-‘ u~ -_ _\
`
`~
`
`‘1page(s)‘ have been i
`E
`’ - removed because it
`_
`' g contains trade secret
`and/or confidential
`A information thatIS not
`disClosable. ,
`
`

`

` ' CLINICAL REVIEW
`
`
`
`Clinical Review Section
`
`
`
`
`
`Safety
`
`Disposition: As shown in the table below, 90% of placebo-treated subjects and 97% of
`cinacalcetetreated subjects experienced adverse events during the study.
`
`I“ Cinaccalet
`n (%)
`
`Subjects evaluable for safety
`
`Deaths on study
`Severe adverse events ‘
`
`~
`
`A
`
`I“
`
`
`
`3 (10)
`Serious adverse events
`2 6
`Withdrawal_due to adverse events
`28 90
`All adverse events
`' Includes severe, lifethreatening and fatal adverse events
`
`i—
`
`1(3)
`
`'
`
`' Vi
`
`.
`
`‘ Exposure: A total of 61 (30 cinacalcet, 31 placebo) received study medication (see table below).
`The mean (range) number of days of exposure to study drug was 106 (19 to 116) days for the
`cinacalcet group and 105 (22, 115) days for the placebo group. The mean (range) cumulative
`dose of cmacalcet was 7293.7 (
`\ mg.
`
`
`
`Cinacalcet Placebo
`
`
`Number ofda srof exosure
`
`
`
`Mean
`,
`-,
`105.4
`
`
`SD
`__ M‘
`19._9
`
`
`Min, Max 22,115
`
`
` Cumulative dose of cinacalcet (mnng
`
`
`
`
`____ 7293.7
`7 32.7.2.9
`. m
`
`Mean
`
`Page 163
`
`

`

`
`
`
`Placebo
` C1nacalcet
`
`Dose com' liance %
`‘
`
`
`
`“—
`
`
`
`7 9
`3.5
`.
`
`
`1 m‘.‘
`Min Max
`Dosing Compliance (%) = 100 x (number of days dose taken / number of days prescnbed).
`
`Mean
`SD
`
`Deaths: No deaths occurred during the study.
`
`Serious Adverse Events: Serious adverse events were reported by 3 (10%) placebo-treated .
`subjects and one (3%) cinacalcet—treated subjects. None of the serious adverse events occurred in
`more than one subject.
`
`
`
`
`
`
`
`“’71 (3)
`
`.0 (9)...
`0(0)
`
`1
`
`l (3)
`
`Adverse Events Leading to Withdrawal: A total of 4 subjects withdrew from the study due to
`. adverse events [2 (7%) from the cinacalcet group and 2 (6%) from the placebo group] In the
`cinacalcet group, both withdrawals were due to hypocalcemiain one subject who had a baseline
`calcium of 10.2, and an initial low calcium of 7.3 mg/dL with symptoms at week 5, on the 70mg
`dose. He continued to have calcium levels from 7.3 — 8.2 mg/dL despite supplementation and
`ultimately withdrew from the study at week 15. A second subject, receiving cinacalcet withdrew
`from the study due to nausea and vomiting while on the 50mg dose. In the placebo group, one
`subject withdrew due to nausea and anorexia and a second subject withdrew due to a
`cerebrovascular event.
`Adverse Events; Ninety-seven percent of subjects in the cinacalcet group and 90%vof subjects in
`the placebo group reported at least 1 adverse event during the study (see table below). Ninety-
`seven percent of subjects in the cinacalcet group and 90% of subjects in the placebo group
`reported at least 1 adverse event during the study. The most common adverse events reported by
`cinacalcet-treated subjects were (cinacalcet, placebo) hypocalcemia (47%, 0%), nausea (27%,
`2,3%) myalgia (23%, 23%), diarrhea (20%, 16%) and vomiting (17%, 1.0%)
`
`‘ i!1.,
`3.1
`as
`
`
`
`
`
`
`
`Subjects Receiving Dose
`Subjects Reporting A155
`Events:
`
`Body as a whole
`
`'
`
`.
`
`31
`28 (90)
`
`12 (39)
`
`30
`29 (97)
`
`16 (53)
`
`
`
`
`
`Page 164
`
`

