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FDA Grants Priority Review to GSKs ITP Drug Promacta: the drug increases platelet counts; phase III studies for use in HCV are still ongoing
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04 March 2008
wwww.pharmatimes.com
· The FDA have granted priority review for Promacta for the short term use of Promacta in previously treated chronic ITP patients ONLY
· This review does not cover any data for the use of Promacta in HCV/cirrhotic patients
· Phase III HCV Promacta studies are now ongoing (as previously communicated to you; NCT00516321 and NCT00529568 on http://www.clinicaltrials.gov) and this data will be filed separately with the agencies for review upon completion of these studies.
"After four weeks of treatment in chronic HCV patients, once-daily doses of PROMACTA at 30mg, 50mg and 75mg resulted in elevated platelet counts ≥100,000/μL in 75% (9/12), 79% (15/19) and 95% (20/21) of patients respectively compared to no platelet elevations ≥100,000/μL in patients receiving placebo (p<0.001). Treatment with PROMACTA enabled 71% (30mg dose) to 91% (75mg dose) of patients to initiate antiviral therapy. Up to 12 weeks of antiviral therapy were completed by 36% (5/14), 53% (10/19) and 65% (15/23) of patients in the 30mg, 50mg and 75mg PROMACTA groups, respectively, versus 6% in the placebo group.1...During the four-week pre-antiviral treatment phase, the most common drug-related adverse events (AEs) (generally of mild severity) were dry mouth, headache and nausea."
GlaxoSmithKline has received some good news on the regulatory front after it was announced that US regulators have granted a priority review to the firm's Promacta, an experimental drug designed to treat a rare blood disorder.
The US Food and Drug Administration will look at Promacta (eltrombopag), an oral platelet growth factor therapy being developed to treat chronic idiopathic thrombocytopenic purpura, or ITP. The speeded-up review means that the agency will decide on whether to approve the drug over a six- rather than 10-month period.
ITP is characterised by increased platelet destruction or inadequate platelet production in the blood, which causes an increased risk of bruising and bleeding. There are estimated to be 60,000 people diagnosed with chronic ITP in the USA and a similar number in Europe and GSK plans to submit a marketing application there in 2008, where it will be sold as Revolade.
Eltrombopag was discovered as the result of a research collaboration, begun in 1997, between GSK and Ligand Pharmaceuticals, whose share price shot up over 8.5% to $3.68 when the FDA's decision was announced. The priority review "is very encouraging", said Paolo Paoletti, senior vice president for oncology at GSK, adding that the firm's goal is to make available "a targeted therapy in oral form for patients to help raise their platelet counts without having to suppress the immune system".
The fact that Promacta is delivered orally is expected to give the firm an advantage over Amgen's injectable Nplate (romiplostim) which is set to be reviewed by the FDA's Oncologic Drugs Advisory Committee on March 12. That treatment also has priority review status.
In pivotal studies, the most common adverse events observed in patients taking promacta were headache, nausea, nasopharyngitis, diarrhea and vomiting.
GSK also plans to submit a Marketing Authorization Application (MAA) for eltrombopag in the treatment of chronic ITP in Europe in 2008 where it will be marketed as REVOLADE(R).
Analysts believe that Promacta could be a $1 billion product.
Two studies in the New England Journal of Medicine demonstrated that Promacta (eltrombopag) significantly raised platelet counts in patients with chronic hepatitis c-associated thrombocytopenia and chronic idiopathic thrombocytopenic purpura (ITP)
Data from phase II studies published today in the New England Journal of Medicine (NEJM) report that GlaxoSmithKline's (GSK) investigational compound PROMACTAş (eltrombopag) significantly raised platelet levels in patients with thrombocytopenia (low number of platelets in the bloodstream). The studies were conducted in chronichepatitis C (HCV)[1] (where thrombocytopenia complicates disease treatment) and chronic idiopathic thrombocytopenic purpura (ITP)[2] (where thrombocytopenia increases The risk of bleeding and bruising). Elevating platelet counts in these settings can provide important patient benefits.[3], [4], [5] PROMACTA is an investigational oral, non-peptide platelet growth factor that induces the proliferation and differentiation of cells to produce platelets.[6],[7]
PROMACTA has not received regulatory approval in any market for any indication at this time.
"Thrombocytopenia significantly impacts the clinical progression and ability to successfully treat certain diseases, including chronic hepatitis C and chronic ITP," said Paolo Paoletti, MD, Senior Vice President, Oncology Medicine Development Centre, GSK. "These two studies in the New England Journal of Medicine demonstrated that PROMACTA has the potential to raise platelet counts in these patient populations, which is a critical need to improve treatment. We are committed to the ongoing development of this compound by continuing to study it across several disease categories and work towards providing thrombocytopenia patients with the convenience of an oral therapy."
