CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`. APPLICA TI0N NUMBER: ‘
`21-688
`
`AMEDICAL REVIEW
`
`

`

`Application #:
`Sponsor:
`Pharmaceutical
`Category:
`
`-
`
`Indications:
`
`Calcimimetic
`Treatment of Secondary
`Hyperparathyroidism and
`Parathyroid Carcinoma
`
`Theresa Kehoe, MD
`Patricia Beaston, MD, PhD
`Eric Colman, MD
`
`Application Type: NDA
`Proprietary Name: Sensipar
`Route of
`Administration: Oral
`’
`
`4
`
`.
`
`- Dosage:
`
`30 — 180 mg
`
`Date Review
`Completed: 2/20/04
`
`.
`
`'
`
`Chemistry Reviewer: Sheldon Markofsky, Ph.D.
`Pharmacology Reviewer: Gemma Kuijpers, Ph.D.
`Biopharmaceutics Reviewer: Johnny Lau; PhD.
`Statistical Reviewer: Joy Mele, M.S.
`
`Patricia Beaston, MD. Ph.D.
`
`RECOMMENDED REGULATORY I drive location:
`ACTION:
`New clinical studies
`I DA, Efficacy/Label
`: upplement: °
`
`v
`
`. Clinical Hold
`Approvable
`Approve
`
`.
`
`Study May Proceed
`Not Approvable
`
`IGNATURES:
`
`.
`Medical Reviewers: Theresa Kehoe, MD.
`
`Date:
`
`Medical Team Leader: Eric Colman
`
`’
`
`Date: '
`
`

`

`
`
`Table 0 Contents
`
`1»
`
`Table of Contents2
`
`Executive Summary .......
`......5
`I
`I. '
`I Recommendations ............................... ................................................................. 5
`
`A.
`
`B.
`
`Recommendation on Approvability ..............................................................5
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps .......5
`
`II.
`
`Summary of Clinical Findings .............................
`
`................................ 6
`
`A.
`
`‘ Brief Overview of Clinical Program..... .......................................................6
`
`B. Efficacy ............................................................... 6
`
`C.
`
`D.
`E.
`
`Safety ........................................................................................................... 8
`
`Dosing ............................................
`.........-...............9
`> Special Populations ...........‘.................................................I........................ 10
`
`ClinicalRevnewll
`
`I.
`
`Introduction and Background ........................................................................... 11
`A.
`. Drug Established and Proposed Trade Name, Drug Class, Sponsor’s
`Proposed Indication(s), Dose, Regimens, Age Groups......................~........ 1 l
`State of Armanientarium for Indication(s).......'...............;.......................... l 1
`
`B
`
`C.
`
`D
`
`E.
`
`.
`
`Important Milestones in Product Development ......................................... l l
`
`' Other Relevant Information .............................. ........................................ 12
`
`Important Issues with Pharmacologically Related Agents ........................ 12
`
`II.
`
`Clinically Relevant Findings From Chemistry, Animal Pharmacology and
`Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
`Consultant Reviews ............................................................................................. 12
`
`III.
`
`Human Pharmacokinetics and Pharmacodynamics ........................................ 12
`
`Page 2
`
`

`

` C INICAL REVIEW
`
`A.
`
`B.
`
`Pharmacokinetics ....................................................................................... 12
`
`Pharmacodynamics ....................................,................................................. 13
`
`IV.
`
`Description of Clinical Data and Sources ......................
`
`............................. 13
`
`A.
`
`B.
`C.
`
`D.
`
`OverallData .................................................................. 13
`
`Tables Listing the Clinical Trials............................;.................................. 13
`Postrnarketing Experience...................... 14
`
`Literature Review.........................
`
`....................................... -. ...... 14
`
`Clinical Review Methods ...........
`
`................................................. 15
`
`A.
`
`How the Review was Conducted ............................................................... 15
`
`B.
`
`' Overview of Materials Consulted in Review ............................................. 15
`
`C.
`
`D.
`
`E.
`
`Overview of Methods Used to Evaluate Data Quality and Integrity ......... 15
`
`Were Trials Conducted in Accordance with Accepted Ethical Standards. 15
`
`Evaluation of Financial Disclosure ............................................................ 15
`
`VI.
`
`Integrated Review of Efficacy...............................................'............................ 16
`A.
`Brief Statement of Conclusions ................................................................. 16
`
`B.
`C.
`
`General Approach to Review of the Efficacy of the Drug......................... 16
`Detailed Review ofTrials by Indication.................................................... 17
`
`D.
`
`‘ EfficacyConclusrons ............48
`
`VII.
`
`................... 48:
`Integrated Review of Safety ......................,
`A.
`Description ofPatient Exposure..........................49
`B. - Methods and Specific Findings of Safety Review.....................................49
`
`c.
`D.
`
`120 Day Safety Review....... , ......................................'.........61
`Safety Conclusions...........................................'............'.............................63
`
`VIII.
`
`Dosing, Regimen, and Administration Issues ................................................. 644
`
`' Use in Special Populations.................................................................................. 64
`
`Page 3
`
`

