GSK receives FDA approval of an additional Promacta® (eltrombopag) indication for use in patients with severe aplastic anaemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST)

LONDON, Aug. 26, 2014 /PRNewswire-FirstCall/ -- GlaxoSmithKline plc (LSE/NYSE: GSK) announced today that the U.S. Food and Drug Administration (FDA) has approved a 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).¹

SAA is a blood disorder where the bone marrow fails to make enough red blood cells, white blood cells, and platelets. ² 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.¹

"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:¹

• Forty per cent (95% 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 12.¹
  • 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).¹
• 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).¹
• 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).¹

The most common adverse reactions (>/=20%) in the single-arm, open-label trial, in 43 patients with SAA who received Promacta were: nausea (33%), fatigue (28%), cough (23%), diarrhoea (21%), and headache (21%). 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 7. If new cytogenetic abnormalities are observed, discontinuation of Promacta should be considered.¹

About the NIH Study¹
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%) 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.

About Severe Aplastic Anaemia (SAA)
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.² 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.³ As a result, patients with SAA are at risk for life-threatening infections or bleeding.² In the U.S., approximately 300 to 600 new cases of SAA are identified each year.²

Treatment of SAA is focused on increasing a patient's blood cell count; definitive care includes immunosuppressive therapy (IST) or hematopoietic stem cell transplantation.^3,4 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.⁵

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.⁴ 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.⁶

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.⁷

About Eltrombopag¹ 
Eltrombopag is marketed under the brand name Promacta^® in the U.S. and Revolade™ in most ex-U.S. countries.

In addition to the approval of Promacta for SAA in the U.S., 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.

Important Safety Information¹

The following Important Safety Information is based on the Highlights section of the Prescribing Information for Promacta. Please consult the full prescribing information for all the labelled safety information for Promacta. The revised full U.S. Prescribing Information, including Boxed Warning, will be available soon at https://www.gsksource.com/gskprm/htdocs/documents/PROMACTA-PI-MG-COMBINED.PDF

Hepatotoxicity:
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:
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:
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.

Drug Interactions:
Promacta must not be taken within four hours of any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements.

Adverse Reactions:
The most common adverse reactions (>/=20%) in a single-arm, open-label trial in 43 patients with SAA who received Promacta were: nausea (33%), fatigue (28%), cough (23%), diarrhoea (21%), and headache (21%). 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 7. If new cytogenetic abnormalities are observed, discontinuation of Promacta should be considered.

The most common adverse reactions in three placebo-controlled clinical trials in chronic ITP patients (>/=3% and greater than placebo) for Promacta versus placebo were: nausea (9% vs. 3%), diarrhoea (9% vs. 7%), upper respiratory tract infection (7% vs. 6%), vomiting (6% vs. <1%), increased alanine aminotransferase (ALT) (5% vs. 3%), myalgia (5% vs. 2%), urinary tract infection (5% vs. 3%), oropharyngeal pain (4% vs. 3%), increased aspartate aminotransferase (AST) (4% vs. 2%), pharyngitis (4% vs. 2%), back pain (3% vs. 2%), influenza (3% vs. 2%), paraesthesia (3% vs. 2%), and rash (3% vs. 2%).

The most common adverse reactions in two randomised, placebo-controlled clinical trials in thrombocytopenic patients with chronic hepatitis C (>/=10% and greater than placebo) for Promacta versus placebo were: anaemia (40% vs. 35%), pyrexia (30% vs. 24%), fatigue (28% vs. 23%), headache (21% vs. 20%), nausea (19% vs. 14%), diarrhoea (19% vs. 11%), decreased appetite (18% vs. 14%), influenza-like illness (18% vs. 16%), asthenia (16% vs. 13%), insomnia (16% vs. 15%), cough (15% vs. 12%), pruritus (15% vs. 13%), chills (14% vs. 9%), myalgia (12% vs. 10%), alopecia (10% vs. 6%), and peripheral oedema (10% vs. 5%).

Prior to the revised label being posted online, a copy of the label may be requested from one of the GSK Media or Investor Relations contacts listed in the "GSK enquiries" section at the end of this document.

U.S. journalists, please click here for the U.S. electronic press kit: http://us.gsk.com/en-us/media/press-kits/promacta-eltrombopag/

About GSK Patient Assistance Programmes 
GSK has a number of patient assistance programmes for eligible patients in the U.S. who need help affording their medicines and vaccines. Patients who qualify for the programmes may benefit from GSK's Commitment to Access programme for oncology and specialty medicines which offers services and programmes including co-pay assistance in addition to traditional patient assistance support.  For more information, patients in the U.S. can call 1-8ONCOLOGY1 (1-866-265-6491).

GSK – one of the world's leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit www.gsk.com.

References
¹ GSK. Promacta Prescribing Information. 2014.
² American Cancer Society. "Aplastic Anemia." Accessed on 7 July 2014. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/002279-pdf.pdf. Published 23 April 2013.
³ Aplastic Anemia & MDS International Foundation. "Aplastic Anemia: Causes." Accessed on 7 July 2014. Available at: http://www.aamds.org/about/aplastic-anemia/causes. Accessed 23 June 2014.
⁴ 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.
⁵ 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 Hematol. 2013; 98(1):48-55.
⁶ Valdez JM, et al. "Decreased Infection-Related Mortality and Improved Survival in Severe Aplastic Anemia in the Past Two Decades." Clinical Infectious Diseases. 2011; 52(6):726–735.
⁷ Scheinberg P, Young NS. "How I treat acquired aplastic anemia." Blood. 2011.

SOURCE GlaxoSmithKline plc