April 23, 2011 – In the history of flawed and/or market-withdrawn drugs, Lumiracoxib [Joicela], formely known as [Prexige], may only be a footnote, hardly comparable to the attention received by the high flying but ill-fated Rofecoxib [Vioxx], Troglitazone [Rezulin], and more recently Rosiglitazone [Avandia].
However, Lumiracoxib [Prexige] may make a mark after all in the history of pharma beyond its missed revenue opportunity or beneficial impact on patients. The drug is a selective COX-2 inhibitor, indicated for symptomatic relief of pain from osteoarthritis. COX-2s inhibitors, such as the infamous Rofecoxib [Vioxx], seem all but off the market in the US because of their cardiovascular side effects. Lumiracoxib [Prexige] seems to bind to a different site on the COX-2 receptor, which may give it advantages that lift it from under the Rofecoxib [Vioxx] shadow: minimal cardiovascular side effects, high selectivity, rapid clearing from the circulation and absorption into the inflamed joint.
Lumiracoxib [Prexige] received European marketing authorization in November 2006 and was launched in parts of Europe the following year. Because of its own safety shortcomings such as rare but potentially fatal liver injury at higher doses, from 2007 onwards, Lumiracoxib [Prexige] was withdrawn from most European markets, as well as from the Australian and Canadian markets. Lumiracoxib was never approved by the American Food and Drug Administration (FDA), mostly for safety reasons.
Could the biomarker DQA1*0102 rescue Lumiracoxib?
In a recent study by Singer et al., published in 2010 in Nature Genetics 42, pages 711-714, a case-control genome-wide association study was performed on 41 Lumiracoxib-treated patients with liver injury (cases) and 176 matched Lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 x10 to -10). These findings were replicated in an independent set of 98 Lumiracoxib-treated cases and 405 matched Lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 x 10 to -12). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501 -HLA-DQB1*0602 -HLA-DRB5*0101 -HLA-DQA1*0102, most significant allele P = 6.8 x 10 to -25, allelic Odds ratio = 5.0, 95% CI 3.6 – 7.0).
In princip, these results offer the potential to improve the safety profile of Lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from Lumiracoxib treatment. In fact, Novartis Pharma, the makers of Lumiracoxib, applied with the European Medicines Agency (EMEA) for a centralized marketing authorisation for Lumiracoxib [Joicela], in December 2009. According to this application, Lumiracoxib [Joicela] was intended, in a 100 mg film-coated tablet form, to be used for symptomatic relief in the treatment of osteoarthritis of the knee and hip in patients who are non-carriers of the DQA1*0102 allele. In essence, patients who test negative for the DQA1*0102 allele are expected to have a low risk for the development of serious liver side effects and could therefore safely take the drug. Those patients who test positive for the DQA1*0102 allele, however, should not get the drug.
This approach would constitute the first example throughout the pharmaceutical industry where a biomarker strategy rescued a drug, previously withdrawn from the markets because serious adverse effects (i.e., liver injury). For the pharmaceutical industry, such a strategy for rescuing drugs previously flawed by serious drug adverse effects may hold tremendous appeal (cases such as Exanta, Galvus, etc., come to mind), even if the ultimate market for such rescued drugs may be nowhere near the original projections.
Lumiracoxib [Joicela] and its companion test: Not quite there yet
As we learned by mid-April 2011 from an announcement by the European Medicines Agency (EMEA), the application of the marketing authorisation for Lumiracoxib [Joicela] was withdrawn by Novartis. At the time of the withdrawal it was under review by the Agency’s Committee for Medicinal Products for Human Use (CHMP).
In its official letter, the company stated that its decision to withdraw the application was based on its inability to address the CHMPs request to provide additional data within the time frame allowed in the centralised registation procedure. We should take note here that withdrawal of an application does not prejudice the possibility for the company to make a new application at a later stage. In any case, more information about Lumiracoxib [Joicela] and the state of the scientific assessment at the time of withdrawal will be made available in a question-and-answer document. This document, together with the withdrawal letter from the company, will be published on the Agency’s website after the next CHMP meeting on 16 to19 May 2011.