How to discuss gene therapy for haemophilia? A patient and physician perspective.

Wolfgang Miesbach,Mike Makris,Brian O’Mahony,Nigel S Key

doi:10.1111/hae.13769

Abstract

Gene therapy has the potential to revolutionise treatment for patients with haemophilia and is close to entering clinical practice. While factor concentrates have improved outcomes, individuals still face a lifetime of injections, pain, progressive joint damage, the potential for inhibitor development and impaired quality of life. Recently published studies in adeno‐associated viral (AAV) vector‐mediated gene therapy have demonstrated improvement in endogenous factor levels over sustained periods, significant reduction in annualised bleed rates, lower exogenous factor usage and thus far a positive safety profile. In making the shared decision to proceed with gene therapy for haemophilia, physicians should make it clear that research is ongoing and that there are remaining evidence gaps, such as long‐term safety profiles and duration of treatment effect. The eligibility criteria for gene therapy trials mean that key patient groups may be excluded, eg children/adolescents, those with liver or kidney dysfunction and those with a prior history of factor inhibitors or pre‐existing neutralising AAV antibodies. Gene therapy offers a life‐changing opportunity for patients to reduce their bleeding risk while also reducing or abrogating the need for exogenous factor administration. Given the expanding evidence base, both physicians and patients will need sources of clear and reliable information to be able to discuss and judge the risks and benefits of treatment.

Highlights

While factor concentrates have improved out‐ comes, individuals still face a lifetime of injections, pain, progressive joint damage, the potential for inhibitor development and impaired quality of life
In making the shared decision to proceed with gene therapy for haemophilia, physicians should make it clear that research is ongoing and that there are remaining evidence gaps, such as long‐term safety profiles and duration of treatment effect
The eligibility criteria for gene therapy trials mean that key patient groups may be excluded, eg children/adolescents, those with liver or kidney dysfunction and those with a prior history of factor inhibitors or pre‐existing neutralising associated viral (AAV) antibodies

Summary

Introduction

Recombinant AAV only rarely integrates into host DNA,[8] minimising the potential for genotoxicity.[7] Based on relatively limited data from 35 partici‐ pants, one of the main adverse events that was observed in 17 of 35 participants (48.6%) across all trials was transient alanine aminotransferase (ALT) elevations (Table 3), which has been observed in previous GT trials utilising intramuscular injection.[25] While ALT elevations are not a safety issue per se, as these events were generally asymptomatic and were treated with a course of corticosteroids, in some cases they have been associated with a reduction in factor activity (Table 3).[18,20,21,22,23] ALT eleva‐ tions, along with worse than expected FIX activity,[26] resulted in the discontinuation of AAVrh10FIX (DTX101) a candidate therapy for haemophilia B.

Results

Conclusion