Date: 2014-04-10
Type of information:
phase: 2a
Announcement: publication of results in The Journal of Pharmacology and Experimental Therapeutics
Company: Gene Signal (Switzerland)
Product: aganirsen
Action
mechanism: Aganirsen is an antisense oliglonucleotide that inhibits the expression of insulin receptor substrate-1 (IRS-1). It has also antiangiogenic activities including inhibition of both VEGF and interleukin-1β expression.
Disease: psoriasis
Therapeutic area: Autoimmune diseases - Dermatological diseases
Country:
Trial
details: The randomized, double blind, placebo-controlled six-week exploratory Phase IIa study involved 36 lesions in 12 patients. Each patient with three identified plaque psoriasis (at least two in refractory sites) received topical applications of 0.86 mg/g and 1.72 mg/g of aganirsen or placebo once per day over six weeks. The two doses of aganirsen and placebo were administered consistently to the same psoriasis plaques throughout the treatment period.
Latest
news: * On April 10, 2014, Gene Signal, a company focused on developing innovative drugs to manage angiogenesis based conditions, has announced results from a Phase IIa study in psoriasis which demonstrated that topical application of aganirsen (GS-101), an antisense oligonucleotide, reduced the size of psoriatic lesions and inflammation compared to placebo. The results were published in The Journal of Pharmacology and Experimental Therapeutics. (J Pharmacol Exp Ther 2014;349:107-117 - ‘The Antiangiogenic Insulin Receptor Substrate-1 Antisense Oligonucleotide Aganirsen Impairs AU-Rich mRNA Stability by Reducing 14-3-3β-Tristetraprolin Protein Complex, Reducing Inflammation and Psoriatic Lesion Size in Patients’. http://dx.doi.org/10.1124/jpet.113.209346)
Significant efficacy results and first study to demonstrate nsulin receptor substrate-1 (IRS-)1 as valid target Topical application of both doses of 0.86 mg/g or 1.72 mg/g aganirsen once per day for 6 weeks led to a significant reduction of -14.4% and -12.9% respectively (p<0.05) in the area of the treated psoriatic lesions compared to placebo. By contrast an increase in the lesion area (+24.5%) was observed in placebo-treated patients. Least square mean differences with placebo were -38.9% and -37.4% for the low and high doses of aganirsen, respectively. A significant treatment effect with aganirsen was also observed as early as 3 weeks.
It was particularly interesting to note that aganirsen had the power as a topical therapy to normalize expression levels of the major inflammatory factors involved in psoriasis. Most importantly, this study is the first to demonstrate the therapeutic benefit in psoriasis of downregulating the expression of insulin receptor substrate-1 (IRS-1). The results unveil IRS-1 as a new target which underlies the chronic multifactor inflammation as well as the aberrant angiogenesis. Aganirsen also inhibited the overexpression of vascular endothelial growth factor (VEGF) and consequently the aberrant angiogenesis. The topical application of aganirsen on psoriatic lesions was shown to inhibit tumor necrosis factor alpha (TNFα), which is elevated in psoriasis as part of the human immune response system, and to restore normal levels of CD4+ and CD3+ lymphocytes in psoriatic skin.
The study did not reveal a dose-dependent effect. Results suggest that the two doses tested induced a maximal effect within the current protocol; lower daily doses of aganirsen combined with a longer period of treatment will have to be tested in further clinical studies.
