MEDICAL TEAM LEADER REVIEW
`
`NDA: 21—688
`
`DRUG: Cinacalcet (Sensiparm)
`
`INDICATIONS: Treatment of (i) secondary hyperparathyroidism; (2) primary
`hyperparathyroidism when parathyroidectomy is not an option; and (3) hypercalcemia of
`
`parathyroid carcinoma
`
`‘
`
`PRIMARY REVIEWERS: Patricia Beaston, MD, PhD, and Theresa Kehoe, MD
`
`DATE NDA SUBMITTED: S‘September 2003
`
`DATE OF REVIEW: 14 February-2004
`
`I .0
`
`BACKGROUND
`
`Li
`
`Proposed Indications
`
`Cinacalcet is a first—in—class oral caclimimetic drug that Agmen plans to market for the
`
`following 3 indications:
`
`'
`
`I. The .a---——~ atreatment of secondary hyperparathyroidism in patients with chronic
`kidney disease, receiving or not receiving dialysis.
`2. The treatment of primary hyperparathyroidism when parathyroidectomy is not a treatment
`option.
`
`3. The treatment of hypercalcemia in patients with parathyroid carcinoma.
`
`1 ‘.2
`
`Priority Review
`
`Amgen requested and received’a priority review for this NDA. Several vitamin D compounds are
`
`. approved for the treatment of secondary hyperparathyroidism (secondary HPT); however, for
`many patients, the doses of vitamin D required to adequately lower serum intact PTH (iPTH)
`levels cause hypercalcemia and an elevated calcium X phosphorus ion product (Ca X P). This
`
`problem is often aggravated by the use of calcium—based phosphate binders, and is not entirely
`'obviated by the use of sevelamer, a non—calcium—based phosphate binder. Epidemiological
`data have linked an elevated Ca x P ion product to an increased risk for cardiovascular death.
`
`

`

`Because Cinacalcet interacts directly with the calcium-sensing receptors on the parathyroid
`gland, the drug lowers iPTH levels without increasing serum calcium or Ca X P levels.
`
`The Division believes that Cinacalcet may prove to be an effectiVe therapy for some patients
`
`with secondary HPT who are unable to reach treatment goals with the currently available
`
`vitamin D and phosphate—binder therapies.
`
`J .3
`
`Pharmacology and Pharmacokinetics
`
`Cinacalcet lowers iPTH levels by increasing the sensitivity of the calcium sensing receptor to
`extracellular calcium. The reduction in iPTH is associated with a concomitant decrease in serum
`
`calcium levels. Reduction in iPTH levels correlated with Cinacalcet concentrations. The nadir in
`
`WTH level occurs approximately 2 to 6 hours post—dose, corresponding with the Cmax of
`
`Cinacalcet. The Tmax of the drug is 3—4 hours post—dose. After absorption, Cinacalcet
`concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours
`
`and a terminal half—life of 30 to 40 hours. Steady state drug levels are achieved within 7 days.
`
`The AUC and\Cmam of Cinacalcet increase linearly over the dose range of 30 to 180 mg once
`daily. The drug has a large volume of distribution.
`
`1 .4
`
`Dose Selection ,
`
`ln phase—2 investigations of patient with secondary HPT, doses of Cinacalcet less than 25 mg
`
`did not suppress iPTH over a 24—hour interval in subjects with secondary HPT and doses above
`
`200 mg daily did not increase exposure to the drug. Therefore, a dose range of 30 mg to 180
`
`mg once daily was selected for the pivotal phase—3 studies.
`
`1.5
`
`Treatment Guidelines for Patients with CKD
`
`The following table outlines the current treatment goals for patients with mild—severe CKD.
`
`Table 1 . KIDOQI Target Values for Secondary HPT Metabolic Parameters
`
`Metabolic Parameter
`
`iPTH (pglmL)
`
`'
`
`Target Level
`CKD Stage 3"
`30 to 70
`
`Target Level
`_CKD Stage 4"
`7010 110 ’
`
`'
`
`.
`
`,
`
`
`
`Ca x P (mg/cm2
`
`Not In guideline
`
`Not in guideline
`
`8.4 to 10.3“ ~
`8.4 to 10.3“
`Calcium (mg/dc)
`2.7 to 4.6
`2.7 10 4.6
`Phosphorus (mg/(IL)
`CKD = chronic kidney disease. ESRD = end—stage renal disease. iPTH = intact parathyroid hormone,
`Ca x P = caidum x phosphorus
`' giomeruiar filtration rate (GFR) so to 80 mL/minn .73 m2
`‘7 GFR 15 to 29 mL/min/1,73 rn2
`‘ GFR < 15 mUminI1.73 m2 or diaiysis
`° within normal! range for the laboratory used
`
`‘
`
`