`

`e.
`
`g.‘ I“ .'
`
`.‘
`
`Placebo
`
`Cinacalcet
`
`‘
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-
`
`"
`
`'
`
`’
`
`I
`
`.
`
`Gastrointestinal
`18 (58)
`20 (67)
`Nervous
`13 (42)
`12 (40)
`Cardiovascular
`5 (l6)
`. 0(0)
`Myo/Endo/Pericardial
`1 (3)
`1 (3)
`Respiratory
`9 (29)
`6 (20)
`Endocrine/Metabolic
`4 7 (23)
`16 (53)
`Musculoskeletal
`12 (39)
`13 (43)
`Infectious
`-
`.
`2 (6)
`2 (7)
`Blood and Lymphatic
`1 (3)
`4 (13)
`Skin and Appendages
`6 (l9)
`5 (l7)
`Urinary Disorders
`4 (13)
`3 (10)
`Reproductive
`l (3)
`0 (0)
`Vascular Disorders
`1 (3)
`0 (0)
`Vision Disorders
`2 (6)
`2 (7)
`
`
`Hearing/ Vestibular
`l (3)
`2 (7)
`
` Ps chiatric
`l 3
`
`Adverse Events of Special Interest:
`
`Convulsjons: There were no reports of seizure activity during. the study.
`
`GI Adverse Events: Gastrointestinal adverse events are common with cinacalcet treatment.
`
`. Nausea was reported in 27% of cinacalcet-treated patients and 23% of placebo treated patients.
`Vomiting was reported in 17% of cinacalcet-treated patients and 10% of placebo-treated patients.
`Diarrhea was reported in 20% of cinacalcet-treated patients and 16% of placebo treated patients.
`Dyspepsia was reported in 4 (13%) of cinacalcet-treated subjects and 1 (4%) of placebo-treated
`subjects. There were no reports of esophagitis, gastritis or gastric ulcer.
`'
`
`Cataracts: Cataract formation associated with cinacalcet use was reported in animal studies.
`There were no reports of cataract in this trial.
`
`Laboratory: Safety laboratory assessments were performed at screening and follow-up. Shifi
`tables demonstrated no evidence of a treatment effectin hematologic and blood chemistry
`variables. Specific relevant laboratory evaluations are discussed below
`
`Serum Calcium: Mean (SE) serum calcium concentrations at baseline, were 9.5 (0.1) mg/dL and
`9.4 (0.1) mg/dL in the cinacalcet and placebo groups, respectively. At week 16, mean serum
`‘ calcium concentrations were 8.3 mg/dL in the cinacalcet group and 9.3 mg/dL in the placebo
`group. These values represent a 13% decrease from baseline in the cinacalcet group and a 2%
`decrease in the placebo group.
`
`Serum Phosphorus: The mean (SE) serum phosphorus concentrations at baseline were 4.2 (0.1)
`mg/dL inthe cinacalcet group and 4.1 (0.1) mg/dL in the placebo group. Modest increases in
`serum phosphorus occurred in the cinacalcet group, reflective of reductions in plasma iPTH
`concentrations. At week 16., the mean (SE) serum phosphorus concentrations were 4.9 (1.2)
`
`Page 165
`
`

`

`
`
`Clinical Review Section
`
`mg/dL1n the cinacalcet group and 4.3 (1.2) mg/dL1n the placebo group (normal range: 2.2 to
`5.1 mg/dL).
`
`Creatinine Clearance: The mean (SE) CrCl at baseline was 34.8 (1.6) mL/min in the cinacalcet
`group and 33.1 (1.9) mL/min in the placebo group. The mean CrCl was stable during the study
`in both treatment groups.
`
`_C____ax P: The mean (SE) Ca x P values at baseline were 39.6 (1.1) (mg/dL)2 in the cinacalcet
`group and 38.9 (1.2) (mg/dL)2 in the placebo group. Ca x P values and percentage change from
`baseline were similar between treatment groups throughout the study At week 16, the mean
`(SE) Ca x P value was 41.0 (1.4) (mg/dL)2 for the cinacalcet group and 40.0 (1.6) (mg/dL)2 for
`the placebo group. At week 16, Ca x P had increased by 5%1n the cinacalcet group and by2%
`in the placebo group.
`
`Vitamin D (1,25|OH|2D): The mean (SE) 1,25(OH)2D31 at baseline was 31 3 (3.4) pg/mL in
`the cinacalcet group and 30 l (29) pg/mL1n the placebo group. The mean 1,25(OH)2D3 levels
`were stable during the study1n both treatment groups.
`
`Bone Alkaline Phosphatase (BALP): Median baseline BALP concentrations were 16.4 and 18.6
`ng/mL in the cinacalcet and placebo groups, respectively (normal range: 2.9 to 20.1 ng/mL). At
`week 16, median BALP was 33% lower than baseline1n the cinacalcet group and 6% higher than
`baseline1n the placebo group.
`
`-
`
`Urine Calcium: Mean (range) baseline values for urine calcium excretion were below normal at
`baseline: 42.0 (4.2 to 228.6) mg/24hours in the cinacalcet group and 39.7 (4.9 to 153.4) mg24
`hours in the placebo group (normal range: 50 to 300 mg/24 hours). -At week 16, the mean 24-
`hour urine calcium values were increased from baseline in both treatment groups but remained in
`the normal range with mean values of 63.2 (10.2 to 303.9) and 49.7 (7.9 to 373.5) mg/24 hours in
`the cinacalcet and placebo groups, respectively.
`
`Urine Phosphorus: Mean baseline 24—hour urine phosphorus excretion was 753.4 (range: 320.0 to
`1244.0) mg24 hours in the cinacalcet group and 683.7 (range: 291.0 to 1038.0) mg/24 hours for
`the placebo group (normal range: 400 to 1300 mg/24 hours). At Week 16 (the end ofthe
`efficacy-assessment phase) the mean 24-hour urine phosphorus excretion was 759.4 (range:
`119.0to 3218.0) and 758.5 mg/24 hours (range. 278.0 to 1374.0) mg/24 hours1n the cinacalcet
`and placebo groups, respectively.
`
`Urine Protein: Mean (SE) 24-hour urine protein excretion at baseline was 2089 (325) mg/24
`hours in the cinacalcet group and 2060 (531) mg/24 hours in the placebo group. At week 16, the
`corresponding values were 1643 (297) mg/24 hours in the cinacalcet group and 2385 (691)
`mg/24 hours in the placebo group. The mean percentage change from baseline at week 16 was a
`decrease of 12% (with a median decrease of 30%) in the cinacalcet group and an increase of 32%
`(with a median decrease of 16%) in the placebo group.’
`
`Page 166
`
`

