Pharmacokinetic Exposure Research Articles

Safety, Pharmacokinetics, and Exposure-Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease.

Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30mL/min/1.73m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10participants with normal kidney function (estimated glomerular filtration rate ≥90mL/min/1.73m2 ; Group 3) received a single dose of subcutaneous nedosiran sodium 170mg. Group 1a received nedosiran 8hours before beginning hemodialysis, Group 1b received nedosiran 2hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.

The pharmacokinetic profile of brensocatib and its effect on pharmacodynamic biomarkers including NE, PR3, and CatG in various rodent species.

Brensocatib is a novel, oral, selective, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), which activates several neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG) in the bone marrow during the early stage of neutrophil maturation. These NSPs are associated with pathogen destruction and inflammatory mediation; their dysregulated activation can result in excess secretion of active NSPs causing damaging inflammation and contributing to neutrophil-mediated inflammatory and autoimmune diseases. Pharmacological inhibition of DPP1 in the bone marrow could therefore represent an attractive strategy for these neutrophil-driven diseases. A completed Phase 2 trial in non-cystic fibrosis bronchiectasis patients (ClinicalTrials.gov number NCT03218917; EudraCT number: 2017-002533-32) indeed demonstrated that administration of brensocatib attenuated the damaging effects of chronic inflammation by inhibiting the downstream activation of NSPs. To support a range of preclinical programs and further understand how rodent species and strains may affect brensocatib's pharmacokinetic (PK) profile and its pharmacodynamic (PD) effects on NE, PR3, and CatG, an extensive naïve dosing study with brensocatib at different dosing levels, frequencies, and durations was undertaken. Dose-dependent PK exposure responses (AUC and Cmax) were observed regardless of the rodent species and strain. Overall, mice showed greater reduction in NSP activities compared to rats. Both mice and rats dosed once daily (QD) had equivalent NSP activity reduction compared to BID (twice a day) dosing when the QD dose was 1.5-times the BID daily dose. For both mouse strains, CatG activity was reduced the most, followed by NE, then PR3; whereas, for both rat strains, PR3 activity was reduced the most, followed by CatG, and then NE. Maximum reduction in NSP activities was observed after ∼7 days and recoveries were nearly symmetrical. These results may facilitate future in vivo brensocatib study dosing considerations, such as the timing of prophylactic or therapeutic administration, choice of species, dosage and dosing frequency.

Pharmacokinetics of cenobamate as monotherapy compared with adjunctive therapy

ObjectiveCenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of cenobamate monotherapy, this pharmacokinetic (PK)-based simulation analysis evaluated the predicted PK exposure of cenobamate when used as monotherapy versus adjunctive therapy. MethodsA population pharmacokinetic (PopPK) model of cenobamate was developed using pooled human data from eight phase 1 studies in healthy subjects or special populations, and three phase 2 and 3 studies in patients with focal seizures (N = 960). Concomitant antiseizure medications (ASMs) with a statistically significant effect on the apparent systemic clearance (CL/F) of cenobamate in the PopPK model were used to compare simulated patient plasma exposures (area under the plasma concentration vs time curve [AUC]) following monotherapy versus adjunctive therapy. Treatment equivalence between monotherapy and adjunctive therapy was concluded if the 90% confidence interval (CI) of the geometric mean AUC ratio was within 0.8–1.25. ResultsIn the PopPK model, statistically significant effects on cenobamate CL/F were shown for clobazam (decreased cenobamate CL/F by 19%) and carbamazepine (increased cenobamate CL/F by 15%); these differences were not considered clinically meaningful. Other ASMs (lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate) when coadministered with cenobamate did not have significant effects on the disposition (ie, PK or efficacy) of cenobamate. The geometric mean ratio (90% CIs) of cenobamate AUC for adjunctive therapy/monotherapy was 0.87 (0.816–0.925) for adjunctive carbamazepine and 1.24 (1.147–1.339) for adjunctive clobazam. The 90% CI was within the no-effect limits (90% CIs 0.8–1.25) for adjunctive carbamazepine and partially exceeding no-effect limits for adjunctive clobazam. ConclusionsBased on the results from this PopPK analysis, cenobamate monotherapy can be expected to result in comparable exposures to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures, supporting the use of cenobamate as monotherapy in these patients.

