Switching from Rituxan to Ocrevus: An Interview with Dr. Timothy Vollmer on Both MS Treatments
A multiple sclerosis (MS) trial now underway in Colorado is assessing the safety and tolerability of switching from Rituxan (rituximab) to Ocrevus (ocrelizumab), and its lead investigator, Dr. Timothy L. Vollmer, largely expects no problems. The neurologist believes the two Genentech therapies — both antibody-based drugs that target the CD20 molecule on B-cells — have much in common.
“My sense is that the drugs are very, very similar, so I don’t expect any major differences,” Vollmer told Multiple Sclerosis News Today. “I don’t expect that patients switching will have any more severe reactions on ocrelizumab than they had on rituximab. But we really don’t know yet.”
That’s the reason for the Phase 3 clinical trial (NCT02980042) in 200 relapsing and progressive MS patients underway at the University of Colorado in Aurora, where Vollmer is director of neuroscience clinical research as well as medical director of the Rocky Mountain Multiple Sclerosis Center.
The trial will evaluate the move from the older off-label treatment to Ocrevus, which the U.S. Food and Drug Administration (FDA) approved in March as the first-ever therapy for both forms of the disease. Vollmer does think — indeed, he said he is already seeing — that many patients will jump to the newer drug. He wants to be sure the switch is safe for his patients, and to better understand what reactions might arise.
Our interview shows a pragmatic scientist at work, eager to advance knowledge of MS treatment options, share insights — and freely speak his mind.
A ‘real controversy‘
When Ocrevus was approved, MS advocates and researchers alike hailed it as a true breakthrough. But critical voices were soon heard, claiming Ocrevus was simply Rituxan rebranded, launched to secure Genentech’s patent rights. (The company, it is worth noting, is financially supporting the Colorado trial — an investigator-initiated independent study — with a grant award to cover a portion of its costs.)
MS News Today delved into this issue in a recent article — offering the views of critics, Genentech representatives and researchers not linked to the company. Vollmer was one of those backing the claims of Ocrevus being developed for commercial reasons.
“I think it’s a real controversy,” said Vollmer. “We originally started developing rituximab … and we did the HERMES trial and the OLYMPUS trial, and then the company realized that their patent was going to run out before they could get to market.”
The Phase 2 HERMES (NCT00097188) and Phase 2/3 OLYMPUS (NCT00087529) were early Genentech-sponsored studies, examining Rituxan in MS. He agrees that the two drugs have differences. Ocrevus, he notes, is a modernized and more humanized antibody, lacking the mouse parts present in Rituxan.
But he questions whether this distinction will make much of a difference in efficacy — in part, because no one has evaluated that point.
“At this time, I don’t see any difference between them,” Vollmer said with the confidence of a neurologist who has treated hundreds of patients with Rituxan. The University of Colorado is one of the nation’s few MS centers that has routinely prescribed Rituxan for the past 10 years to MS patients.
“If either one is more safe or effective, or less antigenic [triggering antibody production] than the other is a discussion,” he said. “But there’s no real data.”
Going for data, not debate
Vollmer decided to test one of the aspects claimed to differ between Ocrevus and Rituxan — safety.
The Phase 3 clinical trial, however, is focused on only one safety aspect of the two drugs. It will examine if switching from Rituxan to Ocrevus causes an increase in infusion reactions or production of neutralizing antibodies, which risks making the treatment ineffective.
Although Rituxan is not an approved MS treatment, it has been extensively used off-label — including in more than 1,000 patients at the University of Colorado, Vollmer said. Yet most private insurers have not endorsed Rituxan’s use in MS. Medicaid and Medicare cover the treatment in only a few states, including Colorado.
Its effectiveness, however, led some MS patients to pay out-of-pocket for the treatment.
With the approval of Ocrevus — which is covered by patient support programs and, as an approved therapy, potentially by most private insurance companies as well as government programs — Vollmer expects many of these Rituxan-treated patients will want to switch to Ocrevus. It likely will be cheaper for them, the neurologist said.
Infusion reactions and anti-drug antibodies
But data is currently lacking on the safety of moving between these treatments. Infusion reactions are most common after the first infusion, then decrease over time — a tendency seen in trials of both Rituxan and Ocrevus. Even though the drugs are similar, there is no way of knowing if infusion reactions will remain low when switching between the two, Vollmer pointed out.
“These infusion reactions, by and large, are not life-threatening, but they’re certainly bothersome — particularly if they’re more severe,” Vollmer said.
“So we’re trying to find out is whether patients, when they switch from rituximab to ocrelizumab, will they still have those infusion reactions? Are they different in any way? And also, because we’re switching antibodies, are they more likely to develop neutralizing antibodies to the drug?”
Trials of the two drugs have indicated that the development of anti-drug antibodies was higher among Rituxan- than Ocrevus-treated patients. Some anti-drug antibodies have neutralizing properties, meaning that they prevent a drug from doing its job.
