Idera Pharmaceuticals has completed patient enrollment in its randomized, double-blind, placebo-controlled phase II trial of IMO-3100 in patients with moderate-to-severe plaque psoriasis. IMO-3100 is an antagonist of specific Toll-like Receptors (TLRs) that the Company is developing for the treatment of psoriasis and other autoimmune diseases. Idera anticipates top-line data from this study will be available by year-end 2012.
TLRs are a class of proteins that play a key role in both inflammation and immunity. Through the inhibition of specific TLRs, Idera’s candidates may represent a novel approach for the treatment of psoriasis, lupus and other autoimmune diseases.
“In this phase II proof-of-concept study, we are evaluating multiple endpoints to assess the clinical activity of IMO-3100, including the impact on Psoriasis Area Severity Index (PASI), mean focal psoriasis severity, and Physician Global Assessment (PGA) scores,” said Dr Robert Arbeit, vice president of Clinical Development at Idera. “In addition to the clinical assessments, we are evaluating biopsies of psoriasis plaques for treatment-related changes in epidermal thickness and immune cell infiltrates consistent with the intended mechanism of action.”
“We have made significant progress in advancing our autoimmune disease program, including the completion of enrollment in the phase II trial of IMO-3100 in patients with psoriasis.” said Dr Sudhir Agrawal, chief executive officer of Idera. “In addition, our investigational new drug (IND) application for IMO-8400, a lead candidate for lupus, is now active. We expect our phase II study of IMO-3100 and planned clinical trials of IMO-8400 will help us to establish the benefits of inhibiting Toll-like Receptor-mediated pathways, which include controlling the induction of multiple cytokines, such as TNF-a, IL-12, IL-6, and IL-17, as well as downstream signaling. We look forward to reporting top-line data from the phase II study of IMO-3100 in psoriasis and initiating clinical development of IMO-8400 before the end of 2012.”
Idera also announced that its Investigational New Drug application for IMO-8400 with the US Food and Drug Administration is now active. IMO-8400, an antagonist of TLRs 7, 8, and 9, is Idera’s second lead candidate for use in treating autoimmune diseases, with lupus selected as an initial indication for clinical development. Idera anticipates initiating a phase I dose escalation trial during the fourth quarter of 2012 to evaluate the safety and pharmacodynamics of IMO-8400 in healthy subjects. Following successful completion of the phase I study, Idera expects to initiate a phase II clinical trial of IMO-8400 in patients with lupus.
Toll-like Receptors (TLRs) play a key role in inflammation and immunity. Of the 10 human TLRs identified to date, Idera is developing compounds targeted to TLRs 3, 7, 8, and 9, which are expressed in different cells and serve unique functions. Using its chemistry-based approach, Idera has created novel drug candidates that modulate immune responses through either activation or inhibition of specific TLRs. Inhibition of specific TLRs may be useful in treating autoimmune disorders, such as systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis, by blocking the induction of multiple cytokines and signaling pathways. Idera's lead clinical candidates for application in autoimmune diseases are IMO-3100, an antagonist of TLR7 and TLR9, and IMO-8400, an antagonist of TLRs 7, 8, and 9.
A characteristic of autoimmune diseases such as SLE and psoriasis is the production of immune complexes with self-nucleic acids. These abnormal immune complexes activate TLRs 7, 8, and 9 and induce multiple cytokines that cause further damage to the body's own tissues and organs, thereby releasing more self-nucleic acids. Thus, a pathologic amplification cycle is established, promoting disease maintenance and progression. In preclinical models of several autoimmune diseases, IMO-3100 and IMO-8400 inhibited TLR-mediated immune responses, broke the cycle of disease maintenance and progression through decreases in Th1, Th17 and inflammasome pathways, and led to improvements in multiple measures of disease.
The phase II trial is a randomized, double-blind, placebo-controlled study of IMO-3100 in patients with psoriasis. In the study, 44 patients with moderate to severe plaque psoriasis were randomized 1:1:1 to receive IMO-3100 at 0.16 or 0.32 mg/kg or placebo by subcutaneous injection once weekly for four weeks. Assessments of safety will be performed throughout the treatment and four-week follow-up periods. Psoriasis intensity, using Psoriasis Area Severity Index (PASI), mean focal psoriasis severity and Physician Global Assessment (PGA) scores, will be compared at end of treatment to pre-treatment. Skin biopsies of psoriasis lesions will be obtained to determine mean epidermal thickness prior to treatment and at end of treatment. The biopsy analysis also includes immunohistologic staining for changes in immune cell infiltrates and cytokine expression. This trial is being conducted at multiple sites in the United States, and skin biopsies will be analyzed at a central laboratory.
Psoriasis is a systemic immune-mediated disorder, characterized by inflammatory skin and joint manifestations. The most common form, plaque psoriasis, appears as raised, red patches covered with a silvery white buildup of dead skin cells. Psoriasis can occur on any part of the body and is associated with other serious health conditions, such as diabetes, heart disease and depression.
IMO-3100, an antagonist of TLR7 and TLR9, is a lead drug candidate in development to treat autoimmune diseases, including psoriasis. In preclinical mouse models of psoriasis, IMO-3100 exerted therapeutic activity by inhibiting disease-associated gene expression and cytokines, such as IL-6, IL-22, IL-17, IL-23, NLRP3, and IL-1ß, and proteins in the skin such as S100A7, DEFB4, and LL37. In addition, histological evaluation showed that the psoriatic lesions in IMO-3100 treated animals had reduced epidermal thickness and decreased lymphocyte infiltration compared to control mice.
IMO-8400, an antagonist of TLRs 7, 8, and 9, is a lead drug candidate in development to treat autoimmune diseases, with systemic lupus erythematosus (lupus) as the first indication for development. In preclinical mouse models of lupus, treatment with IMO-8400 has led to a reduction in levels of autoimmune antibodies, including anti-DNA, anti-RNA and anti-SM, compared to untreated mice. In addition, improvements in renal function, such as reductions in blood urea nitrogen, proteinuria, and histopathology changes in the kidney, were observed in IMO-8400 treated mice. Treatment of mice with IMO-8400 inhibited multiple disease-associated cytokines and decreased abnormal gene expression patterns compared to untreated mice.
Lupus is a chronic autoimmune disease where the body's immune system becomes hyperactive and attacks normal healthy tissue. This results in symptoms such as inflammation, swelling, and damage to joints and almost every major organ in the body, including the heart, kidneys, skin, lungs and brain.
Idera Pharmaceuticals applies its proprietary Toll-like receptor (TLR) drug discovery platform which has created immunomodulatory drug candidates and has a clinical development program in autoimmune diseases.