`

`2.0
`
`OVERVIEW OF CLINICAL STUDIES
`
`2.]
`
`Secondary Hyperparathyroidism
`
`2.1.1 Chronic Kidney Disease Receiving Dialysis
`
`The efficacy and safety of Cinacalcet in the treatment of secondary HPT in patients on dialysis
`were examined in three, 6—month, placebo-controlled trials of similar design: Studies I72, 183,
`and 188. For a subset the patients who completed studies I72 and I83, and additional 6
`
`months of double-blind treatment was obtained in study 240..
`
`Studies I72 183 and I88
`
`Obiective: To evaluate theefficacy of cinacalcet compared with placebo by determining the ,
`proportion of subjects with a mean iPTH value 5 250 pg/mL during the Efficacy—Assessment
`
`phase.
`
`Patient Population and Study Design: To be eligible for the three phase-3 studies of patients
`
`with CKD on dialysis, patients had to be at least 18 years of age and have a iPTH Z 300 pg/ml
`and a serum calcium 2 8.4 mg/dl within 30 days of the trial. Exclusion criteria included a
`
`change in brand or dose of phosphate binder or oral calcium supplement within 30 days of the
`
`start of the trial; a change in dialysate calcium concentration within 30 days of trial initiation;
`
`receipt of vitamin D therapy for < 30 days before start of the study, or a change in the brand or
`
`dose of vitamin D within 30 days of study start.
`
`'
`
`~
`As shown in Figure below, the studies were comprised of a 12—week dose—titration phase)
`(Titration) and a 14—week efficacy phase (Efficacy—Assessment). Beginning on day 1, subjects
`
`received study medication at a starting dose of 30 mg Cinacalcet or placebo once daily. Tablets
`
`were taken with food or shortly after a meal if feasible. Study medication was taken at
`
`approximately the same time of day each day. On study visit days, study drug was administered
`
`after blood collection and study evaluations, approximately 24 hours after the last dose (at the
`nadir ‘drug concentration).
`
`

`

`
`
`
`
`End of
`Day 1 Wk! M3 Wk l2 Titration Phase
`Wk 16
`
`End of
`Study
`Wk 26
`
`Subjects could be titrated up to the next sequential dose level of cinacalcet (60 mg, 90 mg, 120
`
`mg, and 180 mg)/placebo at the week 4, 8, 12, 16, 20, and 24 study visits. For each of these
`visits, a site representative called the interactive voice response system (IVRS) within 5 days
`before and 3 days after the scheduled visit in order for a subject to receive the next bottle
`number(s). The site personnel were asked for subject information that included central
`laboratory iPTH and serum calcium values and safety information. If. any of the following criteria
`
`applied, a subject’s dose was not increased:
`
`For weeks 4, 8, 12,16, 20, and 24;
`
`- The central laboratory iPTH value from the preceding study visit was 5 200 pg/mL.
`- The highest dose of study medication was reached.
`,
`- The serum calcium was < 7.8 mg/dL or the subject was experiencing symptoms of
`
`‘
`
`hypocalcemia.
`
`- The subject was experiencing an adverse event that precluded a dose increase.
`
`If iPTH values were < 100 pg/mL for 2 consecutive study visits, study
`medication was reduced to the next lower dose.
`
`If a subject experienced an intolerable adverse event that was considered related to the dose of
`
`study drug (other than hypocalcemia), study drug was decreased to the next lower dose. If a
`
`

`

`subject experienced symptoms of hypocalcemia and/or a serum calcium < 8.4 mg/dL, calcium
`
`supplements and] or phosphate binders could be increased to resolve the symptoms (if present)
`or to increase serum calcium to _>_ 8.4 mg/dL. If these measures were insufficient, the vitamin D
`
`dose could be increased. Figure 7.2 in the Appendix provides the algorithm for management of
`
`hypocalcemia.
`
`Baseline Demographics and Disposition: A total of 47] patients were randomized to placebo
`and 665 to cinacalcet in the three, 6—month studies. The baseline demographic characteristics
`were well—matched for the placebo and Cinacalcet groups. The mean age of the» participants
`was 54 years, 62% were male, and 52% were Caucasian. The average duration of dialysis prior
`
`to study enrollment was 67 months and 96% of the patients were receiving hemodialysis; 4%
`
`were on peritoneal dialysis. The baseline iPTH level was 712 pg/ml, with 26% of subjects having
`
`baseline iPTH levels > 800 pg/ml, and the baseline Ca X P product was approximately 6] .
`
`Sixty—six percent of the subjects were receiving vitamin D therapy at baseline, and 93% were on
`
`some type of phosphate binder.
`
`’
`
`Seventy-eight percent of placebo patients and 71% of the Cinacalcet patients completed the 6—
`
`month studies. Fourteen percent of the Cinacalcet-treated patients and 8% of the placebo
`
`patients discontinued early due to an adverse event — a large proportion of which were nausea
`
`or vomiting or both.
`
`Exposure to Study Drug: The distribution of patients by close of drug at the end of the Titration
`
`and Efficacy—Assessment periods of the studies are shown in Figures 1 and 2 in the Appendix.
`
`Primam Efficacy Outcome: The primary efficacy outcome variable was the proportion of
`patients in each group Who achieved a mean iPTH value 5 256 pg/ml during the Efficacy—
`Assessment phase of the trials. In the ITT population, 40% of cinacalcet subjects vs. 5% of
`
`placebo subjects achieved a mean iPTH value of < 250 p9/ml during the Efficacy-Assessment
`
`phase (p<0.00]). The following figure provides the results of the primary efficacy assessments
`for each. of the three pivotal studies and for studies combined.
`
`NO detmmmmummm S
`
`mM
`
`DIM PM #313!”
`Film We“
`0““
`ammonia, Mm ammo.
`1".
`
`11no:
`{'I-unzat.)
`
`«name;
`
`294*!
`mass.)
`
`3 h
`
`0
`
`.2 0
`
`