Although clinical trials suggest Rituxan tends to trigger antibody development more often, Vollmer doubts this will be much of a problem, noting that “we have put 1,300 patients on rituximab over the last eight years … and we have very few patients who don’t fully take to treatment with rituximab.”
While he acknowledges the potential for differences in how common it is for the two treatments to trigger antibody responses, he again underscored that there are no studies actually comparing this risk.
To find out, Vollmer launched this “real-world” trial, which is enrolling 200 patients. The study is only open to people previously treated with Rituxan at the University of Colorado Outpatient Infusion Center in Aurora. He said enrollment is virtually complete.
While Genentech is supporting the trial with a grant, Vollmer underscored that the San Francisco-based company did not help design the study, nor will it have a say in data interpretation and analysis.
The study will let half the participants switch from Rituxan to Ocrevus. The rest will remain on Rituxan treatment as a comparison group. All patients will be monitored for a year.
Its main outcomes — final data is expected in about 16 months — are differences between the two groups in the proportion of patients who have infusion-related reactions, the total number of reactions, and the proportion of reactions per infusion, as well as their severity.
Researchers will use earlier data from the included patients. The center has registered infusion reactions for all patients for as long as three years — information that will be added to trial data in the analysis phase.
The study will also analyze the presence of anti-drug antibodies, measure the levels of B-cell depletion, cytokine profiles, and effects on T-cells. But there will be no comparison of the two drugs’ efficacy in managing symptoms or disability. The reason for this is size. “That would take a fairly large study. We’d have to be multi-center to do that,” Vollmer said.
The sole reason for the study, he stressed, is to ensure patients can switch treatments safely.
“We want to make sure, as people move back and forth between these drugs, as some certainly will around the world, are there any significant medical issues with doing that? That’s the only reason,” said Vollmer, pointing out that at his MS clinic, neurologists only recommend that patients switch to save money.
“The only reason we would suggest that you switch is that they are paying a significant amount of money out-of-pocket for rituximab because there’s no patient assistance program,” he said.
A different view of MS types
Vollmer also holds a view of MS types — relapsing, primary progressive, and secondary progressive — that might be considered controversial.
Many scientists believe that the disease subtypes are guarded by distinct mechanisms, explaining why drugs that are effective in relapsing MS fail to help people with progressing disease.
Vollmer does not believe neurological differences between the conditions exist.
“The difference is that progressive patients tend to be 15 years older, so that they have more damage and also the disease becomes less inflammatory,” he said, arguing that as MS patients age, the rate of relapses and new brain lesions decline.
This causes a difference in what he refers to as the brain’s “reserve capacity.” So while relapsing patients may get better on a newer treatment, a progressive patient — who lacks this reserve capacity — will only see a slower rate of progression.
“[The] difference we see in clinical trials is just because of that biological fact; the brain’s used up its reserve capacity and they [progressive patients] don’t have the biological capacity to recover function,” Vollmer said, adding that at his center, all patients are treated the same way. “It doesn’t matter what label you put on them.”
Unlike what many insurance companies recommend, neurologists at the University of Colorado clinic put early stage patients on more effective treatments, without taking the long way around by starting with interferons or Copaxone (glatiramer acetate).
In fact, they don’t use older treatments at all. Newer drugs, such as Ocrevus and Rituxan, have a safety profile in line with older drugs but are much more effective, Vollmer said. And the lower effectivity of older, first-generation drugs causes patients to have disease activity despite treatment, he noted.
Although this may not be evident when patients still have sufficient brain reserves, the accumulation of brain damage and brain volume loss takes its toll later in life, Vollmer argued. “CD-20s [Rituxan and Ocrevus] are better at stopping that [damage] than any other drugs we have.”
And this, in his view, represents a “sort of tipping point” in MS treatment. If newer drugs like Rituxan and Ocrevus are used as a first-line treatment, “we can effectively change what MS is in one generation,” he said.
In his view, early treatment could “probably prevent 90 percent of patients from ever becoming disabled. That’s a huge shift. MS has become one of the most treatable diseases in neurology that we have. The problem arises when private insurance companies and government programs demand patients go on the interferons or Copaxone … before they go on the newer generation first-time drugs, and that makes no sense,” Vollmer said.
“They clearly don’t understand the disease and what happens in the progression of this disease and what comes back later in life,” he added, underscoring that he does not refer to the earlier drugs with quite high-risk profiles.
While he thinks Ocrevus and Rituxan have much in common, Ocrevus had the lowest adverse event rates of any MS drug in any study, Vollmer said.
“We do not call it [Ocrevus] an aggressive therapy as some do, we at the clinic call it an optimized therapy … the drug that has the most efficacy for the patient,” he told us.
For now, Vollmer is leaving to others the debate on the two treatments’ potential differences and similarities. His focus is on aiding his patients to get the best treatment possible, at a cost they can manage.