NIH study in NEJM shows Novartis drug eltrombopag as first-line therapy with standard treatment improves responses in severe aplastic anemia.
Novartis announced Wednesday the publication of a study conducted by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) demonstrating that 58 percent of patients with treatment-naïve severe aplastic anemia (SAA) achieved complete response at six months when treated with eltrombopag at the initiation of and concurrently with standard immunosuppressive treatment1.
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 platelets2. 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 activities2.
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 percent of responders will relapse, causing symptoms to return3.
“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, M.D., 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)1. 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 SAA1,4. The overall survival rate at a median follow-up of two years was 97% (95% CI, 94-100%) for all cohorts1.
“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)1. As of May 25, 2016, the addition of eltrombopag did not increase the rate of clonal evolution and was not higher compared to historical data1,5,6,7. Clonal cytogenetic evolution occurred in 7 patients at 2 years (95% CI, 1-14%)1.
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 therapy7. One death occurred on study in a non-responding patient with thymoma three months following treatment, due to paraneoplastic encephalopathy1.
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References:
1 Townsley, D et al. Eltrombopag added to standard immunosuppression for aplastic anemia. The New England Journal of Medicine. 2017;376(16):1540-1550.
2 Aplastic Anemia. U.S. National Institutes of Health website. U.S. National Institutes of Health. Web. 16 Feb 2017.
3 Townsley DM, Desmond R, Dunbar CE, et al. Pathophysiology and management of thrombocytopenia in bone marrow failure: possible clinical applications of TPO receptor agonists in aplastic anemia and myelodysplastic syndromes. Int J Hematology. 2013;98(1):48-55.
4 Your Guide to Understanding Aplastic Anemia. Aplastic Anemia & MDS International Foundation. Web. 17 Feb 2017.
5 Kulasekararaj AG et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood. 2014.124:2698-2704.
6 Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120:1185-96.
7 Townsley, D et al. Myeloid neoplasm gene somatic mutations in patients with severe aplastic anemia treated with eltrombopag and standard immunosuppression. Blood. 2016;128:727.
(Source: PR Newswire)
Filed Under: Drug Discovery
