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Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors
No full textSPPL2a (Signal Peptide Peptidase Like 2a) is an intramembrane aspartyl protease engaged in the function of B-cells and dendritic cells. Despite being an attractive target for modulation of the immune system, selective SPPL2a
inhibitors are barely described in the literature. Recently, we have disclosed a selective, small molecular weight agent SPL‑707 which confirmed that pharmacological inhibition of SPPL2a leads to the accumulation of its substrate CD74/p8 and as a consequence to a reduction in the number of B-cells as well as myeloid dendritic cells in mice. In this paper we describe the discovery of novel hydroxyethylamine based SPPL2a inhibitors. Starting from a rather lipophilic screening hit, several iterative optimization cycles allowed for its transformation into a highly potent and selective compound 15 (SPL-410) which inhibited in vivo CD74/p8 fragment processing in mice at 10 mg/kg oral dose
Secukinumab treatment does not alter the pharmacokinetics of the CYP3A4 substrate midazolam in patients with moderate to severe psoriasis – results from an open label disease-drug-drug interaction study
No full textThis open-label disease drug–drug interaction study assessed whether blockade of the interleukin (IL)-17A pathway by secukinumab and subsequent down regulation of inflammatory cytokines like IL-6 or high sensitivity c-reactive protein (hsCRP) affects the pharmacokinetics of a senstive probe substrate of the cytochrome P450 3A4 isoform (CYP3A4). The pharmacokinetics of midazolam, metabolized by CYP3A4, was evaluated before and after 7 and 35 days of treatment initiation of subcutaneous secukinumab at a dose of 300 mg weekly in 24 patients with moderate-to-severe psoriasis. While demonstarting the expected decrease in downstream inflammatory cytokines, secukinumab had no clinically relevant effects on the pharmacokinetics of midazolam, provided substantial clinical benefit, and was generally well tolerated.
In summary, blockade of IL-17A signaling in moderate to severe psoriasis patients does not significantly affect CYP3A4 enzyme activities and therefore the use of secukinumab is unlikely to influence the pharmacokinetics of CYP3A4 substrates
Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.
No full textThe chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types
European Pharmaceutical Review James Mellman
No full textThe increasing complexity of formulations and active biological products raises new challenges for pre-filled syringe development. James Mellman, Device Manager at Novartis, speaks to Nikki Withers about the challenges of selecting the right primary packaging for injectable formulations and how he has learnt to expect the unexpected
Efficient Distribution of a Novel Zirconium-89 Labeled Anti-cd20 Antibody Following Subcutaneous and Intravenous Administration in Control and Experimental Autoimmune Encephalomyelitis-Variant Mice
No full textObjective: To investigate the imaging and biodistribution of a novel zirconium-89 (89Zr)-labeled mouse anti-cd20 monoclonal antibody (mAb) in control and experimental autoimmune encephalomyelitis (EAE) mice following subcutaneous (s. c.) and intravenous (i.v.) administration. Background: Anti-cd20-mediated B-cell depletion using mAbs is a promising therapy for multiple sclerosis. Recombinant human myelin oligodendrocyte glycoprotein (rhMOG)-induced EAE involves B-cell-mediated inflammation and demyelination in mice. Design/Methods: C57BL/6J mice (n = 39) were EAE-induced using rhMOG. On Day 14 post EAE induction, 89Zr-labeled-anti-cd20 mAb was injected in control and EAE mice in the right lower flank (s.c.) or tail vein (i.v.). Positron emission tomography/computed tomography (PET/CT) imaging and gamma counting (ex vivo) were performed on Days 1, 3, and 7 to quantify tracer accumulation in the major organs, lymphatics, and central nervous system (CNS). A preliminary study was conducted in healthy mice to elucidate full and early kinetics of the tracer that were subsequently applied in the EAE and control mice study. Results: 89Zr-labeled anti-cd20 mAb was effectively absorbed from s.c. and i.v. injection sites and distributed to all major organs in the EAE and control mice. There was a good correlation between in vivo PET/CT data and ex vivo quantification of biodistribution of the tracer. From gamma counting studies, initial tracer uptake within the lymphatic system was found to be higher in the draining lymph nodes (inguinal or subiliac and sciatic) following s.c. vs. i.v. administration; within the CNS a significantly higher tracer uptake was observed at 24 h in the cerebellum, cerebrum, and thoracic spinal cord (p < 0.05 for all) following s.c. vs. i.v. administration. Conclusions: The preclinical data suggest that initial tracer uptake was significantly higher in the draining lymph nodes (subiliac and sciatic) and parts of CNS (the cerebellum and cerebrum) when administered s.c. compared with i.v in EAE mice
Neurofunctional test batteries in safety pharmacology – Current and emerging considerations for the drug development process
No full textRegulatory guidelines recommend specialised safety pharmacology assessments in animals to characterise drug-induced effects on the central nervous system (CNS) prior to first-in-human trials, including the functional observational battery or Irwin test (here collectively termed neurofunctional assessments). These assessments effectively detect overtly neurotoxic drugs; however, the suitability of the in vivo assessments to readily detect more subtle drug effects on the nervous system has been questioned. A survey was formulated by an international expert working group convened by the (NC3Rs) to capture practice in CNS neurofunctional assessment tests and opinions on the perceived impact of in vivo test battery endpoints. Impact was defined as “the impact of measures alone/in combination on decision making in drug development or candidate selection when using the neurofunctional assessment”. The results demonstrate that rodents are predominantly used for small molecule assessments, whereas non-rodents are frequently used to test biotherapeutics. Practice varied between respondents in terms of experimental design. Subsets of test battery endpoints were consistently considered highly impactful (e.g. convulsions, stereotypic behaviors); however, the perceived impact level of other endpoints varied depending whether drugs were designed for CNS targets. Many endpoints were considered to have no or minimal impact, whereas a subset of endpoints in CNS test batteries appears more impactful than others. A critical evaluation is required to assess whether the translational value of CNS in vivo safety pharmacology assessments could be increased by modifying or augmenting standard CNS test batteries. A revised approach to CNS safety assessment has the potential to reduce animal numbers without compromising patient safety
Green Chemistry Benchmarking and improvement proposals for the CHAD Green Chemistry Scorecard Process
No full textThe CHAD Green Chemistry process is the current method, which is applied by Novartis to visualize the envi-ronmental impact of a drug manufacturing process. This report describes the methodology behind the No-vartis method as well as for other advanced methodologies (e.g. Green Aspiration Level, Green Star, Eco Scale, methodology from Bristol-Meyers Squibb, methodology from F. Hoffmann-La Roche etc.).
