Multiple Ascending Dose Phase Research Articles

Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants

PurposeGalectin-3, a β-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants.MethodsThis phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal.ResultsAll 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75–4 h (median) post-dose; mean half-life was 11–16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected.ConclusionGB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211.Clinical trial registrationThe study was registered with ClinicalTrials.gov (identifier: NCT03809052).

217. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of the Lipopeptide QPX9003 in Healthy Adult Subjects

Abstract Background QPX9003 is a fully synthetic lipopeptide with potent activity against MDR Pseudomonas and Acinetobacter spp. This report describes the safety and pharmacokinetics of QPX9003 following single and multiple doses. Methods Twelve healthy subjects were enrolled in 2 cohorts of up to 8 subjects (each cohort randomized to have up to 6 active and 2 placebo) each in the multiple ascending dose phase (100 or 200 mg every 6 hrs). Subjects received a single dose of QPX9003 followed by 48 hours of washout, then were administered QPX9003 q6h for 7 days. All infusions were administered over 1 hour. Intensive plasma sampling was obtained after dosing and assayed for QPX9003 content using validated HPLC/MS methods. Results Single and multiple dose QPX9003 pharmacokinetic parameters (mean +/- SD) are shown below: No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose, and all AEs were mild or moderate in severity. Conclusion QPX9003 was safe and well tolerated at all doses tested. QPX9003 plasma AUC and Cmax increased with increasing dose. QPX9003 plasma exposure accumulated ∼ 1.5 fold over 7 days of q6h dosing consistent with its plasma half-life. Based on the PK and safety profile, QPX9003 produces plasma exposures that exceed the PK-PD target safely and warrants further clinical development. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Yehuda Carmeli, MD, Allecra Therapeutics: Advisor/Consultant|MSD: Advisor/Consultant|Nabriva: Advisor/Consultant|Pfizer: Advisor/Consultant|Qpex Pharmaceuticals: Advisor/Consultant|Roche: Advisor/Consultant|Shinogi: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant Shawnee Gehrke, n/a, Qpex Biopharma: Employee Elizabeth Morgan, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.

A randomized, placebo‐controlled, double‐blind, Phase 1b study to evaluate the safety, tolerability and pharmacodynamics of PRI‐002 in early AD

AbstractBackgroundPRI‐002 is an all‐D‐enantiomeric peptide developed to disassemble Abeta oligomers, which has shown to improve cognition in animal models and which has demonstrated its safety profile in healthy young volunteers (Kutzsche et al. 2020).Method20 AD patients in early disease stages fulfilling the ATN‐criteria were recruited to participate in a single center, randomized, placebo –controlled, double‐blind study. Patients received once daily oral doses of 300 mg PRI‐002 or placebo for 28 days. Safety and efficacy assessments were executed at baseline, day 14, day 28 and day 56 (follow up). Blood sampling was carried out at each time point, EEG and CSF measurements before and at the end of treatment. Imaging (MRI) and functional tests (CERAD, CDR) were performed in parallel to EEG/CSF and additionally at follow up.Result10 patients (age 76.9±3.4, MMSE 28±1.6) received placebo and 9 patients PRI‐002 (72.4±6.9, 27.2±2.9). One patient withdraw informed consent before treatment was started. 13 patients reported in total 27 adverse events while no serious adverse event was noted. There was no statistical difference regarding adverse events between treatment and placebo. EEG and MRI revealed no changes after treatment. While no significant changes were detected in p‐TAU, Abeta1‐42 and Abeta oligomers in CSF before and after treatment, patients receiving PRI‐002 significantly performed better than those receiving placebo in the CERAD word list at follow up (p≤0.05).ConclusionPRI‐002 showed an excellent safety profile in AD patients. While no biomarker changes were detected after 4 weeks of treatment interestingly, an improvement of memory function was noted at follow up. A phase 2 study is scheduled.Kutzsche J, Jürgens D, Willuweit A, Adermann K, Fuchs C, Simons S, Windisch M, Hümpel M, Rossberg W, Wolzt M, Willbold D. Safety and pharmacokinetics of the orally available antiprionic compound PRI‐002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020 Mar 20;6(1):e12001. https://doi.org/10.1002/trc2.12001.

