7196 research outputs found
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Discovery and in vivo exploration of 1,3,4-oxadiazole and α-fluoroacrylate containing IL-17 inhibitors
No full textIL-17 is a pro-inflammatory cytokine produced mainly by Th17 cells that is involved in the immune response to fungal and bacterial infections whereas aberrant production of IL-17 is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like Secukinumab (Cosentyx®) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. The use of heterocycles as amide-isosteres as well as α-F-acrylamides led to the discovery of compounds 15, 18 and 26. All three compounds showed a robust inhibition of knee swelling in a rat model of arthritis. Adverse findings were observed when testing 18 and 26 in early rat and/or dog toxicity studies, preventing their further development
Immunogenicity assessment strategy for a chemically modified therapeutic protein in clinical development.
No full textThe clinical immunogenicity assessment for complex multidomain biological drugs is challenging due to multiple factors that must be taken into consideration. Here, we describe a strategy to overcome multiple bioanalytical challenges in order to assess anti-drug antibodies (ADA) for a novel and unique chemically modified protein therapeutic. A risk-centered approach was adopted to evaluate the immunogenic response to a modified version of human growth differentiation factor 15 (GDF15) connected to an albumin-binding fatty acid via a polyethylene glycol (PEG) linker. Key steps include monitoring anti-drug antibodies (ADAs), using a standard tiered approach of screening and confirmation. To deepen our understanding of ADA response, as a third tier of immunogenicity assessment, novel extensive characterization using a set of assays was developed, validated, and used routinely in clinical sample analysis. This characterization step included performance of titration, mapping of ADA response including anti-GDF15 and anti-PEG-fatty-acid antibody characterization, and assessment of the neutralizing anti-drug antibodies (NAbs) using cell-based assays for immunogenicity in parallel. The analytical methods were applied during two clinical trials involving both healthy volunteers and overweight or obese patients. We observed low incident rates for ADA and no ADAs against the PEG linker with fatty acid conjugation. In one of the clinical studies, we identified neutralizing ADAs. The proposed novel strategy of extensive characterization proved effective for monitoring the presence of ADAs and NAbs and can be used to support clinical development of a broad range of chemically modified proteins and multidomain biotherapeutics
Opportunities and challenges for use of minipigs in nonclinical pharmaceutical development: Results of a follow-up IQ DruSafe survey.
No full textMinipigs are valid nonrodent species infrequently utilized for pharmaceutical research and development (R&D) compared with dogs or nonhuman primates (NHPs). A 2022 IQ DruSafe survey revealed a modest increase in minipig use by pharmaceutical companies compared with a prior 2014 survey, primarily in the development of oral small molecules and parenteral protein molecules. Some companies considered using minipigs more often due to NHP shortages and regional ethical concerns with using NHPs and dogs. However, for most pharmaceutical companies, minipigs still represent ≤5% of their nonrodent animal use. Key challenges noted by companies to wider adoption of minipigs were high test article requirement, limited historical control data, and lack of relevant reagents or assays. Additionally, some companies expressed uncertainties about contract research organization (CRO) capabilities and experience, a perception not shared by respondent CROs. These latest survey results indicate persistence of many concerns previously identified in 2014. Several case studies are included to illustrate areas of expanded minipig use as well as the challenges that hinder broader adoption. Ongoing, focused, and industry-wide initiatives to address the identified or perceived challenges may lead to more frequent or routine consideration of minipigs as a test species in pharmaceutical R&D
An orthogonal analytical platform for determining critical material attributes for in situ formation of thermosensitive hyaluronic acid-poly(N-isopropylacrylamide) copolymers
No full textThe developability assessment of the in situ formation of thermosensitive injectables requires the unequivocal determination of their lower critical solution temperatures (LCSTs). Herein, we established a standardized threshold for LCST detection by harmonizing and cross-validating the orthogonal methods using techniques such as nuclear magnetic resonance spectroscopy, light scattering, turbidimetry, backgrounded membrane imaging, and rheology. The selected techniques were in agreement and promptly disclosed unique features and instrumental biases of otherwise difficult interpretations in the characterization of thermosensitive polymers. Thus, various hyaluronic acid–poly(N-isopropylacrylamide) copolymers were synthesized via strain-promoted azide–alkyne cycloaddition to understand their critical material attributes. Structure–function relationships and behaviors of the copolymers were tested under in vitro-simulated in vivo conditions
Targeting P-selectin and interleukin-1β in mice with sickle cell disease: effects on vaso-occlusion, liver injury and organ iron deposition.
