Neurology: August 2009 Archives
Senator Ted Kennedy succumbed approximately 15 months after his diagnosis of glioblastoma multiforme. In June of 2008, Kennedy underwent neurosurgery at Duke, followed by unspecified chemotherapy (probably temozolomide [Temodar; Schering-Plough]) and radiation therapy at MGH. Kennedy's survival was about 4 months longer than his expected median survival.
Fault the New York Times for what you will, but the paper consistently prints top-notch obituaries. Kennedy's is no exception (although there's been plenty of time to draft it).
Addendum: Highly irreverent, but funny bit from The Onion, America's Finest News Source.
The situation: You plan to launch a novel drug in a therapeutic area, but your sales force has no experience in that therapeutic area. So how do you train your sales force before the drug launch?
Novartis's solution: Obtain approval to market a well-known drug in that therapeutic area before you launch your novel drug.
Today the FDA announced the approval of Novartis's copycat version of Betaseron (Bayer Schering), or subcutaneous interferon beta-1b, for relapsing-remitting multiple sclerosis (RRMS). Novartis's right to market an identical interferon beta-1b product, trade named Extavia, comes by way of an intricate manufacturing deal with Bayer Schering that began 2 years ago.
And all of this maneuvering by Novartis is apparently in anticipation of its launch of fingolimod, a novel oral agent with positive phase 3 clinical data in RRMS. The new drug, also called FTY720, is in an approval horse race with oral cladribine (Merck Serono) for the same indication. Notably, in the United States, Merck Serono has been marketing its own version of interferon beta-1a (Rebif) for RRMS since 2002.
N.B. Novartis does have experience in the neurology market with existing products for Alzheimer disease, Parkinson disease, and epilepsy.
HT: WSJ Health Blog
This month's issue of Lancet Oncology provides a reasonably comprehensive and up-to-date review of progressive multifocal leukoencephalopathy (PML) in the context of monoclonal-antibody (mAb) therapy. The authors draw on data from Northwestern's Research on Adverse Drug Events and Reports (RADAR) project.
Perhaps most surprising is the total number of PML cases that have been reported to date with rituximab treatment—76. Although it's important to remember that the mAb has been on the market for more than 10 years, with greater than 1 million patient exposures (at least according to the drug's web site). By contrast, the latest incidence of PML with natalizumab treatment has been calculated at about 1.2 in 10,000.
A supplemented synopsis of PML with rituximab, natalizumab, or efalizumab therapy is provided here:
Rituximab (Rituxan; Genentech/Biogen IDEC): As of July 29, 2009, a total of 76 cases of PML have been reported in rituximab-treated patients. These cases include 69 oncology patients, 1 patient with autoimmune hemolytic anemia, 5 patients with autoimmune disorders (eg, SLE), and 1 patient whose primary condition is described as unknown. Median time to death is 2 months. Survival in patients with non-Hodgkin's lymphoma is higher in those who develop PML after hemoatopoietic stem-cell transplantation (eg, 38% vs 10%). Rituximab is proposed to increase the risk of PML by indirectly expanding the population of pre-B cells that harbor JC virus.
Natalizumab (Tysabri; Biogen IDEC/Elan): As of July 24, 2009, there have been a total of 11 PML cases in natalizumab-treated patients since the drug's relaunch in July 2006 (multiple sclerosis, 10; Crohn's disease, 1). The risk of PML with natalizumab appears to be increased by the concomitant use of interferon beta and extended monotherapy (eg, ~2 years). Natalizumab may cause PML by enhancing the migration of JC virus-infected CD34+ cells into the CNS.
Efalizumab (Raptiva; Genentech): Four cases of PML were reported with the use of efalizumab, a mAb that was indicated for the treatment of psoriasis. Consequently efalizumab was withdrawn from the US market on June 8, 2009.
Treatment of PML, which is due to the activation (or reactivation) of latent JC* virus in the CNS, has been chiefly informed by experience with PML in patients with AIDS. Therapy requires reconstitution of the immune system (and, in the case of mAb treatment, the discontinuation of the mAb). In patients with AIDS, HAART reduces the severity of PML, but its use in HIV-negative patients is unproven. Treatment with cytarabine is supported by case studies, say the authors. There is also 1 ongoing, international, company-sponsored study of the antimalarial drug mefloquine in PML; however, the outcomes do not include survival endpoints.
AIDS = acquired immunodeficiency syndrome; CNS = central nervous system; HAART = highly active antiretroviral therapy; HIV = human immunodeficiency virus; SLE = systemic lupus erythematosus.
* JC = John Cunningham, a patient with PML (see Padgett BL et al. Lancet. 1971;1:1257-1260.).
Seven Israeli infants who were fed a thiamine-deficient soy-based formula remain moderately to severely neurologically impaired at 5 years. Long-term impairment includes various degrees of mental retardation and motor, brainstem, or basal-ganglia dysfunction. The grave outcomes for these children, who displayed severe epileptic seizures during infancy, are presented in the latest print issue of Neurology.
A total of 20 Israeli infants were "seriously" affected after being fed the kosher baby formula, Remedia Super Soya 1—which was produced in 2003 by Humana, a German company, and imported by Remedia, an Israeli company. Infants quickly developed the known symptoms of cardiomyopathy or neurologic dysfunction that are associated with wet and dry beriberi, respectively. At least 3 infants died. Tests of the formula revealed negligible amounts of thiamine.
In an accompanying editorial, child neurologist Marc Patterson reviews the effects of deficient thiamine, or vitamin B1, which cannot be synthesized or stored to any significant degree by humans. In addition to the long-described forms of beriberi, thiamine deficiency is also manifest in Wernicke encephalopathy and Korsakoff syndrome—amnestic conditions associated with inveterate alcoholism and diencephalic injury. Leigh disease, a metabolic pediatric encephalopathy associated with thiamine deficiency, is neuropathologically similar to Wernicke disease, minus the mammillary-body lesions. Infantile thiamine deficiency, itself, is very rare in developed nations and is seen primarily in infants who are breastfed by thiamine-deficient mothers. It has a better prognosis, however, than Leigh disease.
According to the Jerusalem Post, parents of the affected infants received substantial financial compensation from the formula manufacturer and the Israeli importer. The Israeli State Attorney's office is prosecuting 3 Remedia officials and 5 Health Ministry workers—including pediatrician Dorit Nitzan-Kaluski, the former head of the Food Service Division and coauthor of the 2005 report of the incident in Pediatrics.
Depicted chemical structure of thiamine from Wikipedia.