Once-daily Oral Administration Research Articles

Efficacy and Safety of TAS-303 in Female Patients With Stress Urinary Incontinence: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.

We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).

Efficacy of epetraborole against Mycobacteroides abscessus in a mouse model of lung infection.

Mycobacteroides abscessus (Mab or Mycobacterium abscessus) is a fast-growing mycobacterium that is ubiquitous in the environment and can cause opportunistic disease in people with lung comorbidity and immunodeficiency. There are no Food and Drug Administration-approved drugs for this disease, and repurposed antibiotics have a poor microbiological response. To address the need for effective new antibiotics, we determined the efficacy of epetraborole (EBO) against three Mab clinical isolates in a mouse model of lung Mab infection. Reduction in lung Mab burden over 4 weeks of treatment was the study end point. EBO was administered orally once daily at doses of 25 and 50 mg/kg, which achieved exposures approximating the once-daily dosing of 250 mg and 500 mg, respectively, in humans. EBO administration led to a gradual reduction in the lung Mab burden. After 4 weeks of treatment, the efficacies of 25 and 50 mg/kg EBO against isolates ATCC 19977 and M9501 were comparable. However, against isolate M9530, 50 mg/kg EBO was more efficacious than 25 mg/kg and comparable with parenteral imipenem, one of the most efficacious antibiotics against Mab. We also undertook a dose-ranging study by evaluating the efficacies of once-daily oral administration of 0.5, 5, 10, 25, and 100 mg/kg EBO against M9501 over 4 weeks. Once-daily oral 100 mg/kg EBO was as effective as twice-daily 100 mg/kg imipenem injection. Our study suggests that EBO could address the unmet need for effective oral treatment options for Mab lung disease, given the high rates of Mab drug resistance and limited tolerable intravenous options.

High-dose almonertinib in treatment-naïve EGFR-mutated NSCLC with CNS metastases: Efficacy and biomarker analysis.

2007 Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)mutant non-small cell lung cancer (NSCLC). The pre-specified analysis of the FLAURA and other phase III studies has unveiled encouraging results in patients with CNS metastasis. Nevertheless, the availability of limited biomarkers poses a challenge for the early prediction of clinical effects. Methods: We launched a prospective, open-label, single-arm clinical trial across multiple centers (ACHIEVE). Participants, all diagnosed with EGFR-mutated NSCLC with CNS metastases, received first line treatment with high dose Almonertinib through once-daily oral administration, with each dose being 165 mg. The primary endpoints focused on progression free survival (PFS). Concurrently, we gathered baseline and end-of-first-cycle plasma samples, subjecting them to a comprehensive 520 gene-based sequencing analysis. Results: A total of 63 patients were selected and enrolled between Jul 6,2021 and Aug 31,2022. The median follow-up time, until Nov 30,2023, was 538 days. The confirmed Overall Response Rate (ORR) was 88.9% (56/63), while 42.9% (27/63) of patients progressed, with a median PFS of 17.71 months (11.96-NE). Moreover, a notable 88.9% (56/63) of intracranial lesions achieved either a Complete Response (CR) in 21 cases (33.3%) or a Partial Response (PR) in 35 cases (55.6%). To guide and enhance clinical strategy selection, we conducted a comprehensive biomarker evaluation using cell-free DNA (cfDNA) sequencing. Of the 60 baseline plasmas that passed quality control, 81.7% (46/60) were identified as having at least one somatic mutation (ctDNA+). No significant differences were observed between ctDNA+ and ctDNA- groups in terms of ORR (p = 0.33), intracranial ORR (p = 0.499), PFS (p = 0.363, HR = 1.75), and intracranial PFS (p = 0.562, HR = 1.56). Furthermore, we developed a novel algorithm named MedSR (Median Short cfDNA fragment Ratio) based on cfDNA fragment distribution patterns to quantify ctDNA amount. Notably, higher baseline MedSR values (above the median) predicted significantly poorer PFS (p = 0.001, HR = 0.22) and intracranial PFS (p = 0.067, HR = 0.35), demonstrating superior efficacy compared to traditional cfDNA biomarkers like maxAF. On Cycle 2, those achieving ctDNA clearance in C2D1, regardless of their ctDNA status on baseline, exhibited significantly improved PFS (p < 0.001, HR = 4.63) and intracranial PFS (p = 0.001, HR = 5.71). Conclusions: High dose Almonertinib exhibited promising efficacy and maintained tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The novel MedSR score demonstrated potential value in predicting the efficacy of TKI treatment. Clinical trial information: NCT04808752 .