Trial design - Phase II chronic hepatitis C-associated thrombocytopenia
The study was an international, multicenter, double-blind, randomized, placebo-controlled, dose-ranging Phase II trial. Seventy-four HCV-infected patients with platelet counts between 20,000 and 70,000/mL were randomized to receive PROMACTA (30mg, 50mg, or 75mg daily) or placebo for four weeks (pre-antiviral phase). The primary endpoint was a platelet count increase to≥100,000/mL at week four. Patients could then initiate antiviral therapy and continue PROMACTA or placebo for 12 additional weeks (antiviral phase).
Results - Phase II chronic hepatitis C-associated thrombocytopenia
After four weeks of treatment in chronic HCV patients, once-daily doses of PROMACTA at 30mg, 50mg and 75mg resulted in elevated platelet counts ≥100,000/μL in 75% (9/12), 79% (15/19) and 95% (20/21) of patients respectively compared to no platelet elevations ≥100,000/μL in patients receiving placebo (p<0.001). Treatment with PROMACTA enabled 71% (30mg dose) to 91% (75mg dose) of patients to initiate antiviral therapy. Up to 12 weeks of antiviral therapy were completed by 36% (5/14), 53% (10/19) and 65% (15/23) of patients in the 30mg, 50mg and 75mg PROMACTA groups, respectively, versus 6% in the placebo group.1
During the four-week pre-antiviral treatment phase, the most common drug-related adverse events (AEs) (generally of mild severity) were dry mouth, headache and nausea. Headache was the most common AE, reported in 36%, 16% and 17% of patients who received PROMACTA 30mg, 50mg and 75mg respectively, compared with 17% on placebo. In the antiviral treatment phase - which includes the addition of pegylated interferon alfa plus ribavirin - the most commonly reported AEs were flu-like illness (29%, 26% and 35% in the 30mg, 50mg and 75mg PROMACTA groups respectively), fatigue (29%, 26% and 22% in the 30mg, 50mg and 75mg PROMACTA groups respectively), chills (0%, 32% and 9% in the 30mg, 50mg and 75mg PROMACTA groups respectively) and headache (21%, 16% and 13% in the 30mg, 50mg and 75mg PROMACTA groups respectively).1 The adverse events most commonly reported during this phase were influenza-like illness, fatigue, chills, and headache, all of which are known side effects of interferon-based therapy. The results have supported the initiation of Phase III studies in patients with thrombocytopenia and chronic HCV infection.
"These results published in the NEJM article will be welcomed by clinicians who are familiar with the complications of chronic hepatitis C treatment," said John McHutchison, MD, Professor of Medicine and Associate Director, Duke Clinical Research Institute, Durham, North Carolina, USand lead author on this study. "Thrombocytopenia can seriously inhibit the optimal treatment of chronic hepatitis C - not only can it delay or prevent the administration of effective doses of antiviral therapy, but in some cases treatment may be terminated prematurely because of low platelet counts. In this study, PROMACTA, compared to placebo, increased platelet counts and enabled more patients to complete the first 12 weeks of antiviral therapy, giving them an opportunity to achieve sustained viral response, which is a critical goal in the treatment of these patients. We look forward to the results of the larger, Phase III clinical trials to confirm these initial observations in a larger patient population."
Trial design - Phase II chronic ITP
The study was a multicenter, randomized, double-blind, placebo-controlled trial examining once daily oral dosing of PROMACTA. One hundred and eighteen adults with chronic ITP and platelet counts <30,000/mL who had relapsed or were refractory to at least one ITP treatment were randomized to PROMACTA (30mg, 50mg, or 75 mg), or placebo. The primary endpoint was the proportion of patients with a platelet count ≥50,000 per cubic millimeter after up to six weeks of dosing.2
Results - Phase II in chronic ITP
After six weeks of treatment in chronic ITP patients, PROMACTA at daily doses of 30mg, 50mg and 75mg elevated platelet counts to ≥50,000/μL in 28% (8/29), 70% (19/27) and 81% (21/26) of patients respectively compared to 11% (3/27) of patients receiving placebo (p<0.001). After seven days of treatment 44% and 62% of patients receiving PROMACTA 50mg and 75mg, respectively, achieved a platelet count of ≥50,000/μL. After 15 days, 88% and 81% of patients receiving PROMACTA 50mg and 75mg respectively had responded, with the average platelet counts approaching the normal range (i.e., 150-400,000/μL). Platelet counts rose to >200,000/μL in 4% (1/27) of placebo-treated patients and in 14% (4/29), 37% (10/27) and 50% (13/26) of PROMACTA 30mg, 50mg and 75mg-treated patients respectively. The incidence of bleeding events assessed by the World Health Organization bleeding scale was 17%, 7% and 4% in the PROMACTA 30mg, 50mg and 75mg arms respectively versus 14% in the placebo arm.2
PROMACTA was generally well tolerated in this study. The most common AE, mild-to-moderate headache, was observed at similar rates in both the PROMACTA 30mg (13%), 50mg (10%), 75mg (21%) and placebo (21%) arms. At least one AE was reported in 47%, 47% and 61% of patients in the PROMACTA 30mg, 50mg and 75mg groups respectively, compared with 59% in the placebo arm.2
Based on the results from this global study theauthors concluded that PROMACTA shows promise as an efficacious short-term therapy with over 80% of PROMACTA treated patients achieving the trial's primary endpoint to increase platelet counts to ≥ 50,000/μL within two weeks.2
"Traditional treatments for ITP, such as glucocorticosteroids and intravenous immunoglobulins, focus on reducing platelet destruction," said James B. Bussel, MD, director of the PlateletDisordersCenter, Children's Blood Foundation Division at New York-Presbyterian Hospital/Weill Cornell Medical Center and lead author for this study. "These treatments are associated with a high rate of relapse and may have undesirable side effects. The Phase II results published by NEJM suggest that PROMACTA may not only significantly raise platelet counts in most patients with ITP, but be well tolerated."
