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Vß3 Integrin Antagonist, on Markers of Bone Turnover and Bone Mineral Density in Postmenopausal Osteoporotic Women
Merck Research Laboratories (M.G.M., K.C., A.S., K.G., M.W.), Rahway, New Jersey 07065; and Creighton Osteoporosis Center (R.R.), Omaha, Nebraska 68131
Address all correspondence and requests for reprints to: M. Gail Murphy, M.D., Merck Research Laboratories, Building 5W, Sentry Parkway, Bluebell, Pennsylvania 19422. E-mail: Gail_Murphy{at}Merck.com.
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Abstract |
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Vß3 integrin (vitronectin receptor) plays a pivotal role in bone resorption. We hypothesized that L-000845704, an Vß3 integrin antagonist, would potently inhibit bone resorption, thereby increasing bone mass as assessed by bone mineral density (BMD) in women with postmenopausal osteoporosis. In a multicenter, randomized, double-blind, placebo-controlled, 12-month study, 227 women (average 63 yr) with low lumbar spine or femoral neck BMD were randomly assigned to receive 100 or 400 mg L-000845704 once daily (qd), 200 mg L-000845704 twice daily (bid), or placebo. L-000845704 increased lumbar spine BMD (2.1, 3.1, and 3.5% for the 100-mg-qd, 400-mg-qd, and 200-mg-bid treatment groups, respectively, vs. –0.1% for placebo; P < 0.01 all treatments vs. placebo). Only 200 mg L-000845704 bid significantly increased BMD at the hip (1.7 vs. 0.3% for placebo; P < 0.03) and femoral neck (2.4 vs. 0.7% for placebo; P < 0.05). No L-000845704 group increased total body BMD. All doses of L-000845704 resulted in a similar approximately 42% decrease from baseline of N-telopeptide cross-links (P < 0.001 vs. placebo). L-000845704 was generally well tolerated; adverse events resulting in discontinuation from the study were relatively infrequent.
In conclusion, the antiresorptive effect of the Vß3 integrin antagonist L-000845704 translated into significant increases in lumbar spine BMD. Furthermore, 200 mg L-000845704 bid provided efficacy at the hip sites. These data suggest that the Vß3 integrin antagonist L-000845704 could be developed as an effective therapeutic agent for osteoporosis.
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Introduction |
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Vß3, are transmembrane adhesion receptors that mediate cell-cell and cell-matrix interaction (14, 15). Various studies have indicated that the most abundant integrin in osteoclasts, Vß3, interacts in bone with extracellular matrix proteins that contain the arginine-glycine-aspartic acid (RGD) sequence (16, 17, 18). Osteoclast interaction with extracellular matrix was shown to be inhibited by RGD-containing peptides, by nonpeptides that mimic RGD, and by antibodies to the Vß3 integrin, supporting a critical role for Vß3 in osteoclast adhesion (16, 17, 18). Vß3 antibodies, echistatin (an RGD-containing peptide), and orally active RGD mimetics were also shown to inhibit bone resorption in vivo without notable adverse effects (19, 20, 21). Furthermore, ß3 integrin knockout mice appear to have normal development and growth, besides the defects related to Vß3 integrin-associated osteosclerosis and IIbß3 integrin-associated bleeding. Therefore, Vß3 antagonists are of considerable interest for the treatment of osteoporosis (22, 23, 24).