`

`
`
`Clinical Review Section
`
`Other Safety Tests:
`
`Vital Signs: Mean blood pressure measurements were stable throughout the study and did not
`differ between treatment groups. Any notable changes from baselinem vital signs and physical
`findings were recorded as adverse events
`
`ECGs: Investigator interpretation‘of ECGs was categorized on_ the case report form as normal; .
`abnormal; not clinically significant; and abnormal, clinically significant. The majority of
`subjects (83% in the cinacalcet group and 68% in the placebo group) had an abnormal, but not
`clinically significantly abnormal ECG at baseline. No subject in either treatment group
`developed clinically significant abnormalities during the study.
`
`Safety Conclusions: Sixty-one subjects (30 cinacalcet, 31 placebo) received study drug and
`were evaluable for safety. No subject died during the study. The overall incidence of
`serious adverse events and the incidence of adverse events were comparable between the
`cinacalcet and placebo groups. Two cinacalcet subjects and 2 placebo subjects withdrew
`due to an adverse event.
`V
`'
`
`With cinacalcet treatment, reductions in serum calcium levels were observed, 8.3 versus 9.3
`mg/dL at end of study for the cinacalcet and placebo groups, respectively. Serum calcium
`concentrations decreased 13% from baseline in the cinacalcet group and a 2% in the
`placebo group. Mean serum phosphorus concentrations increased slightly in the cinacalcet
`group but remained in the normal range. At baseline Ca x P levels were similarbetween
`treatment groups and remained stable throughout the study. Increases in 24-hour urine
`calcium were observed, however, no subjects had values above the normal range.
`Similarly, modest decreases'1n urine phosphorus excretion occurred. No changes1n GFR
`were observed'1n this study.
`
`Discussion and Conclusions: Secondary hyperparathyroidism (HPT) is a common and
`serious sequela of chronic renal disease. Approximately 75- 100% of patients with Stage 3
`or 4 CKD have evidence of renal osteodystrophy”. Treatment of secondary HPT to prevent
`renal osteodystrophy'1s one of the major goals of therapy'1n CKD patients.
`
` J
`
`The most common adverse events were hypocalcemia, nausea, myalgia, and diarrhea; these
`events were generally mild to moderate in severity and infrequently resulted in
`
`'4 Elder G. Pathophysiology and recent advances1n the management ofrenal osteodystrophy: J Bone Miner Res
`2002; 17.2094-2105.
`
`Page 167
`
`

`

` fchINICALREViEW _.
`
`Clinical Review Section
`
`discontinuation of therapy One subject withdrew due to a serum calcium < 7.5 mg/dL.
`The median dose of cinacalcet was 90mg and a higher incidence of hypocalcemia was
`observed'1n this study than1n Study 20010239, which1s reviewed below.
`Study 20010239: A RandOmized, Double-blind, Placebo-controlled Study to Assess the Safety
`and Efficacy ofa Calcimimetic Agent (AMG 073)m Subjects with Secondary
`Hypexparathyroidism of Chrbnic Renal Insufficiency
`
`[2
`“\—
`
` : J
`
`Objectives: fi '
`
`
`“w ,3
`
`,
`
`’w
`
`Study Design: :___u
`
`—___——-——-
`
`
`
`
`
`APPEARS'THIS WAY
`0“ ORIGINAL
`
`Page 168
`
`

