Bristol-Myers Squibb (Canada)

<h2>Abstract</h2><h3>Background</h3> There is limited real-world data on the demographic and clinical characteristics of adult patients with obstructive hypertrophic cardiomyopathy (oHCM) treated with mavacamten in Canada. <h3>Methods</h3> This was an observational retrospective cohort study on adult patients with symptomatic oHCM enrolled in the mavacamten Patient Support Program (PSP) in Canada between January 4, 2023, and April 12, 2024. Baseline demographic information, clinical characteristics, medical history, and mavacamten treatment information were collected from the PSP database. <h3>Results</h3> A total of 683 patients met the eligibility criteria for the study. The median age was 65.0 years (IQR: 57.0-73.0), 52.1% of the patients were male, and 67.1% were classified as NYHA class II at baseline. Most patients were on beta blocker monotherapy at baseline (63.7%) and data cut-off (76.3%). Almost all patients (99.4%) were initiated with 5 mg of mavacamten. The median follow-up time was 27.4 weeks (range: 1.6-70.1), and the median treatment duration was 24.6 weeks (range: 0.4-64.4). At data cut-off, 17.1% of patients were on 2.5 mg of mavacamten, 52.6% were on 5 mg, 20.2% were on 10 mg, and 2.2% were on 15 mg. Mavacamten was discontinued by 7.9% of patients, with the main reasons being side effect or adverse event (2.5%; 17/683), undisclosed physician decision (1.8%; 12/683), or lack of efficacy (0.9%; 6/683). <h3>Conclusions</h3> These early results provide the largest dataset on mavacamten utilization in the Canadian oHCM population. Baseline demographic and clinical characteristics and mavacamten dose distributions are comparable to findings from clinical trials and real-world studies. NCT06549608.

Food systems face significant challenges that include increasing demand for agricultural products and accelerating environmental degradation. Regenerative agriculture has emerged as concept to reduce environmental harm while maintaining or even improving productivity. However, adoption of regenerative agriculture remains limited. This partly due to the absence of a shared definition and a standardised process to monitor, assess and report regenerative agriculture outcomes. To address this gap, SAI Platform, a member-led organisation within the food and beverage sector, collaborated with stakeholders to develop a global framework for regenerative agriculture. Drawing from a review of existing frameworks and consultations with SAI Platform members, farmers, and academics, we developed a framework that defines regenerative agriculture as an outcome-based approach that enhances environmental impact. It includes eight regenerative agriculture outcomes across the environmental areas of soil health, biodiversity, water and climate and suggests indicators to quantify progress. The framework process emphasises the need to understand local contexts and farmer needs when implementing regenerative agriculture. It does so through a four-step process that includes (i) a context analysis to identify key material criteria of a production system, (ii) the prioritisation of outcomes based on the context analysis, (iii) the selection of practices to achieve improved performance against prioritised outcomes, and (iv) the development and implementation of continuous improvement plans to monitor and report progress. Farm groups or individual farms can use this framework to independently verify the implementation of the steps defined in the framework and claim different performance levels for progress towards regenerative agriculture. These claims create a foundation for regenerative agriculture programmes, incentive mechanisms, and corporate reporting. While the framework is a starting point, collaboration and refinement are necessary to address evolving challenges in implementation. SAI Platform commits to research and stakeholder engagement to continuously improve the framework and support fair transitions towards regenerative agriculture.

Most complex in vitro models (CIVM) and microphysiological systems (MPS) are composed of human cells, with the goal of evaluating diseases, efficacy, safety, and pharmacokinetic ques­tions specifically for humans. The hope with CIVM/MPS is that they will eventually improve our predictivity of clinical responses and reduce or replace animal use in research, supporting the 3Rs concept of only using animals in research when necessary. Given the potential of animal-based models to advance this field by comparing existing in vivo animal data with new animal-based MPS responses, there are currently few CIVM and MPS utilizing animal tissues. Animal-based MPS may also have specific utility for cross-species comparisons or species-specific mechanistic questions on zoonotic diseases, and therapies for animals. Animal-based MPS may help expand in-vitro-to-in-vivo correlations, advance the field, and establish confidence in the predictive nature of such platforms. The IQ MPS-FDA workshop provided an interactive venue for pharmaceutical companies and regulatory agencies such as the U.S. Food and Drug Administration (FDA), NC3Rs (UK), Health Canada, NIH/NCATS, NIHS and PMDA (Japan), Danish Medicines Agency, European Com­mission, NIEHS/NICEATM, HHS, NIST, EURL ECVAM, and the IQ MPS Affiliate, a collaboration of pharmaceutical companies, to jointly discuss considerations of animal-based MPS and applica­tions where animal-based MPS are of potential value.

Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis1. Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We appliedTMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR-PTPN11-FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.

Aims Nivolumab has been approved for advanced squamous and non-squamous non-small cell lung cancer (NSCLC) following platinum-based chemotherapy in both Canada and Sweden. We aimed to determine the value-for-money of nivolumab versus docetaxel in a Canadian and Swedish setting based on 5-year data. Methods These cost effectiveness analyses used partitioned survival models with three mutually exclusive health states: progression-free, progressed disease, and death. All clinical parameters were derived from two registration phase 3 randomized trials, CheckMate 017 and CheckMate 057, with a minimum follow-up of 5 years. Treatment duration was based on time-on-treatment data from the clinical trials. Costs were derived from published sources. The primary outcomes of the analyses were quality-adjusted life-years (QALYs), life-years gained, and incremental cost-effectiveness ratios (ICERs). The model input parameters for each analysis were chosen in line with guidance from the respective HTA authorities. Results From a Canadian payer perspective, the ICERs were CAN$140,753 per QALY in the squamous population, and CAN$173,804 per QALY in the non-squamous population, assuming a 10-year time horizon and a 5% discount rate for both costs and outcomes. Sensitivity analyses demonstrated that changes to the discount rates for outcomes had the highest impact on the ICERs. In the Swedish analysis, the ICERs were SEK568,895 per QALY in the squamous population and SEK662,991 per QALY in the non-squamous population, assuming a 15-year time horizon, a 3% discount rate, and a 2-year maximum treatment duration for nivolumab. Sensitivity analyses demonstrated that the ICERs were most sensitive to changes in the discount rate for outcomes. Conclusion These updated analyses, based on more mature trial data with a minimum follow-up of 5 years, generate more favorable ICERs versus the previously submitted HTA assessments that resulted in approval of nivolumab for patients with previously treated NSCLC in Canada and Sweden.

ObjectiveOur objective was to evaluate the cost effectiveness of the combination of nivolumab and ipilimumab, referred to as “Regimen”, as a first-line treatment for patients with advanced melanoma from the perspective of Canada’s public healthcare system.MethodsWe developed a partitioned-survival model (progression-free survival, post-progression survival, and death) to determine the clinical and economic outcomes of immunotherapy for advanced melanoma over a 20-year time horizon. Regimen was compared with nivolumab, ipilimumab, and pembrolizumab. Two treatment durations for pembrolizumab were considered: (1) maximum of 24 months or until progression or (2) no maximum duration, until progression. The model used data from CheckMate-067 (28 months’ follow-up) for treatments involving nivolumab and ipilimumab. The efficacy of pembrolizumab was estimated using indirect comparisons. A scenario looking at the cost of subsequent treatments following disease progression was examined.ResultsRegimen had better outcomes and was cost effective compared with all other immunotherapies at a threshold of $CAN100,000 per quality-adjusted life-year (QALY) gained. Compared with nivolumab and ipilimumab, the incremental cost-effectiveness ratios (ICERs) were $CAN47,119 and 66,750 per QALY, respectively. Compared with pembrolizumab with a treatment duration cap, the ICER was $CAN85,436. When assuming no duration cap, Regimen dominated pembrolizumab. With the inclusion of subsequent treatment costs following progression, Regimen’s ICER improved compared with all other comparators.ConclusionsDespite the advent of effective new therapies for advanced melanoma, prognosis remains poor for some patients. Compared with other immunotherapies, Regimen offers marked benefit and may be a cost-effective treatment option.Electronic supplementary materialThe online version of this article (10.1007/s41669-018-0112-1) contains supplementary material, which is available to authorized users.