Basilea Pharmaceutica (Switzerland)

BackgroundCeftobiprole (BPR), an advanced generation cephalosporin, was recently (April 2024) approved by the US FDA for treating Staphylococcus aureus bacteremia (SAB), community-acquired bacterial pneumonia (CABP), and acute bacterial skin and skin structure infections (ABSSSI). This study examined the activity of BPR and the comparator agent ceftaroline (CPT) against a contemporary (2018-2019) collection of methicillin-resistant S. aureus (MRSA) isolates from major pandemic lineages.Genomic features and susceptibility profile of MRSA isolates stratified by clonal group and subgroups.Methods150 MRSA collected from 38 hospitals in 18 countries were susceptibility (S) tested against BPR and CPT using CLSI broth microdilution methods; FDA breakpoints were applied. Total genomic DNA was extracted and sequenced. Assembled genomes were used to determine multi-locus sequence type (ST), clonal complex (CC), spa (not shown) and SCCmec types; results of typing methods were used to assign clonal group (CG).ResultsTwenty-four CGs, including subdivisions, were identified; 3 isolates could not be assigned a CG. Prominent CGs were USA300 (n=53, 35.3%), UK-EMRSA-15 (n=33, 22.0%), USA100 (n=28, 18.7%), and USA800 (n=15, 10.0%); rare CGs (≤ 3 isolates; n=21) totaled 14.0% (TABLE). Against all MRSA, 97.3% were BPR-S and 85.3% were CPT-S. BPR was more active than CPT across CGs and subdivisons: USA300, 100.0% BPR-S/94.3% CPT-S; UK-EMRSA-15, 93.9% BPR-S/69.7% CPT-S; USA100, 96.4% BPR-S/75.0% CPT-S; USA800, 100.0% BPR-S/CPT-S. Against rare or unknown CGs, 95.2% were BPR-S and 90.5% were CPT-S. Four (2.7%) and 22 (14.7%) isolates were BPR- and CPT-NS, respectively; all BPR-NS isolates were CPT-NS whereas 81.8% of CPT-NS isolates were BPR-S. No CG feature united BPR-NS isolates (n=2 UK-EMRSA-15, CC22/ST22/SCCmec-IV(2B); USA100-Swiss, CC5/ST105/SCCmec-II(2A); Hungarian-Brazilian; CC8/ST239/SCCmec-III(3A)), whereas 19/22 (86.4%) CPT-NS isolates were from subgroups of UK-EMRSA-15, USA100, or Hungarian-Brazilian CGs.ConclusionThis study reports the potent activity of BPR against a global collection of MRSA from prominent pandemic lineages. The low frequency of BPR-NS isolates, particularly among highly represented CGs including UK-EMRSA and USA100, and its activity against CPT-NS isolates, support the use of BPR in the treatment of MRSA-associated SAB, ABSSSI, and CABP.DisclosuresRodrigo E. Mendes, PhD, GSK: Grant/Research Support Jennifer Smart, PhD, Basilea Pharmaceutica International Ltd: Employee|Basilea Pharmaceutica International Ltd: Stocks/Bonds (Public Company) Mark E. Jones, PhD, Basilea Pharmaceutica International Ltd: Employee|Basilea Pharmaceutica International Ltd: Stocks/Bonds (Public Company)

The use of geomaterials spans long back into human history and relicts of man’s endeavours remain as evidence of practical use of rocks and minerals for the benefit of evolving societies [...]

