“I am excited to see how future developments in hemophilia will fit into or change our current thinking,” said Gerard Dolan, MD, Consultant Hematologist, University of Nottingham and Chair of the first medical plenary at the WFH 2018 World Congress in Glasgow. Dolan introduced John Pasi, MD, Professor of Haemostasis and Thrombosis at the Royal London Hospital who led the session on how upcoming hemophilia treatments will raise new questions and considerations for patients, providers and payers.
Extended half-life (EHL) products have the potential to reduce the frequency of infusions required to maintain factor to the trough levels achieved with standard half-life products. Pasi highlighted the potential safety issue with PEGylated proteins in EHL treatments. “Polyethylene glycol (PEG) is generally not easily biodegradable, it is either metabolized by oxidization of alcohol groups or by urinary clearance,” stated Pasi. “Metabolism by these mechanisms can in theory pose toxicity problems.” However, PEG has a large therapeutic index and there have not been any safety signals in clinical trials to strongly suggest cause for concern.
EHL factor VIII products have demonstrated positive results for mean annualized bleed rate (ABR) in clinical trials. There is no doubt that EHL factor VIII products are efficacious in a prophylactic setting, but variations in clinical trial design make it difficult to compare one product to another. Similarly, variations in study design of EHL factor IX (FIX) therapies have hindered their comparison. For example, the recombinant FIX Fc fusion protein trial was designed around maintaining trough levels while altering the dose or the frequency of infusion accordingly. In contrast, the FIX albumin fusion protein study initially used fixed-interval dosing and then adjusted depending on clinical response.
“Clearly these treatments have to be marketed and priced, and without head-to-head comparisons it is important to use health economics,” declared Pasi. “Is there a simple multiplier we can use, or is it more complicated?” Pasi carried out a speculative study with the hypothesis that treatment frequency will be the driver of choice. He looked at relative potential cost modelling using a lower frequency, same trough levels and same accepted ABRs for a severe hemophilia A patient. “Although the results were limited by their hypothetical nature, this model reinforced the belief in most healthcare economy settings that use is likely to be heavily influenced by cost,” said Pasi. “Furthermore, significant price differences between standard and extended half-life therapies could strongly influence choice and treatment options that are available in some health economies.”
Pasi wondered about patient selection for new generation EHL products. People who find treatment burden difficult and those requiring higher trough levels are potential candidates, but in reality, everyone has something to gain from EHL therapies. “With the evidence base and the ability to individualize, we can offer a good, cheap and fast-acting product,” stated Pasi.
Emerging therapies such as bispecific antibodies, RNA silencing therapy, anti-tissue factor pathway inhibitor and gene therapy will completely change the market again. Pasi said, “Comprehensive, comparable data are required. Safety is always the most important factor, but novel therapies provide an exciting and transformational opportunity for the future.”