Debiopharm (Switzerland)

Xevinapant, an inhibitor of apoptosis protein (IAP) inhibitor, has shown promising activity in combination with anticancer agents, including radiotherapy, and, in preclinical studies, anti-PD-(L)1 antibodies. This, in part, is due to its ability to restore apoptosis and increase antitumour immunity. We report efficacy, safety and exploratory biomarker analyses of xevinapant plus avelumab (anti-PD-L1) in a two-part, open-label, nonrandomised, phase Ib study. Part A assessed patients with advanced solid tumours who received xevinapant (100, 150, 200 or 250 mg/day, with no random allocation, on Days 1-10 and 15-24) in combination with avelumab (10 mg/kg) on Days 1 and 15 in 28-day cycle. Part B assessed patients with advanced non-small-cell lung cancer (NSCLC) who received xevinapant at the recommended phase II dose (RP2D) plus avelumab (maximum 26 cycles). Part A assessed the safety and tolerability of the combination and established the maximum tolerated dose (MTD) and RP2D of xevinapant. Part B assessed the antitumour activity of xevinapant at the RP2D combined with avelumab compared with a historical control (avelumab alone). Exploratory biomarker analyses were also conducted. In part A (n = 16), xevinapant 200 mg/day was established as the RP2D with avelumab and the MTD was not reached. The most common treatment-emergent adverse events (TEAEs) irrespective of xevinapant dose were nausea and fatigue (n = 11 (68.8%) each). In part B (n = 38; four patients received prior anti-PD-(L)1 antibody), the objective response rate (ORR) was 10.5% (95% confidence interval (CI), 2.9-24.8; partial response, n = 4) and the most common TEAE was decreased appetite (n = 13 (34.2%)). Levels of plasma IL-10, IL-1β, IL-13 and CD8+ T cells increased during the study, and circulating levels of CD4+ T cells and Tregs increased during cycle 1. Macrophage-related gene expression signatures increased in patients with a partial response or stable disease. Low baseline Ki-67 expression in tumour samples correlated with a partial response. The RP2D of xevinapant with avelumab was established; however, the ORR was not superior to the historical control (avelumab alone). The combination had a manageable safety profile in both study parts. Biomarker analyses provide insights into drivers associated with efficacy in patients with NSCLC receiving xevinapant plus avelumab. NCT03270176 (https://clinicaltrials.gov/study/NCT03270176). Registered on ClinicalTrials.gov on 29 August 2017.

Abstract Background Staphylococci are the most common causative pathogens in bone and joint infections (BJI). Treatment for BJI is a major clinical challenge, with recurrent and persistent infections occurring in 40% of patients. Afabicin is the most advanced FabI inhibitor in clinical development and has the potential to be the first microbiome-sparing anti-staphylococcal antibiotic. Currently, a Phase 2 trial in BJI (NCT03723551) is enrolling patients to be treated for 3-6 weeks with afabicin or standard of care (SoC). Results of the first cohort in this study (2-3 weeks treatment) are presented here Methods In an ongoing multicenter, open-label, Phase 2 study, the safety, tolerability, and efficacy of afabicin was compared to those of SoC, in the treatment of patients with BJI. Patients with osteomyelitis, septic arthritis, or prosthetic joint infections were randomized (5 afabicin: 1 SoC) to receive IV and oral treatment for 14 to 21 days. Afabicin treatment (55 mg IV/ 80 mg PO BID) was compared to a pre-defined SoC treatment. Results Twenty patients were included in microbiological intent-to-treat (mITT) population and were treated for up to 21 days with afabicin or SoC (17 afabicin and 3 SoC). The mean treatment duration was 20.1 days for afabicin and 19.7 days for SoC. Overall, osteomyelitis was the most common diagnosis (85%). The most frequent baseline pathogen was Staphylococcus aureus (19 patients), and 18 patients had methicillin-sensitive S. aureus. All 20 patients were treatment responders at End of Treatment (EoT) visit. The clinical response at 4 weeks post EoT was 13 of 15 patients in the afabicin arm, consistent with patient exposure being above PK/PD targets derived from non-clinical modeling. All 3 patients in the SOC arm achieved clinical response at 4 weeks post EoT. At 12 weeks post EoT, the clinical response rate was 13 of 15 patients in the afabicin arm and 2 of 3 patients in the SoC arm. A similar safety profile was observed in the afabicin arm versus SoC arm. Conclusion The clinical response rate and safety profile of 2-3 weeks treatment of staphylococcal BJI with afabicin was comparable to SoC. These data support exploring longer durations of treatment in the study. Additionally, the impact of Afabicin on BJI patient’s gut microbiota will be explored. Disclosures Alireza Shamaei Tousi, PhD, Debiopharm International: Salary Moritz Marquardt, n/a, Debiopharm International: Salary Annick Menetrey, n/a, Debiopharm International: Salary Justyna Nowakowska, n/a, Debiopharm International: Salary Justine Dao, n/a, Debiopharm International: Salary David Cameron, PhD, Debiopharm International S.A.: Salary Charlotte Catala-Goldschmidt, n/a, Debiopharm International: Salary Ricardo Chaves, n/a, Debiopharm International S.A.: Salary

