Dose-proportional Increase Research Articles

CTIM-16. SAFETY AND PRELIMINARY EFFICACY OF AZD1390 + RADIATION THERAPY FOR GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma is an aggressive cancer; intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide is the first-line standard of care. AZD1390, an ataxia telangiectasia mutated kinase inhibitor, aims to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood–brain barrier penetration, confirmed in healthy volunteers (NCT03215381) and patients with glioblastoma (Phase 0; NCT05182905). This Phase 1, open-label study (NCT03423628) evaluated safety and efficacy of AZD1390 and IMRT in patients with glioblastoma. METHODS Adult patients received escalating once-daily AZD1390 doses with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent glioblastoma) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly-diagnosed O-6-methylguanine-DNA methyltransferase unmethylated glioblastoma). Patients received 2 additional weeks of adjuvant AZD1390 post-IMRT. Primary objective was safety; secondary objectives included efficacy and pharmacokinetics. RESULTS As of Feb 6, 2024, 115 patients (Arm A=75; Arm C=40) received AZD1390 10–900 mg/day. Pharmacokinetics were linear, with a slightly more-than dose-proportional increase and mean elimination half-life ~9–11 hours. Most patients had ≥1 treatment-emergent adverse event (AE), most commonly fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade ≥3 AZD1390-related AEs occurred in 18/115 patients. The maximum tolerated dose was 400 mg (Arm A) and 300 mg (Arm C). Dose-limiting toxicities included creatinine kinase elevation (Arm A) and radiation skin injury (Arm C). AEs led to AZD1390 discontinuation in 15/115 patients. Safety profiles were mostly consistent across Arms despite different radiation schedules. At target-engaging doses, median overall survival was 12.7 months (95% CI: 10.7–18.9; Arm A) and still maturing (Arm C). CONCLUSIONS Concurrent AZD1390 and IMRT demonstrated manageable safety at doses with known target engagement. Preliminary efficacy is encouraging (Arm A). AZD1390 can potentially act as a radiosensitizer for glioblastoma treatment. Clinical investigation is ongoing.

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Assessing the safety and pharmacokinetics of casirivimab and imdevimab (CAS+IMD) in a cohort of pregnant outpatients with COVID-19: results from an adaptive, multicentre, randomised, double-blind, phase 1/2/3 study

ObjectivePregnant women with COVID-19 are at elevated risk for severe outcomes, but clinical data on management of these patients are limited. Monoclonal antibodies, such as casirivimab plus imdevimab (CAS+IMD), have...

Safety, pharmacokinetics, and pharmacodynamics of ART-648, a PDE4 inhibitor in healthy subjects: A randomized, placebo-controlled phase I study.

Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an invitro whole-blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART-648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide-induced TNFα release in exvivo whole-blood assay. In the single rising dose study, ART-648 was safe and well tolerated with a dose-proportional increase in exposures up to 4 mg. Single doses of ART-648 demonstrated dose-dependent PD response, indicating target engagement at 2-8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART-648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.

Preclinical investigations and a first-in-human phase 1a trial of JS007, a novel anti-CTLA-4 antibody, in patients with advanced solid tumors

Abstract Background Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) shows substantial antitumor efficacy. Here, we report the preclinical data and outcomes of a first-in-human phase 1a trial of JS007, a novel anti-CTLA-4 antibody, in advanced solid tumors. Methods In preclinical studies, both in vitro characteristics and in vivo characteristics of JS007 were investigated. The clinical trial included a dose escalation phase and a dose expansion phase. Eligible patients with previously treated advanced solid tumors were enrolled. In the dose escalation phase, JS007 was administered intravenously every 3 weeks at doses of 0.03, 0.3, 1, 3, and 10 mg/kg. Then, 3 and 10 mg/kg were chosen for the dose expansion phase. The primary endpoints included the maximum tolerated dose (MTD) of JS007 based on dose-limiting toxicities (DLTs) and safety. Results JS007 could effectively bind to CTLA-4 and induce an immune response in vitro. Potent in vivo antitumor activity of JS007 was observed. Increased T cell infiltration and T regulatory (Treg) cell depletion in tumor microenvironment of cancer cell xenografts were detected after treated with JS007. Pharmacological analysis in experimental animals showed a dose-proportional increase in exposure. In the clinical trial, a total of 28 patients were treated with JS007 across 5 dose levels. No DLTs occurred. The MTD did not reach at the highest dose tested (10 mg/kg). Twenty-three (82.1%) patients experienced at least one treatment-related adverse event (TRAE). The incidence of Grade ≥ 3 TRAEs was 28.6% (8/28) with alanine aminotransferase increase (7.1%, 2/28) being the most frequently reported TRAE. No severe immune-related adverse event (irAE) occurred. Pharmacological profiles of JS007 in patients were similar to those in animal models. Serum concentration of JS007 showed a dose-dependent escalation, and the half-life of JS007 was 9.4 ~ 12.2 days. Treatment-induced anti-drug antibody was detected in 2 patients. The disease control rate was 50% (14/28), and the median overall survival was 14.7 months. Conclusions JS007 preliminarily demonstrates good tolerance and encouraging antitumor activity in patients with previously treated advanced solid tumors. Trial registration ClinicalTrials.gov identifier: NCT05049265 (Sep 20, 2021).

