An Early Cost-Utility Model of mRNA-Based Therapies for the Treatment of Methylmalonic and Propionic Acidemia in the United Kingdom.

BACKGROUND AND OBJECTIVE: Novel messenger RNA (mRNA)-based therapies, currently in development, are emerging as a promising potential treatment modality for a broad range of life-threatening and life-limiting inherited liver diseases, including methylmalonic acidemia (MMA) and propionic acidemia (PA). However, owing in part to their complexity, they are likely to come at considerable financial cost to healthcare systems. The objective of this research was to synthesize available evidence on the costs and clinical consequences associated with MMA and PA for the purpose of exploratory economic evaluation of novel mRNA-based therapies using an early cost-utility model from the United Kingdom payer perspective. METHODS: A Markov model was constructed to simulate the costs and outcomes associated with novel mRNA therapies, compared with a combination of dietary management and organ transplantation (standard of care) among hypothetical cohorts of new-born patients with MMA and PA. Key model drivers were identified, and a price threshold analysis was performed to estimate value-based price ranges for future mRNA therapies given willingness-to-pay thresholds for orphan diseases. RESULTS: mRNA therapy was associated with an additional 5.7 and 1.3 quality-adjusted life-years (QALYs) gained per patient lifetime among patients with MMA and PA, respectively. Key drivers of cost-effectiveness were relative improvement in utility among patients who receive mRNA-based therapy and transplantation, and the cost of mRNA therapy. Assuming a willingness to pay range of £100,000-£300,000 per QALY gained, the model demonstrated mRNA therapy to be cost-effective in MMA and PA at an annual treatment cost of £70,452-£94,575 and £31,313-£36,695, respectively. CONCLUSIONS: Despite the lack of a strong evidence base in MMA and PA, this model provides a useful tool to estimate the cost-effectiveness, and inform value-based pricing, of new mRNA-based therapies. Our analyses also identified areas for research that will have the greatest value in reducing uncertainty in future health economic evaluations of such treatments.

An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand.

BACKGROUND: Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. METHOD: A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. RESULTS: The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. CONCLUSION: At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem.

Cost-effectiveness of liver transplantation in methylmalonic and propionic acidemias.

Propionic acidemia (PA) and classical methylmalonic acidemia (MMA) are rare inborn errors of metabolism that can cause early mortality and significant morbidity. The mainstay of disease management is lifelong protein restriction. As an alternative, liver transplantation (LT) may improve survival, quality of life, and prevent further neurological deterioration. The aim of our study was to estimate the incremental costs and outcomes of LT versus nutritional support in patients with early-onset MMA or PA. We constructed a Markov model to simulate and compare life expectancies, quality-adjusted life years (QALYs), and lifetime direct and indirect costs for a cohort of newborns with MMA or PA who could either receive LT or be maintained on conventional nutritional support. We conducted a series of 1-way and probabilistic sensitivity analyses. In the base case, LT on average resulted in 1.5 more life years lived, 7.9 more QALYs, and a savings of $582,369 for lifetime societal cost per individual compared to nutritional support. LT remained more effective and less costly in all 1-way sensitivity analyses. In the probabilistic sensitivity analysis, LT was cost-effective at the $100,000/QALY threshold in more than 90% of the simulations and cost-saving in over half of the simulations. LT is likely a dominant treatment strategy compared to nutritional support in newborns with classical MMA or PA.

Tandem mass spectrometry and newborn screening: pilot data and review.

United States legislatures are debating whether to use tandem mass spectrometry to expand the roster of inherited disorders tested in newborn screening programs. The debate is hampered because published financial data comparing charges associated with late vs early diagnosis are not readily available. We provide pilot financial data comparing late diagnosis vs presumptive diagnosis and early management taken from consecutive patients with propionic acidemia diagnosed from 1995-1998 in New Hampshire. We extrapolated from these data and the incidence of treatable inborn errors of metabolism to estimate the projected yearly savings of critical care charges if expanded newborn screening were instituted. We conclude that institution of expanded screening will bring diminished morbidity and large savings in yearly chronic care and critical care charges.