With the recent announcement confirming the increased number of PML cases, other information has become available as well. Of the 24 cases, two-thirds have been in Europe and one-third in the U.S. This is surprising considering that about 60% of exposed patients have been in the U.S. and only 40% in Europe. Why there appears to be a higher risk of PML in European MS patients on Tysabri is unclear. Additionally, the bulk of the cases have occurred in year three of Tysabri treatment. Specifically, in year one the risk is less than 1/30,000; in year two, it is approximately 1/3,000; and in year three the risk increases to approximately 1/800. The risk is real: in addition to the four reported deaths due to PML, mild to severe disability has been reported in those who have survived their bouts with the brain infection.
The above data suggest that the longer patients are treated with Tysabri, the higher the risk of PML. Does that mean that in year four and year five the risk increases? Few patients have reached four and five years of treatment, so we do not yet know the answer. As to the skewing between the number of cases in the U.S. and Europe, European patients may be more likely to have been treated with chemotherapy before beginning Tysabri. Does that mean that chemotherapy treatment increases the risk of PML, as some MS-specialists speculate? That remains unclear, but we do know that most Tysabri patients who develop PML have no history of other immunosuppressant therapies, which makes that hypothesis unlikely.
Despite the risks, Tysabri has proven itself to be a very effective and tolerable MS treatment, with an average efficacy rate of 70% compared to 30% for the first-line agents (Avonex, Betaseron, Copaxone and Rebif). Aside from the concern regarding PML, the therapy’s safety profile is well-developed and positive. According to Dr. Vollmer, were it not for PML, Tysabri would most certainly be a first-line agent for most MS patients. Therefore, one must wonder: what is the future of this effective, yet worrisome, therapy?
Three main possibilities exist, among them that the FDA and the manufacturers may opt to change the label so that Tysabri would be recommended for only 2 years of treatment or less; that research may advance to the point of identifying patients who innately have a higher risk of PML, although to date very few advances have been made in this area; or that Tysabri doses may be changed and/or the therapy used in combination with other treatment agents.
The latter of these three options seems to be, according to Dr. Vollmer, the most likely future path of the therapy (barring what the FDA may do unilaterally). Already a number of experimental avenues have been initiated. By adjusting Tysabri dosage and/or using the therapy in combination, each of these avenues aims to maintain efficacy levels while reducing the risk of PML.
The first possibility is to switch back to an available first-line agent after one to two years of Tysabri therapy. One major consideration with this treatment option, however, is the fact that recent data suggest that when people go off Tysabri, there is a 20% to 50% chance of a rebound effect. This means that disease activity could flair-up above the levels previously experienced by the patient. According to Dr. Vollmer, it is therefore very important that treatment of this nature be done as a study within an intense safety monitoring program.
One study that is looking at the use of Tysabri in combination with the first-line agent Copaxone is about to be launched at the Rocky Mountain MS Center at Anschutz Medical Campus. These agents are being combined for a 3-month period, and then study participants are continuing solely on Copaxone. The safety of using these therapies in combination was already established in the GLANCE study. This method will be deemed a success or failure based on whether Copaxone is able to maintain a high level of treatment effect. If the treatment approach does not maintain the high level of disease control typical of Tysabri, there is no reason to pursue a larger study to determine if this approach reduces the risk of PML. The current study requires only 100 study participants, whereas a study specifically looking at the risk of PML would require 10,000 study participants or more, making it a huge undertaking.
The second possibility is the use of drug holidays, meaning that patients would be given annual “holidays” from their Tysabri treatment with the goal of reducing the risk of PML. According to Dr. Vollmer, however, the method is racked with concerns, including the above-mentioned disease rebound effect and the possibility of building up neutralizing antibodies to Tysabri. Normally, that risk of developing these antibodies is only 6%, but if patients were to go on and off Tysabri a number of times, that risk could possibly go up and the drug could lose its treatment effect.
Additionally, the fact that there is no evidence that the preclinical phase of PML lasts more than a few weeks or a month, annual “holidays” are not likely to protect against the brain infection. In all actuality, patients would have to take “holidays” on a frequent basis in order to effectively protect against PML, which is not a feasible option.
The third possibility is that after one to two years of monthly treatment, Tysabri infusions could be changed from once a month—as they are currently prescribed—to every other month. The current 300 mg dose is designed to maintain saturation for approximately 6 weeks. If the dose were adjusted and given every 8 weeks, it is possible that on average there would be one week that full blockade of transmigration would not occur and immune surveillance would kick in—meaning that the immune system would function regularly during that week. The thought is that this one week out of 8 of normal immune function might minimize the risk of PML.
Although PML is a very serious risk associated with the agent, Dr. Vollmer stresses that to lose the therapy would be to lose the current MS therapy with the most potential, and that which has shown great efficaciousness. The loss would be a great detriment to the MS community. Because we do not currently know the minimum effective dose of Tysabri, it is critical to explore adjustments in dosage and combination use in order to most effectively and safely treat with Tysabri in the future.
Furthermore, there is a key role that Tysabri patients and their families can play in the fight against PML: educate yourself about the signs associated with the infection, and notify your doctor if you notice any red flags. The best way to minimize the chances of incurring disability from PML is to catch it early. Because patients on Tysabri are usually very stable, psychological and cognitive issues—such as changes in personality or signs of memory loss—can be associated with PML. If you have MS, make sure those around you are on the lookout for any personality or cognitive changes.
It is important that patients and families empower themselves through education regarding the signs of PML and alert medical professionals of any noted changes. Together, we—patients, families, and physicians—can fight PML and find new avenues through which to safely and effectively use Tysabri.