麻豆传媒

WASHINGTON -- Freedom from relapse was maintained in multiple sclerosis patients on natalizumab (Tysabri) who received the infusion drug less frequently than the recommended 4-week interval, with lower risk of progressive multifocal leukoencephalopathy (PML), preliminary results from an ongoing analysis indicated.

Among 886 patients treated with "extended" dosing at 10 multiple sclerosis centers nationwide, the mean annualized relapse rate was the same at 0.1 per year as in 1,078 patients receiving natalizumab at the standard 4-week interval, according to , of NYU Langone Medical Center in New York City. MRI lesions counts were also similar.

Although patients testing positive for the JC virus -- the pathogen whose reactivation triggers PML, a sometimes fatal brain inflammation -- comprised 59% of the extended dosing group, none have so far developed PML, she reported here at the .

With a total of 1,023 patient-years of exposure to natalizumab in this JC-positive subgroup, published risk algorithms show an expected incidence of 2.5 cases, Zhovtis-Ryerson and colleagues calculated.

At this point the finding of zero cases with extended dosing is not statistically significant, the researchers cautioned -- but if the exposure reaches 1,248 patient-years with still no cases, it will be significant at P<0.05, Zhovtis-Ryerson indicated.

Meanwhile, two PML cases have developed in the standard-dosing group, among whom 41% are JC-positive and who have received a mean of 30 natalizumab doses (SD 22).

, of the Mayo Clinic, who was not involved with the study, told 麻豆传媒 that the approach deserves more study but urged caution in adopting it clinically.

He noted that if just one patient in the extended dosing group developed PML, "it would have completely negated any trend to reduced risk."

PML has been the primary concern with natalizumab almost since it was introduced in 2004. When several cases turned up shortly after its approval, the drug was withdrawn for some months, then relaunched with a restricted distribution program that included clinician and patient education on the risk.

The question of how to reduce PML risk with natalizumab -- which exceeds 1% in patients positive for JC virus and who have two other risk factors (treatment duration >2 years and history of immunosuppressant therapy) -- has occupied MS neurologists since the relaunch. Most studies have shown that patients who discontinue the drug or take long "holidays" experience a spike in relapse risk. Switching to another drug has not prevented such spikes because a months-long washout period after natalizumab discontinuation is needed before starting a different agent.

Some clinicians have been experimenting instead with longer dosing intervals, in the belief that the 4-week schedule keeps the drug's target -- alpha4beta1 integrin, an adhesion molecule involved in immune cell trafficking -- so saturated that JC virus immune surveillance is eliminated. Extending the interval may relax the immune suppression just enough to keep latent JC virus under control while still maintaining the anti-relapse effect.

In the current study, Zhovtis-Ryerson and colleagues sought to capture this empirical experience by canvassing centers that have adopted the strategy with some patients.

They defined extended dosing as any interval from 31 days up to 61 days. They further subdivided the extended dosing patients into those with early extended dosing (31 to 48 days; n=284) and late extended dosing (49 to 61 days; n=293). Another 309 patients had dosing that varied and could not be classified into either of those groups.

Patients in the extended dosing groups were at somewhat higher risk for PML than those treated at the recommended interval, with a higher proportion testing positive for JC virus, more patients with a history of immunosuppressant therapy (18% versus 11%), and more total natalizumab doses (mean 39 versus 30). Patient age, disease duration, and gender balance did not differ markedly between standard and extended dosing groups, however.

Among extended dosing patients, the mean duration of that schedule was 23 months overall (SD 14, range 3-116). These varied only modestly between the early, late, and variable dosing regimens.

Treatment efficacy (natalizumab's forte) was excellent irrespective of dosing interval. Some 65% of standard and 65% of extended dosing groups showed no evidence of disease activity (NEDA) -- that is, no active MRI lesions and no clinical activity. The variable extended dosing group suffered a little bit in this respect, with 55% meeting the NEDA standard compared with about 70% for both early and late dosing (P<0.001 versus early extended dosing, P=0.126 versus late dosing).

Weinshenker commented that selection of patients for extended dosing, which was not random, might have involved "biases against committing more aggressive MS patients on the extended interval program, which might reduce the ability of the investigators to detect reduction in efficacy."

Nevertheless, he said, extended dosing "is a promising and sensible approach that might turn out to be effective."

Zhovtis-Ryerson and colleagues have established a registry called EXTEND to which other clinicians may contribute, at . They are also planning a prospective study to examine effects of the different regimens on disability progression over time.

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