†A Cross-Study Comparison Investigating the Effect of CSL112 (Apolipoprotein A-I [Human]) on Cholesterol Efflux Capacity (Encore ACC 2022)

Lead Author's Financial Disclosures Nothing to disclose. Study Funding CSL Behring, LLC. Background/Synopsis Following an acute myocardial infarction (AMI), patients are at high risk of secondary major adverse cardiovascular events (MACE) that are associated with increased morbidity and mortality. Cholesterol efflux capacity (CEC), a key marker of high- density lipoprotein (HDL) function, is inversely correlated with the incidence of MACE. CSL112 (human-derived apolipoprotein A-I [apoA-I]) is a novel agent in Phase III development, aimed to reduce the risk of MACE following AMI. In Phase I and II clinical trials, CSL112 has demonstrated significant increases in CEC; these studies were conducted across different patient populations, including healthy individuals of different ethnicities known to have variations in lipid metabolism, and have shown CSL112 is well tolerated with a favorable safety profile. Objective/Purpose This cross-study analysis aims to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of CSL112 across prior clinical studies, to assess the impact of ethnicity and disease status on apoA-I exposure and CEC. Methods Data from five CSL112 clinical trials were combined: single and multiple ascending dose Phase I studies in healthy volunteers (N=57 and N=36, respectively), a Phase I Japanese ethno-bridging study (N=52), a Phase IIa study in subjects with stable atherosclerotic disease (N=45), and a Phase IIb study in post-AMI subjects AEGIS-I (N=1267). Dose-normalized and baseline corrected PK parameters and CEC responses were compared between the subpopulations. Results Comparison of PK parameters confirmed that the dose-normalized exposures (measured by the maximum concentration [Cmax] and area under the curve [AUC]) of apoA-I were similar across healthy Caucasian and Japanese subjects, subjects with stable atherosclerosis, and subjects post-AMI. PD parameters were also comparable; dose-normalized baseline-corrected CEC were comparable between Japanese, Caucasian, and post-AMI subjects. In addition, following intravenous infusions of 6 g CSL112, similar fold elevations of apoA-I in Japanese, Caucasian and post-AMI subjects (median 2.08, 2.33, 2.08-fold increase, respectively) and total CEC (median of 2.74, 2.92 and 2.55 fold, respectively) were observed. Conclusions CSL112 induces comparable, immediate and robust increases in key biomarkers across different subpopulations. The comparable distribution range and patterns of CSL112 PK/PD parameters between the subpopulations suggests that disease status or ethnicity do not confer any clinically relevant differences on apoA-I exposure and CEC following CSL112 infusion. These results support the use of a fixed 6g dose in the ongoing global Phase III trial (AEGIS-II), investigating the impact of CSL112 on cardiovascular event risk reduction post- myocardial infarction. Nothing to disclose.

Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers

PurposeEvaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors.MethodsA randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability.ResultsSingle-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo.ConclusionsPaltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors.Trial registrationNCT03276858, registered September 8, 2017, retrospectively registered.

IBI362(LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple ascending dose phase 1b study.

BackgroundIBI362 (LY3305677) is a novel weekly-dose glucagon-like peptide-1 and glucagon receptor dual agonist being developed for the treatment of obesity and type 2 diabetes. The aim of this randomised, placebo-controlled, multiple ascending dose phase 1b study was to evaluate the safety, tolerability, pharmacokinetics and efficacy of IBI362 in Chinese adults with overweight or obesity.MethodsThis study enrolled adults with overweight (body mass index [BMI]≥24 kg/m2) accompanied by hyperphagia and/or at least one comorbidity or obesity (BMI≥28 kg/m2) from six study centres in China. Eligible participants were randomised 2:1 to receive once-weekly subcutaneous injection of IBI362 or placebo in each of the three ascending dose cohorts for 12 weeks with additional 8 weeks of safety follow-up. The dose-escalation regimens were: 3.0 mg cohort (1.0 mg weeks 1–4; 2.0 mg weeks 5–8; 3.0 mg weeks 9–12); 4.5 mg cohort (1.5 mg weeks 1–4; 3.0 mg weeks 5–8; 4.5 mg weeks 9–12); 6.0 mg cohort (2.0 mg weeks 1–4; 4.0 mg weeks 5–8; 6.0 mg weeks 9–12). The participants, investigators and study site personnel involved in treating and assessing participants within each cohort were masked to treatment allocation. The primary endpoints were safety and tolerability of IBI362. This study is registered with ClinicalTrials.gov, number NCT04440345.FindingsBetween June 15th, 2020 and January 15th, 2021, 12 participants were enrolled and randomised in each cohort. Throughout the study, no participant discontinued the treatment due to safety reason and no serious adverse event was reported. Gastrointestinal adverse events and decreased appetite were the most common adverse events and mostly mild in severity. Three participants receiving IBI362 reported mild and asymptomatic cardiac disorders revealed by electrocardiogram. Estimated percent changes in mean body weight from baseline to week 12 were −4.81% (95%CI −6.61 to −3.02), −6.40% (−8.23 to −4.58) and −6.05% (−7.91 to −4.18) for participants receiving IBI362 in the 3.0 mg, 4.5 mg and 6.0 mg cohort, respectively, compared with 0.60% (−0.86 to 2.07) for those receiving placebo.InterpretationIBI362 was well tolerated and showed a body weight-lowering effect in Chinese adults with overweight or obesity.FundingInnovent Biologics.

Donanemab (LY3002813) dose-escalation study in Alzheimer's disease.