Abstract Background: Avanbulin (BAL27862) is a microtubule-targeting agent (MTA) that promotes tumor cell death by modulating the spindle assembly checkpoint. Preclinical studies in glioblastoma (GBM) have shown that avanbulin is also active in human cancer cells resistant to other MTAs used in the clinic. Lisavanbulin (BAL101553) is a water-soluble, oral, lysine prodrug of avanbulin, currently in phase 1/2 for patients with recurrent GBM and, in combination with radiotherapy, for newly diagnosed GBM patients. Preclinical studies and clinical signals have also suggested an association between lisavanbulin activity and expression of microtubule plus-end binding protein (EB1). MTAs are active agents for lymphoma patients, as exemplified by the inclusion of vincristine in the R-CHOP regimen, standard treatment for diffuse large B cell lymphoma (DLBCL). Thus, our aim was to evaluate avanbulin, the active moiety of lisavanbulin, for its potential anti-lymphoma activity. Methods: Lymphoma cell lines derived from activated B cell like (ABC) and germinal center B cell type (GCB) DLBCL were exposed to increasing doses of avanbulin; cell proliferation was measured with MTT. Apoptosis induction was performed with annexin V staining on cells incubated in a live cell imaging system (Incucyte) treated with 5, 10, 20 or 40nM avanbulin. Images were taken every 4h for 72h. Cell cycle analysis was performed after 24, 48 and 72h of drug exposure at 20nM. Results: 26 DLBCL cell lines, treated for 72h with increasing avanbulin doses, showed high anti-proliferative activity of the compound, with a median IC50 = 11nM. No differences in terms of IC50 were observed comparing ABC (n=8) to GCB (n=18) DLBCLs, nor based on MYD88, TP53 and BCL2 status. Cell lines with MYC translocation were less sensitive than the ones without translocation. All lymphoma cell lines exhibited high EB1 RNA expression, with no correlation with sensitivity to avanbulin.Live cell imaging demonstrated a strong apoptosis induction in 15 out of 17 cell lines tested at 20 and 40nM. Among the 15 cell lines undergoing apoptosis, 8 cell lines already showed an apoptosis induction within 24h of drug exposure, 6 lines between 24 and 48h and 1 line after 48h exposure. These data confirmed the high activity of avanbulin already seen with the MTT assay.Cell cycle experiments performed at 24, 48 and 72h confirmed the strong cytotoxic effect of avanbulin in 4 DLBCL cell lines, including 2 ABC (OCILY3 and TMD8) and 2 GCB (SUDHL5 and SUDHL16) lines. Sub-G0 accumulation was already present at 24h in all 4 cell lines tested, with an increase over time. Especially at 24h, where we also observed a G2-M arrest in 3 out of 4 cell lines. Conclusions: Our data demonstrate the high cytotoxic anti-lymphoma activity of avanbulin, suggesting a potential activity of its prodrug lisavanbulin in lymphoma patients. Citation Format: Filippo Spriano, Luca Aresu, Luciano Cascione, Alberto J. Arribas, Nicole Forster-Gross, Felix Bachmann, Heidi Lane, Francesco Bertoni. Avanbulin, the active moiety of the tumor checkpoint controller lisavanbulin (BAL101553), has anti-lymphoma activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2575.

The decarbonisation of CaCO3 is essential for the production of lime (Ca(OH)2 and CaO), which is a commodity required in several large industries and the main precursor for cement production. CaCO3 is usually decarbonised at high temperatures, generating gaseous CO2 which will require post-process capture to minimise its release into the environment. We have developed a new process that can decarbonise CaCO3 under ambient conditions, while sequestering the CO2 as Na2CO3·H2O or Na2CO3 in the same stage. Here, the effects of increasing stirring rates and residence times on reaction efficiency of the key reaction occurring between CaCO3 and NaOH solution are studied. It is shown that the reaction is enhanced at lower stirring rates and longer residence times up to 300 seconds of contact between the reactants. The mass balance performed for Ca and CO2 revealed that up to the 95% of the process CO2 embodied in CaCO3 was sequestered, with maximum capture rate assessed at nn moles CO2 captured per second of reaction progress. A deeper insight into the precipitation of Na2CO3·H2O or Na2CO3 under different reaction conditions was gained, and SEM-EDX analysis enabled the observation of the reaction front by detection of Na migrating towards inner regions of partially-reacted limestone chalk particles.

BackgroundMultidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) present significant treatment challenges and can cause serious morbidity and mortality. Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced cephalosporin approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Ceftobiprole is currently in phase 3 clinical development to support a New Drug Application in the United States for acute bacterial skin and skin structure infections and S. aureus bacteremia. Here, the activity of ceftobiprole and comparators was evaluated against recent MDR S. aureus and MRSA clinical isolates.Methods13,868 S. aureus isolates were collected from patients with various infection types at 34 US medical centers from 2016–2020. Susceptibility to ceftobiprole and comparator agents was tested by CLSI methods. Current CLSI and EUCAST interpretive criteria were applied (Table). Isolates were categorized as MDR if they were non-susceptible (NS; CLSI criteria) to ≥3 of the following antimicrobials: clindamycin (CM), daptomycin (DAP), erythromycin (ERY), gentamicin (GM), levofloxacin (LEV), linezolid (LZD), tetracycline (TET), tigecycline (TGC), trimethoprim-sulfamethoxazole (TMP-SMX), or vancomycin (VAN). Isolates displaying oxacillin MIC values ≥4 mg/L were categorized as MRSA.ResultsCeftobiprole was more active than ceftaroline (CPT) against MRSA (99.2% susceptible [S] versus 94.0% S, respectively) (Table). Ceftobiprole maintained activity against 88.0% of the CPT-NS isolates, but CPT was only active against 6.5% of the ceftobiprole-NS isolates. Ceftobiprole was also highly active (97.7–100.0% S) against isolates NS to CM, DAP, ERY, GM, LEV, LZD, TET, TGC, or TMP-SMX. No VAN-NS isolates were detected. Importantly, ceftobiprole was more active (97.7% S) than CPT (83.0% S) against the subset of MDR-MRSA isolates.ConclusionConclusions: Ceftobiprole was highly active in vitro against MRSA and MDR S. aureus collected at US medical centers during 2016–2020. These results support the further development of ceftobiprole to treat S. aureus infections in the US.DisclosuresLeonard R. Duncan, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Shionogi (Research Grant or Support) Kamal Hamed, MD, MPH, Basilea Pharmaceutica International, Ltd (Employee)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C) Jennifer Smart, PhD, Basilea Pharmaceutica International, Ltd. (Employee)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C) Michael A Pfaller, MD, Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Pfizer, Inc. (Research Grant or Support) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)

