MS Speaks

Excerpted from MedPage Today, October 7, 2015:

New Data Show Longer Tysabri Dosing Interval in MS Is Feasible

But available data remain underpowered to confirm PML risk reduction

 
by John Gever
Managing Editor, MedPage Today


BARCELONA -- Updated data from an ongoing study indicate that relapse rates and MRI lesion activity may actually be improved among multiple sclerosis patients receiving natalizumab (Tysabri) every 8 weeks as compared with the standard 4-week interval, with a possibly reduced risk of progressive multifocal leukoencephalopathy (PML).

With almost 2,000 patients enrolled in the study -- a prospectively scheduled chart review of patients at 11 U.S. centers who are receiving natalizumab on either the standard schedule or some type of extended-dosing interval -- the percentage of patients with relapses or clinical worsening, annualized relapse rate, and the percentage of patients with new T2 lesions were all significantly lower among those on extended dosing, said Lana Zhovtis-Ryerson, MD, of NYU Langone Medical Center in New York City, who presented the findings at a platform session during the European Committee for Treatment and Research in Multiple Sclerosis annual meeting here.

Moreover, there have been four PML cases among those on standard dosing versus none in the extended-dosing group, she reported. But the difference is not statistically significant, because the numbers of patients and duration of treatment have not yet met the threshold needed to demonstrate a significant difference, Zhovtis-Ryerson said.

But at this point, it may not be premature to state that the extended-dosing strategy does not sacrifice efficacy. Specific findings were as follows:

~Percentage of patients with relapse or clinical worsening: 23% with standard dosing, 18% with extended dosing (P=0.03)

~Annualized relapse rate: 0.14 standard, 0.09 extended (P=0.02)

~Percentage with new T2 lesions: 17% standard, 14% extended (P=0.02)

~Percentage with gadolinium-enhancing lesions: 7% standard, 9% extended (P=0.08)

~Percentage with no evidence of disease activity (clinical and radiographic): 62% standard, 61% extended (P=0.83)

Earlier this year, when Zhovtis-Ryerson and colleagues reported initial results from the study, there were two cases of PML in the standard-dose group versus none receiving extended dosing, and relapse rates and MRI activity levels were similar. At that time, and again here, she said that 1,248 patient-years of exposure would be needed to pronounce a significant advantage for one dosing strategy over the other at the P<0.05 level.

Currently, she said the standard-dose group had 1,052 patient-years among JC virus-positive participants and 1,090 patient-years in the extended-dosing group.

However, accrual of patient-years of exposure is proceeding slowly, she told MedPage Today here, and the research team expects it will be another 18 months before both groups reach the 1,248 mark.

Label instructions for natalizumab dosing call for the drug to be given every 4 weeks. But researchers have wanted to determine whether the same degree of clinical efficacy, in reducing risk of relapses and MRI lesion activity, can be maintained with longer intervals -- the point being to reduce the overall drug exposure and with it, presumably, the risk of developing PML.

Rates of PML have been found to increase with years of natalizumab exposure, but it remains unknown whether reducing the exposure in terms of milligrams per year will also cut the PML risk.

PML has been the biggest barrier to use of natalizumab, which otherwise is a highly effective and relatively safe agent for relapsing-remitting MS. Among patients positive for JC virus (the actual causative agent) who remain on natalizumab for more than 2 years at standard dosing, about 0.5%-1% will develop PML, depending on prior exposure to immunosuppressants. Roughly 20% of PML cases are fatal and many survivors have permanent disabilities.

The current study's design involves regular chart reviews, conducted on a prospective basis but without randomized treatment assignments, of patients receiving natalizumab on a variety of dosing schedules chosen by their treating physicians. Zhovtis-Ryerson and colleagues have stratified patients into the following groups:

Standard dosing (every 4 weeks)
Extended dosing (every 31 to 61 days)

That no patients in the latter group developed PML, versus four with standard dosing, is all the more impressive because the recognized risk factors for PML were more common in those receiving the extended dosing -- as might be expected since clinicians may be inclined to recommend less frequent natalizumab dosing for patients deemed to have high PML risk.

Of the 905 patients in this group, 59% were positive for JC virus and 18% had received prior immunosuppressants, compared with 48% and 12% of the standard-dosed patients, respectively (both P≤0.01). Moreover, Zhovtis-Ryerson said, the percentage receiving natalizumab for longer than 2 years was higher in the extended-dosing group, although she didn't present specific numbers.

Zhovtis-Ryerson said that recent data from other studies support the concept that a longer dosing interval could preserve natalizumab efficacy. These data point to the drug's saturation of its target, the alpha-4/beta-1 integrin molecule, as a key factor.

Specifically, it appears that target saturation need not be 100% to stop relapses and lesion activity. Partial saturation may be all that's necessary, and by allowing a degree of the target's normal function, it may allow immune surveillance and function in the nervous system to remain strong enough to maintain JC virus suppression. PML is believed to result from a diminution of immune surveillance and function that allows latent JC virus infection to become active within the brain.

Zhovtis-Ryerson emphasized that data from the current study may never be fully adequate to justify extended dosing as a routine strategy. She urged that a prospective, randomized non-inferiority trial be conducted.
The current study had no commercial funding.

____________________

Zhovtis-Ryerson and several co-authors reported research support and/or consulting relationships with Biogen Idec, manufacturer of natalizumab. Authors reported relationships as well with other commercial entities including Teva, EMD Serono, Novartis, Genzyme, Genentech, Acorda, Shire, and Questcor

But what about this?

~Percentage with gadolinium-enhancing lesions: 7% standard, 9% extended (P=0.08)

It looks to my untrained eye as if those on the extended dose were at greater risk of having gadolinium-enhancing lesions.

Also,

Standard dosing (every 4 weeks)
Extended dosing (every 31 to 61 days)

At least some of those on the experimental extended dosing were receiving Tysabri more often than once every 8 weeks. In fact, those who were receiving it every 31 days, for instance, were getting Tysabri only slightly less often than those on the standard dose. Or don't I understand this right?