IntroductionThis study explored the safety and tolerability features of donanemab (LY3002813) in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild to moderate AD dementia.MethodsPatients with AD were enrolled into the single‐ascending dose phase and were administered a single, intravenous (IV) dose of donanemab (five dosing cohorts from 0.1 to 10 mg/kg) or placebo followed by a 12‐week follow‐up period for each dose level. After the follow‐up period, the same patients proceeded into the multiple‐ascending dose (MAD) phase (five cohorts) and were administered IV doses of donanemab (0.3 to 10 mg/kg) or placebo approximately once per month for up to four doses depending on the initial doses (only cohort 1 went from 0.1 mg/kg to a higher dose of 0.3 mg/kg during the MAD phase). This phase concluded with a 12‐week follow‐up period. The relative exposure assessment of an unblinded, single, subcutaneous 3‐mg/kg dose of donanemab in patients with AD was also performed, followed by a 12‐week follow‐up period. One cohort of healthy subjects received an unblinded, single, IV 1‐mg/kg dose of donanemab. These two cohorts did not continue to the MAD phase.ResultsDonanemab was generally well tolerated up to 10 mg/kg. After single‐dose administration from 0.1 to 3.0 mg/kg, the mean terminal elimination half‐life was ≈4 days, increasing to ≈10 days at 10 mg/kg. Only the 10‐mg/kg dose showed changes in amyloid positron emission tomography. Amyloid reduction of 40% to 50% was achieved. Approximately 90% of subjects developed anti‐drug antibodies at 3 months after a single intravenous dose.DiscussionIntravenous donanemab 10 mg/kg can reduce amyloid deposits in AD despite having a shorter than expected half‐life.

Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis

BackgroundInhibition of dihydroorotate dehydrogenase (DHODH) is an established mechanism for the treatment of relapsing-remitting multiple sclerosis (RRMS). Currently approved treatments have several shortcomings. Consequently, new and effective treatments with improved safety and convenience profiles are sought after by patients. ObjectiveTo explore the overall profile of vidofludimus for the treatment of RRMS. MethodsPreclinical investigations were done exploring the species-dependency of DHODH inhibition of vidofludimus. In addition, the preclinical efficacy in a rat experimental autoimmune encephalomyelitis (EAE) model and the inhibition of cytokine release from activated PBMC were investigated. Pharmacokinetic data were also obtained in a Phase 1 multiple ascending dose trial of the formulation IMU–838 (vidofludimus calcium). ResultsIt was shown that vidofludimus is 2.6 times more potent in inhibiting DHO oxidation by human DHODH compared to teriflunomide. Although both compounds increased cell apoptosis, vidofludimus was more efficacious in the inhibition of T-lymphocyte proliferation compared to teriflunomide. The same was also observed for the secretion of IL–17 and IFN–γ. Interestingly, the potency or vidofludimus to inhibit rat or mouse DHODH is 7.5 and 64.4 time lower than the for the human DHODH, respectively. The rat EAE study clearly exhibited a dose-dependent inhibition of cumulative disease scores by vidofludimus. In the multiple ascending dose Phase 1 clinical trial, the serum half-life of about 30 h provides a favorable profile for once daily dosing of IMU–838, with quick dosing to steady state through levels within 5 days and the ability to wash out drug quickly, if required. ConclusionsThe investigations highlighted that the desired selective immunomodulatory properties can be separated from general antiproliferative effects seen and related adverse events in first-generation DHODH inhibitors. Based on data obtained from a series of pre-clinical as well as phase 1 and phase 2 studies, IMU–838 is a promising next-generation candidate for the oral treatment of RRMS. However, this will need to be confirmed in the currently ongoing Phase 2 study in RRMS patients.

Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial.

IntroductionAllopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well‐established preclinical safety efficacy make it a viable candidate.MethodsA randomized, double‐blinded, placebo‐controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once‐per‐week for 12 weeks with a 1‐month follow‐up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini‐Mental State Examination score of 20–26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers.ResultsA total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 [22%]) and fatigue (n = 3 [17%]). A single non‐serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose‐response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/−7.31), 42.05 ng/mL (+/−14.55), 60.07 ng/mL (+/−12.8), and 137.48 ng/mL (+/−38.69), respectively. The MTD was established based on evidence of allopregnanolone‐induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging–based imaging outcomes were evident.ConclusionsAllopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial.Trial registrationClinicalTrials.gov‐NCT02221622

Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study.

IntroductionPRI‐002 is an orally available anti–amyloid beta (Aβ) prionic compound developed for direct disassembly of toxic Aβ oligomers relevant to Alzheimer's disease.MethodsTwo placebo‐controlled clinical phase I trials with oral dosing of PRI‐002 were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg PRI‐002 or placebo) in 40 participants followed by a multiple ascending dose study with daily 160 mg PRI‐002 for 14 days or 320 mg for 28 days in 24 participants. The main objectives were safety, tolerability, and evaluation of pharmacokinetic (PK) parameters.ResultsPRI‐002 was safe and well tolerated after single and multiple oral administration up to the highest doses. PRI‐002 was absorbed rapidly and drug exposure increased proportional to dose. During repeated daily administration, the drug accumulated by a factor of about three. Steady‐state conditions were reached after 1 to 2 weeks.ConclusionsThe safety and PK results encourage further clinical development of PRI‐002.

