诺华

Most novel anti-cancer therapies involve combining multiple immuno-oncology and/or targeted drugs. The historical paradigm of exploring combination regimens only after approval of the individual drugs is changing rapidly leading to clinical development of ‘novel-novel’ combination therapies consisting of at least two investigational agents. Initiating those combination efforts early in development is an important strategy to accelerate evolution of the standard of care for high unmet need cancer indications. However, there are specific challenges associated with such development programs, with additional complexity if more than one company is involved. Representing a consortium of major oncology drug developers, we critically discuss those challenges and suggest potential solutions to encourage the development of novel multi-company combination therapies for solid and hematological tumors. The areas covered include trial strategies for early and late clinical development, including dose/regimen optimization, statistical considerations, optimizing safety profiles, dose modification approaches, contribution of components, choice of standard of care backbone and comparator regimens as well as regulatory strategies.

This report summarises the Clinical Endpoints Special Session held during the 62nd annual symposium of the International Society for Clinical Electrophysiology of Vision (ISCEV), convened at Tivoli Vredenburg, Utrecht, The Netherlands. The session brought together clinicians, regulators, industry representatives, and a patient voice to consider the state of clinical endpoints in trials for inherited retinal disorders (IRDs). Discussions covered the adequacy of current endpoints, challenges of disease heterogeneity, regulatory expectations, operational feasibility, and the perspectives of patients. The session highlighted the need to anchor emerging endpoints to clinically meaningful outcomes and to minimise assessment burdens.

Abstract Introduction Chronic spontaneous urticaria (CSU) is a skin disorder for which short-course systemic corticosteroids are recommended only as rescue medication during acute exacerbations. Here, we describe real-world corticosteroid use, adverse events (AEs) occurring post-corticosteroid initiation, and health care resource utilization (HCRU) of patients with CSU in the USA. Methods This retrospective cohort study used data from the US HealthVerity claims database of adults with diagnosed CSU (January 2016–March 2023). Only prescription and non-antihistamine claims were included in the analysis of treatment patterns. In the AE and HCRU analyses, patients were stratified into five cohorts on the basis of total days of systemic corticosteroid supply as a proxy for duration of use: ≤ 31 days, > 31 to ≤ 60 days, > 60 days, ≥ 90 days (subcohort of > 60 days), and non-corticosteroid users. Results Of 200,298 patients, corticosteroids were the most prescribed treatment (78.3% all; 68.2% systemic) following CSU diagnosis, excluding over-the-counter medication and antihistamines. The ten most common AEs occurring after systemic corticosteroid initiation (hypertension, lipid disorders, anxiety, obesity, fatigue, depression, diabetes, insomnia, cataracts, and gastritis) occurred in higher proportions of all corticosteroid user types versus non-users. The proportion of patients experiencing AEs generally increased with longer duration of corticosteroid use. More frequent HCRU was generally observed after the first systemic corticosteroid prescription and with increasing duration of corticosteroid use. Conclusions Patients with CSU who were prescribed corticosteroids reported a higher proportion of AEs and more frequent HCRU than those who were not. These trends in AEs and HCRU were more prominent with increasing duration of corticosteroid use.

IntroductionParkinson's disease is a progressive neurodegenerative condition; there are no treatments currently available to slow disease progression, and no cure. Scientists are studying new treatments, such as disease-modifying therapies (DMTs), that may help slow progression of Parkinson's. Here, we discuss our approach to initiating a collaboration between industry and the Parkinson's community that explores the needs of people with early-stage Parkinson's and their care partners. The aim was to examine ways to build knowledge for newly diagnosed patients, align on the potential of DMTs and support discussions around any future clinical trial participation.MethodsAn exploratory workshop with patient advisors, patient advocacy groups (PAGs), and industry representatives was conducted to evaluate perceptions and identify challenges related to understanding disease modification in early-stage Parkinson's, including the development of a preliminary DMT narrative. Patients and care partners also completed a DMT perceptions questionnaire and tested the narrative for readability. A Strategic Patient Council (SPC) then guided refinement of the narrative and co-created a knowledge-building guide for the Parkinson's community.ResultsA total of 181 people with Parkinson's and their care partners completed the questionnaire. Of these, 72% strongly agreed on the need for new Parkinson's treatments, yet 59% felt that they lacked sufficient knowledge around symptom progression. Based on these data and feedback from the SPC, which comprised nine people from five PAGs, the DMT narrative was revised, leading to improved health literacy from 40% to 61%, within the 'adequate' range of the Suitability Assessment of Materials tool. The knowledge-building guide, informed by SPC input, incorporated a patient-centric framework and described key elements of living with early-stage Parkinson's, ranging from coping with diagnosis to clinical trial involvement.ConclusionA collaboration between industry and the Parkinson's community enabled successful development of knowledge-building materials tailored for people living with early-stage Parkinson's, empowering them with a clearer understanding of emerging innovative therapies.

In the VISION trial, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care significantly improved overall survival and radiographic progression-free survival compared with standard of care alone in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. This VISION dosimetry substudy quantified absorbed doses of 177Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177Lu-PSMA-617 at 7.4 GBq per cycle for up to 6 cycles. Blood samples, whole-body conjugate planar image scintigraphy, and abdominal SPECT/CT images were collected. SPECT/CT images were collected at 2, 24, 48, and 168 h after administration in cycle 1 and at a single time point 48 h after administration in cycles 2-6. Outcomes were absorbed dose per unit activity per cycle and cumulative absorbed dose over all cycles. Cumulative absorbed doses were predicted by extrapolation from cycle 1, and calculation of observed values was based on measurements of cycle 1 and cycles 2-6. Safety was also assessed. Results: Mean (±SD) absorbed doses per cycle in the kidneys were 0.43 ± 0.16 Gy/GBq in cycle 1 and 0.44 ± 0.21 Gy/GBq in cycles 2-6. The observed and predicted 6-cycle cumulative absorbed doses in the kidneys were 15 ± 6 and 19 ± 7 Gy, respectively. Observed and predicted cumulative absorbed doses were similar in other at-risk organs. Safety findings were consistent with those in the VISION study; no patients experienced renal treatment-emergent adverse events of a grade higher than 3. Conclusion: The renal cumulative absorbed 177Lu-PSMA-617 dose was below the established limit. 177Lu-PSMA-617 had a good overall safety profile, and low renal radiotoxicity was not a safety concern. Cumulative absorbed doses in at-risk organs over multiple cycles can be predicted by extrapolation from cycle 1 data in patients with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617.