At long last, and for the first time in medical history, people with both relapsing and primary progressive forms of multiple sclerosis have reason to celebrate. The U.S. Food and Drug Administration (FDA) today approved Ocrevus (ocrelizumab) as a disease-modifying therapy for both forms of MS, a chronic autoimmune disease.
The FDA’s decision is historic for primary progressive (PPMS) patients, who until now had no accepted means of slowing the relentless march of their illness, and it’s historic for relapsing MS patients — studies showed that Ocrevus effectively halted the disease in nearly half of treated RMS patients.
It’s also historic for the future of MS research and treatment. Ocrevus defied all norms by targeting immune system B-cells and, in clinical studies, surpassed most expectations to become what may be the most powerful drug yet developed against MS.
“The FDA’s approval of OCREVUS is the beginning of a new era for the MS community and represents a significant scientific advance with this first-in-class B-cell targeted therapy,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a late-breaking press release.
European health authorities are also reviewing Genentech’s request for EU approval (called a marketing application), and decisions in other countries are likely to follow.
“This is an exciting day for everyone touched by MS, a disease that strikes in the prime of a person’s life when she or he may be starting a career or family. For many people living with MS, this FDA approval is a source of hope,” said June Halper, chief executive officer at the Consortium for MS Centers, said in the release.
“[I]f everything works out, it looks as if Ocrevus, although not a cure, has all the makings of a wonder drug for MS, at least for most people who have the disease,” Ian Franks, chief columns editor for BioNews Services, the parent company of Multiple Sclerosis News Today, wrote earlier this month, adding that the March 28 choice of approval date was “quite poetic really, in that it is MS Awareness Month.”
Upon learning of the FDA’s action, Franks said: “While there are other DMTs [disease-modifying therapies] for relapsing MS, I find it tremendously encouraging that Ocrevus has been approved for treating primary progressive. Looking to the future, perhaps we might not be so far away from developing treatment specifically for secondary progressive.” Franks, who was diagnosed with multiple sclerosis in April 2002, has non-relapsing SPMS.
B is the new buzz
Ocrevus is not just another MS treatment. It is the first with demonstrated benefit for primary progressive patients, using a new approach in fighting MS. Most treatments focus on keeping immune T-cells in check, but Ocrevus works to prevent certain B-cells from doing harm.
About 15 years ago, Genentech started exploring with academic researchers the importance of B-cells in MS. It soon became apparent that B-cells carrying the CD20 molecule on their surface played a more prominent role in disease processes than previously thought.
Early experiments with B-cell depletion eventually led to a Phase 2 study (NCT00676715) of Ocrevus, a drug that had failed trials in other autoimmune conditions.
In 2011, nearly two years into that study and patient treatment, Genentech surprised many when it announced that two-thirds of the people given this B-cell-based therapy were free from any disease activity: no new brain lesions, no relapses, no progression in neurological disability. Findings led the trial’s lead investigator to call the results “among the most remarkable seen in a phase II RRMS study.”
Development continued, with an expanded view. A Phase 3 clinical trial program was launched with two studies in relapsing MS — the OPERA I and OPERA II trials (NCT01247324 and NCT01412333) — and a third, ORATORIO (NCT01194570), to assess whether Ocrevus might also benefit primary progressive patients.
Early reports of considerable efficacy across all three trials were announced in 2015. Full trial data followed, published in December 2016, dispelling doubts that Ocrevus had the potential to be quite effective. (Genentech is continuing to analyze data from these studies.)
That same month, however, the FDA surprised and disappointed many by delaying an expected decision on Ocrevus. The agency’s postponement did not reflect concerns about Ocrevus’ effectiveness or safety, Genentech announced; rather, it was due to questions about the drug’s manufacturing process. A new decision date, March 28, was set.
What makes Ocrevus so successful, and what exactly does this success look like?
Results from the clinical trials suggest that CD20 B-cells directly cause damage to the myelin sheath — an insulating layer allowing signals to pass swiftly through neuronal extensions, known as axons. Researchers also believe that these B-cells damage the neurons themselves.
“The ocrelizumab Phase 3 studies have redefined our understanding of the underlying biology of MS and shows that B-cells, a type of immune system cell, play a central role in the disease,” Dr. Peter Chin, a neurologist and principal medical director of Global Neuroscience Development at Genentech, said in a February interview with Multiple Sclerosis News Today.
