Are Ocrevus and Rituxan Similar? Neurologists Respond to Patients’ Concerns

While many multiple sclerosis patients celebrated the recent approval of Ocrevus (ocrelizumab), others argued that the drug is largely a rebranded version of rituximab. Rituximab — sold as Rituxan for indications like non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis — is used off-label to treat relapsing MS.

In online forums and social media, claims circulated that this rebranding of an existing drug was a way for Genentech — Ocrevus’ developer — to make more money at the expense of patients.

These claims drew upon the fact that the U.S. patent covering Rituxan will soon expire. This allows other companies to produce so-called biosimilar versions of the drug, which might be marketed at lower costs — a development already taking place outside the U.S.

The debate was further fueled when a former Genentech employee, Dr. Annette Langer-Gould, called Ocrevus a “fake breakthrough” in an interview published in an April 3 blog in HealthNewsReview.

Langer-Gould said that the choice to develop Ocrevus — instead of working to get Rituxan approved for MS — delayed the approval of a highly effective MS treatment for a decade.

So are Rituxan and Ocrevus really the same therapy?

Multiple Sclerosis News Today attempted to clarify this issue — comparing a number of online statements with those given by a neurologist at Genentech, Dr. Peter Chin, and by Dr. Robert Lisak, a neurologist and past president of the Consortium of Multiple Sclerosis Centers (CMSC).

Genentech on Langer-Gould

In a Genentech statement provided to MS News Today, the company acknowledges that Langer-Gould was an employee with insights into the development of Ocrevus while working there — some 10 years ago.

“Dr. Annette Langer-Gould worked at Genentech from September 2006 to September 2007. She had no involvement in the strategic and clinical decisions regarding Ocrevus’ development after she left the company,” the statement read.

At the time, Ocrevus had not yet entered the first Phase 2 trial (NCT00676715) in MS patients. Langer-Gould is now a research scientist with Kaiser Permanente in California, and an MS specialist at Los Angeles Medical Center. She works with a clinic that treats MS patients with Rituxan.

Rituxan is not approved for MS, but it has been used off-label within the U.S. and, particularly, outside the country, where other health insurance regulations may enable the practice.

“We encourage HCPs [healthcare practitioners] to make their own decisions on what’s right for their patient,” Genentech wrote in the statement.

The molecular side of things

Both Ocrevus and Rituxan are drugs that target B-cells that have CD20 molecules on their surface, as critics have pointed out. According to a statement issued by the International Multiple Sclerosis Management Practice (IMSMP), the two drugs “should have almost identical anti-B cell activity.”

At IMSMP/TISCH MS Research Center of New York, physicians have been prescribing Rituxan to MS patients for the past 16 years. The center had persuaded Medicare in New York to cover the off-label drug, using data of its effectivity as an argument. Since it is not an approved MS treatment, most health insurance plans do not cover Rituxan.

Chin, who is group medical director, Neuroscience, at Genentech, said the two therapies have distinct differences.

“Although Ocrevus and Rituxan both target CD20-positive B cells, they are different molecules in their structure and how they interact with the immune system,” Chin said, adding that the two drugs bind overlapping but different epitopes on the CD20 molecule. An epitope is the part of a protein that an antibody recognizes and binds to.

The drugs, subsequently, differ in how efficiently they directly, and indirectly, kill B-cells. Ocrevus has a higher capacity for direct, antibody-dependent, cell toxicity compared to Rituxan. And, Chin added, it has a lower capacity for indirect, complement-mediated cell killing.

The complement system is part of the immune defense, and both Rituxan and Ocrevus activate it as a part of each drug’s cell-killing mechanism.  But Ocrevus — by having a more direct, or controlled, action — may have fewer indirect and damaging effects on the immune system.

Chin also pointed out that while Rituxan is a chimeric antibody, composed of both mouse and human parts, Ocrevus is a humanized molecule. “This important distinction reduces the chance that an MS patient’s immune system may form antibodies against the medicine (known as anti-drug antibodies) and may reduce the chance these anti-drug antibodies will decrease the effectiveness of the medicine over time.”

All biological drugs might be recognized by the immune system as something foreign that needs to be eliminated. So-called neutralizing anti-drug antibodies can render a treatment totally ineffective.

According to the Genentech statement, early studies of Rituxan in MS showed that many patients developed anti-Rituxan antibodies — 28.6% and 24.6% in two trials in relapsing patients, and 7% in a trial with primary progressive MS patients.

In the Ocrevus trials, 0.4 percent of relapsing patients developed antibodies against Ocrevus. Of these, only one had neutralizing antibodies. Among primary progressive Ocrevus-treated participants, 1.9 percent developed anti-drug antibodies. Again, only one person showed antibodies of the neutralizing type.

But while such comparisons can provide an idea of how the two drugs differ, Lisak pointed out that a study which directly compares the drugs is needed to prove whether they differ in efficacy and side effects.

“One can believe or even think that there are no differences between rituximab and ocrelizumab in RRMS [relapsing-remitting MS], you cannot prove there are no differences without a head-to-head study,” he told MS News Today in an email.

Such a study is underway. University of Colorado researchers have launched a clinical trial (NCT02980042) that will explore the safety of switching from Rituxan to Ocrevus, and compare the two therapies for safety and tolerability. Its lead investigator, Dr. Timothy Vollmer, is among those who — “at this time” —  considers the two drugs to be similar. “[I]f either one is more safe or effective … than the other is a discussion,” Vollmer said in an interview. “But there’s no real data.”

