The results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing–remitting multiple sclerosis

Abstract

Objective Two pilot studies were conducted to evaluate safety, tolerability, and efficacy of two doses of Protiramer in patients with relapsing-remitting multiple sclerosis. Background Both glatiramer acetate and TV-5010 are synthetic copolymers comprised the same four amino acids in a defined molar ratio. TV-5010 has higher average molecular weight than Glatiramer acetate and might be hypothesized that glatiramoids with higher molecular weight might be more immunoreactive than lower molecular weight peptides, thus increasing therapeutic potential and allowing for less frequent dosing. Methods In the two separate studies, after a 10 week pretreatment period, TV-5010 was given subcutaneously once weekly at 15 mg and 30 mg for 36 weeks. The primary end point was a reduction in the number of magnetic resonance imaging active lesions (i.e., T1-weigthed gadoliniumenhancing and new T2-weighted lesions) between the pretreatment period and the end of study. Results Both TV-5010 doses were generally well tolerated. The treatment with TV-5010 at a dose of 15 mg/wk did not show any significant effect. In contrast, in patients treated with at a dose of 30 mg/wk, a significant reduction in the mean number of gadolinium-enhancing (−58.8%; P = 0.0013) and new T2-W (−50%; P = 0.0002) lesions was observed. However, a large decrease in the mean number of both gadolinium-enhancing (−55%) and new T2-W (−40%) lesions during the pretreatment period made difficult the interpretation of the efficacy assessments. Conclusions Further studies are needed to confirm these preliminary data on safety and efficacy of TV-5010 at a weekly dose of 30 mg. Multiple Sclerosis 2009; 15: 238-243.

Comparative Long-Term Preclinical Safety Evaluation of Two Glatiramoid Compounds (Glatiramer Acetate, Copaxone®, and TV-5010, Protiramer) in Rats and Monkeys

“…These adverse effects were observed in 50% of patients in the low protiramer dose (15 mg/wk) and 89% of patients in the higher dose (30 mg/wk; De Stefano et al 2009). …”

“…This minor change results in a product with a different MW distribution and different biological properties than GA (De Stefano et al 2009;Varkony et al 2009). Based on encouraging preclinical safety results from short-term toxicity studies, protiramer's safety, tolerability, and efficacy were evaluated in two small phase II clinical trials in MS patients; it demonstrated good general safety and tolerability (De Stefano et al 2009). Later, long-term preclinical toxicity studies in monkeys and rats revealed marked progression in the severity of injection site reactions, which was also accompanied by kidney and liver damage, and death of some high-dose animals.…”

Interferon Beta and Glatiramer Acetate Therapy

“…As the branded patent is set to expire, competition with biosimilars may emerge. Glatiramoid compounds are under study and may add to the competition [103]. The field of effective treatments for RRMS continues to grow.…”

Peptide-Based Polymer Therapeutics

“…Copaxone ® is a random copolymer based on four amino acids (L-alanine, L-lysine, L-glutamic acid and L-tyrosine) with Mw within the range of 5000-10000 Da for the treatment of multiple sclerosis [113,114]. After subcutaneous administration, it reduces frequency of relapse and disease progression [115]. In the early 90s, Poly(Arg-Gly-Asp) was demonstrated to inhibit lung metastasis and migration of B16-BL6 melanoma in mice [116,117].…”