Popular multiple sclerosis drug tied to greater risk of a potentially lethal infection.


When the drug natalizumab (Tysabri) was approved by the FDA for treatment of multiple sclerosis (MS) in 2004, it was quickly regarded as a blockbuster. Natalizumab far surpassed other therapeutics at the time at alleviating symptoms, preventing relapse and improving outcomes in patients with MS. The drug was also quickly withdrawn. Within a few months of approval, it was linked to three cases of a rare viral disease known as progressive multifocal leukoencephalopathy (PML), causing its manufacturers to voluntarily remove it from market.

Despite the potential ties to this often fatal disease, MS patients, their families and physicians lobbied to have the drug returned to market due to its immense efficacy. The FDA eventually relented and re-approved natalizumab, and it has served as a popular treatment option ever since. In the ensuing decade, research teams worked to develop a biomarker, or a chemical signature, that could predict whether a patient on the medication would be at risk for developing PML. The biomarker used today is a blood test that measures the levels of antibodies against the virus that causes PML-a proxy way of measuring viral load.

In a large-scale study involving more than 1,200 MS patients, an international team of researchers have now demonstrated that natalizumab can trigger a 10-fold increase in this biomarker, suggesting that patients taking the drug do indeed have greater risk for developing PML. However, it's not all bad news.

Publishing alongside the study in the journal Neurology: Neuroimmunology and Neuroinflammation, University of Chicago neurologists Adil Javed, MD, PhD, and Anthony Reder, MD, explain in a corresponding editorial how natalizumab is still an outstanding treatment option for MS, as long as there is proper physician oversight. We spoke with Javed on why patients shouldn't have anything to fear.

UChicagoMed: What is natalizumab and how does it work?

Adil Javed: MS is an autoimmune disease, meaning that it's a disease of mistaken self identity. The body's own immune system attacks myelin, an essential layer of insulation around nerve fibers. Without this protective layer, neurons in the central nervous system misfire or fail to fire at all, causing muscle weakness, balance and coordination problems, i.e. disability.

Natalizumab blocks migration of immune cells into the brain and thereby leads to an immunosuppressive state in the central nervous system. It's by this mechanism that it prevents immune cells from destroying the body's own myelin. Due to its potent effects on the immune system and the demonstrated high efficacy of the drug in clinical trials in comparison to the older agents, natalizumab was a game changer when it came out in 2004. MS neurologists all thought, 'why shouldn't every MS patient be on this drug?'

How is it linked to PML?

PML is a terrible neurological infection that destroys white matter in the brain. It's caused by a normally benign virus known as the JC virus, which is present in certain tissues of the body in up to 60% of the population. In people with weakened immune systems, however, it can be a problem. Natalizumab prevents immune cells from reaching the brain. The lack of immune cells, and perhaps other factors, allows the JC virus to infect the brain and cause PML-but at very low rates. The risk of a patient being treated with the medication for two years and developing PML is still less than 1 in 1000.

This new study shows that people treated with natalizumab have a dramatic increase in antibody levels against the JC virus. Does that mean they are 10 times more likely to develop PML?

Absolutely not. When we see rising antibody levels, or titer, we assume that there must be more replication of the virus. The higher the replication rate of the virus, the higher the chance that the virus could infect brain cells. But this is all based on assumptions and circumstantial evidence. There has never been a good study that shows that rising antibody titers are proportionally correlated with higher viral replication or load.

The fact remains that even though JC virus-antibody levels rise over time while on natalizumab therapy, the risk of PML over time continues to remain relatively low. This study did see a 10-fold increase in titer, but in no way is it associated with a 10-fold increase of risk for PML. We don't know what the association between viral load and antibody titer level means at any given point.

What do antibody levels tell us then?

Say, for example, you get the flu. The virus multiplies and eventually your body revs up the immune system and produces lots of antibodies. Fortunately for people with the flu, these antibodies are protective and clear the virus from your body. For the JC virus, they are not protective. So these rising antibody levels could mean more replication of the virus in the body. Since the risk of PML still remains low with the rising JCV antibody levels, there are other stochastic factors that are involved in production of a PML infection, which remain to be determined.

What should MS patients know about these new findings?

Based on the finding of a 10-fold increase in the JC virus antibody levels during natalizumab therapy, patients should not stop taking the medication out of fear that now they have a 10-fold increase risk of getting PML. All this study says is that more monitoring is needed. Your neurologist can track your antibody levels, and discuss with you the risk associated with the medication over time. It's all about risk and benefits.

With proper monitoring over time, it's up to the physician and patient to determine at what point the risks outweigh the benefit and what point the medication should be stopped. If you're negative for the JC virus, then the risk for developing PML is incredibly low and the benefits of natalizumab are huge. This medication could keep a patient very stable over a long period of time. If you are JC positive, and your titers are low, you could still stay on the medication as long as your titers remain low.

In my practice, if JC titers reach a certain threshold and continue to rise, I have advised patients to switch to a different MS medication. After informing the patients of the risks and benefits, it's ultimately their choice. There are many patients who continue to stay on natalizumab irrespective of JC virus-antibody levels, due to their own personal experience with the high effectiveness of this agent.