A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Study of Fostamatinib Disodium in the Treatment of Warm Antibody Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is an acquired disorder manifested by
autoantibody-mediated red blood cell (RBC) destruction. The estimated incidence
is 0.8-3 per 100,000/year with a mortality rate of 11%. AIHA is subclassified
as either warm or cold, some 80% of cases
are warm AIHA, and can be either primary or secondary to an underlying disease
such as autoimmune disease, 20%, lymphoproliferative disorder, 20%, or
infections and tumors.
The diagnosis of AIHA is typically made when hemolysis is associated with a
positive direct antiglobulin test (DAT), indicating that RBC autoantibodies
and/or complement proteins are bound to red cells. Additional abnormalities
include a reduced serum haptoglobin level, an
increased indirect bilirubin, and an elevated lactate dehydrogenase (LDH).
The first-line treatment of AIHA generally consists of steroids. Up to 85% of
patients will respond, however fewer than 20% of patients will be cured.
Splenectomy has traditionally been the second line therapy of choice for this
disease, with 60-70% of patients having a sustained response. Other therapeutic
approaches that can be used, following the failure of front-line treatment,
include rituximab, IVIg, cyclosporine, mycophenolate mofetil, azathioprine, and
cyclophosphamide. The availability of these alternative therapies has
challenged the role of splenectomy as the preferred second-line treatment.
Fc receptor * (FcR*) signaling in monocytes and macrophages plays an important
role in the initiation and propagation of autoimmune responses. The activating
FcR* is associated with a signaling subunit, referred to as the FcR* chain,
whose phosphorylation subsequent to receptor activation results in the
recruitment and activation of spleen tyrosine kinase (Syk). Syk is an important
component of the signaling system of activated Fc receptors, as well as the
B-cell receptor (BCR).
Aggregation of the Fc receptors, induced by antibody-antigen complexes, can
activate a multitude of cellular functions (including degranulation,
arachidonic acid metabolism, antibody dependent cellular cytotoxicity,
phagocytosis and cytokine secretion) depending on the cell type, and leads to
tissue damage and the propagation of inflammatory responses. FcR* have been
implicated in immune destruction of RBCs. Accelerated clearance of circulating
IgG-coated RBCs via FcR*-bearing macrophages in the spleen and liver is
believed to be a pathogenic mechanism in AIHA. Fostamatinib (R788) is the
prodrug of R940406 (R406), a potent and relatively selective inhibitor of Syk
and, consequently, of the FcR and BCR signaling pathways.
R406 inhibits Syk and FcR signaling at concentrations generally achieved with
fostamatinib doses of 100-150 mg twice daily (bid) and above, and nonclinical
data have affirmed its activity in AIHA.

* The primary objective of this study is to compare the proportion of warm
antibody autoimmune hemolytic anemia (wAIHA) subjects who
achieve a durable hemoglobin response between the fostamatinib and placebo
groups.

* The secondary objectives of this study are:
o To compare the proportion of subjects with hemoglobin response on at least
one visit between the fostamatinib and placebo groups.
o To compare the proportion of subjects who achieve a change from Baseline in
hemoglobin level of * 2 g/dL between the fostamatinib and
placebo groups.
o To compare the change in hemoglobin value from Baseline to the End of
Treatment between the fostamatinib and placebo groups.
o To compare the proportion of subjects who use permitted rescue medications
after Week 4 between the fostamatinib and placebo groups.
o To compare the change from Baseline to Week 24 in Functional Assessment of
Chronic Illness Therapy - Fatigue scale (FACIT-F).

* The safety objective is to assess the safety of fostamatinib in subjects with
wAIHA.

* Additional efficacy and pharmacoeconomic objectives will compare the
fostamatinib and placebo groups for the endpoints noted on protocol
section 4.5.

