When Tysabri Stops, Multiple Sclerosis Lesion Counts May Rebound

September 13, 2007

AMSTERDAM -- Stopping natalizumab (Tysabri) may result in a rebound in multiple sclerosis activity, particularly after a short course of drug therapy, reported investigators in a small study.

AMSTERDAM, Sept. 13 -- Stopping natalizumab (Tysabri) may result in a rebound in multiple sclerosis activity, reported investigators in a small study.

MRI scans of patients taken before natalizumab therapy and again more than a year after the last infusion showed a mean three-fold increase in the number of lesions compared with baseline, reported Machteld Vellinga, M.D., of VU University Medical Center here, and colleagues.

The rebound effect was most pronounced among patients who had received only two monthly natalizumab infusions. They had a five-fold increase in lesion counts post-therapy, the investigators reported online in Neurology, in a study scheduled for the Dec. 11 print version.

"It is intriguing that our observation is mainly driven by the patients who had only been exposed to a small number of natalizumab infusions," the investigators wrote. "Although we have no clear explanation for this, the finding of partial immunosuppression giving rise to extra disease activity was previously observed in rats with experimental allergic encephalomyelitis being treated with low-dose cyclosporine A."

The authors conducted a formal analysis of patients who had been enrolled in two phase III trials of natalizumab, AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) and SENTINEL (Safety and Efficacy of Natalizumab in combination with Interferon beta-1a in patients with Relapsing Remitting Multiple Sclerosis).

The trials were suspended in 2005 after three patients on natalizumab developed progressive multifocal leukoencephalopathy (PML), a rare viral infection of the brain. Two of the cases were fatal.

Natalizumab was reintroduced, with restrictions, in 2006, after an independent safety analysis of all patients in phase III trials found no additional cases of PML.

The authors were prompted to further explore the possibility of a rebound effect of natalizumab cessation after a neuroradiologist detected significant increases in MS lesion between MRI images taken after the suspension of the drug, and baseline scans taken before natalizumab therapy was restarted - an interval of about 15 months.

In the current study, they obtained pre-treatment and 15-month post-treatment scans from patients who had been randomized to natalizumab treatment during the double-blind and extension portions of two phase III studies These patients had received a median of 36 infusions (range 30 to 37).

The authors also looked at those patients who had been randomized to placebo in the double-blind phase and who had received natalizumab only during the extension phase; these patients had received a median of two infusions (range one to eight).

The lesions were scored on T2 MRI sequences, all of which had performed with the same 1.5 tesla magnet. Suitable scans were available for 21 of the 23 patients enrolled in the trials.

A neuroradiologist scored the scan pairs in random order for new and enlarging T2 lesions according to published guidelines. The investigators compared annualized lesion numbers at both intervals using the Wilcoxon matched pairs signed rank test. They also conducted subgroup comparisons, including enrollment in AFFIRM or SENTINEL, placebo or active drug in the double-blind phase, gender, age, disease duration, and amount of lesions on MRI.

They found that among all patients the median annualized number of active T2 lesions was increased in the post-cessation period interval compared with the pre-treatment period (10.32, interquartile range 2.71 to 16.42 post-withdrawal, compared with 3.43 interquartile range 0.99 to 6.96 pre-treatment. P=0.014).

There were no apparent effects on change in lesions burden for either age, gender, disease duration, MRI lesion load, or trial enrollment.

But when they looked at the placebo/natalizumab group versus. the natalizumab/natalizumab groups, they saw that the increase in disease activity was much more pronounced among the placebo patients, who had received the active drug for only a few infusions.

Patients in the placebo/natalizumab group had a mean increase from 2.24 pre treatment to 10.37 post withdrawal, a roughly five-fold increase. In contrast, patients who had natalizumab throughout the studies had an increase from 3.47 pre-treatment to 4.81 post-withdrawal. For all patients, the median annual relapse rate was 1.15 in the pre-treatment MRI interval, and 0.73 in the post-withdrawal interval.

The authors noted that their findings conflict with those of a study presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis in 2006, which involved clinical and MRI analyses of MS patients following cessation of natalizumab.

"In that study, where most patients received around six infusions, there was no evidence of rebound, but the six-month follow-up period may have been too short to study this phenomenon as biologic effects of natalizumab may be observed up to six months after withdrawal," Dr. Vellinga and colleagues wrote. "Furthermore, that study focused on a transient phenomenon of MRI disease activity (gadolinium enhancement), whereas we study the cumulative burden of disease (T2 lesions)."

Dr. Vellinga said that it's too early to draw conclusions about possible changes in natalizumab therapy.

"For now the recommendations remain the same-patients and their doctors should choose the most applicable treatment for them," she said.