First Oral Treatment Specific for Postpartum Depression

Postpartum depression is one of the most common perinatal mood disorders. The U.S. Food and Drug Administration approved the first oral medication developed specifically for the treatment of postpartum depression in August 2023. Zuranolone, marketed under the brand name Zurzuvae (Sage Therapeutics, Inc. and Biogen), is thought to work similarly to other positive allosteric modulators of gamma-aminobutyric acid A receptors such as benzodiazepines. It can be used alone or as an adjunct to other oral antidepressant medication. Its 2-week regimen of once-daily oral administration provides women with postpartum depression the opportunity to maintain their daily routines in an outpatient setting. This article provides an overview of zuranolone, including indications, mechanism of action, potential adverse reactions, and implications for nursing practice.

Abstract 1974: Discovery of TRX-211-399, a potent, CNS-penetrant, highly selective inhibitor of EGFR exon 20 insertion mutations

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Various types of EGFR-activating mutations are one of the most important oncogenic drivers in non-small cell lung cancer (NSCLC). Among NSCLC patients with EGFR mutations, 5-10% of patients have EGFR exon 20 insertion (ex20ins) mutations that are insensitive to clinically available EGFR tyrosine kinase inhibitors (TKIs). Recently, as mobocertinib (EXKIVITY®) failed to improve progression-free survival in Phase 3 clinical trial, there remains a high unmet medical need to develop new drugs with wider therapeutic window to treat NSCLC harboring EGFR ex20ins mutations. Herein, we report a novel EGFR-TKI, TRX-211-399, specifically designed to target ex20ins mutations. TRX-211-399 potently inhibited the proliferation of not only Ba/F3 cells overexpressing near-loop (A767dupASV, S768dupSVD) and far-loop (H773insNPH, H773dupH) mutations but also patient-derived NSCLC cell line. In particular, TRX-211-399 demonstrated high selectivity against wild-type EGFR. With favorable DMPK profiles, once-daily oral administration of TRX-211-399 showed significant tumor regression in multiple Ba/F3 xenograft models carrying different EGFR exon20ins mutations. Furthermore, in a PC-9-luc cell intracranial xenograft model, TRX-211-399 induced substantial anti-tumor effects and prolonged survival without body weight loss. TRX-211-399 is currently undergoing further preclinical evaluation as a potential candidate for clinical development for patients with EGFR exon20ins mutations. Citation Format: Kwangwoo Chun, Sumin Lim, Joohyun Lee, Seulgi Choi, Seongrak Kim, Youngil Choi, Areum Park, Bohee Kim, Yongseo Park, Eunhyun Choi, Sungwon Lee, Koo Lee. Discovery of TRX-211-399, a potent, CNS-penetrant, highly selective inhibitor of EGFR exon 20 insertion mutations [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 1974.

Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.

Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK)of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics(PD) of the CYP2C9-sensitive substrate warfarin. In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. Midazolam maximum plasma concentration(Cmax) and area under the plasma concentration-time curve from 0 to 24 h(AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. This trial (NCT05480488) was registered on 29 July, 2022.

An orally available compound suppresses glucagon hypersecretion and normalizes hyperglycemia in type 1 diabetes.

Suppression of glucagon hypersecretion can normalize hyperglycemia during type 1 diabetes (T1D). Activating erythropoietin-producing human hepatocellular receptor type-A4 (EphA4) on α cells reduced glucagon hypersecretion from dispersed α cells and T1D islets from both human donor and mouse models. We synthesized a high-affinity small molecule agonist for the EphA4 receptor, WCDD301, which showed robust plasma and liver microsome metabolic stability in both mouse and human preparations. In islets and dispersed islet cells from nondiabetic and T1D human donors, WCDD301 reduced glucagon secretion comparable to the natural EphA4 ligand, Ephrin-A5. In diabetic NOD and streptozotocin-treated mice, once-daily oral administration of WCDD301 formulated with a time-release excipient reduced plasma glucagon and normalized blood glucose for more than 3 months. These results suggest that targeting the α cell EphA4 receptor by sustained release of WCDD301 is a promising pharmacologic pathway for normalizing hyperglycemia in patients with T1D.

