Saturday, January 10

Will the anti-B-cell therapies (Rituximab) supplant Campath (alemtuzumab) and Tysabri (natalizumab) in MS?

"Rituximab is a B cell depleting agent that works in MS. The phase 2 results were spectacular and shifted the paradigm in MS. The anecdotal experience from the off-label use of rituximab in MS has confirmed this; I have personally used rituximab in a handful of cases and have been very impressed with its ability to switch-off disease activity."

"Due to complex, scientific and business, reasons Genentech-Roche decided against taking rituximab forward in MS. Instead they decided  to develop the follow-on compound ocrelizumab. This latter decision will delay the access of an anti-CD20 therapy for MSers by about 4 years.
 At the time Genentech-Roche made  the decision not to develop rituximab and to go with ocrelizumab a lot of us felt this was unacceptable, because it would be denying or delaying MSers access to a very effective therapy.

 Despite our protests the decision was made and the ocrelizumab program is now quite advanced. There are currently three phase 3 ocrelizumab studies running (two in RRMS and one in PPMS) that are due to report in late 2015 and early 2016. The question is not about whether or not ocrelizumab will be effective or not, but rather about safety. There is little doubt that ocrelizumab will be a highly effective DMT. Will it be safe? The rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE) ocrelizumab development programmes were halted due to safety concerns. Whether or not the same safety issues will arise in MS is yet to be ascertained. I suspect not as MSers are generally much healthier than people with severe RA and SLE. Ocrelizumab will also be an induction therapy and will be given every 6 months for at least 2 years. What is not known is how often redosing will be needed after completing the first 2 years of treatment. The phase 2 extension results presented at the AAN, by Prof. Hauser and suggest that the treatment effects may last at least 18 months, and may be longer, after the last dose. What this NMO study below provides is a framework for developing a redosing schedule based on the recovery of peripheral B cells counts."

"Why the paradigm shift? Anti-CD20 therapies target B cells by depleting them from the peripheral blood and to some extent from  the peripheral tissues. What nobody expected was for these therapies to be so effective in MS; MS was always considered to be a T-cell mediated disease. B cells are the immune cells that make antibodies and are also involved in other immune functions. The B cell is also the niche where EBV resides once you become infected with the virus. Therefore anti-CD20 therapies are also anti-EBV drugs; in fact rituximab is the only licensed drug to treat EBVassociated diseases. In short anti-CD20 therapies have multiple potential modes of action. The onset of action of anti-CD20 therapies is too quick, i.e. within weeks of dosing, for them to be having their effect via antibody production. Most of feel the mode of action anti-CD20 therapies in MS must be related to its impact on the other immunological functions or against EBV. Because of the latter I have branded the anti-CD20 therapies as being anti-EBV and challenge people in the field to prove that these drugs are not working via EBV. Unfortunately, to date no one has risen to the challenge."

"Apart from ocrelizumab (Roche) GSK is currently developing ofatumumab for MS; both drugs target CD20 on the surface of B-cells. Another target is CD19, which to me is even more appealing than CD20 as it is expressed on a larger number of cells including plasmablasts. At present we are recruiting RRMSers for a trial of MEDI-551, which is an antibody that depletes B cells via the CD19 receptor ("