A New Drug, a New Test, and a Final Word on CCSVI


Andrew N. Wilner, MD: Hello. I am Dr. Andrew Wilner, speaking from Lyon, France, at the 2012 ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) meeting. Joining me is Dr. Mark Freedman, Professor of Neurology at the University of Ottawa in Canada, and an expert in MS. Mark, we have a few minutes to talk about some of the highlights of this very large meeting, with 7000 attendees and well over 1000 posters. A few years ago, the first oral drug for MS became available. I understand that we now have a new one. You were one of the investigators [for clinical trials with this drug], giving you an inside view. Can you tell us a little bit about teriflunomide?

Mark S. Freedman, MD: Teriflunomide has been around for 10 years in one of the widest clinical development programs we have had, yet most people have not heard of it. It has been a bit of a "sleeper." Teriflunomide derives from leflunomide, which is used for treatment of rheumatoid arthritis. Unfortunately, leflunomide has a black box warning because of potential liver dysfunction. This actually never panned out but the warnings were there. The FDA also placed leflunomide into the "X" category for teratogenicity (contraindicated; benefit does not outweigh risk).

Teriflunomide is much safer than the mother molecule and has been extensively studied in patients with MS, with 3 phase 3 studies all reaching completion. TOWER is the second large phase 3 randomized controlled efficacy trial of teriflunomide. In both TOWER and TEMSO, which was published earlier this year, teriflunomide [was superior to placebo] on all the outcomes. It is the only oral medicine for MS that showed an impact on relapse rates, MRI [parameters], and disease progression in 2 large phase 3 studies. It is easily tolerated and is a once-a-day therapy. Why haven't we heard more about it? It has this baggage that it brought from the mother molecule, leflunomide. But we really have not seen any sign of liver damage with teriflunomide, despite the warning on leflunomide, and we have not seen any evidence of teratogenicity in either molecule to date.

Dr. Wilner: The official launch [of teriflunomide] was within the [last few months]. I am sure we will learn more about this drug and how it works. Patients now have the option of 2 oral [disease-modifying therapies].

Dr. Freedman: Exactly, and one such as teriflunomide seems a lot safer than perhaps fingolimod, which has received a bit of a bad rap in the last year.

Dr. Wilner: I want to follow up on the safety issue of the MS therapies. One of the problems with natalizumab is progressive multifocal leukoencephalopathy (PML). Now we can test to see if patients are JC virus positive, if they have antibodies or not, indicating that they have been exposed to the JC virus, which puts them at risk for PML.

Dr. Freedman: Theoretically [those with JC virus antibodies] are at higher risk. The risk is also higher if they have taken natalizumab for longer than 24 months and if they have been exposed to immunosuppressant drugs, which is thought to be important. What we are really talking about are data that have been derived from fewer than 100 patients who have developed PML and from whom we have the serology studies. In the past year, we have seen several cases of antibody-negative patients who have developed PML. Now, how could that happen? Two of those cases seroconverted to seropositive just before they developed PML, which could not have been anticipated. We now have the first case that is absolutely seronegative, never been shown to be seropositive before the patient developed actual PML, no history of immunosuppressive use, and probably less than 2 years that they were on the [natalizumab].

Dr. Wilner: How often do you test? How often should you test? You cannot test every day.

Dr. Freedman: No. The authorities and even the [manufacturer] strongly suggest testing at least once every 6 months, plus a yearly MRI. But the test is falsely negative up to 3% of the time and people seroconvert at a rate of roughly 3% a year. Even if you think you are out of the woods, you have a 6% chance of actually being positive. The added measure would be to do a scan once a year, hoping to find something on that scan that might predict that you will develop PML; even then, if the lesion starts out very small, there is really no way of differentiating it from a typical MS lesion.

Dr. Wilner: An early PML lesion on MRI can look very similar to MS, and only later might you be able to sort that out.

Dr. Freedman: Retrospectively, you could say, "Oh, that looked like a PML lesion," but there is no radiologist who would call it PML before it became PML. We are still dealing with that drug. Now, almost 300 cases of PML have been reported worldwide, with over 100,000 people treated with natalizumab, so the numbers are not that high. The mortality rate is 22% if you do get PML, however, with a high morbidity rate for those people who survive. I think people have to really weigh the risks and benefits of natalizumab.

Dr. Wilner: I want to touch on one more topic. We have talked a lot in the past, and have read and seen a lot on the Internet, about CCSVI (chronic cerebrospinal venous insufficiency).

Dr. Freedman: I was afraid you were going to ask me about that.

Dr. Wilner: Now we have new data. Tell us about that.

Dr. Freedman: I do not know how much of this type of quasi-science we need, but there was not good science behind the whole theory to begin with. CCSVI is a theory [about the etiology of MS] put forth by an Italian researcher who is not a neurologist but a vascular surgeon who works with ultrasound. A real controversy exists about the ability to reproduce [ultrasonography] as a detection method to show whether or not the blockages in the large veins draining the head are truly there. [The originator of the theory] is probably the only one who has demonstrated it. He published an absurd article in which he said he found it in 100% of patients but in none of the controls. We know right away that something is wrong with that. In the best of hands, perhaps 50% [of patients with MS] will have these abnormalities, so how they could cause MS is already going beyond what we have already found, which is, at best, a quasi-association.

The Italians and others worldwide have been trying to find out if there is something there or not. One of the largest studies was done in Italy and we are hearing about it this week. Two studies [are being reported at this meeting]. One study was a follow-up of interventions that had been performed in nearly 500 patients.In the other study, almost 2000 patients were screened by blinded examiners, so they did not know which patients had MS. The patient population includes a mixture of controls and normals and about 600 patients with MS. The incidence of so called CCSVI in the patient population [was found to be] a whopping 3%.

Dr. Wilner: So, very, very small.

Dr. Freedman: Yes. Is it there? Is it meaningful? Is it associated? I hope these large studies will put it to rest. When you look at the nearly 500 people who have had a mixture of procedures to open the veins, either with angioplasty or the insertion of a stent (which was never designed for veins), you will see a perfect demonstration of a placebo effect. About half of the people felt great, but this disappeared within 6 months, and several complications were seen, such as blocked veins or blocked stents, which will have lifelong consequences. Why would you perform procedures for something that is not there and could potentially cause harm? I hope [these studies] put it to rest.

Dr. Wilner: This is not recommended for people with MS?

Dr. Freedman: The FDA has come out against it, and I understand that the Italian MS society has stopped all funding of CCSVI projects as a result of the findings that we were shown at this meeting.

Dr. Wilner: Mark, thank you very much for joining us here and sharing your insights on the research that has been presented so far.

Dr. Freedman: It is always a pleasure. I look forward to doing it again next year.