The FDA Arthritis Advisory Committee recommended Bristol-Myers Squibb’s Orencia (abatacept), one of a new class of drugs designed to treat rheumatoid arthritis by inhibiting the activation of immune cells known as T cells.

Rheumatoid arthritis is a complex disease and many cell types are involved,” explained Gary Firestein, professor and chief of rheumatology, allergy, and immunology at University of California San Diego. “Every investigator has a favorite cell but most agree that T cells play a role very early and can help orchestrate an immune response that ultimately becomes rheumatoid arthritis.”

    T cell activation is the first step in an “inflammatory cascade” that leads to an immune response, said Jeff Macdonald, a spokesman for BMS. This response is overactive in people with rheumatoid arthritis, an autoimmune disease that causes chronic inflammation of joint tissue and pain, Firestein said.

    T cells are activated by multiple interactions with an antigen-presenting cell, which has already bound an invading molecule on its surface, Macdonald said. The T cell recognizes the combination of antigen-presenting cell and bound foreign particle. Or in the case of an autoimmune disease, it mistakes a bound indigenous molecule for a dangerous invader. This is the first step of activation, Macdonald said. 

    The second step occurs when a protein on the antigen-presenting cell called CD80/86 binds with a protein on the T cell called CD28. This interaction further activates the T cell, which then goes on to activate other cells involved in inflammation and in the production of the immune response, according to Firestein, who is also a former member and chair of the Arthritis Advisory Committee.

The CD80/86 cell binds to abatacept more selectively than to the CD28 protein, which suppresses T cell activation, Firestein said. This, in turn, derails the chain of activation that some scientists believe is propagated by T cells, according to Macdonald.

    Abatacept is more attractive to the CD80/86 receptor because it contains a modified protein called CTLA4, Macdonald said. This naturally occurs on the surface of T cells and is used to inhibit T cell activation in the body, according to BMS data presented to the advisory committee. This synthetic CTLA4 is attached to a modified fragment of another protein, IgG1, which Macdonald described as a part of an antibody molecule that does not bind the antigen.

    But any time the immune response is suppressed, Firestein explained, people can become more susceptible to infections. According to BMS data the frequency of infection and cancer for trial participants on abatacept was higher than placebo. But the advisory committee found that the risks were not significant enough to prevent them from recommending approval.

    Firestein said rheumatoid arthritis therapies “walk a fine line” between an over active immune system and a susceptible immune system.

    “It’s naïve to try and seek only a 100 percent safe therapy for rheumatoid arthritis,” he said. “At least in the sight of current science, it’s impossible.”

According to Firestein, previous attempts to treat rheumatoid arthritis by modifying the T cell response had mixed responses. The role of T cells in the disease was studied frequently in the 1990s but, abatacept is the first drug that is definitely “doing something,’ he said.

    But he added that the drug is not a “magic bullet” that will treat all cases of rheumatoid arthritis. Firestein predicted that if abatacept is approved, most patients would use it in combination with other drugs.

    “Targeting a single molecule, thus far, has not been truly effective it the majority of patients,” Firestein said. “That means combination therapy.”

Articles

A look at the science behind a new class of rheumatoid arthritis drugs that act by suppressing an early stage of inflammation, the activation of T cells.

Arthritis Advisory Committee Recommends Orencia by Bristol-Myers Squibb

Researchers at University of California San Diego revealed the mechanisms of three nuclear receptors involved in immune response. The receptors have differing but overlapping abilities to inhibit inflammation, offering opportunities to improve treatment of autoimmune diseases, according to the study published in the Sept. 9 issue of 

    Inflammation is part of the immune response that normally results from bacterial or viral infection, lead author Christopher Glass said. The study focused on immune cells known as macrophages, which activate a number of genes in response to being exposed to a foreign agent. This response prepares the cell to kill an organism or recruit aid of other cells.

    But these immune responses are also central to chronic inflammatory diseases such as lupus, rheumatoid arthritis, and arteriosclerosis, Glass explained. The researchers wanted to identify how the process of inflammation could be controlled. They identified the three nuclear receptors in macrophage cells that were most potent in inhibiting inflammation. 

    The glucocorticoid receptor is known to diminish inflammation and is the target of drugs for asthma, rheumatoid arthritis, and lupus. The PPAR gamma receptor is already the target of TZD drugs for type II diabetes. The third receptor is called LXR.

Because the receptors are involved with turning on and off different genes that have anti-inflammatory effects, they each regulate different parts of the immune response, Glass said. Compounds that promote activity for these receptors can be used in conjunction to create anti-inflammatory effects, he continued. 

