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Abstract

Odanacatib represents a novel treatment option in the approach of postmenopausal women. Postmenopausal women with osteoporosis experience a disturbance in bone remodeling wherein bone resorption exceeds bone formation. Cathepsin K is a lysosomal cysteine protease found primarily in osteoclasts that plays a major role in the breakdown of bone via its collagenase properties. Targeting a new area of pathophysiology, odanacatib inhibits cathepsin K to reduce bone resorption while preserving bone formation. Phase II and III trials have shown efficacy in increasing bone mineral density in the target treatment group. Overall, safety studies have found odanacatib to be well-tolerated and comparable to placebo; however, some imbalances in adverse events have been observed in the Phase III trials. Current and future studies will analyze the long-term ability of odanacatib in preventing bone fracture.

Keywords

bone mineral density cathepsin K drug review odanacatib postmenopausal osteoporosis

Menopause is associated with a decrease in estrogen levels and subsequent reduction in bone density [1]. This relationship stems from an imbalance in bone remodeling that occurs with aging and menopause. Bone loss follows this imbalance, causing altered skeletal structure and findings of decreased bone mineral density (BMD) [2,3]. The diagnosis of osteoporosis can be determined by BMD measurements or the presence of an adult hip or vertebral fracture secondary to an event such as a fall that would be unlikely to cause a fracture in a younger adult [4].

It is estimated that more than 9 million Americans have osteoporosis, making it the most common bone disease and an especially prevalent health problem in postmenopausal women [2,5]. Osteoporosis causes 2 million fractures every year, leading to major medical consequences for patients [2]. These fractures are associated with significant morbidity and mortality, often requiring the extended use of long-term care facilities and causing severe disability as evidenced by restricted movement, digestive problems and decreased lung function [6]. With a rapidly growing elderly population, the cost of care for osteoporosis is estimated to rise to US$25.3 billion by 2025 [7]. The medical and financial impact of osteoporosis underscores the need for timely screening and diagnosis, and the implementation of effective prevention and treatment strategies.

Even with current US FDA-approved medications, which are cost effective and generally well-tolerated, only 23% of post-menopausal women with osteoporosis fractures get the diagnostic testing or prescription medications they need within 6 months after fracture [8]. Osteoporosis therapies target the bone remodeling process. Their primary focus is on osteoclast bone resorption (antiresorptive, anticatabolic options); but they also can affect osteoblast bone formation (bone-forming, anabolic options) [9]. Although much is known about osteoporosis medications, there are still many unanswered questions. For example, the use of combination and sequential multiple agents to improve bone density and strength might be a new avenue for osteoporosis treatment [4,10]. Additionally, the optimal length of treatment and long-term side effects of many medications are not fully understood or known [4,6,11]. As more questions are answered about osteoporosis, there will continue to be new medications introduced to the market. This article focuses on a novel medication currently in Phase III trials, odanacatib, for the treatment of postmenopausal osteoporosis.

Overview of the market: osteoporosis treatments in postmenopausal women

All osteoporosis patients should consider the use of calcium, vitamin D and exercise [4]. Particularly in patients with deficiencies of calcium and/or vitamin D. In addition to these, most patients will also require prescription medications for osteoporosis treatment. Current options include the bisphosphonates, calcitonin, estrogen, estrogen agonist/antagonists, tissue-selective estrogen complex, recombinant parathyroid hormone and RANK-L inhibitors.

Bisphosphonates, which bind to bone and inhibit resorption by inhibiting the mevalonate pathway enzyme within osteoclasts, are considered first-line therapy in osteoporosis treatment [4,12]. In fact, alendronate has been the most commonly prescribed drug for postmenopausal osteoporosis, and as a class, the bisphosphonates are associated with significantly increased BMD and fracture risk reduction [13]. Bisphosphonate clinical trials were initially conducted for a treatment length of 3 years, with consequent extensions to as long as 10 years [14]. These studies have indicated that long-term use of bisphosphonates in postmenopausal women reduces fracture risk, but increases in BMD appear to plateau after 3 years of treatment [14]. There is evidence showing long-term use of bisphosphonates could be associated with atypical femur fractures [15 –17]. Additionally, a rare but serious adverse effect of bisphosphonate use is osteonecrosis of the jaw. This side effect is more common in intravenous administration, high-dose treatment and in patients with underlying malignancies [18,19].

