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First Drug for Aggressive MS Wins FDA Approval

April 10, 2017

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Editor’s note: For us at THI, the Hauser goal and its challenges, reads like an exciting adventure story. Couldn’t put it down.

Graphic credit: Mikael Häggström - Public Domain, Wikipedia Commons

Multiple sclerosis is the most common autoimmune disorder affecting the central 1) ___ system. The name multiple sclerosis refers to the scars (sclerae - better known as plaques or lesions) that form in the nervous system. In 2013, about 2.3 million people were affected globally with rates varying widely in different regions and among different populations. That year about 20,000 people died from MS, up from 12,000 in 1990. While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune 2) ___, or failure of the myelin-producing cells. Proposed causes for this include genetics and environmental factors such as being triggered by a viral infection.

Apart from demyelination, the other sign of the disease is inflammation. Fitting with an immunological explanation, the inflammatory process is caused by T cells, a kind of lymphocyte that plays an important role in the body’s defenses. T cells gain entry into the brain via disruptions in the blood-brain 3) ___. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called “autoreactive lymphocytes”. The attack of myelin starts an inflammatory processes, which triggers other immune cells. The blood-brain barrier is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the 4) ___. There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks. Medications used to treat MS, while modestly effective, can have side effects and be poorly tolerated.

Nerve axon with myelin sheath. Graphic credit: Public Domain, Wikipedia Commons

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 5) ___ 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. Last week, after decades of false starts, struggles to persuade disbelieving colleagues, and a tortuous path through the maze of drug discovery - Roche Holding AG, announced that the FDA 6) ___and ___ ___ 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.

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. The FDA approved ocrelizumab for treatment of primary-progressive MS, making it the first drug ever approved for the most aggressive form 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 10-15% of MS cases.

The decision was based largely on results of a 732-patient clinical trial that showed primary-progressive patients on the drug were about 25% less likely to have their disability worsen. 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.

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 7) ___ 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. 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, when they tried certain antibodies that are produced by B cells, that didn’t work. Finally, when they used both T cells and the B cell antibodies together, 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. 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. Hauser and other researchers then applied for a grant from the NIH, 8) ___ ___of ___ to run a pilot study of rituximab in people. The NIH said no. The idea was “biologically implausible,” Hauser said they were told. In 2001, Hauser 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%. However, 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 9) ___ 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. The study enrolled 104 patients, 69 of whom were treated with rituximab. The moment of truth came 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% 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. However, 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. But, Genentech said that they had another molecule that was better suited for MS. Ocrelizumab 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, Roche, which had long held a majority stake in Genentech, moved to take over the rest of the company. 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 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% compared to patients on Rebif.

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.

B Cells:

B cells are a type of white blood cell and, specifically, a type of lymphocyte. Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells. All the plasma cells, descended from a single B cell, produce the same antibody which is directed against the antigen that stimulated it to mature. The same principle holds with memory B cells. Thus, all of the plasma cells and memory cells “remember” the stimulus that led to their formation. The maturation of B cells takes place in birds in an organ called the bursa of Fabricus. B cells in mammals mature largely in the bone marrow. The B cell, or B lymphocyte, is thus an immunologically important cell. It is not thymus-dependent, has a short lifespan, and is responsible for the production of immunoglobulins. It expresses immunoglobulins on its surface. 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 10) ___ 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. Credit: Ron Winslow, 2017, www.statnews; Wikipedia

ANSWERS: 1) nervous; 2) system; 3) barrier; 4) brain; 5) sclerosis; 6) Food and Drug Administration; 7) model; 8) National Institutes of Health; 9) ethical; 10) T cells

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