Low-Contrast Visual Tests Reveal Better Alemtuzumab Efficacy

Daniel M. Keller, PhD

October 08, 2013

VIENNA, Austria — Compared with subcutaneous interferon β-1a (IFNB-1a; Rebif/EMD Serono/Pfizer), treatment with alemtuzumab (Lemtrada, Genzyme/Sanofi) improved visual outcomes in treatment-naive patients with relapsing-remitting multiple sclerosis (MS), a new study shows.

Detecting the treatment effect depended on using Sloan low-contrast acuity metrics. Visual deficits in MS include impaired contrast sensitivity and contrast letter acuity.

"Low-contrast acuity allows us to see treatment differences and allows us to better understand the visual difficulties that patients have if we were not to use that type of low-contrast metric...that are not captured by high-contrast acuity charts," Steven Galetta, MD, chairman of the Department of Neurology at New York University Langone Medical Center in New York City, told Medscape Medical News.

Alemtuzumab has been studied in 3 clinical trials in MS and has been shown to significantly reduce relapse rates compared with treatment with IFNB-1a. In a phase 2 trial, alemtuzumab was also associated with significantly greater improvement in visual contrast sensitivity vs IFNB-1a (P = .01).

The European Medicines Agency recently approved the drug, but in the United States, the Food and Drug Administration is still reviewing the company's application.

Low-contrast acuity allows us to see treatment differences and allows us to better understand the visual difficulties that patients have if we were not to use that type of low-contrast metric...that are not captured by high-contrast acuity charts. Dr. Steven Galetta

As part of the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS I) trial, 1 of the 2 pivotal phase 3 trials in MS, researchers examined the effects of the 2 drugs on visual outcomes in treatment-naive patients with relapsing-remitting MS.

The trial randomly assigned patients to alemtuzumab, 12 mg intravenously daily, for 5 days at time 0 and then daily for 3 days at month 12 (n = 376) or to IFNB-1a, 44 μg subcutaneously 3 times per week, for 24 months (n = 187). Raters were blinded to the treatment allocation.

Patients had active disease (2 or more attacks within 24 months or 1 or more attack within 12 months), Expanded Disability Status Scale score (EDSS) of 0 to 3, and disease onset less than 5 years earlier. The groups were well matched in terms of age (mean, 33 years), sex, time since initial episode, EDSS score, Multiple Sclerosis Functional Composite (MSFC) score, and number of relapses in the prior year.

Patients were tested for binocular acuity on Sloan Low-Contrast Visual Acuity charts at contrasts of 1.25%, 2.5%, and 100% (high contrast). They were scored on the number of letters identified correctly. Dr. Galetta said low-contrast acuity testing is a sensitive clinical measure of visual dysfunction in MS and predicts changes in disability and functionality.

Presenting the results here at the XXI World Congress of Neurology (WCN), Dr. Galetta said that at 24 months, Sloan scores favored alemtuzumab when 2.5% contrast was used.

The alemtuzumab group had no change in Sloan scores at 2.5% contrast from baseline vs a worsening in the IFNB-1a group. Both groups had worsening at 1.25% contrast and improvement at 100% contrast.

Table. Effect of Alemtuzumab vs IFNB-1a on Sloan Scores* at 24 Months

Contrast Level (%) Alemtuzumab IFNB-1a P Value
1.25 –0.08 –0.21 .051
2.5 0.01 –0.07 .031
100 0.25 0.19 .26

*Negative score indicates worsening visual acuity; positive score indicates improvement (numbers interpreted from bar chart).


The mean changes in Sloan scores from baseline were significantly better with alemtuzumab compared with IFNB-1a for 1.25% contrast at months 12 and 18 (P = .021 and P = .038, respectively). The proportion of patients worsening, remaining stable, or improving in 1.25% contrast tests did not differ significantly at month 12 or 24 between the treatment groups.

Contrast Acuity as Fourth Measure of Disability

The MSFC is a sensitive, composite measure of MS disability. It incorporates measures of ambulation/gait, upper-extremity coordination, and cognition. A positive score indicates that a patient is better than the study population as a whole.

By incorporating Sloan contrast testing as a fourth measure in the composite, MSFC-4 captures visual deficits as an additional dimension of disability, the researchers point out.

"Vision wasn't really captured well by the current disability systems that we use, the Kurtzke scale for instance, and it wasn't incorporated into the Multiple Sclerosis Functional Composite," Dr. Galetta explained. "Yet, half of the brain's circuits are dedicated to vision, and vision is so commonly affected in MS. So we just needed a more sensitive measure for visual dysfunction because patients would complain despite reaching 20/20 [acuity] on the standard black-on-white lettering that their vision was still impaired, their quality of life was still impaired visually."

As assessed by MSFC-4, using 1.25% or 2.5% contrast, the alemtuzumab group improved significantly over the 24 months (P = .003 and P < .001, respectively), whereas the IFNB-1a group did not (P= .40 and P = .89, respectively). The between-treatment difference favored alemtuzumab at both 1.25% (P < .001) and at 2.5% (P = .002).

Dr. Galetta said that low-contrast visual acuity testing has been used in clinical trials and ultimately should be important for clinical practice because it can pick up subtle defects that would not otherwise be detected. He added that the testing is "absolutely easy to do. It takes a minute or so. The patient just views an easel full of those letters."

Simple Way of Testing

When asked to comment on the study, Bruce Sigsbee, MD, MS, from Rockport, Maine, and immediate past president of the American Academy of Neurology, told Medscape Medical News, "The current metrics such as the EDSS...really do not directly measure visual function, and yet we know optic neuritis and other visual symptoms are a common manifestation in MS, and their contrast sensitivity study really showed that this was an effective way but a very simple way of testing visual function and the impact of MS on the visual pathways."

He praised the study for using an active comparator group. "Very often new drugs are compared with placebo, and so you really don't have good comparison across different treatments and you're always wondering is this drug better than something we've been using. And they appear to demonstrate that this does have a statistical benefit beyond using just the interferon alone," he said.

But Dr. Sigsbee cautioned that in choosing a drug, one needs to look at the totality of effects, including untoward effects.

"So far they've been fairly limited, but they only so far had about 5000 people in various trials on [alemtuzumab]." Referring to the experience with natalizumab (Tysabri, Biogen Idec), he said that only once the drug was on the market and with greater exposure did problems relating to progressive multifocal leukoencephalopathy appear.

"Certainly patients need to be closely monitored, particularly during the first few years of release," he advised.

Finally, he said that visual dysfunction is an important issue in MS, and therefore, low-contrast acuity testing should perhaps be part of a standard battery of tests for these patients.

CARE-MS I was sponsored by Genzyme/Sanofi. Dr. Galetta has received consulting honoraria from Teva, Biogen Idec, and Questcor Pharmaceuticals. Dr. Galetta presented on behalf of first author Laura Balcer, MD, from New York University. Dr. Sigsbee, who was not involved in the study, has disclosed no relevant financial relationships.

XXI World Congress of Neurology (WCN). Free Papers Session 17. Presented September 24, 2013.


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