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.