Amplyx Pharmaceuticals (United States)

Abstract Disclosure: Background: Post-bariatric hypoglycemia (PBH) is an increasingly recognized and often serious condition characterized by hyperinsulinemic hypoglycemia in individuals who have undergone bariatric surgery, believed to be driven by an excessive glucagon-like peptide-1 (GLP-1) response. PBH can cause debilitating hypoglycemic events associated with neuroglycopenia, including impaired cognition, loss of consciousness, and seizures. Avexitide is an investigational, first-in-class GLP-1 receptor antagonist designed to competitively inhibit GLP-1-mediated insulin secretion and stabilize glucose levels. In PREVENT, a phase 2, randomized, placebo-controlled crossover trial (N=18 enrolled, 17 evaluable), results showed a reduction in rates of Level 2 and Level 3 hypoglycemic events in participants with PBH after Roux-en-Y gastric bypass (RYGB) following treatment with avexitide 30 mg twice daily (BID) and 60 mg once daily (QD) compared with placebo. In a phase 2b, open-label, investigator-initiated, crossover trial (N=16), avexitide 45 mg BID and 90 mg QD reduced rates of Level 2 and Level 3 hypoglycemic events in participants following RYGB, vertical sleeve gastrectomy, and other upper-gastrointestinal surgeries. Avexitide was well-tolerated with no treatment-related serious adverse events or discontinuations. The phase 3 LUCIDITY trial, which will further evaluate avexitide in PBH, has a primary efficacy outcome of composite reduction of Level 2&3 hypoglycemic events. Objective: To understand the composite reduction of Level 2&3 hypoglycemic events in prior phase 2 trials of avexitide in PBH. Methods: For each avexitide dose, the rate of composite Level 2&3 events was calculated as the number of distinct events divided by number of days for a given treatment period then normalized to one week. A least-squares (LS) mean rate ratio vs placebo of hypoglycemia during the treatment period was then calculated. Results: In the PREVENT phase 2 trial, both avexitide regimens resulted in reductions in the composite rate of Level 2&3 events. The LS mean rate ratio vs placebo for avexitide 30 mg BID and 60 mg QD were 0.60 (95% confidence interval (CI): [0.357, 1.016]; p=0.0571) and 0.45 (95% CI: [0.281, 0.717]; p=0.0012), respectively. Composite data from the phase 2b trial with a 45mg BID and 90 mg QD dose will also be presented. Conclusions: Avexitide 30 mg BID and 60 mg QD led to a 40% and 55% reduction in the composite rate of Level 2&3 events, respectively. The impact of avexitide on composite rates of Level 2&3 hypoglycemia in the phase 2b trial, including at the higher 90 mg QD dose being tested in LUCIDITY, will be presented. Results of the complete analysis will provide valuable context given the planned LUCIDITY trial, which has topline data anticipated in 1H 2026. Presentation: Sunday, July 13, 2025

This study is registered with ClinicalTrials.gov as NCT04166669 and with EudraCT as number 2019-003586-17.

Melioidosis is an endemic disease in numerous tropical regions. Additionally, the bacterium that causes melioidosis, Burkholderia pseudomallei, has potential to be used as a biological weapon. Therefore, development of effective and affordable medical countermeasures to serve regions affected by the disease and to have medical countermeasures available in the event of a bioterrorism attack remains critical. The current study evaluated the efficacy of eight distinct acute phase ceftazidime treatment regimens administered therapeutically in the murine model. At the conclusion of the treatment period, survival rates were significantly greater in several of the treated groups when compared to the control group. Pharmacokinetics of a single dose of ceftazidime were examined at 150 mg/kg, 300 mg/kg, and 600 mg/kg and were compared to an intravenous clinical dose administered at 2000 mg every eight hours. The clinical dose has an estimated 100% fT > 4*MIC which exceeded the highest murine dose of 300 mg/kg every six hours at 87.2% fT > 4*MIC. Based upon survival at the end of the treatment regimen and supplemented by pharmacokinetic modeling, a daily dose of 1200 mg/kg of ceftazidime, administered every 6 h at 300 mg/kg, provides protection in the acute phase of inhalation melioidosis in the murine model.

Introduction/AimsTrials incorporating placebo‐to‐active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank‐preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo‐controlled and open‐label extension (OLE) phases.MethodsIntent‐to‐treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed.ResultsHazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35–0.92) on ITT analysis and 0.39 (0.17–0.88) in the primary on‐treatment RPSFTM analysis (p = .023). Median ITT survival duration for PB and TURSO (25.8 mo) was 6.9 mo longer than placebo (18.9 mo) on ITT analysis and 10.6 mo longer than the median RPSFTM‐adjusted survival duration for placebo (15.2 mo). Median survival duration was 18.8 mo longer in the PB and TURSO–randomized subgroup who continued into the OLE phase versus the placebo‐randomized subgroup who did not continue into the OLE phase (p < .0001), although OLE phase selection bias may have potentially confounded these results.DiscussionSimilar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.

We demonstrate a compact picosecond master-oscillator power-amplifier (MOPA) system based on an Yb-doped polarization-maintaining double-clad tapered fiber (T-DCF) delivering pulses with over 1.26 MW peak power and average output power up to 200 W preserving near diffraction limited beam quality. The unique properties of an active tapered fiber enable to amplify the seed pulses directly with no need for applying of additional stretching technique. This simplified laser system can find the practical implementation in industrial micromachining.

ABSTRACTAn ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are pan-resistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug, fosmanogepix, is currently in Phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50 and MIC90 0.03 mg/L; range 0.004-0.06 mg/L). The MGX epidemiological cutoff value (ECV, 99% cutoff) for the tested C. auris isolates was 0.06 mg/L. MGX was 8-32-fold more active than the echinocandins, 16-64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators’ MIC50, MIC90, or GEOMEAN values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris pan-resistant isolates was 0.008-0.015 mg/L, and the median and mode MIC values were 0.015 mg/L, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

Oprozomib is an oral, second-generation, irreversible proteasome inhibitor currently in clinical development for haematologic malignancies, including multiple myeloma and other malignancies. Oprozomib is a rare example of a small molecule drug that demonstrates cytochrome P450 (CYP) mRNA suppression. This unusual property elicits uncertainty regarding the optimal approach for predicting its drug-drug interaction (DDI) risk. The current study aims to understand DDI potential during early clinical development of oprozomib. To support early development of oprozomib (e.g. inclusion/exclusion criteria, combination study design), we used human hepatocyte data and physiologically-based pharmacokinetic (PBPK) modelling to predict its CYP3A4-mediated DDI potential. Subsequently, a clinical DDI study using midazolam as the substrate was conducted in patients with advanced malignancies. The clinical DDI study enrolled a total of 21 patients, 18 with advanced solid tumours. No patient discontinued oprozomib due to a treatment-related adverse event. The PBPK model prospectively predicted oprozomib 300mg would not cause a clinically relevant change in exposure to CYP3A4 substrates (≤30%), which was confirmed by the results of this clinical DDI study. These results indicate oprozomib has a low potential to inhibit the metabolism of CYP3A4 substrates in humans. The study shows that cultured human hepatocytes are a more reliable system for DDI prediction than human liver microsomes for studying this class of compounds. Developing a PBPK model prior to a clinical DDI study has been valuable in supporting clinical development of oprozomib.