Oral bisphosphonates have highly specific administration directions, and they are associated with gastrointestinal side effects, both often leading to poor adherence [12,20]. Alternatives do exist in the forms of intravenous formulations of bisphosphonates as well as other costly medications, such as subcutaneously delivered teriparatide and denosumab [12,21]. Denosumab is usually reserved for more severe cases of osteoporosis and for patients who cannot tolerate or have poor adherence to other therapies. It is administered every 6 months and is associated with an increased hypocalcemia and infection risk [22]. Using denosumab in combination with teriparatide has been shown to increase BMD more than using either agent as mono-therapy [23]. Teriparatide is used as an alternative treatment for osteoporosis and reserved for more severe cases, due to its cost and daily injections regimen [23].

The use of estrogen replacement therapy is employed for no longer than 10 years after menopause due to its potential for adverse cardiovascular effects after this time [24]. Estrogen agonists/antagonists, formerly referred to as selective estrogen receptor modulators, have the benefit of estrogen agonist activity on bone, while having estrogen antagonist effects on breast and endometrium [25]. They have not, however, been shown to reduce the risk of hip or nonvertebral fractures as is observed with estrogen.

While these medications are all effective options in osteoporosis treatment, there is still a need for the development of long-term therapies with improved safety profiles. Cathepsin K inhibitors are the latest in novel approaches to osteoporosis treatment. Studied compounds in this class include balicatib, relacatib, ONO-5334 and odanacatib. Balicatib research was discontinued due to poor cathepsin K selectivity, and skin adverse effects such as pruritus, skin rashes and rare morphea-like skin changes [26]. It is unclear whether these effects were causally related to the poor selectivity. Relacatib reduced bone turnover in animals but currently has unknown efficacy in humans with osteoporosis [27]. ONO-5334 was in development by Ono Pharmaceutical Company in Osaka, Japan; after reaching Phase II trials the company discontinued the drug due to the competitive nature of the osteoporosis market [28]. Odanacatib continues to be evaluated in clinical trials and has the potential to be the first FDA-approved medication of its kind in the treatment of osteoporosis, pending data on long-term safety and efficacy.

Introduction to the compound

Merck is responsible for the development of odanacatib, also known as MK-0822, a selective inhibitor of cathepsin K activity in bone that has been proven to improve important biomarkers in bone health and especially in those with postmenopausal osteoporosis. Figure 1 depicts the chemical structure of this agent. The selectivity of odanacatib for cathepsin K is unparalleled by other agents in this class such as balicatib and relacatib; because of this selectivity, there is less collagen accumulation in the lysosomes. By minimizing this accrual, serious dermatological side effects may be avoided [29].

Figure 1.

Chemical structure of odanacatib. Figure 1 was created using ChemDraw Pro 14 Suite.

The long-term clinical utility of this drug has yet to be fully determined as Phase III clinical trials are ongoing. However, because of its oral bioavailability, weekly administration and positive findings regarding its efficacy and safety profile, thus far, it may come to serve as another effective option as monotherapy or adjunctive therapy in osteoporosis or for those with refractory disease [30].

Chemistry

Postmenopausal women with osteoporosis experience a disturbance in bone remodeling wherein bone resorption exceeds bone formation [31]. Cathepsin K is a lysosomal cysteine protease found primarily in osteoclasts and it plays a major role in the breakdown of bone via its collagenase properties [28]. C-terminal telopeptide of type I collagen (1-CTP) is the main target of cathepsin K as it targets collagen breakdown [28]. The cleavage products of this enzymatic breakdown are N-terminal telopeptide and C-terminal telopeptide (CTX) [28]. The expression of protease cathepsin K is increased in response to RANK-L and reduced in response to estrogen [28].

