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.

Patent Cliffs in the Era of Complex Therapies and Biologics.

INTRODUCTION: The rise of new product classes such as biologics and complex molecules over the past two decades have brought to light some of the unique market dynamics that such products face. While we have seen and experienced the inception, growth and expansion phase of such products, the ongoing incumbent decline due to loss of exclusivity (LoE) is yet to be fully experienced. This raises the question of how one may go about modelling such a scenario given that forecasting the expected erosion curves accurately can ensure full brand value is retained for pharmaceutical companies. OBJECTIVES: This research looks to analyze the 'patent cliff' across varying product classes and, in doing so, understand the drivers behind the different market dynamics post-LoE for traditional molecules, complex molecules and biologics. METHODS: An extensive list of molecules across various therapeutic areas succumbing to loss of patent exclusivity between 2014 and 2019 were categorized according to product class, and sales data were analyzed to reveal trends across different product classes. RESULTS: The analysis of sales behavior of these compounds revealed distinct tendencies in terms of sales erosion across the various product classes. The largest determinant for the behaviour of a prescription drug post-LoE is the degree of generic competition, which in turn is primarily influenced by the barriers to entry. This research details some of the key challenges relating to regulatory, legal and manufacturing aspects that distinguish biologics and complex molecules from traditional small molecules and ultimately lead to different market dynamics post-LoE. CONCLUSIONS: Unlike for traditional small-molecule generics where originator manufacturers have limited options to fend off generics, the greater degree of 'brand-brand' competitive dynamics seen in the biologics and complex generics space allows manufacturers of originators to protect market share. This analysis represents a meaningful addition to understanding LoE across various class types and thus highlights the importance of strategic decision making that pharmaceutical companies need to take at LoE.

An Accessible Method for DFT Calculation of 11B NMR Shifts of Organoboron Compounds.

The study of boron-mediated reactions in organic synthesis and reactions of organoboron compounds is greatly facilitated by the use of 11B NMR. However, the identification and characterization of reaction intermediates in often complex systems is far from trivial, as 11B NMR does not provide any detailed structural information. Greater insight into the structures present in such systems can be obtained by using DFT chemical shift calculations to support or exclude proposed reaction intermediates. In this article, we report a rapid and accessible approach to the calculation of 11B NMR shifts that is applicable to a wide range of organoboron compounds.

Mechanistic insights into boron-catalysed direct amidation reactions.

The generally accepted monoacyloxyboron mechanism of boron-catalysed direct amidation is brought into question in this study, and new alternatives are proposed. We have carried out a detailed investigation of boron-catalysed amidation reactions, through study of the interaction between amines/carboxylic acids and borinic acids, boronic acids and boric acid, and have isolated and characterised by NMR/X-ray crystallography many of the likely intermediates present in catalytic amidation reactions. Rapid reaction between amines and boron compounds was observed in all cases, and it is proposed that such boron-nitrogen interactions are highly likely to take place in catalytic amidation reactions. These studies also clearly show that borinic acids are not competent catalysts for amidation, as they either form unreactive amino-carboxylate complexes, or undergo protodeboronation to give boronic acids. It therefore seems that at least three free coordination sites on the boron atom are necessary for amidation catalysis to occur. However, these observations are not consistent with the currently accepted 'mechanism' for boron-mediated amidation reactions involving nucleophilic attack of an amine onto a monomeric acyloxyboron intermediate, and as a result of our observations and theoretical modelling, alternative proposed mechanisms are presented for boron-mediated amidation reactions. These are likely to proceed via the formation of a dimeric B-X-B motif (X = O, NR), which is uniquely able to provide activation of the carboxylic acid, whilst orchestrating the delivery of the amine nucleophile to the carbonyl group. Quantum mechanical calculations of catalytic cycles at the B3LYP+D3/Def2-TZVPP level (solvent = CH2Cl2) support the proposal of several closely related potential pathways for amidation, all of which are likely to be lower in energy than the currently accepted mechanism.

Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts.

Amidation of unprotected amino acids has been investigated using a variety of 'classical" coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.

Enantioselective transformation of fluoxetine in water and its ecotoxicological relevance.

European legislation focusing on water quality is expected to broaden to encompass several pharmaceuticals as priority hazardous substances. This manuscript aims to challenge current regulatory approaches that do not recognize stereochemistry of chiral pharmaceuticals by testing the hypothesis that environmental transformation and effects of chiral pharmaceuticals are stereoselective. Our experiments revealed that, while degradation of chiral fluoxetine (FL) in river water occurs via non-enantioselective photochemical and mildly-enantioselective microbial processes favoring the (R)-enantiomer, a pronounced enantioselectivity favoring (S)-FL (leading to the formation of (S)-NFL (norfluoxetine)) is observed during activated sludge treatment. Toxicity tests proved strong enantiomer-specific toxicity in the case of Tetrahymena thermophila, protozoa that are utilized during activated sludge treatment ((R)-FL is 30× more toxic than (S)-FL; (S)-NFL is 10× more toxic than (S)-FL). This is of paramount importance as preferential degradation of (S)-FL in activated sludge microcosms leads to the enrichment of FL with 30× more toxic (R)-FL and formation of 10× more toxic (S)-NFL. It is commonly assumed that a decreased concentration of FL leads to decreased biological impact. Our study proves that despite the overall decrease in FL concentration, accumulation of toxic (R)-FL and formation of toxic (S)-NFL leads to much higher than presumed toxicological effects.

Borate esters: Simple catalysts for the sustainable synthesis of complex amides.

Chemical reactions for the formation of amide bonds are among the most commonly used transformations in organic chemistry, yet they are often highly inefficient. A novel protocol for amidation using a simple borate ester catalyst is reported. The process presents significant improvements over other catalytic amidation methods in terms of efficiency and safety, with an unprecedented substrate scope including functionalized heterocycles and even unprotected amino acids. The method was used to access a wide range of functionalized amide derivatives, including pharmaceutically relevant targets, important synthetic intermediates, a catalyst, and a natural product.

Direct amidation of unprotected amino acids using B(OCH2CF3)3.

A commercially available borate ester, B(OCH2CF3)3, can be used to achieve protecting-group free direct amidation of α-amino acids with a range of amines in cyclopentyl methyl ether. The method can be applied to the synthesis of medicinally relevant compounds, and can be scaled up to obtain gram quantities of products.