RESUMO
Background: NICE in England, and ICER in the US both use cost-utility analyses (CUA) and budget impact analyses (BIA) to assess value for money and affordability, however the thresholds used differ greatly. Objective: To perform a cross-country comparison of the results of the CUA and BIA and detail the implications for reimbursed price and volumes, for a novel gene therapy for Parkinson's disease (PD). Methods: A Markov model was built to perform country-specific CUAs and BIAs Findings: The US ceiling price identified through CUA is ~ 1.8 times higher than in England (aligning to our previous US/UK price comparison analysis of high-cost drugs). However, the net budget impact corresponding to these price levels would limit number of patients treated in order not to exceed the BIA threshold. Performance-based annuity payments can increase patient access at launch without exceeding the thresholds while reducing payers' data uncertainty. Conclusion: Our cost-utility analysis in PD shows a difference in price potential between the US and England that aligns with what is observed in practice for other high-cost drugs. Furthermore, the budget impact threshold operational in England imposes a greater downwards pressure on price and/or volumes than the one applied by ICER in the US.
RESUMO
Catalase-peroxidase is a multi-functional heme-dependent enzyme which is well known for its ability to carry out both catalatic and peroxidatic reactions. Catalase-peroxidase from Mycobacterium tuberculosis(mtCP) is of particular interest because this enzyme activates the pro-antitubercular drug isoniazid. It is estimated that 2 billion people are infected with M. tuberculosis, the principal causative agent of tuberculosis, and that 2 million people die from the disease each year. The rise of drug-resistant strains continues to be of critical concern and it is well documented that mutations which reduce activity or inactivate mtCP lead to increased levels of isoniazid resistance in M. tuberculosis. The recent determination of the crystal structure for M. tuberculosis mtCP has aided the understanding of how the enzyme functions and provides a three-dimensional framework for testing hypotheses about the roles of various residues in the active site. Here we report site-directed mutagenesis studies of three conserved residues located near the heme of mtCP, His-108, Trp-107 and Trp-321 including the construction of the double mutant W107F-W321F. Resulting mutants have been purified and their catalatic and peroxidatic activities have been determined. Data are compared in the context of related studies aimed at dissecting the roles of these residues in the different activities of the enzyme. Analyses of single and double mutants studied here emphasise that the hydrogen bonding network surrounding the heme in the active site appears more important for maintenance of catalatic rather than peroxidatic activity in CP enzymes.