Therefore, following menopause and the subsequent decline in estrogen concentrations, the selective inhibition of the cathepsin K protease by odanacatib contributes to preserved bone formation, and while there is not a decline in the number of osteoclasts, odanacatib does lead to a decrease in bone resorption via its inhibition of cathepsin K [28]. Extracellular processing and transcytotic removal of catabolized matrix proteins in the osteoclasts is inhibited by odanacatib, leading to the decrease in bone resorption efficiency [31]. Development of selective, reversible inhibitors of cathepsin K can lead to a therapeutic benefit in the treatment of osteoporosis because the drug works on a specific part of the osteoclasts in contrast to current antiresorptive medications in the market [31]. When osteoclasts are inhibited by cathepsin K, there is a decrease in the ability for the osteoclasts to properly perform the resorption process [31]. However, the inhibition by cathepsin K does not impair other roles of the osteoclast such as the differentiation, migration and secretory functions cell [31]. This is because the osteoclast is still capable of cellular functions including releasing signaling factors and releasing osteogenic factors from resorbed bone matrix [31].

Pharmacokinetics & pharmacodynamics

A 25 mg dose of odanacatib taken by the oral route in healthy men, ages 18–45 years, results in a T_max for the initial peak between 4 and 8 h postdose while a second peak, occurs at 24 h or later [32]. The cause of this second peak is not entirely understood as it may be due to systemic distribution and/or changes in protein binding and/or hepatic recirculation. The pharmacokinetic parameters of area under the curve (AUC_{0–24 h}), concentration at 24 h and C_max all increase after drug administration, but the increases are not directly proportional to the dose with doses ranging from 2 to 600 mg [33]. Odanacatib has a long half-life, with a mean half-life of 66–95 h depending on the dose studied [34,35]. The pharmacokinetic parameters (AUC_{0–24 h}, C_{max, day 1'} C_{max, overall'} C_{24 h} and T_{max, overall}) have been observed to increase when subjects consumed a high-fat breakfast prior to medication administration [33]. The pharmacokinetic parameters of the planned weekly dose of 50 mg have also been evaluated in postmenopausal women [35]. The AUC_{0–168 h'} C_{168 h} T_max 37.9 μM^*h (95% CI: 31.9 ± 45.0), 85 nM (95% CI: 59 ± 121) and 6.0 h (95% CI: 2.0–12.0), respectively. The main metabolic pathway is CYP3A4 [32].

The bone resorption markers, serum C-terminal telopeptide (sCTx) and urine amino-terminal cross-linked telopeptide of type I collagen/creatinine (uNTx/Cr), are decreased in a dose-dependent manner when odanacatib is administered [33,34]. Twenty four hours after the oral administration of 50 mg odanacatib, there was a 66% decrease in sCTx and 51% decrease in uNTx/Cr in comparison with placebo [33]. After 168 h, the decrease in sCTx and uNTx/Cr in comparison with baseline in the patients administered odanacatib was 70 and 78%, respectively [33]. This decrease in the bone resorption markers, SCTx and uNTx/Cr, is true in both males, age 50–75 years, and postmenopausal females when patients were given 50 mg by oral route of odanacatib once weekly [35]. In addition, C_max' T_max and half-life were similar between the sexes which suggest that pharmacokinetic and pharmacodynamic properties of odanacatib do not differ between men, age 50–75 years, and postmenopausal women [35]. See Table 1 for a summary of pharmacokinetic parameters.

Table 1.

Summary of mechanism of action and pharmacokinetic parameters.

Drug mechanism of action and related parameters	Results/findings
Mechanism of action	Inhibition of cathepsin K enzyme which prevents the osteoclasts from destroying the bone matrix
Half-life	Approximately 66–93 h
Time to achieve steady state	3 weeks
T_max	4–8 h
Main metabolic pathway	CYP3A4

Data taken from [35].

Clinical efficacy

Phase I clinical trials

A safe dosage of odanacatib was determined in Phase I trials [33 –35]. Double-blind, randomized control trials were performed with both men and postmenopausal women receiving varying doses in order to assess safety, tolerability, pharmacodynamics and pharmacokinetics [33 –35]. Postmenopausal women who received 50 mg of the drug had 66 and 51% reduction in CTx and uNTx/Cr, respectively, at 24 h after administration [33]. Bone resorption biomarkers, CTx and uNTx/Cr, were inhibited after 3 weeks in both trials; however, the suppression was not directly proportional to the increase in dosages [34]. The results show that the drug is well-tolerated, has a long half-life regardless of dosage administered in the trials and that once weekly dosing would be appropriate [34]. See Table 2 for a detailed summary of Phase I clinical trial results.