`

`.- ‘_ -._...__»
`
`'
`
`
`
`' 7 i lpage(S) have been
`removed because it
`‘ Contains trade secret ;
`
`-
`
`and/or confidential
`information thatIS not
`disclosable.
`
`

`

`
`
` CLINICAL REVIEW
`
`Clinical Review Section
`
`
`
`
`
`Safety
`
`Disposition: As shown in the table below, 96% of placebo-treated subjects and 100% of
`cinacalcet-treated subjects experienced adverse events during the study.
`'
`
`Page 176
`
`

`

`
`
`. Deaths on study
`Severe adverse events?
`4__|
`Serious adverse events
`' Withdrawal due to adverse events
`26 96
`All adverse events
`' Includes severe, life-threatening and fatal adverse events
`
`.
`
`-
`
`Placebo
`
`n (%)
`
`Cmacalcet
`
`n (%)
`
`
`
`3
`27 100
`
`Exposurei A total of 54 (27 cinacalcet, 27 placebo) received study medication (see table below).
`The mean (range) number of days of exposure to study drug was 102 (6 to 133) days for the
`cinacalcet group and 102 (4, 135) days for the placebo group. The mean (range) cumulative dose
`of cinacalcet was 5044.4
`
`
`
`
`
`
`
`
`
`
`
`
`Dose_eompliance_(%)
`Mean
`
`Dosing Compliance (%)—= 100 x (number of days dose taken/ number of days prescribed).
`
`Deaths: Two deaths occurred during the study. Both subjects received placebo treatment. One
`58 year old mane died of cardiac failure on day 22. The second subject was an 87 year old man .
`who suffered a myocardial infarction and died on Day 6 of the trial.
`
`Serious Adverse Events: Three subjects (11%) in the cinacalcet group. and 6 subjects (22%) in
`'the placebo group reported serious adverse events‘. In the cinacalcet group one subject
`experienced abdominal pain, one subject experienced peripheral edema and hypertension, and a
`third subject was hospitalized with pulmonary edema; it was coincidentally noted that this
`subject was hypocalcemic (serum calcium of 7.2 to 7.8 mg/dL). "In the placebo group, 2 subjects
`experienced serious adverse events of pulmonary edema and 2 subjects experienced cardiac
`failure. 'One subject each reported serious adverse events of myocardial infarction and atrial
`fibrillation. An additional placebo subject experienced multiple serious adverse events
`culminatingm a fatal event of cardiac failure.
`
`Adverse Events Leading to Withdrawal: A total of 6 subjects withdrew from the study due to
`adverse events [5 (19%) from the cinacalcet group and 1 (4%) from the placebo group]. In the
`
`Page 177
`
`

`

`
`
`Clinical Review Section
`
`cinacalcet group, one subject ‘withdrew because of nausea and 4"Subjects withdrew because of
`hypocalcemia. At baseline, iPTH ranged from 119 to 594 pg/mL in these subjects, with a mean
`percent reduction in PTH of 85% at Week 1. In 3 of the 4 subjects, no symptoms were associated
`with the low serum calcium values, whereas the fourth experienced paresthesia. In each case,
`serum calcium increased to normal levels shortly after discontinuation of study drug. One subject
`withdrew from the placebo group because of cardiac failure.
`
`Adverse Events: All subjects in the cinacalcet group and 96% of subjects in the placebo group
`reported at least 1 adverse event during the study The most common adverse events were
`(cinacalcet, placebo) nausea (33%, 7%), myalgia (26%,15%), and diarrhea (22%, 15%) (see table
`below).
`
`
`
`H
`,
`Subjects Receiving Dose
`Subjects Reporting AEs
`Events:
`Body as a whole
`Gastrointestinal
`Liver and Biliary
`Nervous
`Cardiovascular
`Heart Rate / Rhythm
`Myo/Endo/Pen'cardial
`Respiratory
`Endocrine/Metabolic
`Musculoskeletal
`Infectious
`Blood and Lymphatic
`Skin and Appendages
`Urinary Disorders
`Reproductive
`Vascular Disorders
`Vision Disorders
`Hearing / Vestibular
`Ps chiatric
`
`.
`
`'
`
`'
`
`'
`
`.
`
`Placebo
`27
`26 (96)
`'
`12 (44)
`ll (41)
`l. (4)
`9 (33)
`3 (11)
`3 (11)
`2 (7)
`1 l (41)
`3 (11)
`8 (30)
`1 (4)
`1 (4)
`4 (15)
`3 (l 1)
`0 (0)
`1 (4)
`0(0)
`
`Cmacalcet
`.
`27
`27 (100)
`
`12 (44)
`15 (56)
`0 (0) .
`9 (33)
`3 (11)
`0 (0)
`1 (4)
`7 (26)
`7 (26)
`ll (41)
`l (4)
`0(0)
`8 (30)
`2 (7)
`2 (7)
`0 (0)
`1 (4)
`
`'
`
`.
`
`'
`
`‘
`
`*
`'
`
`Adverse Events of Special Interest: "
`
`Convulsions: There were no reports of seizure activity during the study.
`
`GI Adverse Events: Gastrointestinal adverse events are common with cinacalcet treatment.
`' Nausea was reported in 33% of cinacalcet-treated patients and 7% ofplacebo treated patients.
`Vomiting was reported in 15% of cinacalcet—treated patients and 7% of placebo treated patients.
`Diarrhea was reported in 22% of cinacalcet—treated patients and 15% of placebo treated patients.
`Dyspepsia was reported in 2 (7%) of cinacalcet-treated subjects and 1 (4%) of placebo-treated
`subjects. There were no reports of esophagitis, gastritis or gastric ulcer.
`
`Cataracts: Cataract formation associated with cinacalcet use was reported1n animal studies.
`There were no reports of cataract in this trial
`
`Page 178
`
`

