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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-double-blind-placebo-controlled-phase-2-trial-of-a-novel-toll-like-receptor-7-8-9-antagonist-imo-8400-in-dermatomyositis/