Table 2.

Summary of Phase I clinical trials.

Clinical trial	Study parameters	Results	Conclusion	Ref.
NCT00863590	50 mg, once weekly Six postmenopausal women	66% reduction in sCTx at 24 h postdose vs placebo 70% reduction in sCTx at 168 h relative to baseline 51% reduction in uNTx/Cr at 24 h postdose vs placebo 78% reduction in uNTx/Cr at 168 h relative to baseline	The long half-life of odanacatib and robust sustained reduction of biomarkers of bone resorption through 168 h suggests that once weekly dosing can achieve sustained pharmacological activity and provides the first pharmacological proof-of-concept for a once weekly regimen of a cathepsin K inhibitor	[33]
	100 mg, once weekly Four postmenopausal women	43% reduction in sCTx at 24 h postdose vs placebo
		57% reduction in uNTx/Cr at 168 h postdose vs placebo
NCT00770159	25 mg, once weekly Nine postmenopausal women	49.43% reduction in CTx (ng/ml) at 21 days 30.34% reduction in NTx/Cr (nmol/mmol Cr) at 21 days 116.42% increase in 1-CTP (μg/l) at 21 days	Odanacatib exhibits robust and sustained suppression of bone resorption biomarkers (CTx and NTx/Cr) at weekly doses ≥25 mg	[34]
	50 mg, once weekly Nine postmenopausal women	62.29% reduction in CTx (ng/ml) at 21 days 61.94% reduction in NTx/Cr (nmol/mmol Cr) at 21 days 108.99% increase in 1-CTP (μg/l) at 21 days
	100 mg, once weekly Nine postmenopausal women	62.64% reduction in CTx (ng/ml) at 21 days 50.42% reduction in NTx/Cr (nmol/mmol Cr) at 21 days 129.81% increase in 1-CTP (μg/l) at 21 days
NCT01068262	50 mg, once weekly Nine postmenopausal women	42.7% reduction in uNTx/Cr at 28 days relative to baseline 68% reduction in sCTx at 28 days relative to baseline	PD effect of odanacatib are similar among older men and postmenopausal women	[35]

CTP: C-terminal peptide; PD: Pharmacodynamic; sCTx: Serum C-terminal telopeptide; uNTx/Cr: Urine amino-terminal cross-linked telopeptide of type I collagen/creatinine.

Phase II clinical trials

The efficacy of odanacatib was largely studied in what began as a dose-ranging 12-month clinical trial with a planned extension to 24 months (n = 399); this was later extended to 3 years (n = 189) and then 5 years (n = 141) [36 –38]. 5 years of treatment with odanacatib was found to be generally well-tolerated, with an increased incidence of urinary tract infections over placebo in years 3 through 5 being most noteworthy [38,39]. Subjects who received odanacatib 50 mg by mouth weekly for 5 years (n = 13), experienced a mean increase in lumbar spine BMD from baseline of 11.9% (95% CI: 7.2–16.5%) versus a 0.4% decrease (95% CI: −3.1–2.3%) for women who were switched from odanacatib 50 mg to placebo after the initial 2 years of the 5-year study (n = 14) [38]. The trials showed progressive BMD increases in the spine and hip for up to 5 years of treatment, differing from bisphosphonates which seem to plateau after 3 years of treatment [39 –41]. Subjects receiving weekly odanacatib (10–50 mg, n = 26–29), showed an approximate 55% decrease in bone resorption markers, N-terminal telopeptide/Cr and CTX, at year 5; bone formation markers of bone-specific alkaline phosphatase and amino-terminal propeptide of type I procollagen (P1NP) were temporarily decreased, but by year 5, increased toward baseline levels [38]. This supports the ability of odanacatib to effectively inhibit bone resorption without drastically hindering bone formation. Of interest, patients who were re-randomized at the start of year 3, from treatment to placebo groups, exhibited a return of BMD and biochemical markers to approximately baseline values at five [38]. This decrease in BMD and increase in biochemical markers indicates that odanacatib treatment may need to be chronic in order to preserve its benefits.

