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Abstract Number: 6L

Efficacy and Safety of Ustekinumab, an Interleukin 12/23 Inhibitor, in Patients with Active Systemic Lupus Erythematosus: Results of a Phase 2, Randomized Placebo-Controlled Study

Ronald van Vollenhoven1, Bevra H. Hahn2, George C. Tsokos3, Carrie Wagner4, Peter Lipsky5, Benjamin Hsu4, Marc Chevrier4, Robert Gordon4, Manon Triebel6 and Shawn Rose4, 1Amsterdam Rheumatology and Immunology Center ARC, Amsterdam, Netherlands, 2UCLA David Geffen School of Medicine, Los Angeles, CA, 3Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 4Janssen Research & Development, LLC, Spring House, PA, 5Ampel BioSolutions LLC, Charlottesville, VA, 6Janssen Biologics Europe, Leiden, Netherlands

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: October 19, 2017

Keywords: Biologic agents, Late-Breaking 2017, Lupus and SLE

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Session Information

Date: Tuesday, November 7, 2017

Title: ACR Late-Breaking Abstract Session

Session Type: ACR Late-breaking Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: The IL-12/23 pathway has been implicated in the pathogenesis of SLE. The anti-IL12/23 monoclonal antibody ustekinumab (UST) is efficacious in the treatment of psoriasis, psoriatic arthritis, and Crohn’s disease. Here, we evaluated the safety and efficacy of UST in patients (pts) with active SLE.

Methods: We conducted a phase 2, placebo (PBO)-controlled study in 102 adults with seropositive (ANA, anti-dsDNA, and/or anti-Smith antibodies) SLE by SLICC criteria and active disease (SLEDAI score ≥6 and ≥1 BILAG A and/or ≥2 BILAG B scores) despite standard-of-care therapy. Pts (n=102) were randomized (3:2) to receive UST IV ~6 mg/kg or PBO at wk0, followed by SC injections of UST 90mg q8w or PBO, both added to standard care; stratification factors were consent for skin biopsy (y/n), disease features, (eg, presence of lupus nephritis, baseline concomitant SLE medications, SLEDAI score), site/region, and race. The primary endpoint was the proportion of patients achieving SLE response index (SRI)-4 response at wk24. Major secondary endpoints at wk24 included change from baseline in SLEDAI-2K, change from baseline in Physician’s Global Assessment (PGA), and proportion of pts with BICLA response. Endpoint analyses included all pts who received ≥1 dose of study agent, had ≥1 measurement prior to administration, and had ≥1 post-baseline measurement. Patients with missing data and treatment failures were imputed as nonresponders.

Results: Baseline pt demographic and disease characteristics were well-balanced between treatment groups (female=91%; mean age=41 (18-66) years; mean SLEDAI-2K= 10.9). At wk24, 60% of pts in the UST group had an SRI-4 response vs 31% in the PBO group (p=0.0046), with a treatment effect favoring UST beginning at wk12. Pts in the UST group had greater median change from wk0 to wk24 in SLEDAI-2K and PGA vs PBO (Table). No difference was observed in the proportion of pts achieving a BICLA composite response at wk24, although among BICLA nonresponders, a greater proportion of UST pts had no BILAG worsening vs PBO. The risk of a new BILAG flare (≥1 new BILAG A or ≥2 new BILAG B) was significantly lower in the UST group vs. PBO (HR 0.11 [95% CI 0.01-0.94]; p=0.0078). UST demonstrated improvement in musculoskeletal and mucocutaneous disease features vs PBO. Improvements in anti-dsDNA and C3 levels were also noted through wk24 with UST. Through wk24, 78% of UST pts and 67% of PBO pts had ≥1 adverse event; 8.3% and 9.5%, respectively, had ≥1 serious adverse event (Table). There were no deaths in the study. Safety events were consistent with the UST safety profile in other studied indications.

Conclusion: UST showed significantly better efficacy in clinical and laboratory parameters in the treatment of active SLE compared with placebo, while demonstrating a comparable safety profile. UST may be an effective therapy with a novel mechanism of action in the treatment of SLE.

Table. Efficacy and safety results at Week 24.

