New Glatiramer Dosing Convenient, Possibly Safer, in MS

Pauline Anderson

May 14, 2014

PHILADELPHIA — The new 40-mg dosing of glatiramer acetate (GA; Copaxone, Teva Pharmaceuticals) given 3 times a week not only may be more convenient than the traditional 20 mg daily for patients with relapsing-remitting multiple sclerosis (RRMS) but also may avoid adverse effects linked to long-term injections, new study results suggest.

Jerry S. Wolinsky, MD, interim chair, Bartels Family and Opal C. Rankin Professor, Neurology, and director, Multiple Sclerosis Research Group and MRI-Analysis Center, University of Texas Health Science Center, Houston, discussed results of the GLACIER (Glatiramer Acetate low frequency safety and patient ExpeRience) study at a platform presentation during the American Academy of Neurology (AAN) 66th Annual Meeting here.

GLACIER compared the safety and tolerability of subcutaneous GA, 20 mg/1 mL once daily (GA20), with those of GA, 40 mg/1 mL 3 times weekly (GA40), in patients with RRMS; the study was not placebo-controlled. Results showed that the higher dose was associated with a 50% lower rate of injection-related adverse events an the same magnitude of reduction in injection site reactions (such as pain, swelling, and erythema), and that both doses were well tolerated.

"What we glean from this study is that this 40-mg, more concentrated form of glatiramer acetate 3 times a week is a reasonable alternative for people who are growing weary of, or anxious about, daily injections of this particular drug," said Dr. Wolinsky. "It's important to know about GLACIER because in some ways it has practical implications, although it's not a critical study."


GA is random polymer composed of 4 amino acids found in myelin basic protein. It's believed to modify immune processes responsible for the pathogenesis of MS.

The 20-mg dose of GA has been approved since 1995, while the 40-mg dose has been available only since earlier this year.

GLACIER included 210 patients aged 18 years and older with RRMS (according to McDonald 2010 criteria) at 31 sites who were ambulatory and relapse-free, had an Expanded Disability Status Scale score of 0 to 5.5, and had not received steroid treatment in the previous 60 days.

Patients were excluded if they had progressive MS or neuromyelitis optica; used other disease-modifying, experimental, or investigational therapies; or had participated in other clinical studies within the past 6 months.

For this open-label study, all patients were treated with GA20 for at least 6 months before screening. They were randomly assigned to continue receiving GA20 or convert to GA40. They were assessed at months 1, 2, and 4, at which time they could receive GA40 during the optional extension phase.

Dr. Wolinsky noted that this was not a placebo-controlled trial. It would have been "extraordinarily complicated" to organize placebo injections on days patients weren't getting the 40-mg dose, he explained.

The study found that the annualized rate of injection related adverse events — the primary endpoint — was 35.3 in the higher-dose group compared with 70.4 in the lower-dose group (relative risk [RR], 0.50; 95% confidence interval [CI], 0.34 - 0.74; P = .0005).

It's perhaps not surprising that injecting a drug 3 times a week rather than daily results in fewer injection site reactions, Dr. Wolinsky told Medscape Medical News. "In my mind this is a phase 4 study," he said, but the company views it as a phase 3b study.

As for the secondary endpoint of injection site reactions, the 40-mg group had a rate of 35.2 compared with 70.4 for the lower-dose group (RR, 0.50; 95% CI, 0.34 - 0.74; P = .0006).

Less Pain

Rates for pain, erythema, swelling, bruising, and other adverse events were consistently lower in the group receiving the higher dose than in those getting the lower dose.

There were no differences between the 2 groups in physical or psychological scores on the MS Impact Scale questionnaire, and no difference on the satisfaction score of the Treatment Satisfaction Questionnaire for Medication-9. However, patients perceived the 40-mg dose to be more convenient.

Not all patients, however, are keen to try the new dosing regimen. For some who have been receiving the 20-mg dosing for many years, it has become something of "an old friend," said Dr. Wolinsky.

