Ofatumumab, an investigational B-cell therapy being developed by Novartis, demonstrated encouraging results in lowering relapse rates and active brain lesions in people with relapsing multiple sclerosis (MS) enrolled in the ASCLEPIOS trials.
For Stephen L. Hauser, MD, an investigator in the ASCLEPIOS trials, these results represent a decades-long journey to better understand MS and what he calls a “magnificent success story” in the overall treatment of the disease.
According to Hauser, who presented the trial data last month at the 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), these results warrant a deeper exploration to determine ofatumumab’s effects on “silent” progression, or progression independent of relapse activity (PIRA), along with its dose-dependent and long-term benefits in lessening disability progression.
Efforts have been focused on so-called anti-CD20 therapies — antibodies that homes in on a specific protein called CD20 on the surface of B-cells, targeting these cells for destruction and resulting in B-cell depletion.
Ofatumumab is one such antibody and may represent a highly effective and more convenient option for patients, as it is administered by an under-the-skin injection that can be done at home.
Monthly injections of ofatumumab proved superior to Aubagio (teriflunomide) pills to treat both relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS) in the Phase 3 ASCLEPIOS I and II trials (NCT02792218; NCT02792231). The therapy led to a more than 50% decrease in relapse rate, and more than 90% reduction in active brain lesions, compared with Aubagio.
“Ofatumumab shuts down new focal inflammatory activity nearly completely. It reduces relapse-independent disability progression, and at least in the clinical trial data to date, it has a very favorable safety profile. I believe that clinicians should consider the use of highly effective therapy with an agent like ofatumumab very early in the disease course,” said Hauser, who is a professor of neurology and the director of the University of California, San Francisco (UCSF) Weill Institute for Neurosciences.
With a research focus on the genetic basis, immune mechanisms, and treatment of MS, Hauser’s work has been instrumental in developing B-cell therapies for MS. He was involved in the early research and clinical trials that ultimately led to the approval of Ocrevus in 2017 in the U.S.
“In the ofatumumab trials, there were also some patients who improved from baseline [study start],” he said. However, this is likely “a result of the body’s inherent repair mechanism that is unleashed when disease activity is turned off, rather than to any direct regenerative effect of ofatumumab.” But, he adds, the exact reason for this improvement is still not known and will continue to be studied.
Despite the impressive results favoring ofatumumab’s efficacy in the trials, the effects on six-month confirmed disability improvement were not statistically significant compared with Aubagio.
Hauser believes that a longer monitoring period might be needed. “There was a strong trend favoring a beneficial effect of ofatumumab versus [Aubagio], and I would predict that with larger numbers of patients or longer duration of follow-up … these strong trends would become statistically significant.”
Ofatumumab vs. Ocrevus and rituximab
Ofatumumab’s promising results in the ASCLEPIOS trials raises questions as to its benefits compared with other anti-CD20 B-cell therapies such as Ocrevus and rituximab, but no head-to-head studies with these therapies have been done yet.
The decision to compare ofatumumab with Aubagio in the ASCLEPIOS trials “was made by Novartis in consultation with our advisory committee,” Hauser said. “There is no perfect comparator drug. Had we chosen a more highly effective comparator, the trial would have needed to be much larger to demonstrate superior efficacy.”
Without studies directly comparing ofatumumab with Ocrevus or rituximab, “true comparison is not possible, and there is great danger in inferring relative value from different trials performed at different times,” Hauser said.
However, he points out, “one advantage of ofatumumab is that it can be administered at home by the patient without need to visit an infusion center or clinic for intravenous administration,” as Ocrevus and rituximab require.
Another advantage is that “ofatumumab is a fully human antibody molecule unlike a chimeric or humanized molecule that has some mouse protein,” as do Ocrevus and rituximab. It’s argued that this could potentially lower the chance that patients will develop antibodies against the medicine, known as anti-drug antibodies, which decrease a treatment’s effectiveness over time.
Furthermore, “even though these three monoclonal antibodies, and a fourth called ublituximab, currently in development, are all targeting CD20, they target different regions of the CD20 molecule and neutralize B-cells in overlapping but different ways. So these drugs are not true biosimilars and should not be assumed to be equivalent,” Hauser said.
He also notes that there are advantages of into-the-vein (intravenous) infusion therapies like Ocrevus and rituximab, one being “that the drug is administered far less frequently — only once every six months, compared with an injection that needs to be administered monthly. In addition, intravenous infusions ensure that the patient has received the medication and there is less of a problem with compliance-related issues.
“But in general, I think that the results of the three trials to date with rituximab, [Ocrevus], and ofatumumab look roughly similar in that all are highly effective against the relapsing component of MS, and suggest a benefit on relapse-independent progression as well,” Hauser said.
Possibilities for inactive SPMS and PPMS
“Patients with inactive disease today and secondary progressive MS could have active disease in six or 12 months sometime down the road, so disease activity is a phenomenon that fluctuates over time,” Hauser said.
Because those with inactive SPMS were not included in the ASCLEPIOS trials, Hauser cautions “against extending any conclusions beyond the patient populations specifically studied.”
Data presented at ECTRIMS was a summary of the earliest analyses of the trials, but “a deeper exploration of this data is ongoing, and will certainly result in more information that can be disseminated,” he said.
“Data from multiple sources now convincingly indicate that multiple sclerosis is a unitary disease with inflammatory and neurodegenerative features present in most or all patients. Progressive MS begins the day that MS begins in most or all patients. We don’t detect it early on because patients are young, and they have resilient nervous systems that are able to repair and compensate for the damage that occurs.
“It is likely that B-cell therapies as a class will be effective against the neurodegenerative progressive component of MS, but that the size of the effect will be determined by the duration of the progressive symptoms, being more effective the earlier that treatment is started during the disease course,” he said.
A dose dependency may also occur, with higher doses being more effective, although the safety consequences of different doses will need to be defined in well-controlled clinical studies in the future.
Evolution of MS therapies
There are a number of important metrics that have not yet been fully explored with ofatumumab.
One is “the effect of ofatumumab on relapse-independent progression, known as ‘silent’ progression, or PIRA — progression independent of relapse activity — during relapsing multiple sclerosis,” Hauser said.
“Understanding if there is a dose or exposure dependency of ofatumumab on progression variables” is another important metric, as is a longer-term follow-up of patients enrolled in the ASCLEPIOS “to identify both safety and efficacy over longer periods of time,” he said.
For Hauser, “it’s been a 42-year generational journey to see the evolution of our understanding of the biology of multiple sclerosis.
“The results have been clearly that patients whose MS is just beginning can reasonably expect dramatic benefits in terms of halting their long-term disability. They can aspire to a life free from disability, and I think that this is a magnificent success story not only for the B-cell therapies but with the other highly effective therapies that approach different pathways involved in the MS disease process.
“This is a story that needs to be appreciated by the public. It supports the public’s investment in basic biomedical research, and in the training of clinician-scientists who every day move from the bench to the bedside and back,” Hauser concluded.
Novartis plans to submit a marketing application to the U.S. Food and Drug Administration for ofatumumab to treat relapsing MS by the end of this year. Under the brand name Arzerra, ofatumumab is already FDA-approved to treat certain leukemias.