Contributions
Abstract: EP1664
Type: Poster Sessions
Abstract Category: Therapy - Risk management for disease modifying treatments
Background: Copaxone (glatiramer acetate, Teva), has provided a safe effective treatment option for multiple sclerosis for 20+ years. In April 2016, a 20 mg/mL follow-on glatiramer acetate product (FoGA, Synthon) was approved in the EU. Employing high resolution physicochemical (PCC) methods, Teva Pharmaceuticals, the manufacturer of Copaxone, has reported consistent differences between Copaxone lots and Synthon FoGA lots in attributes of surface charge distribution and compositional parameters of molecular and spatial size. Also, while within Copaxone specifications for potency, average observed relative potency of Synthon EU lots was higher than mean estimated values of Copaxone lots and 2 of 6 Synthon EU lots were out-of-Copaxone specification range for cytotoxicity testing, showing higher activity and higher lot-to-lot variability.
Objective: Present analyses focus on the genomic profiling and in vivo rat local toxicity assessment conducted to determine the functional characteristics of the active substances in the Synthon FoGA lots as compared to Copaxone lots.
Methods: Three lots of Synthon EU FoGA were compared to 3 randomly selected Copaxone lots for the genomic profile assays (THP-1 cells and ex-vivo activated mouse splenocytes immunized with FoGA or Copaxone). A 13 week rat toxicity study with daily dosing was conducted.
Results: Comparisons of Copaxone vs. Synthon EU FOGA with mannitol correction showed 1802 probesets to differ at adj. p < 0.05 in the THP-1 model, and 510 (Copaxone immunization) and 460 (Synthon EU FoGA immunization) probesets in splenocyte model. Many of immunologically relevant expressed genes that differ between Copaxone lots and Synthon EU FoGA lots are relevant to the mechanism of action of Copaxone and exhibit concordance with previously reported PCC and biological attribute differences. In the in vivo toxicity study, the number of skin swelling and induration episodes recorded (minimal-slight severity) following subcutaneous injections of Synthon EU FoGA was higher than that recorded for Copaxone (201 vs 122, p< 0.0001; 95 vs 68, p=0.0177, respectively).
Conclusions: Consistent differences were observed in genomic profiling and functional characteristics of the active substance in the Copaxone and Synthon EU FoGA lots. Together with the PCC and biological differences previously noted, these observations raise concern for possible immunogenicity differences, particularly in (repeated) substitution settings.
Disclosure: Authors SK, JZ, JF, and BZ are employees of Immuneering Corporation which was contracted by Teva Pharmaceuticals to perform gene expression analyses. Authors NA, BT, OB, AK, JA, PL, MV, VW, SM-G, IG, SN and MRH are employees of Teva Pharmaceuticals Ltd.
Abstract: EP1664
Type: Poster Sessions
Abstract Category: Therapy - Risk management for disease modifying treatments
Background: Copaxone (glatiramer acetate, Teva), has provided a safe effective treatment option for multiple sclerosis for 20+ years. In April 2016, a 20 mg/mL follow-on glatiramer acetate product (FoGA, Synthon) was approved in the EU. Employing high resolution physicochemical (PCC) methods, Teva Pharmaceuticals, the manufacturer of Copaxone, has reported consistent differences between Copaxone lots and Synthon FoGA lots in attributes of surface charge distribution and compositional parameters of molecular and spatial size. Also, while within Copaxone specifications for potency, average observed relative potency of Synthon EU lots was higher than mean estimated values of Copaxone lots and 2 of 6 Synthon EU lots were out-of-Copaxone specification range for cytotoxicity testing, showing higher activity and higher lot-to-lot variability.
Objective: Present analyses focus on the genomic profiling and in vivo rat local toxicity assessment conducted to determine the functional characteristics of the active substances in the Synthon FoGA lots as compared to Copaxone lots.
Methods: Three lots of Synthon EU FoGA were compared to 3 randomly selected Copaxone lots for the genomic profile assays (THP-1 cells and ex-vivo activated mouse splenocytes immunized with FoGA or Copaxone). A 13 week rat toxicity study with daily dosing was conducted.
Results: Comparisons of Copaxone vs. Synthon EU FOGA with mannitol correction showed 1802 probesets to differ at adj. p < 0.05 in the THP-1 model, and 510 (Copaxone immunization) and 460 (Synthon EU FoGA immunization) probesets in splenocyte model. Many of immunologically relevant expressed genes that differ between Copaxone lots and Synthon EU FoGA lots are relevant to the mechanism of action of Copaxone and exhibit concordance with previously reported PCC and biological attribute differences. In the in vivo toxicity study, the number of skin swelling and induration episodes recorded (minimal-slight severity) following subcutaneous injections of Synthon EU FoGA was higher than that recorded for Copaxone (201 vs 122, p< 0.0001; 95 vs 68, p=0.0177, respectively).
Conclusions: Consistent differences were observed in genomic profiling and functional characteristics of the active substance in the Copaxone and Synthon EU FoGA lots. Together with the PCC and biological differences previously noted, these observations raise concern for possible immunogenicity differences, particularly in (repeated) substitution settings.
Disclosure: Authors SK, JZ, JF, and BZ are employees of Immuneering Corporation which was contracted by Teva Pharmaceuticals to perform gene expression analyses. Authors NA, BT, OB, AK, JA, PL, MV, VW, SM-G, IG, SN and MRH are employees of Teva Pharmaceuticals Ltd.