`

`Ca x P Ion Product: The mean percent reductions from baseline to Week 26 in the Ca x P
`product ion were -0.02% in the placebo group and -14.0% in the Cinacalcet group.
`
`KlDOQl Treatment Goals: The following table provides the proportion of patients in the two
`
`treatment groups who achieved the various K/DOQI treatment goals during the Efficacy—
`
`Assessment Phase. A larger percentage of patients treated with Cinacalcet met the new
`
`treatment goals than did patients who received placebo.
`
`m ..
`..
`Placebo Chm Plawbo
`
`Cinacalcet
`
`$311 20000!“
`Placebo
`0mm Pineal»
`
`Cinacalcet
`
`(M205)
`
`("2205’
`
`(Miss)
`
`(bl-‘36)
`
`(ti-=10” 01:29“ beam)
`
`(“665)
`
`15( 93 man
`
`15(9)
`
`was)
`
`at 8)
`
`55(27)
`
`{05(52)
`
`37(22)
`
`87(52)
`
`26(26)
`
`34(29)
`
`,
`121(41)
`
`62 (30)
`
`79( 39)
`
`50(30)
`
`76066}
`
`45(45)
`
`134 (46)
`
`41(9)
`
`205(31)
`
`118(25)
`
`.
`157 ( 33)
`
`314(47)
`
`289(43)
`
`-d :
`
`Hawaii.)
`150-300
`
`Serum calcium (mgdL)
`lid-9.5
`
`.
`
`Serum phosphorus (Ho'dL)
`3.5- 5.5
`
`sewn/a)”
`s55
`
`69(34)
`
`t23(60)
`
`Wamwntd 9( 4}
`lPTfl150-300pglmLaM
`CaxPSSS
`
`58(28)
`
`58(35)
`
`11( 7)
`
`i09(66)
`
`45(45)
`
`wuss)
`
`172(37)
`
`418(63)
`
`31(19)
`
`'
`
`5( 5)
`
`67(23)
`
`25( 5)
`
`156(23)
`
`Adverse Events: There were no meaningful differences between treatment groups in the
`incidence of deaths or serious AEs during the 3 trials. Fifteen percent of Cinacalcet subjects and
`8% of placebo subjects discontinued prematurely due to adverse events. A large percentage of
`: patients in the Cinacalcet groups withdrew because of nausea or‘vomiting or both. Nausea and
`’ vomiting were also the two most commonly reported treatment—emergent adverse events, with
`31% and 27% of Cinacalcet subjects reporting these events, respectively. This compares with
`.1 9% and 1.5% of placebo-treated patients who reported at least one episode of nausea and
`
`vomiting. There was a clear dose—response relationship for vomiting, but not nausea.
`
`Serum Calcium Levels: Given Cinacalcet's mechanism of action, hypocalcemia would be an ‘
`expected safety issue. in the pooled data from Studies 1 72, 183, and 188, 66% of Cinacalcet
`
`subjects vs. 25% of placebo patients developed at_|east one serum calcium level 5 8.4 mg/dl.
`Approximately 5% of CinacalCet and 0.9% of placebo patients had 2 consecutive serum calcium
`
`values < 7.5 mg/dl. Seven percent of subjects receiving Cinacalcet and 0.9% of subjects
`
`receiving placebo had study drug withheld due to decreased serum calcium. All of these
`
`subjects subsequently resumed study medication. There was no major imbalance between
`
`groups in the incidence of adverse events that could be attributed to hypocalcemia.
`
`Among the Cinacalcet subjects who experienced a serum calcium < 8.4 mg/dL, a majority (64%)
`
`had only one or two values below this level during the 6-month trial period. It appears that the
`
`risk of hypocalcemia (< 8.4 mg/dl) was similar during the Titration and Efficacy—Assessment
`
`phases of the studies.
`
`