Some, he said, fear that they won't get used to a new injection schedule. "Some say they tolerate daily injections very well and want to stay on this because otherwise they might become anxious that it won't work as well or that they'll forget to take it."

However, long-time daily users might develop skin-related adverse effects, said Dr. Wolinsky, who has been working with GA for more than 20 years. "Some of our patients in the original studies have now been on this drug for more than 17 or 18 years. If patients are injecting a drug every day for that length of time, some eventually may develop lipoatrophy."

This condition, he explained, leads to loss of subcutaneous tissue, and the skin can take on a "scalloped" effect. "The longer some patients are on the drug, the more likely they are to develop lipoatrophy," he said.

The condition may prevent them from easily injecting the drug or wanting to stay on the agent even if they're doing well, added Dr. Wolinsky. "If we reduce the number of injections from 7 a week to 3 a week, we're probably going to prolong the time until patients who are prone to lipoatrophy might say they've had enough."

Dr. Wolinsky estimated that about 40% of his patients with RRMS are receiving GA, although the rate would vary from practice to practice. "It's now one of the most common, if not the most common, of the currently approved drugs," but this is shifting quickly with the recent approval of 3 oral drugs, he said.

The adverse effect profile is an important determining factor. "I tend to worry about serious side effects rather than a patient has some discomfort where they inject themselves," said Dr. Wolinsky.


Another study — an open-label extension of the GALA (Glatiramer Acetate Low Frequency Administration) study — was also discussed during the same platform session here.

GALA, which included 1404 patients who were randomly assigned to GA40 or placebo, showed that after 12 months, the active treatment was associated with a 34.0% reduction in risk for confirmed relapses compared with placebo (mean annualized relapse rate, 0.331 vs 0.505; P < .0001).

These patients experienced highly significant reduction (P < .0001) in the cumulative number of gadolinium-enhancing T1 and new or newly enlarging T2 lesions. The study also found GA40 to be safe and well tolerated (Ann Neurol. 2013;73:705-713).

That study, commented Dr. Wolinsky, "showed that the effects of this higher dose used 3 times a week vs placebo were very similar, in terms of the clinical attack rate and effects on MRI, to what had been seen in all previous studies with the 20 mg used every day."

Results of a 24-month open-label extension of the GALA trial, presented here by Omar Khan, MD, from Wayne State University, Detroit, Michigan, looked at outcomes in patients who received treatment during both the placebo-controlled and the open-label extension (the early initiation group) and outcomes in patients who first received placebo during the trial and then were switched to treatment (the delayed initiation group).

From baseline to 24 months, the adjusted annualized relapse rate was significantly lower for the early initiation group than the delayed initiation group (0.18 vs 0.26; RR, 0.69; P = .0002). Significantly fewer early initiation patients were relapse-free during follow-up compared with delayed initiation patients, and they had numerically lower rates of 6-month confirmed disability progression.

Adverse events were "generally mild, and consistent with the well-established Copaxone safety profile," the researchers note.

Yet another GA study of note compared the 20-mg and 40-mg doses (Ann Neurol. 2011;69:75-82) and found that both were safe and well tolerated, with no gain in efficacy for the higher dose, commented Dr. Wolinsky.

"What the company hoped to show was that if you give more, you get better results, but here they showed that if you give more, you get what looks to be an equivalent result without an increase in side effect profile, so the safety profile was the same," he said.

GLACIER and GALA were funded by Teva Pharmaceuticals. Dr. Wolinsky received compensation for service on steering committees or data monitoring boards for Novartis, Roche, Sanofi, and Teva; reimbursement for services as a consultant to Athersys, Genzyme, Novartis, Roche, RND, Teva, and XenoPort; and royalty payments through the University of Texas Health Science Center at Houston for monoclonal antibodies out?licensed to Chemicon International. He also received research support from Genzyme, Sanofi, and the National Institutes of Health through the University of Texas Health Science Center at Houston.

American Academy of Neurology (AAN) 66th Annual Meeting. Abstract S31.002, S31.003. Presented April 30, 2014.


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