`

`
`
`A.
`
`B.
`
`Evaluation of Sponsor’s Gender Effects Analyses and Adequacy of
`Investigation .................. , ............................................................................64
`
`Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or
`Efficacy ......................................................................................................64
`
`Conclusions and Recommendations................................................................ 655 '
`
`Appendix” 68
`
`A.
`
`Other Relevant Materials ................................~............ ..............................68
`
`Individual More Detailed Study Reviews ..................................................71
`B.
`Study 20000172: A Phase 3 Study to Assess the Efiicacy and Safety of an Oral Calcimimetic Agent
`‘
`,
`(AMG 073) in Secondary Hyperparathyroidism of End Stage Renal Disease Treated with HemodialysisL... 7|
`
`Study 20000183: A Phase 3 Study to Assess the Efficacy and Safety of an Oral Calcimimetic Agent
`(AMG 073) in Secondary Hyperparathyroidism of End Stage Renal Disease Treated with
`Haemodialysis ........, ........................................................................................................................................ 91
`
`Study 20000188: A Placebo-controlled, Double-blind, Multicenter Study to Assess the Efficacy and
`Safety of an Oral Calcimimetic Agent (AMG 073) in Secondary Hyperparathyroidism of Chronic
`Kidney Disease (Hemodialysis and PeritonealDialysrs) ................. 111
`
`Study 20010141: A Multicenter, Randomized, Placebocontrolled, Double-blind, 12—month Study to
`Assess the Effects of an Oral Calcimimetic Agent (AMG 073) on Renal Osteodystrophy in
`Hemodialysis Patients with Secondary Hyperparathyroidism ....................................................................... 137
`
`Study 20000236: A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and
`Efficacy of a Calcimimetic Agent (AMG 073) in Subjects with Secondary Hyperparathyroidism of
`Chronic Renal Insufficrency.................................... 154
`
`Study 20010239: A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and
`Efficacy of a Calcimimetic Agent (AMG 073) in Subjects with Secondary Hyperparathyroidism of
`Chronic Renal Insufficiency.......................................................................................................................... 168
`
`Study 20000204: An Assessment of the Calcimimetic Agent AMG 073 for the Treatment of Subjects
`with Parathyroid Carcinoma or Intractable Primary Hyperparathyroidism ................................................... 181
`
`_ Study 990120: A Double-Blind, Randomized, Placebo-Controlled, Multi-center Dose-Titration Study
`to Assess the Efficacy and Safety of Twice-Daily Dose Regimens of an Oral Calcimimetic Agent
`(AMG 073)in Primary Hyperparathyroidism (HPT)................................... 195
`
`Page 4
`
`

