Transplantation as disease modifying therapy in the era of gene therapy medicinal products - health policy considerations.

Transplantation in patients with inherited metabolic diseases [IMDs] can be used as supportive therapy or as disease modifying therapy to alter the disease course or even provide cure. Data have suggested that transplantation as a disease modifying therapy for patients with IMDs is underutilized [] and this is particularly a problem in adults []. There is a new variable to consider in the form of novel gene therapy medicinal products [GTMP] as patients and clinicians may delay transplantation, hoping these GTMP will provide a safer alternative. These diverse therapies may be one-time treatments, such as addition of a target gene or gene editing, or ongoing RNA based therapies which stimulate or silence target gene expression or provide direct expression of an enzyme to function as enzyme replacement therapy. Clinical trials test GTMP against medical management but, in some conditions, LTx is a more appropriate comparator as both modalities offer potential for significant disease modification or even cure. We discuss the role of liver [LTx] transplantation in the era of rapidly advancing GTMP, focusing on four IMDs for which human data on GTMP are available [glycogen storage disease type 1a [GSD1a; OMIM 232,200], mut methylmalonic acidemia [MMA; OMIM 251,000], propionic acidemia [PA; OMIM 606,054], and urea cycle defects [UCD]. Even though few GTMPs are currently available outside the clinical trial setting, we feel this discussion is timely, as patients and physicians are already considering upcoming GTMP when making decisions on LTx. Similarly, health policy makers must make decisions on which GTMPs should be reimbursed and for which patients. We review information on efficacy and safety of LTx and GTMP from the health policy perspective and discuss challenges such as limitations in available data, access and opportunity costs related to these therapies. We highlight challenges faced by the adult population but do not focus solely on adults as the challenges facing health policy makers require consideration of all age groups to avoid creating inequity in allocation of resources. LTx is a highly invasive procedure with short and long term complications typically performed in patients with end-stage liver disease or liver cancer which impacts outcomes. However, even with these caveats, transplantation outcomes are good, with a 1-year survival of 90% in children and 88% in adults and a 10 year survival of 84 and 62% respectively []. The data in adults in the 18–45 age range [more relevant to the adult IMD population] are even better with 1 year survival is 90% and 10 year survival 74%] in patients transplanted for all indications []. Quality of life following liver transplantation approaches that of the general population and remains superior to the preoperative status up to 20 years post LTx [].