Orion Corporation (Finland)

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.

TPS299 Background: Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. Opevesostat showed antitumor activity in participants with heavily pretreated mCRPC in the phase 1/2 CYPIDES trial. The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) is designed to evaluate the efficacy and safety of opevesostat in participants with mCRPC after a prior ARPI. Methods: Eligible participants have mCRPC that progressed during androgen deprivation therapy ≤6 months before screening and on or after 1 ARPI for metastatic or nonmetastatic hormone-sensitive prostate cancer (HSPC) or CRPC for ≥8 weeks (≥14 weeks with bone progression). Prior ARPI plus docetaxel for HSPC is permitted if participants received no more than 6 cycles of docetaxel without radiographic disease progression. Approximately 1314 participants will be randomized 1:1 to opevesostat 5 mg orally twice-daily plus dexamethasone 1.5 mg and fludrocortisone 0.1 mg orally once daily or abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily (if prior enzalutamide, darolutamide, or apalutamide) or enzalutamide 160 mg orally once-daily (if prior abiraterone). Stratification factors are metastatic site (bone only vs liver vs other), androgen receptor ligand binding mutation (AR-LBDm) status (positive vs negative), and prior docetaxel treatment for HSPC (yes vs no). Once the predefined enrollment threshold for participants with either mutation status (AR-LBDm-positive, ~400 participants or AR-LBDm-negative, ~914 participants) is met, no additional participants with that mutation status will be permitted to enroll. The protocol was amended to use radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR), analyzed separately in participants with AR-LBDm–positive and –negative disease, as the primary end point and overall survival as a key secondary end point. Other secondary end points include time to initiation of first subsequent anticancer therapy or death, objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR, time to pain progression; time to prostate-specific antigen (PSA) progression, PSA response rate, time to first symptomatic skeletal-related event, and safety and tolerability. Enrollment is ongoing. Clinical trial information: NCT06136650 .

ABSTRACTPatients with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop biochemical recurrence (BCR), which requires effective treatment to delay disease progression. The ARASTEP study (NCT05794906) aims to determine whether the addition of darolutamide to androgen-deprivation therapy (ADT) improves radiologic progression-free survival (rPFS) using prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) compared with placebo plus ADT in patients with high-risk BCR.Approximately 970 patients from 243 sites globally will receive either darolutamide 600 mg or placebo twice daily, both with ADT, for 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent. Eligible patients will have been treated by primary RT or RP ± adjuvant RT (ART) or salvage RT (SRT), and present with high-risk BCR (prostate-specific antigen [PSA] doubling time <12 months and PSA ≥0.2 ng/mL after RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), ≥1 PSMA PET/CT-positive lesion (negative on conventional imaging), serum testosterone >150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. The primary endpoint is rPFS using PSMA PET/CT, with secondary endpoints including metastasis-free survival, time to castration-resistant prostate cancer, overall survival, quality of life, and safety.CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05794906.

Reliable prediction and prevention of adverse drug reactions (ADRs) remains a key challenge in the development of new medicines. Advanced mathematical and computational modelling approaches, which incorporate cutting-edge mechanistic understanding of ADRs in concert with systematically collected data addressing knowledge gaps, are integral components of model-informed drug discovery and development (MID3). These approaches provide a precise, quantitative framework for predicting and mitigating safety risks in the earliest phases of drug development. Here, we highlight recent developments in the burgeoning field of quantitative systems toxicology (QST), including insights into the current state-of-the-art, as well as outcomes from the Innovative Medicines Initiative (IMI) 2 TransQST project. QST models that describe the disruption of cardiovascular, gastrointestinal, hepatic and renal physiological functions following drug exposure are presented, along with recommendations for their application in drug discovery and development.