L-000845704 is an orally active, novel, potent, nonpeptide small molecule inhibitor of the Vß3 integrin (25). This compound is highly selective against IIBß3 integrin, inactive in a platelet aggregation assay, and selective against Vß5 integrin. This Vß3 integrin inhibitor exhibits a good pharmacokinetic profile in preclinical species. Additionally, L-000845704 inhibits bone resorption in the growing rat and prevents bone loss in the ovariectomized rat model of osteopenia. It also decreases markers of bone resorption in the adult ovariectomized rhesus monkey; this decrease normalizes within 2 d of treatment discontinuation. Furthermore, administration of 400-mg once-daily (qd) L-000845704 to older women for 2 wk in phase I studies decreased urinary N-telopeptide cross-links (NTx), a marker of bone resorption, on average by approximately 40% and was generally well tolerated (Merck Research Laboratory, data on file). Furthermore, data from this 2-wk multiple-dose study suggest that a 400-mg qd dose of L-000845704 will result in plasma exposures similar to those associated with changes in BMD in preclinical species. Nevertheless, the half-life of L-000845704 is short in humans, and 400 mg qd may not result in a persistent inhibition of bone resorption. Because it was important to assess the potential of this class of compounds to inhibit bone resorption, a 200-mg twice-daily (bid) regimen of L-000845704 was also evaluated. In phase I studies, this dose regimen resulted in maintenance of higher trough concentrations compared with those seen after 400-mg qd dosing. The 100-mg qd dose was anticipated to be a minimum effective dose.
We determined therefore the effects of chronic administration of three dose regimens of L-000845704 on biochemical markers of bone formation and resorption and BMD in women with postmenopausal osteoporosis.
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Subjects and Methods |
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Two hundred twenty-seven women (mean ± SD, 63.4 ± 8.1 yr) were selected for participation at 20 study centers. To be eligible for the study, subjects had to be postmenopausal (without menses for at least 3 yr), with a lumbar spine or femoral neck BMD at least 2.0 SD below the mean peak value for healthy young women (<0.827 or 0.627 g/cm2, respectively, as measured by Hologic 1000W, 2000, or 4500) but no more than 3.0 SD below the age-specific mean. Other than osteoporosis, the patients were in good health. Patients with any fracture attributed to osteoporosis or any disease or drug therapy (including any bisphosphonate, fluoride, GH, glucocorticoid, or estrogen therapy within the past 6 months or any time for bisphosphonates) potentially affecting bone metabolism were excluded. The following were additional exclusion criteria: abnormal renal function (estimated creatinine clearance 
60 ml/min·1.73 m2 based on the Cockcroft-Gault equation), low 25-hydroxyvitamin D (<15 ng/ml), or a history of myocardial infarction, angina, or heart failure. The women were recruited by direct mailings or telephone contacts and advertisements in the media. Institutional Review Board approval was obtained at each participating site, and written informed consent was obtained from each subject consistent with standards established by the Declaration of Helsinki.
Study design
This was originally planned as a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 3-month study. One-year animal safety studies completed during the conduct of this study as well as ongoing review of safety from this study supported extension of the treatment period to 12 months. Therefore, the study was twice amended to extend treatment duration from 3 to 6 and subsequently 6 to 12 months, although the study design was unchanged except for treatment duration and additional evaluations at specified time points up to 12 months. Institutional Review Board approval and written informed consent was obtained from each subject before their participation in study extensions.
After a 2-wk, open-label calcium carbonate plus 25-hydroxyvitamin D (OSCAL 500 + 250 IU 25-hydroxyvitamin D) run-in period, 227 women were assigned according to a computer-generated randomized allocation schedule in a 1:1:1:1 ratio to one of four daily treatment groups. The four treatment groups from month 0 to month 12 were L-000845704 100 mg qd (in the evening at approximately 2000 h), L-000845704 400 mg qd (at approximately 2000 h), L-000845704 200 mg bid (at approximately 0800 and 2000 h), or placebo daily (at approximately 0800 and 2000 h). Patients randomized to receive qd dosing received matching placebo at approximately 0800 h to maintain study blindness. Patients took two tablets of a 250-mg elemental calcium supplement plus 125 IU 25-hydroxyvitamin D (OSCAL 250 + D, Smithkline Beecham Consumer Healthcare, L.P., Pittsburgh, PA) with dinner daily to ensure nutritional adequacy of calcium and 25-hydroxyvitamin D for all patients. Compliance was monitored by pill count and patient report of missed doses. Patients were evaluated every 4 wk until month 3 and then at 6- to 12-wk intervals, with a possible total study participation of 12 months. The changes from baseline in urinary NTx and lumbar spine BMD were the primary and secondary endpoints of the study, respectively.