O013 Preliminary Results from a Phase 1 Study of ALKS 2680, an Orexin-2 receptor Agonist, in Healthy Participants and Patients with Narcolepsy or Idiopathic Hypersomnia

Abstract Introduction ALKS 2680, a potent, brain-penetrant, highly selective orexin-2 receptor (OX2R) agonist, is being developed for treatment of narcolepsy and other hypersomnias. We report preliminary results from the ALKS 2680 first-in-human study. Methods This randomized, double-blind, phase 1 study of ALKS 2680 is being conducted at two Australia sites. Healthy participants received single- (n=48, 6 dosages) or multiple- (n=32, 4 dosages once-daily for 10 days) oral doses of ALKS 2680 or placebo. Patients with narcolepsy type 1 (NT1) or type 2 (NT2) or idiopathic hypersomnia (IH; up to 8 patients for each indication) will also be studied, receiving single doses ALKS 2680 or placebo in a 4-way crossover design with 3 active dose levels. Pharmacodynamic assessments will include the Maintenance of Wakefulness Test, Karolinska Sleepiness Scale, and tracking of sleep and cataplexy episodes. Results In healthy participants, ALKS 2680 was orally absorbed and showed biphasic distribution/elimination, with a terminal half-life suitable for maintaining daytime wakefulness with once-daily administration. There were no systematic changes in vital signs, safety laboratory tests, or ECG at any dose level, and no serious or severe adverse events (AEs). Most drug-related events were mild and resolved without medical intervention. There was a single discontinuation due to a nonserious AEs that resolved without treatment. Conclusions Preliminary results suggest that the OX2R agonist ALKS 2680 is generally well-tolerated with a pharmacokinetic profile potentially suitable for once-daily oral administration to promote daytime wakefulness. Effects of ALKS 2680 in patients with NT1, NT2, and IH are being evaluated.

Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

Abstract 6273: CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors

Abstract MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors. Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6273.

Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

Evaluating Islatravir Administered Via Microneedle Array Patch for Long-Acting HIV Pre-exposure Prophylaxis Using Physiologically Based Pharmacokinetic Modelling.

Technologies for long-acting administration of antiretrovirals (ARVs) for the prevention and treatment of HIV are at the forefront of research initiatives aiming to tackle issues surrounding drug adherence with the current standard of once-daily oral administration. Islatravir (ISL) is an emerging ARV that shows promising characteristics for long-acting prevention and treatment both orally as well as through alternative routes of administration. Microneedle array patches (MAPs) are a pain-free and discreet transdermal delivery technology that offer extended-release administration of nanoparticulate drugs. This study aimed to utilise physiologically based pharmacokinetic (PBPK) modelling to predict the pharmacokinetics resulting from ISL administered via MAP and to identify key MAP characteristics required to sustain effective concentrations over extended dosing intervals. A PBPK model describing the conversion of ISL to ISL-triphosphate (ISL-TP) and its whole-body disposition was developed and verified against observed clinical data for orally administered ISL in healthy adults. An intradermal PBPK model was integrated with the ISL PBPK model to predict the dose and nanoparticle release rate required for MAP administration strategies capable of achieving a minimum ISL-TP target concentration of 0.05 pmol/106 PBMCs over extended dosing intervals. MAP design was limited to a maximum therapeutic area of 20 cm2 with a dose loading of 4.09 mg/cm2 and a minimum duration of 3 months. Due to the lack of available clinical data, a range of nanoparticle release rates and MAP bioavailability scenarios were simulated to provide an overview of potential clinical outcomes. The ISL PBPK model was successfully verified, with predicted vs observed ratios falling within 0.5-2-fold. ISL MAP doses ranging from 15 to 80 mg were predicted to sustain ISL-TP concentrations above the minimum target concentration at 3, 6 and 12 months after administration. Nanoparticle release rate and MAP bioavailability were found to have a major impact on whether dosing strategies achieved the criteria. Minimum doses of 15 mg and 60 mg with a nanoparticle release rate of 0.0005 h-1 and bioavailability ranging from 25 to 100% were predicted to achieve effective ISL-TP concentrations up to 3 and 6 months, respectively. Doses of 15 mg and 30 mg with a nanoparticle release rate of 0.0005 h-1 were also able to attain the target concentration up to 6 months after MAP administration, albeit with a minimum bioavailability of 75% and 50%, respectively. Furthermore, when simulating a bioavailability of 100%, an 80 mg ISL MAP was predicted to sustain ISL-TP concentrations above the minimum target concentration up to 12 months after administration. The ISL PBPK model successfully predicted ISL and ISL-TP pharmacokinetics across a range of orally administered regimens. The integrated intradermal PBPK model outlined optimal MAP dose and nanoparticle release rates for effective ISL-TP concentrations up to 12 months, providing justification for further investigation of ISL as a candidate for MAP administration.

Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.

Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood–brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure–activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC50, 1.5 nM in vitro) and selectivity (>450-fold vs thyroid peroxidase in vitro), the mechanism of irreversible inhibition, and the safety profile. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with HFpEF, a phase 2b/3 efficacy study of AZD4831 in patients with HFpEF started in 2021.

753-P: RGT-075, an Orally Efficacious Small Molecule GLP-1R Full Agonist in Cynomolgus Monkey Models

Activation of Glucagon-like peptide-1 receptor (GLP-1R) by peptides has been proven clinically to be a very effective treatment approach for type 2 diabetes (T2D) and obesity. Here we describe a small molecule GLP-1R full agonist RGT-075 identified through Computer Accelerated Rational Design (CARD) (Ma et al., Cell Research 2020) with nM potency in G-protein coupled cAMP signaling. RGT-075 displayed much reduced activity in receptor-mediated β-arrestin recruitment and subsequent internalization. It was shown to be selective against other class B G protein-coupled receptors (GPCRs) and was only active for human and monkey GLP-1R. It demonstrated favorable oral bioavailability and pharmacodynamic profile for once-daily oral dosing in monkeys. In food-induced glucose intolerant and prediabetic cynomolgus monkeys, oral administration of RGT-075 improved glucose tolerance to a level comparable to injectable liraglutide. In food-induced type 2 diabetic monkeys, once-daily oral administration of RGT-075 reduced food intake and fasting plasma glucose levels. Together, these data support the development and advancement of RGT-075 into the clinic as a potential therapeutic for T2D and obesity. Disclosure F.Liu: Employee; Regor Pharmaceuticals Inc. X.Sun: Employee; AutoDrug Biotech Co. Ltd., Qilu Regor Therapeutics Inc. W.Huang: None. W.Guo: None. J.Lin: None. W.Zhong: None.

A critical review of ozanimod for the treatment of adults with moderately to severely active ulcerative colitis

Introduction: Ozanimod is a sphingosine-1-phosphate (S1P) modulator that inhibits lymphocyte trafficking from lymph nodes to the circulation. It is approved by the U.S. Food and Drug Administration (FDA) for treatment of relapsing multiple sclerosis and most recently for the management of moderate-severe ulcerative colitis (UC). Areas covered: Here we review the status of drugs approved for moderate-severe UC, the unmet needs in the management of UC, proposed mechanisms of action of S1P modulators, clinical data regarding ozanimod in UC and emerging S1P modulators being evaluated in inflammatory bowel disease. Expert opinion: Ozanimod is superior to placebo in inducing and maintaining clinical and endoscopic remission in UC. Adverse events include transient asymptomatic bradycardia and first-degree atrioventricular blocks, transient asymptomatic hepatotoxicity, macular edema in patients with pre-existing risk factors, and increased risk of nasopharyngitis. Ozanimod is contraindicated in patients with clinically significant cardiovascular diseases, type II second- or third-degree atrioventricular blocks, and females of child-bearing age not using contraception. Ozanimod is the first S1P modulator to be approved for UC, offering a new therapeutic class option for patients. It has the advantages of being convenient with a once daily oral administration, non-immunogenic, and overall safe when used in patients without contraindications.

Omadacycline pharmacokinetics and soft-tissue penetration in diabetic patients with wound infections and healthy volunteers using in vivo microdialysis.