EFFECTIVENESS AND PHARMCOKINETICS OF FIRST-LINE ANTI TUBERCULOSIS DRUGS IN CHILDREN: A SYSTEMATIC REVIEW

Background: The optimal doses of first-line drugs for treating drug-susceptible tuberculosis in children and adolescents are still uncertain.&#x0D; Aim: The purpose of this study was to determine whether children treated with recommended or increased doses of first-line drugs achieve successful outcomes and adequate pharmacokinetic (PK) exposures. &#x0D; Methods: A systematic search strategy was conducted across several electronic reference databases (PubMed, Cochrane Library, Google Scholar) and included articles published between 2010–2023. Duplicate publications, review articles, editorials, and incomplete articles were excluded.&#x0D; Results: Database searches identified a total of 59.123 articles. Of these, 300 articles passed the screening process, resulting in 47 articles for full-text assessment. Among them, 28 articles did not evaluate the outcome of interest. Hence, we found 19 appropriate studies included.&#x0D; Conclusion: The outcomes are highly variable. Children have lower drug exposures than adults. Rifampicin exposure is inadequate for younger infants and/or those with HIV. For optimal administration, standardisation of pharmacokinetic paediatric studies and individual patient data analysis with safety assessment are required.

Preclinical and early clinical data of ZN-1041 in combination with trastuzumab deruxtecan to treat breast cancer with or without CNS metastases.

1041 Background: While treatment options for advanced HER2+ breast cancer have improved, HER2+ breast cancer brain metastases (BCBM) remain a clinical challenge warranting the development of additional, brain permeable HER2-targeted therapies. ZN-1041 is a brain permeable, selective HER2-targeted oral tyrosine kinase inhibitor. Preclinical studies have demonstrated efficacy and safety of ZN-1041 warranting clinical development alone and in combination with approved monoclonal antibodies or antibody drug conjugates for patients (pts) with HER2+ BCBM. Methods: Anti-tumor activity of ZN-1041 alone or in combination with trastuzumab emtansine (TDM1), trastuzumab deruxtecan (TDXd), or trastuzumab (H) plus pertuzumab (P) was evaluated in BT474 BM orthotopic xenograft models. ZN-A-1041-101-US (NCT05593094) is an on-going phase 1, multicenter, open-label study. The study comprises dose escalation of ZN-1041 monotherapy (Phase 1a) in pts with HER2+ solid tumors with or without BM, dose escalation (Phase 1b) and expansion (phase 1c) of ZN-1041 in combination with TDM1 (Arm 1), TDXd (Arm 2), or HP as maintenance therapy (Arm 3) in pts with HER2+ mBC with or without BM. The primary objectives were safety, tolerability and recommended phase 2 dose. The secondary objective includes pharmacokinetics (PK) and preliminary efficacy per RECIST 1.1. Results: Preclinically, ZN-1041 alone or combined with TDM1, TDXd or HP demonstrated significant improvement in intracranial tumor growth inhibition compared to TDM1, TDXd, or HP alone. As of data cutoff, Phase 1a (n = 7 pts) and Arm 2 of Phase 1b (n = 3 pts) were completed. Among 10 pts enrolled, 8 pts had received prior HER2 TKI. In Phase 1a, ZN-1041 was well tolerated with no dose-limiting toxicities (DLTs) or drug discontinuation due to toxicity up to a dose of 800 mg BID. Adverse reactions were mainly grade 1. The most common treatment related adverse reactions (TRAEs≥15%) were grade 1 nausea (43%) and vomiting (29%), with no ≥ grade 2 diarrhea reported. PK exposure was increased with dose escalation. In Phase 1a, one pt with mBC (without BM) achieved a confirmed partial response (PR) at 400 mg BID dose for &gt; 15 months; one with gastric cancer achieved stable disease at the first dose level of 50mg BID for nearly 1 year. In Phase 1b, pts who had previously progressed on TDXd and/or TKI were enrolled and received ZN-1041 at a dose of 800 mg BID in combination with TDXd. Combination therapy was well tolerated with no DLTs reported. One pt with BCBM who was previously on tucatinib and TDXd had a confirmed PR. Conclusions: Safety and tolerability was observed for ZN-1041 with maximum tolerated dose 800 mg BID as monotherapy and combined with TDXd in pts with advanced HER2+ malignancies. Encouraging efficacy was observed in treatment-refractory settings. Additional safety and efficacy data of ZN-1041 in combination with TDM1, TDXd or HP are warranted. Clinical trial information: NCT05593094 .

Phase 1/2 study of XTX101, a masked, tumor-selective Fc-modified anti-CTLA4, in patients with advanced solid tumors.