`

`
`
`Executive Sumtnary Section
`
`' Clinical Review for NBA 21-688 '
`
`Executive Summafl .
`
`I. 4
`
`Recommendations
`
`.A'
`
`Recommendation on Approvability
`
`Approve for the treatment of secondary hyperparathyroidism in patients with
`chronic kidney disease receiving.
`
`Approve for the treatment of hypercalcemia associated with parathyroid
`carcinoma.
`
`x.
`
`Approvable for the treatment of secondary hyperparathyroidism in patients with
`chronic kidney disease not receiving dialysis
`
`Approvable for the treatment of primary hyperparathyroidism when
`parathyroidectomy is not a treatment option.
`
`B.
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps
`
`Seizure: (1) Product labeling should clearly state that a small percentage of
`patients treated with cinacalcet suffered seizures during participation in pre-
`approval trials. The mechanism responsible for this finding, if not a chance
`occurrence, is probably inappropriately low serum calcium levels. (2) In vitro
`enzyme induction studies should be done to examine the potential for cinacalcet
`to increase the activity of enzymes known to metabolize common anti-seizure
`medications. (3) Amgen should provide the Division with biannual reports.
`summarizing seizure data from Ongoing trials and spontaneously-submitted
`MedWatch reports.
`
`Cardiac Repolarization: Although the phase-3 data provide only a weak signal
`that cinacalcet may prolong the QT interval, a thorough QT study would provide a
`- precise estimate of the drug’s overall affect on cardiac repolarization, and if
`properly designed, would clarify whether cinacalcet’s affect on the QT interval is
`due solely to its action to lower serum calcium levels.
`
`Page 5
`
`

`

`
`
`Executive Summary Section
`
`H.
`
`Summary of Clinical Findings
`
`A.
`
`Brief Overview of Clinical Program '
`
`Cinacalcet is the first oral calcimimetic drug submitted for market approval for the
`
`' C,
`:1 treatment of secondary hyperparathyroidism (HPT)1n patients with
`chronic kidney disease (CKD).
`
`Amgen1s requesting approval of cinacalcet for (1) theH treatment of
`secondary HPT1n patients with CKD, receiving and not rece1vmg dialysis; (2) the .
`treatment ofprimary HPT whenparathyroidectomyis not a treatment option; (3) the
`treatment ofhypercalcemia1n patients with parathyroid carcinoma
`
`The principal components of the cinacalcet clinical development program included three,
`6-month, randomized, double-blind, placebo-controlled phase-3 studies of patients with
`CKD and secondary HPT receiving dialysis; a double-blind, placebo-controlled 6-month
`- extension study of patients who completed two of the three CKD dialysis studies; two
`randomized, double—blind, placebo—controlled studies of patients with pre-dialysis CKD
`and secondary HPT; and an ongoing 3-year, open-label, single-aim study that enrolled 3
`separate groups of patients: 2 with primary HPT who “failed” parathyroidectomy, 3 with
`.primaryHPT in whom parathyroidectomy was not an option, and 10 patients with
`parathyroid carcinoma.
`
`B.
`
`Efficacy '
`
`Secondary Hyperparathfloidism in Patients with CKD Receiving Dialysis:
`
`Studies 20000172 20000183 and 20000188
`
`To be eligible for these studies, patientshad to be at least 18 years of age, have a serum
`iPTH > 300 pg/ml, and a serum calcium 3 8.4 mg/dL. The studies consisted of a 12- ,
`week, dose-titration phase and a 14-week efficacy-assessment phase. Patient were started
`on 30 mg once daily cinacalcet of placebo The dose could be titrated up to 60 mg, 90
`mg, 120 mg, and 180 mg at 4—week intervals. The dose was increased unless one of the
`following applied: LPTH 5 200 pg/ml, serum calcium < 7. 8 mg/dL, or the subject was
`experiencing an adverse event that precluded a dose increase. If a patients experienced
`. symptoms of hypocalcemia and/or a serumcalcium < 8.4 mg/dL, calcium supplements
`and/or phosphate binders could be increased. If these measures were insufficient, the
`vitamin D dose could be increased.
`'
`
`All serum iPTH levels were measured using the Nichols IRMA assay. A total of471
`patients were randomized to placebo and 665 patients to cinacalcet. 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 61(mg/dL)2. Sixty—six percent of the subjects
`
`Page 6
`
`