ObjectivesWe assessed the plasma and soft-tissue pharmacokinetic exposure of omadacycline in infected patients with diabetic foot infection (DFI) and healthy volunteers using in vivo microdialysis.MethodsEight patients and six healthy volunteers were enrolled and received an omadacycline IV loading dose (200 mg) followed by two oral doses (300 mg) every 24 h. Microdialysis catheters were placed in the soft tissue near the infected diabetic foot wound (patients) or thigh (healthy volunteers). Plasma and dialysate fluid samples were collected, starting immediately prior to the third dose and continued for 24 h post-dose. Protein binding was determined by ultracentrifugation.ResultsThe mean ± SD omadacycline pharmacokinetic parameters in plasma for infected patients and healthy volunteers were: Cmax, 0.57 ± 0.15 and 1.14 ± 0.26 mg/L; t½, 16.19 ± 5.06 and 25.34 ± 12.92 h; and total omadacycline AUC0–24, 6.27 ± 1.38 and 14.06 ± 3.40 mg·h/L, respectively. The omadacycline mean plasma free fraction was 0.21 and 0.20 for patients and healthy volunteers, corresponding to free plasma AUC0–24 of 1.13 ± 0.37 and 2.78 ± 0.55 mg·h/L, respectively. Omadacycline tissue AUC0–24 was 0.82 ± 0.38 and 1.37 ± 0.48 mg·h/L for patients and volunteers, respectively.ConclusionsThe present study describes the plasma and soft-tissue exposure of omadacycline in patients with DFI and healthy volunteers. Integrating these data with the microbiological, pharmacokinetic/pharmacodynamic and clinical efficacy data is foundational to support clinical assessments of omadacycline efficacy specifically for DFI. This, coupled with the once-daily oral administration, suggests omadacycline could be an advantageous translational therapy for the hospital and outpatient setting.

Abstract P051: Identification of an orally bioavailable dual Cyclin K glue degrader - CDK12/13 inhibitor

Abstract CDK12 and CDK13 regulate gene expression through translation and splicing of mRNA. Impaired activity of CDK12 has been shown to reduce the expression of a range of genes involved in DNA homologous repair leading to the induction of a ‘BRCAness’ phenotype in cells. CDK12 inhibitors have the potential in many different indications, including overcoming emergent resistance to PARP inhibition, enhancing the efficacy of PARP inhibition in patients with BRCA1/2 wt status [1] and extending the efficacy of immune checkpoint inhibition through immunogenic cell death [2]. Recently, certain classes of CDK12 inhibitors have also demonstrated ‘glue degrader’ properties [1]: causing proteosomal degradation of the obligate co-factor for CDK12 and 13, Cyclin K. Such glue-degraders have the capability of enhancing cellular potency and specificity over classical kinase inhibitors. Taking as a starting point the selective CDK7 inhibitor samuraciclib, we have taken a rational design approach to develop inhibitors that preferentially inhibit CDK12. By utilising differences in the active site between CDK7 and CDK12 we were able to increase potency against CDK12 in biochemical assays by > 100 fold, with no significant inhibition of kinases outside the CDK class. Cellular potency of these molecules was evaluated in the Ewing’s sarcoma cell line A673, which is known to be sensitive to CDK12 inhibition [4]. Remarkably the potency of the molecules to induce cell death was greater than their biochemical potency against CDK12 by > 10 fold. Analysis of Cyclin K levels in cells demonstrated that the molecules lead to Cyclin K degradation. Furthermore, cellular potency was reduced by the presence of the neddylation inhibitor MLN4924 confirming that the compounds enhanced potency was mediated by glue degradation of Cyclin K. The molecules were found to cause potent inhibition of DNA homologous repair genes including BRCA1, FANCF and ERCC4 and lead to the accumulation of DNA strand breaks as assessed by the marker γ-H2AX. In the BRCA wt ovarian cancer cell line, OV-90, strong synergy was observed in the ability to induce cell death with a range of PARP inhibitors. In A673 tumour bearing mice, dosing with the compounds was found to cause significant reduction in the levels of cyclin K in tumours, which was sustained for 24 hr. Additionally, assessment of CDK12 protein in these tumours also showed a reduction, suggesting greater turnover of CDK12 protein in the absence of Cyclin K. Repeat dose studies at doses that lead to Cyclin K degradation in tumours demonstrated that the compounds were well tolerated, with no weight loss in mice. Two molecules, CT7439 and CT7510, were found to have oral bioavailability in mice that indicate that they would be suitable for once-daily oral administration in humans and are being progressed through regulatory toxicity studies. [1] Johnson, et al, (2016) Cell Rep. 17, 2367 [2] Li, et al, (2020) Cancer Lett. 495, 12 [3] Słabicki, et al, (2020) Nature 585, 293 [4] Iniguez, et al, (2018) Cancer Cell 33, 202 Citation Format: Edward K. Ainscow, Adrian Campbell, Michael Cripps, Robert Workman, Stuart Thomson, Kam Chohan, Damien Crepin, Mahiro Sunose, Jamie Patient, Jane Kendrew, Ash Bahl. Identification of an orally bioavailable dual Cyclin K glue degrader - CDK12/13 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P051.

