A Phase I, Randomized, Double-blind, Placebo-controlled, Single Center, Single-dose Escalation to Investigate the Safety, Tolerability, and Pharmacodynamics of Subcutaneously Administered DEN-181 in Adult Patients with ACPA+ Rheumatoid Arthritis on Stable Methotrexate

Amee Sonigra ¹, Hendrik Nel ², Nishta Ramnoruth ², Meghna Talekar ², Joanne Tesiram ³, Frederik Stuurman ⁴, Lavinia Proctor ⁵, Helen Roberts ⁶, Robin Thurmond ⁷, Phillip Vecchio ³, Ian Gourley ⁸, Mark Rigby ⁹, Nathan Felix ¹⁰, Stephane Becart ¹¹, Kim Campbell ¹² and Ranjeny Thomas², ¹Princess Alexandra Hospital, Woolloongabba, Queensland, Australia, ²University of Queensland, Woolloongabba, Australia, ³Princess Alexandra Hospital, Woolloongabba, Australia, ⁴Centre for Human Drug Research, Leiden, Netherlands, ⁵Dendright, Woolloongabba, Australia, ⁶Dendright, Woolloongabba, Queensland, Australia, ⁷Janssen Research & Development, La Jolla, CA, ⁸Janssen Research & Development, Springhouse, ⁹Janssen Research & Development, La Jolla, ¹⁰Janssen R&D, Spring House, PA, ¹¹Janssen R&D, La Jolla, CA, ¹²Janssen Research & Development, LLC, Spring House, PA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: antigen and human leukocyte antigens (HLA), clinical trials, immune tolerance, rheumatoid arthritis, treatment

Session Information

Date: Tuesday, November 12, 2019

Title: 5T092: RA – Treatments IV: Novel Therapy & Predicting Response (2768–2773)

Session Type: ACR Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Antigen-specific immunological tolerance strategies leverage the natural process of antigen presentation by dendritic cells (DCs) to regulate pathogenic T cells and B cells. We developed a nanoparticulate liposome formulation that encapsulates autoantigenic peptide and NF-kB inhibitor, 1,25 dihydroxycholecalciferol (calcitriol), to target DCs. In mouse models of autoimmune arthritis, multiple doses of liposomes promote disease suppression as well as stable regulation of effector-memory T cells with an increase in the proportion of naive T cells in an antigen-specific manner. We carried out a dose-ranging double-blind placebo-controlled phase I clinical trial of a single dose of liposomes encapsulating 40mg/ml collagen II_259-273 (CII) peptide + 400ng/ml calcitriol (DEN-181). The primary objective was assessment of safety and tolerability, and the secondary objectives were assessment of peripheral blood (PB) total and CII-specific naïve, effector and regulatory T cells, clinical response, and calcitriol levels after DEN-181 treatment.

Methods: Vehicle or 3 different dose levels of DEN-181 were administered via single s.c. injection to 17 anti-citrullinated peptide antibody (ACPA)+ HLA-DRB1*0401 or *0101+ RA patients on methotrexate. CII-specific and total CD4+ T cells were evaluated 0, 7 and 28 days post-treatment by flow cytometry using haplotype-specific tetramers. Plasma calcitriol was measured using an ultra-sensitive assay, hourly for 4h post-dose.

Results: Seventeen enrolled patients with a mean age of 50 (range 20-64), methotrexate dose 17.1 (5-25) mg/week, disease duration 4.9 (0.5-18) years, and DAS28CRP 2.66 (1.36-4.65) received vehicle or 3 different dose levels of DEN-181 (6x placebo, 4x 0.3ml, 3x 1ml and 4x 3ml). DEN-181 was generally well tolerated. One treated (1ml) and 1 control patient had AST >1.5x normal. Disease flares requiring steroids occurred in 1 control and 1 treated (3 ml) patient Plasma calcitriol levels were greater than placebo in the 3 ml but not in the 1 or 0.3 ml cohort.. Pre-treatment, CII-specific CD45RO+ memory T cells were identified in PB (range 30-66%). Relative to baseline, the % naïve CII-specific T cells increased and DAS28CRP decreased 7 days after a dose of 0.3ml, while the 3ml dose had the opposite effect (p=0.02 naïve, p=0.06 DAS). Changes in CII-specific naïve T cells differed between dose cohorts over time (p=0.04). After 7 days, reduced DAS28CRP of DEN-181-treated patients was associated with decreases in %CII-specific PD1+ T cells, CII-specific TCR expression, and ACPA IgG/IgA titre.

Conclusion: DEN-181 immunotherapy was safe and modulated antigen-specific T cells in RA patients of appropriate HLA type, where the pharmacodynamic effect of the 0.3ml dose suggests a skew toward immunological tolerance.

Disclosure: A. Sonigra, None; H. Nel, None; N. Ramnoruth, None; M. Talekar, None; J. Tesiram, None; F. Stuurman, None; L. Proctor, Dendright, 3; H. Roberts, Dendright, 3; R. Thurmond, Janssen, 3, 4; P. Vecchio, None; I. Gourley, Janssen, 3; M. Rigby, Janssen, 3; N. Felix, Janssen, 3; S. Becart, Janssen, 3; K. Campbell, Janssen, 1, 3, Janssen Research & Development, LLC, 3; R. Thomas, Janssen, 2, 8, Merck, 2, Abbvie, 8, Dendright, 6.

To cite this abstract in AMA style:

Sonigra A, Nel H, Ramnoruth N, Talekar M, Tesiram J, Stuurman F, Proctor L, Roberts H, Thurmond R, Vecchio P, Gourley I, Rigby M, Felix N, Becart S, Campbell K, Thomas R. A Phase I, Randomized, Double-blind, Placebo-controlled, Single Center, Single-dose Escalation to Investigate the Safety, Tolerability, and Pharmacodynamics of Subcutaneously Administered DEN-181 in Adult Patients with ACPA+ Rheumatoid Arthritis on Stable Methotrexate [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-phase-i-randomized-double-blind-placebo-controlled-single-center-single-dose-escalation-to-investigate-the-safety-tolerability-and-pharmacodynamics-of-subcutaneously-administered-den-181-in-a/. Accessed .

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