Pauline Anderson

June 02, 2014

DALLAS — Switching to fingolimod (Gilenya, Novartis) or an injectable therapy after 2 years of treatment with natalizumab (Tysabri, Biogen Idec Inc) is associated with a statistically significant increase in disability progression reported by patients with multiple sclerosis (MS), a new study has found.

The study is important because the risk for progressive multifocal leukoencephalopathy (PML) tends to peak at 2 years of natalizumab therapy, so it's at this time that doctors might want to raise the issue of changing therapy.

"Discussions on continuing, switching, or stopping medications should happen frequently between MS patients and their physician," said lead researcher Stacey S. Cofield, PhD, associate professor, School of Public Health, University of Alabama at Birmingham. "The conversation should weigh the benefits and the risks for each individual patient."

Dr. Cofield presented results of the study during the 6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS). It was funded in part by Biogen Idec.

Infection Risk

Natalizumab is an effective treatment against disability progression in patients with relapsing-remitting MS (RRMS), the authors note. Two major studies — AFFIRM (Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis) and TOP (Tysabri Observational Program) — showed decreased risks in 6-month confirmed disability progression of 54% and 84% (5-year interim analysis), respectively, said Dr. Cofield.

However, natalizumab was the first RRMS treatment that substantially increased concerns about infection risk, particularly PML, a disease of the white matter of the brain. PML is caused by lytic infection of oligodendrocytes with the JC virus.

According to data from Biogen, the postmarket incidence of PML linked to the agent tends to increase over time of treatment; before 2 years of treatment, the risk is low in patients with MS, but at 2 years of exposure, the risk increases substantially, although it doesn't appear to continue to increase beyond 2 years.

The new study looked retrospectively at disability progression using data collected in semi-annual updates of the North American Research Committee on MS (NARCOMS) database. NARCOMS is a global patient registry, with about 38,000 patients having enrolled since 1996 and about 25,000 having some form of follow-up starting in 2000, said Dr. Cofield.

"We have a standard set of immunotherapy questions, where we ask participants what they have taken in the prior 6 months, and if they have switched therapies," said Dr. Cofield.

The researchers categorized the participants who had taken natalizumab for at least 2 years into 3 groups: (1) those who remained on natalizumab (n = 406), (2) those who transitioned to fingolimod (n = 60), and (3) those who switched to an injectable therapy: either glatiramer acetate (Copaxone, Teva Pharmaceutical Industries Ltd) or an interferon β-1a (n = 71).

Dr. Cofield stressed that all participants must have been receiving natalizumab at least 2 years before switching to fingolimod or an injectable medication.

Some Caveats

She noted a few "caveats." Seven participants in the fingolimod group indicated that they had also tried an injectable after stopping natalizumab, although they took the injectable for less than 6 months. Thus, most of their follow-up time was during receipt of fingolimod. Participants could also use symptomatic therapies.

Dr. Cofield pointed out that patient characteristics did not differ at the start of natalizumab therapy. The mean age was about 50 years, and most patients were female, white and unemployed. Not unexpectedly, their mean age at time of diagnosis was mid-30s.

About 20% of participants recorded a relapse in the 6 months before beginning natalizumab. "These are not clinically confirmed relapses, just a patient-reported relapse," said Dr. Cofield.

Participants had been asked about disease progression using the patient-determined disease steps (PDDS). The PDDS is an 8-point scale with 0 indicating normal; 1, mild disability (little or no effect on lifestyle); 2, moderate disability (but no walking limitations); 3, gait disability; 4, early cane (required for 3 blocks); 5, late cane (required for 25 feet); 6, bilateral support (required for 25 feet); 7, needing wheelchair or scooter; and 8, being bedridden.

The mean PDDS scores at the start of natalizumab for the natalizumab, fingolimod, and injectable therapy groups were 3.4, 3.6, and 3.9, respectively. "That's somewhere around gait disability but not quite early cane use, which we define as needing a cane for 3 or more blocks of walking," said Dr. Cofield.

