Pharmacokinetics of Serelaxin in Patients with Severe Renal Impairment or End-Stage Renal Disease Requiring Hemodialysis: A Single-dose, Open-label, Parallel-group Study

Serelaxin, a recombinant human relaxin-2, is currently in clinical development for treating acute heart failure. This open-label parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-h intravenous infusion (10μg/kg) in patients with severe renal impairment (n=6) or end-stage renal disease (ESRD) requiring hemodialysis (with PK on the day of dialysis [n=6] or during dialysis-free interval [n=6]) compared with healthy subjects (n=18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with a mean terminal elimination half-life of 6.5–8.8h. Compared to healthy subjects, a moderate decrease in serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4-h hemodialysis in ESRD patients, serelaxin was partially removed (30%) from blood with dialysis clearance constituting approximately 52% of total systemic clearance. Anti-serelaxin antibodies were not detected in any participant, and serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. The observed serelaxin PK differences in patients with severe renal impairment compared with matched healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients

Effective methods for assessing the saturation concentration of an API in a topical formulation

In topical development, the characterization of the solubility of a molecule in the formulation is paramount. Fick's law of diffusion states that the permeation of a molecule through the skin depends on the concentration of the molecule in its vehicle, which is maximal at its saturated state. Accordingly, a topical drug should be ideally formulated as a suspension, where the thermodynamic activity for flux through the skin is maximal. Unfortunately, topical suspensions - whether in a cream, gel or ointment - bear the risk to change over stability. Extensive characterization is required, making development time intensive and costly. To avoid risks and costs, companies usually prefer a physically stable formulation, where the molecule remains in solution over the entire shelf-life. In this paper we present powerful analytical tools such as Raman, TEM and SC-XRPD to assess solubilization and crystallization properties of a topical API - CEE321 - to optimize both - thermodynamic activity for skin flux and physical stability in the formulation over shelf-life

Dual therapeutic approaches to rhodopsin retinitis pigmentosa through Hsp90 inhibition

Retinitis pigmentosa (RP) is characterized by the progressive degeneration of retinal photoreceptor neurons. Mutations in rhodopsin are the most common cause of autosomal dominant Retinitis pigmentosa (adRP). Therapies targeting multiple classes of mutations would be of a great value for retinal dystrophies. It has been previously shown that pharmacological interventions can improve the folding and traffic, or reduce protein aggregation of the class II rod opsin misfolding mutant, P23H. We investigated the capacity of these interventions to modulate the class III rod opsin mutant, R135L, which binds arrestin and disrupts vesicular traffic. R135L acted as a dominant negative, and recruited wild-type rod opsin to intracellular vesicles. Treatment with retinoids or kosmotropes did not improve the vesicular disruption caused by R135L. By contrast, Hsp90 inhibition reduced the intracellular accumulation of R135L and abolished arrestin binding. This effect was mediated by a requirement for Hsp90 in kinase (GRK1) function, which is upstream of arrestin binding. Furthermore, prolonged high dose Hsp90 inhibition reduced photoreceptor GRK1 and PDE without affecting photoreceptor viability. Interestingly, a single low dose inhibition of Hsp90 protected against photoreceptor degeneration caused by P23H rod opsin, without affecting these components but correlated with an activation of HSF1 and heat shock protein induction. These data suggest that Hsp90 could be used as a potential therapeutic target for different types of rhodopsin adRP, but that inhibition might also affect the visual function through the requirement for Hsp90 in the biogenesis of phototransduction machinery components

Molecular basis of mRNA cap recognition by Influenza B polymerase PB2 subunit

Influenza virus polymerase catalyzes the transcription of viral mRNAs by a process known as “cap-snatching”, where the 5'-cap of cellular pre-mRNA is recognized by the PB2 subunit and cleaved 10-13 nucleotides downstream of the cap by the endonuclease PA subunit. Although this mechanism is common to both influenza A (FluA) and B (FluB) viruses, FluB PB2 recognizes a wider range of cap structures including m7GpppGm-, m7GpppG-, and GpppG-RNA, while FluA PB2 utilizes methylated G-capped RNA specifically. Biophysical studies with isolated PB2 cap-binding domain (PB2cap) confirm that FluB PB2 has expanded mRNA cap recognition capability although the affinities towards m7GTP are significantly reduced when compared to FluA PB2. The X-ray co-structures of the FluB PB2cap with bound cap analogs m7GTP and GTP reveal an inverted GTP binding mode that is distinct from the cognate m7GTP binding mode shared between FluA and FluB PB2. These results delineate the commonalities and differences in the cap-binding site between FluA and FluB PB2 and will aid structure-guided drug design efforts to identify dual inhibitors of both FluA and FluB PB2

