Mechanism of action: I have heard it said that the development of compounds without a well-understood mechanistic target is ‘bad science’. There are many such compounds used as pharmaceuticals, so this may represent an extreme or even naive view. Various hypotheses have been advanced for DMF’s mechanism of action, including modulation of the intracellular redox system resulting in consequential effects on nuclear factor kappa B, TNF-alpha, interleukin (IL)-8 and IL-1b. From then, we see effects on anti-inflammatory cytokines such as IL-10 and IL-1RA; decreased expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selectin; stimulation of TH1 and down-regulation of TH2 T-cell subtypes; and induction of apoptosis in antigen-presenting cells and induction in anti-inflammatory stress protein heme oxygenase 1.
But no precise mechanistic target: so is this a deficiency in the regulatory package that Biogen-Idec will submit to the FDA; or if not, how will it address this question?
Reversible leucopenia, lymphopenia and transient eosinophilia are also frequently observed . Leucopenia occurs in a quarter of patients [8,29]. A reduction in lymphocyte count occurs in around 70% of patients [6,8,25,29] and can exceed 50% in about 10% of patients . The dose of Fumaderm® should be reduced if lymphocytes fall below 0.5x109/L or leucocytes fall below 3.0x109/L; if blood counts improve, treatment can continue at the reduced dose, but otherwise Fumaderm® should be stopped . It has been reported that patients with lymphopenia are significantly more likely to show improvement in psoriasis than those whose lymphocyte count stays within the normal range [6,22,24].
In particular,Biogen recently posted some troubling information about the safety and effectiveness of Panoplin (dimethyl fumarate) capsules, also known as BG-12, on a publicly accessible website.43 In addition to constituting unlawful, pre-approval promotion of an unapproved drug product, the website contained animal toxicology data suggesting that dimethyl fumarate ("DMF"), the active ingredient in BG-12, may carry potential risks for renal adverse events.
43 Panoplin Website Screenshots (Exhibit 7) (accessed December 6, 2012). The website for Panoplin is active and publicly available at http ://warden.7te.net/index.html . Although it was revised in mid-December to refer to "Product X," it currently contains detailed product information about Panoplin as a "new" and "approved" oral MS medicine in direct contravention of FDA's pre-approval promotion restrictions.
44 Panoplin Website Screenshots (Exhibit 7).
45 Recent scientific evidence also suggests that DMF may be associated with PML and KS . In trials, BG-12 therapy resulted in substantial declines in white blood cell and lymphocyte counts, and grade 3 or higher lymphopenia (lymphocyte counts ofless than 0.5x 109 per liter) was seen in between 4% and 5% of patients in the BG-12 groups versus less than 1% in the placebo groups. Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis, New England Journal of Medicine, 367:12, pp. 1087-1097 (Sept. 20, 2012);
Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis, New England Journal of Medicine, 367:12, pp. 1098-1107 (Sept. 20, 2012). Although there were no reported cases of PML or KS in the pivotal clinical trials for BG-12, at least three cases of PML and one case of KS have been reported in patients treated with Fumaderm.
"PML as a complication of BG-12 therapy is a potential risk that is currently undefined. The risk is likely to be very low and limited to patients with lymphopaenia. We will monitor your blood counts for lymphopaenia and if your counts drop too low we would obviously stop the drug."
Tysabri use is currently limited to between 10 and 12 percent of treated MS patients, due to the risk of PML, and analysts said the hoped-for wider approval would improve uptake and send a positive signal to doctors.
Berenberg analysts said Tysabri's share of the MS market could increase to about 15 percent by 2015, representing sales of $2.9 billion, while today's share price for Elan implied peak sales of only some $2 billion.
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