乌鸦传媒

BOSTON -- A copycat version of the multiple sclerosis (MS) drug Copaxone, known generically as glatiramer acetate, performed similarly to the original product in a large head-to-head clinical trial, paving the way for it to win regulatory approval as a generic drug.

With T1 gadolinium-enhancing lesions during treatment months seven to nine as the primary endpoint in the trial -- which enrolled nearly 800 patients with relapsing-remitting MS -- outcomes were nearly identical: estimated geometric means for the primary endpoint were 0.42 for generic glatiramer acetate versus 0.39 for Copaxone, reported Jeffrey Cohen, MD, of the Cleveland Clinic.

The lesion ratio in the two groups was 1.097 (95% CI 0.884-1.362), well within the predefined limits of what would be considered clinically equivalent, Cohen told attendees at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting here, held jointly this year with its North American counterpart.

Secondary efficacy outcomes including other MRI measures, annualized relapse rate, change in Expanded Disability Status Scale (EDSS) score, and proportions of patients free from relapses and from all disease activity were also very similar.

And the generic product's adverse effect profile was virtually identical to Copaxone's as well, Cohen reported.

The product's commercial future remains somewhat murky, though.

Glatiramer acetate is actually a mixture of various peptides, which, although well-characterized, is complicated to manufacture. Several firms have developed their own recipes for producing versions that they believe are functionally identical to the original Copaxone, which is made by Teva Pharmaceuticals. The product tested in the current trial is made by the Dutch firm Synthon.

As a synthetic peptide cocktail, glatiramer acetate isn't exactly a biologic nor is it a small-molecule drug. The FDA has not yet ruled finally on whether it will regulate these copycat forms as generic drugs or as so-called biosimilars, the recently established classification for copies of biologic agents.

Synthon had filed an Abbreviated New Drug Application (ANDA) -- the pathway for generic drugs -- for its version with the FDA in 2011, on the basis of its physicochemical analyses of the two products. But the European Medicines Agency has told the firm that it should conduct a full-blown clinical trial to establish functional equivalence both for efficacy and safety -- hence, the current study. Synthon also expects the trial to help it win ultimate approval from the FDA, which hasn't yet acted on the firm's ANDA.

Cohen said in an interview that Synthon and the trial investigators sought to strike a balance in the trial design -- keeping it relatively short and simple, compared with the trials typically conducted with new MS drugs. If the company had to run a 3-year study involving more than a thousand patients -- a standard phase III design -- the development cost savings that allow generics to be sold for less than branded drugs would vanish.

Synthon hasn't said what it expects to charge for its product, which is not surprising since the regulatory pathway remains uncertain.

Another factor has been Teva's legal and marketing efforts to keep generic versions at bay. It has lost several court battles but these are continuing, and in the meantime the firm is also trying to persuade clinicians that generic versions are inferior. For example, it sponsored an in vitro study being presented here that identified differential gene expression patterns in human monocytes exposed to Copaxone, versus generic copies.

Teva has also brought out a new -- and freshly patented -- version of Copaxone that can be administered three times weekly, instead of the once-daily dosing needed with the original form. The generics will perforce be daily-dosed products.

In the clinical study Cohen reported, just over 700 patients with relapsing-remitting MS were randomized to either the generic Synthon product or to Copaxone, with another 84 assigned to placebo.

The randomized phase lasted for 9 months, with all patients then switched to the generic for an additional 15 months of open-label treatment. MRI scans and clinical evaluations were performed periodically.

Patients in the trial were reflective of early- to mid-stage MS, with EDSS scores of 0 to 5.5, a recent history of relapses, and from one to 15 gadolinium-enhancing T1 lesions at screening.

Not only were both glatiramer acetate versions highly similar to each other in efficacy and safety outcomes, but they were both more effective than placebo in terms of lesion counts at months 7 to 9 and in other MRI measures -- a further confirmation that the glatiramer acetate products were working as expected.

On the other hand, annualized relapse rates were nearly identical in the Copaxone and placebo arms, at 0.41 and 0.39, respectively (versus 0.31 for the generic product).

Session co-moderator , of the Università Vita-Salute San Raffaele in Milan, called attention to this finding, for which Cohen said he had no good explanation.

Safety profiles of both active products were also similar to that seen previously with Copaxone, with injection-site reactions typical of the agent that were not seen with placebo.

, of University Hospital Basel in Switzerland, who was not involved with the study, commented that the exclusion of patients without gadolinium-enhancing lesions at baseline was a significant limitation of the study.

Cohen said the open-label phase of the trial was not yet completed, with results expected next year. Fuller data on the products' immunogenicity should be available then as well.

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