9.2 (n=22). Up to 12-months follow up, 3 clinically driven TLR were reported (3.4%). No cardiac death, no TV-MI and no scaffold thrombosis were reported up to 12 months. Full data set of the 116 subjects will be available upon presentation. Conclusions The novel third-generation drug-eluting magnesium scaffold, DREAMS 3G, showed a continuous favorable safety and efficacy profile up to 12 months and stable angiographic parameters between 6 and 12 months. Intravascular imaging assessment showed a preservation of the lumen area between 6 and 12 months.

Abstract 15137: microRNA-132 Inhibition Improves Cardiac Function and Reduces Remodeling in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): An Exploratory Subgroup Analysis of the CDR132L First-in-Human Study

Background: The CDR132L first-in-human (FiH) study examined safety, tolerability, pharmacokinetic, and exploratory pharmacodynamic effects of different ascending doses of the novel antisense oligonucleotide CDR132L targeting microRNA-132-3p (miR-132) in patients with stable heart failure (HF) of ischemic origin receiving standard-of-care (n=28). The study population was not stratified according to their left-ventricular ejection fraction (LVEF), and therefore heterogenous, but equally distributed among heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Research question: In an exploratory post-hoc analysis of pharmacodynamic parameters we specifically focused on patients with HFrEF (with a LVEF<45% at baseline, n=14) and, based on our predictive PK/PD modeling, categorized patients into ‘non-pharmacodynamically active’ (non-PD active; placebo and 0.32 mg/kg CDR132L group) and 'pharmacodynamically active' (PD active; patients receiving 1, 3, or 10 mg/kg CDR132L). Results: The PD active group showed a significant median reduction in NT-proBNP by 37.1% between baseline and study endpoint (day 112) while this HF biomarker was increased by 17.7% in the non-PD active group (p=0.0152, Mann-Whitney U test). CDR132L treatment provoked a trend towards 6.1% improvement in LVEF. For the non-PD active group only +1.4% were noted. An additional biomarker related to HF and cardiac fibrosis, lipocalin-2 (NGAL), tended to decrease in the PD active, but not in the non-PD active group. Conclusion: Analysis of the HFrEF subgroup in this FiH trial, although limited by the small patient numbers, indicatively underlines the encouraging benefits of CDR132L, a novel antisense drug, on LV function and cardiac remodeling as established in previous large animal HF models.

Double Step-up Dosing (2SUD) Regimen Mitigates Severe Icans and CRS While Maintaining High Efficacy in Subjects with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL) Treated with AZD0486, a Novel CD19xCD3 T-Cell Engager (TCE): Updated Safety and Efficacy Data from the Ongoing First-in-Human (FIH) Phase 1 Trial

