Main findings on clinical benefit and remaining issues in hemophilia gene therapy
| Various outcomes and aspects of gene therapy . | Findings in favor of gene therapy . | Remaining issues of gene therapy . |
|---|---|---|
| Clinical benefit | Great clinical benefit in most patients: Reduction of bleeding and cessation of prophylaxis for patients after a single IV infusion of AAV-based gene therapy | Uncertainty about the long-term efficacy |
| Eligibility of patients | Treatment of both hemophilia A and B patients | Not available for patients with AAV antibodies, with liver disease, children, and with severe comorbidity |
| Expression levels | Factor levels sufficient to reduce bleeding and stopping prophylaxis in a large majority of patients | Variability in expression levels of FVIII and FIX, from 0 to >200 IU/dL; reason for variability with similar gene constructs is yet unknown |
| Durability | Stable expression in FIX based gene therapy for over 8 y; despite reduction of FVIII levels over time, duration of clinical response at least 4 y | Limited durability of expression in hemophilia A in the only study with long-term data after 4 y; some patients lose expression early because of immune response; unknown why expression levels of FVIII decrease over time |
| Antibodies against factor VIII and FIX | None reported thus far | Patients with a history of inhibitors have been excluded from phase 1-3 trials |
| Toxicity | Limited infusion-related toxicity | Some patients experience infusion-related reactions, including fever and hypotension; unexplained liver function abnormalities in around 30% of patients, not only related to short-term immune response but also >3 mo after infusion, requiring corticosteroid treatment; in AAV based trials in other genetic disorders severe hepatic toxicity with very high vector doses |
| Immune response | In a minority of patients, depending upon vector dose and construct, leading to ALT elevation, but in most cases well responding to corticosteroids preventing decline of factor levels | If not treated appropriately and timely this may lead to reduction of FVIII and FIX levels and even failure of therapy; some gene therapy programs use prophylactic corticosteroids and other immunosuppressive therapy to prevent liver function abnormalities |
| Availability | Studies are performed in various countries in Europe, United States, and Asia | Thus far available only in centers with gene therapy study expertise; gene therapy will not be available for many patients in the world because of logistic reasons and high costs |
| Costs | May be cost-effective by reducing the need for prophylaxis with expensive long-term factor concentrate | Expected high costs for one single treatment, although exact costs are yet unknown |
| Safety | Limited integration of AAV, mainly episomal located | Integration does occur in the host genome. Potential of developing malignancy and association with malignancy should be investigated |
| Redosing | May be possible in the future with non–AAV-based gene therapy | Not possible with similar AAV-based technology because of high and persistent AAV antibodies after gene therapy |
| Various outcomes and aspects of gene therapy . | Findings in favor of gene therapy . | Remaining issues of gene therapy . |
|---|---|---|
| Clinical benefit | Great clinical benefit in most patients: Reduction of bleeding and cessation of prophylaxis for patients after a single IV infusion of AAV-based gene therapy | Uncertainty about the long-term efficacy |
| Eligibility of patients | Treatment of both hemophilia A and B patients | Not available for patients with AAV antibodies, with liver disease, children, and with severe comorbidity |
| Expression levels | Factor levels sufficient to reduce bleeding and stopping prophylaxis in a large majority of patients | Variability in expression levels of FVIII and FIX, from 0 to >200 IU/dL; reason for variability with similar gene constructs is yet unknown |
| Durability | Stable expression in FIX based gene therapy for over 8 y; despite reduction of FVIII levels over time, duration of clinical response at least 4 y | Limited durability of expression in hemophilia A in the only study with long-term data after 4 y; some patients lose expression early because of immune response; unknown why expression levels of FVIII decrease over time |
| Antibodies against factor VIII and FIX | None reported thus far | Patients with a history of inhibitors have been excluded from phase 1-3 trials |
| Toxicity | Limited infusion-related toxicity | Some patients experience infusion-related reactions, including fever and hypotension; unexplained liver function abnormalities in around 30% of patients, not only related to short-term immune response but also >3 mo after infusion, requiring corticosteroid treatment; in AAV based trials in other genetic disorders severe hepatic toxicity with very high vector doses |
| Immune response | In a minority of patients, depending upon vector dose and construct, leading to ALT elevation, but in most cases well responding to corticosteroids preventing decline of factor levels | If not treated appropriately and timely this may lead to reduction of FVIII and FIX levels and even failure of therapy; some gene therapy programs use prophylactic corticosteroids and other immunosuppressive therapy to prevent liver function abnormalities |
| Availability | Studies are performed in various countries in Europe, United States, and Asia | Thus far available only in centers with gene therapy study expertise; gene therapy will not be available for many patients in the world because of logistic reasons and high costs |
| Costs | May be cost-effective by reducing the need for prophylaxis with expensive long-term factor concentrate | Expected high costs for one single treatment, although exact costs are yet unknown |
| Safety | Limited integration of AAV, mainly episomal located | Integration does occur in the host genome. Potential of developing malignancy and association with malignancy should be investigated |
| Redosing | May be possible in the future with non–AAV-based gene therapy | Not possible with similar AAV-based technology because of high and persistent AAV antibodies after gene therapy |