Pharmacokinetics of nano- and microcrystal formulations of low solubility compounds after intramuscular injection to mice.

The aim of this study was to investigate the pharmacokinetics (PK) of poorly soluble compounds when administered intramuscularly (i.m.) as crystalline particles of different sizes. Three uncharged compounds (griseofulvin, AZ'72, and AZ'07) with varying aqueous solubility were dosed to mice at 10 and 50mg/kg as nano- and microparticle formulations. The PK of the compounds was evaluated. The smaller particles of the drugs resulted in higher maximum plasma concentration (Cmax) and area under the plasma concentration-time profile (AUC) at 50mg/kg. There was a dose-proportional increase in AUC but less than dose dose-proportional increase in Cmax. The evaluation at 10mg/kg was more complex as increased exposure for nanoparticles was only observed for griseofulvin which has the highest solubility. In addition, there was an increase in half-life with an increase in dose. This study highlights that general expectations based on in vitro dissolution (i.e. that smaller particles dissolve faster than larger particles when surrounded by liquid) do not always translate to in vivo and demonstrates the importance of understanding the physicochemical properties of the drug, the characteristics of the formulations and the microphysiology at the delivery site.

56 Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship Confirms Best-in-class Potential of Casdatifan (AB521), a Small Molecule Inhibitor of HIF-2α Being Developed in Renal Cancer

Abstract Background Casdatifan, an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. The objective of this analysis was to develop an understanding of the relationship between clinical dose, casdatifan PK, erythropoietin (EPO), a PD biomarker for peripheral (non-tumor) HIF-2α inhibition, and hemoglobin and to use this information to guide dose selection in future clinical trials. Methods Casdatifan plasma concentrations, serum EPO concentration, and hemoglobin data were obtained from 79 healthy participants in two Phase 1 studies, ARC-14 (NCT05117554) and ARC-28 (NCT05999513), and from 71 patients with clear cell renal cell carcinoma (ccRCC) and other solid tumors in an ongoing Phase 1 study, ARC-20 (NCT05536141). The available PK and PD data were collected following single oral doses of casdatifan ranging from 3 mg to 100 mg in healthy participants, and multiple oral doses of casdatifan ranging from 15 mg to 150 mg once daily (QD) in healthy participants and cancer patients. Serial PK, EPO, and Hb data were gathered in all study participants pre-dose till end of treatment. The population PKPD model was developed using mixed effects methodology with NONMEM software to relate dose, PK, and PD (EPO and Hb) data. Results Casdatifan showed dose-proportional increases in plasma exposure over the 3-150 mg dose range after single and multiple doses. Casdatifan PK was also invariant over time in patients with an approximately 2.0-fold accumulation at steady-state compared to first dose. The mean terminal half-life of casdatifan was approximately 24 h. The PK was similar in healthy participants and cancer patients. Dose-dependent reduction in EPO was observed after single and multiple doses in healthy participants and patients. A two-compartment model with first-order absorption adequately described the casdatifan plasma PK across the dose range tested. The effect of casdatifan plasma concentrations on EPO production rate was modeled using an inhibitory function. Analysis of the casdatifan dose-PD (EPO suppression) relationship indicated that casdatifan 20 mg once daily provided a similar level of EPO suppression in patients as belzutifan 120 mg daily (benchmark peripheral PD). Furthermore, due to the dose-proportional PK of casdatifan, the selected dose (100 mg daily) for further development results in plasma levels approximately 5 times higher than those associated with the benchmark peripheral PD. Conclusions Casdatifan exhibits dose-linear and time-invariant PK in the dose range 15-150 mg. Dose-dependent reduction in EPO levels, consistent with the mechanism of action of HIF-2α inhibition, was seen after casdatifan administration. A PKPD analysis of available data indicated that 20 mg daily dose of casdatifan would result in similar EPO effect as the registered dose of belzutifan. Available PKPD data and analyses indicated best-in-class properties of casdatifan.