SAT-429 Final Results from the First in Man Phase 1 Clinical Trial of CRN00808, an Orally Bioavailable sst2-Selective, Nonpeptide Somatostatin Biased Agonist, for the Treatment of Acromegaly: Safety, Pharmacokinetics, Pharmacodynamics, and Midazolam Drug Interaction in Healthy Volunteers

Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808 is a small molecule nonpeptide selective somatostatin receptor 2 agonist whose safety, pharmacokinetics (PK), and pharmacodynamics (PD) has been characterized in preclinical studies. This study describes the final results from a first-in-human, single and multiple ascending dose Phase 1 study in healthy volunteers to measure the safety, PK, PD, and midazolam drug interaction potential of CRN00808 (NCT03276858; preliminary results with blinded safety data presented at ENDO 2018). In the single dose arm of the study, cohorts of 8 subjects (6 active: 2 placebo) received CRN00808 as an oral solution or capsules (1.25 mg to 60 mg, or placebo). The effect of food on CRN00808 PK was also evaluated. In the multiple dose arm, cohorts of 9 subjects (6 active: 3 placebo) received CRN00808 capsules once daily (5 mg to 30 mg, or placebo) for 7-10 days. In the drug-interaction arm, a single cohort of 8 subjects received 20 mg of CRN00808 for 7 days; midazolam PK was assessed before (Day -2) and after (Day 7) administration of CRN00808. Safety and PK were assessed in all phases of the study. Suppression of GHRH-induced GH secretion and suppression of serum IGF-1 were measured as PD endpoints in the single and multiple dose phases of the study, respectively. Once daily administration of 5-30 mg CRN00808 capsules exhibited dose-dependent increases in peak (Cmax) and total (AUC) plasma exposures. The apparent terminal elimination half-life was determined to be of 42-50 hours and steady state was achieved in 3-5 days. Capsules taken with a standard high fat, high calorie meal resulted in a markedly lower plasma CRN00808 AUC (83%). Oral administration of CRN00808 resulted in dose-dependent suppression of both GHRH stimulated GH and IGF-1 secretion; a single 10 mg dose was found to cause 91% suppression of GHRH-stimulated GH and 10 mg once per day for 10 days resulted in maximal suppression of serum IGF-1. Midazolam PK was unaffected by co-administration of 20 mg CRN00808, suggesting little or no risk of drug interaction with CYP3A4/5 substrates. Treatment emergent adverse events associated with CRN00808 were generally mild and transient, and consistent with those reported with other somatostatin agonists. In conclusion, results from this Phase I clinical trial in healthy volunteers support further clinical development of CRN00808 as a once-daily oral treatment of patients with acromegaly.

Multiple Ascending Dose Phase I Study in Order to Define Lanifibranor (IVA337) Supra-thjerapeutic Dose

Multiple Ascending Dose Phase I Study in Order to Define Lanifibranor (IVA337) Supra-thjerapeutic Dose

1401. A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Pharmacokinetics of Single and Repeat Doses of VNRX-5133 in Healthy Subjects

BackgroundVNRX-5133 is a novel, non-β-lactam, β-lactamase inhibitor with potent and selective direct inhibitory activity against serine- and metallo-β-lactamases. VNRX-5133, combined with the β-lactam antibiotic cefepime, is being developed for the treatment of serious infections due to multidrug-resistant Gram-negative bacteria, including ESBL-producing organisms and carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. This study evaluated the safety and pharmacokinetics (PK) of VNRX-5133 after single and multiple intravenous (IV) doses.MethodsThis was a Phase 1, randomized, single-center, double-blind, placebo-controlled, sequential group study in healthy subjects. In a single ascending dose (SAD), phase subjects received 62.5, 125, 250, 500, 1000, and 1500 mg VNRX-5133 via a 2-hour IV infusion. In a multiple ascending dose (MAD) phase, subjects received 250, 500, and 750 mg VNRX-5133 q8h for 10 days. PK samples were collected predose and at frequent intervals. Safety was assessed from adverse events (AEs), laboratory tests, physical examination, vital signs, and electrocardiogram (ECG).ResultsAll subjects completed the SAD (n = 48) and the MAD phases (n = 36). VNRX-5133 plasma exposure exhibited dose proportionality and linearity. Total clearance (CL) was ~6 L/h and volume of distribution (Vz) was ~30 to 50 L. The t1/2 based on a noncompartmental analysis was ~6.5 hours. Modeling of VNRX-5133 plasma concentrations showed that the PK fit a 2-compartment model with most of the drug exposure accounted for within the initial phase of ~2 hours. Minimal accumulation of VNRX-5133 was observed following q8h dosing over 10 days. In the SAD phase, AEs occurred in four subjects (33.3%) with placebo and seven (19.4%) with VNRX-5133. In the MAD phase, AEs occurred in three subjects (33.3%) with placebo and eight (29.6%) with VNRX-5133. The most common AEs with VNRX-5133 were headache (11.1%), nausea (7.4%), and constipation (7.4%).ConclusionAfter single doses of 62.5–1,500 mg and multiple doses of 250–750 mg q8h, VNRX-5133 demonstrated a linear and dose-proportional PK profile with low variability. No safety issues were identified.Disclosures B. Geibel, VenatoRx Pharmaceuticals, Inc.: Employee, Salary. J. Dowell, VenatoRx Pharmaceuticals, Inc.: Consultant, Consulting fee. D. Dickerson, VenatoRx Pharmaceuticals, Inc.: Research Contractor, Research support. T. Henkel, VenatoRx Pharmaceuticals, Inc.: Employee, Salary