Biochemical analyses
Urine (fasting second morning voided specimen) chemistry values (NTx and creatinine) and special serum bone biochemistry assessments (serum C-telopeptide collagen cross-links, osteocalcin and bone-specific alkaline phosphatase) were obtained at baseline (after 2-wk placebo run-in; before study drug) and at wk 2 and months 1, 2, 3, 4.5, 6, 9, and 12 of treatment. Samples for each subject were assayed together up to prespecified time points for analyses (i.e. 6 and 12 months).
Urine NTx were measured using the NTx Reagent Pack kit from Ortho-Clinical Diagnostics (Amersham, Little Chalfont, UK) for quantitative determination of NTx in urine on the Vitros Immunodiagnostic automated system ECI. Interassay coefficients of variation (CVs) range from 3.8–6.3% at urine analyte values of 88–1152 nM bone collagen equivalent (BCE). Serum type I collagen C-telopeptides (CTx) was measured using the Crosslaps kit from Roche Diagnostics (Mannheim, Germany) for the quantitative determination of serum type I collagen breakdown products using the Elecsys analyzer from Roche Diagnostics. Interassay CVs range from 5.6–7.9% at serum analyte values of 0.6–2.6 ng/ml. Serum bone-specific alkaline phosphatase (BSAP) was measured using the OSTASE assay (Beckman Coulter, Fullerton, CA) with an interassay CV of 7.4%. The manufacturer reports these values in mass units; this is the standard unit of expression in medical literature for BSAP. Serum osteocalcin was measured using the Elsa-Osteo kit from Cis Bio International for quantitative determination of osteocalcin in serum with interassay CVs of 4.3 and 5.5% at serum concentrations of 1.5 and 3.4 nmol/liter, respectively.
BMD measurements and radiographic assessment
BMD of the lumbar spine, femoral neck, hip, and total body was measured by dual-energy x-ray absorptiometry using Hologic models 1000W, 2000, or 4500 or Lunar model. BMD was determined twice (lumbar spine) or once (hip, femoral neck, and total body) at baseline and at 3, 6, 9 (lumbar spine only at 9 months), and 12 months of treatment. A common, standardized procedure for patient positioning and use of software was incorporated into the Quality Assurance manual procedures provided by the central Quality Assurance center. The baseline scan was evaluated before follow-up scan acquisition. Patient positioning was duplicated as closely as possible, and identical scan parameters were used. As the scan was acquired, the identical starting point and positioning used at baseline was verified. If the match of baseline and follow-up acquisitions was not optimal, then the patient was repositioned or rescanned. Internal dual-energy x-ray absorptiometry calibration was maintained at each center, and calibration across centers was performed using spine and linearity phantoms. Synarc, Inc. (Maynard, MA), was responsible for handling all aspects of quality assurance for BMD measurements, including assessment of consistency of acquisition, analysis, and data management at the study sites without knowledge of treatment assignment. Lateral thoracic and lumbar spine radiographs were evaluated at each center for the presence of prevalent or incident vertebral fractures at baseline. Radiographic fractures were defined as an x-ray report from an expert reader noting one or more definite fractures.
Assessment of treatment safety
Patients were questioned about intercurrent health problems at each visit. Standard clinical evaluations and laboratory analyses, including hematological and chemistry values, were performed at least every 6 wk during the first 6 months of treatment and every 3 months thereafter. Physical examinations were performed at baseline and at 6 months of treatment and after the study. Radiographs were obtained during the study if needed to assess a clinical syndrome consistent with fracture. All adverse events (including clinical reports of fracture) were recorded by the physician investigator, who rated each event as to whether it appeared causally related to the study drug. Study drug referred collectively to any combination of L-000845704, placebo, and calcium plus 25-hydroxyvitamin D supplement.
