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GSK, Ligand Dealt Blow as U.S. FDA Committee Casts Doubts Over Promacta's Efficacy
29 May 08
Uncertainty looms over the U.S. approval of blood-clotting drug Promacta (eltrombopag) as an FDA advisory committee has deemed the drug not significantly better than placebo in reducing bleeding.
Global Insight Perspective | | Significance | The U.S. FDA has made publicly available one of its advisory committee's conclusions on GlaxoSmithKline (GSK)'s platelet-boosting and blood-clotting drug Promacta. The bottom line is that the committee felt that the submitted clinical data were not "robust" enough to support the proposed labelling. | Implications | GSK, which is set to meet with the FDA tomorrow to discuss Promacta's NDA, will has some serious legwork to do to convince the U.S. regulator to go against its committee's recommendations when evaluating the drug. Realistically, the review is likely to delay Promacta's U.S. market entry. | Outlook | The committee's conclusions cast doubt over the approvability of Promacta. This leaves the field wide open for rival drug Nplate, which was previously unanimously backed by the FDA's advisory committee and is expected to clinch marketing authorisation within the next two months. Worryingly for GSK, long-term safety concerns over its drug could not only toll the bell on the IPT indication but also on any other indication extension where long-term use of Promacta would be required. |
U.K. pharmaceutical company GlaxoSmithKline (GSK) and development partner Ligand Pharmaceuticals Inc. (U.S.) were dealt a blow when the U.S. FDA Oncologic Drugs Advisory Committee (ODAC)'s conclusions on blood-clotting drug Promacta (eltrombopag) were published on the regulator's website yesterday. The review was made available ahead of tomorrow's meeting between GSK and the U.S. regulator during which Promacta's New Drug Application (NDA) will be discussed. GSK, which is responsible for the drug's licensing, is seeking Promacta's approval for the short-term (six weeks) treatment of chronic idiopathic thrombocytopenic purpura (IPT) in relapsing patients. The drug's proposed U.S. labelling states that Promacta is designed to boost platelet counts and prevent bleeding. The ODAC raised the following main points: - the clinical data, submitted as part of the application, do not support the drug's labelling as a statistical reviewer found that "the decrease in bleeding events from baseline is generally similar between eltrombopag and placebo";
- the proposed short-term indication does not reflect the chronic nature of the disease;
- patients relapse upon treatment discontinuation;
- uncertainty remains over long-term safety data, as animal studies have suggested that chronic treatment with Promacta induces hepatic, renal and ocular toxicity; and
- in light of the potential long-term risks associated with the drug's uptake, the ODAC has questioned the "appropriateness" of GSK's proposed risk-management plan.
Chronic IPT is an auto-immune disease that affects an estimated 60,000 Americans. The disease results in platelet destruction and inappropriate blood clotting. In rare cases chronic IPT is deadly. Current treatments consist of corticosteroids, intravenous gamma globulin, anti-D immunoglobulin and in some extreme cases, treatment with immunomodulatory drugs. According to the National Institutes of Health's National Heart Lung and Blood Institute (NHLBI), there are approximately 150 new cases per every 1 million people reported each year in the United States. Outlook and Implications The ODAC's conclusions do not bode well for GSK and Ligand. Although the final decision on the drug's commercial future in this indication lies with the FDA, the U.S. regulator usually follows its committee's recommendations. Nevertheless, there is a possibility that the FDA and GSK could come to some sort of backup plan for Promacta tomorrow but this is likely to delay the drug's regulatory approval. This is all the more heartbreaking for the two development partners that are currently in a race to get their drug approved ahead of rival product Nplate (romiplostim, Amgen, U.S.), which is expected to be approved by 23 July 2008 (see United States: 11 April 2008: Three-Month Delay for Amgen as FDA Extends Nplate Risk-Management Review). Up till now, GSK had hoped to come out on top as the FDA granted Promacta orphan status in March (see United Kingdom: 4 March 2008: GSK's Platelet-Count Boosting Drug Promacta Gets FDA Priority Review Status), reducing the evaluation time from 10-12 months to six months and meaning that its regulatory fate should theoretically have been sealed by 19 June 2008. The news casts even more of a shadow on Promacta's potential as a short-term treatment for chronic IPT as the ODAC unanimously recommended rival drug Nplate for regulatory approval (see United States: 13 March 2008: FDA Advisory Committee Recommends Approval of Amgen's Platelet Drug). While Amgen's drug seems set to be approved, it is far from being certain for Promacta. A quick fix-up could be to modify the drug's label to reflect its platelet-boosting ability and reduce emphasis on the bleeding control claims. Nevertheless, this could position Amgen's drug as a stronger contender in the segment, should both drugs clinch regulatory approval. The other thorn in GSK's side is the long-term safety concerns surrounding the drug. There is a significant chance that the drug be used off-label for periods extending beyond six weeks as chronic IPT is a long-term condition and patients relapse upon Promacta-treatment discontinuation. It is highly likely that the FDA will demand long-term safety data before allowing the commercialisation of the drug. Although the trials are ongoing, it will add to the delays that GSK can now expect. If the safety data are unfavourable, it could also affect the drug's future in its other pursued indications, namely hepatitis C-associated thrombocytopenia and chemotherapy-induced thrombocytopenia (see United Kingdom: 31 October 2006: GSK's Promacta Boosts Platelet Counts in Hepatitis C-Associated Thrombocytopenia). Europe will also be watching closely as GSK intends to file the drug for European regulatory approval, under the name Revolade in the second half of the year.
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