e14685 Background: XTX101 is a tumor-selective, anti-CTLA-4 monoclonal antibody (mAb) engineered with covalently linked peptides that mask CTLA-4 antigen-binding regions. The masking peptides are cleaved by matrix metalloproteases that are more active in the tumor microenvironment (TME) compared with healthy tissues. XTX101 is designed with 2 Fc domain mutations (S239D and I332E) which enhance binding to Fcγ receptors and are intended to improve effector function, resulting in depletion of regulatory T-cells in the TME. In a murine model, XTX101 at 0.3 mg/kg achieved similar tumor growth inhibition as 3 mg/kg of an ipilimumab analog, suggesting higher relative potency of XTX101 over ipilimumab (Powderly SITC 2021). Methods: Interim results of first-in-human, Phase 1 portion of study XTX101-01/02-001 (NCT04896697) are reported here. Part 1A examines XTX101 monotherapy in 3+3 dose escalation. Part 1B is evaluating pharmacodynamic (PD) biomarkers. Results: As of January 27, 2023, 22 patients (pts) with advanced solid tumors were enrolled including colorectal (n = 3), pancreatic (n = 3), non-small cell lung (n = 3), squamous cell skin (n = 2), breast (n = 2), uterine (n = 2), cervical, prostate, Fallopian tube cancer, leiomyosarcoma and Merkel cell carcinoma in Part 1A, and melanoma and colorectal cancer in Part 1B. Pts had a median of 3 prior lines of therapy (1-10). Dose levels (DL) of 7, 20 and 60 mg every 3 weeks (Q3W) were cleared (1 dose limiting toxicity (DLT) of colitis among 8 patients treated at 60 mg Q3W), while 2 DLTs of colitis were reported among 6 pts at 180 mg Q3W. An alternative dosing schedule of 150 mg every 6 weeks (Q6W) was implemented based on clinical and pharmacokinetic (PK) data, and no DLTs were reported among 5 pts at this alternative schedule. There were no grade (G) 4 or 5 treatment-related (TR) adverse events (AEs) on the study. G3 TRAEs included colitis (n = 4), infusion reaction (IR, n = 3) and lymphopenia (n = 2). There were no skin, endocrine or liver-related TRAEs of any grade. One patient with squamous cell lung cancer treated at 150 mg Q6W dose had an unconfirmed partial response and continues on treatment. PK exposure with 150 mg Q6W schedule were comparable to 2 cycles of 60 mg Q3W. Among 8 pts treated at 60 mg Q3W and 5 treated at 150 mg Q6W, 2 out of 13 patients (15%) experienced G3 colitis, 1 pt G2 colitis and 1 pt G2 diarrhea. All colitis AEs improved with immunosuppression and resolved. There were 2 IRs at 60 mg Q3W, while no IR occurred with the Q6W schedule. Based on the totality of clinical and PK data, 150 mg Q6W is the recommended Phase 2 dose (RP2D), and enrollment in part 1B is ongoing at this dose. Conclusions: XTX101 is a Fc-engineered, masked, tumor-activated, anti-CTLA-4 mAb in development for advanced solid tumors. At RP2D, the preliminary safety profile is differentiated from systemically active anti-CTLA4 mAb. Updated clinical data, PK, immunogenicity and PD data from the study will be presented. Clinical trial information: NCT04896697 .

Preliminary results from a phase I/II study of IMM0306, a CD47 and CD20 bispecific monoclonal antibody-trap, in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma.

7527 Background: IMM0306 is a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα on both heavy chains. It has a higher affinity for CD20 than for CD47, thus enabling its preferential and simultaneous binding to CD20 and CD47 on malignant B cells rather than to CD47-postive normal tissues. Here, we report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy results of the dose escalation stage in a phase I/II study in patients (pts) with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma. Methods: This is a first-in-human, open-label, phase I/II study of IMM0306. The ongoing Phase I part (0.04, 0.1, 0.25, 0.5, 0.8, 1.2, 1.6, 2.0 mg/kg, IV) followed an accelerated titration and standard 3+3 design. IMM0306 was administered once per week after a 2-week single-dose period, until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated in the first 28 days. Safety was evaluated per CTCAE 5.0, tumor assessments performed once every 8 weeks, PK and PD were also assessed. Results: As of the data cut-off date on Dec 15th, 2022, 42 pts were enrolled. 18 (43%) pts received 3 or more prior lines of therapy, all pts received prior anti-CD20 therapy. No DLTs were observed up to 2.0 mg/kg. The most frequent treatment related adverse events (TRAEs) were lymphocyte decreased (61.9%), white blood cell (WBC) decreased (61.9%), anemia (59.5%), neutrophil (ANC) decreased (40.5%), platelet (PLT) decreased (40.5%), infusion-related reactions (31.0%). Grade ≥ 3 TRAEs occurred in 30 (71.4%) pts, the most frequent grade ≥ 3 TRAEs were lymphocyte decreased (59.5%), WBC decreased (16.7%), ANC decreased (11.9%). Three treatment related SAEs were PLT decreased (grade 4), chest pain (grade 2) and diarrhea (grade 3). In 38 response evaluable pts, 2 follicular lymphoma (FL) pts achieved CR, 1 marginal zone lymphoma (MZL) pt and 2 FL pts achieved PR and 13 pts showed SD. 26 pts were treated at doses ≥ 0.8 mg/kg, among whom 11 were FL pts. Of these 11 FL pts, 4 (36%) responded including 2 CR both at 1.2 mg/kg and 2 PR at 1.2 and 1.6 mg/kg respectively. IMM0306 exhibited approximate dose-proportional increase in PK exposure from 0.5 to 2.0 mg/kg and no obvious accumulation was observed after repeated dosing. B-cell counts depleted rapidly at doses ≥ 0.8 mg/kg. Elevated cytokines levels were observed after first dosing of IMM0306, but multiple dosing did not stimulate further cytokine activation. Conclusions: IMM0306 was well-tolerated and with a robust preliminary anti-tumor activity especially in pts with R/R FL and MZL. The phase I/II study is ongoing. Clinical trial information: CTR20192612 .

