AB016. A double-blind, placebo-controlled, phase 2 trial of a novel toll-like receptor 7/8/9 antagonist (IMO-8400) in dermatomyositis

Abstract

Background/Purpose : Dermatomyositis (DM) is a rare inflammatory disease of skin and muscle associated with characteristic skin findings, muscle weakness, interstitial lung disease, pruritus, and malignancies. Increased interferon (IFN) signaling is a prominent feature of DM, but the mechanisms leading to IFN production in DM are not understood. As toll‐like receptor (TLR) 7/8/9 activation can lead to type I IFN production, TLR7/8/9 antagonism may provide therapeutic benefit in DM. Methods : A double‐blind, randomized, placebo‐controlled, 24‐week trial of IMO‐8400 (a novel investigational oligonucleotide TLR7/8/9 antagonist [Idera Pharmaceuticals, Inc.]) was conducted with 30 eligible participants with definite or probable DM based on the criteria of Bohan and Peter. Participants were randomized to treatment with IMO‐8400 0.6 mg/kg, IMO‐8400 1.8 mg/kg, or placebo. The primary endpoint was the change in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score after 24 weeks of treatment. Exploratory analysis included type I IFN signaling as measured by a 10‐gene expression score and patient‐reported 5‐D Itch Scale, a validated inventory for pruritus. Blood and skin samples were obtained at baseline and end of treatment to measure changes in type I IFN signaling. Results : CDASI activity scores decreased in all trial arms by the end‐of‐trial visit, per repeated measures mixed model analysis: ‐9.3 in 0.6 mg/kg, ‐8.8 in 1.8 mg/kg, and ‐7.3 in placebo. We observed no change in skin and blood type I IFN signature scores or CDASI activity scores across treatment arms. We found an association between CDASI and skin IFN signature scores (β = 12.9, P = 0.0002), a moderate association between 5‐D Itch Scale and skin IFN signature scores (Rho = 0.65, P < 0.0001), a lack of association between 5‐D Itch Scale and blood IFN signature scores (Rho = 0.22, P = 0.24), and a positive correlated trend that did not reach significance between CDASI and 5‐D Itch Scale scores. 5 patients experienced treatment‐emergent adverse effects prompting discontinuation: 3 in low‐dose (abdominal discomfort/flu, anxiety, urticaria), 1 in high‐dose (thrombocytopenia), and 1 in placebo (muscle weakness). Conclusion : IMO‐8400 did not reach clinical efficacy in reducing cutaneous DM disease activity nor in decreasing the type I IFN signature in skin or blood, suggesting that TLR7/8/9 signaling may not play a causal role in IFN dysregulation in DM. Furthermore, our exploratory findings suggest that skin type I IFN signature scores provide a stronger indication of DM skin disease activity than blood type I IFN signature scores and that skin type I IFN signaling may be a pathway to target in improving pruritus symptoms in DM patients.