`

`Seizures: Five percent of the patients in both the placebo and Cinacalcet groups reported
`
`having a history of a seizure disorder at baseline. During the trials, 2 patients in the placebo ~
`
`groups and l 1 subjects in the Cinacalcet groups were coded as having had at least one
`
`“seizure" - the majority of which were described as grand mal (nominal p = 0.054).
`
`[For the entire population of patients who participated in any of the secondary HPT + dialysis
`
`studies, 5/ 738 (0.7%) of placebo patients and 17/ l 166 (1.5%) of Cinacalcet patients were coded
`
`as having had at least one “seizure" (nominal p = 0.12).]
`
`In Studies l72, 183, and 188, 5 of the l 1 Cinacalcet-treated subjects who experienced an on—
`
`study seizure had a previous history of a seizure disorder. Of these 5 subjects, 3 had one or
`
`more clinical conditions that were possible confounding factors, such as subdural hematoma
`
`secondary to head trauma; ventriculo—peritoneal shunt and concurrent urinary tract infection;
`isoniazid administration; promethazine administration; and cefazolin administration. Two of the
`5 subjects with a history of seizures were on anticonvulsant medications at the time of study
`enrollment. The 2 placebo subjects who experienced convulsions also had a history of
`
`convulsions and were on anticonvulsant medications at the time of study enrollment.
`
`In preclinical studies,
`Preclinical data indicate that Cinacalcet crosses the blood brain barrier.
`seizures associated with acute and severe reductions in serum calcium were observed in rats
`
`and dogs‘at the highest Cinacalcet dose levels. As shown in the following table, 4 of the
`
`Cinacalcet subjects had low serum calcium levels prior to or after the reported seizure.
`
`History of
`Seizures
`
`Confounding Factors
`
`Catclum'
`
`(mgldL)
`
`Dose
`level
`
`Treatment
`(rugs) ' Relationship"
`
`W'
`30608
`33510
`31002
`
`30202
`34204
`10602
`
`‘ °7°6
`2051 1
`
`Study No.
`
`20010240
`20000183
`20000103
`
`20000183
`20000183
`20000172
`200001 72/
`20010240
`20000188
`
`88
`
`isoniazld
`subdural hematoma
`HTN. tremaao:
`
`-
`
`11.3 I 102
`8.8 I --
`0.0 I 10.0
`
`.
`
`'
`
`VP shunt, UTl
`befazolln '
`mm
`
`.
`
`.
`
`low phenytoln level
`
`30
`~ 60
`120
`R?o
`
`8288033gag88
`
`9.1 I 7.8
`9.0 I 3.0
`‘8.6 I 9.5
`8.3 l 8.6
`7.3 I 9.2
`
`9.6, 16.7
`9.4 I 1 1 .0
`7.8 [9.3
`
`82 l 8.9
`9.0 l 8.6
`
`20000188
`20010240
`20000188
`
`10911
`16703
`13107
`Elm
`20000172
`14302
`promethazine
`20000172
`13105
`‘ Nearest on-smdy serum calcium values before and afler event
`” investigator‘s assessment
`
`'
`
`Of the l l Cinacalcet subjects who reportedly suffered an on—study seizure, 2 were receiving 30
`
`mg Cinacalcet, 3 were receiving 60 mg, 2 were receiving 90 mg, 3 were receiving 120 mg, and
`
`l was receiving 180 mg at the time of the seizure."
`
`