`

`
`
`Ex'ecutivé Summary Section
`
`were receiving vitamin D therapy at baseline, and 93% were on some type of phosphate
`binder. The mean dose of study drug during the efficacy-assessment phase for subjects
`who achieved a iPTH g250 was 85.0 mg. Seventy-eight percent of placebo patients and
`71% of the Cinacalcet patients completed the 6-month studies.
`
`In the primary analysis of efficacy, 40% of Cinacalcet patients compared with 5% of
`placebo subjects achieved a serum iPTH level < 250 pg/ml during the efficacy-
`" assessment phase ofthe trials (p<0.001).
`Regarding secondary efficacy analyses, the following table provides the proportion of
`patients in each group who achieved the Kidney Disease Outcomes Quality Initiative
`(K/DOQI) treatment goals during the efficacy-assessment phase of the trials. A
`significantly larger percentage of patients treated with Cinacalcet achieved the new .
`treatment goals than did patients treated with placebo.
`
`‘
`
`iPTH 150— 300 pg/ml
`Serum Ca 8.4- 9.5 mg/dl
`Serum Phos 315 — 5.5 mg/dl
`
`iPTH 150-300 & Ca x P < 55
`
`Ca x P < 55 mg/dl2
`
`Secondm Hyp‘emarathfloidism in Patients with CKD Not Receiving Dialysis:
`Study 20000236
`
`F
`
`Page 7
`
`

`

` CLINICAL REVIEW
`
`Executive Summary Section
`
`N
`
`’F—f—fl
`
`“Intractable” Primary Hyperparathfloidism and Parathfloid Carcinoma
`Study 20000204
`
`A total of 10 patients with parathyroid carcinoma were enrolled in this ongoing, 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 trial.
`The company refers to these five patients as having “intractable” primary
`Hyperparathyroidism. At the end of a 16-week titration phase, 7/10 subjects with
`: parathyroid carcinoma and 4/5 with intractable hyperparathyroidism had a reduction in
`serum calcium of at least 1.0 mg/dL. The doses of cinacalcet required to treat these
`patients populations, 30 mg BID to 90 mg QID, were much larger than those used to treat
`patients with secondary hyperparathyroidism.
`
`C.
`
`Safety
`
`The most common treatment-emergent adverse events in patients with CKD receiving
`dialysis were nausea and vomiting, which were reported by 31% and 27% of cinacalcet
`subjects compared with 19% and 15% of placebo~treated patients. There was a clear
`
`Page 8
`
`

`

`
`
`Executive Summary Section
`
`dose-response relationship for vomiting, but not nausea. Nausea and vomiting were also
`commonly reported by patients with pre-dialysis CKD, although the incidence rates were
`lower in this population.
`
`In CKD patients on dialysis, inappropriately low serum calcium levels (< 8.4 mg/dL) ,
`were noted in 66% of cinacalcet subjects vs. 25% of placebo patients. Approximately 5%
`of cinacalcet and 0.9% of placebo patients had 2 consecutive serum calcium values < 7.5
`mg/dL. Of the patients who developed a serum calcium level < 8.4 mg/dL, 40% of
`cinacalcet patients Vs. 34% ofplacebo subjects had their dose of calcium-based
`phosphate binder increased during the remainder of the trials.
`
`In CKD patients not receiving dialysis, serum calcium levels < 8.4 mg/dL developed in
`84% of cinacalcet patients and 9% ofplacebo patients. Of the patients who developed a
`serum calcium level < 8.4 mg/dL, 17% of cinacalcet patients vs. none of placebo subjects
`had their dose of calcium-based phosphate binder increased during the remainder of the
`trials; and 17% of active-drug treated patients compared with none of the placebo patients
`had theirdose of vitamin D sterol increased during the remainder of the trials.
`
`In the three, phase-3 studies of patients with CKD receiving dialysis, 1.4% (9/656) of
`cinacalcet—treated patients and 0.4% (2/470) of placebo-treated patients reported suffered
`a seizure — primarily grand mal. Some of the cinacalcet patients had a history of a seizure
`disorder and a few were taking anti-seizure medication at baseline. The doses of
`cinacalcet patients were taking at the time of the seizures ranged from 30 to 180 mg QD.
`Although it’s unknown what the serum calcium levels were immediately before the
`seizures occurred, if cinacalcet does in fact increase the risk for seizures, it likely does so
`by way of hypocalcemia.
`
`Regarding cardiac repolarization, limitations of the preclinical and clinical data do not
`allow for a comprehensive assessment of cinacalcet’s potential to prolong the QT
`interval. It is unclear if the minor QT prolongation observed in the phase 3 trials is due to
`lowering of serum calcium levels or to direct effects of cinacalcet or its metabolites.
`Given this uncertainty, a thorough QT study, ifproperly conducted, would provide
`valuable informationregarding the safety profile of cinacalcet.
`
`Confirming findings from a non-human primate study, treatment of male dialysis patients
`with cinacalcet for 6 months led to minor-to-modest reductions in mean serum total and
`
`free testosterone levels, without significant changes in FSH or LH concentrations. The
`mechanism responsible for and the clinical significance of these findings are unknown.
`
`D.
`
`Dosing '
`
`One of the striking features of the phase-3 data was the wide range of cinacalcet doses
`patients were taking at the end of the studies. For example, at the completion of the three,
`6-month CKD — dialysis studies, 40% of patients were receiving 180 mg once-daily of
`cinacalcet, while the remaining 60% of subjects were equally divided among the 30 mg,
`60 mg, 90 mg, and 120 mg doses. This may reflect a host of factors, including baseline
`
`Page 9
`
`

