Twenty years ago, the idea that B-cell depletion could treat multiple sclerosis would have been greeted with a hearty laugh by any well-respected neurologist or MS researcher — or perhaps a scoff. But times change and research advances.
Today, a medicine that gets rid of certain B-cells may be the most powerful drug yet developed against MS — even benefitting primary progressive patients who, until now, had no approved therapies for their condition.
The early days
“The journey of ocrelizumab in MS started about 15 years ago,” Dr. Peter Chin, a neurologist and the principal medical director of Global Neuroscience Development at Genentech, said when Multiple Sclerosis News Today spoke to him in February.
For academic researchers, the work started even earlier. On a backdrop of skepticism, some began thinking outside the box. They had noted that autoantibodies seemed to be involved in MS disease processes, but only in conjunction with disease-causing T-cells.
But since the antibodies, seen in both human patients and animal models, were of so many different sorts, the researchers turned their sights to B-cells. A proportion of B-cells become antibody-producing plasma cells; by targeting these cells, the scientists reasoned, maybe it would be possible to get to the autoantibodies.
At that point, Genentech began to work with the academic researchers to launch a small clinical trial in patients.
The first small proof-of-concept studies yielded surprising results: It was apparent that B-cells carrying the CD20 molecule on their surface played a more prominent role in disease mechanisms than anyone had previously thought.
While the research community at large remained highly skeptical about treating MS with B-cell depleting drugs, the science began speaking for itself. The first clinical trial showed that a single administration of a B-cell depleting drug reduced the presence of inflammatory brain lesions by 91 percent, and significantly reduced relapses, measured six months after treatment.
First tested for MS was a different Genentech B-cell depleting compound — Rituxan (rituximab). It had been developed for B-cell cancers, and was gaining ground as a treatment for autoimmune conditions.
While study results showed that B-cells were, indeed, involved in MS, they largely excluded the possibility that antibodies were driving disease. The treatment effect was noted almost immediately, making it highly unlikely that the benefits were linked to reduced levels of antibodies, which take longer to control.
Genentech had initially judged the success rate for B-cell depletion in MS as “lower than 15 percent,” but quickly realized that a B-cell strategy could be more effective than any other approach taken so far.
“At that time, we had a number of B-cell targeted anti-CD20 molecules in our portfolio with different properties,” Chin said in the interview. “We advanced ocrelizumab, a humanized anti-CD20 antibody, into late-stage development because we believed it had the best potential for efficacy and safety in people with MS, a disease where long-term treatment is warranted.”
Ocrelizumab had failed in previous clinical trials involving patients with rheumatoid arthritis and systemic lupus erythematosus (both autoimmune conditions), but its path in MS would take another route.
The first report of Ocrevus’ efficacy came in 2010, when an early analysis of a Phase 2 trial (NCT00676715) confirmed what researchers had seen with Rituxan. The study’s lead investigator called the results “among the most remarkable seen in a phase II RRMS study.”
A year later, Genentech reported that two-thirds of patients were free of disease activity in the form of brain lesions, relapses, or disability progression after being treated for nearly two years.
In addition to these preliminary, but very promising, effects, analyses showed that the treatment triggered only very low levels of anti-drug antibodies. Biological drugs, such as Ocrevus, always run the risk of becoming ineffective because of a neutralizing immune response, in which the body produces antibodies that prevent the drug from working.
These encouraging findings spurred Genentech to advance development. Not only did the company launch two Phase 3 trials — the OPERA I and OPERA II studies (NCT01247324 and NCT01412333) — in relapsing MS, it also started recruiting primary progressive patients into a third Phase 3 trial, named ORATORIO (NCT01194570).
The two relapsing MS studies compared Ocrevus with high doses of the standard-of-care drug Rebif (interferon beta-1a). Primary progressive patients were treated with either Ocrevus or placebo.
As researchers and patients kept working on the Phase 3 studies, several quiet years followed with few updates on the drug’s progress. Then, in 2015, Genentech released first results from the OPERA I and II trials.
Both studies had met primary and key secondary endpoints: Ocrevus reduced relapse rates, slowed the progression of disability, and minimized the number of brain lesions compared to Rebif-treated patients.