In a study to evaluate the safety, tolerability and efficacy of odanacatib, postmenopausal women (n = 243) with osteoporosis who had been previously treated with alendronate for 3 years or more, were given 50 mg of odanacatib or placebo once weekly for 24 months [36]. In the treatment group, BMD changes from baseline at the femoral neck, trochanter, total hip and lumbar spine at 24 months were significantly higher (1.7, 1.8, 0.8 and 2.3%, respectively) than the placebo group, while both groups had comparable safety data [36]. This study also showed a difference in fracture events, recorded as a safety parameter, when comparing placebo (13.2%) to odanacatib (4.9%) [42]. See Table 3 for a detailed summary of Phase II clinical trial results.

Table 3.

Summary of Phase II clinical trials.

Clinical trial	Study parameters	Results	Conclusion	Ref.
NCT00112437: years 1–2	50 mg, once weekly 58 postmenopausal women	5.7% increase in lumbar spine BMD at 24 months relative to baseline 4.1% increase in total hip BMD at 24 months relative to baseline 4.7% increase in femoral neck BMD at 24 months relative to baseline 5.1% increase in trochanter BMD at 24 months relative to baseline 2.9% increase in a third radius BMD at 24 months relative to baseline	During 2 years of weekly odanacatib treatment, there was a substantial and progressive increase in BMD in postmenopausal women with low BMD	[36]
NCT00112437: year 3	16 of the 58 women that received 50 mg, once weekly in years 1–2 were switched to placebo in year 3	1.4% increase in lumbar spine BMD at end of year 3 relative to baseline 0.7% decrease in trochanter BMD at end of year 3 relative to baseline 1.8% decrease in total body BMD at end of year 3 relative to baseline 2.3% increase in femoral neck BMD at end of year 3 relative to baseline 2.7% decrease in a third radius BMD at end of year 3 relative to baseline	3 years of odanacatib treatment resulted in progressive increases in BMD. BMD increases with odanacatib were substantially reversed within a year of discontinuation	[37]
	19 of the 58 women who received 50 mg, once weekly in years 1–2 continued 50 mg, once weekly in year 3	2.3% increase in lumbar spine BMD from year 2 to 3; 7.9% increase from baseline 2.4% increase in total hip BMD from year 2 to 3; 5.8% increase from baseline 1.6% increase in femoral neck BMD from year 2 to 3; 5% increase from baseline 2.7% increase in trochanter BMD from year 2 to 3; 7.4% increase from baseline
NCT00112437: years 4–5	13 of the 19 women that continued 50 mg, once weekly in year 3 continued in years 4–5	11.9% increase in lumbar spine BMD relative to baseline at end of year 5 8.5% increase in total hip BMD relative to baseline at end of year 5 9.8% increase in femoral neck BMD relative to baseline at end of year 5 10.9% increase in trochanter BMD relative to baseline at end of year 5	5 years of odanacatib treatment resulted in progressive increases in BMD	[38]
NCT00885170	50 mg, once weekly 83 postmenopausal women	1.7% increase in femoral neck BMD at 24 months relative to baseline 1.8% increase in trochanter BMD at 24 months relative to baseline 0.8% increase in total hip BMD at 24 months relative to baseline	Odanacatib provided incremental BMD gains in osteoporotic women after alendronate treatment	[42]
	50 mg, once weekly 80 postmenopausal women	2.3% increase in lumbar spine BMD at 24 months relative to baseline

BMD: Bone mineral density.

Phase III clinical trials

There are currently several Phase III clinical trials in various stages of completion. However, only one has published results at the time of manuscript preparation. This study examines the efficacy of odanacatib in improving bone density, turnover and estimated strength in postmenopausal women using a randomized, double-blind, placebo-controlled study design [43]. Participants included 214 postmenopausal women with lumbar spine, total hip, femoral neck or trochanter T-scores between −3.5 and −1.5. Participants were randomized to treatment with either oral odanacatib 50 mg or placebo. Both treatment groups received vitamin D3 5600 IU weekly and calcium 1200 mg daily, unblinded. The end points of the study were: bone turnover markers, including CTX and P1NP; densitometry and imaging, including areal BMD by dual x-ray absorptiometry, quantitative computed tomography imaging by CT scan; finite element analysis, using nonlinear 3D finite element analysis which estimates femoral or vertebral strength for a simulated fall or compression, respectively; and bone biopsy. The trial had enough power to show statistically significant differences between study groups for BMD end points at 1 year [43].

This trial illustrated statistical significance (p < 0.001) at the primary end point of areal BMD. There was a 3.5% greater increase in areal BMD at the lumbar spine in women treated with odanacatib compared with those given placebo after 1 year of the study [43]. This remained statistically significant at 2 years with an even greater difference, 5.4%, between treatment and placebo groups. Lumbar spine, femoral neck, total hip and trochanter BMD were significantly higher (p < 0.001) in the odanacatib treatment group. Other statistically significant (p < 0.001) results included decreased serum concentrations of bone remodeling biomarkers (CTX and P1NP). P1NP, however, returned to baseline levels in odanacatib-treated participants after 2 years treatment with odanacatib. Efficacy of odanacatib was supported by quantitative computed tomography analyses at the femoral neck (6.0 and 4.9% difference between odanacatib and placebo in cortical thickness and cortical area, respectively) [43].

While this study showed significant increases in BMD and bone strength with odanacatib, it did not examine the efficacy on fracture risk in postmenopausal women with osteoporosis. However, fractures were observed as adverse events in this study and found to be more frequent in the placebo group versus the odanacatib group (9.5 and 2.8%, respectively) [43]. And while this study was not powered to determine the significance of fracture occurrence, the completed LOFT does evaluate the drug's impact on fracture risk [44]; fracture prevention results are available via abstract [45]. Fully published data are expected to be forthcoming.

Safety & tolerability

The safety and tolerability of odanacatib has been studied and published in several trials to date. The safety and tolerability data were obtained via adverse event (AE) monitoring, clinical examination (including vital signs) and laboratory assessment (which included serum chemistry and hematology findings). Monitoring occurred at baseline, during the study and, in most studies, ceased 2 weeks after the final dose of treatment [33 –38,43,46].

The first Phase I trial to study odanacatib in humans (32 males, eight postmenopausal females) reported that the most common adverse events observed in single dose administration were headache, flu-like symptoms and sore throat. No drug-related effects were seen in laboratory or clinical exam results [33]. In another Phase I trial where odanacatib was dosed weekly for 4 weeks, 22 subjects reported 82 clinical AEs [35]. Similar to the first Phase I trial, nausea and headache were the most frequently reported events and others included arthralgia, musculoskeletal pain and nasal congestion or rhinorrhea. Placebo and treatment groups displayed similar incidences of these AEs. Treatment was discontinued in this trial due to vomiting, arthralgia and pityriasis rosea (rash), however the incidence of discontinuation for odanacatib versus placebo was not reported [35]. Finally, neither Phase I study reported serious clinical or laboratory AEs.

The overall combined safety results from the Phase I and II clinical studies (excluding extension studies) are favorable for odanacatib. A total of 559 adverse events were reported by 651 patients receiving odanacatib [33,35,37 –38]. Of these events, 77 (13.8%) were recorded as serious and 16 (2.9%) of these lead to therapy discontinuation. The incidence of adverse events was not found to be dose dependent and therefore did not significantly vary from 3 mg once weekly to 50 mg once weekly. Placebo groups in these studies reported 223 AEs in a sample size of 277 patients. Comparable with active drug, serious AEs accounted for 33 (14.8%) of these and five (2.2%) resulted in discontinuation in the study. Serious skin and respiratory AEs, including morphea-like skin reactions and upper respiratory infections, were specifically noted in two of these studies as AEs of interest because of concern regarding another cathepsin K inhibitor shown to cause these AEs. The two Phase II trials that emphasized monitoring for these AEs found no significant difference between placebo and odanacatib [36,37].

1- and 3-year extensions of one Phase II trial revealed similar AE incidences between placebo and odanacatib treatment groups which included back pain, arthralgia, extremity pain and nasopharyngitis as the most common [37,38]. A noteworthy safety difference between placebo and treatment groups was discovered in the 1-year extension. It was found that total urinary tract infections or cystitis was higher in the odanacatib group (12/97 [12.4%]) versus placebo group (3/92 [3.3%]). This discrepancy was also noted in the second and third year of extension [37,38]. However, all patients had been exposed to odanacatib by this stage of the trial, including those who had previously been treated with placebo. Therefore, the significance of this difference cannot be determined.