`

`
`
`Executive Summary Section
`
`iPTH and serum calcium levels, varying sensitivities to cinacalcet-induced nausea and
`vomiting, and varying rates of use of concomitant medications such as calcium
`supplements, phosphate binders, and vitamin D sterols. The dosing of cinacalcet is much
`more complicated than that for most other drugs because the dose is titrated not to a
`single endpoint, such as serum iPTH, but to changes in serum calcium and phosphate as
`well. The concomitant use of phosphate binders and vitamin D sterols also influence the
`dosing of cinacalcet.
`
`E.
`Special Populations
`Because cinacalcet is metabolized by the liver, patients with moderate-to-sever hepatic
`impairment must be closely monitored if treated with this drug. The pharmacokinetcs of
`cinacalcet is similar in patients less than and over the age of 65.
`
`Page 10
`
`

`

`
`
`Clinical Review Section
`
`Clinical Review
`
`I.
`
`Introduction and Background
`
`LA. Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed
`lndication(s), Dose, Regimens, Age Groups
`-
`
`Amgen, Inc. has submitted this new drug application for AMG 073, cinacalcet hydrochloride [N-
`[1 (R-)-()---(1-naphthyl)ethyl]-3--[3 -(trifluoromethy1)pheny1]--1-aminopropane hydrochloride
`364782-34-3 (aR)—(-)-'a—methyl‘-N—[3- [3-(trifluoromethyl)phenyl]], proposed trade name
`Sensipar.Sensipar1s a calcimimetic agent. Calcimimetic agents are organic small molecules that
`act as modulators of the calcium-sensing receptor (CaR) present on the surface of parathyroid
`and other cells. By targeting the CaR, calcimimetics regulate plasma PTH secretion by
`amplifying the receptor’s sensitivity to extracellular calcium. Amgen‘proposes to market
`
`cinacalcet once daily for theE
`:1 treatment of secondary HPT associated with chronic
`kidney disease, end stage renal disease (dialysis), secondary HPT associated with chronic renal
`insufficiency (pre-dialysis),
`intractable primary HPT, and e parathyroid carcinoma-induced
`hypercalcemia.
`
`LB.
`
`State of Armamentarium for lndication(s)
`
`_
`
`Current medications available for treatment of secondary HPT include phosphate binders
`(calcium and non—calcium based) and vitamin D sterols. Dietary phosphate restriction and
`phosphate binders are used to reduce serum phosphorus levels, while calcium supplements and -
`vitamin D sterols are used to control PTH. Calcium-based phosphate binders and vitamin D
`sterols are limited by their propensity to increase serum calcium and phosphorus. These
`complications frequently require that treatment be withheld for safety considerations.
`
`LC.
`
`Important 'Milestones in Product Development
`
`0
`
`In discussions with regulatory authorities in the US and Europe, it was agreed that a
`reduction in iPTH to less than 250 pg/mL was an appropriate primary endpoint for
`evaluating the efficacy ofcinacalcet in CKD subjects receiving dialysis with secondary
`HPT.
`
`,
`
`. 0 Additional recommendations included the collection of bone histomorphometrydata
`(conducted- study 20010141).
`‘
`j 0 Based on a meeting with the Division on November 9, 2001, the clinical program .was
`modified in accordance with this recommendation as follows:
`0 The phase 3 20000188 (randomized, double-blind, placebo-controlled, phase 3 study in
`CKD subjects receiving hemodialysis or peritoneal dialysis) study design was modified
`to be double-blind and placebo-controlled
`o Amgen initiated a 6-month, placebo-controlled, double-blind, extension study to the 6-
`month, phase 3 studies 20000172 and 20000183, providing 12-month exposure datain
`CKD subjects receiving dialysis (study 20010240).
`In May 12, 2003, cinacalcet received Orphan Designation from the US FDA for the
`treatment of hypercalcemia1n patients with parathyroid carcinoma.
`
`o
`
`-
`
`Page 11 -
`
`

