Ofatumumab Shows Efficacy & Safety in New MS Patients

Only a few weeks prior to MSVirtual2020, the fully human anti-CD20 monoclonal antibody ofatumumab was approved by the FDA for the treatment of relapsing multiple sclerosis (MS). In the open-label extension study ALITHIOS, ofatumumab’s safety profile was shown to be consistent with data from the core phase 3 ASCLEPIOS I/II trials.

“Ofatumumab is the first FDA-approved high efficacy disease-modifying therapy that can be self-administered at home, as demonstrated in the phase III ASCLEPIOS trials,” says principle investigator and presenter at MSVirtual2020, Stephen Hauser, MD. “Despite the availability of many disease-modifying therapies for treatment of relapsing multiple sclerosis, there remains an unmet need for highly efficacious therapies that have a favorable safety profile and are easy to use,” he says.

The indication of ofatumumab is for clinically isolated syndrome, relapsing-remitting MS, as well as active secondary progressive MS in adults, and self-administered by a once-monthly injection, delivered subcutaneously.

Study Breakdown

In the ASCLEPIOS trials, ofatumumab demonstrated superior efficacy versus teriflunomide and a favorable safety profile in relapsing MS patients; ofatumumab reduced the annualized relapse rate by 51% (0.11 vs 0.22) and 58% (0.10 vs 0.25) in ASCLEPIOS I and II, respectively (P<0.001 in both studies) [1]. Long-term safety data from these cohorts continue to be collected within the open-label phase 3b ALITHIOS extension study, which was reported at MSVirtual2020.

Participants came from three sources (n=1,230): patients who were randomized to ofatumumab in the phase 2 APLIOS (12 weeks) or phase 3 ASCLEPIOS I/II (up to 30 months) trials and continued in ALITHIOS (median duration of ofatumumab treatment: 21 months); patients who completed/discontinued the core study yet continued in the safety follow-up; and the patients (n=643) who were randomized to teriflunomide in ASCLEPIOS I/II and then crossed over to ofatumumab in ALITHIOS (median duration of ofatumumab treatment: 4.4 months). The overall exposure was 2,118 patient-years.

Minimal Safety & Adverse Events

Overall safety at 2 years was promising. The most frequently reported adverse events (AEs) in ALITHIOS were injection-related reactions and upper respiratory tract infections. Most reported AEs were mild-to-moderate in severity. The overall safety profile was consistent with reports from the core ASCLEPIOS I/II trials. There were no deaths. In the cross-over group, injection-related reactions were mild-to-moderate; none were serious or led to treatment discontinuation. With regard to AEs of special interest, there were no opportunistic infections, hepatitis B reactivation, or progressive multifocal leukoencephalopathy events. Also, there were no new cases of malignancies in either the continuous or cross-over patients. This post-hoc analysis with safety extension data indicates that extended exposure to ofatumumab does not appear to pose increased risk, and opens the door for long-term use in MS patients.

In commenting on the study, Asaff Harel, MD, Assistant Professor of Neurology at Lenox Hill Hospital/Hofstra School of Medicine/Northwell Health, New York City, says, “This is a subgroup analysis of the newly FDA-approved B-Cell therapy that is administered subcutaneously once a month. The idea is that it allows people to take control of their own schedule if they want.”

Dr. Harel says injections are similar to people with diabetes taking insulin injections, and self-injection is common among older patients with MS who have been on injectable medications for that disease. “The good news about this is that the treatment is just once monthly, and the injection site reactions reported in the study were much milder than what we have observed with other medications,” he says.

“This particular group of patients did not have experience with subcutaneous injections, so that made it an interesting group to analyze. Compliance appeared to be really, really good, and I think that speaks to the fact that the injection site reactions weren’t too bad,” he continues. “We know that ofatumumab is a highly-efficacious option, and this analysis shows us that even as a first-line option and with relatively small numbers, there was still an effect in slowing disability compared to teriflunomide.”

Insights from Senior Investigator, Phase 3 ASCLEPIOS I/II Trials, Stephen Hauser, MD

In an in depth interview with Physician’s Weekly, Dr. Hauser helps contextualize his recent presentation of data at MSVirtual 2020. “The ASCLEPIOS studies found that ofatumumab produced a significant reduction in new inflammation, as well as fewer clinical relapses and progression events. These new data speak to the long-term safety profile of ofatumumab. This is one of the great success stories in modern molecular medicine. MS relapses are really in the rear-view mirror,” Dr. Hauser says.

He continues, “There is a 99% effect size of B-cell therapies on new areas of scarring, new areas of sclerosis, and with that, relapses are brought down to extraordinarily low levels. What we have learned is that when we eliminate relapses, we can see progression in most people with MS from day 1, so-called ‘silent progression’ [3,4]. Now we recognize that the two faces of MS, a focal adaptive inflammatory component and a neurodegenerative component, aren’t distinct, but form a continuum.”

The ability to completely control new focal scarring and demyelination has changed the treatment of MS, according to Dr. Hauser. The clinical goal is control of progression. He advises that clinicians need to begin to pivot from a “treat-to-target” concept to more of a cancer model, considering inducing remission with subsequent monitoring and maintenance. “For neurodegenerative problems, complete remission would be elimination of disease progression above the surface but also below the surface.”

Dr. Hauser points out that because researchers are grasping what’s below the surface, it’s time to target the pathophysiology. “My take-home message is that we will judge these B-cell therapeutics by their efficacy in halting progressive disease, and the mode of administration will matter.”

Based on solid data, the ongoing hypothesis is that relapses are mediated by B-cells in the bloodstream, and the periphery that migrate to the nervous system and that progression are mediated by B-cells that are already in the nervous system and protected there in niches, ectopic lymphoid follicles. “We are going to compare ofatumumab with ocrelizumab and other B-cell drugs on the horizon, as well as BTK inhibitors, and maybe CD38 or CD19 inhibitors, based on how well they do against progression,” says Dr. Hauser. “I think that we have solved the relapsing aspect of this disease. To me this is one of the enormous success stories of medicine; there are real advantages to ofatumumab because it is a fully human molecule. After the first dose there is really zero evidence of any injection reaction that was greater than placebo. The safety over 2 years looks very good.”

Dr. Hauser says that ultimately, for relapsing patients, right-sizing the dose of B-cell therapy and understanding this concept of ‘treat maximally at onset’ will deliver the greatest benefit. He feels the greatest effects against progression are soon to come with regard to the drugs, the regimen, and the method of administration. “In the next couple of years, researchers really need to laser in on accelerating the efficacy against progression, convenience for the patient, and safety.”


Dr. Hauser has no relevant disclosures.
Dr. Harel disclosed relationships with Biogen, Banner Life Sciences, and Alexion.


  1. Hauser SL, et al. N Engl J Med. 2020;383:546–57.
  2. Cross AH, et al. MSVIRTUAL2020, Abstract P0234.
  3. Hauser SL. JAMA. 2020;324(9):841-842.
  4. Greenfield AL, Hauser SL. Ann Neurol. 2018;83(1):13-26.