The single Phase III trial with published results examined bone density, turnover and estimated strength in 214 postmenopausal women. Safety and tolerability was also elicited from this study and odanacatib was found to be generally well-tolerated. Fewer skin AEs were reported in odanacatib treatment group (11%) as compared with placebo (18%) [43]. Box 1 summarizes the safety and tolerability findings among the odanacatib clinical trials to date.

Regulatory affairs

Odanacatib has not been approved as a new pharmacologic entity by any regulatory association. Merck expects to submit a new drug application for odanacatib with the FDA in 2015.

Conclusion

Odanacatib represents a new class of drugs to be considered in treating postmenopausal osteoporosis. It has been shown to be safe and effective in increasing BMD. By targeting a new mechanism of action, odanacatib may find a role in replacing or supplementing current therapeutic approaches. The once weekly oral formulation provides a desirable route and frequency of administration that appears to be well-tolerated. Most observed AEs have been transient and mild, including headache. Phase III clinical trials are currently being conducted, and preliminary results may indicate clinical efficacy as evidenced by reduced number of fractures.

Box 1.

Summary of safety and tolerability findings.

Phase I trials

Most commonly observed AEs were headache, nausea and sore throat

Similar incidence of adverse events were observed between odanacatib and placebo groups

Phase II trials

Similar incidence of AEs were observed between odanacatib and placebo groups

Serious AEs – placebo (32/223 [14.8%]) vs odanacatib (77/559 [13.8%]) [36 –38]

AEs resulting in drop out – placebo (5/223 [2.2%]) vs odanacatib (16/559 [2.9%]) [36 –38]

Skin AEs – placebo (28/204 [13.7%]) vs odanacatib (85/438 [19.4%]) [36,38]

Respiratory AEs – placebo (31/204 [15.2%]) vs odanacatib (56/438 [12.8%]) [36,38]

1-year extension of a Phase II trial showed higher incidence of cystitis and urinary tract infections (12/97 [12.4%]) in odanacatib treatment groups vs placebo (3/92 [3.3%]) [38]

Phase III trials

Placebo and odanacatib were found to be well-tolerated

Skin AEs: placebo (18%) and odanacatib (11%) [44]

AE: Adverse events.

Executive summary

Mechanism of action

Oral odanacatib, 50 mg weekly, works by inhibiting cathepsin K to prevent osteoclast destruction of bone matrix.

Pharmacokinetic properties

The half-life of odanacatib is 66–93 h and requires 3 weeks to achieve steady-state concentrations.

Odanacatib is predominantly metabolized inthe liver via CYP450 3A4.

Food high in fat increases the absorption of odanacatib.

Clinical efficacy

Significant increases in bone mineral densityhave been seen in clinical trials using odanacatib compared with placebo.

Ongoing studies are evaluating the ability of odanacatib to reduce bone fracture risk; previous trials have seen potential efficacy in this aspect.

Safety & tolerability

Compared with placebo, odanacatib has been foundto have a similar toxicity profile.

Most observed adverse events have been mild and transient and include headache and nasopharyngitis.

Some studies indicate higher incidence (>10%) of urinary tract infections in patients treated with odanacatib. Drug interactions

No information has been provided regarding interactions of odanacatib with other drugs.

Dosage & administration

Odanacatib is available as an oral tablet to be administered once weekly.

Footnotes

In addition to the peer-review process, with the author(s) consent, the manufacturer of the product(s) discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made at the discretion of the author(s) and based on scientific or editorial merit only.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Odanacatib: An Emerging Novel Treatment Alternative for Postmenopausal Osteoporosis

Abstract

Keywords

Overview of the market: osteoporosis treatments in postmenopausal women

Introduction to the compound

Chemistry

Pharmacokinetics & pharmacodynamics

Clinical efficacy

Phase I clinical trials

Phase II clinical trials

Phase III clinical trials

Safety & tolerability

Regulatory affairs

Conclusion

Footnotes

References