Pharmacokinetics of Serelaxin in Patients with Severe Renal Impairment or End-Stage Renal Disease Requiring Hemodialysis: A Single-dose, Open-label, Parallel-group Study

Serelaxin, a recombinant human relaxin-2, is currently in clinical development for treating acute heart failure. This open-label parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-h intravenous infusion (10μg/kg) in patients with severe renal impairment (n=6) or end-stage renal disease (ESRD) requiring hemodialysis (with PK on the day of dialysis [n=6] or during dialysis-free interval [n=6]) compared with healthy subjects (n=18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with a mean terminal elimination half-life of 6.5–8.8h. Compared to healthy subjects, a moderate decrease in serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4-h hemodialysis in ESRD patients, serelaxin was partially removed (30%) from blood with dialysis clearance constituting approximately 52% of total systemic clearance. Anti-serelaxin antibodies were not detected in any participant, and serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. The observed serelaxin PK differences in patients with severe renal impairment compared with matched healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients

Ligand-free regioselective hydrogenation of naphthyl-P(V) scaf-folds to access phosphine oxide ligands.

Herein, we described the first semi- and regioselective hydrogenation of P(V)-substituted naphthalenes. This iridium-catalyzed reaction delivers phosphine oxides or phosphonates in almost quantitative yields and with total regioselectivi-ty. This report also exposed a novel pathway toward the preparation of H8-BINAP ligands derivatives. The importance of HFIP solvent is evidenced. Catalyst analysis also demonstrated the involvement of ultrasmall iridium(0) nanoparticles, with potential recycling of the catalyst

Self driving chemical space exploration

We describe an algorithmic approach to lead optimization. We take inspiration from geostatistics methods which consider the uncertainty in predictions as well as the predictions themselves. This leads to approach which has a concept of a chemical space. From a current dataset the approach will suggest both large and small changes aimed finding chemical matter that is better than what is known. This approach is also called 'active learning'. We use data from SHP2 project, as a retrospective example to show how the approach works

Medicinal Chemists Don’t Just Make Drugs – the Art of Developing Low Molecular Weight Imaging Agents in Switzerland

Radiolabeled molecular imaging agents are useful to study drug distribution, target engagement and disease progression in human patients. Medicinal chemists often develop them in parallel to drug discovery programs, to facilitate clinical development or to better understand physiological and pathological processes. While the properties required for imaging agents differ from those of drug candidates, their optimization follows similar principles. Developing them for clinical use also requires a multidisciplinary approach, and is best conducted in a close partnership between pharmaceutical and academic research centers. This article reviews recent scientific advances towards the identification and development of low molecular weight imaging agents in Switzerland

MEB/NC3Rs Questionnaire on the optimal duration of non-clinical studies to assess the safety of monoclonal antibodies: Building an evidence-based approach to justify the duration of longer-term toxicity studies with monoclonal antibodies

The EPAA, the Netherlands Medicines Evaluation Board (MEB) and the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) are collaborating on a project to investigate the optimal duration of non-clinical studies to assess the safety of monoclonal antibodies (mAbs). The NC3Rs (www.nc3rs.org.uk) are developing the survey, will collect and anonymise the data, which will then be analysed within the MEB. An expert working group consisting of industry partners within Europe and USA has been convened. The aims of the working group are to share data from general regulatory toxicology studies for various mAb modalities and disease indications, to make evidence based recommendations on when it may (or may not) be appropriate to perform chronic toxicity studies (up to 6 month duration), to support longer-term clinical trials. This will include collecting information on species tested, NOAEL and differences between short and long-term toxicity study findings. Some of the data will serve to follow-up previous NC3Rs projects to track implementation of best-practice recommendations or to collect further information (e.g., group sizes, recovery animals etc) to promote further opportunities to reduce animal use and/or streamline processes. All data collected in this survey will be treated in strict confidence and made anonymous. The NC3Rs data management policy is available on request. Please answer as many questions as possible with as much information as possible