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BLU Amp at AAN 2014 (part I): Generics or Generation Next In MS?

Teva: Copaxone too complex to copy

In anticipation of the pending expiration of the Copaxone Orange Book patents on May 25th, three different companies (Sandoz, Mylan, and Synthon) have already filed an abbreviated NDA for their glatiramer generic. While awaiting FDA action, Teva is reminding us that Copaxone is a complex drug, requiring a specified ratio of four different amino acids to form a mix of heterogeneous polymers which are difficult to quantify. Teva’s position is that an abbreviated NDA, which only requires demonstration of bioequivalence in healthy volunteers, is not sufficient to establish safety and efficacy of a potential generic formulation.

In a recent press release, the company noted:

“The inability to fully characterize the active ingredients of the product leads many experts to believe that the only way to ensure the safety, efficacy and immunogenicity of any purported generic version of COPAXONE® would be through full-scale, placebo-controlled clinical trials with measured clinical endpoints (such as relapse rate) in RRMS patients”.

To back up this proposition, TEVA scientists used an in vitro model to compare gene expression profiles of mouse splenocytes which were exposed to either Copaxone or a generic glatiramer (Natco Pharma). The data suggested that Copaxone promotes tolerance-inducing Tregs, while generic glatiramer may actually impair tolerance by upregulating myeloid lineage cells [Towfic et al., PLoS One. 2014].

Synthon: generic glatiramer works just fine

In March of this year, Synthon announced that their generic glatiramer showed equal efficacy with a similar safety profile compared to Copaxone (press release). GATE (NCT01489254), a double-blind, randomized Phase III study directly compared Copaxone to Synthon GTR and included a placebo reference arm. This study was designed in consultation with the EMA and, if the full data is as implied in the press release, market authorization will be a given. 

EMD Serono: building a better glatiramer instead

Meanwhile, EMD Serono is diligently working on the development of a second-generation amino acid copolymer, plovamer (PI-2301). An ongoing, rater-blinded, phase II trial compares different doses of weekly plovamer to a Copaxone reference arm (NCT01963611).

  • AAN 2014: EMD Serono presented research comparing plovamer and glatiramer in a preclinical model of Multiple Sclerosis. Using the same dose level and schedule, plovamer significantly decreased inflammation and demyelination compared to glatiramer. Plovamer was also associated with a stronger Th2-biased immune response. [Savinainen et al., AAN 2014; P1-187]

Speaking of EMD Serono…

Its sphingosine 1-phosphate (S1P) receptor agonist, ceralifimod (ONO-4641) has now entered late stage development with the initiation of a phase III trial in March [EUCTR2013-002351-15-LV]. This double blind, double dummy trial will randomize approximately 1176 RRMS patients to either interferon beta-1a (Avonex) or one of two different doses of ceralifimod (0.05 or 0.1 mg/day).

  • AAN 2014: EMD Serono presented interim data from the extension phase of the phase II DreaMS study [NCT01081782]. Primary data for this study, which compared ceralifimod to placebo, provided solid proof of concept data, supporting the initiation of a late stage trial [Zipp et al., ECTRIMS 2013]. The interim look at the MRI data from the extension study reported sustained efficacy for patients on continuous active treatment and confirmed the activity of ceralifimod in the patients that were initially receiving placebo [Bar-Or et al., AAN 2014; P3.161]

Receptos: building a better S1PR agonist?

EMD Serono is joining Receptos, who also recently initiated a late stage trial of its selective S1P Receptor agonist RCP1063. The RADIANCE study [NCT02047734] is a double-blind, dummy-controlled phase III trial that will randomize 1200 patients with relapsing MS to either interferon beta-1a or one of two different doses of RPC1063. To differentiate itself from the other S1P Receptor agonists, Receptos is highlighting the, potentially, improved cardiac safety profile of RCP1063. Phase I data showed no relevant effect on cardiac polarization, and dose titration attenuated first dose impact on heart rate [Olsen et al., AAN 2013; Hartung et al., ECTRIMS 2013]