    As a result, drugs that activate these receptors could be used in conjunction, with smaller doses to diminish side effects. For example, glucocorticoids are known to have serious side effects such as high blood pressure, elevated glucose levels, thinning of skin, and bone loss, Glass said. He indicated that these side effects could be diminished if the patient took a low dose of glucocorticoids in combination with drugs that promote PPAR gamma or LXR receptors. 

    Together, multiple drugs that activate nuclear receptors in the inflammation pathway could have a “synergistic effect” by maximizing anti-inflammatory results while minimizing side effects, Glass explained.

    “If you added the drugs together there would be a much stronger anti-inflammatory effect than by themselves,” Glass, a professor of cellular and molecular medicine, said.

    The authors compared this to “fine tuning” the body to balance immune responses with inflammatory responses that could lead to chronic autoimmune diseases.

    Glass said the results of this study could enable drug combinations to be tested in a clinical environment.

    He also indicated that these findings have implications for drug development. Knowing how these receptors interact with genes to elicit an anti-inflammatory response could be used to create new classes of drugs to act on these receptors more selectively.

    Understanding a mechanism that inhibits inflammation could allow researchers to develop tests to measure the specific activity of the receptor when exposed to different compounds, Glass said. This could be used as a screen for potential drugs, he continued.

A University of California San Diego professor explains the results of his research on nuclear receptors and why these findings could lead to new therapies for autoimmune diseases.

Anti-Inflammatory Treatment Could Change as a Result of New Findings on Nuclear Receptor Proteins

Faster approval times have not lead to increased withdrawals due to safety problems, according a new report by the Tufts Center for the Study of Drug Development. Reforms in the 1990s instituted user fees and sped up the approval process.

    Tufts researchers found that of the 20 drugs that have been withdrawn since 1980, nine came off the market before the 1993 user fee changes. According to the report, seven of 217 drugs approved in the 1980s were withdrawn and 11 of 311 drugs approved in the 1990s were withdrawn. Two of these 11, however, were withdrawn prior to the reforms that led to user fees. So far only two of the 120 drugs approved since January 2000 have been withdrawn. 

    The report also indicates that quickly approved drugs are no more likely to face safety withdrawals than other drugs. For example, data indicate that drug approvals took an average of 2.3 years in the 1980s. But approval times for withdrawn drugs averaged 2.9 years. In the 1990s, approvals for withdrawn drugs took 1.1 years as compared with 1.3 years overall. 

    But Tufts CSDD director Kenneth Kaitin said that this difference is small enough that there is “no discernible pattern.” He also indicated that the time differential for drugs approved since 2000 is not reliable because of the small number of withdrawals.

     “FDA’s process was inordinately lengthy in previous years,” Kaitin said. “Now we have an application process that does not limit FDA’s ability to detect safety problems.” 

    Further research, Kaitin said, should examine how to identify risks after a drug is on the market.

    Charles Bennett, professor at Northwestern University’s Feinberg School of Medicine, agreed that optimizing post-marketing risks is more important than changing the speed of approval. 

    “A little faster or a little slower, I don’t think it’s short-cutting safety steps,” he said. “It’s not the approval that’s the issue; it’s after approval.”

    Bennett also criticized the Tufts study for not differentiating between drugs approved under the regular process and those with accelerated approval. He stressed that it is especially important to understand the assessment of post-marketing risk for accelerated drugs, which have smaller clinical trials.

    The Tufts study also found that 70 percent of the drugs withdrawn since 1980 were in three classes --- anesthetic/analgesic, cardiovascular, and anti-infective. Kaitin speculated that the first two classes of drugs might have lead to more safety issues because they are generally taken over a longer period of time.

    “Increasing the length of treatment increases the likelihood that you will have safety problems due to long-term toxicity,” he said.

    He also thought that anti-inflammatory drugs might lead to safety problems because the processes targeted by these drugs are often part of a variety of physiological functions.

    He indicated that almost all of the anti-infective drugs pulled off the market were in one class, quinolones, which were associated with liver toxicity.

    On the other hand, Brian Strom, professor of public health and preventive medicine at the University of Pennsylvania, said that these three classes probably have some of the highest numbers of drugs in them. So, the larger number of withdrawals for these classes is most likely proportional.

    Bennett suggested that instead of focusing on classes of drugs, future research looks at the types of toxicities that lead to the withdrawals. He suggested looking at liver and bone marrow registries or at data from plasmapheresis centers. Information on toxicities from these samples or registries could be compared with knowledge about what drugs the people with these symptoms were taking.

Analysis of a new report that says safety-related product withdrawals have not increased since the approval process sped up in the 1990s.

Pharmaceutical Executive-09-13-2005

Arthritis Advisory Committee Recommends Orencia by Bristol-Myers Squibb

Anti-Inflammatory Treatment Could Change as a Result of New Findings on Nuclear Receptor Proteins

Study Shows Faster Approval Does Not Affect Safety