Statistical methods
The analysis of biochemical markers included urine NTx (primary endpoint), serum Ctx, osteocalcin, and BSAP. An analysis-of-covariance model was used for the biochemical markers with the natural log of the baseline value as a covariate and a factor for treatment groups. Data were transformed to natural log (ln) (fraction of baseline) for the analysis and back transformed to percent change from baseline (±SEM) for presentation. A per-protocol approach was taken to the analysis of biochemical markers as prespecified in the study protocol. This approach excluded data from patients with serious protocol deviations (described below in Results) and made no attempt to replace missing values.
The analysis of BMD included the effect of the four treatments on lumbar spine BMD (prespecified secondary endpoint) as well as total hip, femoral neck, and total body BMD. The percentage change from baseline to wk 52 was analyzed. As specified in the study protocol, a modified intent-to-treat approach was taken to the analysis of BMD data. This approach included all patients who had a baseline and at least one on-treatment measurement; missing data were imputed by carrying the last available on-treatment value forward. Analysis based on the per-protocol population that excluded protocol violators (described below in Results) from the subset of completers was also undertaken and corroborated the conclusions from the modified intent-to-treat approach.
There was 80% power ( = 0.05, two-tailed test) with a sample size of 45 patients per treatment group to detect between-group differences from baseline in NTx and lumbar spine BMD of 35 and 3.0 percentage points, respectively.
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Results |
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Biochemical markers of bone turnover
Urinary NTx/creatinine levels (NTx) were used as a marker for monitoring the effect of L-000845704 on bone resorption. At wk 52, all L-000845704 treatment groups experienced significant, yet similar, decreases in NTx to approximately 28.8, 27.0, and 29.0 nmol BCE/mmol creatinine (i.e. decreased from baseline by approximately 24.9, 27.9, and 26.8% for the 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively; P < 0.001 vs. placebo; Fig. 1
and Table 1). These decreases were significantly different from the placebo group, which showed a borderline (P = 0.098) significant increase from baseline of 15.0%. Compared with NTx levels at wk 24, all four treatment groups experienced increases in the second half of the 52-wk study as noted in Fig. 1. The net treatment effects (vs. placebo) were approximately –42% in the active treatment groups. Of note, there was no evidence of a dose response between 100 and 400 mg qd in the effect on urinary NTx. The significant response was reached at the first time point markers were measured, i.e. within 2 wk of administration of L-000845704. The time course of change from baseline for NTx was in general similar among the L-00845704 treatment groups.
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and Table 1). The significant response was reached at the first time point markers were measured, i.e. within 2 wk of administration of L-000845704. The magnitude and time course of change from baseline for CTx was in general similar among the L-00845704 treatment groups.
Serum BSAP and osteocalcin levels were used as markers for monitoring the effect of L-000845704 on bone formation. As shown in Fig. 1, after an initial increase in all active treatment groups at wk 2, BSAP levels dropped steadily over the first 24 wk of the study and remained relatively stable thereafter. At wk 52, all L-000845704 treatment groups experienced significant decreases in BSAP to approximately 11.9, 10.9, and 11.1 ng/ml (i.e. decreased from baseline by approximately 21.8, 22.2, and 30.8% for the 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively; P < 0.001 vs. placebo; Fig. 1 and Table 1). Similar to BSAP, after wk 2, osteocalcin levels dropped steadily up to 26 wk and remained relatively stable thereafter (Fig. 1 and Table 1).
BMD
Lumbar spine BMD was the key parameter to examine the effect of L-000845704 on bone density. Over the period of 52 wk, administration of L-000845704 significantly increased BMD at the lumbar spine with mean increases from baseline of 2.1, 3.1, and 3.5% for the 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively (P < 0.01 vs. placebo; Fig. 2 and Table 2). The three active treatment groups clearly separated themselves from placebo from wk 12 through wk 52. The effect on lumbar spine BMD appeared relatively stable after 24 wk at the 100-mg qd dose, although additional increases in spine BMD were seen in the 400-mg qd and 200-mg bid groups at wk 52 (Fig. 2). Consistent results were observed from the per-protocol analysis with increases from baseline of 2.1, 3.2, and 3.9% for the 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively.
