The Reality of Gene Therapy
While the hope of gene therapy is curative treatment, the reality is otherwise. As shown in table 1, currently approved treatments are not curative.9,11,12,24,25 Even if not curative, a reduced burden of medication administration and a “bleed-free” mindset would still be beneficial.26 Unfortunately, as judged by the ABR in phase 3 studies, the bleed reduction benefits of gene therapy are marginal. Both hemophilia A and B phase 3 studies showed a dramatic drop in bleeding rates compared to the lead-in period.24,25However, none of the subjects in the hemophilia A study were treated with Emicizumab or Efanesoctocog Alfa during the lead-in. When compared to previous investigations, the ABR for hemophilia A gene therapy was marginally better than Emicizumab and actually higher than Efanesoctocog Alfa.11,12,24,25 For hemophilia B, only 57% of the subjects were treated with an enhanced half-life (EHL) factor IX product during the lead-in, and the ABR for gene therapy compared to EHL factor IX was the same.9,25
Both phase 3 gene therapy trials achieved hemostatic levels and reduced factor replacement after treatment. However, the factor levels achieved were highly variable and unpredictable.24,25 Some patients did not respond at all, while others achieved supratherapeutic levels. In addition, there were differences in sustainability that impact the risk/benefit assessment. In the hemophilia B study, 52 of the 54 subjects were able to achieve a mean factor IX activity above baseline of 36 IU/dL at 6 months and dropped minimally by 18 months to 34 IU/dL above baseline.25 Based on this, it has been estimated that >80% of subjects will maintain factor IX level >2% at 25 years post treatment.27 In contrast, factor VIII expression was not sustained in the hemophilia A study with an estimated median factor VIII activity of 6 IU/dL by 5 years after treatment. Within 2 years of treatment roughly one-fourth of subjects had factor levels less than 5 IU/dL, 5 of whom resumed prophylaxis.24 Preliminary results of other hemophilia A gene therapy trials with AAV are also demonstrating non-sustained factor VIII expression.28
Neither phase 3 study described treatment strategies used for surgical procedures. Based on the mean factor levels achieved, it is anticipated that a sizable proportion of subjects will still need factor replacement for surgical procedures.
The principal toxicity reported in both studies was elevated transaminases due to liver inflammation (hepatitis). Again, there were significant differences in toxicity between hemophilia A and B gene therapy. For the hemophilia B trial, 17% of subjects were treated with glucocorticoids due to elevated liver aminotransferase levels for a mean duration of 11 weeks.25 Whereas 89% of subjects in the hemophilia A trial had elevated transaminases and were treated with glucocorticoids for a mean of 35 weeks. Subjects were also treated with Tacrolimus (18%) and Mycophenolate (10%). Three subjects in the hemophilia A trial developed serious adverse events attributed to glucocorticoids.24
In summary, the principal benefit of AAV gene therapy seen thus far is not a dramatic reduction in bleeding risk, but the need for frequent medication administration. Thus, gene therapy provides an added measure of convenience and potentially reduced cost. For hemophilia B, this benefit may outweigh the known risks described in the clinical trials. For hemophilia A, this is less clear. However, there may be additional risk to hemophilia gene therapy with AAV vectors that were not evident in the clinical trials.