Placebo

Ustekinumab

Patients randomized, n

42

60

Efficacy

Patients with SRI-4 response, n (%)

13 (31.0)

36 (60.0)

P value

0.0046a

Change from baseline in SLEDAI-2K, median (range)

-2.0 (-20; 10)

-6.0 (-10; 3)

P value

0.0265a,b

Change from baseline in PGA, median (range)

-1.6 (-5.6; 2.7)

-2.5 (-6.6; 2.8)

P value

0.2110a,b

Patients with BICLA response, n (%)

14 (33.3)

21 (35.0)

P value

0.9939a

Proportion of BICLA nonresponders with no BILAG worsening, n/N (%)

11/28 (39.2)

29/39 (74.4)

P value

0.0043

Patients with 50% improvement from baseline joint disease activityc, % (95% CI)

63.2 (61.7-64.6)

87.7 (86.8-88.6)

P value

0.0208d

Patients with 50% improvement from baseline CLASI activity scored, % (95% CI)

25.2 (23.1-27.4)

58.7 (57.4-60.1)

P value

0.0429e

Change from baseline in anti-dsDNA (kIU/L)f, median (range)

-12.6 (-168.8; 233.1)

-30.7 (-2919.6; 132.9)

P value

0.1073h

Change from baseline in Complement C3 (mg/dL)g, median (range)

0.15 (-12.4; 21.8)

6.60 (-17; 50.8)

P value

0.0636h

Adverse events

Patients with ≥1 TEAE, n (%)

28 (66.7)

47 (78.3)

Most Common TEAEs, n (%)

Upper respiratory tract infection

9 (21.4)

5 (8.3)

Urinary tract infection

5 (11.9)

6 (10.0)

Nasopharyngitis

3 (7.1)

6 (10.0)

Headache

5 (11.9)

4 (6.7)

Patients with ≥1 SAE, n (%)

4 (9.5)

5 (8.3)

aPrespecified analyses; all other analyses shown here were post-hoc.

bOne-sided test for no difference between two treatment groups based upon a Wilcoxon non-parametric median test for difference of location

cPatient subpopulation (67% of total population) with at least 4 joints with pain and signs of inflammation at baseline

dPatient subpopulation (58% of total population) with CLASI activity score of at least 4 at baseline

eProportions of responders and p values based on a modified intention to treat analysis using a multiple imputation model for missing data from weeks 16 to 24

fPatient subpopulation (42% of total population) with anti-dsDNA autoantibodies present at baseline

gPatient subpopulation (41% of total population) with low Complement C3 levels present at baseline

hOne-sided test for no difference between two treatment groups based upon a Wilcoxon non-parametric median test for difference of location

BICLA, BILAG-based Combined Lupus Assessment; BILAG, British Isles Lupus Assessment Group; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; ; PGA, physician’s global assessment; SRI-4, SLE Response Index TEAE, treatment emergent adverse event


Disclosure: R. van Vollenhoven, Janssen Research & Development, LLC, 5; B. H. Hahn, BMS, Squibb, Janssen, 5; G. C. Tsokos, Janssen Research & Development, LLC, 5; C. Wagner, Janssen Research & Development, LLC, 3,Johnson & Johnson, 1; P. Lipsky, Janssen Research & Development, LLC, 5; B. Hsu, Johnson & Johnson, 1,Johnson & Johnson, 3; M. Chevrier, Johnson & Johnson, 1,Janssen Research Development LLC, 3; R. Gordon, Janssen Research & Development, LLC, 3,Johnson & Johnson, 1; M. Triebel, Janssen Biologics Europe, 3; S. Rose, Janssen Research & Development, LLC, 3,Johnson & Johnson, 1.

To cite this abstract in AMA style:

van Vollenhoven R, Hahn BH, Tsokos GC, Wagner C, Lipsky P, Hsu B, Chevrier M, Gordon R, Triebel M, Rose S. Efficacy and Safety of Ustekinumab, an Interleukin 12/23 Inhibitor, in Patients with Active Systemic Lupus Erythematosus: Results of a Phase 2, Randomized Placebo-Controlled Study [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/efficacy-and-safety-of-ustekinumab-an-interleukin-1223-inhibitor-in-patients-with-active-systemic-lupus-erythematosus-results-of-a-phase-2-randomized-placebo-controlled-study/. Accessed .
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