Strategy or science?

Genentech has been accused of developing Ocrevus based on commercial considerations. Or, in less flattering words, of cheating patients by developing a new medicine that could bring in more money, instead of expanding the indication of an already approved drug.

According to Genentech, Rituxan was essential to the company proving that B-cells played a role in MS. But Ocrevus, as ocrelizumab, was chosen for development instead of Rituxan, because Ocrevus was better suited to treating a chronic disease like MS.

“At that time, Genentech had a number of anti-CD20 targeted molecules in our portfolio with different features,” the company wrote in the statement. “We advanced ocrelizumab, a humanized anti-CD20 antibody, into late-stage development because we believed it had the best potential efficacy and safety profile for people living with MS, a disease where long-term treatment is warranted.”

Genentech also underscored that drug development is a science-based process.

“As a company, we take a data-driven approach to drug development and bringing new medicines to patients. We stand by all of the information we have provided to the media about Ocrevus as accurate and transparent.”

Part of the Rituxan versus Ocrevus debate has circled around primary progressive MS (PPMS) patients. Early research showed that Rituxan was not effective in this patient group, except for a subset of PPMS patients.

Some argue that this subset made up a large part of the ORATORIO trial (NCT01194570), allowing the company to get Ocrevus approved for progressive MS even though many PPMS patients might not benefit from the treatment.

But, said Lisak, this is a claim that cannot be proven.

“It is possible that ORATORIO treated patients represented some of that same subset but there wasn’t enough power in ORATORIO to definitely prove that theory,” he said.

Too high a dose?

In the HealthNewsReview article, Langer-Gould raised another question about the Ocrevus trial data. She stated that Ocrevus was given to patients at far too high dose, which was not tested adequately.

Chin said that the decision to develop Ocrevus for both relapsing and primary progressive MS at a 600 mg dose was a result of “an evolution of scientific understanding from rigorous controlled clinical trials spanning a decade.”

During the first study of Ocrevus in rheumatoid arthritis (NCT00077870), Genentech tested five doses, ranging from 20 mg to 2,000 mg. Based on this trial’s results, the company started evaluating two doses of Ocrevus in a Phase 2 trial (NCT00676715) of relapsing MS — 600 mg and 2,000 mg.

Chin also underscored that the choice of Ocrevus dose involved regulatory agencies, in addition to Genentech scientists.

“Dose selection for the MS Phase 3 studies was made in consultation with both the FDA and European Medicines Agency,” he said, and added that this dose is effective and safe, as has been demonstrated in three Phase 3 clinical trials.

No other MS physicians or researchers have raised concerns about the dose, so far. When asked about it, Lisak pointed out that for non-cancer diseases treated with Rituxan, researchers do not really know how low the B-cell counts need to be to provide a therapeutic benefit.

He cited results from a study of another CD20-targeting antibody, ofatumumab, which showed that although the lowest doses did not completely deplete B-cells in the peripheral blood stream, they seemed to benefit relapsing MS patients equally well as the higher doses.

But, adding that the trial was only Phase 2, Lisak said: “We don’t know if a higher dose of any of these monoclonal antibodies might matter with regard to meningeal B-cells.”

Meningeal B-cells can be found in the membranes covering the brain.

Is Ocrevus safe?

While reports from clinical trials of Ocrevus stated that the drug was generally safe, with mild-to-moderate infusion reactions and upper respiratory tract infections being the most common side effects, there is one safety aspect of Ocrevus that has caught the public’s eye.

In the three Phase 3 trials, more Ocrevus-treated patients developed cancer than those in the respective control groups. According to Chin, this means that “an increased risk cannot be ruled out.”

This issue has been used as an argument by some who recommend MS patients continue with the older drug, Rituxan, off-label rather than switch. Since Rituxan has been used for a long time, plenty of data exists about its potential side effects.

But Chin pointed out that, although more patients in the Ocrevus groups developed tumors, the numbers were not higher than what is known to occur in studies assessing MS patients in general. And, he added, Genentech does not take these findings lightly.

“Patient safety is very important to us at Genentech and we are committed to conducting long-term post-approval safety studies on Ocrevus,” Chin said. Long-term extension studies of the initial Phase 3 trials that ran for three years, among other studies, are now underway.

But the IMSMP, in its March 31 statement, called the number of cancer-affected patients in the Ocrevus-treated trial groups “alarmingly high” — a stark contrast in wording from Genentech.

The IMSMP also noted that an early trial of Ocrevus in rheumatoid arthritis was cut short when patients developed life-threatening infections.

Although the rates of severe infections were similar in the Ocrevus-treated and respective control groups in the three trials, many neurologists, including Lisak, have underscored that new risks may only become apparent when long-term data become available.

“Although it is, indeed, progress that the first medication for PPMS has been approved, the patients should be fully informed of its’ potential risks,” IMSMP wrote. “For patients who can obtain Rituximab, it would be safer to continue with this therapy, until with time, we are better able to advise patients about the risks associated with Ocrelizumab.

Chin stated that, to date, no increased cancer rates with a longer Ocrevus treatment have been detected in the follow-up extension studies.

The debate about the potential similarities between Rituxan and Ocrevus is likely to continue. Future research into the two drugs, as well as into the science of B-cell depletion in MS in general, are likely to provide answers to many of the concerns raised by patients.