Hemophillia Gene Therapy

1. RECENT DATA On Gene
Therapy for Hemophilia A

2. About Hemophilia A
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Hemophilia A, also called factor VIII deficiency or
hemophilia, is an X-linked genetic disorder caused by
missing or defective factor VIII, a clotting protein.
Although it is most-commonly passed down from parents to
children, about 1/3 of cases are caused by a spontaneous
mutation, a new mutation that was not inherited.
Approximately 1 in 10,000 people have Hemophilia A.

3. STUDY RUNDOWN
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Severe hemophilia A, characterized by factor VIII activity <1
international unit (IU)/dL, causes soft tissue bleeding and
hemophilic arthropathy.
Existing prophylactic therapies have improved these
outcomes, but breakthrough hemorrhages still occur.

4. CURRENT THERAPY – FACTOR VIII
CONCENTRATE
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The standard of care for adults with severe hemophilia A is a
prophylactic regimen of replacement factor VIII infusions
administered intravenously up to two to three times per week, or
100 to 150 infusions per year.
Despite these regimens, many people continue to experience
breakthrough bleeds, resulting in progressive and debilitating
joint damage, which can have a major impact on their quality of
life.

5. REPLACEMENT THERAPY - EMICIZUMAB
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Emicizumab is an approved antibody based therapy is designed
to prevent bleeding by mimicking he activity of factor VIII protein.
The therapy administered by subcutaneous weekly injections.
FDA approved drug
It is also approved in india as Prophylactic treatment to reduce
the frequency of bleeding episodes.
Given as loading dose at 3mg/kg once per week for 4 weeks
Thereafter give maintenance dose at 1.5mg/kg once weekly or
3mg/kg every 2 weeks

6. OBJECTIVE
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The gene therapy was given as a one-time infusion
and endpoints were assessed at 49 to 52 weeks after treatment.
It was found that participants achieved an elevated endogenous
factor VIII activity level, along with significantly reduced bleeding
events and the need for factor VIII concentrate.
The primary end point was the CHANGE FROM BASELINE IN
FACTOR VIII ACTIVITY (measured with a chromogenic substrate
assay) during weeks 49 through 52 after infusion.
Secondary end points included the CHANGE IN ANNUALIZED
FACTOR VIII CONCENTRATE USE AND BLEEDING RATES. Safety
was assessed as adverse events and laboratory test results.

7. BACKGROUND
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Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-
associated virus 5 (AAV5)–based gene-therapy vector containing a
coagulation factor VIII complementary DNA driven by a liver-
selective promoter.
transducing a modified human factor VIII encoding sequence, which
has been shown in phase 1-2 trials to provide sustained endogenous
factor VIII production
The efficacy and safety of the therapy were previously evaluated in
men with severe hemophilia A in a phase 1–2 dose-escalation study.
The current phase 3 trial is to evaluate the efficacy and safety of
valrox in men with severe hemophilia A.

8. METHODS
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The study conducted an open-label, single-group, multicenter, phase 3
study to evaluate the efficacy and safety of valoctocogene
roxaparvovec in men with severe hemophilia A
Severe hemophilia defined as a factor VIII level of 1 IU per deciliter or
lower.
Participants who were at least 18 years of age and did not have
preexisting anti-AAV5 antibodies or a history of development of
factor VIII inhibitors
These people receiving prophylaxis with factor VIII concentrate
received a single infusion of 6×1013 vector genomes of valoctocogene
roxaparvovec per kilogram of body weight.

9. INITIAL STUDY
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We infused a single intravenous dose of a codon-optimized
adeno-associated virus serotype 5 (AAV5) vector encoding a B-
domain–deleted human factor VIII (AAV5-hFVIII-SQ) in nine
men with severe hemophilia A.
Participants were enrolled sequentially into one of three dose
cohorts
low dose [one participant],
Intermediate dose [one participant],
High dose [seven participants])
Those were followed through 52 weeks.

10. INFERENCE
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The infusion of AAV5-hFVIII-SQ was associated with the
sustained normalization of factor VIII activity level over a period
of 1 year in six of seven participants who received a high dose,
In the high-dose cohort, the median annualized bleeding rate
among participants who had previously received prophylactic
therapy decreased from 16 events before the study to 1 event
after gene transfer,
and factor VIII use for participant-reported bleeding ceased in
all the participants in this cohort by week 22.
with stabilization of hemostasis and a profound reduction in
factor VIII use in all seven participants. In this small study, no
safety events were noted, but no safety conclusions can be
drawn.

11. Actual Study Start Date : December 19, 2017
Actual Primary Completion Date : November 16, 2020
Estimated Study Completion Date : November 2024

12. Study Type : Interventional (Clinical Trial)
Actual Enrollment : 134 participants
Allocation: Not allocated as random groups
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

13. ONGOING TRIAL – PHASE 3
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Overall, 134 participants received an infusion and completed
more than 51 weeks of follow-up.
Among the 132 human immunodeficiency virus–negative
participants, the mean factor VIII activity level at weeks 49
through 52 had increased by 41.9 IU per deciliter (95%
confidence interval [CI],
median change, 22.9 IU per deciliter;
All the participants had at least one adverse event; 22 of 134
(16.4%) reported serious adverse events.
No development of factor VIII inhibitors or thrombosis occurred
in any of the participants.

14. VISUAL ABSTRACT

15. CONCLUSIONS
• In patients with severe hemophilia A, valoctocogene
roxaparvovec treatment provided endogenous factor VIII
production and significantly reduced bleeding and factor VIII
concentrate use relative to factor VIII prophylaxis. (Funded by
BioMarin Pharmaceutical;

16. INFERENCE OF CURRENT DATA
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New England Journal of Medicine Publishes Editorial: Prepare
the Way for Hemophilia A Gene Therapy
Significantly Reduced Bleeding and Factor VIII Utilization
Compared to Baseline Factor VIII Prophylactic Therapy
Mean Annualized Bleeding Rate (ABR) Reduced by 84% (p-value
<0.001)
Mean Annualized Factor VIII Utilization Rate Reduced by 99% (p-
value <0.001

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Journal acknowledging the potential benefit of zero bleeds and
avoiding the use of prophylactic therapy.
The original research article reports that following a single
infusion of valoctocogene roxaparvovec participants
experienced
1. substantially reduced annualized bleeding rates,
2.reduced factor VIII utilization, and
3.increased factor VIII activity
Valoctocogene roxaparvovec has been studied longer than any
other gene therapy for hemophilia A

18. ADVERSE EFFECTS
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Overall, the most common adverse events (AE) associated with
valoctocogene roxaparvovec occurred early and included transient
infusion associated reactions
Mild to moderate rise in liver enzymes with no long-lasting clinical
sequelae.Among 134 members
Alanine aminotransferase (ALT) elevation (119 participants, 89%)
headache (55 participants, 41%),
arthralgia (53 participants, 40%),
nausea (51 participants, 38%),
aspartate aminotransferase (AST) elevation (47 participants, 35%),
and fatigue (40 participants, 30%)

19. THANK YOU…!!!!