`

`Subjects
`enrolled
`com I
`
`_
`
`’
`
`Complete Date
`
`—_-E-_-_
`20000188
`32;
`-
`ESRD, 111) or PD
`PTH_< 250 pg/mL
`P3, R, DB, Pc
`- PTH >300 pg/mL
`3/28/2003
`
`‘
`
`'
`
`__ '
`P122150
`533
`%
`ESRD, HD
`415‘ PTH>300pg/mL
`266
`‘38
`smd‘cs '72 '83
`128
`
`Study 990101
`
`C—inacalcet
`_otal
`Placebo
`Cin
`lcet
`T_otal
`
`32
`
`50 9
`’
`
`i
`1
`
`-
`
`ESRD, HD
`PTH >300pg/ml.
`
`20000237
`P2,R,DB,PC
`'
`20010240
`DB, Pc Extension
`
`990126
`Subset of990101
`
`20010141
`P2, R, DB, PC
`
`20010239
`P2, R, DB, PC
`
`990120
`P2, R, DB, PC
`
`Uncontrolled Studies ESRD
`i
`0L extension
`Studies 101,102,740237
`i 170
`Cinacalcet
`'30
`2
`Uncontrolled Stndi Prim:
`I! re arath oidism and Parath old Carcinoma
`20000159
`0L extension
`
`522mm]
`
`PTH_< 250 pg/mL
`7/19/2001
`Safety
`6/23/2003
`
`Bone Histomorph
`4/11/2000
`
`Bone Histomorph
`5/14/2003
`
`-
`
`‘
`
`U
`
`18-29d
`
`-
`
`ongomg
`Safety
`
`,
`Serum calcium
`ongoing
`
`terminated
`
`Safety
`
`32-136
`
`safe."
`ongomg
`
`
`
`—“——-15’
`
`[_ 47.5
`i Parath roid Cancer
`5
`67 4
`intractable PHP'I‘
`'
`Ca > 12.5
`
`20000204
`P2. 0L, single 'arrn
`
`2001eo142
`
`Cinacalcet
`
`20°20'53“,“
`01.,extens
`
`macalcet
`
`i
`
`(plan140)
`
`563
`(open enroll,
`Ian850
`
`Study20000236.
`
`.
`,
`Studies 172, 183, 188, 141, 240
`
`,
`
`IV.C. Postmarketing Experience
`
`Cinacalcet is' not approved for marketing in any country.
`
`IV.D. Literature Review
`
`A MEDLINE review was conducted for Cinacalcet and revealed 17 articles. The majority of the
`articles were included in the sponsor’s references. The information included in the articles does
`not add materially to the information provided in the NDA.
`
`Page 14
`
`