Phase I study of the safety and clinical activity of the interleukin-8 inhibitor AMY109 combined with atezolizumab in patients with advanced solid cancers

BackgroundImmunosuppressive conditions within the tumor microenvironment (TME) can allow tumors to evade the immune system, including by hampering programmed death ligand 1 (PD-L1) inhibitor activity. Interleukin (IL)-8 contributes to immunosuppression...

Preclinical Pharmacokinetics in Tumors and Normal Tissues of the Antigene PNA Oligonucleotide MYCN-Inhibitor BGA002.

Although MYCN has been considered an undruggable target, MYCN alterations confer poor prognosis in many pediatric and adult cancers. The novel MYCN-specific inhibitor BGA002 is an antigene peptide nucleic acid oligonucleotide covalently bound to a nuclear localization signal peptide. In the present study, we characterized the pharmacokinetics (PK) of BGA002 after single and repeated administration to mice using a novel specific enzyme-linked immunosorbent assay. BGA002 concentrations in plasma showed linear PK, with dose proportional increase across the tested dose levels and similar exposure between male and female and between intravenous and subcutaneous route of administration. Repeated dosing resulted in no accumulation in plasma. Biodistribution up to 7 days after single subcutaneous administration of [14C]-radiolabeled BGA002 showed broad tissues and organ distribution (suggesting a potential capability to reach primary tumor and metastasis in several body sites), with high concentrations in kidney, liver, spleen, lymph nodes, adrenals, and bone marrow. Remarkably, we demonstrated that BGA002 concentrates in tumors after repeated systemic administrations in three mouse models with MYCN amplification (neuroblastoma, rhabdomyosarcoma, and small-cell lung cancer), leading to a significant reduction in tumor weight. Taking into account the available safety profile of BGA002, these data support further evaluation of BGA002 in patients with MYCN-positive tumors.

Integrating Dynamic in vitro Systems and Mechanistic Absorption Modeling: Case Study of Pralsetinib

Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V., Weteringbrug​, The Netherlands) is a dynamic in vitro model with close simulation of the successive physiological conditions of the human stomach and small intestine. Tiny-TIM runs with pralsetinib were performed at doses of 200 mg and 400 mg under fasting conditions. Mechanistic modeling of absorption was performed in Simcyp V21 (Certara, Manchester, UK). Pralsetinib fasted bioaccessibility in the Tiny-TIM system was 63% at 200 mg and 53% at 400 mg; a 16% reduction at 400 mg was observed under elevated gastric pH. Maximum pralsetinib solubility from the small intestinal compartment in Tiny-TIM directly informed the supersaturation/precipitation model parameters. The PBPK model predicted a similar fraction absorbed at 200 mg and 400 mg, consistent with the dose proportional increases in observed pralsetinib exposure. Integrating dynamic in vitro systems with mechanistic absorption modeling provides a promising approach for understanding and predicting human absorption with challenging low solubility compounds.

Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants.

There is an unmet need for safe and efficacious oral therapies for COVID-19 with low potential for drug-drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS-CoV-2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS-443902), which acts as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first-in-human, randomized, placebo-controlled, phase I study following oral administration of obeldesivir and a phase I, open-label absorption, distribution, metabolism, and excretion study following oral administration of [14C]-obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT-concentration analysis. The exposures to GS-441524 increased dose proportionally in the 100-900-mg dose range. GS-441524 accumulated by 35% after twice-daily and 12% after once-daily dosing for 5 days. Dose-proportional increases in the intracellular concentration of GS-443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS-441524 was not significantly altered by food intake. Following oral administration of [14C]-obeldesivir (500 mg; 100 μCi), the mean cumulative [14C]-dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS-441524 was the predominant plasma component (90% of 14C-area under the concentration-time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice-daily dosing regimen for further evaluation in phase III studies for COVID-19.

