Copaxone® (glatiramer acetate)
FDA-Approved Medications: Administered by Self-Injection
Company: Teva Neuroscience, Inc.
- Given via daily (20 mg) or three-times-weekly (40 mg) subcutaneous injections
- Approved for RRMS and CIS
Copaxone has been shown to significantly reduce the annual relapse rate in RRMS and reduce the risk of people with CIS for developing clinically definite MS (CDMS) at two years.
Copaxone is a synthetic polypeptide that mimics myelin basic protein, a key component of the myelin sheath (the protective covering of the nerves) that is damaged in MS. This therapy appears to decrease immune-system T cells that damage myelin, and may decrease inflammation by favorably shifting the balance among T-cell subtypes as well as by affecting several interleukins. (Interleukins are a type of cytokine, which are small proteins that may stimulate or inhibit the function of other cells.) Copaxone may also induce lymphocytes (immune-system cells produced to fight infection and disease) to produce factors that enhance the survival of cells that produce myelin, and may have a neuroprotective action that prevents damage to axons (nerve fibers).
An international European study called PreCISe was conducted to determine whether immediate treatment with Copaxone is better than delayed treatment in preventing conversion to clinically definite MS (CDMS). This study has shown that early treatment with Copaxone reduced the risk of converting to CDMS. The five-year extension data from this study were presented recently. The delay in the development of CDMS (resulting from early initiation of Copaxone) over placebo was maintained in the extension study with a CDMS risk reduction of 41 percent at five years. These results establish the importance of initiating treatment with Copaxone as early as possible to protect patients from the accumulation of disease activity.
In 2013, results were reported from the COPTIMIZE study,2 a two-year observational survey of 672 patients with RRMS switching to Copaxone – due to a lack of efficacy or treatment intolerability with a different disease-modifying therapy. Patients who switched to Copaxone from other disease-modifying drugs generally improved in measures of fatigue, cognition, quality of life, and depression; mobility remained stable, although the Expanded Disability Status Scale (EDSS) increased slightly from baseline. A total of 72.7 percent of the patients who switched to Copaxone remained relapse-free.
Several years ago, the PROMISE study of 943 patients with primary-progressive MS (PPMS) failed to show that Copaxone was effective in this population of people with MS. Approximately 10 percent of the MS population is diagnosed with PPMS, where individuals experience a steady worsening of symptoms from the start, and do not have the periodic relapses and remissions found with relapsing-remitting MS (RRMS).
A smaller number of individuals are diagnosed with progressive-relapsing MS (PRMS), which begins as PPMS, but subsequently develops relapses. PRMS is similar to PPMS as it steadily worsens from the onset, but symptom flare-ups (with or without remissions) are also present. This is considered the least common form of MS.
There has been some debate as to whether categorizing PRMS separately from PPMS – in terms of clinical course and prognosis – can be justified. A sub-study of the PROMISE data3 evaluated differences in baseline characteristics and disability progression between patients with PPMS and PRMS.
In this PROMISE sub-study, 42 of the 943 PPMS patients ultimately developed relapses and converted to PRMS. Although the numbers of PRMS patients analyzed in this study were small, the results suggested that disease progression is more rapid in this clinical sub-group. Since PRMS falls under the category of “relapsing forms” of MS, the use of disease-modifying therapies may be considered for individuals with this type of MS.
The initial FDA-approved dose for Copaxone is 20 mg per day, given subcutaneously. The GALA trial was a randomized, placebo-controlled trial of Copaxone dosed at 40 mg given by subcutaneous injection three-times weekly versus placebo.
Data from this trial were first presented in Fall 2012.4 This three-times weekly dosing strategy of Copaxone reduced relapse rates by 34 percent compared with placebo, and reduced new MRI lesions by 35 percent. This is comparable with the expected efficacy of Copaxone given at the standard dose of 20 mg injected daily, and no new safety concerns were identified.
In January 2014, the three-times per week dosing of Copaxone (at the new, 40-mg dose) was approved by the FDA. This new formulation enables individuals who take Copaxone to reduce their number of subcutaneous injections by 60 percent (from seven to three injections per week), once they are prescribed the new dosing regimen. In addition to the newly approved dose, daily Copaxone (at the 20-mg dose) will continue to be available.
Although in MS the standard of care has been to use one disease-modifying therapy at a time, many other conditions from high blood pressure to cancer are often treated with combinations of medicines to achieve the best outcome. Combining medications safely and effectively requires careful long-term studies, as drug interactions can be complex and difficult to predict.
Results were presented in 2012 for the Combi-Rx trial,5 designed to assess if the combination of Copaxone and Avonex is more effective at reducing relapse rates than either agent alone. This National Institutes of Health (NIH)-funded trial recruited 1,008 patients, who were randomized to three study arms: combination of Copaxone and Avonex; Copaxone alone; and Avonex alone.
Although all participants were on one or both of the active treatments, the trial was placebo-controlled. This means that for individuals not given the combination of Copaxone and Avonex, they would receive either Copaxone and a placebo, or Avonex and a placebo. This allowed researchers to compare all three treatment groups equally.
Interestingly, the combination of Copaxone and Avonex taken together was not statistically superior to either therapy taken alone at preventing relapses. It is worth noting that these are the lowest relapse rates ever recorded in a clinical trial of these available agents, with the Combi-Rx trial continuing to support the excellent efficacy of these medicines, particularly when utilized early in the disease course. In this trial, the treatment group that received Copaxone alone had the lowest number of relapses.
Interestingly, in the Combi-Rx trial,6 the combination was found to be superior to individual drugs for new MRI-lesion activity and the accumulation of total lesions. However, combination therapy failed to show an advantage on several other MRI outcomes.
A Phase II trial to study the effect of combining Copaxone and estriol (a naturally-occurring estrogen hormone) on relapse rate in women with RRMS finally reported preliminary results in 2014.7 MS relapses are known to be significantly decreased during pregnancy.
This trial was designed to evaluate whether oral treatment with estriol, the major estrogen of pregnancy, would decrease relapses in RRMS when used in combination with injectable Copaxone. The preliminary results showed that the combination of Copaxone and estriol appeared safe over the two-year trial period, and there were no severe adverse events attributed to the treatment.
After the first year of the study, those on the combination of Copaxone and estriol had a significant reduction in relapse rates compared to those on Copaxone plus placebo, and cognitive testing suggested possible cognitive benefits of the estriol combination as well. However, the trial was designed to assess these outcomes at the end of two years.
Unfortunately, after the second year of the study, there was no statistical difference in relapse rates between those on Copaxone combined with estriol versus those on Copaxone combined with placebo. It is not clear if these results will justify continued investigation of estriol in a large clinical trial, but it is another example of the difficulty in proving that a combination strategy is both safe and effective.