The US Food and Drug Administration (FDA) has approved GlaxoSmithKline's supplemental New Drug Application (sNDA) for the once-daily use of Promacta (eltrombopag) in patients with severe aplastic anaemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).

SAA is a blood disorder where the bone marrow fails to make enough red blood cells, white blood cells, and platelets. Eltrombopag, an oral thrombopoietin (TPO) receptor agonist, works by helping to induce proliferation and differentiation of bone marrow stem cells to increase production of blood cells.

“FDA approval of Promacta addresses a significant treatment need for this very rare but serious blood disorder in those who have failed current treatment options,” said Dr. Paolo Paoletti, president of oncology, GSK. “Through collaboration with the National Institutes of Health, whose studies demonstrate the potential for Promacta to achieve a haematologic 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.”

Promacta gained Breakthrough Therapy designation status from the FDA in January 2014 and Priority Review in April 2014. Today’s approval by the FDA is based on results from an investigator-sponsored Phase II study (09-H-0154) conducted by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH). The study demonstrated a haematologic response in SAA patients treated with eltrombopag who had an insufficient response to IST:

Forty per cent (95 per cent CI, 25, 56) of patients (N=17) experienced a haematologic response in at least one lineage platelets, red blood cells (RBC), or white blood cells (ANC) after Week 12.

In the extension phase, eight patients achieved a multi-lineage response; four 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).

The most common adverse reactions (=20 per cent) in the single-arm, open-label trial, in 43 patients with SAA who received Promacta were: nausea (33 per cent), fatigue (28 per cent), cough (23 per cent), diarrhoea (21 per cent), and headache (21 per cent). In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported, including five patients who had complex changes in chromosome. If new cytogenetic abnormalities are observed, discontinuation of Promacta should be considered.

In the single-arm, single-centre, open-label phase II 09-H-0154 study, eltrombopag was evaluated in 43 patients with SAA who have had an insufficient response to at least one prior IST and who had a platelet count =30 x 109/L. At baseline, the median platelet count was 20 x 109/L, haemoglobin was 8.4 g/dL, absolute neutrophil count (ANC) was 0.58 x 109/L, and absolute reticulocyte count was 24.3 x 109/L.

The treated population had a median age of 45 years (range 17 to 77 years) and 56 per cent were male. The majority of patients (84 per cent) received at least two prior immunosuppressive therapies.

Eltrombopag was administered at an initial dose of 50 mg once daily for two weeks and increased over two-week periods up to a maximum dose of 150 mg once daily. The primary endpoint was haematologic response which was initially assessed after 12 weeks of treatment with eltrombopag. Treatment was discontinued after 16 weeks if no haematologic response was observed. Additional efficacy assessments included median duration of response in months.

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 US, approximately 300 to 600 new cases of SAA are identified each year.

Treatment of SAA is focused on increasing a patient’s blood cell count; definitive care includes immunosuppressive therapy (IST) or hematopoietic stem cell transplantation. Supportive treatments including blood transfusions, platelet transfusions that typically occur once a week, iron chelation therapy, and treatment of infections help in the short term to relieve specific symptoms.

Of patients treated with IST, one-quarter to one-third will not respond and 30-40 per cent of responders will relapse, causing symptoms to return. Approximately 40 per cent of SAA patients who don’t respond to initial IST die from infection or bleeding within five years of their diagnosis.

Currently, no established standard of care exists for SAA patients who have had an insufficient response to IST or are ineligible for hematopoietic stem cell transplantation.

Eltrombopag is marketed under the brand name Promacta in the US and Revolade in most ex-US countries.

In addition to the approval of Promacta for SAA in the US, eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Promacta should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.chronic hepatitis C to allow the initiation and maintenance of  interferon-based therapy.   Promacta should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. Safety and efficacy have not been established in combination with direct acting antiviral agents used without interferon for treatment of chronic hepatitis C.

Promacta can cause liver enzyme elevation, therefore, monitoring of liver function before and during therapy is required. If abnormalities are confirmed, monitoring of serum liver tests should continue until resolved or stabilised. Promacta should be discontinued if abnormalities are progressively increasing, persistent, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. Hepatotoxicity may reoccur if Promacta is reinitiated.

Thrombotic/thromboembolic complications may result from increases in platelet counts with Promacta. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and normal platelet counts. The potential for an increased risk of thromboembolism when administering Promacta to patients with known risk factors for thromboembolism should be considered. To minimise the risk for thrombotic/thromboembolic complications, Promacta should not be used in an attempt to normalise platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts.

Cataracts have been reported in patients taking Promacta. A baseline ocular examination should be performed prior to administration of Promacta. During therapy with Promacta, regularly monitoring of patients for signs and symptoms of cataracts is required.