The Cost of Biotech Innovation: Exploring Research and Development Costs of Cell and Gene Therapies.

BACKGROUND: Clinical development paradigms for cell and gene therapies appear to be different to those of more conventional treatments: therefore, it is informative to explore this from the perspective of investments required to bring a new cell and/or gene therapy to the market. While there are a number of studies in the literature analyzing clinical-stage R&D costs for novel therapeutics, these are 'modality-agnostic' and thus do not elucidate costs specifically for the emerging class of cell and gene therapies. OBJECTIVES: The objective of this study was to understand the research and development (R&D) costs associated with the clinical development of new cell and gene therapy assets METHODS: As part of our analysis of clinical-stage R&D costs for cell and gene therapies, we focused our efforts on cell and gene therapy assets recently approved by the US Food and Drug Administration (FDA) or expected to receive FDA approval by the end of 2024. A total of 25 therapies were identified for the study, 11 of which had sufficient level of detail for our clinical-stage R&D costing study. We calculated the clinical-stage R&D costs to bring a new cell and/or gene therapy to the market following a three-step approach, starting with (1) calculation of the out-of-pocket investment reported in US SEC reports; (2) we adjusted these figures for the risk of failure by applying a clinical trial phase-dependent attrition risk rate; (3) we accounted for the cost of capital of 10.5%. RESULTS: After accounting for R&D attrition rate (i.e., costs of failed programs) and applying a cost of capital at 10.5%, we estimate that the clinical-stage R&D investment required to bring a new cell and/or gene therapy to market is US$1943 M (95% CI US$1395 M, US$2490 M). CONCLUSION: This knowledge can inform financial planning for biopharma companies looking to enter the space and inform policy makers within the context of the commercialization and pricing of such therapies.

Pricing and Market Access Challenges in the Era of One-Time Administration Cell and Gene Therapies.

With a large number of one-time administration cell and gene therapies expected to come to the market in the coming years, there is a renewed need to understand the existing and future challenges that such modalities bring about, especially as it relates to their assessment of value, pricing and access. Payer, health technology assessment (HTA) bodies and manufacturers alike are faced with a number of unprecedented challenges stemming from the fact that such therapies are 'one-time' and/or have curative intent, but often lack sufficient evidence to support such claims at the time of launch (i.e., during pricing and access negotiations). There are a number of different approaches to assessing economic value for cell and gene therapies across regions (e.g., US vs Europe), which ultimately lead to further disconnect in pricing and reimbursement outcomes across countries; yet, in many cases, affordability concerns relating to high upfront costs are raised by providers. To that end, cell and gene therapies have been frequently criticized by payers for their 'high sticker price' based on relatively limited evidence to support durability claims. New contracting solutions are increasingly being employed to overcome concerns specifically relating to the durability of clinical benefit, the comparative effectiveness of a therapy and affordability (i.e., the one-time high cost of therapy). Indeed, recent launches of cell and gene therapies have often leveraged outcome-based agreements, instalments, coverage with evidence generation, subscription models, stop-loss and payer reinsurance, etc. to mitigate concerns from payers and providers and drive access. In this paper, we aim to review challenges for cell and gene therapies from a pricing and access perspective and explore the growing role of innovative contracting solutions to overcome aforementioned challenges.

Evolution of pattern of injury and quantitative MRI on days 1 and 3 in term newborns with hypoxic-ischemic encephalopathy.

BACKGROUND: Brain injury in term neonatal hypoxic-ischemic encephalopathy (HIE) emerges on magnetic resonance imaging (MRI) by day 3. This study aimed to address the relationship of MRI, diffusion tensor imaging (DTI), and MR spectroscopic imaging (MRSI) findings on days 1 and 3 in a prospective cohort of term newborns with HIE. METHODS: A total of 24 term newborns with HIE were prospectively studied with MRI on days 1 and 3; 19 were imaged with DTI and MRSI on days 1 and 3. MRI was assessed using validated scores. The relationship between MRI, DTI, and MRSI values on days 1 and 3 was determined using linear regression for repeated measures. RESULTS: Conventional MRI showed a complex variation of findings from day 1 to 3. In gray matter, mean diffusivity (Dav) and metabolite ratios measured on day 1 were predictive of values on day 3 (all P ≤ 0.04). In white matter, Dav, fractional anisotropy (FA), and N-acetylaspartate (NAA)/choline on days 1 and 3 were strongly related (all P ≤ 0.003). Hypothermia appeared to attenuate the severity and progression of brain injury in the six treated newborns. CONCLUSION: In term newborns with HIE, quantitative MR values on days 1 and 3 are strongly associated, providing an objective measure of injury before qualitative images.

Agonist-evoked inositol trisphosphate receptor (IP3R) clustering is not dependent on changes in the structure of the endoplasmic reticulum.

The size and number of IP3R (inositol 1,4,5-trisphosphate receptor) clusters located on the surface of the ER (endoplasmic reticulum) is hypothesized to regulate the propagation of Ca2+ waves in cells, but the mechanisms by which the receptors cluster are not understood. Using immunocytochemistry, live-cell imaging and heterologous expression of ER membrane proteins we have investigated IP3R clustering in the basophilic cell line RBL-2H3 following the activation of native cell-surface antigen receptors. IP3R clusters are present in resting cells, and upon receptor stimulation, form larger aggregates. Cluster formation and maintenance required the presence of extracellular Ca2+ in both resting and stimulated cells. Using transfection with a marker of the ER, we found that the ER itself also showed structural changes, leading to an increased number of 'hotspots', following antigen stimulation. Surprisingly, however, when we compared the ER hotspots and IP3R clusters, we found them to be distinct. Imaging of YFP (yellow fluorescent protein)-IP3R transfected in to living cells confirmed that IP3R clustering increased upon stimulation. Photobleaching experiments showed that the IP3R occupied a single contiguous ER compartment both before and after stimulation, suggesting a dynamic exchange of IP3R molecules between the clusters and the surrounding ER membrane. It also showed a decrease in the mobile fraction after cell activation, consistent with receptor anchoring within clusters. We conclude that IP3R clustering in RBL-2H3 cells is not simply a reflection of bulk-changes in ER structure, but rather is due to the receptor undergoing homotypic or heterotypic protein-protein interactions in response to agonist stimulation.