Neuropathic pain is a common and debilitating symptom with limited treatment options. Genetic studies, which can provide vital evidence for drug development, have identified only 3 genome-wide significant signals for neuropathic pain traits. To address this, we performed the largest genome-wide association study (GWAS) to date of all-cause neuropathic pain and neuropathic pain subtypes. We defined all-cause neuropathic pain and 33 neuropathic pain subtypes using DeepPheWAS software in the UK Biobank, taking advantage of the longitudinal drug prescription data alongside clinical and self-reported records. We performed a GWAS of all-cause neuropathic pain (33,278 cases, 140,134 controls) as our primary analysis and GWASs of neuropathic pain subtypes as secondary analyses. We used 8 variant-to-gene criteria to identify putative causal genes. We identified 7 independent novel genome-wide associations for neuropathic pain phenotypes, which mapped to 22 novel putative causal genes. NCAM1 was the only gene identified from the primary analysis of all-cause neuropathic pain and met the most variant-to-gene criteria (4) of any identified gene. Of the 21 other genes, ASCC1, CHST3, C4A/C4B , and KCNN2 had the most compelling evidence for mechanistic involvement in neuropathic pain. We have performed the largest GWAS to date of all-cause neuropathic pain and more than doubled the number of genome-wide significant associations for neuropathic pain traits, identifying putative causal genes. There is strong evidence for the involvement of NCAM1 in neuropathic pain, which merits for further study for drug development.

ABSTRACTThe study evaluated pharmacokinetics, effects on functional alertness, and cardiovascular parameters of tasipimidine oral solution (Tessie, Orion Corporation) alone and in combination with oral clomipramine in six healthy laboratory dogs. Pharmacokinetics and functional alertness were studied after a single dose (Phase 1) and after 4 days of repeated twice daily dosing of tasipimidine 30 μg/kg and clomipramine at approximately 1 mg/kg, alone and in combination (Phase 2). Additionally, the combination was studied with a reduced dose of tasipimidine (20 μg/kg) as single and repeated dosing (Phase 3). Alertness was slightly reduced by the combination of tasipimidine 30 μg/kg with clomipramine. Decreasing tasipimidine dose to 20 μg/kg caused less reduction in alertness. Tasipimidine alone and in combination with clomipramine was well tolerated in respect to cardiovascular effects (BP, HR, and ECG). The exposure levels of tasipimidine were similar alone and in combination with clomipramine when administered as a single dose. After repeated dosing, tasipimidine exposure was higher when combined with clomipramine. Slightly slower absorption of clomipramine was observed when dosed concomitantly with tasipimidine, but there was no significant difference in plasma exposure. Effect on functional alertness supports the use of the lower dose of tasipimidine (20 μg/kg) when combined with clomipramine 1 mg/kg.

TPS5131 Background: Patients with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop BCR – a prostate-specific antigen (PSA) increase with no evidence of metastases on conventional imaging (e.g. magnetic resonance imaging/computed tomography). Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) is more sensitive than conventional imaging and may detect lesions in patients with BCR that conventional imaging cannot. BCR is an indicator of disease progression and warrants effective treatment to delay further progression, particularly if lesions are detected by PSMA PET/CT. The androgen receptor inhibitor darolutamide is structurally different by design to deliver robust clinical efficacy with a differentiated tolerability profile. In the phase 3 ARAMIS trial, darolutamide significantly improved metastasis-free survival (MFS) and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). ARASTEP is a phase 3 trial (NCT05794906) evaluating whether darolutamide plus ADT improves radiological progression-free survival (rPFS) by PSMA PET/CT vs placebo plus ADT in patients with high-risk BCR and PSMA PET/CT-positive lesions following primary therapy. Methods: Key eligibility criteria included: prior primary RT or RP ± adjuvant RT (ART) or salvage RT (SRT), with high-risk BCR (PSA doubling time [PSADT] &lt;12 months and PSA ≥0.2 ng/mL after primary RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), ≥1 PSMA PET/CT-positive prostate cancer lesion with no visible lesions on conventional imaging, and serum testosterone ≥150 ng/dL. ARASTEP is planned for 750 patients from 23 countries to be randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, both with ADT, for 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent. During the 24-month treatment period, patients will be monitored for safety every 12 weeks, and every 24 weeks for PSMA PET/CT and conventional imaging events. After 24 months, patients with PSA values ≥0.2 ng/mL will continue study treatment as part of active follow-up until PSMA PET/CT progression is confirmed by blinded independent central review (BICR), followed by long-term follow-up for conventional imaging progression. Patient stratification factors are PSADT (&lt;6 vs ≥6–&lt;12 months), intent to treat baseline PSMA PET/CT lesions with image-guided RT/surgery (Yes vs No), and distant ± locoregional vs locoregional-only lesions. The primary endpoint is rPFS by PSMA PET/CT assessed by BICR. Secondary endpoints include MFS on conventional imaging by BICR, time to CRPC, OS, quality of life, and safety. As of January 2025, 458 patients have been randomized from 220 sites. Clinical trial information: NCT05794906 .