A randomized, double-blind, placebo-controlled, single, and multiple dose-escalation Phase I clinical trial to investigate the safety, pharmacokinetic, and pharmacodynamic profiles of oral S086, a novel angiotensin receptor-neprilysin inhibitor, in healthy Chinese volunteers

Background This study evaluated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of single ascending doses (SAD) and multiple ascending doses (MAD) of S086 in healthy Chinese volunteers. Research design and methods This randomized, double-blind, placebo-controlled, Phase I clinical trial enrolled 113 subjects, including 65 subjects in the SAD (60–1080 mg) study and 48 subjects in the MAD study (180–720 mg). The safety, PK (sacubitril, LBQ657, and EXP3174) and PD (MAD study: blood pressure, pulse) of S086 were assessed. Results There were no deaths, serious adverse events, or discontinuations due to TEAEs, and there were no significant safety concerns associated with S086. PK parameters for sacubitril, LBQ657, and EXP3174 increased in a dose-dependent manner after single oral doses of S086. Plasma concentrations of sacubitril, LBQ657, and EXP3174 were maintained at steady state within 5 days of once-daily oral administration of S086. In the MAD study, S086 administration was associated with a dose-dependent decrease in mean diastolic and systolic blood pressure compared to baseline. Conclusions The safety and PK profile profiles of S086 support the use of S086 240mg once daily in a future Phase II study in patients with heart failure. Trial Registration The trial is registered at chinadrugtrials.org.cn (CT.gov identifier: CTR20182350 and CTR20182351).

Absence of QTc Prolongation with Sodium N-(8-[2-Hydroxybenzoyl] Amino) Caprylate (SNAC), an Absorption Enhancer Co-Formulated with the GLP-1 Analogue Semaglutide for Oral Administration.

IntroductionOral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable QTc interval prolongation with SNAC. QT is defined as interval on the electrocardiogram, measured from the start of the QRS complex to the end of the T wave.MethodsPart A of the study sought to identify an appropriate dose of SNAC (which was substantially higher than that used in the oral semaglutide co-formulation) for QTc assessment. Three sequential healthy volunteer cohorts were randomised to escalating single oral doses of SNAC (1.2, 2.4 or 3.6 g) or placebo. Following identification of an appropriate dose, a cross-over trial was conducted (Part B). Healthy volunteers received one of four treatment sequences, including single oral doses of SNAC, moxifloxacin (positive control) and placebo. Primary objectives were to (1) assess adverse events (AEs) with escalating SNAC doses and (2) confirm that SNAC does not cause unacceptable QTc interval prolongation versus placebo, using the Fridericia heart rate-corrected QT interval (QTcF).ResultsAll subjects completed Part A (N = 36) and 46 subjects completed Part B. In Part A, all AEs were mild to moderate in severity; no relationship was identified between AE incidence and SNAC dose. SNAC 3.6 g, the maximum investigated SNAC dose, was selected for Part B. There was no unacceptable prolongation of the QTcF interval with SNAC 3.6 g, and assay sensitivity was demonstrated with moxifloxacin as the positive control. There was no significant exposure–response relationship between SNAC concentration and QTcF interval, and no instances of QTc interval > 450 ms or increases > 30 ms.ConclusionThis QT/QTc trial demonstrates that SNAC doses 12-fold higher than the 300 mg dose used in the oral formulation of semaglutide do not cause unacceptable prolongation of the QTcF interval.Trial RegistrationClinicaltrials.gov identifier: NCT02911870.

Viloxazine: Pediatric First Approval.

Viloxazine (QELBREE™), a selective norepinephrine reuptake inhibitor, is being developed by Supernus Pharmaceuticals as a non-stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients. This is a novel formulation of a pharmacological agent formerly marketed in Europe for the treatment of depression in adults. Viloxazine received its first pediatric approval in April 2021 in the USA for the treatment of ADHD in pediatric patients aged 6-17 years. Approval was based on positive results from a series of short-term phase III clinical trials in which viloxazine improved the severity of ADHD symptoms in children and adolescents with diagnosed ADHD. Viloxazine is available as extended-release capsules for once-daily oral administration. This article summarizes the milestones in the development of viloxazine leading to this first pediatric approval for ADHD.