Dose-proportional Manner Research Articles

Pharmacokinetics and Pharmacodynamics of Rusfertide, a Hepcidin Mimetic, Following Subcutaneous Administration of a Lyophilized Powder Formulation in Healthy Volunteers.

Hepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide. A randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials. Rusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24h for doses of 10-30 mg and 2-4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration-time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration-time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus. Rusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration.

Elritercept, a modified activin receptor IIA ligand trap, increased erythropoiesis and thrombopoiesis in a phase 1 trial

AbstractThe transforming growth factor β (TGF-β) superfamily plays a crucial role in regulating biological processes of virtually every tissue and system in the body, including hemostasis and hematopoiesis. Elritercept (KER-050) is an investigational, modified activin receptor type IIA ligand trap designed to bind and inhibit activin A and other select TGF-β superfamily ligands, including activin B, growth differentiation factor 8 (GDF-8), and GDF-11. The objectives of this phase 1 randomized, placebo-controlled study of elritercept were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of activin inhibition and hematopoiesis in healthy postmenopausal women (N = 48). This study comprised 2 parts: single ascending doses ranging from 0.05 to 4.5 mg/kg; and multiple (up to 2 doses) ascending doses of 0.75 mg/kg administered subcutaneously (SC) every 4 weeks. Elritercept was generally well tolerated at all dose levels, with no dose-limiting toxicities observed. There were no severe or serious adverse events nor clinically significant changes in safety laboratory measures. Serum concentrations increased in dose-proportional manner after single SC doses, with peak concentrations achieved in 4.5 to 6 days and a mean elimination half-life of 12 days. These parameters were comparable after multiple doses. Elritercept elicited rapid, sustained, and dose-dependent increases in reticulocytes, red blood cells, hemoglobin, and platelets without eliciting detrimental changes in white blood cells such as neutrophils and lymphocytes. The time course and duration of changes in these cell populations supported a differentiated pharmacologic profile that is consistent with the stimulation of both early- and late-stage hematologic pathways. The trial was registered at www.anzctr.org.au/ as #ACTRN12619000318189.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies

BackgroundSHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects.MethodsTwo randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18–45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55–80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg).ResultsSixty-two (part 1/2, n = 50/12; age range, 18–42/55–63 years) and 30 subjects (age range, 18–42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2–60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed.ConclusionsA single intravenous dose of SHR-1707 at 2–60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development.Trial registrationNCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

8406 A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZP-3813, a Novel Small Peptide Growth Hormone Receptor Antagonist, in Healthy Subjects

Abstract Disclosure: S. Allas: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. G. Ravel: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. C. Farrell: Employee; Self; ICON plc. S. Fillon: Employee; Self; Amolyt Pharma. O. Taha: Employee; Self; Amolyt Pharma. M.D. Culler: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Ovize: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Sumeray: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. A.J. Van der Lely: Consulting Fee; Self; Amolyt Pharma. Acromegaly is a rare disease typically caused by a benign growth hormone (GH)-secreting pituitary adenoma that stimulates over-production of insulin-like growth factor-1 (IGF1) from the liver. Treatment with somatostatin analog (SSA) monotherapy does not provide optimal control of circulating IGF-1 levels in the majority of patients. AZP-3813, a 16-amino acid, bicyclic GH receptor antagonist (GHRA) binds to the GH receptor and prevents endogenous GH from stimulating the production of IGF-1. The compound is being developed as an add-on therapy for the treatment of acromegaly in patients insufficiently controlled with SSAs. In normal animals, AZP-3813 potently decreases circulating levels of IGF-1 and further suppressive effects are observed when combined with the SSA, octreotide. Randomized double-blind placebo-controlled single and multiple ascending dose studies (SAD and MAD, respectively) are being conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZP-3813 in healthy subjects. Here we report data from all SAD cohorts and the first 3 MAD cohorts. In the SAD study, 5 subjects received a single subcutaneous administration of 3 mg AZP-3813 or placebo (3:2) and 8 subjects received 10, 20, 40, 60, 90, 120 mgAZP-3813 or placebo (6:2). In the MAD study, 8 subjects received 10, 20, 40 mg AZP-3813 or placebo (6/2) QD for 14 consecutive days. In both SAD and MAD studies, treatment was well tolerated in all subjects with no safety concerns. Cmax and AUC increased in a dose-proportional manner. The half-life of AZP-3813 was estimated to be 18-22 hours. In the SAD study, AZP-3813 induced a dose-related decrease in circulating IGF-1 levels at doses of 10 mg and above with a more prolonged reduction up to 72 hours at higher doses. In the MAD study, AZP-3813 induced a gradual and sustained dose-related decrease in circulating IGF-1 levels at 20 and 40 mg/day, with a larger effect after 2 weeks of dosing as compared to single administration at the same dose, consistent with a cumulative effect of repeated administration. Mean placebo-adjusted % change from baseline for the 20 and 40 mg cohorts were 19% and 44%, respectively. This study is ongoing, and updates on additional MAD cohorts will be reported at the meeting. These data clearly demonstrate that AZP-3813, the novel GHRA, substantially decreases circulating IGF-1 levels in healthy individuals, thereby supporting further testing in patients with acromegaly. Presentation: 6/1/2024

Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400mg (n = 12); group 3-single dose study with pivmecillinam 600mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600mg) or multiple-dose (400mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors. In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n= 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance.

Lisavanbulin (BAL101553), a novel microtubule inhibitor, plus radiation in patients with newly diagnosed, MGMT promoter unmethylated glioblastoma.

Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models. This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Dose escalation followed a modified 3 + 3 design. Secondary objectives included estimation of OS and PFS and pharmacokinetic analysis. Twenty-six patients with uGBM (median age, 63 years, 42.3% male, 61.5% with gross total resection, median Karnofsky performance status 80) were enrolled; 2 tumors had an IDH1 mutation. Predefined dose levels of Lisavanbulin, administered daily concomitantly with RT, were: 4mg (5 pts), 6mg (5 pts), 8mg (7 pts), 12mg (5 pts), and 15mg (4 pts). The initial starting dose was 8mg. Due to grade 4 aseptic meningoencephalitis in the first patient, the dose was decreased to 4mg. Dose escalation resumed and continued to 15mg with dose-limiting toxicities of grade 2 confusion and memory impairment observed at 12mg. Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15mg. Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15mg daily.

Pharmacokinetics and Safety of Spesolimab in Healthy Chinese Subjects: An Open-Label, Phase I Study.

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening inflammatory skin disease. Interleukin (IL)-36 signalling may play a central role in GPP pathogenesis. Spesolimab is a humanized anti-IL-36 monoclonal antibody inhibiting the IL-36 signalling pathway. Here, we investigated the pharmacokinetics and safety of spesolimab in healthy Chinese subjects. In this Phase 1, single-dose, parallel-group, open-label study, healthy Chinese subjects aged 18-45years received a single spesolimab dose by intravenous infusion (IV; 450mg, 900mg, or 1200mg) or subcutaneous (SC) administration (300mg or 600mg). Primary endpoints were spesolimab exposure (area under the plasma concentration-time curve and maximum plasma concentration); secondary endpoints were treatment-emergent adverse events (TEAEs) and drug-related adverse events (AEs). Fifty subjects received IV (n = 30) or SC (n = 20) spesolimab (n = 10 per dose group); 60.0% were male, mean ± standard deviation age was 31.5 ± 6.6 and 31.0 ± 6.5years in the IV and SC groups, respectively. Spesolimab exposure increased in a dose-proportional manner in both groups. TEAEs were reported in 83.3% and 80.0% of subjects in the IV and SC groups, the most common TEAE was upper respiratory tract infection (20.0% and 25.0%, respectively). One serious AE of hand fracture was reported in the 900mg IV group that was not considered drug-related. Drug-related AEs were reported in 53.3% and 55.0% of subjects in the IV and SC groups. All laboratory-related AEs were mild and resolved. Spesolimab exposure increased in a dose-proportional manner after a single dose by IV and SC administration. Spesolimab was well tolerated in healthy Chinese subjects. Clinicaltrials.gov registration: NCT04390568.

