Ofatumumab Impresses in MS; Competition for Ocrelizumab Soon?

September 16, 2019

STOCKHOLM ― A new B cell–depleting anti-CD20 monoclonal antibody has shown impressive results in two phase 3 studies in relapse-remitting multiple sclerosis (RRMS).

Ofatumumab (Novartis) yielded a reduction in relapse rates of more than 50%, a reduction in disability progression of more than 30%, and a reduction in gadolinium-enhancing T1 lesions of more than 90% in comparison with teriflunomide (Aubagio, Sanofi Genzyme) in the ASCLEPIOS I and II trials. Tolerability was also good; adverse events were similar in the ofatumumab and teriflunomide groups, and there were no unexpected safety signals.

The findings were presented at last week's 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019.

Ofatumumab, under the brand name Arzerra, is currently available for the treatment of chronic lymphoid leukemia. Approval applications for use in MS, for which it is expected to have a different brand name, are expected by the end of the year.

The drug will provide competition for ocrelizumab (Ocrevus, Genentech/Roche), the first B cell–depleting anti-CD20 drug approved for MS, which became available in 2017.

Both drugs have shown similarly good efficacy against active controls (ocrelizumab was compared with interferon β-1a in its pivotal studies). The main difference between the two products is the route of administration. Ocrelizumab is given as an IV infusion every 6 months, which requires medical supervision; by contrast, ofatumumab is administered by monthly subcutaneous injection, which can be done by the patient at home.

Presenting the data from the ASCLEPIOS trials, Stephen Hauser, MD, University of California, San Francisco, concluded: "Ofatumumab ― with a monthly 20-mg subcutaneous injection dosing regimen following a 3-dose load ― demonstrated a very high efficacy and a favorable side effect profile."

Asked how the new drug compared with ocrelizumab – for which Hauser also led the phase 3 studies in RRMS – he said that subcutaneous dosing is "an attractive feature.

"A fully humanized molecule is also an attractive feature," Hauser said. "Both molecules have attractive mechanisms of action. I would say that at least at the 35,000-foot level, we are looking at similar efficacy, but a more definitive answer will have to wait for a deeper dive into the data."

On the different routes of administration, he added: "Young people who may not be compliant may do well with a treatment under observation. Many other people would prefer a home-based therapy."

Commenting for Medscape Medical News, the co-chair of the session at which the ASCLEPIOS studies were presented, Tobias Derfuss, MD, University Hospital of Basel, Switzerland, said: "This is very interesting data showing very strong effects on relapse rates and disability and very impressive MRI data, especially gadolinium-enhancing lesions, which were dramatically reduced. When you take into account this was against teriflunomide as an active comparator, this makes it even more convincing."

Regarding how it will compare with ocrelizumab, Derfuss suggested that infusion-related reactions may be less frequent with ofatumumab. "Ocrelizumab can cause infusion-related reactions and needs a pretreatment for this. No pretreatment was given with ofatumumab, and infusion-related reactions seemed less severe."

For clinicians who may have to choose between the drugs, Derfuss said it will probably come down to patient preference regarding the route of administration.

"Ocrelizumab is given just once every 6 months, so that's convenient in one way," he said. "Patients only have to think about their MS twice a year, but they have to come to the clinic. With ofatumumab, they can do subcutaneous injections at home, and they won't have to come to the clinic at all. Some patients will prefer that."

On the other hand, he added, "the infusions with ocrelizumab mean that the physician can control the treatment ― we know if the patient is compliant because we give the treatment. If the patients give themselves treatment at home, we won't be able to control whether they are actually receiving it."

ASCLEPIOS Data

The ASCLEPIOS I and II trials, which had identical double-blind double-dummy designs, compared subcutaneous ofatumumab with oral teriflunomide (14 mg once daily).

Hauser noted that the ofatumumab injection has "a very small volume ― just 0.4 mL." It was given under observation for the first 3 weekly doses of 20 mg each. Then at home, patients continued to self-administer with monthly injections.

