Treating Multiple Sclerosis with Monoclonal Antibodies: A 2010 Update

Mathias Buttmann

Disclosures

Expert Rev Neurother. 2010;10(5):791-809. 

In This Article

Ocrelizumab

Ocrelizumab is a humanized monoclonal IgG1 mAb against CD20.[92,93] It was derived from the murine anti-CD20 mAb 2H7. Compared to RTX, OCRE binds to a different, but overlapping epitope of the large extracellular loop of CD20.[93] It is being developed by Genentech (Basel, Switzerland)/Roche (CA, USA) and Biogen Idec.

Indications

As of February 2010, OCRE was not FDA- or EMEA-approved for the treatment of human disease. It was successfully tested in a placebo-controlled Phase I/II dose-finding study in 237 patients with active RA (A Study to Evaluate the Safety of Escalating Doses of Ocrelizumab in Subjects with Rheumatoid Arthritis [ACTION]),[94] and positive interim results were reported in 2007 from a Phase I/II trial in RTX-pretreated patients with non-Hodgkin lymphoma, which has not yet been finally published.[95] OCRE is currently undergoing a large Phase III program for RA, where it was recently announced to have met its primary end point in the Study of Ocrelizumab Compared to Placebo in Patients with Active Rheumatoid Arthritis Continuing Methotrexate Treatment (STAGE) trial, but was also associated with a higher rate of serious infections.[213] Further Phase III RA trials and a Phase III lupus nephritis trial were partially or completely put on hold in 2009 owing to opportunistic infections, not further specified by the manufacturer until December 2009.[214] As detailed later, OCRE was further investigated in a Phase II trial in patients with RRMS, where it was recently announced to have met its primary end point.[214]

Modes of Action

Like RTX, OCRE acts as a B-cell-depleting mAb via ADCC and CDC. However, in comparison to RTX, OCRE was found to induce increased ADCC and decreased CDC.[92] As infusion-related adverse reactions after RTX administration are mainly attributed to CDC,[96] OCRE might theoretically induce less infusion-related AEs than RTX. In a placebo-controlled clinical trial investigating OCRE as an add-on treatment in 237 patients with RA on methotrexate therapy, infusion-associated mild-to-moderate AEs were observed in 51% (placebo 27%) of the patients after the first infusion and in 17% (placebo 20%) after the second infusion 2 weeks later. No infusion-associated serious AEs were reported in this trial.[94] Patients were allowed parallel treatment with up to 10 mg prednisolone equivalent per day and with nonsteroidal drugs, which might have influenced the incidence of infusion reactions. Study participants did not receive intravenous glucocorticosteroid infusions prior to OCRE administration. A direct comparison of OCRE with RTX has not been published to date.

Pharmacology & Human Anti-human Antibodies

After administration of two doses of 10, 50, 200, 500 or 1000 mg OCRE 2 weeks apart in patients with RA rapid peripheral B-cell depletion was observed in all patients. However, more rapid B-cell recovery was observed in the low-dose groups receiving 10 or 50 mg, while peripheral B-cell kinetics were comparable in patients receiving doses of more than 200 mg. On average, absolute B-cell counts in the high-dose groups returned to a third of baseline levels within 72 weeks, and were above the lower limit of normal (40 per µl) in more than half of the patients at that time point.[94]

The presence of human anti-human antibodies was inversely correlated to the administered OCRE dose in the ACTION trial.[94] While 19% (seven out of 36) of patients receiving 10 mg, and 10% (four out of 40) receiving 50 mg, had detectable human anti-human antibodies, 0% receiving 200 mg (zero out of 40) and 500 mg (zero out of 40), and 5% (two out of 40) receiving 1000 mg tested positive at weeks 2, 4, 12, 24 or 36. No relationship was reported between the presence of human anti-human antibodies and adverse effects or clinical efficacy in patients with RA.[94]

Ocrelizumab for MS

A partially blinded Phase II multicenter trial conducted in the USA compared two doses of OCRE with placebo and once-weekly intramuscular IFN-β1a (Avonex®) injections in 250 patients with RRMS (NCT00676715). The total number of Gd-enhancing MRI lesions at weeks 12, 16, 20 and 24 was defined as a single primary outcome measure. The same primary end point had been chosen for the completed Phase II HERMES trial, investigating RTX in patients with RRMS.[81] Annualized relapse rate, proportion of relapse-free patients and change of total T2 lesion volume at week 24 were defined as secondary end points. The study started in April 2008 and was recently announced to have met its primary end point.[214]

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