A Phase 3b Clinical Study To Assess Whether Regular Administration Of Advate In The Absence Of Immunological Danger Signals Reduces The Incidence Rate Of Inhibitors In Previously Untreated Patients With Hemophilia A

The formation of neutralizing antibodies (inhibitors) against FVIII is the most
serious disease-related complication of hemophilia A treatment, typically
occurring in approximately 30% of severe PUPs. The highest risk of developing
inhibitors to FVIII occurs during the first 20 exposure days (EDs). Of those
patients who develop inhibitors, 50% of will develop inhibitors within the
first 20 EDs and 95% during the first 50 EDs. Prophylactic factor replacement
therapy is now an established approach to prevent severe joint bleeds and
arthropathy.
Inhibitor development is a complex, multifactorial immune response involving
both patient-specific and treatment-related factors. Of the known risk factors,
intensive treatment at an early age has been shown to be significant, and
clinical observations have suggested that early prophylaxis (ie, first exposure
to FVIII in the absence of a bleed) may protect patients from inhibitor
development with the goal to induce tolerance against FVIII.
One of the patient-specific factors predisposing to inhibitor development is
severe defects in the FVIII gene, such as large deletions, inversions (most
commonly intron inversion) and stop mutations. Such mutations mean that there
is no endogenous FVIII production, and therefore the FVIII protein cannot be
presented to the immune system to establish central immune tolerance. If such
patients are then given a FVIII product, it is seen as a foreign protein by
their immune systems.
Most prophylactic regimens use relatively high doses of FVIII, for example 50
IU/kg three times weekly, with treatment started at or just after the first
significant joint bleed. This means that the FVIII antigen is being given at
high doses and at the same time when danger signals are present. This clinical
study is based on the hypothesis that if such danger signals are prevented and
low doses of FVIII are used, the risk of developing FVIII inhibitors can be
decreased.

To date, no prospective study has been done to investigate whether regular,
systematic exposure to low doses of FVIII during the first 50 EDs can reduce
the risk of inhibitor formation. This study will determine if a low dose, early
prophylaxis regimen starting with once weekly infusions can reduce the
inhibitor incidence rate in severe and moderately severe hemophilia A patients.

Primary objective:
Determine the incidence rate of inhibitor formation in PUPs with severe and
moderately severe hemophilia A during the first 50 exposure days (EDs) to
starting with a once weekly prophylactic regimen together with the minimization
of immunological danger signals

Secondary objectives:
- Determine the general safety and efficacy during the first 50 EDs to ADVATE
of an once weekly early prophylactic regimen starting once
weekly in PUPs with severe and moderately severe hemophilia A
- Gather information about the temporal associations and molecular and cellular
mechanisms involved in the development of an immune response to factor VIII
(FVIII) during the first 50 EDs to ADVATE

This is a Phase 3b, prospective, historically controlled, single arm,
international, multicenter study in PUPs with severe and moderately severe
hemophilia A. The inhibitor incidence rate observed using this early
prophylaxis regimen will be compared to that previously observed in historical
cohorts, including the ADVATE PUP Study (Baxter study number 060103; historical
control). The estimated number of study subjects is 100, and the estimated
number of global study sites is approximately 75.

ADVATE will be administered by intravenous infusion at a dose of 25±5 IU/kg
once per week.
Additional on-demand ADVATE infusions (25-50 IU/kg) for bleeds should be
administered as indicated. The maximum dose for any once weekly on-demand
infusion will be 50 IU/kg.

It has been demonstrated in Phase 3/4 and post-authorization surveillance
studies that ADVATE was safe and effective for the treatment and prevention of
bleeding episodes in various settings and patient populations, including PUPs.
Based on the available evidence, as described above, there are no additional
risks anticipated other than those described in the IB.
This new prophylaxis regimen incorporates several factors:
• Low number of EDs before prophylaxis starts
• Low dose and low frequency regimen
• Young age at start of regimen
• Minimization of immunological danger signals
It has been shown in the pilot study and other studies, that starting
prophylaxis at a young age does not increase the risk of inhibitor development.
If prophylaxis is started earlier this may result in fewer joint bleeds and
better joint scores, and thus a better outcome for the patient. Other benefits
of the regimen would include the following:
• Central venous access device (CVAD) is not necessary because of once a week
administration; this eliminates the need for a surgical procedure and prevents
the associated cell damage and generation of danger signals.
• The dosing frequency and the dose can be increased if the initial dose is
ineffective.
• Weekly dosing aids subject compliance: the best-case scenario is only one
visit to the HTC required per week (in contrast to the normal 3 times weekly
regimen)
• Lower doses, less frequent treatments, and the prevention of inhibitors offer
pharmacoeconomic benefits.