A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.

Vupanorsen is a GalNAc3-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia. The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG). In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80mg or 160mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed. Absorption of vupanorsen was rapid (median time to maximum concentration [Tmax]: 2.0h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80mg] and 465.2h [160mg]). Exposure (area under curve [AUC] and maximum plasma concentration [Cmax]) generally increased in a greater than dose-proportional manner from 80mg to 160mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study. This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted. ClinicalTrials.gov identifier: NCT04916795.

Safety, tolerability, and pharmacokinetic of HY0721 in Chinese healthy subjects: A first-in-human randomized, double-blind, placebo-controlled dose escalation phase I study

BackgroundHY0721 is a novel inhibitor of sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. MethodsThe study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. ResultsThe administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. ConclusionThis study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. Trial registrationChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020.

20-Week intramuscular toxicity study of rotigotine behenate extended-release microspheres for injection via intramuscular injection in cynomolgus monkeys

Continuous dopaminergic stimulation (CDS) has become an important strategy for the development of drugs to treat Parkinson's disease (PD). Rotigotine behenate extended-release microspheres (RBEM) for injection represents a new treatment regime for CDS and is being applied for clinical trial. Our study in cynomolgus monkeys was a 20-week repeat dose toxicity investigation with RBEM at dosages of 90, 180, 360, with a 12-week recovery period. The results observed some irritations in the application site and surrounding tissues in Placebo microspheres and each dose of RBEM, was accompanied with increased white blood count and fibrinogen. RBEM-treated monkeys were additionally noted with a pharmacological action-related decrease in prolactin. These findings showed certain reversibility after the 12-week recovery phase. No clear sex difference was noted in the plasma exposure to rotigotine. The exposure generally increased in a dose-proportional manner. In summary, major toxicological effects are associated with the dopamine agonist-related properties of rotigotine, and the removal of foreign bodies caused by p oly (lactide-co-glycolide) (PLGA)and sodium carboxymethyl cellulose (SCMC), and the no-observed-adverse-effect-level (NOAEL) was 360 mg/kg.

Clinical update related to the first-in-human trial of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate.

3151 Background: SYS6002 (CRB-701) is a novel, nectin-4 targeting antibody drug conjugate (ADC) that take advantage of a third generation, site-specific cleavable linker with novel conjugation chemistry. This technology is designed to establish a stable linker across antibody and payload, to produce an ADC with a homogenous drug antibody ratio of 2.0, with the additional aim to reduce the concentration of free-MMAE and thereby improve known payload related toxicities. SYS6002 (CRB-701) also contains a novel monoclonal antibody with a prolonged half-life that can support Q3W dosing. Methods: This is a multicenter, open-label, single-arm, phase I study using Bayesian optimal interval design. Eligible patients were aged ≥18 years with histologically confirmed Nectin-4 positive solid tumors (no Nectin-4 testing was required for urothelial carcinoma [UC]) who had failed or were intolerant to standard of care options. In the dose escalation, patients were given SYS6002 (dose level 0.2, 0.6, 1.2, 1.8, 2.7, 3.6, and 4.5 mg/kg) administered Q3W by intravenous infusion. The primary endpoints were safety, tolerability, and the recommended phase 2 dose. Results: As of January 2024, SYS6002 (CRB-701) has established a differentiated safety profile across a broad dose range (0.2-3.6 mg/kg) with no dose limiting toxicities and the majority of adverse events representing grade 1 or 2. No low-grade peripheral neuropathy, skin rash or fatigue, known toxicities that rate limit the usage of enfortumab vedotin (EV) have occurred. Herein, we report the anti-tumor activity of SYS6002 (CRB-701) in patients with nectin-4 positive solid tumors with a median of 4 prior therapies. The first confirmed stable disease was observed at 0.6 mg/kg and the first confirmed partial response was at 1.2 mg/kg. Anti-tumor activity in nectin-4 positive patients at doses ≥ 2.7 mg/kg ( n=6) would suggest an overall unconfirmed objective response rate of 50%, and among them, the ORR of patients with UC was 50% (1/2), and that of patients with cervical cancer reached 67% (2/3). Across this group of patients, 4/6 had moderate to high nectin-4 expression (H-score ≥ 150) and 3 achieved a partial response, suggesting SYS6002 (CRB-701) could achieve a highly differentiated ORR of 75% in patients with moderate to high Nectin-4 expression. After single IV infusion of SYS6002 0.2-3.6 mg/kg, the exposure of TAb, ADC and MMAE generally increased in a dose proportional manner. The half-lives of TAb, ADC and MMAE were 4-6 days, 4-5 days and 5-10 days, respectively. SYS6002 (CRB-701) exhibited a longer ADC half-life and lower free-MMAE exposures relative to EV at comparable dose levels. Conclusions: SYS6002 (CRB-701) demonstrates promising anti-tumor activity with a well-tolerated safety profile in patients with advanced nectin-4 positive solid tumors. Dose escalation at 4.5 mg/kg Q3W and dose expansion at 3.6 mg/kg Q3W are ongoing. Clinical trial information: ChiCTR2200066256.

