Drugs in Research & Development最新文献

Background and objective: Acute myelogenous leukemia (AML) is a common blood cancer marked by heterogeneity in disease and diverse genetic abnormalities. Additional therapies are needed as the 5-year survival remains below 30%. Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor that is widely used in solid tumors and also in tumors with activating RAS mutations. A subset of patients with AML carry activating RAS mutations; however, a small-scale clinical trial with trametinib showed little efficacy. Here, we sought to identify transcriptomic determinants of trametinib sensitivity in AML.

Methods: We tested the activity of trametinib against a panel of tumor cells from patients with AML ex vivo and compared this with RNA sequencing (RNA-Seq) data from untreated blasts from the same patient samples. We then used a correlation analysis between gene expression and trametinib sensitivity to identify potential biomarkers predictive of drug response.

Results: We found that a subset of AML tumor cells were sensitive to trametinib ex vivo, only a fraction of which (3/10) carried RAS mutations. On the basis of our RNA-Seq analysis we found that markers of trametinib sensitivity are associated with a myeloid differentiation profile that includes high expression of CD14 and CLEC7A (Dectin-1), similar to the gene expression profile of monocytes. Further characterization confirmed that trametinib-sensitive samples display features of monocytic differentiation with high CD14 surface expression and were enriched for the M4 subtypes of the FAB classification.

Conclusions: Our study identifies additional molecular markers that can be used with molecular features including RAS status to identify patients with AML that may benefit from trametinib treatment.

Background and objective: Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [¹⁴C]tinengotinib following a single oral dose in healthy subjects.

Methods: Six healthy male subjects received a single oral dose of [¹⁴C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism.

Results: Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (T_max) of 1.0-4.0 h post-dose and a long terminal half-life (t_½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration-time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4.

Conclusions: Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent.

Registration: ChinadrugTrials.org.cn identifier: CTR20212852.

Background and objective: Biological medicinal products improve patients' lives, but access is limited, mainly due to high costs. Patents for many existing biological products are expiring, and generic versions, which are referred to as biosimilars, are produced to serve as an alternative to the reference medicinal product (RMP) cutting down the costs and expanding access. The present paper assesses the analytical similarity between Formycon's FYB206 pembrolizumab biosimilar candidate and Keytruda^®, an RMP that is approved to treat various types of cancer, with the intention of determining FYB206's suitability to enter clinical biosimilar trials.

Methods: Monoclonal antibodies (mAbs) are biological medicinal products that are characterized by a high overall heterogeneity. Due to the complex nature of these molecules, a comprehensive comparative analytical assessment was designed to demonstrate analytical similarity in all clinically relevant quality attributes between RMP and the corresponding biosimilar candidate. This exercise addresses physicochemical, biophysical as well as functional characteristics.

Results: The comparative analytical evaluation results demonstrate that the proposed biosimilar is structurally and functionally highly similar to the RMP, showing only minor differences for some quality attributes that are justified to be noncritical for clinical efficacy and safety.

Conclusion: Based on physicochemical and biological characteristics, FYB206 is suitable to enter the clinical phase.

Background: Dolutegravir (DTG), an integrase strand inhibitor, is currently used as the first-line treatment for HIV. Despite relatively poor tissue penetration, the risk of adverse effects in metabolic and excretory systems should be considered. The trace aminergic system and trace amines are emerging as relevant role players in many chronic diseases that are commonly diagnosed but poorly understood. Trace amines are biogenic amines that are endogenously produced and can also be ingested by the intake of trace amine-rich food. Trace amines are known to differentially regulate inflammatory and neurological outcome.

Objective: This study investigated the effects of DTG on the trace amine profile in a wistar rat model.

Methods: A total of 24 healthy wistar rats were randomly divided into four experimental groups: male and female controls and male and female DTG-treated. Blood and tissue samples were collected following a 12-week DTG administration study. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was used to determine trace amine concentrations in urine, plasma, brain, and gastrointestinal tissue.

Results: Current data illustrate that polyamines differ significantly (p < 0.05) between males and females in various matrices. DTG significantly (p < 0.05) reduced jejunal tyramine and urinary synephrine levels.

Conclusion: Data do not raise major concerns about DTG in the context of the trace amine profile. However, given the importance of the dysregulated trace amine profile in various diseased states, including HIV, current data warrant clinical investigation to further evaluate the significance of DTG-associated effects on the trace amine profile.

Background and objective: While successful treatment paradigms for BRAF V600 mutations have been developed, 10% of BRAF mutations are not at V600 and lack a standard treatment regimen. This study summarizes the current body of knowledge on the treatment of non-V600 mutations and reports a single institution experience.

Methods: We conducted a literature review to summarize relevant preclinical and clinical published data on the response of non-V600 mutations to targeted therapies. We performed a retrospective analysis of INOVA Schar Cancer patients registered in our Molecular Tumor Board database with non-V600 BRAF mutations who were recipients of targeted therapy and assessed their time to next treatment and best response.

Results: Published preclinical and clinical data have demonstrated limiting results in the response of non-V600 mutated cancers to targeted therapies. Response rates were variable for the major classes of BRAF mutations including class II and class III mutations as well as, BRAF fusions. Data collected from our INOVA cohort offered promising results with one patient achieving partial remission and two patients achieving stable disease.

Conclusions: This article reflects the current understanding of targeted therapies in non-V600 mutations. Further large-scale studies separating BRAF mutations based on their mechanism of activation will  expand our understanding.