Efficacy, safety, pharmacokinetic (PK), and pharmacodynamic (PD) support for talquetamab (tal) QW and Q2W dosing in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Analyses from MonumenTAL-1.

8041 Background: Tal is a first-in-class bispecific antibody targeting the novel antigen G protein–coupled receptor family C group 5 member D. In MonumenTAL-1 (NCT03399799/NCT04634552), tal demonstrated an overall response rate (ORR) of &gt; 70%, with clinically manageable safety in pts with RRMM. We summarize efficacy, safety, PD, and PK results supporting the recommended phase 2 doses (RP2Ds) of tal: 0.4 mg/kg QW and 0.8 mg/kg Q2W SC. Methods: In MonumenTAL-1, pts received IV (0.5–180 µg/kg) or SC (5–1600 µg/kg) tal doses in phase 1 and at the RP2Ds in phase 2, preceded by step-up doses. Blood samples were collected for the measurement of tal serum concentration and anti-tal antibodies (ADAs). Covariate effects on PK and efficacy were characterized. Efficacy and safety exposure–relationships (E–R) were evaluated using predicted PK metrics, ORR, and key treatment-emergent adverse events (TEAEs), including neurotoxicity, infections, cytopenia, ageusia, dysgeusia, weight loss, and cytokine release syndrome (CRS). Results: PK exposure was approximately dose proportional across IV and SC doses, with a SC bioavailability of 61.9%. At the RP2Ds, the mean concentration–time profiles were comparable and maintained at or above the concentration associated with the 90% maximal drug effect identified in an ex vivo cytotoxicity assay. The incidence of ADAs was 29% (QW) and 20% (Q2W). Presence of ADAs had no apparent impact on PK, safety (CRS, systemic administration–related reaction, or injection site reaction), or efficacy (ORR). At the RP2Ds, PD changes indicative of the proposed mechanism of action, such as T-cell activation, induction of cytokines, and T-cell redistribution, were comparable. Body weight, myeloma subtype, and International Staging System stage were identified as covariates for tal PK; however, there was no clinically relevant impact of age, sex, race, or mild/moderate hepatic or renal impairment on PK. Across SC doses in phase 1, ORR increased with exposure and reached a plateau at or above the RP2Ds, supporting the selected RP2Ds. Baseline myeloma subtype and extramedullary plasmacytoma status were identified as prognostic factors for ORR at the RP2Ds. There were no observed E–R for key TEAEs, including grade ≥3 infections or cytopenia, grade ≥2 weight loss, or grade 2 ageusia. No E–R for grade ≥1/≥2 CRS and peak tal exposure for any step-up doses, irrespective of tocilizumab administration, was observed. Dysgeusia rates were comparable between the 2 RP2Ds. Conclusions: Efficacy, safety, PK, and PD analyses support the selection of tal 0.4 mg/kg QW and 0.8 mg/kg Q2W SC regimens as RP2Ds. The RP2Ds provided comparable PK, PD, efficacy, and safety profiles. Covariates for PK exposure had no impact on E–R, and dose adjustment was not warranted. Clinical trial information: NCT03399799 , NCT04634552 .

Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

7569 Background: B-cell lymphoma 2 inhibitors (BCL-2i) are well tolerated and effective in treating B-cell lymphoproliferative disorders such as CLL. Investigational agent lisaftoclax is a novel, oral, highly selective and potent BCL-2i. Preclinical data show a strong synergistic effect of lisaftoclax plus ibrutinib in an ibrutinib-insensitive PDXWM1 model. Methods: This global, open-label, multicenter study evaluates the safety and efficacy of lisaftoclax alone and combined with ibrutinib or rituximab in pts with WM. Pts were enrolled in 3 arms: Arm A (lisaftoclax), BTKi-resistant/intolerant pts; Arm B (lisaftoclax plus ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax plus rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high TLS risk. Primary objectives were pharmacokinetics (PK), safety, and efficacy assessments; responses were assessed per IWWM criteria. Results: As of January 25, 2023, 46 pts were enrolled (Arm A [n = 14]; up to 1,000 mg; Arm B [n = 24]; up to 1,200 mg; Arm C [n = 8]; up to 800 mg). Baseline characteristics are shown in the table. Median (range) treatment duration was 6 (1-18; Arm A), 14 (1-27; B), and 8 (2-26; C) months. Overall response rates (ORRs) were: Arm A, 25% (median time to response [MTTR], 4.3 months); Arm B, 90.9% (MTTR, 1.9); Arm C, 37.5% (MTTR, 4.4). No significant difference was observed between pts with and without CXCR4-mut. At 1,200 mg, 1 DLT (grade 3 clinical TLS), due to pre-existing renal impairment, was reported. At 1,000 mg, 1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic therapies; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (13%), leukocytopenia (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmias were not observed. Only 1 pt required dose reduction (due to neutropenia). MTD has not been reached. A total of 14 pts discontinued study treatment because of disease progression (n = 5) and AE (n = 1). Lisaftoclax plus ibrutinib showed a PK exposure comparable to ibrutinib alone, indicating no potential DDI. Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. Internal study identifier: APG2575WU101. *SA and ML are co-first authors. Clinical trial information: NCT04260217 . [Table: see text]