`

`No studies have been done to examine whether Cinacalcet induces the activity of enzymes that
`metabolize common anti—seizure medications.
`
`COMMENT: With the available data. it’s not possible to accept of reject the hypothesis that
`cinacalcet increases the risk for seizure. If the drug does in fact increase the risk for seizure, it
`
`most likely close so by way of hypocalcemia. Despite the uncertainty of a cause and effect
`relationship between cinacalcet and seizures, several measures should be taken in response to
`
`the findings from the phase 3 CKD studies. First, a series 'of in vitro enzyme induction studies
`should .be conducted‘to deterntinevVhether cinacalcet increases the activity of enzymes known
`toimetabolize common anti-seizure medication. Second, the Warnings section of the labeling
`should include a clear description of the seizure findings from Studies 172, 183, and 188,
`
`along with a recommendation that serum calcium levels be closely monitored, particularly in
`
`patients with a known seizure disorder. Third, following approval, Amgen should commit to
`providing the Division with regular (i.e., semi—annual) analyses of all seizure data from
`cinacalcet clinical trials and MedWatch reports.
`
`Cardiac Regolarization 19!): There is a growing interest within. CDER to closely scrutinizing new
`
`molecular entities for their potential to adversely affect cardiac repolarization. The Cinacalcet
`
`NDA contains some data on cardiac repolarization, but by no means does it include a
`
`comprehensive assessment of the drug's proarrhymthmic potential.
`
`The in vitro testing included 7 ion channel assays. For details of these studies please see Dr.
`
`Gemma Kuijper's review. According to Dr. Kuijper’s, 4 of the 7 ion channel studies (3 K+ and l
`Na+) were “positive". Although only one drug concentration was tested in the HERG assay, the
`ICso was > 500 ng/mL, a concentration that is i0 times the free plasma levels obtained with the
`
`maximum propoSed clinical dose of 180 mg. No additional in vitro testing was done.
`
`‘
`
`Regarding in Viva data, in a 3—month study of monkeys, a QT prolonging effect (> 20 ms) was
`observed in animals that received the two highest doses of Cinacalcet: 100 mg/kg/day and 150
`mg/kg/day. In a 12—month of monkeys, dosed at 0 mg, 5 mg/kg/day, 50 mg/kg/day, 106
`mg/kg/day Cinacalcet, there were QT prolonging effects noted for the higher doses‘at Months
`3 and 6, but not at Months 9 and 12. The company attributed the prolongation of the QT
`’
`interval to drug—induced reductions in serum calcium levels, which is a plausible explanation.
`Of note, it is unknown when the ECGs were obtained relative to Tmax of Cinacalcet.
`
`‘
`
`Electrocardiogram (ECG) data were collected in a larger proportion of the l 126 patients who
`took part in the three, 6—month phase 3 CKD — dialysis studies. The ECGs were read manually
`and obtained at trough drug levels. The mean Qch intervals at baseline were 426 ms and 427
`ms in the placebo and cinacalcet patients, respectively. The mean changes in Qch from baseline
`to Endpoint were 4.4 ms and 5.7 ms in the placebo and cinacalcet groups, respectively.
`
`

`

`The following table provides the percentage of patients within each category of change in Qch
`from baseline to Endpoint.
`
`
`' Endpoint
`
`Placebo n = 470
`
`Cinacalcet n = 656
`
`Decrease
`
`'
`
`Increase < 30 ms
`Increase 30 - 60 ms
`
`46%
`
`34%
`15%
`
`‘
`
`42%
`
`37%
`17%
`
`4%
`5%-
`Increase > 60 ms'
`24%
`21%
`'
`> 450 ms (6') > 470 1715(9)
`
`> 500 ms 3% . 3%
`
`
`
`,
`
`'
`
`The following table provides the proportion of subjects with normal baseline Qch intervals but
`
`prolonged QT“, intervals [> 450 ms ((5') > 470 ms (9)] by serum calcium levels at Week 14/18 and
`Week 26.
`
`' C
`
`alcium Level
`
`Placebo n = 470
`
`Cinacalcet n = 656
`
`Week 14/18
`
`< 7.5 mg/dl
`_>_ 7.5 to < 8.4 mg/dl
`z 8.4 to 10.3 mg/dl
`> 10.3 mg/dl
`'
`
`Week 26
`
`1
`
`< 7.5 mg/dl
`2 7.5 to <‘ 824 mg/dl
`_>_ 8.4 to 10.3 mg/dl
`
`> 10.3 mg/dl
`
`,
`
`0.3%
`0.6%
`7%
`3%
`
`0%
`1%;
`9%
`
`3%
`
`.
`
`'
`
`‘
`
`.
`
`>
`
`0.9%
`6%
`9%
`2%
`
`0.2%
`3%
`)1 1%
`
`2%
`
`The table below provides the proportion of subjects with Qch intervals > 500 ms by serum
`calcium levels at Week 14/18 and Week 26.
`
`‘ C
`
`alcium Level
`
`»
`
`‘
`
`Placebo n = 470
`
`Cinacalcet n= 656
`
`Week 14/18
`
`< 7.5 mg/dl
`_>_ 7.5 to < 8.4 mg/dl
`2 8.4 to 10.3 mg/dl
`> 10.3 mg/dl
`
`Week 26
`
`< 7.5 mg/dl
`
`3 7.5 to < 8.4 mg/dl
`3 8.4 to 10.3 mg/dl
`
`.
`
`.
`
`0%
`0.2%
`2%
`0.5% >
`
`0%
`
`0%
`3%
`
`V
`
`'
`
`0.2%
`2%
`1%
`0.2%
`
`0.2%
`
`2%
`0.6% ,
`
`

