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Eltrombopag (Promacta) offers hope of an effective oral treatment for bleeding due to thrombocytopenia

Field Report Posted on: 03 Jan 07


Thrombocytopenia, the bleeding disorder caused by a deficiency of platelets, has no easy-to-administer or satisfactory treatment at present. However, eltrombopag (Promacta) a new oral drug in development by GlaxoSmithKline (GSK) has progressed to phase III
Thrombocytopenia, the bleeding disorder caused by a deficiency of platelets, has no easy-to-administer or satisfactory treatment at present. However, eltrombopag (Promacta) a new oral drug in development by GlaxoSmithKline (GSK) has progressed to phase III following encouraging early results regarding efficacy and tolerability. Latest results of a phase II study were presented at the annual American Society of Hematology (ASH) meeting in Orlando, Florida.
Patients with too few circulating platelets (thrombocytes) experience problems with bleeds into mucous membranes and other sites. For example, they can experience epistaxis (nosebleeds), they tend to bruise easily, their gums bleed and in a life-threatening complication, they can suffer intracranial haemorrhage. Dental and surgical operations can be hazardous on account of excessive bleeding. Whilst a healthy individual typically has around 150,00 to 400,000 platelets per microlitre (mL) of blood, people are considered thrombocytopenic once their platelet count falls below the norm. Treatment is usually reserved for patients with a chronic or marked deficiency. In studies of the new therapeutic agent in development, eltrombopag (Promacta), patients have a baseline platelet count as low as 30,000/mL or fewer.
A number of medical conditions can result in too few platelets. It is estimated for example, that 5 to 10 per cent of all patients admitted to hospital for any cause are thrombocytopenic. The main conditions of concern and of investigation with new therapeutic agents are the auto-immune disorder chronic idiopathic thrombocytopenic purpura (ITP), chronic liver disease and chemotherapy-treated cancer.
Until now, treatment for ITP has involved steroids to damp down activity in the immune system or surgical removal of the spleen to prevent the destruction of platelets. But both of these methods have drawbacks of which the chief one is leaving patients vulnerable to infection.
In liver disease, such as chronic viral hepatitis C (HCV), thrombocytopenia is the result of damage to liver cells that produce thrombopoietin, the body’s own natural growth factor, that stimulates platelet formation. It can also occur secondary to cirrhosis, affecting between 15 to 70 per cent of patients. Treatment with antiviral interferon therapy to tackle HCV, can itself cause thrombocytopenia. This complication stops patients receiving the required >80% therapeutic dose of pegylated interferon-alpha and ribavirin shown in clinical trials to achieve a good clinical response.
A new treatment paradigm
GlaxoSmithKline (GSK)’s oral, once-daily therapy, eltrombopag (Promacta), developed originally in a research collaboration with Ligand Pharmaceuticals, is currently being investigated as an alternative to the above treatment modalities in ITP, HCV and in cancer patients undergoing chemotherapy. ITP is rare, affecting around one in every 10,000 population but 3 per cent of the world’s population is infected with HCV. Around 130 million people are chronic carriers of the disease and 3 to 4 million cases are diagnosed each year. Of these, 70 per cent go on to develop chronic hepatitis. Only about half of patients are diagnosed currently in developed countries but 2 out of 3 patients should be receiving antiviral treatment.
Eltrombopag is a small molecule thrombopoietin receptor agonist that functions as a platelet growth factor. It is believed to act by stimulating the proliferation and differentiation of specific bone marrow cells – megakaryocytes - that produce platelets. Because it is a small molecule it is believed to be less likely to provoke an immune reaction
Data in ITP
GSK recently announced in its Q3 statement, that positive phase III data for eltrombopag have been received and will be presented at scientific congresses during 2007. An open label Phase III study called EXTEND is continuing following a phase II/III short-term (6-week) study in ITP. Meanwhile, a further and longer-term phase III study, RAISE (Randomised placebo controlled ITP study with eltrombopag) was announced in December 2006 which will enrol 189 patients at 135 centres in 26 countries.
Phase II efficacy data on platelet counts were presented first in June 2006 at the European Society of Hematology’s annual congress whilst bleeding data were presented in December 2006 at The American Society of Hematology (ASH) meeting in Orlando, Florida, USA . Lead investigator Dr James Bussell, Director of the Platelet Disorder Center, Children’s Blood Foundation Division at the New-York-Presbyterian Hospital/Weill Cornell Medical Center, New York, discussed both sets of data at an ASH Media Conference.
One phase II study was an international randomised double-blind placebo-controlled trial that originally planned to enrol 270 adult patients with chronic ITP with baseline platelet counts of <30,000/mL, he explained. It is one of a pair of studies that so far constitute the largest double-blind trials ever conducted in an ITP patient population and was designed to evaluate the effect of placebo versus oral eltrombopag given daily in doses of either 30mg, 50mg or 75mg for six weeks. All patients had a diagnosis of ITP persisting over six months duration with a platelet count below 30,000/mL and had failed at least one previous therapy. “The trial was stopped after only 117 patients had been recruited on account of the interim analysis of the first 90 patients showing that eltrombopag was significantly more effective than placebo at the 0.001 level” he told journalists.