`

`
`
`Clinical Review Section
`
`Laboratory: Safety laboratory assessments were performed at screening and follow-up. Shifl
`tables demonstrated no evidence of a treatment effect in hematologic and blood chemistry
`variables. Specific relevant laboratory evaluations are discussed below.
`'
`
`Serum Calcium: The mean (SD) serum calcium concentration at baseline was 9.7 (0.5) mg/dL
`and 9.7 (0.5) mg/dL in the cinacalcet and placebo groups, respectively. At Week 18, mean serum
`, calcium concentrations were 9.0 mg/dL in' the cinacalcet group and 9.6 mg/dL in the placebo
`group, which was within the normal range. These values represent a 7% decrease from baseline
`in the cinacalcet group and a 0.1% decrease in the placebo. Below is the shift table for decreases
`in calcium concentration.
`
`
`ax1mum ra e or Decreased Value
`2"3-.
`
`6.5—7.6‘ 5.7— 6.5 <5.7
`
`O(O%)1 ogfilLE
`0(0%);
`0g0%2E 0g0%)
`E 0 0% :
`i
`
`
`
`0(9%)__
`0(0%L_E
`2(8%) E 0(0%)
`
`0 0%
`0 0% i
`0(0% 1 0 0%
`
`0g0°a)“
`0 (000
`i 0g0%),__0g0%)
`0(_O%) L0(0_%)E 010%) 0(0%
`0 0%
`E
`0 0%
`0 0%
`
`1
`
`Ionized Calcium: Ionized calcium concentrations were determined in a subset of subjects who
`participated in this study. Reductions in ionized calcium in subjects treated with cinacalcet
`mirror reductions in serum calcium.
`
`Serum Phosphorus: The mean (SD) serum phosphorus concentration at baseline was 4.1 (0.5)
`mg/dL in the cinacalcet group and-4.0 (0.7) mg/dL in the placebo group. Modest increases in
`serum phosphorus occurred in the cinacalcet group, reflective of reductions in plasma iPTH
`concentrations. At week 18, the mean serum phosphorus concentrations were 4.6 mg/dL in the
`cinacalcet group and 4.2 mg/dL in the placebo group (normal range: 2.2 to 5.1 mg/dL).
`Glomerular Filtration Rate: The mean (SD) GFR at baseline was 22.6 (7.1) mL/m1n/l73m2 in
`the cinacalcet group and 23.1 (6.6) ml../mm/1.73m2 in the placebo group. The mean GFR was
`stable during the study1n both treatment groups.
`
`_C___ax P: The mean (SD)2Ca x P value at baseline was 39.6 (5.5) (mg/dL)2 in the cinacalcet group
`and 38.8 (6.4) (mg/dL)2 in the placebo group. Ca x P values and percent change from baseline
`were similar between treatment groups throughout the study. At week 182, the mean (SD) Ca x P
`value was 41 .6 (8.7) (mg/dL)2 for the cinacalcet and 40.2 (11.0) (mg/dL)2 for the placebo group.
`The mean percent change1n Ca x P was 7%1n the cinacalcet group and 3%1n the placebo group.
`
`Page 179
`
`