A cell culture system to model pharmacokinetics using adjustable-volume perfused mixing chambers

The pharmacokinetic (PK) profile of a drug is an essential factor in determining its efficacy, yet it is often neglected during in vitro cell culture experiments. Here, we present a system in which standard well plate cultures may be “plugged in” and perfused with PK drug profiles. Timed drug boluses or infusions are passed through a mixing chamber that simulates the PK volume of distribution specific to the desired drug. The user-specified PK drug profile generated by the mixing chamber passes through the incubated well plate culture, exposing cells to in vivo-like PK drug dynamics. The effluent stream from the culture may then optionally be fractionated and collected by a fraction collector. This low-cost system requires no custom parts and perfuses up to six cultures in parallel. This paper demonstrates a range of PK profiles the system can produce using a tracer dye, describes how to find the correct mixing chamber volumes to mimic PK profiles of drugs of interest, and presents a study exploring the effects of differing PK exposure on a model of lymphoma treatment with chemotherapy.

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. We aimed to develop alternative dosing regimens to reduce drug expenses. We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

Abstract 3077: Pharmacological profiling of KSHN001034 - A novel prodrug of Fulvestrant with improved efficacy

Abstract Purpose: KSHN001034, a Fulvestrant (FLV) prodrug, was developed to enhance solubility and achieve higher FLV plasma exposures. Currently, Faslodex® (500 mg) intramuscular depot achieves a steady-state plasma concentration of 24-28 ng/mL in humans translating to efficacy. However, it achieves insufficient estrogen receptor (ER) blockade due to suboptimal pharmacokinetic (PK) exposures. KSHN001034 was studied in the MCF-7 xenograft model to evaluate the pharmacodynamic impact of increased FLV exposure. Methods: Higher strength formulations of KSHN001034 were prepared and 150 mg/mL FLV equivalent (eq.) strength was selected based on PK studies of KSHN001034 and Faslodex® in beagle dogs and cynomolgus monkeys. The MCF-7 xenograft study was executed in comparison with FLV where treatment was initiated with an average tumor volume (TV) of ~160 mm3 or ~450 mm3. KSHN001034 or Faslodex® were dosed at 1mg/mouse, and 5mg/mouse either alone or in combination with oral Palbociclib 50mg/kg, QD for 28 days. The plasma as well as brain concentrations (KSHN001034, FLV) and ER expression in tumor tissue were assessed at the end of the study. The toxicity studies were conducted on rats (50, 100, 250 mg/kg) and dogs (15, 30, 75 mg/kg), respectively, using 1x, 2x, and 5x eq. clinical dose of FLV. Results: Single dose PK in dogs and monkeys generated ~2.5-fold higher FLV AUC from KSHN001034 compared to Faslodex®. In the xenograft study, Faslodex® 1mg/mouse treatment in low tumor burden resulted in inhibition of tumor progression (Day 0: 160.8 vs. Day 28: 180.6 mm3) whereas KSHN001034 displayed regression (Day 0: 160.8 vs. Day 28: 143.5 mm3) due to improved FLV exposures. The brain FLV concentration (~60ng/g) post KSHN001034 dosing was observed versus BLQ after Faslodex®. The xenograft study with high tumor burden emphasized the impact of higher FLV release from KSHN001034. The results showed a &amp;gt;30% decrease in initial TV with KSHN001034 in 2-5 days which was not observed even after 28 days of Faslodex® treatment. Also, KSHN001034 showed significantly higher tumor regression in all treated animals compared to Faslodex® (100% vs. 62.5% animals). The safety studies established a rat dose of 250 mg/kg (2.5 g human eq.) and a dog dose of 30 mg/kg (1.0 g human eq.) as the maximum tolerated dose of FLV eq. KSHN001034. Repeat-dose 28 days toxicity studies currently underway in rodent and non-rodent species. Conclusion: Higher FLV exposures with KSHN001034 resulted in improved tumor control, addressing a significant unmet need to slow disease progression as well as its potential in window-of-opportunity trials. Citation Format: Parva Purohit, Heta Pandya, Vishal Unadkat, Sandip Mehta, Ketan Variya, Sonam Sinha, Mahesh Barmade, Vamsi Krishna, Ganesh Sangle. Pharmacological profiling of KSHN001034 - A novel prodrug of Fulvestrant with improved efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3077.