Phase 1 clinical trial of AMG 340, a prostate-specific membrane antigen (PSMA)-targeted T-cell engager with a novel low-affinity CD3 binding domain designed to mitigate toxicity for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

e14587 Background: PSMA, a transmembrane protein highly expressed on the surface of prostate cancer cells, is a validated target in prostate cancer; however, achieving a favorable therapeutic index has been challenging for PSMA-directed T-cell engagers (TCE’s). AMG 340, a PSMA-targeted TCE with a novel low-affinity CD3 binding domain specifically engineered to mitigate cytokine release syndrome (CRS) toxicity and maintain efficacy was investigated in a phase 1, open-label, dose-escalation study (NCT04740034). Methods: Patients (pts) with mCRPC who had received ≥2 prior lines of therapy were treated with AMG 340 monotherapy (1.5–800 mg intravenously every 3 weeks [Q3W]) during dose escalation. The primary outcome measures were dose-limiting toxicities, treatment-emergent adverse events (TEAEs), and pharmacokinetic profile. Secondary outcomes included prostate antigen specific (PSA) response and objective response per response evaluation criteria in solid tumors (RECIST). Results: As of September 6, 2023, a total of 42 pts (mean ± SD age, 68.5±7.8 years) received AMG 340 step up dosing across 11 cohorts. At doses up to 800 mg Q3W, AMG 340 had a manageable side effect profile. Any grade TEAEs reported in ≥30% of pts included CRS (52%), nausea (52%), vomiting (52%), fatigue (48%), diarrhea (38%), increased aspartate aminotransferase (36%), increased alanine aminotransferase (33%), and hypocalcemia (31%). Treatment-related toxicities included CRS (52%; Grade 1, 26%; Grade 2, 24%; Grade ≥3, 2%) and thrombocytopenia (24%; Grade 2, 10%; Grade ≥3, 14%). Step dosing was implemented at doses >40 mg and successfully mitigated CRS incidence and severity after the first dose. The maximal tolerated dose was not reached, as increasing the dose beyond 800 mg was predicted to minimally increase the potential AMG 340 activity. Exposure increased in an approximately dose-proportional manner with no evidence of clinically significant anti-drug antibodies. AMG 340 demonstrated evidence for pharmacodynamic engagement as shown by cytokine induction. Of the 41 PSA evaluable pts, PSA responses were seen across dose levels (PSA50, n=4), but were not dose dependent. Eight of 42 pts remained on treatment after 6 months. Among 27 RECIST evaluable pts, no RECIST responses were observed (n=14 stable disease, n=0 partial or complete response). Conclusions: Despite reaching high doses, no dose response was observed, and AMG 340 did not generate sufficient clinical activity to warrant further exploration. However, AMG 340 demonstrated manageable CRS toxicity showing that decreased CD3-binding strength mitigates CRS, the main toxicity of TCEs. Clinical studies are ongoing evaluating the PSMA protein as a molecular target for prostate cancer. Clinical trial information: NCT04740034 .

Safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509, a soluble guanylyl cyclase activator, in healthy volunteers: Results from two randomized controlled trials

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509 after oral single rising doses (SRDs) or multiple rising doses (MRDs) in healthy volunteers. In the SRD trial (NCT02694354; February 29, 2016), within each of the three dose groups (DGs), six subjects received BI 685509 (1.0, 2.5, or 5.0 mg) and two received placebo (N = 24). In the MRD trial (NCT03116906; April 17, 2017), within each of the five DGs, nine subjects received BI 685509 (uptitrated to 1 mg once daily [qd; DG1], 2.5 mg twice daily [DG2], 5.0 mg qd [DG3]; 3.0 mg three times daily [tid; DG4] or 4.0 mg tid [DG5]) and three received placebo, for 14–17 days (N = 60). In the SRD trial, 7/24 subjects (29.2%) had ≥ 1 adverse event (AE), most frequently orthostatic dysregulation (n = 4). In the MRD trial, 26/45 subjects (57.8%) receiving BI 685509 had ≥ 1 AE, most frequently orthostatic dysregulation and fatigue (each n = 12). Tolerance development led to a marked decrease in orthostatic dysregulation events (DG3). BI 685509 was rapidly absorbed after oral administration, and exposure increased in a dose-proportional manner after single doses. Multiple dosing resulted in near–dose-proportional increase in exposure and limited accumulation. BI 685509 pharmacokinetics appeared linear with time; steady state occurred 3–5 days after each multiple-dosing period. Increased plasma cyclic guanosine monophosphate and decreased blood pressure followed by a compensatory increase in heart rate indicated target engagement. BI 685509 was generally well tolerated; orthostatic dysregulation may be appropriately countered by careful uptitration.

#1003 Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of AZD2373, an antisense oligonucleotide targeting APOL1

Abstract Background and Aims APOL1 mediated kidney disease (AMKD) is associated with toxic gain of function variants in people of African ancestry carrying the high-risk APOL1 genotypes (G1 and G2). APOL1 protein is part of the innate immune system but not considered essential. AZD2373, an antisense oligonucleotide that targets APOL1 mRNA to reduce its protein synthesis, is in development for AMKD. In genomic APOL1-transgenic mice, AZD2373 reduced APOL1 expression in kidney and liver, reduced plasma APOL1 protein concentration, and prevented development of IFN-γ induced proteinuria in high-risk genotype mice. In a single ascending dose study (NCT04269031), AZD2373 was well tolerated. We assessed the safety and tolerability of AZD2373 in a multiple ascending dose study including pharmacokinetics, and pharmacodynamic effect on APOL1 plasma protein levels. Method In this phase 1, randomized, single-blind, placebo-controlled study (NCT05351047) in healthy male volunteers of West African ancestry, participants were enrolled after a pre-screening study where they were genotyped for APOL1 prospectively; 18 participants had either 1 copy or 2 copies of the G1/G2 APOL1 high-risk allele. Low, medium and high dose cohorts each with 8 participants each receiving six weekly subcutaneous injections of either AZD2373 (n = 6) or placebo (n = 2) and were subsequently followed up for 9-weeks post-last dose. The primary objective was safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD2373. Results In total, 24 participants were randomized and completed the study. No major safety and tolerability concerns were reported up to the highest dose of AZD2373 administered. The most common adverse event was injection site reactions which were dose-dependent, mild to moderate in severity and did not lead to treatment discontinuation. After dosing, AZD2373 had a rapid distribution phase (hours) and prolonged elimination phase (days to weeks). Clearance was similar across dose levels after single and repeated dosing, and the renal contribution to overall clearance was minimal. Exposure generally increased in a dose proportional manner. Plasma APOL1 was knocked down in a dose dependent manner (Figure). Conclusion Repeated doses of AZD2373 were safe and well tolerated, reducing plasma APOL1 concentrations in a dose- and time-dependent manner in healthy males of West African ancestry.

Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulatorof Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers.

Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450mg. At 450mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300mg once and twice daily with a meal for phase 2b studies.

Abstract PO3-18-12: Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269

Abstract Background: Topoisomerase I inhibitors (Topo I) have been shown to be highly effective across a broad range of tumors including breast cancer. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been shown to be effective in BRCAm breast cancers. The combination of Topo I plus PARPi is known to be synergistic beyond the BRCAm subtype but overlapping myelotoxicities have prohibited successful clinical combinations. DAN-222 is a novel therapeutic HDC (High-capacity drug conjugate) whose payload is the topoisomerase 1 inhibitor camptothecin (CPT). Our previously published preclinical data demonstrates synergy of DAN-222 plus a PARPi regardless of BRCA or HRD status. Furthermore, DAN-222 demonstrates reduced bone marrow exposure enabling clinical combinations. Herein we present data for the first-in-human study of DAN-222 as mono- and combination therapy with a PARPi. The expectation is clinical benefit with this complimentary combination for patients with HRD+ and HRD- tumors, and not restricted to BRCAm, while minimizing overlapping myelotoxicities. Methods: A phase 1 study of DAN-222 as monotherapy and in combination with niraparib is being conducted in heavily pretreated patients with metastatic breast cancer. The objectives are to evaluate the safety, tolerability, and pharmacokinetics of DAN-222, and initial clinical activity based on RECIST v1.1 criteria to determine the recommended phase 2 dose. PK will be characterized for the total conjugated and the unconjugated CPT. Adults (≥18 years) with HER2-negative metastatic breast cancer that progressed on standard therapies were enrolled, without restriction on BRCA or HRD status. Results: As of June 2023, 30 patients had enrolled in dose escalation of monotherapy (2-16 mg/m2) or combination therapy with niraparib (100 mg). The median age was 61.5 years old (range, 36-75). The median number of prior treatment lines was 6. All patients were PARPi naïve and BRCAwt. In the monotherapy cohorts, the hematological adverse events (AEs) were neutropenia (28%; grade [Gr] ≥3: 17%), thrombocytopenia (22%; Gr ≥3: 6%) anemia (17%; Gr ≥3: 0%), and lymphopenia (11%; Gr ≥3: 0%), the non-hematologic adverse events Gr ≥3 was one case of cystitis. In the combination cohorts, the hematological AEs were anemia (25%; Gr ≥3: 17%), thrombocytopenia (17%; Gr ≥3: 8%), neutropenia (8%; grade Gr ≥3: 8%), and lymphopenia 8%; Gr ≥3: 0%) and there was no Gr ≥3 non-hematologic adverse events. The exposure of DAN-222 was linear and increased in a dose-proportional manner. The mean half-life ranged from 25.2 to 33.5 hours across all cohorts. Clinical activity during dose escalation was demonstrated with stable disease in 28% of patients with monotherapy and 67% of patients with combination therapy across all dose levels. Conclusions: No DLTs were observed in monotherapy or combination therapy in the dose escalation phase of this study. This study demonstrates the feasibility for DAN-222 to be combined with a PARPi at clinically relevant doses. The reduced myelotoxicity of DAN-222 will also enable combination with other therapies to treat patients with other types of cancer. The promising antitumor activity seen with DAN-222 in combination with PARPi in BRCAwt, supports continued clinical development. Citation Format: Sara Hurvitz, Erika Hamilton, Timothy Pluard, Aki Morikawa, Hatem Soliman, Kay Yeung, Adam Brufsky, Amy Tiersten, Wajeeha Razaq, Kristen Foye, Timothy Hagerty. Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269] [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-12.

