NIH study shows Novartis drug eltrombopag as first-line therapy with standard treatment improves responses in SAA

The study evaluated three sequential treatment groups, or cohorts. Cohort 3 added eltrombopag at the initiation of immunosuppressive therapy and showed a higher complete response rate than cohorts 1 and 2, where eltrombopag was initiated on day 14. The data is published in the latest issue of The New England Journal of Medicine.

SAA is a rare and serious blood disorder in which a patient's bone marrow fails to make enough red blood cells, white blood cells and platelets. As a result, people living with SAA may experience debilitating symptoms and complications, such as fatigue, trouble breathing, recurring infections and abnormal bruising or bleeding that can limit their daily activities. The current standard of care includes immunosuppressive therapy (IST) or hematopoietic stem cell transplantation. However, one-quarter to one-third of patients will not respond to IST and 30-40% of responders will relapse, causing symptoms to return.

"Our research in NEJM shows that eltrombopag plus standard immunosuppressive therapy appeared to increase the overall response rate and substantially increase the frequency, speed and robustness of hematologic recovery in patients with SAA compared to historical controls," said the study's lead author, Danielle Townsley, MD, researcher in the NHLBI.

In the NIH study, the primary efficacy endpoint of complete response rate with eltrombopag plus standard immunosuppressive treatment at six months exceeded the historic rate (10%) across all three treatment cohorts (cohorts differed in length of eltrombopag administration; dose adjusted by age). Patients in cohort 1 received eltrombopag from day 14 to six months and achieved a complete response rate of 33%. The complete response was lowest in cohort 2 (26%), in which eltrombopag exposure was shortest (day 14 to three months). Furthermore, overall increases in platelet and neutrophil blood level counts were higher in comparison to the historic cohort, which is a key treatment goal for SAA. The overall survival rate at a median follow-up of two years was 97% (95% CI, 94-100%) for all cohorts.

"We are committed to improving the care of people living with serious conditions over the long term, particularly those with few options and great unmet need," said Vasant Narasimhan, global head, drug development and chief medical officer, Novartis. "Eltrombopag is the  only thrombopoietin receptor agonist to be used in the second-line treatment of SAA, and these results from the NIH study now show its potential as a first-line treatment, which we look forward to discussing with health authorities."

The study also looked at clonal evolution, which is a major complication of SAA (with potential for development of myelodysplastic syndrome and acute myeloid leukemia). As of May 25, 2016, the addition of eltrombopag did not increase the rate of clonal evolution and was not higher compared to historical data. Clonal cytogenetic evolution occurred in 7 patients at 2 years (95% CI, 1-14%).

The safety profile was consistent with the known safety profile of eltrombopag. Eltrombopag was briefly discontinued during the first two weeks in 7 patients who experienced transient liver enzyme elevations. Two severe adverse events, grade 2-3 cutaneous eruptions, were attributed to eltrombopag and required discontinuation of the drug. Adverse events not attributed to eltrombopag were due to neutropenic infections and known toxicities from immunosuppressive therapy. One death occurred on study in a non-responding patient with thymoma three months following treatment, due to paraneoplastic encephalopathy.

The phase I-II, non-randomized study is being conducted bythe National Heart, Lung and Blood Institute through a Cooperative Research and Development Agreement (CRADA) with Novartis Pharmaceuticals Corporation. The primary analysis included 92 patients with treatment-naïve severe aplastic anemia in three treatment cohorts, and nearly 80% of patients were over the age of 18. Eltrombopag was administered at 150 mg daily for patients 12 years or older, 75 mg daily for those 6 to 11 years, and 2.5 mg/kg/day for children 2 to 5 years. Duration of treatment with eltrombopag varied per cohort (cohort 1: day 14 to six months; cohort 2: day 14 to three months; cohort 3: day one to six months). ATG and cyclosporine were administered as standard immunosuppression therapy.

The study's primary efficacy endpoint was hematologic complete response at six months defined by absolute neutrophil count >=1,000/Mu l, hemoglobin >=10 gm/dL, and platelets >=100,000/Mu l. Secondary endpoints included partial and overall hematologic responses at three months, six months, and yearly; survival; self-reported health outcomes; relapse, paroxysmal nocturnal hemoglobinuria (PNH) and clonal evolution as defined by a new clonal cytogenetic abnormality or characteristic dysplastic or leukemic changes in marrow consistent with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

Eltrombopag, marketed as Promacta in the US and Revolade in countries outside the US, is approved in more than 100 countries worldwide for the treatment of thrombocytopenia in adult patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an inadequate response or are intolerant to other treatments, in over 45 countries worldwide for the treatment of patients with severe aplastic anemia (SAA) who are refractory to other treatments, and in more than 50 countries for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy. Eltrombopag is approved in the United States and in the European Union for the treatment of thrombocytopenia in pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Nih study shows novartis drug eltrombopag, first-line therapy with standard treatment improves responses in saa