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), whereas the 400-mg qd regimen maintained its moderate treatment effect. After 52 wk, mean increases from baseline of 1.4 (P = 0.002), 0.8 (P = 0.09), and 1.7% (P < 0.001) were noted for the 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively; however, only the 200-mg bid regimen resulted in a significant effect vs. placebo (P = 0.03; Fig. 2 and Table 2). Similarly, a significant increase from baseline of 2.4% in femoral neck BMD over the 52 wk of the study was seen only after administration of L-000845704 200 mg bid (P < 0.001 vs. placebo; P < 0.05 vs. both qd treatments; Fig. 2 and Table 2). Moreover, although significant increases from baseline in total body BMD in the three active treatment groups of 1.3–1.6% were seen, these values were not significantly greater than the increase of 1.0% seen in the placebo group (Fig. 2 and Table 2). Safety and tolerability
Administration of L-000845704 was generally well tolerated based on review of patient discontinuations, serious and nonserious adverse events, and laboratory parameters. A total of six of 227 patients discontinued the study because of clinical adverse events; four (1.7%) were on active treatment (headache, decreased appetite, hot flashes, and arthralgia), and two (dyspepsia and painful limb) were on placebo. All adverse events but arthralgia were judged to be drug related by the investigator. There were six patients who had serious adverse events. Of these six patients, two were on study drug and four were on placebo. None of these events were considered drug related. No deaths and no adverse events of myocardial infarction, angina, or heart failure occurred during the study. During the study period, seven patients experienced a clinical syndrome of fracture of distal upper or lower extremity reported as adverse experiences (five and two in the treatment and placebo groups, respectively). The majority of fractures were associated with trauma.
There was a trend to an increase in the number of headaches in the higher-dose groups: 12.5, 14.3, 17.2, and 19.3% in the placebo, 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively. Additionally, there was an increased incidence of the combined endpoint of dermatitis, pruritis, rash, and urticaria in the active treatment groups vs. the placebo group with combined incidences of 5.4, 8.9, 15.5, and 15.8% in the placebo, 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively. A trend to a larger decrease in mean serum alkaline phosphatase and calcium levels was seen only in the L-00845704 bid treatment group. There were no other significant changes noted in creatinine, liver function tests, or other chemistry parameters.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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vß3 integrin antagonist, as produced by L-000845704, would result in clinically meaningful increases in BMD was confirmed.
In the current study, administration of 100 mg qd, 400 mg qd, and 200 mg bid L-000845704 for 12 months to osteoporotic postmenopausal women achieved similar mean decreases from baseline relative to placebo in urinary NTx (
42%) and serum CTx (48%). The decreases in urinary NTx and serum CTx were evident through month 12, supporting a persistent antiresorptive effect. There was no dose response noted in effect on markers of bone resorption. Administration of all dose regimens of L-000845704 also achieved significant decreases in the bone formation marker BSAP relative to placebo. Of note, the 200-mg bid regimen achieved a greater reduction in BSAP (31%) than either the 100- or 400-mg qd (both 22%) dose regimens (P < 0.05 for 200 mg bid vs. 100 mg qd; P = 0.06 for 200 mg bid vs. 400 mg qd). The same pattern was seen in osteocalcin, another marker of bone formation. Therefore, based on markers of bone formation, there appeared overall to be greater effects of the 200-mg bid regimen of L-000845704 compared with the same total dose given qd. With other classes of antiresorption agents, e.g. bisphosphonates, the decrease in bone resorption is followed by a subsequent secondary reduction in bone formation that plateaus by 6 months, as shown by a reduction in bone formation markers such as BSAP and osteocalcin (26). This sequence of events is anticipated because of the well established coupling of bone resorption and formation (27). It is of interest in this study that although the effect of qd and bid regimens of L-000845704 was similar for markers of bone resorption, the effect on bone formation markers was significantly greater for the bid compared with the qd regimens.