This is a Phase 3 multi-center, randomized, double-blind, placebo-controlled,
parallel group study to investigate the efficacy of 24 weeks of treatment with
fostamatinib (R935788) vs. placebo in achieving a durable hemoglobin response
in subjects with wAIHA who have failed at least one prior treatment
regimen. After qualifying for the study, approximately 90 subjects will be
randomized in a 1:1 ratio to 1 of 2 treatment groups: fostamatinib 100 mg by
mouth (PO), twice a day (bid), or matching placebo. Subjects will
self-administer the study drug in the morning and evening throughout the
24-week treatment period.
Randomization will be stratified by concomitant steroid use at baseline (*20 mg
and <20 mg daily) and by severity of anemia at screening (baseline hemoglobin
<9 vs. *9 g/dL).
Starting at Week 4, the initial fostamatinib dose of 100 mg PO bid or matching
placebo will be increased to fostamatinib 150 mg PO bid or matching placebo if
subjects have adequately tolerated the study drug in the investigator*s
judgment. The dose may be reduced at any time to a dose as low as fostamatinib
100 mg PO once daily (qd) or matching placebo if dose-limiting adverse events
are observed per the dose adjustment table
below.
Dose Adjustment
Starting Dose Dose Level -1 Dose Level -2 Dose Level -3
Dose Level -4
100 mg PO bid 150 mg PO qd 100 mg PO qd discontinue ----
150 mg PO bid 100 mg PO bid 150 mg PO qd 100 mg PO qd
discontinue
Over the course of the study, subjects will be expected to visit the clinic
approximately 15 times. Safety assessments and hemoglobin levels will be
performed at each visit to evaluate the safety and efficacy of study drug
(fostamatinib or placebo), and to determine if a dose adjustment is
required. The end of the trial will be when the last subject has completed
either the Week 24 visit or their last study visit, whichever is later.

All patients will receive the following interventions:
- ECG
- Vital signs and physical examination
- Urine collection
- Pregnancy test (for females of childbearing potential only)
- Blood draws for safety (hematology and chemistry)
- Blood draws for PK
- Blood draws for Biomarkers (optional)
- Questionnaires

Potential Benefit-Risk Summary
Nonclinical data support the potential benefit of fostamatinib, a SYK
inhibitor, in wAIHA. SYK plays a central role in FcR*-bearing macrophage
clearance of circulating IgG-coated RBCs, which is believed to be a pathogenic
mechanism in AIHA (Section 3.1).(2) Fostamatinib administration in an animal
model of wAIHA showed protection from anemia.
As described in Section 3.4 of the Protocol V5.0 (p25), an interim data cut of
the open label Phase 2 study assessing fostamatinib in treatment of wAIHA
patients who failed at least one prior therapy showed that 8/17 subjects (47%)
in the Efficacy Evaluable Population responded during the 24-week evaluation
period (lower bound of the exact 95% confidence interval is 23%); one
additional subject met the response criteria in the extension period (after 24
weeks of dosing) for an overall response rate of 53% (9/17) on fostamatinib
(lower bound of the exact 95% confidence interval is 31%). Thus preliminary
data indicate that fostamatinib may benefit wAIHA patients who have failed at
least one prior therapy.
The risks of fostamatinib have been characterized and consistent across
programs including, healthy subjects, and patients with ITP, rheumatoid
arthritis (RA), malignancies, IgA nephropathy and wAIHA (see Investigator*s
Brochure). The AEs most commonly related to fostamatinib include effects on
blood pressure, hepatic transaminase elevations, gastrointestinal complaints
(especially diarrhea) and neutrophil counts. These AEs are mostly mild to
moderate in intensity. They are reversible and manageable with appropriate
safety monitoring, medical intervention and at times fostamatinib dose
reduction, interruption or discontinuation. The safety results from the Phase 2
wAIHA interim datacut (described in Section
3.6.1 of the Protocol V5.0 (p26)) are consistent with those in the entire
fostamatinib safety database. SAEs in the Phase 2 wAIHA study were often
related to the underlying disease or its treatment and complications. None of
these SAEs were judged by investigators as related to fostamatinib.
In sum, the potential benefit of fostamatinib treatment in wAIHA patients
outweighs the risks and supports the conduct of a Phase 3 study in this
indication.