A phase 2, double-blinded, placebo-controlled trial of toll-like receptor 7/8/9 antagonist, IMO-8400, in dermatomyositis

Abstract

To the Editor: Dermatomyositis (DM) is a rare inflammatory disease of muscle and skin. DM severity is thought to be driven, in part, by type I interferon signaling.1Huard C. Gullà S.V. Bennett D.V. Coyle A.J. Vleugels R.A. Greenberg S.A. Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis.Br J Dermatol. 2017; 176: 1224-1230Crossref PubMed Scopus (50) Google Scholar Because interferon is primarily induced by toll-like receptors (TLRs) 7/9, we hypothesized that antagonizing TLR7/9 could improve DM disease activity.2Baechler E.C. Bauer J.W. Slattery C.A. et al.An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity.Mol Med. 2007; 13: 59-68Crossref PubMed Scopus (196) Google Scholar,3Walsh R.J. Kong S.W. Yao Y. et al.Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis.Arthritis Rheum. 2007; 56: 3784-3792Crossref PubMed Scopus (205) Google Scholar We conducted a phase 2, multicenter, double-blind, randomized, placebo-controlled trial of IMO-8400, an oligonucleotide antagonist of TLR7/8/9, in DM.4Suárez-Fariñas M. Arbeit R. Jiang W. Ortenzio F.S. Sullivan T. Krueger J.G. Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation.PLoS One. 2013; 8: e84634Crossref PubMed Scopus (80) Google Scholar,5Jiang W. Zhu F. Tang J. Kandimalla E. La Monica N. Agrawal S. IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in mouse models of psoriasis (119.8).J Immunol. 2012; 188: 119.8Google Scholar Thirty patients with Cutaneous Dermatomyositis Disease Area and Severity Index version 2 (CDASIv2) scores of 15 or greater were enrolled between November 2015 and June 2018. Patients were allowed to remain on stable prednisone (≤20 mg/d) and up to 1 immunomodulatory therapy from a prespecified list (Table I and Supplemental Table 1, A and B; available via Mendeley at https://doi.org/10.17632/f9vx46p3fc.1).Table IBaseline characteristics of the intent-to-treat populationCharacteristicsPlaceboIMO-84000.60 mg/kg1.8 mg/kgn11910Age, y, mean (SD)51.3 (10.6)48.3 (14.2)54.6 (14.1)Sex, n (%) Female7 (63.6)7 (77.8)9 (90.0) Male421Race, n (%) White11 (100)8 (88.9)9 (90.0) Black or African American01 (11.1)1 (10.0)CDASI, n (%) 15-201 (9.1)02 (20.0) ≥2110 (90.9)9 (100)8 (80.0)CDASI activity score, mean (SD)30.2 (9.8)33.0 (8.4)33.5 (14.7)Treatment-concomitant drugs, n (%) Systemic corticosteroids∗Methylprednisolone, prednisolone, and prednisone. (%)8 (72.7)5 (55.6)5 (50.0) DMARDs†Azathioprine, leflunomide, methotrexate, mycophenolate mofetil, and mycophenolic acid. (%)5 (45.5)6 (66.7)6 (60.0) Immunoglobulins (%)1 (9.1)01 (10.0)CDASI, Cutaneous Dermatomyositis Disease Area and Severity Index; DMARD, disease-modifying antirheumatic drugs; SD, standard deviation.∗ Methylprednisolone, prednisolone, and prednisone.† Azathioprine, leflunomide, methotrexate, mycophenolate mofetil, and mycophenolic acid. Open table in a new tab CDASI, Cutaneous Dermatomyositis Disease Area and Severity Index; DMARD, disease-modifying antirheumatic drugs; SD, standard deviation. Participants were stratified into 2 groups by CDASIv2 activity score (15-20 vs ≥21) and randomized 1:1:1 to receive weekly subcutaneous injections of IMO-8400 0.6 mg/kg, IMO-8400 1.8 mg/kg, or placebo for 24 weeks. Because IMO-8400 is associated with injection site reactions, the primary outcome used a modified CDASIv2 activity score (CDASI-a) excluding the injection site. Secondary assessments included the Manual Muscle Test 8 (MMT8). Participants were predominantly white (93.3%) and female (76.7%), with a median age of 54.5 years (Table I). The mean baseline CDASI-a was 32.1 and was generally equal across treatment arms (30.2 for placebo, 33.0 for 0.6 mg/kg, and 33.5 for 1.8 mg/kg). The most common injection site reactions were erythema, pain, and induration (Supplemental Tables II and III; available via Mendeley at https://doi.org/10.17632/f9vx46p3fc.1). Out of 30 patients, 11 discontinued the study—5 (16.7%) because of adverse events, 4 (13.3%) for lack of efficacy, and 2 (6.7%) because of withdrawal by the participant. CDASI-a improved for all groups over 24 weeks (−9.3 for 0.6 mg/kg, −8.8 for 1.8 mg/kg, and −7.3 for placebo) (Fig 1). There was no significant difference between placebo and treatment groups; the repeated-measures mixed model analysis of CDASI-a across visits of the combined IMO-8400 group compared to that of placebo showed a least squares mean difference of −1.9 (P = .238). The average changes in MMT8 between the end of trial and baseline were as follows: +3.8 for placebo, +1.8 for 0.6 mg/kg, and +2.8 for 1.8 mg/kg. Across visits, in comparison to the placebo, the least squares mean difference of MMT8 in the 0.6 mg/kg group and 1.8 mg/kg group was +0.4 (P = .846) and +2.3 (P = .250), respectively. IMO-8400 did not show clinical efficacy over placebo in treating DM skin or muscle disease. IMO-8400 may not have achieved high enough doses for the pharmacologic blockade of TLR7/9, or there may be roles for pathways outside of TLR7/9 in DM. Limitations of the study include the small sample size and patient use of concomitant medications. The authors would like to thank Dr Kristin Lynn Sainani and the members of the Sarin Lab for their critical review and feedback of the manuscript.