768-P: A Phase 1b/2a Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of PB-718, a GLP-1R/GCGR Dual Agonist in Subjects with Obesity

Introduction: PB-718 is a fixed dose combination of PB-119 (GLP-1 receptor agonist) and PB-722 (glucagon receptor agonist in clinical development. Compared with a single molecule approach, PB-718 may offer the balance between GLP-1 and GCGR through adjusting the molar ratio of PB-119 and PB-722 to achieve optimal efficacy and safety. Linear pharmacokinetics, good tolerability and promising effect of weight loss have been demonstrated in a phase 1 study conducted in US. Here we report a phase 1b/2a study in Obesity Methods: Thirty-six patients with obesity (BMI 30.5-40.0 kg/m2) without diabetes were randomized to this 3-sequential cohorts study (NCT06147544). In each cohort, 12 subjects were randomized (3:1) to receive PB-718 (PB-119/PB-722 600/1560 μg, 900/2340 μg or 1600/4160 μg) or placebo SC. injections once a week for 12-18 weeks. The primary endpoints were safety and PK profile. The secondary efficacy endpoints included changes in body weight (BW), BMI, lipids and HbA1c levels. Liver MRI-PDFF and body composition analysis were also assessed. Results: Both PB-119 and PB-722 demonstrated dose-proportional increases in AUC0-last and Cmax ,showing linear, and synergic pharmacokinetics. At 12 weeks, BW, FPG, HbA1c, Lipid, insulin level and HOMA-IR all decreased dose-dependently, and significant reduction in BW of over 4-6% were observed. Serum uric acid was also decreased. Liver fat content and visceral fat mass also showed significant and dose-related reduction with PB-718 treatment. Meanwhile, PB-718 groups lost more fat mass than lean mass. GI side effects were the most common AEs, and were all grade 1 in severity. Conclusions: PB-718 was safe, had predicted PK profile, and led to greater reductions in BW, HbA1c, blood lipids, uric acid, liver fat content and visceral fat mass. These data highlight the potential for PB-718 to provide additional benefit, and support the development of PB-718 as a promising treatment for obesity and NASH. Disclosure K. Ding: None.

Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors.

Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.

FOUR-WEEK ORAL ADMINISTRATION OF BALOXAVIR MARBOXIL AS AN ANTI-INFLUENZA VIRUS DRUG SHOWS NO TOXICITY IN CHICKENS.

High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens (Gallus domesticus, order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens (n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity.

Updated results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine cancers (NEC).

8090 Background: Delta-like canonical Notch ligand 3 (DLL3) is highly expressed on the cell surface of neuroendocrine carcinomas, which have few approved treatment options in the refractory, metastatic setting. HPN328 is DLL3-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. Methods: Pts with relapsed/refractory, metastatic SCLC, neuroendocrine prostate cancer (NEPC) and other NEC associated with DLL3 expression are eligible. Primary objectives are safety, maximum tolerated dose (MTD) and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. Overall response rate (ORR) is determined using modified RECIST v1.1 to include extracranial response assessment for pts treated with radiotherapy for brain metastases while on treatment. HPN328 is administered IV QW or Q2W with priming dose preceding target dose in higher dose cohorts. Results: As of January 5, 2024, 86 pts received HPN328 doses of 0.015-24 mg across 14 cohorts (SCLC [n = 54;63%]; other NEC [n = 32;37%]). The median (range) number of prior regimens was 3 (1-7); 83% previously received a PD-1/PD-L1 blocker. Treatment is ongoing in 24 of 46 (52%) pts in the dose optimization cohorts (1 mg priming dose with 12 or 24 mg target doses QW or Q2W). Treatment-related AEs in ≥ 10% of pts included CRS (59% [30% G1, 26% G2, 3% G3+]), dysgeusia (36%), fatigue (34%), diarrhea (19%), nausea (17%), vomiting (14%), decreased appetite and decreased neutrophil count (13% each), and weight decreased (11%). No G3-4 CRS was seen at target doses. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9% of pts, all G1-2. The maximum tolerated priming dose was 1 mg; dose escalation of target dose continued up to 24 mg QW without reaching a maximum tolerated target dose. Among efficacy evaluable pts treated in dose optimization cohorts, the confirmed ORR in SCLC was 50% (12/24), with one complete response (CR). In NEC (other than NEPC) the confirmed ORR was 44% (4/9), with one CR. Four of eleven pts with NEPC had unconfirmed PRs in 1 mg priming dose cohorts, with 5 NEPC pts remaining on treatment > 20 weeks. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active in SCLC, NEC, and NEPC. Current dose optimization cohorts have completed enrollment and data continue to mature; selection of a recommended phase 2 dose will be made based upon complete mature data. Updated safety and efficacy results will be presented. Clinical trial information: NCT04471727 .

Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.

Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis. A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data. Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study. This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations. This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Clinical Trials NCT01805024.

Phase 1/2 trial of the HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab: Clinical update.

3083 Background: NDI-101150 is a potent, selective, oral inhibitor of hematopoietic progenitor kinase 1 (HPK1), with a different immunotherapy mechanism to other checkpoint inhibitors. NDI-101150 reactivates anti-tumor activity of T-cells, B-cells and dendritic cells (DCs), even under immunosuppressive conditions. Methods: Safety and preliminary efficacy (primary endpoints) of NDI-101150 alone (50–200 mg once-daily in 28-day cycles) and in combination with pembrolizumab are being assessed in patients (pts) with relapsed or metastatic solid tumors. NDI-101150 monotherapy expansion cohorts in renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and gastric/gastroesophageal (G/GEJ) cancer are also being assessed. Results: Dose escalation/expansion data as of Dec 13, 2023 are presented. Treatment (tx)-related adverse effects (TRAEs) in the safety set (N=39) for NDI-101150 monotherapy are presented in the table. 30 (76.9%) pts reported ≥1 TRAE and 5 (12.8%) pts reported grade ≥3 TRAEs. Most common TRAEs were nausea, vomiting, diarrhea and fatigue. Combination tx TRAEs (N=7) recapitulate the monotherapy profile (data not shown). NDI-101150 induced clinical benefit in 4/24 (16.7%) response-evaluable pts: complete response in 1 pt with clear cell RCC; stable disease (SD) ≥6 months in 3 pts (RCC [21 months], pancreatic cancer and endometrial cancer). Unconfirmed SD was noted in 2 pts with RCC, and in 1 pt each with NSCLC and G/GEJ cancer. Nearly dose-proportional increases in exposure were observed on Day 1 of Cycle 1 (C1) across 50–200 mg, with steady state achieved between Days 15 and 28 of tx. Pharmacokinetic profiles of monotherapy and combination tx cohorts were similar. Sustained inhibition of pSLP76 of >50% relative to pre-tx levels (predicted to achieve efficacy in nonclinical models) was observed at all doses tested by Day 15 of C1. Using a custom 12-plex immunofluorescence assay to monitor changes in the tumor immune microenvironment, an on-tx biopsy assessment from a pt with RCC showed increased infiltration of activated CD8+ T-cells and DCs compared to archival biopsy, aligning with the proposed mechanism of action. Conclusions: The observed clinical benefit and safety profile support continued evaluation of NDI-101150 as a viable next-generation immunotherapeutic. Clinical trial information: NCT05128487 . [Table: see text]

Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma.