`

`
`
`Clinical Review Section
`
`Urine Calcium: Mean (range) baseline values for urine calcium excretion were below normal at
`baseline: 34.9 (0.9 to 185.3) mg/24 hours in the cinacalcet group and 33.7 (4.3 to 126.9) mg/24
`hours in the placebo group (normal range: 50 to 300 mg/24 hours). At week 18, the mean 24-
`hour urine calcium values were increased from baseline but remained in the normal range with
`mean values of 74.0 (5.8 to 295.7) and 53.9 (5.0 to 203.7) mg/24 hours in the cinacalcet and
`‘ placebo groups, respectively. No subjects in either treatment group experienced 24-hour urine.
`calcium values above the normal range during the study. ,
`
`Mean (SD) baseline values for the ratio of spot urine calcium to creatinine were 0.03 (0.04) for
`the cinacalcet group and 0.03 (0.05) in the placebo group. At week 18, mean values were 0.04
`and 0.03 in the cinacalcet and placebo groups, respectively. Mean percent change in fasting spot
`urine calcimn/creatinine ratios was 59.6% and 38.9%, and median percent change was -5.9%
`and 29.0% in the cinacalcet and placebo groups, respectively.
`
`Urine Phosphorus: Mean (SD) baseline 24-hour urine phosphorus excretion was 538.4 (220.5)
`mg in the cinacalcet group and 614.4 (278.4) mg/24 hours for the placebo group (normal range:
`400 to 1300 mg/24 hours). At week 18, the end of the efficacy-assessment phase, the mean 24-
`hour urine phosphorus excretion was 497.4 (range: 107.0 to 956.0) mg/24 hours and 678.3
`(range: 244.0 to 1337.0) rug/24 hours in the cinacalcet and placebo groups, respectively.
`
`Urine Protein: Mean (SD) 24-hour urine protein excretion at baseline was 1 131 (1225) mg in the
`cinacalcet group and 2200 (2883) mg/24 hours in the placebo group. At week 18, the
`corresponding values were 929 (989) mg/24 hours in the cinacalcet group and 1742 (2265)
`mg/24 hours in the placebo group. The mean (median) percentage change from baseline was
`25.5% (-l9.7%) in the cinacalcet group and 15.5% (14.6%) in the placebo group.
`
`Other Safety Tests:
`
`Vital Signs: Mean blood press‘uremeasurements were stable throughout the study and did not
`differ between treatment groups.
`
`ECGs: Investigator interpretation of ECGs was categorized on the case report form as normal;
`abnormal, not clinically significant; and abnormal, clinically significant. The majority of
`subjects (63% [17/27] cinacalcet, 67 % [18/27] placebo) had an abnormal ECG at baseline. Of *
`these, 4 (15%) subjects in the cinacalcet group and 1 (4%) subject in the placebo group had
`baseline ECGs that were considered clinically significantly abnormal.
`
`Safety Conclusions: In this 18 weeks in this randomized, placebo-controlled trial, the most '
`frequent cinacalcetdose was 30 or 60mg once daily, although doses of 90 to 180 mg were
`used by approximately 20% of the subjects. Two deaths were reported in the placebo.
`group during the study. Overall, adverse event rates were similar between treatment
`groups, with the cinacalcet group experiencing fewer serious adverse events than the
`placebo group. More subjects receiving cinacalcet compared to the placebo group reported
`gastrointestinal adverse events, primarily nausea and diarrhea. Four subjects in the
`cinacalcet group withdrew due to a serum calcium < 7.8 mg/dL on the lowest dose of study
`drug.
`'
`
`Page 180
`
`