More than 70 per cent of patients treated with the 50mg dose and more than 80 per cent given the 75mg dose had reached the primary endpoint of a platelet count exceeding 50,000 after a six-week treatment course.
Median platelet counts increased progressively and by the end of the six-week period were 16,000/mL for placebo, and for the 30mg, 50mg and 75mg doses were 26,000/mL, 128,000/mL and 183,000/mL respectively.
“In fact 40 per cent of patients had to stop treatment during the study period because their platelet count exceeded 200,000/mL. These patients were therefore taken off treatment but continued to be monitored” he noted.
At the end of the six-week treatment period, median platelet counts were 16,000/mL for placebo, 26,000/mL for 30mg, 128,000/mL for 50mg and 183,000/mL for 75mg. Platelet counts returned to baseline values within approximately two weeks of discontinuing medication. There were no side effects other than mild headache, he added.
Bleeding events reduced
New data presented at ASH revealed the incidence of bleeding events during the treatment period. “At the two effective doses there was a trend for these to decrease in proportion to the increase in platelet count,” said Dr Bussell. Incidence was 10% for placebo, and 16%, 3% and 4% for the 30mg, 50mg and 75mg doses respectively. During the treatment follow-up period, bleeding events were 14% for placebo, and 13%, 10% and 7% for the 30mg, 50mg and 75mg doses.
In a further study, 114 patients were randomised in a ratio of 2:1 to eltrombopag or placebo. The 76 patients randomised to eltrombopag started at a dose of 50mg but could increase this to 75mg if necessary. “Results confirmed the findings of the first study with the majority meeting the primary endpoint with a dramatic increase in platelets and a significant decrease in bleeding events among responders”, he disclosed. “There was a significant difference between therapy and placebo and no significant toxicity. So I believe eltrombopag is a major advance in the management of ITP. Whereas previously all treatment paradigms concentrated on decreasing platelet destruction, eltrombopag, given orally, once daily, boosts the formation of new platelets.” The presence of higher numbers of platelets helps to overcome formation of antibodies to platelets, he added.” It appears that if treatment continues over one to two years, a number of patients may lose their auto-immune response to platelets.”
Data in hepatitis C
Phase II data for eltrompobag in hepatitis C were presented at the American Association for the Study of Liver Disease meeting on 30th October this year and were also positive. In a study of 74 patients, 95 per cent treated with the highest dose of eltrombopag had increased platelet counts and two thirds of patients in all treatment groups were able to be maintained on anti-viral treatment.
At this year’s Digestive Disease Week conference in Los Angeles, results were presented for a double-blind multicentre phase II study of eltrombopag in 33 chronic hepatitis C patients. This patient group had compensated cirrhosis and baseline platelet counts between 20,000 and 70,000/mL. They were randomised to placebo or either 30mg, 50mg or 75mg of eltrombopag for four weeks. At the end of this time, patients achieving platelet counts above 70,000/mL were to be allowed to start pegylated interferon-alpha and ribavirin treatment.
Results showed that among patients achieving a platelet count of 100,000/mL or more, the highest response rate (90%) occurred among those receiving the 75mg dose. At lower dosages, there was still a good response rate but no patients achieved this target in the placebo group.
Data in chemotherapy-induced thrombocytopenia (CIT)
A phase II study of eltrombopag has also been conducted in cancer patients undergoing chemotherapy. Although platelet count increased with eltrombopag treatment, there were insufficient data to differentiate eltrombopag from placebo. This was because the chemotherapy agent used did not induce the expected level of thrombocytopenia normally associated with this form of treatment. The primary endpoint of the study was not met in this instance but further studies in CIT are planned.
GSK says it plans to file eltrombopag with US and European regulatory authorities for at least one indication in 2007 or 2008. In the company’s 2006 Q3 statement it announced it is working with regulatory authorities to determine whether currently-available phase III data are sufficient to file for approval in 2007. Patients who suffer from thrombocytopenia must hope they are. They are eagerly awaiting a simple but effective means of controlling their condition, Dr Bussell explained. Although other agents are also in development, they are less advanced than eltrombopag in clinical trials. Not only will a safe, effective treatment protect patients from the risk of serious side effects but it will improve quality of life. “For example, children with a platelet count of 10,000 can’t do any sports for fear of injury and parents have to watch them all the time to see they avoid any risk or accident” he noted. “Women with thrombocytopenia who develop a headache cant take anything for the pain because effective pain-killing drugs interfere with platelets.” There is even a suggestion that effective treatment for thrombocytopenia will alleviate depression. “Platelets carry serotonin – a substance in short supply in people with depression – so its conceivable that boosting platelet count in depressed thrombocytopenic individuals will improve mood.” Phase III trials will include quality of life measures to study these potentially important benefits, he added.
Olwen Glynn Owen
Field Reporter

Olwen Glynn Owen

Last updated on: 27/08/2010 11:40:18

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