Background: Two main types of galenic formulation, immediate release and prolonged release, have been developed to optimize melatonin bioavailability. We recently described the kinetic profile of a prolonged-release form generating a peak of plasma melatonin 1 h (T_max) after intake, followed by a prolonged decay over time. We have developed a new oral form of melatonin with the aim of producing a melatonin peak several hours after intake.

Objective: The objective is to investigate melatonin bioavailability after administration of this new delayed-release form (DR form).

Methods: In this single-centre open-label study, 12 healthy male volunteers received one tablet of the DR form containing 1.9 mg melatonin, 10 mg zinc and 200 mg lemon balm extract (Melissa officinalis L aerial parts). Blood samples were collected for 12 h, beginning at 8:00 am. Plasma concentrations of melatonin and 6-sulfatoxymelatonin (6-SMT), the main hepatic melatonin metabolite, were determined by radioimmunoassay.

Results: A progressive increase in plasma melatonin concentrations was observed from 20 min and a peak about 3 h after intake (C_max 740 ± 824 pg/mL; T_max 179 ± 60 min). Concentrations remained high between 140 and 220 min, the concentration remaining physiologically significant (over 100 pg/mL) up to 7 h after intake. The DR form was well tolerated.

Conclusions: The melatonin release profile was consistent with what was anticipated for the DR form. The DR form generated a 2 h delayed T_max compared with a prolonged-release form previously evaluated. This suggests that the DR form is suitable for the treatment of certain sleep disorders such as short sleep duration or early awakening.

Trial registry: Registration number: NCT05419466.

Damoctocog alfa pegol (BAY 94-9027, Jivi^®), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate^®), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta^®; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate^®/Adynovi^®; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate^®; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences.

Background and objective: The EphA2 receptor inhibitor ALW-II-41-27 has proven to be an effective in vitro antagonist of Pneumocystis β-glucan-induced proinflammatory signaling. This suggests its potential as a candidate for initial anti-inflammatory drug testing in the rodent model of Pneumocystis pneumonia (PCP).

Methods: Initially, single-dose intraperitoneal (IP) injections of ALW-II-41-27 were administered at concentrations of 0, 10, 15, 20, and 30 mg/kg over a 24-h treatment period. Pharmacokinetics were assessed in plasma, bronchoalveolar lavage fluid (BALF), and epithelial lining fluid (ELF). Following these assessments, a final single mg/kg dosing was determined. Mice received daily IP injections of either vehicle or 20.0 mg/kg of ALW-II-41-27 for 10 days, with their weights recorded daily. On day 11, mice were weighed and euthanized. Lungs, liver, and kidneys were harvested for H&E staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines using enzyme-linked immunosorbent assay (ELISA) and extracellular matrix production using quantitative PCR (qPCR). Postmortem blood collection was conducted for complete blood count (CBC) blood chemistry analysis. Lastly, ALW-II-41-27 was administered to mice prior to fungal β-glucans challenge to determine in vivo effects on lung inflammation.

Results: This report describes the PK assessment of ALW-II-41-27 given via IP in C57BL/6 mice. After PK data were generated, we tested ALW-II-41-27 at 20 mg/kg IP in mice and noted no significant changes in daily or final weight gain. ELISA results of proinflammatory cytokines from lung tissues showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts were statistically similar. Examination and pathology scoring of H&E slides from lung, liver, and kidney in all groups and subsequent pathology scoring showed no significant toxicity. Blood chemistry and CBC analyses revealed no major abnormalities. Additionally, administering ALW-II-41-27 before intratracheal inoculation of fungal β-glucans, known to induce a strong proinflammatory response in the lungs, significantly reduced lung tissue IL-1β levels.

Conclusions: In our initial general safety and toxicology assessments, ALW-II-41-27 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.

Background and objective: Orodispersible tablets (ODT) rapidly dissolve in the oral cavity and can improve patient's convenience. This pharmacokinetic study assessed the bioequivalence of a novel 20 mg ODT formulation of bilastine compared with bilastine 20 mg tablets in healthy volunteers under fasting conditions.

Methods: A phase I, single-center, open-label, two-period, two-sequence crossover randomized clinical trial was conducted. The study comprised two periods, in which participants were administered a single oral dose of bilastine 20 mg in the form of ODT as the test product, or conventional tablets as the reference product, and a washout of 7 days between each period. Blood samples were collected for up to 72 h. Bioequivalence was established if the 90% confidence intervals of the C_max and AUC_0-t were within the acceptance range (80-125%). Safety was evaluated at the follow-up visit (days 4-7 after the second dose) and throughout the study.

Results: A total of 42 healthy volunteers were randomized, and 41 completed the study. Pharmacokinetic parameters were comparable for both formulations after a single dose of 20 mg. Bilastine ODT and conventional tablets were bioequivalent as the 90% confidence intervals of the test over reference ratios were within the predefined range (80-125%). Both formulations were well tolerated and showed a similar safety profile.

Conclusions: Bilastine ODT was bioequivalent to the reference treatment formulated as conventional tablets when administered as a single oral dose of 20 mg under fasting conditions. Both formulations showed a similar tolerability and safety profile, with no serious adverse events or significant analytical alterations reported.

Trial registration: 2019-004071-39. Date of authorization: 10 December 2019.