Morphea-like Skin Lesions Reported in the Phase 3 Long-Term Odanacatib Fracture Trial and Extension in Postmenopausal Women with Osteoporosis

Kenneth G. Saag¹, Tobie de Villiers², Peter Alexandersen³, Heidi Jacobe⁴, Carrie Kovarik⁵, Victoria P. Werth⁶, Albert Leung⁷, Avani Desai-Merchant⁸, Julie Mattaliano⁸ and Deborah Gurner⁸, ¹Department of Medicine, Division of Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA, Birmingham, AL, ²Mediclinic Panorama and Department of Obstetrics & Gynecology, University of Stellenbosch, Cape Town, South Africa, Cape Town, South Africa, ³Center for Clinical and Basic Research, Vejle, Denmark, Ballerup, Denmark, ⁴Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, ⁵Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA, Philadelphia, PA, ⁶Philadelphia VAMC, Philadelphia, PA, USA, Philadelphia, PA, ⁷Formerly Merck & Co., Inc., Kenilworth, NJ, USA, Kenilworth, NJ, ⁸Merck & Co., Inc., Kenilworth, NJ, USA, Kenilworth, NJ

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: cathepsin k inhibitor, Morphea, osteoporosis, safety and skin

Session Information

Date: Sunday, November 13, 2016

Title: Osteoporosis and Metabolic Bone Disease – Clinical Aspects and Pathogenesis

Session Type: ACR Concurrent Abstract Session

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

Background/Purpose: Odanacatib (ODN) is a selective oral inhibitor of cathepsin K (CatK) in development for the treatment of osteoporosis. Because of reports with the CatK inhibitor balicatib, morphea-like skin lesions were deemed Events of Clinical Interest in the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT; NCT00529373).

Methods: LOFT was a double-blind, placebo-controlled trial. Women ≥65 years with total hip (TH) or femoral neck (FN) bone mineral density (BMD) T-score ≤-2.5, or with a radiographic vertebral fracture and T-score ≤-1.5 at TH or FN, were randomized (1:1) to ODN 50 mg/week or placebo. In a preplanned double-blind extension, 51% of patients continued on their originally assigned treatment up to 5 years. As part of the safety evaluation, external adjudication committees evaluated specific adverse event (AE) categories, including AEs with skin changes suggestive of morphea or systemic sclerosis.

Results: Of 16,713 participants randomized at 388 centers in 40 countries, 16,071 were included in the safety analysis; of these, 12,290 completed the base study, 8,257 continued into and 6,047 completed the extension. Adjudication confirmed morphea-like skin lesions occurred in 13 patients (0.16%) treated with ODN versus 3 patients (0.04%) treated with placebo. The time of onset varied from Study Day 115 to 1315, with 3 cases occurring in the first year of the study and 10 cases occurring within the first two years. Lesions were characterized most consistently as indurated (often termed “hardened” or “thickened”), with pallor, pruritus, and erythema reported less frequently. Although histopathology was generally consistent with that of spontaneous (idiopathic) morphea, atypical features included pandermal involvement and occasionally dense eosinophilic infiltrates. Most lesions affected the trunk or lower extremities. There were no reports of accompanying constitutional symptoms or systemic involvement. All ODN-treated patients were negative for autoantibodies. Study medication was discontinued in all but one patient (ODN). As of the last follow-up, 12/16 cases (10 ODN, 2 placebo) were reported as fully recovered (including the patient who continued on ODN), 3/16 (3 ODN) as improved or recovering, and the remaining patient (placebo) declined further contact.

Conclusion: Confirmed morphea-like skin lesions were uncommon but occurred more often with ODN than placebo. Although the gross features and histopathology of these lesions were generally consistent with those of spontaneous morphea, in all patients in whom follow-up was obtained improvement or full recovery was reported.

Disclosure: K. G. Saag, Amgen, Lilly, Merck, 2,Amgen, Lilly, Merck, 5; T. de Villiers, Pfizer, Merck, Abbott, Adcock Ingram, 5,Pfizer, Merck, Abbott, Adcock Ingram, Bayer, 8; P. Alexandersen, CCBR, 3; H. Jacobe, Merck Co., 5; C. Kovarik, Merck Co., 5; V. P. Werth, Amgen, Rigel, Janssen, Novartis, Invion, 2,Medimmune, Genentech, Novartis, Pfizer, Cephalon, UV Therapeutics, Rigel, Biogen, Lupus Foundation of America, Sanofi-Aventis, Stiefel, Merck, RPS, Idera, Canfield, Celgene, 5,Amgen, Merck, 8,UV Therapeutics, 1,Philadelphia VAMC and University of Pennsylvania - employment;, 3,Head MAB, International Pemphigus and Pemphigoid Foundation - non-remunerative, 9; A. Leung, Merck Co. - former employee, 3; A. Desai-Merchant, Merck Co., 3; J. Mattaliano, Merck Co., 3; D. Gurner, Merck Co., 3.

To cite this abstract in AMA style:

Saag KG, de Villiers T, Alexandersen P, Jacobe H, Kovarik C, Werth VP, Leung A, Desai-Merchant A, Mattaliano J, Gurner D. Morphea-like Skin Lesions Reported in the Phase 3 Long-Term Odanacatib Fracture Trial and Extension in Postmenopausal Women with Osteoporosis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/morphea-like-skin-lesions-reported-in-the-phase-3-long-term-odanacatib-fracture-trial-and-extension-in-postmenopausal-women-with-osteoporosis/. Accessed .

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