Follow-up times varied somewhat. The total mean time (including the 2 years on natalizumab) was about 4 years for both the natalizumab and fingolimod groups (although the latter group continued receiving natalizumab for a relatively long period before switching to fingolimod) and about 5 years for the injectable group.

The study found that the mean increase in PDDS score was lower in the natalizumab treatment group: 0.3 vs 0.5 for the fingolimod and 0.6 for the injectable groups (P = .0141). After adjustment for multiple testing, the difference between natalizumab and the injectables remained statistically significant, but there was no difference between nataluzimab and fingolimod or between fingolimod and the injectable groups, said Dr. Cofield.

Worsening Predictors

Predictors of increased PDDS worsening were older age (P = .0014), male sex (P = .0235), and lower baseline PDDS score (P < .0001). Follow-up time was not significantly related to PDDS change (P = .6930).

The proportions of participants with a 1-point or greater increase on the PDDS were 30.8% for natalizumab, 46.0% for fingolimod, and 42.3% for injectables. Again, there was a statistically significant difference across the 3 groups (P = .0296), said Dr. Cofield.

The researchers also looked at another endpoint, the SF-12 PCS (the physical component of the shortened health survey) and found a worsening of scores. The mean changes were –1.3 for natalizumab, –4.2 for fingolimod, and –4.3 for injectables. This, said Dr. Cofield, mirrored worsening on the PDDS. The worsening from baseline in all 3 groups was statistically significant, although the differences between the groups was not, she noted.

Older age and higher baseline score on the SF-12 PCS (both P < .0001) were predictors of SF-PCS worsening. Follow-up time and sex were not significantly related to SF-12 PCS change.

Because the size of the natalizumab group was imbalanced compared with sizes of the other groups, the researchers carried out a propensity score analysis, matching patients for age, sex, starting PDDS score, and prior relapse activity. This analysis uncovered a similar pattern with regard to PDDS scores.

"The directional differences are similar to what they were when we looked at them in the larger sample size," said Dr. Cofield. "Again, we see a difference here between natalizumab and fingolimod, which we saw in the full group analysis, and not a significant difference between natalizumab and injectables, although again, the differences are in the same direction and are of similar magnitude."

It was much the same story for SF-12 propensity matching; although the differences were not statistically significant, the changes were in the same direction.

Still, while patients who switched therapy in the current study experienced a statistically significant worsening, "this was on average," Dr. Cofield told Medscape Medical News. "The amount of worsening may be acceptable to some patients given the known risks of natalizumab," she said.

JC Virus Status

Asked by an audience member whether most participants switched from natalizumab because they were positive for JC virus antibodies, a known risk factor for PML with natalizumab that also precludes starting natalizumab therapy, Dr. Cofield said she and her colleagues didn't start asking about JC virus testing until 2011, so it did not affect this cohort. "That question didn't come about until further along in the NARCOMS analyses."

The researchers hope to investigate more closely the reasons why patients decided to switch medications and the relationship between relapses in the follow-up period and changes in medication, said Dr. Cofield.

Approached for her opinion of this analysis, Lily Jung Henson, MD, a neurologist specializing in MS at the Swedish Medical Center, Seattle, Washington, said the findings are consistent with what she and most of her colleagues see clinically.

"The million dollar question is why this occurs, why patients switched in the first place," said Dr. Jung Henson. "Should the patient have stayed on natalizumab but switched due to fears about PML, or because he or she was failing natalizumab, or for some other reason?"

The study was supported in part by Biogen Idec. Dr. Cofield reports that she has received personal compensation from TEVA Pharmaceuticals, Medimmune, Orthotech, and the American Academy for Orthopedic Surgery for consulting services research funds, and/or data safety and monitoring board service. Dr. Jung Henson reports receiving research funding, consulting, and speaker's fees from both Biogen and Novartis, as well as from Genzyme/sanofi. She also receives speaker fees from Teva, Pfizer, and Serono. 

6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS). Abstract DX06. Presented May 30, 2014.

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