Forty years ago, one of Dr. Stephen Hauser’s first patients was a young Harvard Law School graduate and White House aide with a case of multiple sclerosis that raced like a brush fire through her brain. She quickly lost her ability to speak, swallow, and breathe. She got married in a wheelchair in her hospital room, tethered to breathing and feeding tubes and dressed in her wedding gown.
“We had nothing to treat her with,” recalled Hauser, now director of the Weill Institute for Neurosciences at the University of California, San Francisco. It was such a searing moment for the young doctor, then at the beginning of his neurology training, that he decided to dedicate his career to MS research.
On Tuesday night — after decades of false starts, struggles to persuade disbelieving colleagues, and a tortuous path through the maze of drug discovery — Swiss drugmaker Roche Holding AG announced that the Food and Drug Administration had approved its new drug for MS based on Hauser’s research. Researchers say the medication is a significant improvement over other treatments for the debilitating disease, which afflicts more than 400,000 Americans and by some estimates more than 2 million more patients worldwide.
“It’s personally incredibly rewarding,” Hauser said of the decision. “This is a big deal for people with MS.”
The drug, called ocrelizumab, takes a different approach than the more than a dozen other MS drugs on the market. It blocks certain immune system cells called B cells that Hauser’s lab discovered play a critical role in the disease. The other drugs target the immune system’s T cells, long thought to be the main culprit in MS.
“This is a major therapeutic advance,” said Dr. Harold L. Weiner, director of the Partners MS Center at Brigham and Women’s Hospital in Boston, who wasn’t involved in research related to the drug. “And it opens a whole new area of understanding about MS.”
The FDA approved ocrelizumab for treatment of primary-progressive MS, making it the first drug ever approved for the most aggressive from of the disease. It is marked by a gradual worsening of neurological symptoms, especially difficulty walking and in some patients paralysis below the waist, and accounts for between 10 percent and 15 percent of MS cases.
The decision was based largely on results of a 732-patient, Roche-sponsored clinical trial that showed primary-progressive patients on the drug were about 25 percent less likely to have their disability worsen.
While the clinical benefit was “modest,” said Bruce Bebo, executive vice president of research at the National Multiple Sclerosis Society, having a treatment reach the market “is huge. “We have nothing to offer people with primary-progressive MS.”
The FDA also cleared the drug for the more common relapse-remitting form of the disease, which is characterized by inflammatory attacks that trigger such early symptoms as vision problems, tingling in the feet, weakness, and muddled thinking.
In a market already bulging with expensive drugs for that form of MS, Roche set an annual price of $65,000 for the twice-a-year infusions. A study in the journal Neurology in 2015 that looked at nine of about a dozen MS drugs that modify the course of relapse-remitting disease found that none was priced under $50,000 a year, not including drug company rebates. Prices have generally risen since.
Roche acknowledged concerns about drug pricing in disclosing the amount, saying that the National Multiple Sclerosis Society recently noted that MS medicines cost almost four times what they did 12 years ago. Roche said its list price is 25 percent less than Rebif, the drug ocrelizumab outperformed in two of of the major studies leading to approval. Rebif lists for $86,000 a year, the company said, adding that the “industry needs to start reversing” the pricing trends.
Roche said the drug, which it will market under the brand name Ocrevus, would be available to US patients within two weeks.
MS is an autoimmune disease, which occurs when the immune system goes awry, attacking the body’s own healthy tissue. What provokes the immune system in the case of MS is a mystery, but for most patients, it results in an inflammatory attack on the myelin sheaths that protect the nerves and the transmission of signals from the brain to other parts of the body.
The disease typically hits people between 20 and 40 years old and is more common in women. Medicines and treatment strategies have vastly improved since Hauser’s encounter with his early patient at Massachusetts General Hospital, but new approaches are needed.
“It’s the most common neurologic crippler of young adults,” Hauser said. While many patients do well for decades, “more than half of our patients are worse 10 years later despite treatment.”
Finding a new culprit
When Hauser began his quest for better MS remedies in the late 1970s, the prevailing belief was that T cells were the sole offenders behind MS. That would turn out to be wrong.
