Orion Corporation Inc.

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex's next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90-95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics.

Treatment options for metastatic castration-resistant prostate cancer (mCRPC) include androgen receptor pathway inhibitors (ARPIs), taxanes, radium-223, Lu-PSMA, poly (ADP-ribose) polymerase inhibitors, and immunotherapy in select patients. Resistance to ARPIs and hormone-based therapies has been associated with AR-ligand-binding domain mutations that can lead to promiscuous stimulation by other steroid hormones. There is a need to explore alternative targets and develop next-generation ARPIs or combination therapies that overcome this resistance. We describe the rationale and design of the randomized phase III trials OMAHA-003 (NCT06136624) and OMAHA-004 (NCT06136650), which will evaluate the efficacy and safety of opevesostat, a steroidogenesis inhibitor, versus ARPI switch in previously treated mCRPC. Results may support opevesostat as a potential new treatment option for mCRPC.Clinical trial registration: www.clinicaltrials.gov identifiers are NCT06136624 and NCT06136650.

In recent years, the environmental assessment and optimization of pharmaceutical dosage forms have received increasing attention. Consequently, interest in Life Cycle Assessments (LCA) has grown, and LCA is rapidly becoming the standard method of environmental evaluations across many industries, including the pharmaceutical sector. LCA is, however, a high entry barrier method requiring expertise, software- and database access, and process specific experimentally obtained performance data (e.g. electricity consumption). In the context of pharmaceuticals, significant challenges arise due to the limited availability of input data. Because of these limitations, we wanted to investigate the feasibility of using a scoping review as an alternative to LCA for evaluating the environmental implications of pharmaceuticals. In this literature review, a total of 8788 articles were screened, of which 117 were relevant. The search was anchored in a formulation previously developed. In this formulation, 3.0 mm minitablets were manufactured by direct compression from a spray-dried amorphous solid dispersion of indomethacin in polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) with the additional use of milled lactose monohydrate (LACT), microcrystalline cellulose (MCC) and magnesium stearate (MgSt) as tablet excipients. Through the systematic literature review, relevant environmental information was found for most of the processes and excipients investigated. Research currently undertaken at the intersection of environmental review and pharmaceutical manufacturing shows an upward trend. Most notably, recent research indicates that excipients generally regarded as safe (GRAS) may not necessarily be without environmental concern. Furthermore, excipients may be manufactured through multiple different routes which muddles the environmental comparison of different options. Still, this literature review identified a marked absence of sustainability-themed research specific to pharmaceutical manufacturing. With the issues uncovered, more research is sorely needed to provide guidance in formulation choices.

ortho-Substituted boronic acids have demonstrated significant potential as catalysts for direct amidation reactions, providing a sustainable alternative to conventional coupling reagents. We report the screening of ortho-functionalized arylboronic acids, including four literature benchmarks, as catalysts for the direct condensation of amines and carboxylic acids. The commercially available ortho-aminophenylboronic acids, specifically (2-(piperidin-1-yl)phenyl)boronic acid (2-PPBA), emerge as the optimal catalyst, providing amides from a range of carboxylic acids and amines.

To assess evolving practices in Investigative Toxicology (I-Tox) across the pharmaceutical industry, a 30-question survey was conducted in 2025, following earlier editions in 2015 and 2020. Seventeen mid- to large-sized pharmaceutical companies participated, all active in both traditional (NCEs, NBEs) and emerging modalities. Respondents included in vitro toxicologists from the Investigative Toxicology Leadership Forum, providing company-level input on team structure, objectives, assay capabilities, and future outlook. Most companies reported a dedicated I-Tox function embedded within nonclinical safety organizations. While I-Tox teams remain lean—around 1% of R&D staff—their focus has shifted toward high-impact project support, with greater reliance on CROs and GLP-compliant outsourcing. Internal laboratory activities have become more streamlined, but scientific scope remains broad, with growing emphasis on general toxicology and in silico approaches. I-Tox involvement now occurs earlier in discovery to enable proactive safety de-risking. Core I-Tox contributions span the R&D continuum, from target selection to clinical support. Compared to 2015, greater emphasis is placed on early-phase activities, including SAR guidance, off-target risk assessment, and chemistry support. In later phases, I-Tox focuses on elucidating mechanisms of toxicity, translational relevance, and signal interpretation in both nonclinical and clinical settings. The growing proportion of GLP work managed by I-Tox prompted further exploration of adjacent disciplines. Safety Pharmacology (SP) and Genetic Toxicology (GT) are now integrated into I-Tox functions in 50% and 75% of companies, respectively. These functions are supported by GLP-compliant assays conducted internally (25%), at CROs (58%), or through a combination of both (17%). Notably, one-third of respondents reported incorporating SP into I-Tox within the past five years. Assay availability has improved over the past decade, particularly for in vitro and in silico platforms targeting key organ systems. However, translational confidence remains a limiting factor. Technologies such as iPSC models and high-content imaging are now routinely applied, while others—like organ-on-chip and metabolomics—are still maturing. Respondents also highlighted emerging tools with near-term disruptive potential. Overall, I-Tox continues to evolve as a strategic enabler of drug safety, increasingly contributing to early de-risking, mechanistic insight, and the integration of innovative, non-animal technologies across pharmaceutical R&D.