Abstract Background: Derazantinib (DZB) is an oral fibroblast growth factor receptor (FGFR) inhibitor with clinical activity in intrahepatic cholangiocarcinoma. Kinase assays indicate activity against other important targets in oncology, including CSF1R and VEGFR2. We have shown that DZB can inhibit phosphorylation of CSF1R upon ligand stimulation in mouse macrophages ex vivo (GI50=100 nM); suggesting tumor-associated macrophages (TAMs) as an important target for DZB. Paclitaxel also reduces M2-TAM function, suggesting a potential synergy when combined with DZB. DZB monotherapy showed strong efficacy in some gastric (GA) PDX tumor models, so we have investigated the combination of DZB and paclitaxel in several GA-models in vivo. Materials and Methods: Four human tumor GA cell lines were studied in vitro: SNU-16, Fu97, AGS and KATOIII. SNU-16 (FGFR2-fusion) was grown s.c. in Balb/c mice as a xenograft (CDX), and 5 different patient-derived xenografts (PDX) with various FGFR-aberrations (fusion, amplification, over-expression or mutation) were grown in the same host. Mice were treated with different doses of DZB (p.o., qd) alone, and/or with paclitaxel (15 mg/kg, i.v., qw) for 3-4 weeks when tumors were 150 mm3. At the endpoint, tumors were ablated and snap-frozen or paraffin-embedded (FFPE) for western-blot/qPCR or immunohistochemistry (IHC), respectively. Efficacy was summarized as the endpoint dT/C, and the interaction assessed formally as synergy/additivity/antagonism by the Clarke-Combination-Index (CCI). The statistical significance of M2-TAMs was assessed using a one-tailed Fisher contingency test. The tumor models were run by CrownBio Inc, which also provided data on the FGFR-aberrations. Results: In vitro, DZB showed synergy with paclitaxel in SNU-16 and Fu97 models at concentrations known to be achievable in mouse plasma. In vivo, three experiments with the SNU-16 model showed reproducible synergy (mean CCI = -0.64) with the combination causing at least stasis and some complete-regressions. A PD-study after 3-days treatment showed a significant decrease in Ki67 and increase in the M1-TAMs in the combination group. Plasma PK showed no indication of a drug-drug interaction between the two compounds. In the 5 PDX-models, the combination showed synergy in three models and additivity in two. IHC analysis of M2-TAM levels in vehicle-treated mice of all 6 models showed that the two additive models had M2-TAM levels ≤0.8%, while synergy was seen in the 4 models with M2-TAMs of 1.1-8.7%. (p=0.03, using a cut-off of 1%). Conclusions: DZB combined with paclitaxel in vivo showed synergy/additivity in GA-tumor models with FGFR aberrations including FGFR2-fusions/amplifications, and FGFR1-3 over-expression or mutations. Additionally, the number of M2-TAMs may also play a role in sensitivity to the combination, which is consistent with the CSF1R kinase being an important target for DZB. Citation Format: Paul M. McSheehy, Mahmoud El Shemerly, Felix Bachmann, Laurenz Kellenberger, Heidi Lane. Derazantinib, an inhibitor of fibroblast growth factor receptors 1-3, synergises with paclitaxel in pre-clinical gastric tumor models [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 P238.

Isavuconazole is a broad-spectrum triazole for the treatment of invasive fungal disease (IFD). To investigate the clinical experience with isavuconazole in Chinese individuals. Participants were Chinese healthy volunteers from a Phase I pharmacokinetics (PK) and safety study of single/multiple doses of isavuconazole (n=36) and Chinese patients from the global PhaseIII SECURE study that assessed safety and efficacy of isavuconazole vs voriconazole for IFD treatment (n=26). No clinically relevant differences in PK were found between Chinese and Western participants, although exposure was increased in Chinese volunteers. Treatment-emergent adverse events (TEAEs) were reported in 75.0% of healthy volunteers, many of which were infusion-related. No serious AEs were reported. In SECURE, findings in Chinese patients (n=26) were similar to the global population. For patients who received ≥1dose of study drug, allcause mortality from first dose to Day 42 was 10.0% (1/10) with isavuconazole and 25.0% (4/16) with voriconazole (treatment difference [95% confidence interval, CI]: -15.0% [-43.2%, 13.2%]). Overall response at the end of treatment for patients with proven/probable IFD was 25.0% and 16.7% with isavuconazole and voriconazole, respectively (treatment difference [95% CI] -8.3% [-60.2%, 43.5%]). Isavuconazole was associated with lower incidence of hepatobiliary, eye, skin, subcutaneous tissue and psychiatric disorders compared with voriconazole and lower incidence of treatment-related TEAEs, serious TEAES or death overall. Although further research is required, this study demonstrated a favourable risk-benefit profile of isavuconazole in Chinese patients.