7060 Background: IMM0306 is a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα on both heavy chains. It exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement. Here, we report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy results of phase I study in patients (pts) with relapsed or refractory (R/R) CD20-positive B-cell non-Hodgkin's lymphoma (B-NHL). Methods: Eligible pts with R/R CD20-positive B-NHL were enrolled in this multicenter phase I study (NCT05805943). IMM0306 was administered as monotherapy at escalating doses of 0.04, 0.1, 0.25, 0.5, 0.8, 1.2, 1.6, 2.0 mg/kg intravenously once a week until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated in the first 28 days. Safety was evaluated per CTCAE 5.0, PK and PD analysis were also assessed, tumor assessments performed once every 8 weeks by Lugano 2014 criteria. Results: As of Nov 21, 2023, 48 pts were enrolled. The median age was 56 years with 30 (62.5%) males. The median prior lines of therapy were 2. All pts received previous anti-CD20 therapy. No DLTs were observed. Recommended phase II dose was determined as 2.0 mg/kg. The most frequent treatment related adverse events (TRAEs) were WBC decreased (66.7%), anemia (64.6%), lymphocyte decreased (58.3%), ANC decreased (47.9%), PLT decreased (45.8%), infusion-related reactions (35.4%). ≥grade 3 TRAEs occurred in 33 (68.8%) pts, with the most common being lymphocyte decreased (56.3%), WBC decreased (18.8%), ANC decreased (18.8%). 8 (16.7%) pts experienced treatment related serious adverse event. Discontinuation due to AEs occurred in 1 pt (grade 4 PLT decreased at 1.6mg/kg without bleeding). No AE led to death. 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. At 1.2 mg/kg and higher dose, CD47 receptor occupancy on peripheral lymphocytes was saturated, suggesting IMM0306 is well tolerated from perspective of CD47 engagement. B-cell 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. Among 33 pts who received doses ≥ 0.8 mg/kg, 5 CR (4 follicular lymphoma [FL], 1 marginal zone lymphoma [MZL]), 5 PR (3 FL, 1 MZL, 1 diffuse large B cell lymphoma) and 11 SD were seen; the median PFS was 10.58 months (95% CI, 2.2, NA) and the median OS was not reached. Among 17 FL pts, 7 (41%) responded including 4 CR and 3 PR; among 6 MZL pts, 2 (33.3%) responded including 1 CR and 1 PR. Conclusions: IMM0306 was well-tolerated and with promising preliminary anti-tumor activity especially in pts with R/R FL and MZL. The phase Ⅱ study is ongoing. Clinical trial information: NCT05805943 .

ARTEMIS-001: Data from a phase 1a/b study of HS-20093 in patients with relapsed small cell lung cancer (SCLC).

8093 Background: SCLC is characterized by a high rate of proliferation and poor prognosis, and new therapies are urgently needed. B7-H3 is highly expressed in SCLC. HS-20093, a B7-H3-targeted antibody-drug conjugate (ADC), demonstrated antitumor activity in advanced solid tumors in the dose escalation part of ARTEMIS-001 study (Jie Wang et al., JCO, 2023) (NCT05276609). Here, we present results on the efficacy and safety of the expansion doses in patients (pts) with SCLC from phase 1a/b. Methods: ARTEMIS-001 study consisted of dose escalation (1a) and expansion (1b) part. Pts were treated with doses of 1.0 to 16.0 mg/kg HS-20093 every 3 weeks in dose escalation, and were treated with doses at 8.0 mg/kg and 10.0 mg/kg randomly in dose expansion. Pts with SCLC were required to have received prior platinum-based standard therapy. B7-H3 expression was retrospectively evaluated by IHC. Results: As of data cutoff November 30th 2023, a total of 56 pts with extensive stage SCLC (ES-SCLC) were enrolled and received ≥1 dose of HS-20093 with doses at 8.0 mg/kg (n=31) or 10.0 mg/kg (n=25). Median prior lines of therapy was 2.0 (range: 1-6). All pts received platinum plus etoposide and 73.2% (41/56) received immunotherapy. Safety profile was consistent with previous reports. The most common grade≥3 treatment-related adverse events (≧10%) were neutropenia, leukopenia, lymphopenia, thrombocytopenia and anemia. Out of 56 pts, 52 pts were efficacy evaluable (8.0 mg/kg: 31 pts; 10.0 mg/kg: 21 pts). HS-20093 showed encouraging efficacy in relapsed ES-SCLC (Table). Tumor shrinkage in target lesions occurred in 96.2% (50/52) pts with a post-baseline scan. Deep response defined as tumor shrinkage ≥50% was obtained in 44.2% (23/52) pts. Median overall survival has not yet reached. Responses were observed regardless of B7-H3 expression. Pharmacokinetic (PK) showed approximately dose-proportional increase in exposure with a half-life of 3-7 days. PK profiles of total antibody and ADC were similar and exposure to payload was considerably low. Conclusions: HS-20093 demonstrated promising antitumor activity and manageable safety in pts with previously-treated SCLC. Phase 3 study is planned to compare the efficacy and safety of HS-20093 with standard-of-care chemotherapy in relapsed SCLC. Clinical trial information: NCT05276609 . [Table: see text]