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Challenges in Extrapolating Phase I Healthy Volunteer Pharmacokinetics to Oncology Populations: Advocating for a Holistic Perspective
No full textPhase I clinical pharmacology (CP) studies in healthy volunteers (HVs) are conducted to assess factors influencing drug pharmacokinetic (PK) properties and guide potential dose adjustments or restrictions for specific subpopulations within the target patient population. However, for oncology drugs, direct extrapolation from HV data may not always yield accurate outcomes. This review examines three published examples—ribociclib, ceritinib, and midostaurin—where substantial changes in drug exposure observed in CP studies conducted in HVs (or non-cancer subjects) did not align with the more modest effects seen in patient trials. While HV CP studies are crucial for detecting factors that alter drug exposure, their findings may not always translate to the oncology patient population. The underlying reasons are likely multifaceted but can at least be attributed to differences in study populations and study designs. To address this potential discrepancy, the relevance of intrinsic and extrinsic factors identified in HV studies should be validated in patient trials by assessing their impact on drug PK, safety, and efficacy. These examples highlight the importance of a holistic approach that integrates data from both HV and patient studies. Such a framework ensures more informed decisions about the safe and effective use of oncology drugs in the real-world settings
A Pragmatic Radical Strategy for Dearomative Hydroalkylation of Unactivated Indoles.
No full textDearomative functionalization offers a direct approach for transforming planar aromatics into C(sp3)-rich frameworks with potentially improved drug-like properties. Herein, we report a metal-free and operationally simple method with broad functional group tolerance for the dearomative hydroalkylation of indoles using alkyl boronates. This strategy advances the radical-based dearomatization strategy to previously unreactive indole substrates, enabling access to a variety range of three-dimensional indolines. Notably, it highlights the use of transient indolenium ions in radical-mediated C-C bond formation, establishing a new platform for rapidly diversifying indole-derived scaffolds
Assessment of antigen-specific T cell recall responses in non-human primates using a composite AIM assay
No full textIntroduction: Characterizing antigen-specific T cell responses is essential for understanding the immunogenicity of biotherapeutics and mitigating drug-specific immune reactions.Methods: This study describes a flow cytometry composite Activation-Induced Marker (cAIM) assay for cynomolgus monkeys that allows quantification of T cell recall responses to multiple antigens using up to ten AIM pairs. The procedure incorporates two composite metrics (cAIM-index and cAIM-score) that facilitate the summation of T cell recall responses into interpretable numeric values, reducing reliance on multiple graphical comparisons. The assay is compatible with human and mouse samples and can utilize peripheral blood mononuclear cells or whole blood. Additionally, the method is well suited for the mass cytometry platform, enabling the detection of antigen-specific CD4+ and CD8+ T cell recall responses while providing deep immunophenotype information and consuming minimal blood sample volumes.Results: The assay successfully enables quantification of antigen-specific T cell recall responses across multiple antigens and species, while composite metrics streamline interpretation.Discussion: These protocols shall support preclinical and clinical immunogenicity assessments, advancing biotherapeutic development
Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase‑2 (ALK2) for the Treatment of Fibrodysplasia Ossificans Progressiva.
No full textFibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease leading to progressive soft tissue heterotopic ossification (HO) with no curative treatment available to date. It is caused by gain-of-function mutations in the activin A type-1 receptor ACVR1/ALK2, a member of the bone morphogenetic protein (BMP) type I receptor family. Most recent clinical trials in FOP have adopted for the first time on-target therapies to normalize the aberrant ALK2 receptor activity. Here we describe the discovery and preclinical characterization of zilurgisertib, a novel small-molecule inhibitor of ALK2 kinase with high biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and excellent oral bioavailability in preclinical species. Zilurgisertib fully suppresses HO in a pediatric mouse model of injury-induced FOP and therefore holds great potential as a novel targeted disease-modifying therapy for FOP. The candidate is being evaluated in clinical trials
Predictive Stability in Biopharmaceuticals and Vaccines: Perspectives and Recommendations towards Accelerating Patient Access
No full textIndustry position paper elucidating a 360-degree cross-functional and cross-company perspective on predictive stability approaches for large molecules with intent to influence the field and health authorities
ASKCOS: Open-Source, Data-Driven Synthesis Planning.
No full textConspectusThe advancement of machine learning and the availability of large-scale reaction datasets have accelerated the development of data-driven models for computer-aided synthesis planning (CASP) in the past decade. In this Account, we describe the range of data-driven methods and models that have been incorporated into the newest version of ASKCOS, an open-source software suite for synthesis planning that we have been developing since 2016. This ongoing effort has been driven by the importance of bridging the gap between research and development, making research advances available through a freely available practical tool. ASKCOS integrates modules for retrosynthetic planning, modules for complementary capabilities of condition prediction and reaction product prediction, and several supplementary modules and utilities with various roles in synthesis planning. For retrosynthetic planning, we have developed an Interactive Path Planner (IPP) for user-guided search as well as a Tree Builder for automatic planning with two well-known tree search algorithms, Monte Carlo Tree Search (MCTS) and Retro*. Four one-step retrosynthesis models covering template-based and template-free strategies form the basis of retrosynthetic predictions and can be used simultaneously to combine their advantages and propose diverse suggestions. Strategies for assessing the feasibility of proposed reaction steps and evaluating the full pathways are built on top of several pioneering efforts that we have made in the subtasks of reaction condition recommendation, pathway scoring and clustering, and the prediction of reaction outcomes including the major product, impurities, site selectivity, and regioselectivity. In addition, we have also developed auxiliary capabilities in ASKCOS based on our past and ongoing work for solubility prediction and quantum mechanical descriptor prediction, which can provide more insight into the suitability of proposed reaction solvents or the hypothetical selectivity of desired transformations. For each of these capabilities, we highlight its relevance in the context of synthesis planning and present a comprehensive overview of how it is built on top of not only our work but also of other recent advancements in the field. We also describe in detail how chemists can easily interact with these capabilities via user-friendly interfaces. ASKCOS has assisted hundreds of medicinal, synthetic, and process chemists in their day-to-day tasks by complementing expert decision making and route ideation. It is our belief that CASP tools are an important part of modern chemistry research and offer ever-increasing utility and accessibility
2024 White paper on recent issues in bioanalysis: Impact of LDT in US and IVDR in EU; AI/ML for High Parameter Flow Cytometry; The rise of Olink Technology; CDx for AAV Gene Therapies; Integrative Bioanalysis by Multiple Platforms; Super Sensitive ADA/NAb LBA (PART 2A - Recommendations on Advanced Strategies for Biomarkers, IVD/CDx Assays (BAV), Cell Based Assays (CBA), and Ligand-Binding Assays (LBA) PART 2B - Regulatory Agencies' Input on Biomarkers, IVD/CDx, and Biomarker Assay Validation).