All L-000845704 treatment groups experienced significant mean increases from baseline in lumbar spine of 2.1, 3.1, and 3.5% for the 100-mg qd, 400-mg qd, and 200-mg bid treatment groups, respectively; these increases were significantly greater than BMD change from baseline in the placebo group. The differences in treatment response for lumbar spine BMD among the L-000845704 groups were numerical. In contrast, administration of the 200-mg bid regimen of L-000845704 consistently provided higher efficacy among the three active treatment regimens at the cortical-rich femoral neck hip site and maintained an upward trend over the 52 wk of the study. These observations regarding the effect of various dose regimens of L-000845704 on BMD and biochemical markers of bone turnover suggest that the efficacy of L-000845704 was most consistently demonstrated in the 200-mg bid group.
Treatment duration and sample size in our study were sufficient to evaluate the effect of L-000845704 on BMD in women with postmenopausal osteoporosis. Although no active comparator was included in this study, the effect on lumbar spine, total hip, and femoral neck BMD in this study at the 200-mg bid dose was similar to that seen in studies in similar populations with 35 mg alendronate (28) and risedronate dosed once weekly (29) and tended to be less than that seen with 70 mg alendronate dosed weekly (30, 31).
All L-000845704 treatment regimens were generally well tolerated. Only seven of 227 patients discontinued the study because of clinical adverse events; four (1.7%) were on active treatment, and three were on placebo. Of those patients on active treatment, one patient discontinued the study because of hot flashes, insomnia, and night sweats, and one each discontinued because of appetite decrease, headache, and arthralgia. All except arthralgia were judged to be related to study treatment and reversed after discontinuation of treatment. Nonserious adverse events with increased incidences in the L-000845704 treatment group were limited to headache and combined incidences of dermatitis, pruritis, rash, and urticaria. The relationship of these adverse events to L-000845704 and dose regimen would need to be assessed in future studies.
In conclusion, the antiresorptive effect of the Vß3 integrin antagonist L-000845704 translated into significant increases in BMD of the lumbar spine. Furthermore, the 200-mg bid dose regimen of L-000845704 produced greater effects at the cortical-rich femoral neck hip site than the 400-mg qd dose regimen when given in divided doses bid. These data suggest that Vß3 integrin antagonists are promising potential agents for the treatment and prevention of postmenopausal osteoporosis.
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Acknowledgments |
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Bone marker measurements were performed in a specialized central laboratory (Synarc, Molecular Markers, Lyon, France; Director, Dr. P. Garnero).
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Footnotes |
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First Published Online February 1, 2005
Abbreviations: BCE, Bone collagen equivalent; bid, twice daily; BMD, bone mineral density; BSAP, bone-specific alkaline phosphatase; CTx, type I collagen C-telopeptides; CV, coefficient of variation; NTx, N-telopeptide cross-links; qd, once daily.
Received October 29, 2004.
Accepted January 26, 2005.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Vß3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. J Clin Invest 99:2284–2292[Medline]
Vß3 (the vitronectin receptor). Drug Discov Today 5:397–408[CrossRef][Medline]
Vß3 antagonists. Part 5: identification of potent RGD mimetics incorporating 2-aryl ß amino acids as aspartic acid replacements. Bioorg Med Chem Lett 12:3483–3486[Medline]
Vß3 antagonists. Part 6: design and synthesis of Vß3 antagonists containing a pyridone or pyrazinone central scaffold. Bioorg Med Chem Lett 13:1809–1812[Medline]
Vß3 antagonists. 8. In vitro and in vivo evaluation of a potent Vß3 antagonist for the prevention and treatment of osteoporosis. J Med Chem 46:4790–4798[Medline]
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