Extended Dosing With Eltrombopag for Severe Aplastic Anemia

Severe aplastic anemia (SAA) is a life-threatening blood disease that can be successfully
treated with immunosuppressive drug regimens or allogeneic stem cell transplantation.
However, 20-40% of patients are ineligible for transplant due to lack of an appropriate
donor, age, or comorbidities. Immunosuppression can be more broadly utilized, but about 1/3
of patients do not respond to a single course of horse ATG and cyclosporine and have
persistent severe cytopenias. Among patients who do respond to immunosuppression, responses
may be partial, with persistent thrombocytopenia, neutropenia, and/or anemia. About 30% of
responding patients either relapse or are dependent on continued cyclosporine administration.
Patients with refractory severe cytopenias are at risk of dying from infection or bleeding,
and they require regular platelet and/or red blood cell transfusions, which are expensive and
inconvenient, Patients with refractory SAA are also at risk for progression to other
hematologic disorders, including myelodysplasia and leukemia.

Thrombopoietin (TPO) was first identified as the principal protein regulating platelet
production, and it stimulates the proliferation of megakaryocytes and release of platelets.
TPO was later shown to stimulate proliferation of more primitive bone marrow stem and
progenitor cells in vitro and in animal models, suggesting it could have an impact of
production of red and white blood cells as well as platelets.

The 2nd generation oral small molecule TPO-agonist eltrombopag (Promacta ) has been shown to
increase platelets in healthy subjects and in thrombocytopenic patients with chronic immune
thrombocytopenic purpura (ITP) and hepatitis C virus (HCV)-infection. Eltrombopag has been
well-tolerated in clinical trials, and unlike recombinant TPO, it does not induce
autoantibodies. Eltrombopag received FDA accelerated approval on November 20, 2008 for the
treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic
purpura who have had an insufficient response to corticosteroids, immunoglobulins, or
splenectomy. In November 2012, FDA approval was received for hepatitis C associated
thrombocytopenia.

We conducted a pilot dose finding study in patients with severe aplastic anemia who had
refractory thrombocytopenia following standard immunosuppressive therapy. Patients began at a
dose of 50 mg/day and escalated every two weeks to a maximum dose of 150 mg/day. We reported
that 11 of 25 patients (44%) achieved hematological response in at least one lineage
following 12 weeks of dose-escalating eltrombopag therapy, with minimal toxicity. Responding
patients as assessed at 12 weeks were invited to continue on drug in an extension phase. With
a median follow-up of 27 months on drug, 7 eventually became tri-lineage responders. Nine
became transfusion-independent for platelets (median increase in platelet count 34,000/micro
l), six had improved hemoglobin levels (median increase of 3.8g/dL), including three
previously dependent on red cell transfusions achieving transfusion-independence, and eight
exhibiting increased neutrophil counts (median increase 590 cells/mico L). Serial bone marrow
biopsies demonstrated normalization of tri-lineage hematopoiesis in responders, without
increased fibrosis.

In the previous study, response assessment occurred at 12 weeks, and patients not fulfilling
response criteria at that time had the drug discontinued. Several patients began to have
detectable changes in transfusion requirements or blood counts by 12 weeks, but did not
fulfill response criteria by that time point and therefore had to discontinue eltrombopag.
Other patients who barely met response criteria at 12 weeks showed very marked further
improvements in blood counts in all lineages during the extension phase, in some cases not
reaching maximal responses until one year after initiating eltrombopag. We hypothesize that a
larger fraction of patients may respond if eltrombopag is continued for longer than 12 weeks.

We, therefore propose a follow-up Phase 2 study giving eltrombopag treatment for 24 weeks
prior to definitive response assessment, and initiating study medication at a fixed dose of
150 mg/day (75 mg /day for individuals of East Asian ethnicity), given lack of toxicity at
that dose in the prior study, and no evidence for response in any patient during dose
escalation prior to reaching this dose. Responses will be assessed in all three lineages.
Subjects with platelet, red cell, and/or neutrophil responses at 24 weeks may continue study
medication (extended access) until they meet off study criteria.

The primary objective is to assess the efficacy of 6 months of eltrombopag administration in
improving bone marrow function in SAA patients with persistent severe cytopenias refractory
to treatment with immunosuppressive treatment.

Secondary objectives include assessment of relapse or clonal evolution, pre-treatment
characteristics predicting response, and the impact of treatment and treatment response on
quality of life.

- INCLUSION CRITERIA:

- Previous diagnosis of refractory severe aplastic anemia and following at least one
treatment course of immunosuppression with a regimen containing antithymocyte
globulin, alemtuzumab or cyclophosphamide.

- One or more of the following three clinically-significant cytopenias: platelet count
less than or equal to 30,000/micro L or platelet-transfusion-dependence (requiring at
least 4 platelet transfusions in the 8 weeks prior to study entry); neutrophil count
less than 500/micro L; hemoglobin less than 9.0 g/dL or red cell
transfusion-dependence (requiring at least 4 units of PRBCs in the eight weeks prior
to study entry)

- Age greater than or equal to 2 years old

- Weight > 12 kg

EXCLUSION CRITERIA:

- Infection not adequately responding to appropriate therapy

- Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study
entry.

- Creatinine > 2.5 mg/dL

- Direct Bilirubin > 2.0 mg/dL

- SGOT or SGPT >5 times the upper limit of normal

- Hypersensitivity to eltrombopag or its components

- Female subjects who are nursing or pregnant or are unwilling to take oral
contraceptives or refrain from pregnancy if of childbearing potential

- Unable to understand the investigational nature of the study or give informed consent

- Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,
infectious, or metabolic disease of such severity that it would preclude the patient s
ability to tolerate protocol therapy, or that death within 7-10 days is likely

- Treatment with ATG, cyclophophamide or alemtuzamab within 6 months of study entry.