Treating Multiple Sclerosis With Monoclonal Antibodies

Mathias Buttman, MD; Peter Rieckmann, MD, FRCPC

Disclosures

Expert Rev Neurother. 2008;8(3):433-455. 

In This Article

Expert Commentary & Five-year View

We are convinced that the market of disease-modifying RRMS therapeutics will change significantly during the next 5-10 years. On the one hand, new drugs may be approved, which might include some of the mAbs discussed here but also novel orally administered immunomodulators, such as cladribine or FTY720 (fingolimod).[184] On the other hand, the market position of currently approved drugs, especially of NATA, might change owing to new safety data in a larger cohort of patients.

In partial contrast to the inclusion criteria of the NATA Phase III MS trials AFFIRM and SENTINEL,[56,57] NATA was approved in the EU only for patients not sufficiently responding to IFN therapy or for patients with high disease activity as a first-line therapy. This restriction was a compromise based on the observation of PML in two MS patients additionally treated with IFN-β and in one patient with Crohn’s disease having received immunosuppressive therapy before NATA treatment was started.[1,2,3] Currently, more than 20,000 patients worldwide have been treated with NATA monotherapy, and no new PML case has been identified so far. This may allow the cautious conclusion that at least the short-term incidence of PML seems to be significantly lower in patients receiving NATA monotherapy than in patients receiving additional immunomodulatory treatment. As a result, NATA prescriptions might increase in the coming years, mainly at the expense of current baseline therapeutics, such as IFN-β preparations and glatiramer acetate. However, this prediction assumes that the number of PML cases remains low and that no other, so far unrecognized, safety problems such as carcinogenicity are identified.

The manufacturer expects application for ALEM approval for 2011. In our opinion, ALEM approval for RRMS within this time-frame is a realistic goal. Based on the CAMMS223 Phase II trial, ALEM may become a potent monotherapy in RRMS patients, however with a relatively high risk of serious adverse events (autoimmune hyperthyroidism and even more importantly ITP). This profile rather places ALEM as a novel escalation therapy, after IFN, glatiramer acetate and NATA have failed. Furthermore, it seems conceivable that ALEM may be used as a first-line therapy for selected, very highly active RRMS patients, currently treated with mitoxantrone as a first-line therapy. Results of the recently started CARE-MS Phase III trial program, investigating ALEM as a monotherapy in RRMS patients, have to be awaited.

Based on preliminary data of the HERMES Phase II trial,[143] it seems conceivable that RTX may become an additional treatment option for patients with RRMS. Since this trial included only 104 patients it is too early to speculate about the possible position of RTX on the market of RRMS therapeutics. The currently conducted OLYMPUS trial raises hope in PPMS patients that a disease-modifying drug may become available to them.[144] So far, there is no approved disease-modifying treatment for approximately 10-15% of MS patients, experiencing a primary progressive course. Despite our strong wish that RTX proves to be effective in PPMS patients and despite indicators that this important trial studies a PPMS cohort with rather high inflammatory disease activity, we have to admit that efficacy of RTX in PPMS would be a surprise to us.

Based on preliminary data of the CHOICE Phase II trial,[183] DAC shows modest efficacy and a favorable adverse-effect profile when used as an add-on therapy to IFN-β treatment in RRMS patients. A Phase III trial has to confirm these results before DAC may become the first approved drug for immunomodulatory add-on therapy in RRMS. The planned SELECT Phase II trial will investigate DAC as a monotherapy for RRMS patients.

Of course the outlook presented here is based on a large number of uncertainties, as exemplified by the unexpected occurrence of PML in NATA-treated patients. Long-term safety data in MS patients for the highly specific immunoactive drugs discussed here are a special need. However, even if details are not really predictable we are optimistic that the next 5-10 years will bring a significant improvement of disease-modifying MS therapy, including the approval of new drugs. One important issue for the future will be the identification of immunological subtypes of MS (e.g., B cell-mediated demyelination) in individual patients, thereby allowing a more focused application of the highly selective mAbs. Furthermore, the development of novel methods allowing risk assessment of a drug in individual patients will be another important step towards a more personalized disease-modifying MS therapy.

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