T cells, as well as B cells, are key components of the arsenal the immune system uses to detect, hunt down, and kill viruses, bacteria, and other “foreign” invaders that harm the body.
The focus on T cells grew in part from researchers’ longtime use of a mouse model with a T cell-driven condition called experimental allergic encephalomyelitis, or EAE, to study and develop drugs for the disease.
Like multiple sclerosis, EAE is characterized by inflammation of the brain and spinal cord, but there, the similarities end. Hauser’s mentor, the late Harvard neurologist Dr. Raymond Adams, told him there was little resemblance between the two conditions.
“It really didn’t look like MS at all,” Hauser said. So his first task was to develop a new animal model for the disease.
It took a decade, but eventually he and his lab came up with a guinea pig-sized monkey called a marmoset that was able to develop MS that looked just like the human version.
“So many of our failures in drug development relate to preclinical models that don’t recapitulate human disease,” Hauser said.
Then, in a series of experiments, they tried to induce the disease by transferring myelin-targeted T cells into the animals. It didn’t work. Next, they tried certain antibodies that are produced by B cells. That didn’t work. Finally, they used both T cells and the B cell antibodies together.
“Bingo,” Hauser said. The animals developed MS.
The experiments showed that MS wasn’t fueled just by T cells, and Hauser’s lab identified B cells and their related antibodies as promising new drug targets. But the scientific establishment wasn’t ready to embrace this new idea.
‘Hoping to see a tiny whiff of effect’
At first, it seemed Hauser’s timing was fortuitous. In 1997, as his group’s research was coming together, the FDA approved the first treatment directed against B cells. It was a genetically engineered antibody called rituximab, from Genentech and its partner Idec Pharmaceuticals Corp.
The drug was for non-Hodgkin lymphoma, but its approval meant an off-the-shelf therapy was available to test their B cell hypothesis in MS patients.
Armed with journal articles describing their research, Hauser and other researchers applied for a grant from the National Institutes of Health to run a pilot study of rituximab in people.
The NIH said no. The idea was “biologically implausible,” Hauser said they were told. The NIH offered to fund the study if they targeted T cells, he added, but they declined.
“Once we get an idea in medicine, we pivot off that idea very slowly sometimes,” Hauser said.
In 2001, he asked Genentech to fund the study. Initially, he met resistance there as well, he said. A team of outside experts the company assembled to evaluate the proposal rated its chances of success at less than 15 percent.
But some top insiders came to support the idea, and in 2003, after 18 months of discussions, Genentech agreed to a trial.
Just as the decision came down, news came from the East Coast that Biogen, the dominant player in drugs for MS, had agreed to merge with Idec, gaining Idec’s rights to rituximab in the process. Working out details with a new corporate partner further delayed the start of the study, Hauser said.
The next hurdle was the FDA, which also had to approve the trial. Hauser and his colleagues proposed a one-year, placebo-controlled trial with two infusions of rituximab six months apart. They would measure the effect of the treatment on formation of new MS lesions in the brain as determined by MRI after a year. They thought the treatment would have a gradual impact on inflammation and that they would need at least a year to see whether the drug was working.
But the FDA said it wouldn’t be ethical to keep patients with active relapsing MS on placebo for a year. Instead, the agency permitted only a single dose of the drug. The researchers would have to measure its effectiveness after just 24 weeks. Their hopes for success dimmed.
“We were hoping to see a tiny whiff of effect to lead to other clinical trials,” Hauser said.
The study enrolled 104 patients, 69 of whom were treated with rituximab. The moment of truth came on what Hauser recalled was a crisp Friday afternoon in late September 2006 when the researchers “unblinded” the data. What they saw astonished them.
The formation of new brain lesions in the rituximab patients was reduced by 91 percent compared with those on placebo. The size of the effect was “unprecedented” in MS, Hauser said. The study showed not only that B cells were critical players in the disease, but that when B cells were depleted by the drug, brain inflammation was almost immediately shut down.
Said Hauser: “It was a grand slam home run.”
It would take a much larger Phase 3 trial to win FDA approval, but he figured rituximab would be available to MS patients within four years — by about 2010.
Genentech ‘had a better molecule’
Genentech had other ideas. Rituximab was an aging medicine, and it had safety issues.
