Balicatib

Balicatib is an inhibitor of cathepsin K with IC50 value of 1.4nM [1].

Balicatib is highly selective against cathepsin K over cathepsin B, L and S in the in vitro enzyme assay. However, the selectivity is not so high in cell-based enzyme assay. The lysosomotropic character of balicatib results in its accumulation in lysosomes and the subsequent nonselective off-target effects. The off-target effects also cause the skin adverse events of balicatib [1, 2].

As a cathepsin K inhibitor, balicatib is developed for osteoporosis. It has been reported to reduce the biochemical markers of bone resorption and increase bone mineral density in ovariectomized monkeys. In addition, balicatib shows benefits in new bone formation of postmenopausal women [2].

References:
[1] Black WC. Peptidomimetic inhibitors of cathepsin K. 2010;10(7):745-51.
[2] Brömme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin Investig Drugs. 2009 May;18(5):585-600.

Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys.[Pubmed:21308366]

Osteoporos Int. 2011 Dec;22(12):3001-11.

UNLABELLED: Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy-induced bone mass changes were partially prevented by Balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased. INTRODUCTION: Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of Balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys. METHODS: Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with Balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry. RESULTS: In both spine and femur, group O animals lost bone mineral density (BMD), and all other groups gained BMD between 0 and 18 months. In Balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of Balicatib significantly increased BMD gain relative to group O, and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with Balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment. CONCLUSIONS: Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.

Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys.[Pubmed:21380636]

Osteoporos Int. 2012 Jan;23(1):339-49.

UNLABELLED: Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy-induced bone mass changes were partially prevented by Balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased. INTRODUCTION: Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of Balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys. METHODS: Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with Balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry. RESULTS: In both spine and femur, group O animals lost BMD and all other groups gained BMD between 0 and 18 months. In Balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of Balicatib significantly increased BMD gain relative to group O and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with Balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment. CONCLUSIONS: Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.

Drug-induced morphea: report of a case induced by balicatib and review of the literature.[Pubmed:18410981]

J Am Acad Dermatol. 2008 Jul;59(1):125-9.

Drug-induced scleroderma has been rarely reported, mostly with the features of diffuse scleroderma or acrosclerosis, and exceptionally with the characteristics of morphea. We report the case of an adult white woman, enrolled in a double-blind, placebo-controlled, multicentric trial evaluating the efficacy and safety of the cathepsin K inhibitor Balicatib for osteoporosis. Typical morphea lesions developed on the patient's trunk 9 months after the beginning of therapy. Lesions completely resolved after drug withdrawal and a single brief course of systemic steroids. No recurrence occurred in a 2-year follow-up. Fifteen cases of drug-induced morphea could be retrieved from the literature. Drug withdrawal determined complete remission in only a few patients. Different drug classes have been implicated. Some of these, including Balicatib, alter directly connective tissue metabolism.

Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib.[Pubmed:21571394]

J Am Acad Dermatol. 2012 Mar;66(3):e89-96.

BACKGROUND: In a multicenter clinical trial in North America and Europe that tested the cathepsin K (catK) inhibitor Balicatib for the treatment of osteoporosis, several patients developed hardening of the skin. OBJECTIVE: We sought to characterize these observed adverse events. METHODS: Patients with skin hardening were examined by a local dermatologist. All of those patients except one had at least one biopsy specimen taken from affected skin, which was read by local and two central dermatopathologists. Workup was directed for consideration of systemic scleroderma. RESULTS: Nine patients of 709 treated with Balicatib developed skin hardening and were given a diagnosis of morphea-like skin changes. No such events were observed in patients taking placebo or the lowest Balicatib dose. After discontinuation of Balicatib, skin changes resolved completely in 8 and partially in one patient. LIMITATIONS: Each patient was seen by a different dermatologist in 6 different countries. CONCLUSIONS: These observations are likely dose-related adverse effects of Balicatib. Although catK was originally thought to be expressed only in osteoclasts, it has more recently also been found in lung and dermal fibroblasts and been implicated in the degradation of the extracellular matrix in the lung and the skin. It is therefore plausible that the observed dermal fibrosis in Balicatib-treated patients is a result of impaired degradation of extracellular matrix proteins and may represent a class effect of catK inhibitors. We recommend that further exploration of catK inhibition for the treatment of osteoporosis or cancer should include monitoring for similar adverse effects.

Effect of cathepsin k inhibitor basicity on in vivo off-target activities.[Pubmed:17940194]

Mol Pharmacol. 2008 Jan;73(1):147-56.

Cathepsin K is a lysosomal cysteine protease that is a pharmacological target for the treatment of osteoporosis. Previous studies showed that basic, lipophilic cathepsin K inhibitors are lysosomotropic and have greater activities in cell-based assays against cathepsin K, as well as the physiologically important lysosomal cysteine cathepsins B, L, and S, than expected based on their potencies against these isolated enzymes. Long-term administration of the basic cathepsin K inhibitors N-(1-(((cyanomethyl)amino)carbonyl)cyclohexyl)-4-(2-(4-methyl-piperazin-1-yl)-1,3 -thiazol-4-yl)benzamide (L-006235) and Balicatib to rats at a supratherapeutic dose of 500 mg/kg/day for 4 weeks resulted in increased tissue protein levels of cathepsin B and L but had no effect on cathepsin B and L message. This is attributed to the inhibitor engagement of these off-target enzymes and their stabilization to proteolytic degradation. No such increase in these tissue cathepsins was detected at the same dose of N-(cyanomethyl)-N(2)-{(1S)-2,2,2-trifluoro-1-[4'-methylsulfonyl)biphenyl-4-yl]eth yl}-l-leucinamide (L-873724), a potent nonbasic cathepsin K inhibitor with a similar off-target profile, although all three inhibitors provided similar plasma exposures. Using an activity-based probe, (125)I-BIL-DMK, in vivo inhibition of cathepsins B, L, and S was detected in tissues of mice given a single oral dose of L-006235 and Balicatib, but not in mice given L-873724. In each case, similar tissue levels were achieved by all three compounds, thereby demonstrating the in vivo cathepsin selectivity of L-873724. In conclusion, basic cathepsin K inhibitors demonstrate increased off-target cysteine cathepsin activities than their nonbasic analogs and potentially have a greater risk of adverse effects associated with inhibition of these cathepsins.

Balicatib(AAE-581) is a potent and selective inhibitor of cathepsin K; 10-100 fold more potent in cell-based enzyme occupancy assays than against cathepsin B, L, and S.

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