The mentioned methods were applied on the real project from Novartis and compared with the results from the current method from Novartis. The other methods were often not distinctive enough or did not taken into account the complexity of the process. Therefore, no other method were available without further change. However, the other methods have shown different advantages.
The collected information from other methodologies were used to propose improvement suggestions. The most promising ideas (using individual values for each solvent, applying HSE criteria on solvent group and categorization of reagents according to their complexity and health concern) were applied on the real pro-jects and compared to the old processes.
All the improvement suggestion leaded to higher score. The impact for the reagents were lower than for the organic solvent, because in average were around four times less reagent used than organic solvents. The impacts of combining the different ideas for solvent results in a significant lower result ( for the project as well as leading to an increased distinction for the projects.
To further illustrate it, projects in different development phases were compared against each other (early phase against commercial) and it could be shown, that using a too simple approach (current Novartis ap-proach) can lead in certain cases to misleading goals
A VP2/3-derived peptide exhibits potent antiviral activity against BK and JC polyomaviruses by targeting a novel VP1 binding site
No full textIn pursuit of effective therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen amino acid peptide binds to major structural protein VP1 in a new location within the pore with a low nanomolar KD. Alanine scanning of the peptide identified three key residues, substitution of each of which results in ~1000-fold loss of affinity with a concomitant reduction in antiviral activity. NMR spectroscopy and an X-ray structurally-guided model demonstrate specific binding of the peptide to the pore of the VP1 pentamer that constitutes the BKV capsid. Cell-based assays with the peptide demonstrate nanomolar inhibition of BKV infection and suggest that the peptide likely blocks the viral entry pathway between endocytosis and escape from the host cell ER. The peptide motif is highly conserved among the polyomavirus clade, and homologous peptides exhibit similar binding properties for JC polyomavirus and inhibit infection with similar potency to BKV in a model cell line. Substitutions within VP1 or VP2/3 residues involved in VP1-peptide interaction negatively impact viral infectivity, potentially indicating the peptide-binding site within the VP1 pore is relevant for VP1-VP2/3 interactions. The inhibitory potential of the peptide-binding site first reported here may present a novel target for development of new anti-polyomavirus therapies. In summary, we present the first anti-polyomavirus inhibitor that acts via a novel mechanism of action by specifically targeting the pore of VP1
Blockade of CD40–CD154 pathway interactions suppresses ectopic lymphoid structures and inhibits pathology in the NOD/ShiLtJ mouse model of Sjögren’s syndrome
No full textOBJECTIVE:
To examine the role of CD40-CD154 costimulation and effects of therapeutic pathway blockade in the non-obese diabetic (NOD/ShiLtJ) model of Sjögren's syndrome (SS).
METHODS:
We assessed leucocyte infiltration in salivary glands (SGs) from NOD/ShiLtJ mice by immunohistochemistry and examined transcriptomics data of SG tissue from these animals for evidence of a CD40 pathway gene signature. Additionally, we dosed MR1 (anti-CD154 antibody) in NOD mice after the onset of SS-like disease and examined the effects of MR1 treatment on sialadenitis, autoantibody production, SG leucocyte infiltration, gene expression downstream of CD40 and acquaporin 5 (AQP5) expression.
RESULTS:
We could detect evidence of CD40 expression and pathway activation in SG tissue from NOD mice. Additionally, therapeutic treatment with MR1 suppressed CD40 pathway genes and sialadenitis, inhibited ectopic lymphoid structure formation and autoantibody production, as well as decreased the frequency of antibody-secreting cells in SGs but had minimal effects on AQP5 expression in NOD/ShiLtJ SGs.
CONCLUSION:
CD40-CD154 interactions play an important role in key pathological processes in a mouse model of SS, suggesting that blockade of this costimulatory pathway in the clinic may have beneficial therapeutic effects in patients suffering from this autoimmune exocrinopathy