Abstract 7167: Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung cancer

Abstract Background: Tarlatamab is a first in class, half-life extended delta-like ligand (DLL3) targeted bispecific T-cell engager (BiTE) immunotherapy that has shown antitumor activity with durable objective responses and promising survival outcomes in the ongoing studies in patients with previously treated small-cell lung cancer (NCT03319940, NCT05060016) (Ahn et al, 2023; Paz-Ares et al, 2023). Here we describe the effects of patient specific factors [age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status, emergence of anti-drug antibodies (ADA)] on tarlatamab exposures. Methods: Tarlatamab serum concentrations were available from 420 subjects (8509 samples) pooled across the ongoing Phase 1 DeLLphi-300 study (dose range 0.003 mg to 100 mg Q2W and 200 mg Q3W) and Phase 2 DeLLphi-301 study (10 mg and 100 mg Q2W). The data were analyzed using a nonlinear-mixed effects modeling approach implemented in NONMEM (v7.5) software. Model selection and evaluation was guided by standard statistical and graphical approaches. Impact of key baseline demographic variables on tarlatamab clearance and volume of distribution were evaluated. Results: Tarlatamab exposures increased in a dose-proportional manner and were not impacted by age, sex, ethnicity, estimates of renal and hepatic function, prior lines of therapy or baseline disease status. Asian race resulted in 14% higher peak serum concentrations relative to Caucasian subjects. Higher body weight (99 kg; 90th percentile) was associated with a 24% decrease in Day 28 pre-dose concentration (Ctrough) relative to median bodyweight (73 kg). Lower body weight (54 kg; 10th percentile) was associated with a 27% increase in Ctrough relative to median bodyweight. Positive ADA status resulted in a 24% decrease in Ctrough. However, at the recommended dose of 10 mg Q2W, neither body weight nor ADA status had a clinically relevant impact on tarlatamab efficacy or safety measures (Ahn et al, 2023). Conclusion: Overall, based on these analyses, no dose adjustment for tarlatamab is required based on age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status or emergence of ADA. Citation Format: Stephanie M. Kong, Mukul Minocha, Po-Wei Chen, Pablo Martinez, Erik S. Anderson, Amanda Parkes, Brett E. Houk, Chih-Wei Lin. Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung cancer [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 7167.

Abstract 7161: Preclinical pharmacology modeling (pharmacokinetics/efficacy) of narazaciclib (HX301 or ON123300) to predict its clinical effective dose

Abstract Background: Acute myeloid leukemia (AML) is an aggressive leukemia of myeloid lineage. CSF1R (colony-stimulating factor 1 receptor) regulates the proliferation, differentiation and polarization of cells of myeloid lineages, e.g. monocytes/macrophages. CSF1R expression is aberrantly upregulated in many AML, leading to a hypothesis that CSF1R is a putative leukemogenic driver in a subset of AML and thus could be a potential target for treating AML. Previous studies demonstrated that Narazaciclib (HX301 or ON123300), an investigational kinase inhibitor (TKi), exhibited high potency activity against CSF1R (IC50 0.285 nM) and inhibition of macrophage proliferation and AML tumor growth both in vitro/in vivo, implicating its potential use as an AML therapeutic1 (An et al., 2023 AACR Annual Meeting). In addition, narazaciclib has recently completed the dose escalation phase 1 study in advanced solid tumors. However, the therapeutic window of narazaciclib as a CSF1Ri for treating AML remains to be determined. The present study attempted to utilize both preclinical PK and in vivo efficacy models to predict the effective clinical dose of narazaciclib for guiding the future AML clinical trials. Methods: A single dose of narazaciclib at various of dose levels was orally administrated in NOD/Scid mice, and plasma samples were collected at designated timepoints. The concentrations of narazaciclib in plasma were analyzed by LC-MS. In a Ba/F3-ETV6-CSF1R in vivo xenograft tumor model in Nod/Scid mice, narazaciclib at various dose levels was orally administrated daily. Tumor volumes were measured twice weekly. Results: The mouse PK study showed that narazaciclib displayed overall similar absorption pattern as seen in unpublished human clinical data. Narazaciclib was absorbed rapidly after oral dosing with a mean Tmax ranging from 1 to 2 hours in mouse. However, narazaciclib was cleared faster in mouse, with a mean T1/2 ranging from 1.9 to 2.8 hours, than in human. In addition, the exposures of narazaciclib, as measured by Cmax and AUC in plasma, increased in a relatively dose-proportional manner, as seen in human patients. In the Ba/F3-ETV6-CSF1R xenograft model where the tumor cell growth is solely dependent on the CSF1R kinase activity, narazaciclib at 10 mg/kg did not induce any anti-tumor effects with a TGI of -14.61%. In contrast, narazaciclib at 50 mg/kg and 100 mg/kg exerted significant anti-tumor effects with a TGI of 85.49% and 94.55%, respectively. Based on the mouse PK results, narazaciclib at 50 mg/kg in mouse is estimated to have an AUC of approximate 2000 h*ng/mL, which is equivalent to the dose of 160 - 200 mg/d in human patients. Therefore, 160 mg dose level is predicted to be an effective dose for narazaciclib in AML patients. Conclusions: Narazaciclib at 160 mg/d is predicted to be an effective dose in AML patients. Citation Format: Tao Yang, Hang Ke, Jinping Liu, Kefeng Gong, Henry Qixiang Li. Preclinical pharmacology modeling (pharmacokinetics/efficacy) of narazaciclib (HX301 or ON123300) to predict its clinical effective dose [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 7161.

Abstract 7179: OBI-992, a novel TROP2 targeting antibody drug conjugate demonstrates superior in vivo PK/PD properties and a favorable safety profile

Abstract Background: TROP2 targeting antibody-drug conjugates (ADC) have demonstrated promising clinical responses for the treatment of various solid tumors. However, these ADCs still exhibit serious safety issues, such as hematologic toxicities and interstitial lung disease. OBI-992, a novel TROP2 targeting ADC, which is derived from the conjugation of an anti-TROP2 antibody with a topoisomerase I inhibitor, exatecan, via an enzyme-cleavable linker. OBI-992 is designed to have high serum stability and broad therapeutic index. Herein, we describe the results from preclinical studies of OBI-992, including in vitro and in vivo stability, pharmacokinetics/pharmacodynamics (PK/PD) profile, and safety evaluation. Material and Methods: To characterize OBI-992, the linker stability was evaluated by ex vivo serum stability and rat PK studies. PK/PD properties, including systemic and tumor exposures as well as receptor occupancy, were evaluated in a human lung cancer xenograft model. In vitro toxicity testing, including ADC toxicity on differentiating neutrophils and FcγR mediated toxicity, was evaluated using human monocyte THP-1 cells. A 6-week repeat dose toxicity study in cynomolgus monkeys was conducted to evaluate the safety and toxicokinetics of OBI-992. Results: Ex vivo serum stability demonstrated that OBI-992 exhibited better linker stability than the benchmark datopotamab deruxtecan (Dato-DXd). In vivo PK evaluation in rats showed that OBI-992 had lower Cmax and AUC of free payload than Dato-DXd, indicating a better PK profile of OBI-992 in rats. A PK/PD study in tumor-bearing mice revealed that OBI-992 exhibited higher tumor exposure of free payload than Dato-DXd, resulting in a better antitumor efficacy. In addition, the antitumor effect positively correlated with percentage of receptor occupancy in a dose-dependent manner. In vitro cytotoxicity testing demonstrated that OBI-992 had lower toxicity in differentiating neutrophils and THP-1 cells compared to Dato-DXd, suggesting that OBI-992 may cause less off-target toxicity. Toxicokinetics of OBI-992 in cynomolgus monkeys revealed that the systemic exposure of ADC was similar to that of total antibody. Furthermore, the systemic exposure of ADC and total antibody were found to increase in a dose-proportional manner. Major toxicities in monkeys were target-related skin lesions. The highest non-severely toxic dose (HNSTD) was determined to be 60 mg/kg. Conclusions: OBI-992 exhibits remarkable antitumor efficacy and a favorable safety profile, supporting further clinical development of OBI-992 in TROP2 positive cancers. Citation Format: Chi-Sheng Shia, Shih-Ni Wen, Ren-Yu Hsu, Jyy-Shiuan Tu, Hui-Wen Chang, Wan-Fen Li, Ming-Tain Lai. OBI-992, a novel TROP2 targeting antibody drug conjugate demonstrates superior in vivo PK/PD properties and a favorable safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7179.