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Type: Journal article
Title: Perhexiline maleate in the treatment of fibrodysplasia ossificans progressiva: an open-labeled clinical trial
Author: Kitoh, H.
Achiwa, M.
Kaneko, H.
Mishima, K.
Matsushita, M.
Kadono, I.
Horowitz, J.
Sallustio, B.
Ohno, K.
Ishiguro, N.
Citation: Orphanet Journal of Rare Diseases, 2013; 8(1):163-1-163-7
Publisher: BioMed Central
Issue Date: 2013
ISSN: 1750-1172
Statement of
Hiroshi Kitoh, Masataka Achiwa, Hiroshi Kaneko, Kenichi Mishima, Masaki Matsushita, Izumi Kadono, John D Horowitz, Benedetta C Sallustio, Kinji Ohno and Naoki Ishiguro
Abstract: Background: Currently, there are no effective medical treatment options to prevent the formation of heterotopic bones in fibrodysplasia ossificans progressiva (FOP). By the drug repositioning strategy, we confirmed that perhexiline maleate (Pex) potentially ameliorates heterotopic ossification in model cells and mice. Here, we conducted a prospective study to assess the efficacy and safety of Pex in the treatment of FOP patients. Methods: FOP patients in this open-label single-center study were treated with Pex for a total of 12 months, and followed up for 12 consecutive months after medication discontinuation. The safety of the treatment was assessed regularly by physical and blood examinations. The efficacy of Pex for preventing heterotopic ossifications was evaluated by the presence of flare-ups, measurements of serum bone markers, and changes in the total bone volume calculated by the three-dimensional computed tomography (3D-CT) images. Results: Five patients with an average age of 23.4 years were enrolled. Within safe doses of Pex administration in each individual, there were no drug-induced adverse effects during the medication phase. Three patients showed no intense inflammatory reactions during the study period, while two patients had acute flare-ups around the hip joint without evidence of trauma during the medication phase. In addition, one of them became progressively incapable of opening her mouth over the discontinuation phase. Serum levels of alkaline phosphatase (ALP) and bone specific ALP (BAP) were significantly and synchronously increased with the occurrence of flare-ups. Volumetric 3D-CT analysis demonstrated a significant increase in the total bone volume of Case 2 (378 cm³) and Case 3 (833 cm³) during the two-year study period. Conclusions: We could not prove the efficacy of oral Pex administration in the prevention of heterotopic ossifications in FOP. Serum levels of ALP and BAP appear to be promising biomarkers for monitoring the development of ectopic ossifications and efficacy of the therapy. Quantification of change in the total bone volume by whole body CT scanning could be a reliable evaluation tool for disease progression in forthcoming clinical trials of FOP.
Keywords: Fibrodysplasia ossificans progressive; perhexiline maleate; clinical trial; biomarker; whole body CT
Rights: © 2013 Kitoh et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
RMID: 0030069191
DOI: 10.1186/1750-1172-8-163
Appears in Collections:Medicine publications

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