H o t T o p i c s
`
`i n T r a n s l a t i o n a l E n d o c r i n o l o g y — E n d o c r i n e R e s e a r c h
`
`J C E M O N L I N E
`
`Pharmacological Inhibition of Myostatin and Changes
`in Lean Body Mass and Lower Extremity Muscle Size
`in Patients Receiving Androgen Deprivation Therapy
`for Prostate Cancer
`
`Desmond Padhi, Celestia S. Higano, Neal D. Shore, Paul Sieber, Erik Rasmussen,
`and Matthew R. Smith
`
`Department of Medical Sciences (D.P.) and Biostatistics (E.R.), Amgen Inc (D.P.), Thousand Oaks,
`California 91320; Department of Medicine (C.S.H.), University of Washington, and Fred Hutchinson
`Cancer Research Center, Seattle, Washington 98109; Carolina Urologic Research Center, (N.D.S.),
`Myrtle Beach, South Carolina 29579; Urological Associates of Lancaster (P.S.), Lancaster, Pennsylvania
`17604; and Massachusetts General Hospital Cancer Center (M.R.S.), Boston, Massachusetts 02114
`
`Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is
`associated with muscle loss and increased body fat, and currently available therapies have limited
`efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly atten-
`uated muscle loss and decreased fat accumulation in orchiectomized mice.
`
`Objective: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle
`efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer.
`
`Methods: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of
`AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass
`(LBM) as assessed by dual x-ray absorptiometry was prespecified.
`
`Results: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%),
`fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure
`increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg
`vs the placebo groups on day 29 by 2.2% (⫾0.8% SE, P ⫽ 0.008); in exploratory fat mass analysis,
`a decrease of ⫺2.5% (⫾1.0% SE, P ⫽ 0.021) was observed. Pharmacodynamic changes in muscle and
`fat were maintained at follow-up, 1 month after day 29.
`
`Conclusion: Four weekly sc doses of AMG 745 were well tolerated and were associated with
`increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer.
`Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.
`(J Clin Endocrinol Metab 99: E1967–E1975, 2014)
`
`Myostatin, a member of the TGF-␤ superfamily, is
`
`expressed almost exclusively in skeletal muscle
`and acts as a negative regulator of muscle growth (1, 2).
`Myostatin inhibits myoblast proliferation by causing the
`up-regulation of cyclin-dependent kinase inhibitors (eg,
`p21), which in turn results in the down-regulation of cy-
`clin-dependent kinase-2 and in G0/G1 cell cycle arrest. In
`
`addition, myostatin negatively regulates myoblast differ-
`entiation through decreased expression of MyoD (3).
`Observations from mice and cattle with loss-of-func-
`tion mutations in the myostatin gene (2, 4 –9), as well as a
`recent case report describing a human child with loss-of-
`function mutations affecting both myostatin alleles (10),
`provide strong evidence that myostatin plays an important
`
`ISSN Print 0021-972X ISSN Online 1945-7197
`Printed in U.S.A.
`Copyright © 2014 by the Endocrine Society
`Received January 29, 2014. Accepted June 2, 2014.
`First Published Online June 27, 2014
`
`Abbreviations: ADT, androgen deprivation therapy; AMG 745/Mu-S murine surrogate of
`antimyostatin peptibody; BMI, body mass index; CT, computed tomography; DXA, dual
`x-ray absorptiometry; EOS, end of study; LDL, low-density lipoprotein; PK, pharmacoki-
`netics; 1-RM, maximum weight lifted for one repetition; SPPB, Short Physical Performance
`Battery.
`
`doi: 10.1210/jc.2014-1271
`
`J Clin Endocrinol Metab, October 2014, 99(10):E1967–E1975
`
`jcem.endojournals.org
`
`E1967
`
`Amgen Exhibit 2026
`Apotex Inc. et al. v. Amgen Inc. et al., IPR2016-01542
`Page 1
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`

`

`E1968
`
`Padhi et al
`
`Myostatin Inhibition and Changes in Lean Body Mass
`
`J Clin Endocrinol Metab, October 2014, 99(10):E1967–E1975
`
`role in regulating perinatal skeletal muscle development.
`In adult mouse muscle, myostatin appears to inhibit the
`activation of regenerative satellite cells (11). Of particular
`interest, by a muscle-specific conditional myostatin gene
`inactivation approach, general muscle hypertrophy can be
`induced postnatally in mice, to an extent similar to that in
`constitutively myostatin-deficient knockout mice (12).
`Skeletal muscle wasting is prevalent and clinically impact-
`ful in a variety of conditions and disease states, such as an-
`drogen deprivation and protein energy wasting due to end
`stage renal disease, cancer cachexia, chronic obstructive pul-
`monary disease, cardiac cachexia, HIV/AIDS, steroid in-
`duced myopathy, disuse atrophy, sarcopenia of the elderly,
`and postoperative immobilization (13–17). Skeletal muscle
`wasting results in reduced muscle strength, physical and psy-
`chological disability, and impaired quality of life (13, 17).
`Current treatment options used for muscle wasting in set-
`tings of illness or immobility, including appetite stimulants,
`nutritional support, corticosteroids, anabolic steroids, and
`GH, are limited in their utility and can be associated with
`significant systemic side effects (13, 16).
`Antimyostatin peptibody (AMG 745) is a novel anti-
`myostatin peptibody. Structurally, it is a fusion protein
`with a human Fc at the N terminus and a myostatin-neu-
`tralizing bioactive peptide at the C terminus. AMG 745
`and/or AMG 745/Mu-S, a murine surrogate of AMG 745,
`have been tested in a variety of mouse models, including
`normal mice, orchiectomized mice (androgen deficiency
`model), five sixths nephrectomized mice (chronic kidney
`disease model) (18), Colon-26 tumor-bearing mice (can-
`cer cachexia model), immune-deficient mice, Duchenne
`muscular dystrophy model of mice, and hind limb-sus-
`pended mice (disuse atrophy model). Effects of AMG 745
`and/or AMG 745/Mu-S in these models have included
`increased body weight gain, increased or improved main-
`tenance of skeletal muscle mass, and increased strength
`compared with control mice. In the orchiectomized mouse
`model of hypogonadism that features muscle loss and fat
`accumulation related to androgen deficiency, AMG 745/
`Mu-S markedly attenuated loss of lean body mass and
`accumulation of fat, as assessed by nuclear magnetic res-
`onance imaging; in vivo myostatin inhibition may enhance
`skeletal muscle growth via an androgen-independent
`mechanism. AMG 745 is being evaluated for the treatment
`of conditions and disease states with a significant compo-
`nent of muscle wasting, in which a selective increase in, or
`maintenance of, lean body mass and skeletal muscle mass
`might be clinically beneficial.
`Prostate cancer is the most common malignancy in men
`and the second most common cause of cancer-related
`death in men in the United States (19). Androgen depri-
`vation therapy (ADT) by the administration of GnRH
`
`agonists, CYP17 inhibitors, and androgen receptor antag-
`onists are the mainstay of treatment for metastatic pros-
`tate cancer (20 –22), resulting in improved overall survival
`in several clinical settings. Chronic treatment with a
`GnRH agonist for biochemical relapse is the most frequent
`clinical indication for ADT (20).
`ADT has a variety of adverse effects including weight
`gain, increased fat mass, decreased lean body mass, and
`fatigue (23). In prospective clinical studies, ADT is asso-
`ciated with decreased lean body mass and muscle size and
`increased fat mass (24 –27). Decreased muscle mass and
`strength may contribute to the overall fatigue and de-
`creased quality of life in men with prostate cancer. Treat-
`ment-related changes in body composition may also con-
`tribute to ADT decreased insulin sensitivity and greater
`risk for diabetes associated with ADT (28 –30).
`To investigate the potential of myostatin inhibition in
`humans, we conducted a study of AMG 745 in prostate
`cancer patients undergoing ADT. The goals of the study
`were to evaluate the safety, tolerability, pharmacokinetics
`(PK), and pharmacodynamics of AMG 745.
`
`Subjects and Methods
`
`Study subjects
`Eligible subjects were men required to have a documented
`history of prostate cancer presenting to academic and private
`urological oncology practices in cities including Seattle, Wash-
`ington; Boston, Massachusetts; Myrtle Beach, South Carolina;
`and Lancaster, Pennsylvania. Subjects had no documented dis-
`tant metastasis at the time of enrollment; received ADT for at
`least 6 months as a primary, adjuvant, or salvage treatment for
`prostate cancer prior to enrollment; if ADT was being adminis-
`tered intermittently, the serum total T level was less than 50
`ng/dL at screening; a stable prostate-specific antigen as deter-
`mined by the investigator; no history of primary muscle disease,
`myopathy, or neuropathy; weight 137 kg (300 lb) or less; and
`height 78 inches or less; Eastern Cooperative Oncology Group
`performance status of 0 at screening; no clinically significant
`elevated creatine phosphokinase; glomerular filtration rate
`greater than 40 mL/min; aspartate aminotransferase or alanine
`aminotransferase less than 2.5 times the upper limit of normal.
`Study subjects provided written informed consent, and the pro-
`tocol was approved by the local institutional review boards, with
`study conduct in accordance with the Food and Drug Adminis-
`tration and International Committee on Harmonization good
`clinical practice guidelines.
`
`Study design
`This was a multicenter, randomized, double-blind, placebo-
`controlled, ascending-multiple-dose study in men with prostate
`cancer receiving ADT. The trial was designed to evaluate the
`safety, tolerability, PK, and pharmacodynamics of AMG 745.
`Subcutaneous doses of 0.3 mg/kg, 1 mg/kg, and 3 mg/kg were
`each administered once weekly for 4 weeks and were evaluated
`in sequential cohorts. Eight subjects, randomized in a 3:1 allo-
`
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`doi: 10.1210/jc.2014-1271
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`jcem.endojournals.org
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`E1969
`
`cation ratio to AMG 745 or placebo, were enrolled in the 0.3-
`mg/kg dose cohort and in the 1-mg/kg dose cohort. To evaluate
`the safety, tolerability, PK, and the effect of 4-week doses on lean
`body mass. Thirty-eight subjects, randomized (1:1 allocation ra-
`tio) to AMG 745 or placebo, were enrolled in the 3-mg/kg dose
`cohort.
`Dose escalation decisions were made after the last subject
`enrolled in the preceding cohort had been followed up for at least
`14 days after receiving the third dose of the investigational prod-
`uct and were based on a blinded review of all available adverse
`events, vital signs, and laboratory data.
`To reduce the risk of bias, medications that might have an
`effect on body composition were prohibited at any time during
`the study including corticosteroids, anabolic steroids, human
`GH, or dietary creatine supplements. Participants were also re-
`quired to maintain a constant level of physical activity through-
`out the course of the study.
`Amgen Inc designed the study in collaboration with the au-
`thors. C.S.H. and M.R.S. (Amgen Inc) conducted the statistical
`analysis of the data. All authors had access to the data, made
`contributions to the manuscript, and vouch for its accuracy and
`completeness.
`
`Study procedures
`The following procedures were performed prestudy and pe-
`riodically during the study for all cohorts: physical examination,
`vital signs, electrocardiogram (ECG), hematology, chemistry,
`urinalysis, anti-AMG 745 antibody screen using a validated sur-
`face plasmon resonance (Biacore International AB)-based bio-
`sensor immunoassay that could detect anti-AMG 745 and anti-
`AMG 745 peptide antibodies equivalent in binding to 800 ng/mL
`or greater of rabbit polyclonal antibody in neat human serum
`(Amgen; data on file), and blood sample draws for PK.
`For the 3-mg/kg cohort, dual x-ray absorptiometry (DXA)
`and lower extremity computed tomography (CT) scans were
`conducted before the first dose and on day 29 (end of study) and
`at the 1-month follow-up visit. All DXA scans were performed
`on a Hologic or GE Lunar scanner using standardized techniques
`for each instrument provided in a central imaging charter. Daily
`phantom L1-L4 bone mineral density was required to be within
`1.5% of the baseline scan to permit the densitometer subject scan
`to proceed. The same scanner was to be used for all visits for an
`individual subject. DXA scans were sent to the central reading
`facility (Image Reading Center, New York, New York) for
`blinded review and analysis. All CT scans were performed on the
`same scanner using the same slice thickness on the same side (left
`or right) at all visits for an individual subject. Muscle cross-
`sectional area was measured by the blinded central reviewer (Im-
`age Reading Center), based on an axial image acquired at the
`midpoint between the iliac crest and the distal end of the femur.
`Lower extremity strength was assessed on the basis of max-
`imum weight lifted for one repetition (1-RM) using a knee ex-
`tension machine and Short Physical Performance Battery (SPPB)
`including an assessment of standing balance, timed walk test,
`and five repetitions of chair stand was assessed.
`Adverse events and concomitant medications were recorded
`at all study visits.
`
`Statistics
`Eight subjects, randomized in a 3:1 allocation ratio to AMG
`745 or placebo, were enrolled in the 0.3 mg/kg dose cohort and
`
`in the 1 mg/kg dose cohort to characterize safety, pharmacoki-
`netics (PK) and pharmacodynamics following multiple-dose ad-
`ministration. In order to characterize safety/ PK and additionally
`to investigate the AMG 745 effect on whole body composition,
`38 subjects were randomized in a 1:1 allocation ratio to AMG
`745 or placebo, and subsequently enrolled in the 3 mg/kg dose
`cohort. A between treatment group difference of 1.5% was es-
`timated for the secondary end point, percentage change in lean
`body mass from baseline to week 5 [SD 2.1; (24)] and provided
`80% power for a one-sided test at the 10% significance level.
`However, all reported P values in this manuscript are two sided,
`using an ANOVA to compare the two groups (placebo vs AMG
`745 3 mg/kg).
`The pharmacokinetic analyses included all treated subjects
`for whom the pharmacokinetic parameters could be estimated
`using noncompartmental methods. Summary statistics by dose
`cohort were generated for each pharmacokinetic parameter.
`Graphs of serum AMG 745 concentration-time profiles for the
`individual subjects and the means for each dose were prepared.
`For safety analyses, all subjects who received AMG 745 or
`placebo were included, and the placebo-treated subjects from all
`cohorts were combined to form a composite placebo group.
`
`Results
`
`The baseline characteristics of the study population are sum-
`marized in Table 1. Median age (SD) was 74 (6.8) years for
`subjects who received AMG 745 3 mg/kg and 73.5 (6.7)
`years for subjects who received placebo, and 48% of the men
`were 75 years of age or older in each of these groups. Char-
`acteristics that might affect body composition including
`baseline height, weight, body mass index (BMI), lean body
`mass, and fat mass were generally well balanced by the ran-
`domization. No deviations for prohibited medications that
`might impact body composition, such as corticosteroids, an-
`abolic steroids, human GH, and dietary creatine supple-
`ments, were reported. No subjects were reported to have
`altered their exercise activity.
`
`Safety
`A total of 54 subjects received the investigational prod-
`uct (31 with AMG 745, 23 with placebo), and all of these
`subjects completed the study. Fifty-three of the 54 subjects
`who received the investigational product received all four
`planned doses.
`Four adverse events (Table 2) were reported for more than
`two subjects: diarrhea (AMG 745, 4 of 31, 13%; placebo, 2
`of 23, 9%); fatigue (AMG 745, 4 of 31, 13%; placebo, 1 of
`23, 4%); contusion [all AMG 745 (3 of 31, 10%)]; and in-
`jection site bruising (AMG 745, 2 of 31, 6%; placebo, 1 of
`23, 4%). No relationship was apparent between the subject
`incidence of adverse events and the dose of AMG 745.
`All adverse events were reported as mild or moderate in
`severity and nonserious except for one serious adverse
`event of syncope that occurred 19 days (approximately 5
`
`Page 3
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`

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`E1970
`
`Padhi et al
`
`Myostatin Inhibition and Changes in Lean Body Mass
`
`J Clin Endocrinol Metab, October 2014, 99(10):E1967–E1975
`
`Table 1. Baseline Characteristics
`
`Placebo
`All Placebo
`Subjects
`(n ⴝ 23)
`
`73.4
`6.7
`
`11 (48)
`
`176.1
`5.2
`
`88.6
`11.4
`
`28.6
`3.8
`
`53.4
`6.3
`
`30.6
`8.3
`
`AMG 745
`
`0.3 mg/kg sc,
`4-Week Dosing
`(n ⴝ 6)
`
`1.0 mg/kg sc,
`4-Week Dosing
`(n ⴝ 6)
`
`3.0 mg/kg sc,
`4-Week Dosing
`(n ⴝ 19)
`
`All AMG 745
`Subjects
`(n ⴝ 31)
`
`Total
`All Subjects
`(n ⴝ 54)
`
`71.8
`7.5
`
`3 (50)
`
`174.7
`4.9
`
`87.0
`11.8
`
`28.4
`2.5
`
`52.1
`7.2
`
`30.6
`6.5
`
`73.2
`8.6
`
`4 (67)
`
`175.9
`7.0
`
`92.7
`13.0
`
`30.2
`5.5
`
`56.6
`5.6
`
`31.9
`10.1
`
`73.5
`6.4
`
`8 (42)
`
`177.2
`8.1
`
`88.2
`15.5
`
`28.0
`4.3
`
`52.9
`8.2
`
`31.1
`8.9
`
`73.1
`6.8
`
`15 (48)
`
`176.5
`7.2
`
`88.8
`14.1
`
`28.5
`4.2
`
`53.4
`7.5
`
`31.2
`8.5
`
`73.3
`6.7
`
`26 (48)
`
`176.3
`6.4
`
`88.7
`12.9
`
`28.6
`4.0
`
`53.4
`6.9
`
`30.9
`8.3
`
`1154.2
`168.2
`
`1147.6
`79.2
`
`1240.2
`119.7
`
`1182.65
`205.83
`
`1187.0
`172.5
`
`1173.0
`169.8
`
`Age, y
`Mean
`SD
`Age ⱖ 75 y
`n, %
`Height, cm
`Mean
`SD
`Weight, kg
`Mean
`SD
`BMI, kg/m2
`Mean
`SD
`Baseline
`whole-body
`lean mass, kg
`Mean
`SD
`Baseline
`whole-body
`fat, kg
`Mean
`SD
`Baseline muscle
`cross-sectional
`area, cm2
`Mean
`SD
`
`half-lives) after the last dose of AMG 745 3 mg/kg. This
`subject had a prior history of first-degree atrioventricular
`block with syncopal episodes, and the investigator con-
`sidered the event to be unrelated to treatment.
`Treatment-related adverse events were reported for
`seven of the 31 subjects (23%) who received AMG 745 at
`any dose, and for one of the 23 subjects (4%) who received
`placebo. No treatment-related adverse events were re-
`ported for more than one subject.
`For one subject, who was receiving AMG 745 in the
`3-mg/kg dose cohort, investigational product administration
`
`was discontinued after the second dose because of adverse
`events of erythema of the abdomen, reported as moderate in
`severity (CTCAE [Common Terminology Criteria for Ad-
`verse Events] v3.0, grade 2) decreasing to mild (CTCAE v3.0,
`grade 1), and related to the investigational product.
`In general, clinically important effects of AMG 745 on
`laboratory variables, ECGs, vital signs, T levels, or pros-
`tate-specific antigen levels were not evident. An adverse
`event of ECG change [severity moderate (CTCAE v3.0
`grade 2)] was reported in association with the serious ad-
`verse event of syncope noted above.
`
`Table 2.
`
`Incidence of Treatment-Emergent Adverse Events Reported by Three or More Subjects
`
`Placebo
`All Placebo
`Subjects, n, %
`(n ⴝ 23)
`1 (4)
`1 (4)
`
`AMG 745
`
`0.3 mg/kg sc
`4-Week Dosing,
`n, % (n ⴝ 6)
`0 (0)
`1 (17)
`
`1.0 mg/kg sc
`4-Week Dosing,
`n, % (n ⴝ 6)
`1 (17)
`0 (0)
`
`3.0 mg/kg sc
`4-Week Dosing,
`n, % (n ⴝ 19)
`3 (16)
`1 (5)
`
`All AMG 745
`Subjects,
`n, % (n ⴝ 31)
`4 (13)
`2 (6)
`
`Total
`All Subjects,
`n, % (n ⴝ 54)
`5 (9)
`3 (6)
`
`2 (9)
`0 (0)
`
`0 (0)
`0 (0)
`
`0 (0)
`0 (0)
`
`4 (21)
`3 (16)
`
`4 (13)
`3 (10)
`
`6 (11)
`3 (6)
`
`Preferred
`Term
`Fatigue
`Injection site
`bruising
`Diarrhea
`Contusion
`
`Page 4
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`jcem.endojournals.org
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`E1971
`
`based biosensor immunoassays for anti-AMG 745 (whole
`molecule) binding antibodies. Samples from two subjects
`gave positive results in one or more of the immunoassays:
`The incidence of anti-AMG 745 (whole molecule) bind-
`ing antibodies among subjects who received AMG 745
`was 1 of 31 (3%). Anti-AMG 745 antibody positivity did
`not appear to affect AMG 745 exposure in subjects.
`Neutralizing antibodies could not be assessed due to
`technical issues with the bioassay.
`
`Pharmacodynamics
`Analyses of the pharmacodynamic effects were limited
`to the 3-mg/kg dose cohort, and the study was designed to
`have 80% power to detect a statistically significant be-
`tween-treatment group difference in percentage change in
`lean body mass. Two-sided P values are reported. The
`DXA analysis of lean body mass was the prespecified pro-
`tocol efficacy end point, and additional prespecified ex-
`ploratory analyses of fat body mass (DXA) and muscle
`cross-sectional area (CT) were also performed.
`
`Lean body mass
`On analysis of DXA data assessed by the blinded cen-
`tral reader, a significant percentage change (least squares
`mean) in lean body mass from baseline to end of study
`(EOS) (d 29) was observed: 1.5% for the AMG 745 sub-
`jects and ⫺0.7% for the placebo subjects, with the be-
`tween-group difference (least squares mean ⫾ SE) being
`2.2% ⫾ 0.8% (P ⫽ .008). This effect was maintained at
`the time of the follow-up visit 1 month after day 29: per-
`centage change in lean body mass was 1.9% for the AMG
`745 subjects and 0.2% for the placebo subjects, and the
`between-group difference was 1.7% ⫾ 0.7% (P ⫽ .023)
`(Table 4 and Figure 2A).
`
`Figure 1.
`In vivo clearance of AMG 745 in men on ADT for prostate
`cancer, who received three different doses of AMG 745. Mean (⫾SD)
`serum AMG 745 concentrations are plotted after treatment with 0.3
`mg/kg sc once weekly, 1 mg/kg sc once weekly, or 3 mg/kg sc once
`weekly. Blood samples were obtained for the measurement of AMG
`745 PK at the indicated times. a, Reduced sample size is attributed to
`an excluded value with sample collection time deviation greater than
`20%; b, reduced sample sizes are attributed to exclusion of an outlier
`subject and a missing sample; c, reduced sample sizes are attributed to
`sample collections that were later removed by protocol amendment,
`an excluded value with sample collection time deviation greater than
`20%, and/or excluded values due to incomplete dosing.
`
`Pharmacokinetics
`AMG 745 exhibited dose-linear pharmacokinetics af-
`ter the 4-week sc dose administrations over the dose range
`of 0.3–3.0 mg/kg. The median time to maximum serum
`concentrations (tmax) ranged from approximately 24 to 72
`hours after the first dose and approximately 24 to 48 hours
`after the fourth dose; the mean apparent serum clearance
`(CL/F) estimated after the fourth dose ranged from 1.89 to
`2.29 mL/h 䡠 kg (Figure 1 and Table 3).
`
`Anti-AMG 745 antibody results
`For the 54 subjects who completed the study, serum
`samples were analyzed by surface plasmon resonance-
`
`Percentage change in fat body mass
`A change in fat body mass from baseline to EOS (d 29)
`was also observed in the DXA data: ⫺1.7% for the AMG
`
`Table 3. Mean (SD) Steady-State Pharmacokinetic Parameters After Four Weekly sc Doses of AMG 745 at 0.3, 1,
`or 3 mg/kg in Men With Prostate Cancer Receiving Androgen Deprivation Therapy
`
`Parameter
`tmax, h
`Cmax, ␮g/mL
`AUC0-␶, ␮g/h 䡠 mLc
`CL/F, mL/h 䡠 kg
`AR
`
`0.3 mg/kg (n ⴝ 6)
`47.8 (8.00 –121)
`1.34 (0.511)
`175 (69.5)
`1.96 (0.754)
`2.55 (0.734)
`
`1 mg/kg (n ⴝ 4 –5)a
`24.0 (23.7–119)
`4.17 (1.42)
`556 (152)
`1.89 (0.427)
`1.92 (0.380)
`
`3 mg/kg (n ⴝ 8 –9)b
`24.0 (23.8 –72.0)
`10.8 (3.68)
`1380 (356)
`2.29 (0.570)
`1.78 (0.189)
`
`Abbreviations: AR, accumulation ratio calculated as AUC0-␶, week 4/AUC0-␶, week 1; AUC0-␶, area under the serum concentration-time curve over one
`dosing interval; CL/F, apparent serum clearance calculated as dose/AUC0-␶, week 4; Cmax, maximum observed concentration; tmax, time of Cmax. All
`parameters are presented as mean (SD) to three significant figures, except tmax, which is presented as median (range).
`a Reduced sample sizes because one subject was excluded as an outlier and week 1 AUC0-␶ and AR were not calculated for another subject due to
`a missing 168-hour sample on week 1.
`b Reduced sample sizes because PK parameters were not estimated for some subjects due to limited data or incomplete dosing.
`c AUC0-␶ is calculated using the last observed concentration of the 7-day dosing interval. AUC was not reported if the last sample was not collected
`7 days after the most recent dose.
`
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`Padhi et al
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`Myostatin Inhibition and Changes in Lean Body Mass
`
`J Clin Endocrinol Metab, October 2014, 99(10):E1967–E1975
`
`Table 4.
`Muscle Size
`
`Percentage Change From Baseline for Lean Body Mass, Whole-Body Fat, and Lower-Extremity
`
`Lean Body Massa
`
`Whole-Body Fatb,c
`
`Lower-extremity
`Muscle Sized
`
`1.5% (0.5%)
`⫺0.7% (0.5%)
`2.2% (0.8%)
`.008
`
`1.9% (0.5%)
`0.2% (0.5%)
`1.7% (0.7%)
`.023
`
`⫺1.7% (0.7%)
`0.8% (0.7%)
`⫺2.5% (1.0%)
`.021
`
`⫺1.5% (1.1%)
`0.5% (1.1%)
`⫺2.0% (1.5%)
`.183
`
`1.2% (0.7%)
`⫺0.7% (0.7%)
`1.8% (1.0%)
`.065
`
`2.7% (0.7%)
`⫺0.1% (0.7%)
`2.8% (1.0%)
`.007
`
`End point: percentage change from baseline to day 29e
`AMG 745
`Placebo
`Between-group difference
`P value
`End point: percentage change from baseline to
`follow-up day 58e
`AMG 745
`Placebo
`Between-group difference
`P value
`
`a As assessed by DXA scan.
`b Prespecified exploratory analysis.
`c As assessed by CT scan.
`d Values are least squares mean (SE), except P values.
`e Lean body mass (minus the head), as assessed by DXA scan.
`
`745 subjects and 0.8% for the placebo subjects, with a
`between-group difference of ⫺2.5% ⫾ 1.0% (P ⫽ .021).
`Change in fat body mass from baseline to follow-up visit
`(1 mo after d 29) was observed during follow-up: ⫺1.5%
`for the AMG 745 subjects and 0.5% for the placebo sub-
`jects, with a between-group difference of ⫺2.0% ⫾ 1.5%
`(P ⫽ .183) (Table 4 and Figure 2B).
`
`Lower extremity muscle size
`The lower-extremity muscle size percentage change
`from baseline to EOS (d 29) was 1.2% for the AMG 745
`subjects and ⫺0.7% for the placebo subjects, with a be-
`tween-group difference of 1.8% ⫾ 1.0% (P ⫽ .065). At
`follow-up (1 month after d 29), the lower-extremity mus-
`cle size percentage change from baseline was 2.7% for the
`AMG 745 subjects and ⫺0.1% for the placebo subjects,
`with a between-group difference of 2.8% ⫾ 1.0% (P ⫽
`.007) (Table 4 and Figure 2C).
`
`Body weight and body mass index
`Consistent with the observed increases in lean body
`mass and concomitant decreases in fat mass, there were no
`overall effects on either body weight or BMI.
`
`Physical functioning (SPPB) and lower extremity
`strength (1-RM knee extension)
`There were no overall effects for either SPPB or 1-RM
`knee extension.
`
`Biochemical parameters
`There were no apparent differences between treatment
`groups (AMG 745 vs placebo) with respect to fasting
`plasma glucose, insulin, cholesterol, low-density lipopro-
`
`tein (LDL), high-density lipoprotein, or trigylercides at
`baseline or day 29. T measured at baseline, day 8, and day
`29 was within the castrate range (⬍50 ng/dL) expected for
`ADT; the maximum postbaseline median T was 8.0 ng/dL
`(range 8.0 –30.0 ng/dL) in the placebo and also 8.0 ng/dL
`(range 8.0 –29.0 ng/dL) in the AMG 745 3 mg/kg group.
`
`Discussion
`
`This randomized, double-blind, placebo-controlled, mul-
`tiple-dose study in men with prostate cancer receiving
`ADT demonstrated that inhibition of myostatin with
`AMG 745 administered sc once weekly for 4 weeks as high
`as 3.0 mg/kg, was generally well tolerated. Most of the
`adverse events observed were reported at similar rates in
`the placebo and treatment groups, and antidrug antibody
`formation was less frequent than typically reported for
`biologicals (31). Additional trials enrolling larger num-
`bers of subjects for a longer period will be required to
`confirm the safety profile of AMG 745.
`The results also provided the first clinical evidence of
`the pharmacodynamic effects of myostatin inhibition: du-
`rable increases in lean body mass, decreased fat mass, and
`increased lower extremity muscle size after only four
`weekly doses.
`AMG 745 is a novel antimyostatin peptibody. A pep-
`tibody represents the component peptide (the pepti) and
`the Fc portion of an immunoglobulin in an overall struc-
`ture that resembles an antibody (the body), and other pep-
`tibodies are under development or have been approved
`(32). In peptibodies, the peptide warhead interacts with
`
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`doi: 10.1210/jc.2014-1271
`
`jcem.endojournals.org
`
`E1973
`
`N= 19 19
`
`18 19
`
`B
`
`N= 19 19 18 19
`
`P=0.021
`
`P=0.183
`
`EOS
`
`FUP
`
`Visit
`3.0 mg/kg SC AMG 745
`Placebo
`
`20%
`16%
`12%
`6%
`2%
`-2%
`-6%
`-10%
`
`% of Baseline
`
`P=0.008
`
`P=0.023
`
`EOS
`
`FUP
`
`Visit
`3.0 mg/kg SC AMG 745
`Placebo
`
`C
`
`12%
`10%
`8%
`6%
`4%
`2%
`0
`-2%
`-4%
`-6%
`
`% of Baseline
`
`N= 18 19 18 19
`
`P=0.065
`
`P=0.007
`
`EOS
`
`FUP
`
`8%
`
`6%
`
`4%
`
`2%
`
`0
`
`-2%
`
`-4%
`
`-6%
`
`A
`
`% of Baseline
`
`Visit
`3.0 mg/kg SC AMG 745
`Placebo
`Figure 2. A, Lean body mass and percentage change from baseline in total lean body mass determined by blinded central review of DXA data in
`men with prostate cancer on ADT receiving AMG 745 or placebo. The bottom and top of the boxes represent the first and third quartiles, and the
`horizontal band inside the box indicates the median value. The ends of the whiskers indicate the minimum and maximum data in the range of
`observations. Black color represents the placebo group, whereas red color indicates the AMG 745-treated group. EOS represents day 29, and FUP
`represents 1 month after day 29. P values are based on ANOVA comparison of the placebo, and AMG 745 3 mg/kg treatment groups are
`indicated. B, body fat and ercentage change from baseline in total body fat determined by blinded central review of DXA data in men with
`prostate cancer on ADT receiving AMG 745 or placebo. The bottom and top of the boxes represent the first and third quartiles, and the horizontal
`band inside the box indicates the median value. The ends of the whiskers indicate the minimum and maximum data in the range of observations.
`Black color represents the placebo group, whereas the red color indicates the AMG 745-treated group. EOS represents day 29, and FUP represents
`1 month after day 29. P values are based on an ANOVA comparison of the placebo, and AMG 745 3 mg/kg treatment groups are indicated. C,
`Lower extremity muscle size and percentage change from baseline in lower extremity muscle size determined by blinded central review of CT data
`in men with prostate cancer on ADT receiving AMG 745 or placebo. The bottom and top of the boxes represent the first and third quartiles, and
`the horizontal band inside the box indicates the median value. The ends of the whiskers indicate the minimum and maximum data in the range of
`observations. Black color represents the placebo group, whereas the red color indicates the AMG 745-treated group. EOS represents day 29, and
`FUP represents 1 month after day 29. P values are based on ANOVA comparison of the placebo and AMG 745 3 mg/kg treatment groups are
`indicated. FUP, follow-up period.
`
`myostatin and inhibits signaling through its receptor. The
`second domain, the Fc component, stabilizes the complex
`in the body, allows for endothelial cell trancytosis, and
`extends residence time into a therapeutically useful range.
`In addition to AMG 745, other potential approaches to
`inhibit myostatin are under investigation. For example a
`myostatin neutralizing monocolonal antibody (MYO-
`029) was evaluated in adult subjects with muscular dys-
`trophy (33). MYO-029 had good safety and tolerability
`
`with the exception of cutaneous hypersensitivity at higher
`doses, and there was a trend reported in a subset of subjects
`toward increased muscle size; however, there was no im-
`provement in exploratory muscle strength or function end
`points. Targeting the receptor for myostatin with anti-
`activin type 2B receptor antibody was studied in sporadic
`inclusion body myostitis, with an abstract reporting an
`acceptable safety profile, increased muscle mass, and lon-
`ger 6-minute-walk test distances (34). A myostatin ligand
`
`Page 7
`
`

`

`E1974
`
`Padhi et al
`
`Myostatin Inhibition and Changes in Lean Body Mass
`
`J Clin Endocrinol Metab, October 2014, 99(10):E1967–E1975
`
`trap (ACE-031), comprised of an activin type 2B recep-
`tor-Fc fusion, was studied in healthy volunteers, and this
`agent was well tolerated except for injection site reactions,
`producing increased lean body mass (3.3%, P ⫽ .03) as
`assessed by DXA (35).
`Despite the improvement in lower-extremity muscle
`mass, our study showed no apparent effect of AMG 745
`on physical functioning or lower extremity strength as
`assessed by the SPPB and one-repetition knee extension,
`respectively. Because preclinical pharmacological inhibi-
`tion of the myostatin signaling pathway not only promotes
`muscle growth but also enhances muscle grip strength or
`contractility (36 – 40) and because early clinical reports of
`myostatin inhibitor antiactivin type 2B receptor antibody
`have observed increased physical function (34), it is likely
`that the lack of effect on physical function and muscle
`strength in our study reflects the relatively short duration
`of treatment, the high functional status of subjects at base-
`line, or the physical function tests selected. Additional tri-
`als of longer duration,