No full textThe 18th Workshop on Recent Issues in Bioanalysis (18th WRIB) took place in San Antonio, TX, USA on May 6-10, 2024. Over 1100 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 18th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on "IVDR Implementation in EU & Changes for LDT in the US" and on "Harmonization of Vaccine Clinical Assays Validation" were the special features of the 18th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2024 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2024 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers in the Part 2A the recommendations on Biomarkers/BAV, IVD/CDx, LBA and Cell-Based Assays and in Part 2B the Regulatory Inputs on these topics. Part 1 (Mass Spectrometry Assays and Regulated Bioanalysis/BMV) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 17 of Bioanalysis, issues 5 and 3 (2025), respectively
Generation of a transgenic P. cynomolgi parasite expressing P. vivax circumsporozoite protein for testing pre-erythrocytic malaria vaccines in non-human primates
No full textMalaria, caused by infection with Plasmodium parasites, exacts a heavy toll worldwide. There are two licensed vaccines for malaria as well as two monoclonal antibodies that have shown promising efficacy in field trials. Both vaccines and monoclonals target the major surface protein (circumsporozoite protein, CSP) of Plasmodium falciparum. Yet Pf is only one of the four major species of Plasmodium that infects humans. Plasmodium vivax is the second leading cause of malaria but Pv vaccine and monoclonal development lags far behind P. falciparum owing to the lack of basic preclinical tools such as in vitro culture or mouse models that replicate the key biological features of P. vivax. Notably among these features is the ability to form dormant liver stages (hypnozoites) that reactivate and drive the majority of P. vivax malaria burden.
Plasmodium cynomolgi is a simian parasite which is genotypically and phenotypically very close to P. vivax, can infect common research non-human primates and replicates many features of Pv including relapsing hypnozoites. Recently, a strain of Pc has been adapted to in vitro culture allowing parasite transgenesis. Here, we created a transgenic P. cynomolgi parasite in which the endogenous Pc CSP has been replaced with Pv CSP with the goal of enabling preclinical study of anti-Pv CSP interventions to protect against primary and relapse infections. We show that the in vitro-generated transgenic Pc[PvCSP] parasite expresses both serotypes of Pv CSP and retains full functionality in vivo including the ability to transmit to laboratory-reared Anopheles mosquitos and cause relapsing infection in rhesus macaques. To our knowledge, this is the first gene replacement in a relapsing Plasmodium species. This work can directly enable in vivo development of anti-Pv CSP interventions and provide a blueprint for the study of relapsing malaria through reverse genetics
Primary sequence dependencies define the specificity and exon target space of splicing-modifying compounds
No full textModulation of splicing has emerged as a promising therapeutic strategy for various diseases, offering the potential to target specific exons to influence gene expression. Recent advancements led to the identification of small molecule splicing modifiers such as Risdiplam and Branaplam. These compounds induce the inclusion of exons that are typically found to be skipped due to their weak 5’ splice site. While Risdiplam has a preference to induce exons with a N-3G-2A-1 sequence at the 3’ exon end, Branaplam has a proclivity towards introducing A-3G-2A-1 -ending exons. However, the variables that determine the selectivity and specificity of splicing modulators are still not completely understood, as evidenced by the hundreds of untargeted N-3G-2A-1 ending exons present in the human genome. In this study, we delve into the molecular mechanisms governing the specificity of splicing-modifying compounds, focusing on their interactions with RNA structures at splice sites. Using biochemical assays, whole transcriptome analyses, and genetic perturbation approaches, our findings reveal contributions of primary structure dependencies that contribute to different aspects to the required secondary structural conformation, thus governing responsiveness to splicing-modulator induction. Based on these learnings, we were able to reprogram the specificity of splicing modulators by genetic manipulation of the U1 snRNA component of the spliceosome. Our findings improve the understanding of splicing modulators and might help to identify novel targets and to design new splicing-modifying compounds
Guidance for Auditing Sterility Testing Laboratories
No full textThis document provides some general guidance/tips and tricks for auditing sterility testing laboratories, emphasising the importance of microbiological release testing for parenteral drug products. It outlines critical elements for ensuring compliance with pharmacopoeial requirements and the integrity of sterility testing processes. There is no Novartis specific business processes or IP/product/project information mentioned in this article