Abstract 4432: A highly differentiated A2AR inhibitor for potential use in cancer therapy

Abstract As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ectonucleotides hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Tumors evade the immune response by usurping pathways that negatively regulate normal immune responses. Resistance to inhibition of immune checkpoint targets arises because of an upregulation in the expression of the CD39-CD73 axis and the resulting increase in production of adenosine in the tumor microenvironment. Inhibition of either adenosine generation or signaling by inhibition of A2AR along with other immune activation strategies have been shown to be effective therapeutic approaches. In view of this, we sought to discover and develop novel small molecule inhibitors that dually target A2AR and an immuno-suppressive ligand expressed in the tumor microenvironment. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and an immuno-suppressive target of relevance in respective biochemical assays. Potent biochemical activity translated into rescue of chemokines and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties and excellent pharmacokinetic exposure in rodents. In a syngeneic tumor model, lead compounds demonstrated significant tumor growth inhibition. Anti-tumor efficacy correlated well with tumor drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumor models and in vivo toxicity studies will be presented. Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, Vijay Kamal Ahuja, Amith A Dhudashiya, Samiulla DS, Girish Daginakatte, Thomas Antony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. A highly differentiated A2AR inhibitor for potential use in cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4432.

Exposure-Response Analyses of Olaparib in Real-Life Patients with Ovarian Cancer.

Olaparib is given in a fixed dose of twice-daily 300mg in patients who are diagnosed with ovarian cancer, breast cancer, prostate cancer or pancreas cancer and has a high interpatient variability in pharmacokinetic exposure. The objective of this study was to investigate whether pharmacokinetic exposure of olaparib is related to efficacy and safety in a real-life patient' cohort. A longitudinal observational study was conducted in patients who received olaparib for metastatic ovarian cancer of whom pharmacokinetic samples were collected. A Kaplan-Meier analyses was used to explore the relationship between olaparib exposure, measured as (calculated) minimum plasma concentrations (Cmin), and efficacy, Univariate and multivariate cox-regression analyses were performed. Also, the Cmin of patients who experienced toxicity was compared with patients who did not experience any toxicity. Thirty-five patients were included in the exposure-efficacy analyses, with a median olaparib Cmin of 1514ng/mL. There was no statistical significant difference in PFS of patients below and above the median Cmin concentration of olaparib, with a hazard ratio of 1.06 (95% confidence interval: 0.46-2.45, p = 0.9)). For seven patients pharmacokinetic samples were available before toxicity occurred, these patients had a higher Cmin of olaparib in comparison with patients who had not experienced any toxicity (n = 33), but it was not statistically significant (p = 0.069). Our study shows that exposure of olaparib is not related to PFS. This suggests that the approved dose of olaparib yields sufficient target inhibition in the majority of patients.

Efavirenz-Based Antiretroviral Therapy but Not Pregnancy Increased Unbound Piperaquine Exposure in Women during Malaria Chemoprevention.

Dihydroartemisinin-piperaquine (DP) is highly effective for malaria chemoprevention during pregnancy, but the standard dosing of DP that is used for nonpregnant adults may not be optimal for pregnant women. We previously reported that the pharmacokinetic exposure of total piperaquine (PQ; both bound and unbound to plasma proteins) is reduced significantly in the context of pregnancy or efavirenz (EFV)-based antiretroviral therapy (ART). However, as PQ is >99% protein-bound, reduced protein binding during pregnancy may lead to an increase in the pharmacologically active unbound drug fraction (fu), relative to the total PQ. We investigated the impact of pregnancy and EFV use on the fu of PQ to inform the interpretation of pharmacokinetics. Plasma samples from 0 to 24 h after the third (final) DP dose were collected from pregnant women at 28 weeks gestation who were receiving or not receiving EFV-based ART as well as from women 34 to 54 weeks postpartum who were not receiving EFV-based ART, who served as controls. Unbound PQ was quantified via ultrafiltration and liquid chromatography-tandem mass spectrometry, with fu being calculated as PQunbound/PQtotal. The geometric mean fu did not differ between pregnant and postpartum women (P = 0.66), but it was 23% (P < 0.01) greater in pregnant women receiving EFV-based ART, compared to that in postpartum women who were not receiving EFV-based ART. The altered drug-protein binding, potentially due to the displacement of PQ from plasma proteins by EFV, resulted in only a 14% lower unbound PQ exposure (P = 0.13) in the presence of a 31% lower total PQ exposure (P < 0.01), as estimated by the area under the concentration time curve from 0 to 24 h post-last dose in pregnant women who were receiving EFV-based ART. The results suggest that the impact of pregnancy and EFV-based ART on the exposure and, in turn, the efficacy of PQ for malaria prevention may not be as significant as was suggested by the changes in the total PQ exposure. Further study during the terminal elimination phase (e.g., on day 28 post-dose) would help better characterize the unbound PQ exposure during the full dosing interval and, thus, the overall efficacy of PQ for malaria chemoprevention in this special population.