`

`lO
`
`
`
`> 10.3 mg/dl
`
`0.5%
`
`0.4%
`
`As shown in the following table of potential adverse events that could be relate'dto a
`
`prolongation of the QT interval, there were no major imbalances between the two groups.
`
`Placebo
`(N = 470)
`
`Cinacalcet
`(N a: 653)
`
`‘ Tech carafe Ventricular
`
`n (96)
`
`87 (19)
`
`-
`
`.
`
`5 (1)
`3 (<1)
`2 (<1)
`6 (1)
`2 (<1)
`3 (<1)
`36 (8)
`O (0)
`7 (1)
`B (2)
`1 1 (2)
`O (0)
`4 (<1)
`1 (<1)
`1B (3)
`
`n (Va)
`
`1 18 (18)
`
`3 (<1)
`2 (<1)
`9 (1)
`9 (1)
`8 (1)
`o (o)
`64 (10)
`1 (<1)
`12 (2)
`5 (<1)
`1 3 (2)
`3 (<1)
`15 (2)
`0 (0)
`21 (3)
`
`.
`
`'
`
`Number of Subjects Reporting an Adverse Event
`
`Arrhythmia
`Av Block
`Bradycardia
`Cardiac Arrest
`Convulsions
`Death Cause Unknown
`Dizziness
`Exuasystoies Venuicuter.
`Fibrillation Atrial
`Woeerdlal lnfm‘cuon
`Palpieefion
`Status Epileptieus
`Synoope
`Tachyarmythmia
`Tachycardia
`Tachycardia Supraventricular
`/
`
`'
`
`COMMENT: The in Vitro data suggest that Cinacalcet has the capacity to inhibit some ion
`
`channels. The in vivo data indicate that high—doses of Cinacalcet are associated with
`
`prolongation of the QT interval. The phase—3 data demonstrate that treatment with Cinacalcet
`
`is associated with a small increase in the mean QT interval and with a slightly higher percentage
`
`of “outliers” (increases > 450 ms and 470 ms).
`
`It is entirely plausible, as the company
`
`'
`
`contends, that these findings are due to Cinacalcet-induced reductions in serum calcium levels. ‘
`
`While the preclinical and clinical data do not raise serious concern that Cinacalcet is a clinically
`
`significant QT-interval prolonging drug, the database examining this question is incomplete.
`
`Furthermore, the phase-3 ECG data that are available are of limited value because the ECGs
`were obtained at trough, rather than peak drug levels.
`I
`
`Another factor that should be kept in mind when evaluating the Cinacalcet-QT issue, is the fact
`that Cinacalcet is metabolized by the CYP3A4 and 2D6 enzyme systems. Despite warnings to
`
`the contrary, once the drug is in wide-spread use, it is inevitable that some patients will be
`
`exposed to supratherapeutic concentration of Cinacalcet following concomitant use with drugs
`that inhibit the 3A4 or 206 enzyme systems.
`
`A thorough QT study, if properly designed, would allow one to separate the intrinsic effect of
`I Cinacalcet on the QT interval (if one exists) from effects due to the lowering of serum calcium
`concentrations. Lacking a strong signal from the available data, i believe a thorough QT study
`could be done post—approval. In this scenario, approval would be limited to the treatment of
`secondary HPT in patients with CKD receiving dialysis. This was the population for which
`
`