No full textContinuous vaso-occlusive and inflammatory processes cause extensive end-organ damage in adults with sickle cell disease (SCD), and there is little evidence that longterm hydroxyurea therapy prevents this. In initial trials, P-selectin blockade with crizanlizumab reduced SCD vaso-occlusive crisis frequency, and interleukin (IL)-1β inhibition in SCD patients, using canakinumab, lowered inflammatory markers. We used murine SCD models to examine the effects of acute and chronic blockade of Pselectin and of IL-1β on vaso-occlusive events, their inflammatory profile and organ health. Both approaches improved impaired cutaneous microvascular perfusion in SCD mice by reducing TNF-α-induced vaso-occlusion. Acute P-selectin blockade markedly reduced TNF-α-induced neutrophil-platelet aggregate formation in SCD mice, and decreased leukocyte-rolling movements in the microvasculature, while acute IL-1β inhibition attenuated microvascular leukocyte adhesion. Six weeks of IL-1β-blocking immunotherapy improved the inflammatory profile of SCD mice, considerably reduced hepatic fibrosis and provided some relief from lung injury. In contrast, although Pselectin blockade reduced glomerular congestion, no significant benefit to overall organ pathology was observed. Unexpectedly, while combining the two immunotherapies reduced microvascular occlusion, their prolonged use caused acute liver injury. Notably, inhibition of IL-1β, but not of P-selectin, remarkably decreased hemosiderosis, in association with reduced tissue macrophage infiltration and the correction of biomarkers of dysregulated iron turnover. Our findings suggest that the attenuation of inflammation, as well as of vaso-occlusive processes, may be crucial for mitigating organ damage in SCD. Future trials should explore the ability of cytokine blockade to prevent multiorgan damage in patients with SCD, beyond evaluating vaso-occlusive crisis frequency
Partial Least Squares in the pharmaceutical industry
No full textno abstract
no data from Novartis is use
Breaking barriers in cancer management: The promising role of microsphere conjugates in cancer diagnosis and therapy
No full textCancer is a significant worldwide health concern, and there is a demand for ongoing breakthroughs in treatment techniques. Microspheres are among the most studied drug delivery platforms for delivering cargo to a specified location over an extended period of time. They are biocompatible, biodegradable, and capable of surface modifications. Microspheres and their conjugates have emerged as potential cancer therapeutic options throughout the years. This review provides an in-depth look at the current advancements and applications of microspheres and their conjugates in cancer treatment. The review encompasses a wide array of conjugates, ranging from polymers such as ethyl cellulose and Eudragit to stimuli-responsive polymers, proteins, peptides, polysaccharides such as HA and chitosan, inorganic metals, aptamers, quantum dots (QDs), biomimetic conjugates, and radio conjugates designed for radioembolization. Conjugated microspheres precisely deliver chemotherapeutics to the intended target while achieving controlled drug release to prevent side effects. It offers a means of integrating several distinct therapeutic modalities (chemotherapy, photothermal therapy, photodynamic therapy, radiotherapy, immunotherapy, etc.) to provide synergistic effects during cancer treatment. This review offers insights into the prospects and evolving role of microspheres and their conjugates in the dynamic landscape of cancer therapy. This review provides a comprehensive resource for researchers and clinicians working towards advancements in cancer treatment through innovative applications in therapy and translational research
Scientific and Regulatory Policy Committee Points to Consider: Review of the United States Food and Drug Administration (FDA) Guidance on Pathology Peer Review in Nonclinical Toxicology Studies.
No full textIn December 2021, the United States Food and Drug Administration (FDA) issued the final guidance for industry titled Pathology Peer Review in Nonclinical Toxicology Studies: Questions and Answers. The stated purpose of the FDA guidance is to provide information to sponsors, applicants, and nonclinical laboratory personnel regarding the management and conduct of histopathology peer review as part of nonclinical toxicology studies conducted in compliance with good laboratory practice (GLP) regulations. On behalf of and in collaboration with global societies of toxicologic pathology and the Society of Quality Assurance, the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP) initiated a review of this FDA guidance. The STP has previously published multiple papers related to the scientific conduct of a pathology peer review of nonclinical toxicology studies and appropriate documentation practices. The objectives of this review are to provide an in-depth analysis and summary interpretation of the FDA recommendations and share considerations for the conduct of pathology peer review in nonclinical toxicology studies that claim compliance to GLP regulations. In general, this working group is in agreement with the recommendations from the FDA guidance that has added clear expectations for pathology peer review preparation, conduct, and documentation
Predicting subgroup treatment effects for a new study: Motivations, results and learnings from running a data challenge in a pharmaceutical corporation
No full textWe present the motivation, experience and learnings from a data challenge conducted at a large pharmaceutical corporation on the topic of subgroup identification. The data challenge aimed at exploring approaches to subgroup identification for future clinical trials. To mimic a realistic setting, participants had access to 4 Phase III clinical trials to derive a subgroup and predict its treatment effect on a future study not accessible to challenge participants. 30 teams registered for the challenge with around 100 participants, primarily from Biostatistics organisation. We outline the motivation for running the challenge, the challenge rules and logistics. Finally, we present the results of the challenge, the participant feedback as well as the learnings, and how these learnings can be translated into statistical practice