Translation of experimental data on antibiotic activity typically relies on pharmacokinetic/pharmacodynamic (PK/PD) indices. Model-based approaches, considering the full antibiotic killing time course, could be an alternative. To develop a mechanism-based modelling framework to assess the in vitro and in vivo activity of the FabI inhibitor antibiotic afabicin, and explore the ability of a model built on in vitro data to predict in vivo outcome. A PK/PD model was built to describe bacterial counts from 162 static in vitro time-kill curves evaluating the effect of afabicin desphosphono, the active moiety of the prodrug afabicin, against 21 Staphylococcus aureus strains. Combined with a mouse PK model, outcomes of afabicin doses of 0.011-190 mg/kg q6h against nine S. aureus strains in a murine thigh infection model were predicted, and thereafter refined by estimating PD parameters. A sigmoid Emax model, with EC50 scaled by the MIC described the afabicin desphosphono killing in vitro. This model predicted, without parameter re-estimation, the in vivo bacterial counts at 24 h within a ±1 log margin for most dosing groups. When parameters were allowed to be estimated, EC50 was 38%-45% lower in vivo, compared with in vitro, within the studied MIC range. The developed PK/PD model described the time course of afabicin activity across experimental conditions and bacterial strains. This model showed translational capacity as parameters estimated on in vitro time-kill data could well predict the in vivo outcome for a wide variety of doses in a mouse thigh infection model.

[68Ga]Ga-DPI-4452, a first-in-class carbonic anhydrase IX-binding radiolabeled peptide, is the imaging agent of a theranostic pair with [177Lu]Lu-DPI-4452, developed for selecting and treating patients with carbonic anhydrase IX-expressing tumors. Here, [68Ga]Ga-DPI-4452 imaging characteristics, dosimetry, pharmacokinetics, and safety were assessed in 3 patients with clear cell renal cell carcinoma. Methods: After [68Ga]Ga-DPI-4452 administration, patients underwent serial full-body PET/CT imaging. Blood and urine were sampled. Safety was monitored for 7 d after injection. Results: Tumor uptake was observed at all time points (15 min to 4 h). Across 36 lesions, the SUVmax at 1 h after administration ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). The kidneys, liver, and bone marrow demonstrated low activity. [68Ga]Ga-DPI-4452 was rapidly eliminated from blood and urine. No clinically significant toxicity was observed. Conclusion: [68Ga]Ga-DPI-4452 showed exceptional tumor uptake in patients with clear cell renal cell carcinoma, with very high tumor-to-background ratios and no significant adverse events, suggesting potential diagnostic and patient selection applications.

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D7.4 ranging from 2.48 (AB-FUBINACA) to 4.95 (4F-ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB-BUTINACA) to 99.9% (BZO-HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser-bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market.

<div>AbstractPurpose:<p>Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.</p>Patients and Methods:<p>Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.</p>Results:<p>Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3–4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.</p>Conclusions:<p>The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.</p></div>

The voltage-gated sodium NaV1.7 channel plays a key role as a mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II is a potent and moderately selective peptide toxin from tarantula venom that inhibits human NaV1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human NaV1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with IC50s of 7 nM and 4 nM for hNaV1.7 and more than 1000-fold selectivity over human NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.8, and NaV1.9 channels. PTx2-3127 inhibits NaV1.7 currents in mouse and human sensory neurons and shows efficacy in rat models of chronic and thermal pain when administered intrathecally. Rationally designed peptide inhibitors of human NaV1.7 channels have transformative potential to define a new class of biologics to treat pain.