Background: AZD0486 (formerly TNB-486) is a novel, IgG4 fully human CD19xCD3 bispecific TCE incorporating a unique low affinity anti-CD3 moiety designed to reduce cytokine release while retaining potent T-cell mediated cytotoxicity of malignant B cells. A silenced Fc prevents nonspecific binding, antibody-dependent cellular cytotoxicity, and confers a long half-life suitable for intermittent administration. Preliminary clinical activity in Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) was reported [ Hou et al, Blood 2022; Jacobs et al, HemaSphere 2023] following fixed and single step-up dosing (1SUD). We now present focused updated safety data following implementation of 2SUD in the ongoing FIH phase 1 study (NCT04594642). Methods: Patients with R/R CD19+ B-NHL failing ≥2 prior lines of therapy, including prior CD19 CART and/or CD20 TCE, were enrolled. AZD0486 was administered in escalating doses in either no SUD (Day (D)1, D15 0.03-2.4mg), 1SUD (D1 0.27-1 mg, D15 2.4-10 mg), or 2SUD (D1 0.27 mg, D8 1 mg, D15 2.4-7.2 mg, FL/DLBCL only) schedules. AZD0486 was given IV every 2 weeks in 28D Cycles (C) up to 2 years. Monthly dosing was considered for patients in complete response (CR) at C6. Responses were assessed by RECIL 2017 by Central Imaging Review, AEs by CTCAE v5.0, and CRS/ICANS by 2019 ASTCT criteria. Results: As of 03 July 2023, 62 patients (27 DLBCL, 25 FL, 5 mantle cell lymphoma, 4 marginal zone lymphoma, 1 other) received AZD0486 and were evaluable for safety. Median age was 68 (range 22-86), with 58% male, 81% stage III/IV. Median prior lines of therapy was 3 (range 2-16) including 23 (37%) failing CART and 3 (4.8%) failing CD20 TCE. Fifteen (24%) were CD20 negative at study entry. The complete response (CR) rate was 91% (10/11) in patients with FL treated in 2.4 mg dose cohorts and for all FL efficacy evaluable subjects dosed at 2.4mg or above, CR was achieved in 14/17 (83%) with an overall response rate (ORR) of 88%. Median duration of response (DOR) has not beenreached. With the implementation of 2SUD regimen, no Grade 3+ CRS or ICANS events were observed (Table 1). Grade 1-2 CRS events decreased from 62.5% to 22.2% (fixed/1SUD, 15/24 and 2SUD, 4/18). Grade 1-2 ICANS events decreased from 20% (5/24) to 5.6% (1/18), presented mainly as confusion, and typically resolved in 1-2 days. The most common AEs (occurring in >20%) of any grade and regardless of drug causality were CRS (48%), anemia (34%), neutropenia (32%), lymphopenia (29%), ICANS (27%) and decreased WBC (20.9%). Treatment-related events of Grade ≥3 included lymphopenia (24%), neutropenia (15%), ICANS (9.7%) and anemia (3.2%). No treatment related deaths were reported (1 death due to COVID19, unrelated) and no treatment-related AEs lead to discontinuation (1 patient discontinued due to COVID-19, unrelated). Preliminary analysis (TNF-a, IL-6, IL-8, IL-10) suggests a decrease in cytokine levels after target dose with 2 SUD compared to fixed dosing and 1SUD, regardless of target dose. Conclusions: AZD0486 (formerly TNB-486) is an active treatment in patients with advanced R/R B-NHL and has a predictable safety profile characterized by mainly low-grade AEs and fully transient and reversible CRS/ICANS events. The 2 SUD schedule reduced the overall rate of low grade CRS and ICANS (Grade 1-2) and abrogated Grade 3 events further improving the risk/benefit profile of AZD0486. Dose escalation is ongoing to identify the RP2D.

Two-Year Follow-up Results of C-CAR066, a Novel Anti-CD20 Chimeric Antigen Receptor Cell Therapy (CAR-T) in Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) Patients after Failure of CD19 CAR-T Therapy

Background: Disease recurrence or progression represents a significant challenge in r/r LBCL treated with CAR-T. In a large analysis of r/r LBCL pts who receive further therapy after CD19 CAR-T treatment failure, the overall response rate (ORR) is 39% (CR 20%; PR 19%) and the median post-treatment-OS and post-treatment-EFS are 8.5 months and 1.9 months respectively. C-CAR066 is a novel 2nd generation CAR-T therapy targeting CD20 antigen. We previously reported that C-CAR066 had shown a favorable safety profile and promising efficacy in pts with r/r LBCL following failure to CD19 CAR-T therapy. At a median follow-up of 4.2 months, the ORR was 100%, with 70.0% (7/10) achieving complete response (CR) (Liang et al. ASCO 2021. #2508). Here we present the updated results to include more pts (n=14) and a longer follow-up period. Methods: This first-in-human (FIH) study is an open-label, dose-finding, phase 1 investigator-initiated trial (IIT) to determine the safety and efficacy of C-CAR066 in r/r LBCL (including DLBCL, tFL and PMBCL) after previous CD19 CAR T-cell treatment failure. This study was conducted at two clinical sites in China. C-CAR066 was administered at doses of 2.0x10 6 CAR-T cells/kg and 3.0x10 6 CAR-T cells/kg after a 3-day conditioning chemotherapy. The primary objective was to assess the safety and tolerability of C-CAR066. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. The secondary objectives were to evaluate C-CAR066 efficacy and pharmacokinetics (PK). Response was assessed per Lugano 2014 criteria. The study follow-up period was 2 years. Results: Between Oct 16, 2019, and Aug 17, 2021, a total of 14 pts received C-CAR066. 11 pts (78.6%) were DLBCL, 3 pts (21.4%) were tFL. The median age was 54.5 years (range, 37-67) with 2 pts (14.3%) ≥65 years. 12 pts (85.7%) were in Ann Arbor Stage III/IV. 7 pts (50.0%) were double-expressor lymphoma. Median number of prior lines of therapy was 5 (range, 2-7). All pts had prior CAR-T therapy, which included CD19 CAR-T (12 pts), CD19/CD22 bispecific CAR-T (1 pts), and CD19/CD79b bispecific CAR-T (1 pts). 12 pts responded to the prior CAR-T therapy (2 CR and 10 PR), and the median duration of response (DOR) was 1.5 months. Median time from prior CAR-T to C-CAR066 infusion were 5.45 months (range, 3.4-14.2). 7 pts (50.0%) received bridging therapy. As of Jan 15, 2023, 12/14 pts (85.7%) experienced CRS, all were grade 1/2, except for 1 pt dosed at 3.0×10 6 CAR- T cells/kg experienced a grade ≥3 CRS. This pt recovered after receiving corticosteroids and tocilizumab. The median time to CRS onset was 5.5 days (range, 2-15), and the median time to resolution was 4.0 days (range, 1-15). No pts experienced ICANS. Grade ≥3 neutropenia, anemia, thrombocytopenia, and infection were reported in 92.9%, 50.0%, 21.4% and 14.3% of pts, respectively. No new safety signals were observed in this updated 2-year follow-up. Investigator assessed ORR was 92.9%, with 57.1% CR. Median time to first response and CR were 1.0 month (range, 0.9-2.8) and 2.5 month (range, 1.0-2.8), respectively. With the median follow-up of 19.5 months, median PFS and DOR were 9.4 months and 8.3 months, respectively. 5 pts remained in CR 12 months after infusion, and 4 of them remained in CR after 24 months. 6 deaths occurred due to progressive disease. Median post-treatment-OS had not been reached at 24 months. 13 of 14 pts had assessable PK and pharmacodynamic data (one pt dropped out before day 28). The median T max was 11 days (range, 10-23), the median C max was 398,996 copies/µg gDNA (range, 51,667-1,286,932), and the median AUC 0-28day of 4,437,474 copies/µg∙day (range, 431,534-17,842,217), the median T last was 59 days (21~571). We have observed that C-CAR066 can effectively expand and eliminate CD19+/CD20+ B cells in patients. The median time to B cell depletion was 5.5 days (range, 4-11). B cell recovery was observed in 6 (46.2%) pts from 53 to 366 days after the C-CAR066 infusion, 3 of them remained in CR by the data cutoff date. Conclusions: Longer term follow-up demonstrated that C-CAR066 can produce a deep and durable response with a favorable safety profile in pts with r/r LBCL who failed prior CD19 CAR-T therapy.

Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors.

The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose-response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose-response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight^-0.25 (AS by W^-0.25) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors.

A review of clinical trials registered in India from 2008 to 2022 to describe the first-in-human trials.

This analysis was conducted to review the number, and describe the characteristics of first-in-human (FIH) Phase 1 clinical trials registered in India from 2008 to 2022. The data were extracted from the Clinical Trials Registry - India database for all FIH Phase 1 clinical trials registered between 2008 and 2022. Early-phase trials that were not FIH trials (e.g., pharmacokinetic studies and drug-drug interaction studies) were excluded from the study. A total of 1891 trials were retrieved and 220 were included in the analysis. Most of the investigational products were drugs (55%) followed by vaccines (38.2%). The most common therapeutic class of drugs was cancer chemotherapy (19.8%), followed by antimicrobial chemotherapy and endocrinology (18.2% each). The most common vaccine was the influenza vaccine (21.4%), followed by the measles-mumps-rubella vaccine (15.5%). The pharmaceutical industry was the predominant sponsor for most (91%) of the Phase 1 trials. Of the top five sites where most of the Phase 1 trials were conducted, three were private nonacademic centers (cumulatively 31%) and two were tertiary care medical colleges (cumulatively 9%). Phase 1 clinical trials seem to be conducted in India predominantly with industry sponsorship. There is a need to have an alternate ecosystem to take forward molecules that do not receive adequate attention from the industry and molecules that are of national health priority other than areas such as chemotherapy, antimicrobials, and endocrinology. The Indian Council of Medical Research is setting up Phase 1 clinical trial capacity for molecules that predominantly may arise from nonindustry channels.

720TiP Phase I, open-label, first-in-human (FIH) study of JZP815 in advanced or metastatic solid tumors harboring mitogen-activated protein kinase (MAPK) alterations

720TiP Phase I, open-label, first-in-human (FIH) study of JZP815 in advanced or metastatic solid tumors harboring mitogen-activated protein kinase (MAPK) alterations

Utility of Coproporphyrin-I Determination in First-in-Human Study for Early Evaluation of OATP1B Inhibitory Potential Based on Investigation of Ensitrelvir, an Oral SARS-CoV-2 3C-Like Protease Inhibitor

Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans.