`
`Clinical Review Section
`
`Enrollment Criteria:
`
`For study 20000204: The study population consisted ofpatients with parathyroid carcinoma or
`intractable primary hyperparathyroidism and serum calcium of > 12.5 mg/dl.
`
`For study 990120: The study population consisted ofpatients with primary hyperparathyroidism
`and with an iPTH concentration of > 45 pg/mL and serum calcium concentration > 10.3 mg/dL
`and S 12.5 mg/dL.
`'
`
`COMMENT: lntractable primary hyperparathyroidism was not clearly defined in study
`20000204. The degree of primary hyperparathyroidism in study 990120 was not clearly
`defined or discussed. The criteria for enrollment did not include failed or contraindicated
`
`surgery although several patients appeared to fall into the former category. The patients
`by inclusion had milder hypercalcemia than those defined as having intractable primary
`HPT in study 20000204.
`
`Study Medication and Dose Titration: All medications were administered orally, with a meal
`0 or shortlythereafier, BID at 12-hours intervals. In study 20000204 all patient started on
`cinacalcet 30 mg BID for Weeks 1-2 and doses were titrated every 2 weeks 50 mg BID, 70 mg
`BID, 90 mg BID, 70 mg 3 times daily (TID), 90 mg TID, 70 mg 4 times daily (QID), and 90 mg
`QID. Serum calcium levels were checked every 8 weeks in the maintenance phase, additional
`increases in dose could be made if serum calcium had increased and the patient was not at the
`maximum study dose. In study 990120 all patients randomized to cin'acalcet started on 30 mg
`BID for Weeks 1-4 and doses were titrated sequentially (weeks 4 and 8) to 40,'or.50 mg, BID.
`Serum calcium levels were checked every 4 weeks during the maintenance phase.
`
`Dose Titration:
`
`For all studies, a patient’s dose was NOT increased if any of the following criteria applied: The
`highest dose of study medication was reached.
`
`,
`
`The subject was experiencing symptoms of hypocalcemia.
`0 The subject was experiencing an adverse event that precluded a doseincrease.
`
`Study 20000204:
`0 The serum calcium was < 10.0 mg/dL
`
`Study 990120:
`0 The serum calcium was < 8.4 mg/dL (2.1 mmol/L)
`
`Treatment of Hypocalcemia: For all studies, if a patient experienced symptoms of hypocalcemia
`and/or a serum calcium < 8.0 mg/dL the study medication was held until symptoms resolved and
`or the serum calcium concentration was 2 8.4. Study medication was then to resume at the next
`lower dose. If the patient was receiving 30 mg BID or placebo, the patient was to have been
`withdrawn from the study.‘
`
`Page 35
`
`

`

`
`
`Clinical Review Section
`
`Withdrawal criteria: Any patient had the right to withdraw from any of these studies at any
`time and for, any reason. Patients could be withdrawn from the study in the event of severe
`hypercalcemia ( 2 12.5 mg/dL) or parathyroidectomy in study 990120; or, protocol violation or '
`noncompliance, adverse event or unacceptable toxicity in either study. Patients continued to be
`enrolled into study 20000203 at the time of submission. The open-label continuation phase of
`study 990120 (study 20000159) was ongoing at the time of submission.
`
`Primary Efficacy Endpoint
`
`Study 20000204:
`
`0 The primary endpoint’for evaluation of cinacalcet clinical effects was the proportion of
`subjects experiencing a reduction of serum calcium by 2 1 mg/dL at the end of the titration
`phase.
`
`Study 990120:
`
`0 The primary endpoint of this study was the proportion of subjects with the mean of the
`maintenance phase serum calcium measurements 5 10.3 mg/dL and with a meandecrease
`of at least 0.5 mg/dL.
`
`Secondary Efficacy Endpoints
`
`Study 20000204:
`
`'
`
`0 The proportion of subjects experiencing a reduction of serum calcium concentration to S
`10.3 mg/dL at the end of titration phase
`I
`0 Absolute concentrations, changes from baseline, and percentage changes from baseline in
`sermn calcium, plasma iPTH, and serum NTx and BALP
`0 The safety and tolerability of cinacalcet as assessed by the incidence, severity, and
`seriousness of adverse events, changes in clinically relevant laboratory tests, and physical
`examination
`Changes in PRO scale scores and summary scores
`The pharmacokinetic profile of cinacalcet (based on plasma cinacalcet concentrations)
`
`’
`
`Study 990120:
`
`0 The safety and tolerability of cinacalcet as measured by incidence of adverse events,
`significant changes in vital signs, electrOCardiograms (ECGs), physical and ophthalmologic
`examinations, and significant changes from baseline in serum chemistry, hematology,
`coagulation, urinary calcium/creatinine ratio, and urinalysis values.
`0 The maintenance phase mean for serum calcium was evaluated by the following: change
`from baseline, percent change from baseline, and the proportion of subjects maintaining a
`12-week maintenance phase mean reduction of serum calcium from baseline of at least 0.5
`mg/dL.
`. o The maintenance phase mean for plasma iPTH was evaluated by the following: change
`from baseline, percent change from baseline, the proportion with baseline > 65 pg/mL who
`decrease to S 65 pg/mL, and the proportion of all subjects with iPTH S 65 pg/mL.
`
`Page 36
`
`

`

`
`
`, Clinical Review Section
`
`0 The proportion of all subjects with maintenance phase mean serum calcium 5 10.3 mg/dL
`and maintenance phase mean iPTH S 65 pg/dL.
`'
`o The change from baseline and percent change from baseline in maintenance phase mean for
`the following variables: serum BALP, serum 1,25(OH)2D3, serum NTx, serum
`phosphorus, urinary calcium/cre'atinine ratio, urinary DPD/creatinine ratio, and urinary '
`NTx/creatinine ratio.
`
`0 The percent change from baseline in BMD at weeks 24 and 52 as assessed by DXA scans
`of proximal femur (total femur and femoral neck), lumbar spine (Ll-L4), forearm (ultra
`distal radius and 1/3 radius), and total body.
`7
`e The pharmacokinetic profile of cinacalcet as determined with population-based methods:
`correlations between the pharmacokinctic parameters (area-under the- plasma-
`concentration time curve from 0 to infinity [AUC(0-inf)]), minimum plasma cinacalcet
`concentrations [Cmin], and maximum plasma cinacalcet concentrations [Cmax]), and the
`clinical measurements of iPTH and serum calcium were computed.
`4
`0 The proportions of subjects completing part or all of the QOLSAQ at baseline, end of
`titration phase (week 12), end of maintenance phase (week 24), week 36, and end of
`follow-up phase (week 52).
`_
`o The internal consistency reliability, discriminant validity, criterion validity, and
`responsiveness of the Medical Outcomes Short Form-36 (SF-36), Brief Symptom Inventory
`(B81), and Visual Analogue Scale (VAS).
`o The change in patient HRQOL between week 24 and‘baseline (exploratory).
`o The total HRQOL as measured by area-under—the—quality-of-life time curve from baseline
`to the end-of-study (AUC_QOL) (exploratory)
`'
`
`. W
`Statistical Analyses: For study 20000204, .
`. _4_. .1_.
`
`Results
`
`Patient Disposition: The disposition of patients is provided in the below table.
`
`Page 37
`
`

`

`
`
`E
`i
`
`.
`Primary HPT
`
`completed
`ongoing
`Maintenance Phase
`
`CO‘
`
`discontinued
`
`l
`
`billia—
`
`completed
`ongoing
`Deaths '
`
`
` Intractable
`.
`Parathyroid
`Primary
`.
`Carcinoma
`I
`HPT
`
`Placebo
`Treatment
`Cinacalcet
`Cinacalcet
`
`
`Enrolled
`
`
`No treatment
`
`
`Titration Phase
`
`
`4
`discontinued
`
`
`
`
`
`
`Treatment
`
`Number Enrolled
`
`Age (years)
`Sex
`
`
`20000204
`990120
`
`
`Parathyrmd
`Intractable
`Primary HPT
`
`
`Carcinoma
`Primary HPT
`Cinacalcet
`Cinacalcet
`Placebo
`
`
`
`
`10
`
`47.5 2!: 15.6
`
`1
`
`
`i
`6
`i
`4
`
`
`
`
`male
`female
`Race
`Caucasian
`I
`10
`
`Black
`l
`0
`
`other
`I
`0
`
`Baseline Labs
`
`serum calcium (mg/dL)
`14.74 i 1.81
`
`
`*Values reported in means :E SD
`
`COMMENT: The ranges in age,‘gender, and baseline labs are consistent with the
`differences in the presentation of the different diseases: younger age with highest serum)
`calcium and l——--" in the patients with parathyroid carcinoma, and older age in the
`_C-.——-——-'-%‘ with lower levels of serum calcium and —’ in the milder disease (study
`9901216.
`
`EfiicacyOutcomes
`
`Study 20000204: Because of the small number of patients in this study a description of the data
`are provided, no statistical analysis is presented.
`
`Page 38
`
`iE E
`
`

`

`
`
`Clinical Review Section
`
`Ten patients with parathyroid carcinoma entered the titration phase with a range of exposure to
`cinacalcet of 2 to 16 weeks. The range of change for serum calcium from baseline to the last
`measurement in the titration phase was -7.5 to 2.7 mg/dL. Three patients entered the
`maintenance phase with a range of exposure of 16 to 48 weeks. The range of change from
`baseline to the last measurement in the maintenance phase was -74 to 0.9 mg/dL.. The final
`dosage reported-range from 70 mg BID to 90 mg QID.
`
`
`
`I;
`
`/’_———————_—,——-
`
`m j
`
`Study 990120: The primary efficacy outcome assessment w
`
`Medical Officer Conclusions: These studies demonstrate that cinacalcet is effective in reducing
`serum calcium levels in patients with I:'m 3
`parathyroid carcinoma; however, normalization of serum calcium was not maintained in these
`patients. The clinical significance of these changes in serum calcium in terms of morbidity or
`mortality is unknown.
`‘.Cm
`
`Page 39
`
`

`

`
`
`Clinical Review Rentinn
`
`
`
`
`VI.C.4. Exploratory Bio-intact PTH Analyses .
`
`'
`
`The concentration of iPTH is an important measure for effective clinical management of patients
`with chronic renal failure. The Nichols first generation immunoradiometn'c iPTH assay is the
`current gold-standard assay for PTH measurement. PTH levels were used for titration of study
`medication and for efficacy analyses in all of the cinacalcet studies. Recent investigations have
`shown that the Nichols assay detects a large PTH fiaginent (amino acids 7-84) in addition to the
`full—length molecule (1—84). A new second generation PTH assay, the bio-intact PTH (biPTH)
`assay, which detects only the full-length molecule, is now available. Published data indicate that
`PTH values obtained with the iPTH and biPTH assays are highly correlated, and that a
`conversion factor can help interpret the biPTH assay results . Amgen collected duplicate
`plasma samples in two studies (20000172 and 20010141) for measurement of PTH
`concentrations using both assays to allow comparison of results obtained.
`
`As shown in the table below, biPTH values are approximately 50% lower than valuesobtained
`with the iPTH assay. Reductions in mean PTH concentrations in the cinacalcet group compared
`. with the placebo group were demonstrated using both the iPTH and biPTH assay.
`
`
`—_fi-—E—-
`_—mmm-
`651 28
`326 14
`636 24
`
`
`Mean SElpercentage change in PTH“
`23% (3.6%)
`10% Q.8%)
`1
`-38% 3.1%
`'
`>30%reductioninmean PTH” n%
`10%
`11%
`1
`56%
`
`"
`4%
`45%
`
`
`
`a During the efficacy-assessment phase (LVCF)
`b The target biPTH and iPTH concentrations were = I40 pg/mL and = 250 pg/ml., respectively
`
`
`
`
`
`61%
`41%
`
`As (shown in the figure below, baseline iPTH and biPTH values were highly correlated (r = 0.89 _
`' for cinacalcet and r = 0.95 for placebo). Similar correlations were present during the efficacy:
`assessment phase (I = 0.96 for cinacalcet and r = 0.95 for placebo). Treatment with cinacalcet did
`not change the relationship between iPTH and biPTH, as evidenced by similar regression
`'
`equations for both treatment groups at baseline andduring the efficacy-assessment phase.
`
`2 Goodman, et a1. Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal osteodystrophy.
`Kidney International, Vol. 6} (2003), pp. 1—11
`
`Page 40
`
`

`

`
`
`Clinical Review Section
`
`“”0 “4.1.mwumwmvmamww
`
`
`
`, mmw ,
`"I Plasebo WW
`ammnmmm moo-mwmpvmm
`
`Similar results were achieved in the 52-week study 20010141, as shown below. Values were
`again highly correlated at baseline (r = 0.83 for placebo and r = 0 84 for cinacalcet) and at the
`
`end ofthestudy 0‘— 0.99 forplacebo and r= 0.83 for cinacalcet)
`
`
`
`Placebo1(N~16)
`iPTH
`biPTH
`
`672.2 L879)
`1011 198.9
`
`1 383.Q_(_.6)
`686.2 155.3
`
`676.4 73.8
`360.7 74.8
`
`3944.81522
`208.2 49.7
`
`915g_27.3)_
`48.8 (4,5,5)
`Meang%changgian
`43%
`6.3% jf'
`sggcts achieving target3111*" 11%)
`6.3% ,
`.
`i
`3 30% reduction in mean PTH“
`'At Week 52. For subjects with no week 52 value, the last post—baseline value was used
`"The target biPTH and iPTH concentrations were <=138 pg/ml and <=250 pg/ml, respectively
`
`'
`
`5.8)
`-514;
`53.1%
`78.1 %
`
`-48.3 7.8
`62.5%
`71.9 %
`
`Medical Officer Conclusions: The bio-intact PTH (biPTH) assay is highly correlated with the
`current gold standard iPTH assay and may offer a more accurate assessment of intact PTH levels
`in patients with secondary HPT associated with renal disease. PTH levels remain an integral part
`of the clinical management of osteodystrophy associated with renal disease. Current National
`Kidney Foundation clinical guidelines and recommendations for titration of therapeutic
`interventions rely upon the iPTH assay. Data presented here-are consistent with published
`literature, showing that biPTH values are approximately 50% of the values derived from the
`' iPTH assays. Based on these data, one could postulate that target biPTH ranges used to initiate
`therapy would be 75 — 150 pg/mL. However, until the relationship between iPTH levels,
`measured by the biPTH assay, and renal bone disease, assessed by biopsy, is defined, the
`management of renal osteodystrophy will likely remain guided by iPTH levels measured with the
`iPTH assay.
`
`’
`
`‘
`
`VI.C.5. Bone Histomorphometry
`
`Three studies assessing the safety and efficacy of cinacalcet use in end stage renal disease
`obtained bone histomorphometry data. Study 990740 was a phase-2 study that obtained bone
`
`Page 41
`
`

`

`
`Clinical Review Section
`
`biopsy on a total of 6 subjects (2 placebo, 4 cinacalcet). Study 990126 was a subset of study
`990101 that obtained bone biopsies on a total of 9 subjects (3 placebo, 6 cinacalcet). This review
`focuses on study 20010141 which obtained bone biopsy on 35 subjects (13 placebo, 22
`cinacalcet). Please see the Appendix for the complete reviews of the individual trials.
`
`Study 20010141:
`
`Objectives: The primary objective of this study was to evaluate the effects of cinacalcet
`compared with placebo on renal osteodystrophy as assessed by bone histomorphometry.
`
`Study Design: This was a randomized, double-blind, placebo-controlled, multicenter, l2-month
`study. Subjects with end stage renal disease on hemodialysis were randomized in a 2:1 ratio to
`cinacalcet or placebo. The study consisted of 3 phases: a 30-day screening phase, a 24-week
`dose-titration phase (visits every other week), and a 28-week maintenance phase (visits every 4
`weeks). No baseline stratification factorswere used.
`
`Study Methods: The following bone turnover parameters were assessed: activation frequency,
`BFR, fibrosis surface (percentage of bone surface covered with fibrous tissue), woven osteoid
`surface (percentage of the bone surface that is woven bone), osteoblast number, and osteoclast
`number. In addition, preservation of bone mineralization also was assessedin each bone biopsy
`specimen by measuring the following parameters: mineralization lag time (the time interval
`between collagen matrix synthesis by osteoblasts and the onset of mineralization), osteoid
`thickness, and osteoid surface. Aluminum surface also was evaluated. A blinded assessment of
`
`each subject’s bone biopsy sample was performed by E:
`‘
`3 to
`determine whether the subject had mild or severe hyperparathyroid bone disease, osteomalacia,
`adynamic bone disease, or mixed uremic osteodystrophy (osteomalacia and hyperparathyroid
`bone disease).
`
`Study Medication: All medications were administered orally with a starting dose of 30 mg
`cinacalcet or placebo. During the titration phase, the dose of cinacalcet or placebo could be
`increased to the next dose level at the Week 4, 8, 12, 16, and 20 study visits. Study drug dose
`changes also were permitted during the maintenance phase. Possible sequential doses during the
`study were 30, 50,70, 90, 120 and 180 mg cinacalcet or placebo. Changes in phosphate binders ‘
`were permitted throughout the study. Changesinvitamin D therapy were only permitted based '
`on protocol-specified guidelines.
`
`Dose Titration: Subjects could be titrated up to the next sequential dose level of study drug at
`Week 4, 8, 12, 16, and 20 study visits. If the central laboratory iPTH value was > 200 pg/mL, the
`subject’s dose of study medication was increased, provided that the serum calcium was _>_ 7.8
`mg/dL and the subject was not experiencing an adverse event that precluded a dose increase.
`During the maintenance phase, a subject’s dose could be adjusted according to the same titration
`rules.
`
`Primary Efficacy Endpoint: A comparison between treatment groups using end-of—study values
`and changes from baseline to the end of the study for the following bone histomorphometry '
`
`Page 42
`
`

`

`
`Clinical Review Section
`
`parameters: activation frequency, BFR/BS, fibrosis surface/BS, woven osteoid surface/BS,
`osteoblast number, and osteoclast number.
`
`Withdrawal criteria: Any subject had the right to withdraw from the study at any time and for
`any reason. Subjects could be withdrawn from the study. in the event of pregnancy,
`parathyroide‘ctomy, or kidney transplant. Withdrawn patients were not replaced.
`'
`
`Statistical Analyses: Activation frequency was considered to have the most variability of all
`bone turnover parameters examined and was used to calculate sample size. A difference of
`0.4/year between the treatment groups in activation frequency was considered clinically
`significant; standard deviation (SD) for this parameter was estimated as 0.5/year. A sample size
`of 45 subjects (2:1 randomization) would provide a 95% confidence interval (CI) of (0.08, 0.72)
`for the difference between placebo and cinacalcet in activation frequency.
`
`Results
`
`Patient Disposition: As shown in the table below, 32 subjects were randomized to receive
`cinacalcet and 16 subjects were randomized to receive placebo Twenty (63%) subjects in the
`cinacalcet group and 13 (81%) subjectsin the placebo group completed the study
`001.0133
`'
`“ ‘ ”a
`
` Enrolled
`
`
`
`
`
`No treatment
`At least one dose
`Withdrew - Total
`Withdrew- AE
`Deaths
`Withdrew- Other
`
`Completed Titration Phase (Weeks 1--24)
`Com nleted Stu
`
`_16 (>1_(_)_0)_ -_
`
`Protocol Violations: Five (10%) subjects had eligibility deviations in this study. The most
`common eligibility deviation was a change in vitamin D sterol dose in the 30 days before study
`day 1. Compliance with studydrug was > 80% and similarin both the cinacalcet and placebo
`, groups.
`
`Demographics: Baseline subject demographics were well balanced across the treatment grbups
`(see table below). The mean age was 51 years. Overall, 60% of subjects were male and 65% of
`subjects were Black. Fifteen percent of enrolled subjects were 2 65 years of age. Baseline iPTH,
`biPTH, serum N-Tx, BALP, Ca x P, serum calcium, and serum phosphorus concentrations were
`‘ similar between treatment groups. Baseline serum N-Tx concentrations were markedly elevated
`(normal range: 5.4 to 24.2 nmol bone collagen equivalents [BCE]) because N-Tx is excreted by
`the kidney and therefore, accumulates in renal failure. Baseline vitamin D and phosphate binder
`use were similar between treatment groups, except for slightly less phosphate binder use in the
`placebo group.
`
`Page 43
`
`

`

`
`
`Clinical Review Section
`
`31 (97)
`
`16 (%)
`52.1 :1: 12.8
`
`32 (%)
`50.3 d: 11.9
`
`11 (69)
`5(31)
`
`5 (31)
`11 (69)
`0 (0)
`
`18 (56)
`- 14 (44)
`
`8 (25)
`20 (63)
`4 (13)
`
`672.2 :1: 351.4
`
`383.0 :1: 230.4
`9.80 :l: 0.91
`6.41 :l: 1.11
`
`676.4 :1: 417.6
`394.8 :1: 295.0
`9.86 :1: 0.79
`6.71 :t 1.40
`
`9 (56)
`7 (44)
`
`13 (81)
`
`16 (50)
`16 (50)
`
`Age (yrs.)
`Sex
`Male .
`Female
`Race
`Caucasian
`Black
`Other
`Baseline Labs
`
`iPTH (pg/mL)
`biP‘l‘H (pymL)
`Serum Ca (mg/dL)
`Serum Phos (mg/dL)
`Baseline Vitamin D Use
`Yes
`No
`
`I: aseline Phosphate Binder Use
`Yes
`N0
`
`Primary Efficacy Outcomes
`
`Bone Histomorphometry Parameters
`
`Nineteen subjects in the cinacalcet group and 13 subjects in the placebo group had both baseline
`and end-of—study bone biopsies. -No subject in either treatment group had aluminum present on
`their bone surface. Results are outlined in the table below (normal levels for each parameter in
`parentheses)
`
`
`
`%Chati_e SE
`Fibrosis Surface / Bone Surface (0%)
`Mean SE
`9.12 1.20
`6.99 1.73
`4.69 1.13
`'
`
`
`- 15.38 28.71
`
` 3.94 (3.46)
`
`Mean Chan_e SE)
`
`Mean Change (SE)
`% Chan eSE
`
`'
`
`6.64 (29.91)
`
`_ 8.26 (29.91)
`
`Page 44
`
`

`

`
`
`13.06 48.74
`%Chane SE
`Osteoclast Number 0.1 — 53 / 100mm
`
`52.82 48.74
`
`
`
`61.46 8.6
`-60.88 19.36
`
`1 100.95 20.0
`E
`-63.79 19.36
`
`
`
`Osteoblast Number 1—200/ 100mm)_
`.
`Mean 31:
`530.29 125.7 575.00 91.02
`
`
`
`
`
`
`
`
`
`
`
`
`
`'
`Mineralizin_ La_ Time <50 da s
`
`MeanQB)
`33.03 (7.05)
`I 46.15 17.15):I::2_9.Z4 (5.82)
`49.07 {1533)
`
`Mean Change @)
`11.24 M
`1M1 7.6.4)~
`
`% Chane SE)
`84.97 (3_6§4)
`‘I
`1335519308
`Osteoid Thickness 4 — 20
`
`Mean LSE)
`11.88 £0.92); 1 1.98920)
`1
`11.11_(0.77)
`11.42 (133)
`
`
`
`0.1_l__(l.52)___
`_,;_2-
`0.30LL33)
`Mean Chan_e SE
`.__.
`
`% ChangelSE)
`1002.03.61)
`WI
`__
`1243:1199»)
`
`
`Osteoid Surface/Bone Surface 1 — 39%
`.
`*
`
`27.96 (3le 1 37.96 (4.31)
`31059.05) J. 27.22 (3.71 )
`Mean ISL
`
`
`
`-
`_.
`10.91.1589. ;
`-_ - 3.33 9.20)“
`-
`Meagan e SE ,
` 81.14 42.82
`- 3.55 12.78
`% Chane SE
`
`
`
`
`
`
`
`
`
`Activation Frequency: Baseline activation frequencies were 1.54/year in the cinacalcet group and
`1.4l/year in the plaCebo group. Both groups had a mean reduction in activation frequency
`(0.51/year in the cinacalcet group and 0.12/year in the placebo group)
`
`Figure 9-8. Mean (95% Confidence intervals) Activation firequency at Baseline
`and End of Study (Anaiysis Set)
`
`
`
`913%"
`
`MM
`
`W
`
`““151?"
`Winnie;
`
`Bone Formation Rate: Baseline BFR values were 6.6 (0.90) mm3/cm2/year in the cinacalcet
`group and 6.51 mm3/cm2/year in the placebo group. The mean end-of-study BFR was 4.53
`mm3/cm2/year in the cinacalcet group and 5.33 mm3/cm2/year in the placebo group, representing
`a mean reduction from baseline of 1.88 mm3/cm2/year in the cinacalcet group and 1.04
`mms/cmz/year in the placebo group.
`
`Page 45
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`

`
`
`Clinical Review Section
`
`Fibrosis. Surface: Baseline fibrosis surface values were 4.69% and 6.99% for subjects in the
`cinacalcet and placebo groups, respectively. The mean fibrosis surface at the end of the study
`was 2.70% in the cinacalcet group and 9.12% in the placebo group, representing a reduction
`fiom baseline by a mean of 2.0% in the cinacalcet group compared with an increase 2.1% in the
`placebo.
`‘
`
`Woven Osteoid Surface: Baseline woven osteoid surface 'values were 4.64% and 7.23% for
`
`subjects in the cinacalcet and placebo groups, respectively. No trend or difference between
`treatment groups was observed for woven osteoid surface at the end of the study: The mean
`woven osteoid surface at the end of the study was 8.58% in the cinacalcet group and 11.04% in
`the placebo group, representing a increase from baseline by a mean of 3.9% in the cinacalcet
`group and 3.8% in the placebo group.
`'
`
`3
`
`Osteoblast Number: Baseline number of osteoblasts was 486/100 mm and 580/100 mm for
`
`subjects in the cinacalcet and placebo groups, respectively. The mean number of osteoblasts at
`end of the study was 284/100 mm in the cinacalcet group and 575/100 mm in the placebo group,
`representing a reduction from baseline by a mean of 202/100 mm in the cinacalcet group
`compared With 5/ 100 mm in the placebo group.
`
`Osteoclast Number: The mean (SE) baseline number of osteoclasts was 101/100 mm and
`122/100 mm for subjects in the cinacalcet and placebo groups, respectively. The mean number
`of osteoclasts at the end of the study was 37/100 mm in the cinacalcet group and 61/100 mm in
`the placebo group; the number of osteoclasts decreased by approximately 60/100 mm in both
`treatment groups at the end of the study.
`
`Bone Mineralization Parameters: A mineralization defect (osteomalacia) is characterized by
`elevations in MLT, osteoid thickness, and osteoid surface. At the end of the study, mean values
`for mineralization parameters in both treatment groups were within the normal range" (MLT [< 50
`days], osteoid thickness [4-20 um], and osteoid surface [1-39%]).
`
`Renal Osteodystrophy Class: Classification of renal osteodystrophy occurred at baseline and end
`of study. At baseline, 16 (84%) of 19 subjects in the einacalcet group and 11 (85%) of 13
`subjects in the placebo group had mild hyperparathyroid bone disease. Of the subjects with mild
`hyperparathyroid bone disease at baseline, 12 subjects in the cinacalcet group and 7 subjects in
`the placebo group did not change their classification during the study. Two subjects in the
`cinacalcet group and 4 subjects in the placebo ‘group developed mixed uremic osteodystrophy
`(defined as a normal or elevated activation frequency/BFR in the presence of an elevated MLT).
`
`.
`
`Adynamic bone disease was defined as low bone turnover (activation frequency/BFR below the
`lower limit of normal), with normal levels of osteoid thickness and osteoid surface. One subject
`in the placebo group had adynamic bone disease at baseline and mixed uremic osteodystrophy at
`the end of the study. In the cinacalcet group, one subject had adynamic bone disease at baseline
`and at the end of the study. This subject did exhibit some improvement in bone turnover
`parameters (increases toward normal in activation frequency and BFR, which led to a reduction
`
`Page 46
`
`

`

`
`Clinical Review Section
`/
`
`in MLT). Three subjects in the cinacalcet group developed adynamic bone disease. In two of
`these subjects, there was over suppression of iPTH. In one subject, iPTH was < 100 pg/mL at 9
`time points during the study while in the second subject iPTH was < 100 pg/mL at 5 time points
`during the study. The third subject who developed adynamic bone disease had a baseline iPTH of
`1502 pg/mL with a lowest level of 547 pg/mL. This, subject was immobilized during a 3-week
`hospitalization which may have contributed to his bone disease as biomechanical forces are
`known to play a role in the stimulation of osteoblasts. In all subjects bone alkaline phosphatase
`values fell too. In these 3 subjects, decreased fibrosis surface was observed, and numbers of
`osteoblasts and osteoclasts were within the normal range at the end of the study.
`
`_ U
`
`Adynamic Bone Disease
`OsteomalaCia
`
`Medical Officer Conclusions: Bone biopsy with double tetracycline labeling is the most
`accurate way to determine the presence and type of bone disease associated with chronic kidney
`disease. In this study at baseline, the most predominant type of bone abnormality was mild
`hyperparathyroid bone disease in approximately 85% of enrolled subjects. One subject (5%
`cinacalcet, 8% placebo) in each treatment group had adynamic bone disease at baseline.
`Improvements in mean bone turnover parameters were observed in the cinacalcet—treated group
`as reflected by reductions in activation frequency, BFR, fibrosis surface, and the number of
`osteoblasts and osteoclasts. The placebo groupalso showed some improvement in bone
`turnover, reflected by reductions in activation frequency, BFR, and osteoclast numbers. No -
`trend or difference between treatment groups was observed for woven osteoid surface. Mean
`values for mineralization parameters (MLT, osteoid thickness, and osteoid surface) were normal
`in both treatment groups at baseline and end of study. However, four (22%) subjects in the
`cinacalcet group and 5 (42%) subjects in the placebo group had an elevated MLT (> 50 days) at.
`the end of the study, compared with 3 (17%)and l (8%), respectively, at baseline.
`
`.
`
`In the cinacalcet group, over the l-year study duration, decreases from baseline in iPTH, biPTH,
`BALP, and serum N-Tx concentrations were observed. A consequence of over-suppression of
`PTHis the occurrence of adynamic bone disease, as seen with several subjects1n this study. The
`current the NKF-K/DOQI guidelines3 recommend iPTH target ranges of 150— 300 pg/mL. In
`this trial, as observedin other cinacalcet studies1n ESRD subjects with secondary HPT, mean
`Ca x P, serum calcium, and serum phosphorus concentrations were reduced in the cinacalcet
`group compared with the placebo group.
`
`3 K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease1n Chronic Kidney Disease. Am J Kidney
`Dis 2003, Oct 42 (4) Supplement 3.
`
`Page 47
`
`
`
`=13 m-
`nit n %
`End ofStud
`End ofStud
`— Baseline
`o 0 m5-
`0 0
`Normal Bone Histolo_
`o o
`
`arath oid Bone Disease
`ll1851‘
`7(54)
`13 68
`{
`Severe Hypgrparathyroid Bone DiseaseML“ 1 (8_)
`_L
`Mixed Uremic Osteod stro.h
`
`l _(5)
`
`s l
`
`

`

`
`
`Clinical Review Section
`
`VI.D. Efficacy Conclusions
`Secondary HPTIS a common and serious sequelae of chronic renal disease. Current therapies for
`the HPT associated with renal disease includes phosphate binders (calcium and non-calcium
`5 based) and vitamin D. Calcium-based phosphate binder and vitamin D use is limited by their
`' propensity to increase serum calcium and phosphorus.
`
`In subjects with secondary HPT associated with end stage renal disease, cinacalcet is more
`effective than placebo in reducing plasma levels of iPTH. This effect was demonstrated in a
`population of patients of which many were being treated with standard phosphate-binder and
`vitamin D therapies. Therapy was more effective in those subjects with less severe HPT, with a
`12% response rate in subjects with iPTH at baseline of greater than 800 pg/mL, compared with a
`61% response rate in subjects with a baseline iPTH 300-500 pg/ml. A higher proportion of
`subjects1n both groups achieved a 30% reduction1n baseline iPTH levels (62%m the cinacalcet-
`treated group vs. 11%in the placebo-treated group).
`
`.
`In subjects with secondary HPT associated with Stage 3 or 4 chronic kidney disease (pre-
`
`dialysis), C
`_ _
`
`
`
`Q
`
`In renal disease, the Ca x P ion product has been associated with a variety of adverse sequelae,
`including increased risk of cardiac,'visceral, and vascular calcifications. In subjects with
`secondary HPT associated with end stage renal disease, the mean Ca )1 P value at baseline was 61
`(mg/dL)2 for subjectsin both treatment groups. Over the course of the studies, the mean Ca x P
`value was reduced by 14%m the cinacalcet group, compared with a 02.1%mcrease in the placebo
`group. The proposed NKF-K/DOQI target for Ca x P18 < 55 (mg/dL)2. The mean Ca x P value
`during the efficacy-assessment phase was 51 (mg/dL)2 for the cinacalcet group vs. 59 (mg/dL)2
`for the placebo group.
`
`One of the main effects of cinacalcet treatment is lowering of serum calcium levels. In subjects.
`with secondary HPT associated with end stage renal disease, the mean serum calcium
`concentration was reduced by 7 % in the cinacalcet group, compared with a < 1% increase in the
`placebo group.
`
`VII.
`
`Integrated Review of Safety
`
`COMMENT: Because of the differences1n patients with secondary hyperparathyroidism
`and primary hyperparathyroidism, bothin the mechanism of the disease and protocol
`designs, an integrated review of safety for these 2 groups in inappropriate. Because only
`one study Was performed in patients with parathyroid carcinoma an integrated review is
`not necessary. Please see the appendix for a complete review of study 20000204.
`
`Page 48
`
`

`

`
`
`Clinical Review Section
`
`VII.A. Description of Patient Exposure
`As shown in the following table, the average number of weeks patients were treated with doses
`of 30 mg — 120 mg was approximately 7 weeks. Subjects were exposed to 180 mg of cinacalcet
`for nearly 13 weeks on average.
`
`mg
`Masses)
`
`60mg
`(N=590)
`
`Curacaloet
`90mg
`120mg
`tN=472)
`(N=363
`
`14114
`
`4568
`
`*
`
`590
`3877
`
`472
`3426
`
`.
`
`363
`2443
`
`130mg
`N=272
`
`AnyDose
`N8856
`
`272
`3484
`
`656
`17501
`
`26.7(05)
`
`362w];
`
`1mm)
`
`8.8(02)
`
`”(0.3)
`
`5.1(03)
`
`128(06)
`
`VILB. Methods and Specific Findings of Safety Review
`
`The focus of this safety review is the pooled data from the core studies 20000172, 20000183, and
`20000188, 6-month, placebo-controlled phase 3 trials of“patients with ESRD receiving dialysis.
`Analyses of data from study 20010240, a double-blind, six-month extension of patients who
`completed studies 20000172, 20000183, and 20000188, is also examined. A total of 1136
`patients were enrolled into the core 6-month studies (1126 received at least one dose of study
`medication), with 266 of them rolling over into the 6-month extension study.
`
`A total of 115 subjects with pre-dialysis CKD were enrolled into two studies, 20000236 and
`20010239, and treated with cinacalcet or placebo for 16 and 18 weeks, respectively. In general,
`this review will only discuss the safety data from these two studies if they differ significantly
`from the findings from ESRD studies 172, 183, and 188.
`
`’VII.B.1.Deaths: All deaths that occurred on-study and within 30 days of discontinuation,
`withdrawal, or completion of the study were recorded.
`
`Core 6-Month Studies
`
`A total of 15 (3%) subjects randomized to receive placebo and 14 (2%) randomized to cinacalcet
`d