Data from an open label extension study (EXTEND)assessing the long-term safety and efficacy of PROMACTA will also be presented at the forthcoming American Society of Hematology 49th Annual Meeting, December 8-11th in Atlanta, GA.
Ongoing PROMACTA Clinical Trials
There are several PROMACTA trials investigating long-term and repeated treatment of chronic ITP.[8] EXTEND (Eltrombopag eXTENded Dosing Study) is an open-label study for patients who had participated in previous PROMACTA trials and were eligible to receive PROMACTA for the long-term treatment of their chronic ITP. RAISE (RAndomized placebo controlled ITP Study with Eltrombopag) is a global, randomized, double-blind, placebo-controlled Phase III trial currently assessing the safety, efficacy and tolerability of PROMACTA in a long-term treatment setting (up to six months) involving 189 patients across 135 centers in 26 countries. REPEAT (Repeat ExPosure to Eltrombopag in Adults with Idiopathic Thrombocytopenic Purpura) involves 50 patients with chronic ITP and will assess the safety and efficacy of repeated administration of PROMACTA. Both RAISE and REPEAT are closed to patient enrollment.
Two parallel trials investigating PROMACTA in the treatment of HCV-associated thrombocytopenia are currently open and enrolling. ENABLE 1 and 2 (Eltrombopag to INitiate and Maintain Alpha interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE) are Phase III, parallel, multi-center, two-part studies assessing the ability of PROMACTA to raise platelet counts sufficiently to permit the initiation of antiviral therapy and to allow sustained antiviral therapy in patients with chronic HCV and thrombocytopenia.
For further information on the trials please visit www.itpstudy.com or www.clinicaltrials.gov.
To access the full manuscript please visit: www.NEJM.org.
About PROMACTA
PROMACTA is an oral, non-peptide thrombopoietin receptor agonist that has been shown in pre-clinical research and clinical trials to stimulate the proliferation and differentiation of megakaryocytes, the bone marrow cells that give rise to blood platelets, and thus can be considered a platelet growth factor.[9] The efficacy and safety profile will be further examined in ongoing clinical trials. PROMACTA was discovered as a result of research collaboration between GlaxoSmithKline and Ligand.
PROMACTA is an investigational compound that has not received regulatory approval in any market for any indication at this time.
About Chronic Idiopathic Thrombocytopenic Purpura
Chronic ITP is characterized by inadequate platelet production and increased platelet destruction. Its cause is currently unknown. Some patients with ITP are asymptomatic or have mild bruising while others develop more serious bleeding that can be life-threatening.[10] A routine blood test is used to measure platelet count and a normal blood platelet count is ≥150,000/μL and …400,000/μL.[11] A reduction in platelet count to a level <150,000/μL is the defining characteristic of any type of thrombocytopenia. An endpoint of >50,000/μL was selected because at a platelet count of <50,000/μL there is a higher risk of developing bleeding complications from low platelet counts. This is consistent with products previously approved to treat chronic ITP and is considered as a target platelet count in chronic ITP treatment guidelines.
About Thrombocytopenia and Chronic Hepatitis C
A reduction in platelet count to a level <150,000/μL is the defining characteristic of any type of thrombocytopenia and diagnosis can be confirmed following a routine blood test. Thrombocytopenia occurs in 5% - 10% of all patients hospitalized for any cause.[12] The severity of thrombocytopenia varies. Mild to moderate cases may resolve spontaneously without treatment, however severe thrombocytopenia can be associated with significant morbidity and mortality.[13],[14] The cause of thrombocytopenia associated with chronic hepatitis C is multi-factorial: inadequate thrombopoietin production by damaged liver, bone marrow suppression by alpha interferon or viruses (HCV), sequestration of platelets in the spleen and increased platelet destruction from an associated autoimmune process.
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