Abstract Background: The first-generation immune checkpoint inhibitors anti-PD1/PDL1 and anti-CTLA-4 either alone or in combination have shown tremendous clinical success in BRAF wild type melanoma cancer patients. However, there is still a high unmet need as great proportion of melanoma patients relapsed after treatment with first generation immune checkpoint inhibitors and BRAF mutant patient relapsed after treatment BRAF inhibitors. Chimeric antigen receptor (CAR) expressing T cells have shown clinical success in hematological malignancies, recent studies have shown that CAR Ts cells were detected in circulation a decade after the first CD19 CART cell injection. Here, we generated a novel SIRPa based extracellular extension TYRP1 targeting CAR T cell, here onwards referred as TYRP1 FiCAR, that work independent of the tumor mutation burden and BRAF status. TYRP1 targeting FiCARs could be an alternative and attractive therapeutic strategy for treatment relapsed melanoma patients. Methods &amp; Results: A well-known anti-TYRP1 binder flanvotumab’s scfv was inserted into FiCAR-structure containing CD28 and CD3zeta intra cellular signaling domain and those CAR T cells were studied for both in vitro and in vivo function. TYRP1 based FiCAR grew normally and good transduction rates with low vector copy numbers were achieved. In addition, upon co-culture of TYRP1 FiCAR T cells with tumor cells expressing TYRP1 a rapid and significant release of pro-inflammatory cytokines was detected. Moreover, killing of the target cells were observed by the TYRP1 FiCAR T cells. To study the in vivo functionality of the TYRP1 FiCAR-T cells, NSG mice were inoculated with melanoma cells subcutaneously. Three weeks after the inoculation mice were intravenously injected with a single dose of TYRP1 FiCAR T cells. Discussion: The data presented here shows a proof-of-concept study for the FiCAR structure to work against TYRP1 antigen. TYRP1 FiCAR T cells upon co-culture with TYRP1 expressing tumor elicited a significant increase in effector cytokines production and has not shown any signs of tonic signaling. Additionally, TYRP1 FiCAR T cells were able to kill tumor cells efficiently reaching 100% maximal killing. In vivo, TYRP1 FiCAR T cells significantly delayed tumor growth. However, full regression of the tumors was not achieved in vivo. Collectively, the in vitro and in vivo data support further optimization of TYRP1 FiCAR T cells to treat melanoma patients refractory to immunotherapy and BRAF inhibitors. Citation Format: Henrik Paavilainen, Sakari Pöysti, Veera Nikoskelainen, Marie Nyman, Anil K. Thotakura. A novel SIRPA based FiCAR T cells therapy targeting TYRP1 to treat melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 863.

TPS301 Background: Androgen receptor (AR) somatic mutation activation is a resistance mechanism to AR-directed therapies (ADT) in mCRPC. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. By blocking the first step of the enzymatic pathway, opevesostat has the potential to inhibit all steroid hormones involved in AR signaling activation. In the phase 1/2 CYPIDES study, opevesostat had antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations (1). The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) will evaluate the efficacy and safety of opevesostat versus abiraterone or enzalutamide in patients with molecularly unselected mCRPC previously treated with 1 prior NHA. Methods: Eligible patients have mCRPC that progressed during ADT ≤6 months before screening and during/after 1 NHA for hormone-sensitive prostate cancer or non-mCRPC. Approximately 1500 patients (375 with, 1125 without AR-LBD mutations) will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in AR-LBD mutation–positive and –negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Recruitment is ongoing. 1. Fizazi et al. NEJM Evid. 2024. Clinical trial information: NCT06136650 .