Asked why teriflunomide was used as the comparator, Hauser said that the question as to which drug to use as comparator had been the subject of considerable discussion. "The rationale was that we wanted to have a comparator that would be present not only against focal disease activity but also potentially against progression, and we were also able to blind the study successfully," he commented.

Each trial enrolled around 900 patients with typical, active relapsing MS who had been neurologically stable for the month preceding enrollment. The average duration of MS at baseline was 8 years, and the average number of relapses in the past year was 1.3; 60% of patients had previously been treated with a disease-modifying therapy, and the average score on the Expanded Disability Status Scale was 2.9.

The primary endpoint was annualized relapse rate (ARR) in each study separately. For this endpoint, there were significant reductions with ofatumumab of 50.5% in ASCLEPIOS I and 58.5% in ASCLEPIOS II.

Table 1. Primary Endpoint: Annualized Relapse Rate

  ASCLEPIOS I ASCLEPIOS II
Teriflunomide Ofatumumab Relative Reduction Teriflunomide Ofatumumab Relative Reduction
ARR 0.22 0.11 50.5% (P < .001) 0.25 0.10 58.5% (P < .001)

 

"We saw a low relapse rate with teriflunomide but a very, very low relapse rate with ofatumumab. The absolute numbers of relapses in the ofatumumab group ― which work out to about one in 10 years ― may come close to the floor that we are going to able see in a population of this type," Hauser stated.

The key secondary endpoints were confirmed disability worsening at 3 and 6 months and confirmed disability improvement at 6 month as a pooled analysis of the two studies together. For these results, there were significant reductions of 3-month disability worsening of 34% and 6-month disability worsening of 32%. In addition, there was a favorable trend of a 35% increased chance of disability improvement that did not reach significance.

MRI Results "Stunning"

For MRI results, there was a greater than 95% reduction in focal gadolinium lesions with ofatumumab, which Hauser referred to as "quite a stunning result." There was a similar reduction in rates of new or enlarging T2 lesions, but of slightly less magnitude, he reported.

Table 2. MRI Results

  ASCLEPIOS I ASCLEPIOS II
Teriflunomide Ofatumumab Relative Reduction Teriflunomide Ofatumumab Relative Reduction
Gd+ T1 lesions 0.45 0.01 97.5% (P < .001) 0.51 0.03 93.8% (P < .001)
New or enlarging T2 lesions 4.00 0.72 82% (P < .001) 4.15 0.64 84.5% (P < .001)

 

On an analysis of neurofilament light chain levels, a biomarker of disease activity, levels remained quite stable in the teriflunomide group, but significant reductions of 7% to 11% were seen in the ofatumumab group by month 3 and of 23% to 24% by month 24, which Hauser described as "quite remarkable."

In contrast, the slope of brain volume change from baseline, although trending in favor of ofatumumab, was not statistically significant.

"This was not unexpected, as we know from previous studies that teriflunomide has quite a remarkable effect on halting brain volume loss. But it is interesting to compare the discordant results between the neurofilament levels and the brain volume atrophy data, which suggest that preserving brain volume is not always the same thing clinically or biologically," Hauser commented.

Adverse events were well balanced between the two groups, with no unexpected safety problems.

Serious adverse events were also low and were balanced. Three malignancies occurred in the teriflunomide groups, vs five in the ofatumumab group, but two of the cancers in the ofatumumab were preexisting, "so I don't think there is a malignancy imbalance," Hauser said.

Regarding injection site reactions, there was only an imbalance between the ofatumumab and sham groups with the first injection, "and even then, reactions were only seen in a minority of patients," Hauser reported. Only one patient discontinued the study because of an injection site reaction.

The ASCLEPIOS studies were funded by Novartis. Hauser serves on boards for Annexon, Alector, Symbiotix, Bionure, and Neurona and has received travel reimbursement from Roche and Novartis for CD20-related meetings and presentations.

35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019: Abstract 336, presented September 13, 2019.

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