麻豆传媒

STOCKHOLM -- Ofatumumab, a B-cell targeting monoclonal antibody being evaluated for relapsing forms of multiple sclerosis (MS), outperformed teriflunomide (Aubagio) in reducing annualized relapse rate (ARR), according to two phase III studies presented here.

In the trial, monthly injections of ofatumumab showed a 50.5% relative reduction in ARR compared with oral teriflunomide; in , the ARR of ofatumumab bested that of teriflunomide by 58.5%.

Ofatumumab also had a favorable safety profile with no unexpected safety signals, said Stephen Hauser, MD, of the University of California San Francisco, in a late-breaking scientific session at the ECTRIMS congress.

"The absolute numbers of relapses -- the annualized relapse rate of about one [relapse] in 10 years -- may come close to the floor that we're going to be able to see in a population of this type," Hauser said. "There were low relapse rates in teriflunomide, but very, very low relapse rates in the ofatumumab group."

Like ocrelizumab (Ocrevus), which was approved in 2017 for relapsing and primary progressive MS, and (Rituxan), which is used off-label in MS, ofatumumab binds to CD20 molecules, resulting in B-cell depletion. In 2009, ofatumumab was approved to treat chronic lymphoid leukemia under the brand name Arzerra.

ASCLEPIOS I and II were with identical design, eligibility, and analysis plans. In both studies, researchers randomized relapsing MS patients -- 927 patients in ASCLEPIOS I and 955 patients in ASCLEPIOS II -- 1:1 to ofatumumab (20 mg every 4 weeks by subcutaneous injection, after an initial loading dose) or teriflunomide, a pyrimidine synthesis inhibitor (14 mg by mouth daily). Besides treatment, patients in the ofatumumab group took a sham pill daily and patients in the teriflunomide group had a sham injection every 4 weeks.

At baseline, participants were an average age of about 38 and had an average Expanded Disability Status Scale () score of about 3 -- indicating mild to moderate disability, but no impairment in walking -- on the 10-point disability assessment tool. Their MS symptoms appeared about 8 years ago and about 60% of participants had been treated previously with other disease-modifying therapies before the study started.

Patients on ofatumumab had a 50.5% reduction in ARR compared with patients on teriflunomide (0.11 vs 0.22) in ASCLEPIOS I and a 58.5% reduction (0.10 vs 0.25) in ASCLEPIOS II (both P<0.001).

Ofatumumab reduced disability worsening, with a pooled analysis showing a 34.4% reduction in disability worsening at 3 months versus teriflunomide and a 32.5% reduction at 6 months. Compared with teriflunomide, ofatumumab also demonstrated (P<0.001 for all):

• A 97.5% relative reduction in the number of gadolinium-enhancing T1 lesions in ASCLEPIOS I and a 93.8% reduction in ASCLEPIOS II
• A 82.0% relative reduction in the number of new or enlarging T2 lesions in ASCLEPIOS I and a 84.5% reduction in ASCLEPIOS II
• Relative reductions in serum neurofilament light levels starting with the first assessment in month 3 and at all subsequent assessments for 2 years

There was no difference in the slope of brain volume change from baseline between the two treatments. Ofatumumab showed a favorable trend toward confirmed disability improvement, but it was not significantly different compared with teriflunomide.

In each treatment group, about 84% of patients experienced adverse events, most commonly injection-related reactions, nasopharyngitis, and headache. Similar proportions in each group had serious adverse events. Five patients in the ofatumumab group (0.5%) and three patients in the teriflunomide group (0.3%) developed malignancies.

"B-cell therapies have been used in other autoimmune diseases -- they're approved for rheumatoid arthritis -- but they are incrementally valuable," Hauser told 麻豆传媒 after the presentation. "In MS, the effect size is so unprecedented."

"We were sure that it was right in the rituximab and in the ocrelizumab trials, but to see it again is really something," he continued. "We're being told something about the cause of this disease that's very profound. This could send us on a path to a cure."

With ocrelizumab, there's extension study data about relapse rates and disability for about 7 years, but the long-term effects of ofatumumab are unknown, Hauser added. From the patient standpoint, self-injected ofatumumab may be more appealing than IV infusion treatments like ocrelizumab, noted Mar Tintore, MD, PhD, of University Hospital Vall d'Hebron in Barcelona, who was not part of the ASCLEPIOS trials.

"The advantage for the patient can be significant; you can give the treatment yourself," Tintore said. But the downside with ofatumumab is that clinicians are less sure about the drug's administration, she pointed out. "We're a little bit afraid to not control the treatment," she said. "With IVs, we know the patient has received the treatment. We're more aware of what happened."

An extension study of ofatumumab is ongoing and will continue for up to 5 years. In 2015, Novartis obtained rights for the drug in all indications from Genmab including MS; the company plans to start submissions for FDA approval by the end of 2019. If approved, ofatumumab could be the first B-cell therapy MS patients can administer at home.

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