Design, synthesis and biological evaluation of novel N-(methyl-d3) pyridazine-3-carboxamide derivatives as TYK2 inhibitors

As a mediator of pro-inflammatory cytokines, TYK2 is an attractive target to treat autoimmunity diseases. Herein, we reported the design, synthesis, and structure–activity relationships (SARs) of N-(methyl-d3) pyridazine-3-carboxamide derivatives as TYK2 inhibitors. Among them, compound 24 exhibited acceptable inhibition activity against STAT3 phosphorylation. Furthermore, 24 showed satisfactory selectivities toward other members of JAK family and performed a good stability profile in liver microsomal assay. Pharmacokinetics (PK) study indicated that compound 24 has reasonable PK exposures. In anti-CD40-induced colitis models, compound 24 was orally highly effective with no significant hERG and CYP isozymes inhibition. These results indicated that compound 24 was worthy of further investigation for the development of anti-autoimmunity diseases agents.

Abstract P3-07-15: Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer

Abstract Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity. CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients (pts) with metastatic breast cancer (MBC) in the first- and second-line settings. However, most patients will progress and newer combinations such as with OP-1250 may provide improved clinical outcome. OP-1250 potently inactivates both wild-type ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESR1 activating mutations, and in models of brain metastasis. A Phase 1/2 monotherapy study of OP-1250 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies (NCT04505826). Monotherapy is well tolerated and the recommended phase 2 dose is 120 mg QD. The aim of this combination trial is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of OP-1250 in combination with palbociclib. Methods: Eligibility criteria include pts with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease. Using a 3+3 design, cohorts are sequentially enrolled, and pts receive escalating doses of OP-1250 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Pts are evaluable for dose limiting toxicities (DLTs) if &amp;gt;75% of both treatments were administered within the first 28-day treatment cycle. Blood is collected for PK on cycle 1 days 1, 2 and cycle 2 days 15, 16 for OP-1250 and cycle 1 day 15 for palbociclib. PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Pts are monitored for adverse events (AE) and tumor assessments (RECIST 1.1) are conducted every two cycles. Results: As of July 7, 2022, 9 pts were evaluable for DLTs after 28 days of treatment in dose levels 30 mg, 60 mg, and 90 mg of OP-1250 in combination with palbociclib. No DLTs occurred at any of the dose levels. As of May 13, 2022, of the 7 pt safety data set, the most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 pts and all were attributed to palbociclib by the investigator. No Grade 4 events were observed. OP-1250 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of OP-1250 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on OP-1250 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDI. Conclusions: In the first three cohorts of OP-1250 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between OP-1250 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of OP-1250 continues to 120 mg, to be followed by dose expansion. Updated data will be presented. (NCT05266105) Citation Format: Arlene Chan, Daphne Day, Rina Hui, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Morena Shaw, Caitlin Murphy. Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-15.

Abstract OT1-01-02: EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET

Abstract Background: Adjuvant ET has been the standard of care for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) EBC. A significant proportion of patients with increased risk still experience disease relapse despite available ET and more optimum ET is needed to prevent patients developing incurable metastatic cancer. Distant recurrence risk ranges from 20% to 40% after 5 years of adjuvant ET, depending on clinicopathological (clin-path) features at diagnosis. Consequently, there is a need to further optimize adjuvant treatment, particularly in those patients who are at increased risk of recurrence. Imlunestrant is an orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties and the potential to overcome ET resistance. In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven). Trial Design: EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant versus physicians’ choice of ET, in patients who are at an increased risk of recurrence based on clin-path features and who have received 2 to 5 years of standard adjuvant ET. Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label). Study treatment duration is 5 years. Males and pre-/peri-menopausal women will receive concomitant treatment with a GnRH agonist if receiving imlunestrant or an AI. Stratification factors include time from initial adjuvant ET, use of prior adjuvant cyclin dependent kinase 4/6 inhibitors, nodal status, menopausal status, and geographic region. Eligibility criteria: Eligible patients are adult males and females (pre-, peri- or postmenopausal) with ER+, HER2- EBC who have completed definitive locoregional therapy and have received 2 to 5 years of prior adjuvant ET without disease recurrence, but who are at increased risk of recurrence based on clin-path features at diagnosis. Prior (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor is permitted. Study endpoints: The primary endpoint is invasive disease-free survival (IDFS), excluding second non-breast primary invasive cancers. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022. Citation Format: Komal Jhaveri, Joyce O’Shaughnessy, Fabrice Andre, Matthew P. Goetz, Nadia Harbeck, Miguel Martín, Francois-Clement Bidard, Zachary M. Thomas, Suzanne Young, Roohi Ismail-Khan, Lillian M. Smyth, Michael Gnant. EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-01-02.