“Ocrelizumab showed remarkable improvements over a standard-of-care medicine across clinical and imaging endpoints in two pivotal studies,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, at the time.
Later that year, Genentech caught the attention of primary progressive MS patients worldwide. A group that had grown accustomed to failed trials now learned that the ORATORIO trial was successful.
“This is an important moment for the MS community,” Xavier Montalban, MD, PhD, chair of the Scientific Steering Committee for the ORATORIO study and a professor of neurology and neuroimmunology at Vall d’Hebron University Hospital and Research Institute in Spain, said in a 2015 press release. “For decades, trial after trial has failed to show the benefit of any medicine for people with primary progressive MS. Now, for the first time, we have a positive Phase 3 study result for people with this debilitating form of the disease.”
For the first time in history, Genentech applied for FDA approval of Ocrevus to treat both relapsing and primary progressive MS. Today, its hard work has been rewarded.
“This pioneering science redefines 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,” Chin said.
In early 2016, the FDA acknowledged the impact Ocrevus had on primary progressive MS by designating it a Breakthrough Therapy. Later that year, the agency also granted Priority Review to Ocrevus’ Biologics License Application (BLA).
Genentech published data from the three Phase 3 trials — data that led to Ocrevus’ approval. The two December 2016 publications in the New England Journal of Medicine confirmed what the company had shared in various conference presentations.
In relapsing patients, the annualized relapse rates were 46% and 47% lower among the Ocrevus-group patients than among those treated with Rebif. Ocrevus-treated patients had 94% to 95% fewer new inflammatory brain lesions over the 96-week trial. The two trials also showed that 64% and 89% more patients receiving Ocrevus had “no evidence of disease activity,” or NEDA — a measure taking into account brain lesions, disability progression, and symptom relapses.
“The consistency of these pioneering data, the effect seen in these clinical studies and the favorable safety profile may support treating MS earlier with a high-efficacy disease-modifying medicine,” Stephen Hauser, MD, chair of the Scientific Steering Committee of the OPERA studies, director of the Weill Institute for Neurosciences, and chair of the Department of Neurology at the University of California, San Francisco, said in a press release at the time. Hauser was among the researchers who first started exploring B-cell mechanisms in MS.
In primary progressive patients, Ocrevus lowered the risk of six-month disability progression by 25% over the 120-week trial compared to placebo. As in relapsing patients, the treatment also lowered the number of brain lesions, which were fewer at the trial’s end than at its start. Placebo-treated patients, however, continued with a steady increase in brain lesions throughout the study.
Genentech continued analyzing trial data after publication. At a recent ACTRIMS 2017 Forum, it revealed that NEDA rates in relapsing patients actually increased as treatment with Ocrevus lengthened, while no such increase was seen among Rebif-treated patients.
It also presented an analysis showing “no evidence of progression” (NEP) in patients with progressive disease. Ocrevus increased NEP by 47% compared to placebo, with a total of 42.7% of patients achieving NEP over the course of the trial.
The drug’s safety profile is surprisingly benign, given its effectiveness. The three trials found a similar extent of adverse events and infections, as well as serious adverse events and serious infections, in both Ocrevus-treated and control groups.
Its efficacy, along with this good safety profile, has people suggesting that Ocrevus should, in fact, be considered as a first-line treatment in MS, much as Hauser earlier hinted might be the case.
This optimism is, however, tempered by concerns of increased cancer risks. In all three trials, cancer rates were twice as high among those who received Ocrevus than among respective control group patients.
“Rates of malignancy with ocrelizumab treatment remain within epidemiological reports and no clear relationship between B-cell suppression and malignancy has been established,” said Chin, who also reassured patients that Genentech is working to understand why the rates were numerically higher.
“Patient safety is very important to us and we are committed to closely and continuously monitoring all safety data, including malignancy rates, in ongoing and future clinical studies.”
Orevus’ approval will also allow for the gathering of safety data beyond a clinical trial setting.
“The B-cell saga in MS has provided a cornucopia of surprises, thrilling insights, several disappointments, numerous still-to-be-solved conundrums, and also a few generic lessons,” Hauser wrote in a lecture on the topic in 2015, voicing perhaps what is now obvious: The last word has yet to be said when it comes to B-cell depletion in MS.
Or, indeed, when it comes to Ocrevus itself.