Background/Purpose: Type I interferons (IFNs) have been implicated in the pathogenesis of scleroderma. This phase 1 study evaluated safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of single and multiple intravenous doses of MEDI-546, a human monoclonal antibody directed against the type I IFN receptor, in adults with scleroderma.

Methods: Subjects (≥18 years) who met the American College of Rheumatology criteria for scleroderma and had a modified Rodnan Total Skin Score ≥2 in an area suitable for repeat biopsy were enrolled in this multicenter open-label, dose-escalation study. Six cohorts received single doses (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg) and 3 received multiple doses (0.3, 1.0, or 5.0 mg/kg weekly x 4) of MEDI-546. Subjects were evaluated through day 84 for single-dose groups and day 105 for multiple-dose groups. Safety assessments included adverse events (AEs) and laboratory tests. Serial blood samples were collected from all subjects for the determination of serum concentration of MEDI-546, the expression of type I IFN-inducible genes, and the presence of antidrug antibodies (ADAs).

Results: Of the 34 subjects, 33 completed the study. No trends in the type, frequency, or severity of AEs reported or laboratory abnormalities assessed were observed with increasing doses of MEDI-546. No deaths occurred during the study. Of the 4 treatment-emergent serious AEs (SAEs) reported, 1 (chronic myelogenous leukemia) was considered to be possibly treatment-related. The other 3 SAEs not considered to be treatment-related occurred in 2 subjects; 1 had vertigo and the other had osteomyelitis and skin ulcer. The most common treatment-emergent AEs were upper respiratory tract infection, headache, diarrhea, nausea, arthralgia, fatigue, and pruritus. Two subjects discontinued MEDI-546 after the first dose: 1 was due to an SAE of vertigo and an AE of head injury and discontinued the study 3 months later; the other was due to a non-SAE of normocytic anemia. MEDI-546 exhibited nonlinear PK at lower dose levels presumably due to the IFN receptor-mediated clearance. ADAs were detected in 2/21 subjects in the single-dose cohorts and 3/11 in the multiple-dose cohorts; 1 subject had persistent titers. The presence of ADAs had no effect on serum drug levels. At baseline, 22 subjects had positive type I IFN gene signature scores in whole blood. Subjects with positive baseline type I IFN gene signature score in whole blood reached or approached maximum inhibition of this signature within 1 day after dosing. The suppression persisted through day 84 in subjects receiving MEDI-546 at single-dose 20.0 mg/kg and multiple-dose ≥1 mg/kg. MEDI-546 at single-dose ≥0.3 mg/kg and multiple-dose ≥1 mg/kg suppressed the type I IFN gene signature in skin 7 and 28 days, respectively, after dosing.

Conclusion: The PK of MEDI-546 was subject to IFN receptor-mediated clearance at low-dose levels. The presence of ADAs had no apparent impact on PK. Decreased type I IFN gene expression in whole blood was seen at doses of ≥3 mg/kg after 1 day of dosing; expression decreased in skin after 7 days. These results and the safety profile observed in this study warrant further clinical development of MEDI-546.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-1-multicenter-open-label-study-of-medi-546-a-human-anti-type-i-interferon-receptor-monoclonal-antibody-in-adults-with-scleroderma/