Analysis of Dynamic Efficacy Endpoints of the Nix-TB Trial.

Safer, better, and shorter treatments for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are an urgent global health need. The phase 3 clinical trial Nix-TB (NCT02333799) tested a 6-month treatment of MDR and XDR-TB consisting of high-dose linezolid, bedaquiline, and pretomanid (BPaL). In this study, we investigate the relationship between the pharmacokinetic characteristics of the drugs, patient characteristics and efficacy endpoints from Nix-TB. Pharmacokinetic data were collected at weeks 2, 8, and 16. Efficacy endpoints including treatment outcomes, time to stable culture conversion, and longitudinal time to positivity in the mycobacterial growth indicator tube assay were each characterized using nonlinear mixed-effects modeling. Relationships between patient, treatment pharmacokinetics, and disease characteristics and efficacy endpoints were evaluated. Data from 93 (85% of the total) participants were analyzed. Higher body mass index was associated with a lower incidence of unfavorable treatment outcomes. Median time to stable culture conversion was 3 months in patients with lower baseline burden compared with 4.5 months in patients with high baseline burden. Participants with minimal disease had steeper time to positivity trajectories compared with participants with high-risk phenotypes. No relationship between any drugs' pharmacokinetics (drug concentration or exposure metrics) and any efficacy outcomes was observed. We have successfully described efficacy endpoints of a BPaL regimen from the Nix-TB trial. Participants with high-risk phenotypes significantly delayed time to culture conversion and bacterial clearance. The lack of a relationship between pharmacokinetic exposures and pharmacodynamic biomarkers opens the possibility to use lower, safer doses, particularly for toxicity-prone linezolid. NCT02333799.

Angelica herbal supplement AGN-CognI.Q acute dose safety and pharmacokinetics (PK) dose-response in patients with prostate cancer (PK Dose Trial).

TPS404 Background: There are currently no FDA approved modalities for intercepting biochemically recurrent prostate cancer (PCa) after standard of care surgery and radiation therapies to delay or prevent the need of androgen deprivation therapy (ADT) for localized disease. Preclinical modeling has suggested herbal alcoholic extracts of Angelica gigas Nakai (AGN) root, their signature pyranocoumarins and metabolite decursinol, as potential novel modalities to address this unmet clinical need. We hypothesize that CognI.Q at the higher doses has an acceptable safety profile in prostate cancer patients and pharmacokinetics (PK) exposure metrics will be increased proportional to dose increment. Methods: This is a single institution, phase 1 PK study, N=12. Primary objective- PK, pharmacodynamic (PD) biomarkers with a single ascending dose (SAD)-PK response design. After a subject is enrolled, a 14-day gap must occur before the next subject can be enrolled. If one subject develops a dose limiting toxicity (DLT) at any dose level, that subject will stop participation; If a 2nd subject develops DLT at the same dose level, the trial will be stopped, and the dose level below will be the maximum tolerated dose (MTD). Any subject at a higher dose level at the time of occurrence of 2nd DLT will also stop participation. All subjects will initially start at the 800 mg x 1dose, with further single dose escalation to 1200mg, 1600mg, 2000mg doses of AGN-CognI.Q; each dose will be 1-2 weeks apart. Inclusion criteria: Treated PCa, not on ADT; no active cancer. Subjects will be assessed for safety- clinical, labs (CBC, CMP, baseline and after 24hrs) and EKGs. PK blood will be taken at hourly intervals from 2-7hrs and 24hrs. Plasma pyranocoumarin content will be measured by LC-MS. Immunophenotyping of NK and T cell subtypes will be assessed at baseline and 24 h. Primary Endpoint: MTD. Secondary Endpoint: PK metrics; genotype CYP 2C19 and 3A4 metabolizer status and explore relationship to PK metrics and safety metrics; NK and inflammatory and immune cytokines as PD biomarkers. Trial is now open to accrual (Clinical trial registration NCT05375539). We anticipate that the acute dose safety and PK/PD information will inform the optimal design and execution of the longer-term safety and efficacy (phase I/II) trials. Research Support: MPI 1R01CA260901-01A. Clinical trial information: Clinical trial registration NCT05375539 .