Safety concerns give Raptiva 'no way back'
Monday , March 02, 2009
Raptiva's safety profile continues to face US and EU regulatory agency scrutiny, which Datamonitor believes will have significant ramifications for the drug's use in psoriasis and any future employment in transplantation. With fresh concern over the safety of Genentech's drug, alternative therapies are likely to impact upon Raptiva's commercial potential, say analysts Datamonitor.
Following a major review of all available safety and efficacy data, the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) has recommended to the European Commission (EC) that Raptiva's marketing authorization should be withdrawn. The CHMP concluded that the benefits of Merck Serono's Raptiva were modest compared with the drug's association with serious side effects including Guillain-Barré and Miller-Fisher syndromes, encephalitis, encephalopathy, meningitis, sepsis and opportunistic infections. The EMEA recommended that EU prescribers should not issue any new prescriptions for Raptiva, also stating that physicians should review the treatment of patients currently receiving the medicine to assess the most appropriate alternatives. This week, Merck Serono reported that it wrote off E195m-worth of technology assets because of significantly lower sales expectations for the drug, an indication that Raptiva's sales will suffer under these safety signals.
At the same time, compounding these significant events in the EU, the FDA's health advisory committee MedWatch issued a medical product safety alert to all dermatologists notifying them of the three confirmed cases, and one reported case, of progressive multifocal leukoencephalopathy (PML) in patients receiving Raptiva. Genentech has repeatedly issued statements regarding Raptiva's safety since its launch in the US in late 2003. In July 2005, the company sent out a warning letter regarding the occurrence of immune-mediated hemolytic anemia. Raptiva's problems continued into October 2008, when Genentech issued a Dear Healthcare Provider letter to inform prescribers of a fatal case of PML. In the same month, the company added a boxed warning highlighting the risk of bacterial sepsis, viral meningitis, invasive fungal disease, PML and other opportunistic infections to Raptiva's label. A second Dear Healthcare Provider letter was issued in November 2008 after another death from PML.
In stark contrast to the EMEA, which called for the suspension of Raptiva's marketing authorization, the FDA has said that it will take appropriate steps to ensure that the risks of Raptiva do not outweigh its benefits, such as asking Genentech to submit a Risk Evaluation and Mitigation Strategy (REMS). This will involve making sure that patients who are prescribed Raptiva are clearly informed of the signs and symptoms of PML, and that healthcare professionals carefully monitor patients for the possible development of the condition.
This is not the first time PML has caused regulatory agencies to take action. Tysabri (natalizumab; Biogen Idec, Elan) was removed from the market in February 2005 due to one confirmed fatal case of PML and one suspected case. The occurrences of PML reported for Raptiva were fewer than those reported for multiple sclerosis (MS) and Crohn's disease drug Tysabri: the proposed incidence of PML for Tysabri is around one in 1,000, whereas there have been only three cases of PML out of an estimated 46,000 patients who have been treated with Raptiva worldwide since its launch (less than one in 15,000). Psoriasis is not a considered life-threatening disease. Patients with severe forms of the illness can have a low quality of life, but it is not a debilitating condition and does not lead to disability. In the dermatology setting, physicians and regulators are less likely to absorb the PML cases positively. In the MS setting, Tysabri is the most effective approved drug and the nature of the disease warrants its use, despite the risks. So far, there have been five cases of PML since the drug was re-launched with its restrictive TOUCH prescribing program in the US in July 2006, an infection rate that is still less than the one in 1,000 warned of in the drug's label. Nearly 18,000 patients have received at least a year of Tysabri. According to a Datamonitor report, there will most likely be additional cases of PML over the coming years, but if the incidence remains under one in 1,000, Tysabri's unparalleled efficacy profile will determine its future requirement by many patients in MS.
The psoriasis market consists of anti-TNFs Enbrel (etanercept; Amgen, Wyeth) and Remicade (infliximab; Centocor, Johnson & Johnson, Schering-Plough, Mitsubishi Tanabe), and more recently Humira (adalimumab; Abbott) and Amevive (alefacept; Astellas), which is a leukocyte function-associated antigen-3 (LFA-3)-immunoglobulin G1 (IgG1) fusion protein. Like Raptiva, Amevive targets T cells, but is available in the US only. While Raptiva launched for psoriasis ahead of Enbrel, its growth has slowed substantially due to the launch of Remicade and Humira.
Recent Datamonitor primary research assessing the prescribing behavior of 180 dermatologists indicated that Raptiva is currently a preferred first- and second-line biologic therapy for psoriasis in the five major EU markets, particularly in Spain and the UK. However, US dermatologists indicated a much greater preference for Enbrel and Humira in this line of therapy. In light of the PML, alternative therapies, including the anti-TNFs, are now likely to capture many of Raptiva's patients.
The future of Raptiva in psoriasis, as well as its chances for development in other indications, looks extremely bleak. Stelara (ustekinumab; Centocor, Johnson & Johnson, Janssen-Cilag), which was approved by the EMEA for psoriasis in January 2009, is hotly anticipated by dermatologists. Stelara is a MAb targeted towards interleukin (IL)-12 and IL-23, and is delivered subcutaneously every 12 weeks. Datamonitor's assessment of physician perception in auto-immune diseases, including psoriasis, indicates that dermatologists rate Stelara highly on attributes such as efficacy, with most respondents scoring it 40% above an average for all biologics in auto-immune disease in terms of predicted efficacy. The ACCEPT study demonstrated that Stelara was superior to Enbrel, a fact that will likely drive uptake of this brand.
Genentech is developing Raptiva for organ transplant rejection, specifically for kidney transplants, and the drug is currently undergoing phase II/III trials. The organ transplant market seeks alternatives to the current oral small molecules that are used. However, these PML cases are likely to spell the end of the road for the drug in this indication. A recent Datamonitor report indicated that, although Raptiva looks interesting conceptually, PML will be a significant barrier to overcome.
Datamonitor does not see a way back for Raptiva in psoriasis. There are other efficacious, safer treatment options for moderate-to-severe psoriasis patients that will replace Raptiva. The anti-TNFs kickstarted Raptiva's downturn, but cases of PML have amplified the situation. The final nail in Raptiva's coffin will be the launch of Stelara, a drug that looks set to become the next big thing in psoriasis.
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