“We recognized this was a very important finding in MS,” Dr. Peter Chin, group medical director for neuroscience at Genentech, said of the pilot study’s results. “It provided the first clinical evidence that B cells really were important in the disease.”
But “we had a better molecule that was better suited for MS.”
That molecule was ocrelizumab.
It had a key advantage over rituximab, which, like other monoclonal antibodies developed during the early days of the technology, is comprised of part human and part mouse protein. Over time, some patients develop immune responses to the mouse component, leading to problematic side effects or undercutting the drug’s benefits.
In contrast, ocrelizumab, like most newer genetically engineered drugs, is fully humanized and much less likely to trigger an immune response in patients.
These were among reasons Genentech decided to place its bet for MS on the new agent, Hauser said.
He agreed that ocrelizumab would likely prove a better drug — both for Genentech and for MS patients. But he believed it would further delay getting a B cell therapy to patients.
Then in 2009, yet another threat emerged. Roche, which had long held a majority stake in Genentech, moved to take over the rest of the company. Hauser worried that in the inevitable resetting of priorities, ocrelizumab might be jettisoned.
But after the acquisition closed, Roche quickly announced that the MS program would move forward. The Phase 3 studies that led to FDA approval were launched in 2011.
The results, which for the studies of relapsing patients were a near-replication of the “grand slam” rituximab findings from 2006, were published by the New England Journal of Medicine in December.
The two Roche-funded studies involving a total of 1,656 patients with relapsing MS showed the drug cut annualized relapse rates for such patients almost in half compared with a commonly used treatment called Rebif. The formation of new lesions in the brain and spinal cord — the key marker of inflammation — was reduced by more than 94 percent compared to patients on Rebif. Why the reduction in relapse rates wasn’t even more pronounced isn’t clear.
“We’ve never had a treatment so successful against new lesions,” said Hauser, who led the two studies. It essentially “stops MS in its tracks.”
Hauser said Roche has reimbursed him for travel expenses related to the trials, but he doesn’t accept honoraria or other compensation from companies with MS drugs on the market or in development. Over the years, the NIH, the National Multiple Sclerosis Society, various foundations and philanthropic gifts have supported research in his lab.
MS experts said ocrelizumab’s price, insurance coverage decisions, and the willingness of physicians and patients to try a medicine with limited long-term safety data will affect how quickly the drug will be adopted in a highly competitive market.
Other effective MS drugs, including Cambridge, Mass.-based Biogen’s Tysabri, have raised a caution flag against early adoption. Tysabri, for instance, is especially effective, but in rare cases can lead to a potentially lethal brain disorder called progressive multifocal leukoencephalopathy, or PML. This has led some doctors to wait until later in the course of a patient’s disease before prescribing some treatments.
PML hasn’t shown up in studies of ocrelizumab, but researchers say longer follow-up is necessary to better understand the drug’s long-term efficacy and safety.
Side effects of the drug were generally mild or similar to comparator agents, but studies raised the possibility of a slightly elevated risk of cancer on the drug, a concern doctors are certain to keep an eye on as use of the medicine grows.
“Anytime a new drug comes out you want to get some experience with it,” said Brigham and Women’s Weiner. “But over time [ocrelizumab] could be accepted and used in a lot of patients.”
If the initial efficacy and safety results hold up for relapsing-remitting disease after longer follow-up and the drug is used early in a patient’s disease, Hauser believes newly diagnosed MS patients will be able to “look forward to a full life without significant disability.”
That ocrelizumab offers only about a 25 percent benefit to patients with primary progressive disease suggests a different biology drives that form of MS. It is just one illustration of the work that lies ahead.
For those patients, Hauser said, “our foot is in the door, but we’re not there yet.”
Validation of the B cell’s role in MS poses an intriguing question for MS researchers. The fact is, Hauser said, that most of the immune system cells found in MS lesions are T cells. So what are B cells doing?
Hauser suspects they are “orchestrating” the process by which T cells do their damage. Many other MS drugs, he added, while viewed as targeting T cells, also interfere with B cells.
“Ocrelizumab’s success has led to a rethinking of how the other MS therapies may be working,” he said.