The Rennes Disaster: Lessons to be Drawn

On 10 January 2016, in Rennes (France), a first-in-human (FIH) phase 1 clinical trial turned into a drama: one healthy volunteer died and four others were hospitalized. It occurred during the multiple ascending dose (MAD) testing of a molecule (BIA 10-2474) acting on the brain « endocannabinoid system » as an inhibitor of the fatty-acid-amide-hydrolase (FAAH). Such an inhibition is expected to increase the levels of anandamide in brain tissues; the resulting effects being complex and partly unknown. Pharmacologically, the BIA 10-2474 is characterized by (i) a much lower potency than most of its predecessors, (ii) a poor selectivity for its target enzyme (FAAH), (iii) a long-lasting action and, (iv) an unusual steepness of its dose-effect curves. The animal toxicology (four species) showed toxic effects at the highest doses, particularly on the neurologic and reproductive systems; none of them made it possible to predict what would happen later in humans. Nothing special occurred in the volunteers (8 cohorts of 8) during the single ascending dose phase (0.25 mg to 100 mg/day). The MAD phase (6 cohorts of 8 volunteers) intended to test 6 doses each for 10 consecutive days. The scheduled dose escalation was 2.5, 5, 10, 20, 50, and 100 mg. The drama occurred on the 6th day of the 50mg administration. Five volunteers were hospitalized presenting various but purely central neurological symptoms: headaches, ataxia, consciousness disorders and memory impairment. One died 3 days after admission. Two presented with sequelae. In four of these volunteers, the MRI scan showed quite unusual, bilateral and symmetrical anomalies of highly variable intensity. They were located in the hippocampus and the pons, predominating in the anterior part and extending to the cerebral cortex in the most severely affected volunteers. This suggested a common mechanism and ruled out a primitive vascular or inflammatory process. After a 3-month assessment period, the temporary specialized scientific committee (TSSC), set up by the Directorate of the French Medicines Agency (ANSM), concluded that was observed in these volunteers (i) was clearly related to the molecule tested, (ii) resulted from a cumulative toxicity beyond a given threshold, (iii) ensued from an “off-target” mechanism, and not from stimulation of the endocannabinoid system, and (iv) was clearly favoured both by the specificities of the molecule tested (low selectivity, long-lasting effect, steep dose-effect curves, non-proportional pharmacokinetics, etc.) and by the design of the trial (geometric dose escalation, pharmacokinetic data of the preceding cohort not available, maximum dose to be tested 20-fold higher than that blocking FAAH activity in humans, etc.). As a result, the TSSC made six recommendations for conducting of FIH trials. Reference ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6daf96b141bc9509e2f85c227e.pdf

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Doses of AG-519, an Allosteric Activator of Pyruvate Kinase-R, in Healthy Subjects

BACKGROUNDPyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R) due to mutations in the PKLR gene. PK catalyzes the last enzymatic step in the glycolytic pathway and is the main source of adenosine triphosphate (ATP) production in red blood cells. PKLR mutations lead to defective proteins that are hypothesized to reduce ATP levels in red cells, leading to hemolysis. Small molecule allosteric activation of PK-R resulting in increases in ATP and decreases in 2,3-diphosphoglycerate (2,3-DPG) in healthy volunteers has been observed with an earlier molecule, AG-348, the first small molecule PK-R activator to enter clinical trials (Yang et al. EHA 2015, S138). AG-519 is the second small molecule PK-R activator to enter clinical trials. AG-519 is a potent, highly selective and orally bioavailable PK-R activator devoid of the aromatase inhibitory effects that were observed with AG-348.AIMSAG-519 is currently being tested in a randomized, double-blind, phase 1 study in healthy volunteers (NCT02630927), with the objective of identifying a safe and pharmacodynamically active dose and schedule to support potential ongoing development in patients with PK deficiency. Here we report the first 4 cohorts of the multiple ascending dose (MAD) phase of this study. The single ascending dose (SAD) phase of the study and the first two cohorts of the MAD phase of the study have been reported previously (Barbier et al. EHA 2016, P752).METHODSHealthymen and women (non-childbearing potential) aged 18-60 years who provided informed consent were eligible. The MAD phase of the study consisted of 5 dose cohorts. The dose levels administered were determined during interim data reviews of each completed MAD cohort, as well as data from completed SAD cohorts. At each dose level, 8 subjects were enrolled and randomized to receive AG-519 (n=6) or placebo (n=2) twice daily (BID; approximately every 12 hours) for 14 days. Safety assessments included adverse events (AEs), vital signs, electrocardiogram and clinical laboratory parameters. Serial blood samples were drawn to measure plasma concentrations of AG-519 and whole blood concentrations of 2,3-DPG and ATP for pharmacokinetic and pharmacodynamic (PD) assessments.RESULTSData are available for 32 subjects enrolled across 4 dose cohorts in the MAD phase of the study: 8 subjects each in cohort 1 (125 mg BID), cohort 2 (375 mg BID), cohort 3 (25 mg BID), and cohort 4 (300 mg BID). Blinded safety reviews indicated that multiple doses up to 375 mg have been well tolerated with no serious AEs or dose-limiting toxicities reported to date. One case of probable drug-induced Grade 2 thrombocytopenia was previously reported in 1 subject in the 375 mg cohort; the event was rapidly reversible with no clinical sequelae. The protocol was amended to require daily monitoring of platelets in subsequent cohorts and no other subjects have developed thrombocytopenia during treatment. The preliminary analysis of free testosterone and estradiol confirmed the absence of aromatase inhibitory activity.AG-519 steady-state was reached the third day after the first dose based on trough concentration values. The clearance of AG-519 after multiple doses was similar to that observed after single doses in the SAD cohorts. Dose-dependent increases in ATP in blood (Figure 1) and decreases in 2,3-DPG in blood correlated with dose-dependent increases in exposure of AG-519, with a peak effect at or below 375 mg BID. ATP response at 25 mg appears to be greater than 50% of maximal response. Results from the fifth MAD cohort, which evaluated the PD results with 10 mg BID, will be presented.ATP = adenosine triphosphate; BID = twice dailyCONCLUSIONAG-519 is well tolerated in healthy subjects at doses ranging from 25 mg to 375 mg BID for 14 days. The robust dose-dependent changes in ATP and 2,3-DPG concentrations in blood from healthy volunteers are consistent with increased activity of PK-R, the expected PD effect of AG-519. These data support the hypothesis that AG-519 may be able to enhance glycolytic activity in red cells of patients with PK deficiency to address the underlying cause of the disease. [Display omitted] DisclosuresBarbier:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bodie:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Connor:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Merica:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kung:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Le:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kosinski:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Silverman:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yuan:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bowden:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cohen:Agios Pharmaceuticals, Inc.: Consultancy.

PHASE 1 DEVELOPMENT OF ALZ-801, A NOVEL BETA AMYLOID ANTI-AGGREGATION PRODRUG OF TRAMIPROSATE WITH IMPROVED DRUG PROPERTIES, SUPPORTING BRIDGING TO THE PHASE 3 PROGRAM

ALZ-801 is a novel, orally bioavailable, small-molecule prodrug of tramiprosate with improved pharmacokinetics and oral tolerability. The initial tramiprosate Phase 3 program in mild-to-moderate Alzheimer’s disease (AD) included two studies with >2,000 patients but did not show significant separation on co-primary outcomes. In these studies, ∼60% of patients were carriers of the e4 allele of the apolipoprotein E gene (APOE4), and ∼14% were homozygous for APOE4. A subgroup intention-to-treat analysis of APOE4/4 patients showed that tramiprosate 150mg BID produced a significant and clinically meaningful improvement on cognition (ADAS-cog), and a positive trend on function (CDR-SB), at 65 and 78 weeks, on top of standard of care symptomatic therapy. Tramiprosate also showed a favorable safety profile: the most common AE was nausea. Safety data from Phase 3 tramiprosate studies support bridging to the ALZ-801 safety database, based on bioequivalence. To advance the clinical development of ALZ-801 into Phase 3, we have completed single dose and 14-day multiple ascending dose Phase 1 bridging studies in healthy elderly volunteers to evaluate safety, tolerability and pharmacokinetics. Compared with oral tramiprosate, oral ALZ-801 delivered an equivalent plasma exposure of tramiprosate with over 50% lower inter-subject variability. Oral ALZ-801 also prolonged plasma tramiprosate terminal half-life to ∼24 hours. Administration of ALZ-801 with food markedly reduced the incidence of GI symptoms as compared to the fasted state, while maintaining plasma tramiprosate exposure. An immediate release tablet formulation of ALZ-801 was developed, which displayed exposure and low variability similar to the loose filled capsule formulation. ALZ-801 also showed excellent dose proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on the single and multiple dose pharmacokinetics of ALZ-801, the steady-state plasma exposure of the active drug tramiprosate following oral BID dosing of ALZ-801 immediate release tablet has been determined. The data indicate that 265mg BID of ALZ-801 will achieve a steady-state tramiprosate exposure that is equivalent to 150mg BID of oral tramiprosate. These bridging data will support the Phase 3 development of ALZ-801, an optimized prodrug of tramiprosate with improved GI toleration and low inter-subject pharmacokinetic variability, in APOE4/4 homozygous AD subjects.