`

`
`
`
`
`Clinical Review Section
`
`
`
`Clinical Review Methods
`V.
`V.A. How the Review was Conducted
`
`This submission includes 47 clinical studies in normal volunteers and patients with primary or
`secondary HPT performed from December 1997 to June 2003. A total of 19 studieswere
`conducted to evaluate safety and efficacy: 15 in subjects with secondary HPT, and 4 in subjects
`with primary HPT and parathyroid carcinoma. The remaining 28 studies provide
`biopharmaceuticand clinical pharmacology information as well as information on initial efiicacy
`and tolerability of cinacalcet. Detailed review was conducted for 8 of the trials: studies
`20000172, 20000183, 20000188, 20010141, 20000236 and 20010239 for the indication of
`secondary HPT and study 20000204 for the indication of parathyroid carcinoma and intractable
`' primary HPT, and study 990120 for safety data in patients with primary HPT.
`
`V.B. Overview of Materials Consulted in Review
`
`This review was conducted utilizing data in the electronic submission of the NDA. All trials
`were conducted under IND 56,010. ‘
`
`V.C. Overview of Methods Used to Evaluate Data Quality and Integrity
`
`The Division of Scientific Investigation (DSI) was'consulted for this NDA and their audits did
`not identify any significant deviations from Standard Operating Procedures.
`
`V.D. Were Trials Conducted in Accordance with Accepted Ethical Standards
`All studies appear to have been conducted in accordance with FDA guidelines on “Good Clinical
`Practice” and the principles of the Declaration of Helsinki.
`
`V.E.‘ Evaluation of Financial Disclosure
`
`Financial disclosure information Was provided by the sponsor and reviewed. In the three Phase 3
`trials evaluating safety and efficacy of cinacalcet in end stage renal disease, 18 of 183 sites had
`investigators who reported significant payments of other sorts and equity interest in the
`sponsoring company. These sites accounted for 12% of the enrolled subjects. In the two trials
`evaluating safety and efficacy of cinacalcet1n stage 3 or 4 renal disease, 1 of 33 sites had
`investigators who reported significant payments of other sorts and equity interest in Amgen,
`while 3 sites had investigators who did not provide financial disclosure information, despite due
`diligence of the company. These sites accounted for 16% of the enrolled subjects. In the four
`trials evaluating safety and efficacy of cinacalcet in primary hyperparathyroidism and
`parathyroid carcinoma, 1 of 26 sites had investigators who reported significantpayments of other
`sorts and equity interest in Amgen, while 1 site had investigators who did not provide financial
`disclosure information. These sites accounted for 2% of the enrolled subjects.
`
`In order to adequately protect against and minimize potential bias, the sponsor conducted
`clinical site monitoring and clinical audits as well as an independent assessment of efficacy
`. response data. The individual study designs were multicenter, randomized and blinded with
`objective endpoints measured in a blinded fashion by a central independent laboratory, which
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`Clinical Review Section
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`will also play a role in minimizing potential bias. It is unlikely that the disclosed financial
`, arrangements would impact the study outcome nor affect the conclusions drawn about the
`efficacy and safety of cinacalcet.
`
`VI.
`
`Integrated Review of Efficacy
`
`VI.A. Brief Statement of Conclusions
`
`'
`
`2 Secondag Hypemarathjgoidism:
`
`In subjects with secondary HPT associated with end stage renal disease, cinacalcet is effective in
`reducing plasma levels of iPTH. Therapy was more effective in those subjects with less severe
`HPT, with a 12% response rate (iPTH < 250 pg/ml) in subjects with baseline iPTH levels of
`greater than 800 pg/mL, compared with a 61% response rate in subjects with a baseline iPTH
`concentrations of 300—500 pg/ml. A higher‘proportion of subjects in both groups achieved a 30%
`reduction in baseline iPTH levels (62% in the cinacalcet-treated group vs 11% in the placebo-
`treated group). The mean Ca x Pion product value was reduced by 14%in the cinacalcet grOup,
`compared with a O. 1%mcrease in the placebo group.
`
`In subjects with secondary HPT associated with Stage 3 or 4 chronic kidney disease (pre—
`dialysis),M
`
`
`3
`
`Prima H e arath oidism
`
`‘
`
`In patients withparathyroid carcinoma and intractable primary hyperparathyroidism, cinacalcet
`
`
`
`
`VI.B. General Approach to Review of the Efficacy of the Drug
`
`This review of the efficacy .of cinacalcet was approached individually for each indication.
