Table 2.

Unanswered questions despite FDA approval of Lygenia and Casgevy

Patient characteristics

•Do results apply to individuals with HbSC disease? •What are the outcomes for individuals age >38 years? •Is Casgevy equally effective in individuals with baseline HbF >15%? •What is the appropriateness of therapy for individuals with a remote history of VOE that are currently doing well on disease-modifying therapy? •Should bone marrow evaluations or peripheral blood next-generation sequencing be performed on every patient before gene therapy to investigate pre-existing myeloid malignancy features? If so, what threshold would exclude a participant from therapy? •Does Casgevy pose any risks to patients with 2 or more α-globin gene deletions? •Should patients with a matched sibling donor be offered gene therapy?

Disease pathology

•What level of HbF and/or HbAT87Q is protective for primary and secondary stroke prevention? •What are the long-term organ specific effects (i.e., brain, lungs, heart, kidney, bone health) after gene therapy? •What happens to pain after gene therapy? Are patients able to wean pharmacologic therapies used for pain management, and if so, what is the expected time course? •What changes, if any, are there to the underlying thrombotic risk posed by SCD?

Access and logistics

•Will patients be able to afford the cost for drug product and the associated care? •How much will insurance cover? •Will patients have access to a qualified treatment center in their state? •Will patients be able to cross state lines to access a qualified treatment center and have it covered by insurance? •The majority of SCD centers did not participate in a clinical trial for gene therapy. How will these centers acquire the skills and resources necessary to provide these therapies? •Will patients have access to fertility preservation and cryopreservation? •Will patients have access and/or financial support to undergo fertility care in the future? •Will patients have access to the mental health resources needed before and after gene therapy? •How will patients continue to receive optimal care if they move states or out of the county in the 15 year follow-up period?

HbF, fetal hemoglobin; SCD, sickle cell disease; VOE, vaso-occlusive event.