Abstract 17521: Safety and Efficacy of Centhaquin as a Novel Resuscitative Agent for Hypovolemic Shock

Centhaquin (PMZ-2010) is a cardiovascular active agent (0.01 to 0.05 mg/kg) which has been shown to have resuscitative effect in a (1) rat model of fixed pressure blood loss, (2) rabbit model of uncontrolled bleeding with trauma, and (3) pig model of massive blood loss. PMZ-2010 produced a decrease in heart rate and vascular resistance; however, it increased mean arterial pressure by increasing cardiac output. We embarked on studies to develop PMZ-2010 as a resuscitative agent for hypovolemic shock. Toxicological studies were carried out and intravenous injection of PMZ-2010 in mice, rats and rabbits showed LD50 >100 mg/kg, 79.43 mg/kg and 9.55 mg/kg, respectively. The No Observed Adverse Effect Level (N.O.A.E.L.) of PMZ-2010 determined after repeated (28 days) intravenous injections of different doses in mice, rats and rabbits was found to be 1.0 mg/kg. A 14 day repeated dose toxicity study of PMZ-2010 (0.01, 0.10 and 1.0 mg/kg, iv) in canine model (beagle dog) was conducted and there were no clinical symptoms of toxicity in low and middle whereas in high dose (1.0 mg/kg) temporary sluggishness, shivering and salivation was observed, while biochemical profile was normal in all groups. We conducted a single center randomized, double-blind, placebo-controlled, single and multiple-ascending dose phase I study in healthy male subjects to evaluate the safety of PMZ-2010 (NCT02408731). The study population comprised 6 cohorts of 4 subjects each, which were randomized so that 3 subjects received the active drug and 1 subject received placebo. For single ascending dose cohorts, the initial dose of PMZ-2010 was 0.005 mg/kg, iv infusion. Based on the safety and tolerability of the administered dose, subsequent escalation of doses 0.01, 0.05 0.10 and 0.15 mg/kg was performed and maximum tolerated dose (MTD) was found to be 0.10 mg/kg. For multiple-ascending dose cohorts, the initial dose/day of PMZ-2010 was equal to maximum tolerated dose (MTD) 0.10 mg/kg (3 X 0.033 mg/kg/day) for 2 days. Subsequent escalation of dose was done up to 2 times MTD 0.20 mg/kg (3 X 0.067 mg/kg/day) for 2 days. It is concluded that MTD of PMZ-2010 in humans is 0.10 mg/kg and can be safely used for its resuscitative effect. (Mr. Tajuddin and Dr. D. Chilkoti are acknowledged for assisting in clinical studies).

Pre-clinical development of the human CD40 agonistic antibody ADC-1013

Activation of CD40 on dendritic cells increases cross-presentation of tumor antigens and as a result the number of activated tumor directed T effector cells. CD40 agonists have been shown to generate powerful systemic anti-tumor responses when administered in situ. The pre-clinical proof of concept data has been generated mainly using an hCD40 transgenic mouse (hCD40tg) strain. Anti-tumor effects has been demonstrated in multiple syngeneic tumor models including bladder tumor (MB49), melanoma (B16) and lymphoma (A20) models. The anti-tumor effects has been shown to induce long term, T cell dependent, tumor immunity. As expected, the anti-tumor effects depends on the immune status of the tumors as evaluated by immunohistochemistry and flow cytometry. Since CD40 agonistic antibodies mainly exert their effects upstream of the checkpoint inhibitors they have the potential to be ideal candidates for combination regimens including e.g. PD-1 antagonists and OX40 antibodies. Combining ADC-1013 with antibodies against these targets has been shown to improve the anti-tumor effects in B16.F10 melanoma. Toxicology studies were performed in cynomolgus monkeys using subcutaneous or intravenous administration. Doses of 1 to 10 mg/kg were evaluated in both studies. ADC-1013 was well tolerated at all dose levels and no major safety concerns were identified. Receptor saturation of approximately 95% was achieved and pharmacodynamic activity, notably B-cell depletion, was observed at all dose levels. In cynomolgus monkey, serum concentrations of ADC-1013 declined in a multi-phasic manner following a single intravenous dose. The mean terminal half-life was approximately 30 hours. Following subcutaneous administration the mean elimination half-life was found to be between 0.6 and 3.2 days. The clearance (CL_F) decreased and the half-life increased with increasing dose indicating target-mediated clearance. Alligator Bioscience has recently started dosing of the first patients in a clinical trial of the CD40 agonistic antibody ADC-1013. The study is a first-in-human, multicenter, open-label, multiple ascending dose Phase I study in patients with advanced solid tumors to determine the safety, pharmacokinetics and pharmacodynamics of intratumorally administered ADC-1013.

Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans

AimA first in human study to evaluate tolerability and pharmacokinetics followed by an early proof of mechanism (POM) study to determine whether the small orally, available molecule, Posiphen tartrate (Posiphen),...

Pharmacodynamic, Biodistribution and Toxicology Results for SNS01-T, a Nanoparticle That Targets eIF5A for the Treatment of Multiple Myeloma

Abstract 2051▪▪This icon denotes a clinically relevant abstractEukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, inflammation, differentiation, and apoptosis and is the only known protein to be post-translationally modified with a hypusine residue. Both hypusinated eIF5A and deoxyhypusine synthase, the enzyme that mediates eIF5A hypusination, have been identified as markers of neoplastic growth and metastasis. Accumulation of unmodified eIF5A is generally only observed during apoptosis and mutants of eIF5A that cannot be hypusinated (eIF5AK50R) are pro-apoptotic. In vitro cell studies and in vivo xenograft models have demonstrated that simultaneous small interfering RNA (siRNA)–mediated suppression of native eIF5A expression and over-expression of eIF5AK50R potently induces apoptosis in multiple cancer cell types, including myeloma, and inhibits human myeloma tumor growth in murine xenograft models. SNS01-T is a nanoparticle comprising: 1) a plasmid encoding the pro-apoptotic eIF5AK50R driven by a B cell specific promoter; 2) an siRNA that inhibits pro-survival hypusine-eIF5A expression; and 3) a polymer that assembles the nucleic acids into a nanoparticle. Pharmacokinetic, pharmacodynamic, biodistribution, and toxicology studies have been conducted with SNS01-T to support studies in multiple myeloma patients.The pharmacokinetics and biodistribution of SNS01-T were evaluated in mice using RT-qPCR to assess the distribution and persistence of plasmid DNA and siRNA. Toxicology includes acute and 6-week studies with twice weekly administration of SNS01-T in male and female mice and dogs. Clinical signs, hematology, histopathology, clinical pathology, pharmacokinetics, and serum cytokines were measured. SNS01-T reached all tissues examined including the bone marrow. No evidence of accumulation of the plasmid or siRNA was observed and levels declined rapidly after the end of treatment. Toxicological findings of SNS01-T administration in mice at 0.25 and 0.5 mg/kg for 6 weeks included clinical signs limited to the injection site, increases in organ weight, increases in IFN-g and GRO, and hematological changes, that could not be attributed solely to the test article. Toxicological findings of SNS01-T administration in beagles at 0.375 and 0.75 mg/kg for 6 weeks included a dose-dependent increase in incidences of clinical signs, resulting in a NOAEL of 0.375 mg/kg.A multiple ascending dose Phase 1b/2a open-label study has been initiated to evaluate the safety and tolerability of six weeks of twice-weekly administration of SNS01-T by intravenous infusion in patients with relapsed or refractory multiple myeloma. Approximately 12–15 patients are being enrolled and administered escalating doses of SNS01-T (Table 1). The patient starting dose is based upon the lower dose evaluated in the mouse toxicology study (0.25 mg/kg). The initial dosage in the clinical study was selected by reducing by a factor of 20 to 0.0125 mg/kg. The primary safety endpoints are the frequency, severity, and duration of treatment-related adverse events in patients following treatment with SNS01-T. Although safety is the primary endpoint of this study, efficacy is being evaluated by time to progression and by changes in values of the following biomarkers: monoclonal (M) protein, hemoglobin, bone marrow plasma cell percentage, plasma cell labeling index, C-reactive protein, and free light chain. Pharmacokinetics of SNS01-T are being assessed by monitoring levels of pExp5A pDNA and eIF5A siRNA in the blood and bone marrow by RT-qPCR. Immunogenicity of SNS01-T is also being assessed in patient samples by monitoring induction of pro-inflammatory cytokines and antibodies to SNS01-T. It is expected that results from the first group of patients will be presented.Table 1:Dose Escalation Schedule by GroupGroupNumber of PatientspExp5A pDNA DoseeIF5A siRNA DoseTotal Nucleic Acid Dose (SNS01-T)130.0083 mg/kg0.0042 mg/kg0.0125 mg/kg230.0333 mg/kg0.0167 mg/kg0.05 mg/kg330.1333 mg/kg0.0667 mg/kg0.2 mg/kg43–60.25 mg/kg0.125 mg/kg0.375 mg/kg Disclosures:Dondero:Senesco Technologies Inc.: Employment, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Thompson:Senesco Technologies Inc.: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding.