FDA has approved a new indication for the once-daily use of eltrombopag (Promacta, GlaxoSmithKline) in patients with severe aplastic anaemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).
FDA has approved a new indication for the once-daily use of eltrombopag (Promacta, GlaxoSmithKline) in patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).
SAA is a very rare but serious blood disorder where the bone marrow fails to make enough red blood cells, white blood cells, and platelets. The exact cause of the disease is still unknown, but most cases of SAA are believed to be triggered by an autoimmune reaction where the body attacks blood-forming stem cells located in the bone marrow. As a result, patients with SAA are at risk for life-threatening infections or bleeding. In the United States approximately 300 to 600 new cases of SAA are identified each year. Treatment of SAA is focused on increasing a patient’s healthy blood cell count. Traditional treatment for SAA includes bone marrow transplant, IST, and blood or platelet transfusions, among others.
“There is a high unmet need for therapies for SAA patients who are unresponsive to IST,” according to Paola Paoletti, MD, president of oncology at GSK. “Treatment of SAA is focused on increasing a patient’s healthy blood cell count, and traditional treatments include IST, hematopoietic stem cell transplantation [HSCT] and blood or platelet transfusions, among others.”
Of patients treated with IST, one-quarter to one-third will not respond, and 30% to 40% of responders relapse. Approximately 40% of SAA patients who don’t respond to initial IST die from infection or bleeding within 5 years of their diagnosis, according to Dr Paoletti.
FDA approval of Promacta addresses a significant treatment need for this disorder in those who have failed current treatment options. Until the approval of Promacta, there was no available therapy or established standard of care for IST-refractory SAA patients who lack a matched, related donor for HSCT. Through collaboration with the National Institutes of Health (NIH), whose studies demonstrate the potential for Promacta to achieve a hematologic response in at least one lineage-red blood cells, platelets, or white blood cells-patients now have a treatment option where one didn’t previously exist.
The drug’s approval is based on results from an investigator-sponsored phase 2 study (09-H-0154) by the National Heart, Lung and Blood Institute (NHLBI) at the NIH.
Given the significant unmet need for patients with SAA who have had failed IST, the NIH designed an exploratory, phase 2 study to test whether eltrombopag would provide benefit and therefore a potential new treatment option where one did not previously exist. When results after 12 weeks showed a 40% response rate, Neal Young, director of hematology at the NHLBI, and his team met with GSK to discuss the significant results.
“The outcome of their meeting was a decision to pursue regulatory approval,” Dr Paoletti said. “Over the course of 14 months, GSK collaborated closely with the NHLBI to create case reports, process data, and retroactively prepare the results from this single-arm, single-centre phase 2 study for submission.
This single-arm, single-center, open-label phase 2 study of 43 patients demonstrated a hematologic response in SAA patients treated with eltrombopag who had an insufficient response to IST:
· Forty per cent (95% CI, 25, 56) of patients (N=17) experienced a hematologic response in at least 1 lineage-platelets, red blood cells (RBC), or white blood cells (ANC)-after Week 12.
· In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment and maintained the response (median follow up 8.1 months, range 7.2-10.6 months).
· Ninety-one per cent of patients were platelet transfusion-dependent at baseline; the platelet transfusion-free period in responders ranged from eight to 1,096 days (median 200 days).
· Eighty-six per cent of patients were RBC-transfusion dependent at baseline; the RBC transfusion-free period in responders ranged from 15 to 1,082 days (median 208 days).
Nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%) were the most common adverse reactions (≥20%) in this trial in 43 patients with SAA who received Promacta. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported, including 5 patients who had complex changes in chromosome 7.
A survey of US hospitals found that 60% of institutions adhere to guidelines that recommend patients with SAA receive platelet transfusions if platelet counts fall below 20,000. Due to the short half-life of platelets, this typically results in the need for platelet transfusions once a week.