`

`ll
`
`Cinacalcet was granted a priority review. This is the population for which one could argue that
`
`asmall risk for QT prolongation would be outweighed by the drug’s unique ability to
`
`simultaneously lower both serum iPTH and the Ca x P ion product. (the poor prognosis and
`
`lack of effective therapies for parathyroid carcinoma—related hypercalcemia also argues for
`approval of this indication before completion of a thorough QT study)-
`
`Serum Testosterone: In a long—term monkey study, serum testosterone levels were noted to
`
`have decreased significantly in the Cinacalcet compared with the placebo-treated animals. To
`evaluate this finding further, Amgen measured serum levels of total testosterone, free
`testosterone. LH, and FSH in 240 men who participated in Study 188.
`
`’
`
`Baseline levels of total and free testosterone were similar in the two groups. The median
`changes from baseline to Week 26 in total testosterone were 2 pg/ml and ~49 pg/ml in the
`placebo and Cinacalcet groups, respectively (nominal p=0.0004); the median changes from
`Baseline to Week 26 in free testosterone were —8 pg/ml and —i 8 pg/ml in the placebo and
`
`Cinacalcet groups. respectively (nominal p=0.02).
`
`Baseline levels of LH were similar in the two groups: approximately 11.3 mlU/ml. The mean
`
`values at Week 26 were 12.3 mlU/ml and 9.9 mIU/mi in the placebo and Cinacalcet groups,
`
`reSpectively. There were very small, insignificant changes in the levels of FSH from baseline to
`
`Week 26 in both groups.
`
`COMMENT: Abnormalities'in the hypothalamic—pituitary—gonadotropin axis are well
`documented in male patients with CKD receiving dialysis. Reduced libido and erectile
`dysfunction are two common manifestations of this altered endocrine milieu. Given the
`- abnormal baseline endocrine profile of male dialysis patients, it’may be difficult to assess the
`clinical significance of modest Cinacalcet-induced reductions in testosterone levels.
`Nevertheless, future long-term studies (i.e., > 1 year) should, at a minimum, include
`
`assessments of bone mineral density and sexual function in male dialysis patients taking
`Cinacalcet.
`
`4 2.1.2 See the Appendix for a summary of Study 240, a 6—month extension trial.
`
`2.1.3 Chronic Kidney Disease Not Receiving Dialysis
`
`Two studies, 236 and 239, were conducted in patients with secondary HPT not yet receiving
`dialysis. "'3W
`A...
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`* Contains trade secret %
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`disclosable
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`15
`
`2.1.4 Parathyroid Carcinoma and “Intractable” Primary_Hyperparathyroidism
`
`A total of 10 patients with parathyroid carcinoma are currently being studied in trial 204, an
`
`open—label, single~arm, 3-year study. Five patients with primary hyperparathyroidism, 2 of
`
`whom reportedly had undergone unsuccessful parathyroidectomies and 3 whom Amgen claims
`
`.
`parathyroidectomy was not a treatment option, were also enrolled into this study. The
`company refers to these fivepatients as having “intractable" primary hyperparathyroidism. Data
`
`up to 31 January 2003 are included in the NDA submission.
`
`Stud 204
`
`Objectivezto assess the ability of cinacalcet to reduce serum calcium concentrations in subjects
`with parathyroid carcinoma or intractable primary HPT.
`
`Patient Population and Study Designf Male and female subjects with a diagnosis of parathyroid
`
`carcinoma or intractable primary HPTH with a serum calcium level > 12.5 mg/dl were eligible
`
`for study participation.
`
`This is a multi—center, open-label, single—arm study that consists of a 30—day screening period,
`a 2 to I6—week titration phase, and a long—term maintenance phase ‘(planned duration of study
`
`is 3 years)(see Figure below). Subjects initially received 30 mg cinacalcet BID and then every 2
`
`weeks were titrated up to the next sequential dosage depending upon the previous week's
`
`serum calcium concentration and an adverse event assessment. Subsequent dosages in‘ the
`
`titration sequence were 50 mg BID, 70 mg BID, 90 mg BID, 70 mg TID, 90 mg TID, 70 mg QID,
`
`and 90 mg QID. Dosage escalation continued until the serum calcium concentration was _<_i 0.3
`mg/dL (2.5 mmol/L), the subject'reached the highest possible dosage, or adverse events
`‘
`precluded funher dosage increases. During the maintenance phase, visits were scheduled every
`
`8 weeks. If serum calcium increased to an unacceptable level and the subject was not already at
`the maximum dosage, additional dosage increases were permitted using the same procedures
`as used in the titration phase.
`
`APPEARS IHIS WAY
`ON ORIGINAL
`
`

`

`16
`
`Titration Phase"
`{weekly warm
`
`90 m
`
`9
`
`Maintenance 95550 3‘
`(visit: every 9 ween)
`
`End of
`Study
`
`inacalcet
`(n- 15)
`
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`
`Ex osure to Stud Dru : At the completion of the titration phase in the carcinoma patients, I
`
`subject was receiving 30 mg BID,
`
`1 was receiving 70 mg BID, 1, 70 mg TID, 3, 90 mg TID, 2, 70
`
`mg QID, and 2, 90 mg QID. For the patients with intractable primary HPTH,
`receiving 30 mg BID, 1, 70 mg BID, 2, 70 mg TID, and I, 90 mg TID.
`
`I patient was
`
`Baseline Demographics and Disposition: Fifteen patients entered~ the study: 10 with parathyroid
`carcinoma and 5 with intractable primary HPTH. Sixty—seven percent were male and 93% were
`
`Caucasian. The average age of the patients with carcinoma was 48 years, and the average age
`of subjects with intractable HPTH was 67 years. Two of the 5 subjects who had intractable '
`
`primary HPT had undergone parathyroid surgery, indicating that the remaining 3 subjects were
`
`contraindicated for parathyroidectomy. All but I subject had used bisphosphonates. Plasma
`iPTH concentrations at baseline were highly variable across subjects, with a mean of 918
`
`pg/mL'In subjects with parathyroid carcinomaM
`/———_—__——————————"—. The mean serum calcium level in the subjects
`
`with carcinoma was 15.0 mg/dl“W
`Of the 10 subjects with carcinoma who entered the trial, 5 remain on—study; of'the 5 patients
`
`with intractable HPTH who entered the trial, 2 remain on—study.-Two of the'premature
`withdrawal (one from each group) were due to death.
`
`COMMENT: Unlike the diagnosis of parathyroid carcinoma, which is well—defined and based on
`
`histOlOgical findings, intractable primary HPT,m—
`
`

