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Abstract Number: 692

A Phase 1 Multicenter, Open-Label Study of MEDI-546, a Human Anti-Type I Interferon Receptor Monoclonal Antibody, in Adults with Scleroderma

Avram Z. Goldberg1, Thomas D. Geppert2, Elena Schiopu3, Tracy M. Frech4, Vivien M. Hsu5, Robert W. Simms6, Stanford L. Peng7, Yihong Yao8, Nairouz Elgeioushi9, Bing Wang10, Linda Chang11 and Stephen Yoo12, 1Div of Rheumatology, North Shore-LIJ Health System, Lake Success, NY, 2Metroplex Clinical Research Center, LLC, Dallas, TX, 3Rheumatology/Internal Medicine, University of Michigan, Ann Arbor, MI, 4Internal Medicine-Division of Rheumatology, University of Utah School of Medicine, SLC, UT, 5Rheumatology, RWJ Med Schl Scleroderma Prog, New Brunswick, NJ, 6Rheumatology, Boston University School of Medicine, Boston, MA, 7Department of Rheumatology, Benaroya Research Institute at Virginia Mason Medical Center, Seattle, WA, 8Translational Sciences, MedImmune, Gaithersburg, MD, 9Medical Biostatistics, MedImmune, Gaithersburg, MD, 10Clinical Pharmacology and DMPK, Medimmune, Mountain View, CA, 11Translational Sciences, MedImmune, Hayward, CA, 12Clinical Development, MedImmune, Gaithersburg, MD

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: biologic response modifiers, clinical trials, interferons, monoclonal antibodies and scleroderma

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes, and Raynaud’s – Clinical Aspects and Therapeutics

Session Type: Abstract Submissions (ACR)

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.


Disclosure:

A. Z. Goldberg,
None;

T. D. Geppert,
None;

E. Schiopu,

MedImmune,

2,

United Therapeutics, Inc.,

8;

T. M. Frech,
None;

V. M. Hsu,
None;

R. W. Simms,
None;

S. L. Peng,
None;

Y. Yao,

AstraZeneca,

1,

MedImmune,

3;

N. Elgeioushi,

MedImmune,

3;

B. Wang,

MedImmune,

3;

L. Chang,

MedImmune,

3;

S. Yoo,

MedImmune,

3.

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