`

`
`
`Clinical Review Section
`
`. Serum calcium concentrations were 9.6 (0.5) mg/dL in the cinacalcet group and 9.7 (0.5)
`mg/dL in the placebo group. With cinacalcet treatment, reductions in serum calcium levels
`were observed, although mean levels remained in the normal range: 9.0 versus 9.6 mg/dL
`at end of study for the cinacalcet and placebo groups, respectively). Mean serum .
`phosphorus concentrations increased slightly in the cinacalcet group but remained in the
`normal range. At baseline Ca x P levels were similar between treatment groups and
`remained stable throughout the study. Increases in 24-hour urine calcium were observed; ,
`’ however, no subjects had values above the normal range. Similarly, modest decreases in
`urine phosphorus excretion occurred. No changes in GFR were observed in this study.
`
`. Discussion and Conclusions: Secondary hyperparathyroidism (HPT) is a common and
`serious sequelae of chronic renal disease. Approximately 75- 100% of patients with Stage 3 .
`or 4 CKD have evidence of renal osteodystrophy5. Treatment of secondary HPT to prevent
`renal osteodystrophy'18 one Of the major goals of therapy1n CKD patients.
`
`This study demonstrates that cinacalcet is effective in reducing plasma levels of iPTH in
`subjects with secondary HPT due to Stage 3 or 4 chronic kidney disease. Intact PTH levels
`were reduced 32% with cinacalcet treatment, compared with an increase of 6% in the
`placebo treated group. Significantly more cinacalcet-treated subjects (56%) than placebo
`treated subjects (19%) achieved the primary endpoint, a > 30% reduction in iPTH (p——
`0.006). Baseline stage of renal disease, when determined by GFR, Was not a significant
`predictor for change1n iPTH.
`
`The most common adverse events were nausea, myalgia, and diarrhea. Hypocalcemia is
`_ recognized as a consequence of cinacalcet therapy. Four subjects withdrew from the study
`with serum calcium < 7.8 mg/dL on the lowest dose‘ of study drug. Overall, there was a 7%
`decrease serum calcium in the cinacalcet group and a 0.1% decrease in the placebo.
`
`Study. 20000204: An Assessment of the Calcimimetic Agent AMG 073 for the Treatment of
`Subjects with Parathyroid Carcinoma or Intractable Primary Hyperparathyroidism
`
`Objective: The primary objectivelof this study was to evaluate the ability of cinacalcet
`hydrochloride to reduce serum calcium concentrations in subjects with parathyroid carcinoma or
`intractable primaryhyperparathyroidism (PHPT).
`
`_ Study Design: This was a multicenter, open-label, dose-titration study.
`
`The study consisted of 3 phases: a 30-day screening period, a variable length dose-titration
`phase, and a maintenance phase. Study medication has been administered for up to 64 weeks
`(data collection closed 31 January 2004).
`
`'5 Elder G. Pathophysiology and recent advances in the management of renal osteodystrophy. J Bone Miner Res
`2002; 17:2094-2105.
`
`,
`
`Page 181
`
`

`

`
`
`Clinical Review Section
`
`Subject Population: The study population consisted of subjects with parathyroid carcinoma or
`intractable primary HPT. Intractable primary hyperparathyroidism was defined as unresolved
`primary HPT after unsuccessful parathyroidectomy or contraindication for parathyroidectomy.
`
`Inclusion Criteria:
`
`, 0 Had either “of the following: '
`-parathyroid carcinoma
`‘
`-intractable primary HPT with a serum calcium concentration > 12.5 mg/dL
`o Agreed to use, in the opinion of the principal investigator, highly effective contraceptive
`measures throughout: the study (all women were required to have a negative serum
`pregnancy test within 30 days before study day 0)
`0 Gave informed consent for participation in the study before any study-specific procedure,
`including screening and study drug administration,
`
`Exclusion Criteria:
`
`0 Undergoing therapy with flecainide or tricyclic antidepressants (except amitriptyline,
`which was allowed)
`0 Undergoing concurrent cancer chemotherapy for an indication other than parathyroid
`carcinoma
`
`0 Diagnosed with a malignancy (within the last 5 years) other than parathyroid carcinoma or
`nonmelanomatous skin cancers or in situ cervical cancer
`
`Diagnosed with hypercalcemia of nonparathyroid malignancy
`Unable to swallow or absorb orally administered medications in tablet form
`Known hypersensitivity to cinacalcet or tablet excipients
`Currently enrolled in, Or < 30 days since completing, other investigational device or drug
`trial(s), or was receiving other investigational agent(s)
`Breast feeding or lactating
`Diagnosed with any condition, including a psychiatric disorder, that would interfere with
`compliance with the protocol unless an acceptable responsible caregiver was identified
`PreviOusly enrolled in this study
`.
`0 Unable to give truly informed consent
`
`COMMENT: The inclusion and exclusion criteria appear appropriate. Because severe
`hypercalcemia in patients with parathyroid carcinoma and intractable primary
`hyperthyroidism is associated with significant morbidity and mortality, the use of an open
`label trial design is appropriate for this subset of patients.
`
`Study Medication and Dose Titration: Study medication was administered orally, with a meal
`or shortly thereafier, BID at lZ-hour intervals. The initial dose was 30 mg BID for 2 weeks.
`Subsequent dosages in the titration sequence were 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. Dosage could be
`increased every 2 weeks during the titration phase. Dosage escalation continued until the serum
`
`Page 182
`
`