`Detailed reviews of each study are found -in the appendix. Presentation and discussion of the
`efficacy data in the following section is based on integrated data for the indication.
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`VI._C. Detailed Review of Trials by Indication
`
`VI.C.1. Secondary Hyperparathyroidism in Patients with End Stage Renal Disease
`
`’
`Amgen’s clinical development program included three phase 3 trials (20000172, 20000183,
`20000188) investigating the safety and efficacy of cinacalcet for the treatment of secondary HPT
`in patients on dialysis. These trials are the main focus of this integrated efficacy review. As well,
`study 20010141 evaluated the bone) histomorphometn'c outcomes of cinacalcet use and study
`20010240 was a 6-month extension of studies 20000172 ‘and 20000183 for continued safety
`evaluation. Please see Appendix XI.B for the detailed reviews of these individual trials.
`
`Objectives: The primary objective in alllthree studies was to investigate the efficacy of
`cinacalcet compared with placebo by determining the proportion of subjects with a mean plasma
`iPTH value 5 250 pg/mL during the efficacy-assessment phase.
`
`Study Design: All studies were randomized, double-blind, placebo-controlled, parallel-group
`and 26 weeks in duration. Trials 2000172 and 20000183 had identical study designs, enrolling
`patients with secondary HPT on hemodialysis and stratifying patients based on iPTH and
`calcium-phosphate ion product level (Ca x P). Trial 20000188 enrolled dialysis (hemodialysis or
`peritoneal dialysis) patients with secondary HPT, although stratification criteria were slightly
`different (see below). In contrast to studies 20000172 and 20000183, no limit Was placed on the
`number of subjects with a baseline iPTH > 800 pg/mL who could enroll in study 20000188. All.
`studies consisted of 2 phases, a dose-titration phase and an efficacy-assessment phase. Studies
`20000172 and 20000183 had a 12-week dose-titration phase followed by a 14-week efficacy-
`assessment phase. Study 20000188 had a 16-week dose-titration phase followed by a 10-week
`efficacy-assessment phase.
`-
`
`Stratification Criteria:
`
`For studies 20000172 and 20000183, subjects were stratified as follows:
`
`0
`
`iPTH > 300 pymL (31.8 pmol/L) to < 500 pg/mL (53 pmol/L) and Ca x P < 70 (mg/dL)2
`(565 [m1hol/L]2)
`.
`iPTH > 300 to < 500 pg/mL and Ca x P > 70 (mg/dL)2
`iPTH > 500 to < 800 pg/mL (84.8 pmol/L) and Ca x P < 70 (mg/dL)2
`iPTH > 500 to $800 pg(mL and Ca x P > 70 (mgdL)2
`iPTH > 800 pg/mL and Ca x P s 70 (mg/dL)2
`iPTH > 800 pg/mL and Ca x P > 70 (mg/dL)2
`
`For study 20000188, subjects were stratified as follows:
`
`‘ hemodialysis, and iPTH Z 300 pg/mL (31.8 pmol/L) to S 500 pg/mL (53 pmol/L)
`hemodialysis, and iPTH Z 500 pg/mL to S 800 pg/mL (84.8 pmol/L)
`hemodialysis, and iPTH > 800 pg/mL
`
`peritoneal dialysis, and iPTH Z 300 pg/mL
`
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`Study Methods: All measurements of iPTH were performed by C <— 3 Laboratory using the
`Nichols IRMA assay.
`
`Study Medication and Dose Titration: All medications were administered orally with meals at
`a starting dose of 30 mg cinacalcet or placebo, once-daily. For all studies, possible sequential
`doses during the study were 30, 60, 90, 120, and 180 mg Cinacalcet or placebo, once-daily. In
`studies 20000172 and 20000183, dose titration occurred at Weeks 3, 6, 9, 12, 16, 20, and 24. For
`study 20000188, dose titration occurred at Weeks 4, 8, 12, 16,20, and 24. Except during the
`screening phase, changes in phosphate binders/oral calcium supplements were permitted
`’
`throughout the study. Changes in vitamin D therapy were only permitted based on protocol-
`specified guidelines.
`
`Dose Titration: For all studies, a subject’s dose was NOT increased if any of the following
`criteria applied:
`
`0 The central laboratory iPTH value from the preceding study visit was 5 200 pg/mL (21.2
`pmol/L).
`0 The highest dose of study medication was reached.
`0 The serum calcium was < 7.8 mg/dL (1.95 mmol/L) or the subject was experiencing
`symptoms of hypocalcemia.
`o The subject was experiencing an adverse event that precluded a dose increase.
`
`If iPTH values were < 100 pg/mL for 2 to 3 consecutive study visits, study medication was
`reducedto the next lower dose.
`
`Treatment of Hypocalcemia: For all studies, if a subject experienced symptoms of hypocalcemia
`and/or a serum calcium < 8.4 mg/dL, calcium supplements and/or phosphate binders may have
`been increased to resolve these symptoms (if present) or to increase serum calcium to z 8.4
`_ mg/dL. If these measures were insufficient, the vitamin D dose could be in