MIRROR: Threshold Identified for Ofatumumab Therapy in MS

April 29, 2014

PHILADELPHIA — Further analysis of data from the phase 2 study with the anti–B cell antibody ofatumumab (Arzerra, Genmab) has suggested that an optimal dose can be found that will give maximal suppression of multiple sclerosis (MS) lesions without completely eradicating all B cells.

Ofatumumab, which is targeted against the CD20 epitope on B cells, is already available as a treatment for chronic lymphocytic leukemia (CLL), but it is being developed for autoimmune diseases under a collaboration agreement between Genmab and GlaxoSmithKline (GSK). It is similar to the other anti–B cell antibody, ocrelizumab (Genentech/Biogen Idec), which is now in phase 3 trials for MS.

Preliminary topline results of the phase 2 study with ofatumumab in MS, known as the MIRROR study, were released in October 2013 by GSK and reported by Medscape Medical News. These showed significant reductions in gadolinium-enhancing lesions with all doses of the drug vs placebo.

Latest results show a linear relationship between suppression of B cells and residual annualized disease activity, with a minimum disease activity of 1 new lesion per year at a threshold of approximately 32 to 64 cells/μL. This compares to 16 new lesions per year without treatment.

Presenting the new analysis at the American Academy of Neurology (AAN) 66th Annual Meeting, Daren Austin, PhD, from GSK UK, explained that the study included a large range of doses in an attempt to pinpoint the lowest dose for significantly reducing MRI lesion activity.

B Cell Threshold Identified

He commented to Medscape Medical News: "We know already that IV [intravenous] doses of 200 mg are very effective at depleting B cells. But rather than using a dose that depletes B cells to below the level of detection, we wanted to see how much B cell suppression was actually necessary to get the maximum effect on multiple sclerosis lesions in the brain.

"And we found that there is a threshold of 32 to 64 cells/μL, below which there is no additional benefit," he said. "This will allow us to define the optimal dose of ofatumumab to give the maximum response without giving too much drug and possibly exposing the patient to additional unnecessary adverse effects."

Dr. Austin would not reveal what that optimal dose is. He said, "We are still fine-tuning some of our assessments to make sure we have identified the lowest dose to give maximal effect, but we will endeavor to keep the vast majority of patients below 32 B cells/μL."

"These results present a possible new target threshold for exploration of therapeutic benefit in relapsing-remitting MS patients undergoing anti-CD20 therapy to give the maximal efficacy," he concluded.

He added: "B cells are involved in the immune response, and presumably it is better to have some B cells around than none at all. When we started developing this drug for MS we wanted to start from first principles. So we looked at doses starting from those that would cause no depletion to those that would give full depletion, so we could find the exact point where MS lesions are maximally reduced with the minimum dose. We are evaluating all phase 2 data before making a definite decision about exactly which dose to take forward to larger trials."

For the MIRROR study, 231 patients with relapsing-remitting MS were randomly assigned to 1 of 4 doses of ofatumumab or placebo. The 4 doses were 3 mg every 12 weeks, 30 mg every 12 weeks, 60 mg every 12 weeks, and 60 mg every 4 weeks. After 12 weeks, the placebo group received 3 mg of ofatumumab. The study treatments were given for 24 weeks. The primary endpoint was suppression of MRI lesion activity during the first 12 weeks.

Results suggested a 90% or greater reduction in the cumulative number of new T1 gadolinium-enhancing lesions for all cumulative doses of ofatumumab 30 mg or greater during weeks 4 to 12.

Table. MIRROR Study: Effect on New Lesion Development of Various Doses of Ofatumumab

Dose Patients (n) Mean Lesions per Scan (n) Reduction vs Placebo (%) P Value
Placebo 67 0.84  
3 mg every 12 wk 33 0.25 71 .002
30 mg every 12 wk 32 0.09 90 <.001
60 mg every 12 wk 33 0.08 91 <.001
60 mg every 4 wk 63 0.07 92 <.001

 

New lesions did appear in the first 4 weeks, which the researchers said was "not surprising" because once the inflammatory process has started, the cascade of events has been put into motion.

The study was supported by GSK. American Academy of Neurology (AAN) 66th Annual Meeting. Abstract S23.006. Presented April 29, 2014.

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