`

` ,V‘CiniiIICAL REVIE
`
`Clinical Review Section
`
`calcium concentration-was S 10 mg/dL, the subject reached the highest possible dosage, or
`adverse events precluded further dosage increases.
`
`Hypocalcemiat'lf, at any time during the study, the subject experienced symptoms of
`hypocalcemia or had a serum calcium measurement < 8.0 mg/dL, study medication was to have
`' been withheld until the symptoms resolved and/or serum calcium concentration was 2 8.41
`mg/dL. Study medication Was then to be resumed at the next lower dose. If the subject was
`receiving 30mg,- the subject was to have been withdrawn from the study.
`
`Concomitant Therapy: Other investigational agents were not permitted. Investigators were.
`pemritted to prescribe any concomitant medications or treatments deemed necessary to provide
`adequate supportive care, with the exception of any excluded medications. Without jeopardizing
`the subject’s safety, the concomitant medication regimen was to be kept as stable as possible
`during the study. Concomitant medications were not collected on the case report form.
`
`Cinacalcet results in a clinically significant inhibition of the cytochrome P450 enzyme CYP2D6.
`Thus, CYP2D6 substrates having narrow therapeutic windows, such as flecainide or tricyclic
`'
`antidepressants (except amitriptyline, which was allowed), were excluded. If a subject required
`such excluded medications while on study, the sponsor was to be contacted to determine whether
`the subject was permitted to continue in the study.
`
`COMMENT: The prohibition of drugs that may interact with the study medication was
`appropriate. Failure to document the use of concomitant medications during this study
`limits the ability to note any potential interaction of drugs;
`
`Efficacy Measures: The key assessments in this study included measurements of serum
`calcium, plasma iPTH, bone markers (serum BALP and NTx), adverse eyents, patient reported
`outcomes (PRO), and pharmacokinetics.
`
`Primary Efficacy Endpoint:
`
`0, The primary endpointfor evaluation of Cinacalcet clinical effects Was the proportion of
`subjects experiencing a reduction of serum calcium by 2 l mg/dL at the end of the titration
`phase.
`‘
`
`Secondary Efficacy Endpoints:
`
`o The proportion of subjects experiencing a reduction of serum calcium concentration to S
`10.3 mg/dL at the end of titration phase
`0 Absolute concentrations, changes from baseline, and percentage changes from baseline in
`serum calcium, plasma iPTH, and serum NTx and BALP
`o 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
`
`_
`,
`0 Changes in PRO scale scores and summary scores
`o The pharmacokinetic profile of Cinacalcet (based on plasma Cinacalcet concentrations)
`
`l’age 183
`
`

`

`
`
`Clinical Review Section
`
`COMMENT: There is no Support in the literature for the clinical significance‘of the
`primary efficacy endpoint.
`4
`
`Safety Endpoints: Included stande laboratory measures (CBC, chemistry) and queries for
`adverse events. EKG data were not collected during this study.
`
`V
`COMMENT: Laboratory" monitoring appeared appropriate. The lack of EKG data is
`concerning. Given the limited data evaluating for QT prolongationand the potential for‘
`the study drug to cause large shifts in serum calcium levels, monitoring EKGs in these
`patients would have been preferred.
`
`Study Methods:
`
`
`
`was used to analyze the samples for
`.e-.-—
`iPTH Measurement: .
`the primary, secondary and safety endpoints. Measurement of iPTH was done with duplicate
`plasma samples to allow comparison of results obtained with the iPTH and biPTH assays. All
`iPTH levels used in the primary analysis were obtained utilizing the manual IRMA methodology.
`
`Withdrawal criteria: Any subject had the right to withdraw from the study at any time and for
`any reason.
`
`The investigator and Amgen also had the right to withdraw subjects from the studyin the event
`of any of the following:
`
`0
`
`Significant protocol violation or noncompliance, either on the part of the subject or
`, investigator
`.
`.5“
`Significant adverse event or unacceptable toxicity
`Decision by the investigator or Amgen that discontinuation was in the subject’s best
`medical interest
`
`Unrelated medical illness or complication
`0 Loss to follow-up
`
`Statistical Analysis: (For a complete discussion of the statistical analysis please refer to Ms. J.
`Mele’ 3 review.)
`,
`.,
`
`Sample size calculation 'was based on the results of a study of subjects with mild-to-moderate
`primary HPT (study 990120), 79% of cinacalcet-treatcd subjects had a reduction in serum
`calcium of S l mg/dL at the end of the titration phase. was assumed for sample size
`considerations. It was assumed that although subjects in this study had more severe disease, a
`similar result would be expected An enrollment of 50 subjects was calculated to give an
`estimated 95% confidence interval (CI) of between 67% and 90% for the proportion of subjects
`achieving this endpoint.
`'
`-
`
`Protocol Amendments: The protocol was amended once, primarily to clarify the background
`, and rationale for the protocol. In addition, it was clarified that the contents of the PRO
`
`Page 184
`
`

`

`
`
`
`
`Clinical Review Section
`
`questionnaire included the SF—36 and the