`

`17
`
`Primam Efficacy Outcome: At the end of the titration phase. 7/10 carcinoma patients had a
`
`decrease in serum calcium ofz 1.0 mg/dl, . _/--——-———————-—————'—'—‘
`
`____________,.‘—————'_‘_"_——’
`
`Secondary Efficacy Outcome: The following figures provides the mean serum iPTH (top) and
`
`calcium (bottom) concentrations for each group of patient throughout the study.
`
`1600
`1400
`
`1200
`
`
`
`2
`2
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`9
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`wa'lmmum-wo—an—‘v no. .~.Mm~um-w .‘u-yv. mum-g
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`

`

`18
`
`3.0
`
`SUMMARY AND CONCLUSIONS
`
`Efficacy
`
`The National Kidney Foundation recently updated the treatment guidelines for patients with
`
`CKD and secondary HPT. Per these guidelines, patients on dialysis should strive for iPTH levels
`of 150 pg/ml to 300 pg/mlW
`
`The Ca x P ion product in dialysis patients should be below 55 (mg/dl)2.
`. These treatment goals aim primarily to reduce the risk for osteitis fibrosa while avoiding
`iatrogenic adynamic bone disease, and reduce the occurrence of soft tissue calcification,
`
`including that involving the coronary arteriesand cardiac valves. Effective management of
`
`secondary HPT is presumed to reduce the risks for cardiovascular disease and fractures, though
`
`. no controlled trials have been conducted to verify this assumption.
`
`Data from three randomized, double-blind, placebo-controlled, 6—month trials of more than
`1000 patients with CKD and secondary HPTH receiving dialysis, indicate that Cinacalcet, when
`
`initiated at 30 mg OD and titrated to a dose as high as 180 mg QD, reduces serum iPTH by
`
`approximately 50% relative to placebo. A much higher percentage of Cinacalcet—treated
`patients (40%) compared with placebo—treated subjects (5%) were able to achieve a serum iPTH
`
`level 5 250 pg/ml, and nearly twice as many Cinacalcet as placebo patients attained a serum Ca
`
`x P ion product of less than 55 mg/dlz. Cinacalcet’s calcimimetic action allows for the
`
`simultaneous reductions of serum iPTH and the Ca x P ion product — a duel treatment effect
`
`that is rarelylachieved with current vitamin D and phosphate—binder therapies. For example,
`whereas 5% of'placebo subjects had concurrent reductions of iPTH to 150 to 300 pglml and Ca-
`
`x P < 55 mg/dlz, almost 25% of Cinacalcet patients achieved these therapeutic goals.
`
`Based on the favorable changes in these biomarkers, it’s not unreasonable to speculate that a
`treatment regimen that includes Cinacalcet might decrease cardiovascular morbidity and
`mortality. While evidence of such a benefit is lacking,
`the Division nevertheless accepts these
`biochemical changes as demonstration of efficacy for Cinacalcet in this population.
`
`
`
`31::
`
`High doses of Cinacalcet had marginal efficacy in lowering serum calcium levels in 10 patients
`
`with parathyroid carcinoma. At the end of a 16-week, open—label, titration phase, 7 out of the
`
`10 patients had reductions in serum calcium ofg 1.0 mg/dL. None of the patients, however,
`normalized their serum calcium levels.
`
`To state the obvious, the data upon which Amgen is requesting approval for the treatment of
`
`parathyroid carcinoma are very limited. Yet, parathyroid carcinoma is a rare disease and
`
`

`

`19
`
`patients have few treatment options for the hypercalcemia associated with the condition.
`
`Cinacalcet offers the potential to satisfy an unmet medical need in this population of seriously
`ill patients.
`
`In addition to the indications for the treatment of secondary HPT and the hypercalcemia of .
`parathyroid carcinoma, Amgen is seeking approval for the treatment of patients with primary
`
`hyperparathyroidism for whom parathyroidectomy is not a treatment option.{;
`
`Safeg
`
`Nausea and vomiting were the two most commonly reported adverse events and the most
`
`frequent reasons for premature withdrawal from the trials. Vomiting was dose-related, nausea
`was not.
`
`The risk of hypocalcemia (< 8.4 mg /dL) is clearly increased in patients treated with Cinacalcet.
`
`The risk does not appear to be dose-related, but is does appear higher in pre—dialysis vs.
`
`dialysis patients. This is particularly true in pre—dialysis patients with relatively mild elevations
`
`In one study, nearly-50% of
`in iPTH who are aggressively treated, (i.e., goal iPTH < 65 pg/ml).
`’ the Cinacalcet patients developed serum calcium levels less than 7.4 mg/dl, whereas none of
`the placebo subj