The new findings do not invalidate earlier claims of T-cell involvement in MS, as Chin pointed out in a 2015 interview with this news website. The science so far, he said, supports the idea that B-cells work together with T-cells to create the inflammatory brain lesions, and resulting disability progression, seen in MS.
But Ocrevus’ effects were obvious in the three Phase 3 trials. Over the 120 weeks of the ORATORIO study, treated PPMS patients had a 25 percent lower risk of six-month progression than those receiving placebo.
Brain lesions also disappeared, with patients demonstrating a lower lesion burden at the trial’s end than was evident at its start. In fact, a graph charting lesion burden in Ocrevus-treated and placebo PPMS patients came to look like the open beak of a hungry bird.
Results presented at the ACTRIMS 2017 Forum showed that Ocrevus not only slowed disability progression, but 42.7 percent of primary progressive patients had “no evidence of progression,” or NEP, at 120 weeks. This amounted to a 47 percent relative increase in NEP in the Ocrevus group compared to placebo.
Among relapsing patients, results were similarly favorable. Ocrevus lowered annualized relapse rates by 46 percent and 47 percent in the two OPERA trials compared to the standard medication, Rebif (interferon beta-1a).
And the proportion of patients with “no evidence of disease activity” (NEDA) was much larger than among those receiving Rebif. Like NEP, NEDA uses a combination of assessments to reach a verdict.
Over the 96 weeks of the two relapsing MS studies, 64 percent and 89 percent more of Ocrevus-treated patients reached NEDA compared to those on Rebif. And a recent analysis demonstrated that the longer patients were treated, the greater the proportion who reached NEDA.
Quality of life for MS patients is, understandably, tightly linked to disability progression and the ability to keep wanted aspects of everyday life, like employment.
Imagining a world where such treatment effects continue year after year makes for optimistic thinking. According to Chin, independent research shows that NEDA at two years predicts NEDA at seven years. But, he cautioned, few things are predictable in a disease as complex as MS.
Still, Ocrevus may indeed be a game-changer. “Based on the pivotal study results of OPERA I, OPERA II and ORATORIO, ocrelizumab has the potential to change the way MS is treated,” Chin told Multiple Sclerosis News Today in February.
Efficacy and side effects
All medications come with side effects, and Ocrevus is no exception. But interestingly enough, they are not what people with MS have become accustomed to when it comes to highly potent MS drugs. Studies of Ocrevus showed most side effects are mild.
Similar rates of adverse effects — including serious side effects — were seen between Ocrevus and Rebif-treated relapsing patients, and between Ocrevus and placebo-treated primary progressive patients. Infections, a concern given that Ocrevus targets an immune cell, were also similar in frequency between the groups. Importantly, no trial participants have so far developed the dreaded condition known as progressive multifocal leukoencephalopathy (PML).
According to Chin, this is because Ocrevus targets neither stem cells, which give rise to other immune cells, nor plasma cells, which produce antibodies. The CD20 protein is not found on many immune system cells, he said, so “they can continue to fight infection and other illnesses.”
With debate in the MS community focused on the benefits of early aggressive treatment, treatment safety and effectiveness are major considerations. This means that Rebif and other interferons as first-line treatments may be seriously challenged by the arrival of Ocrevus.
But a continuing point of concern was seen in Phase 3 study analyses. Across all three trials, cancer rates were twice as high in Ocrevus-treated patients than in controls.
Genentech is actively investigating the reasons for these observations, but underscored that the trials’ cancer rates were not outside epidemiological (general population) norms, and so far researchers have found no evidence that Ocrevus has cancer-promoting properties.
Life after approval
So as patients worldwide digest the news that MS has a new treatment — one that might be a huge step forward in effectiveness for relapsing and primary progressive MS patients alike — thoughts turn to the practical aspects of Ocrevus’ approval.
Who will get access? What will treatment cost? Will health insurance reimburse or otherwise cover its costs?
Genentech says it will continue to work to provide access to all eligible patients, both through its Access Solutions program and by assisting those who are uninsured or underinsured.
The National Multiple Sclerosis Society, like other patient advocate groups, will also be watching and working to make sure a promising treatment reaches those in need.
Ocrevus, which will be available to people in the U.S. within two weeks, is now a part of the MS treatment scene, but its story is only beginning.