IHS Global Insight Perspective | |
Significance | European marketing of psoriasis drug is to be suspended with immediate effect. Prescribers have been advised to seek alternative treatments for their patients. |
Implications | Three confirmed cases of progressive multifocal leukoencephalopathy (PML) prompted an EMEA review of Raptiva, which found that the drug's risks outweighed its benefits. Meanwhile, the U.S. FDA has issued a public health advisory over these same three PML cases, and warned that a review will be forthcoming. |
Outlook | The FDA is likely to follow the EMEA in recommending a marketing suspension for Raptiva. However, the long-term impact is likely to be more noticeable for its European marketer Merck Serono than its U.S. producer Genentech. |
Raptiva's EU Marketing Status Withdrawn
The European Medicines Agency (EMEA) has recommended the immediate suspension of European Union (EU) marketing authorisation for psoriasis drug Raptiva (efalizumab), following a review that found its safety risks outweighed its benefits to patients. Though the recommendation is still awaiting final legal backing from the European Commission, national drug safety agencies across the 24 EU member states in which Raptiva is marketed have wasted no time in replicating the information provided by the EMEA, and issuing warnings to patients and prescribers.
Raptiva is marketed by German biopharmaceutical company Merck Serono in Europe, and by U.S. biotech Genentech in the United States. It works by suppressing the LFA-1 protein on the surface of lymphocytes, which are the cells that cause skin inflammation in psoriasis patients. However, this action also causes immune suppression, which can leave patients more vulnerable to infections. Merck Serono's total Raptiva sales grew by 22% year-on-year (y/y) and reached 93 million euro (US$117.3 million) in 2008, while Genentech derived turnover of US$108 million from the drug, representing a 1% y/y gain.
Safety Concerns Pile Up
Following confirmed reports of three cases of progressive multifocal leukoencephalopathy (PML) between September 2008 and January 2009 in patients taking Raptiva for more than three years, the EMEA's Committee for Medicinal Products for Human Use (CHMP) began a review of all risk-benefit data on Raptiva that had become available since its EU market launch in September 2004. PML is a rare brain infection that often leads to severe neurological disability or death, and two of the three PML cases reported in Raptiva patients ended fatally. There is currently no cure or treatment for the condition. The CHMP concluded that Raptiva's "modest" benefits were outweighed by risks, and used the following points to justify its decision:
- PML is an established risk for patients taking Raptiva
- The drug is also associated with the risk of side effects such as Guillain-Barré syndrome, Miller-Fisher syndrome, encephalitis, encephalopathy, meningitis, sepsis, and opportunistic infections
- There is no accurate way to determine if a patient subpopulation exists for whom Raptiva's benefits outweigh its risks. This means that simply limiting Raptiva's approved patient population instead of removing it from the market completely is an unfeasible option
- The arrival of other treatments for psoriasis on the European market since Raptiva's launch means that there are treatment alternatives available
The EMEA has advised physicians not to make any new prescriptions for Raptiva and to review all patients currently taking the drug with a view to finding a suitable alternative treatment. Patients themselves have been advised not to suddenly stop their treatment with Raptiva, but to seek their doctor's advice on switching therapies. Clinical trials on Raptiva may be halted, depending on the verdict of the authorities of the EU member states in which the trials are being carried out, but the EMEA has expressed its view that such trials should continue in case they shed light on Raptiva's safety and efficacy in patients for whom other treatments are not suitable.
When Raptiva was first approved in the EU, it was as a treatment for adult patients with moderate to severe chronic plaque psoriasis who have either failed to respond, are contraindicated, or intolerant to existing systemic therapies. In the years since its approval, other chronic plaque psoriasis drugs to have been approved in Europe include those of three large U.S companies: Schering-Plough's Remicade (infliximab), Abbott's Humira (adalimumab), and Amgen's Enbrel (etanercept).
FDA Issues Public Advisory
Raptiva has also been making headlines on the other side of the Atlantic, after the U.S. FDA issued a public health advisory on the drug yesterday. The advisory concerned the same three cases of PML, and also highlighted a fourth, unconfirmed, case that resulted in the patient's death. According to the FDA, none of the four patients had been taking any other immune suppressants. The agency has vowed to determine whether Raptiva's risks outweigh its benefits, and also to ensure that patients know how to recognise PML symptoms, and that physicians monitor patients on Raptiva for these symptoms.
Raptiva's U.S. labelling has sported a boxed warning on the risk of life-threatening infections—including PML—since October 2008. Genentech has a risk evaluation and mitigation strategy in place for the drug, following an FDA request last year.
Outlook and Implications
Raptiva was one of Merck Serono's fastest-growing drugs in 2008, but a write-down on production technology assets related to the drug during the fourth quarter meant that Raptiva's overall contribution to the company's performance was one of loss. Further write-downs can now be expected in 2009 and, combined with the effects of the sudden drop in sales, this may cause Merck Serono to reassess its expectations for full-year income. The German firm has already refused to provide financial guidance for 2009 because of the volatility of the financial markets. Strong sales growth of existing top sellers such as Erbitux (cetuximab), and the timely development and launch of six late-stage research and development compounds are now more essential than ever (see Germany: 18 February 2009: Merck Serono Closes 2008 with 12% Y/Y Sales Growth, But Outlook for 2009 Uncertain).
In the United States, the clinical evidence linked to PML, and the existence of several well-known alternative treatments for chronic plaque psoriasis suggests that the FDA's review of Raptiva's risk-benefit profile will be similarly negative to that of the CHMP. If this is the case, Raptiva could face a possible U.S. marketing suspension by the end of 2009. However, the drug's performance will not be as critical to Genentech's bottom line. Of greater importance to the group's future is the ongoing tug-of-war with majority shareholder Roche (Switzerland), which is pursuing its hostile takeover offer by appealing directly to Genentech's shareholders (see United States: 10 February 2009: Roche Commences Genentech Tender Offer, Bid Details Emerge). Increased potential for colorectal and lung cancer drug Avastin (bevacizumab) in early-stage and adjuvant settings should also help offset losses from a possible Raptiva withdrawal.
The devastating effects of PML were central to the CHMP's findings and the EMEA's subsequent recommendation for marketing suspension, and the infection looks set to play a similar role in the FDA review. This raises questions over the well-documented risk of PML in another drug; multiple sclerosis (MS) treatment Tysabri (natalizumab), produced by Irish biotech Elan and U.S. drug maker Biogen Idec. IHS Global Insight believes that greater vigilance over Raptiva's PML links will not cause a knock-on effect for Tysabri. The MS treatment's risk of PML has been widely documented, and recently reported cases have remained within the incidence rate reported on the drug's labelling (see Ireland: 16 December 2008: Pressure Mounts on Elan, Biogen as Tysabri is Linked to Fourth PML Case). Also, patients taking Tysabri are faced with a much more serious and debilitating disease than those taking Raptiva, and with a current lack of next-generation MS treatments on the market, Tysabri can still benefit from its unique status in a way that Raptiva cannot.