‘3'4'6 Local tolerance
`
`Table 2.6.7.163. Local Tolerance (In Vltro)
`Test Article: Clnacalcet Hydrochloride (AMG 073)
`
`Species]
`Strain
`Anticoagulaled
`rat. non-hmnen
`primate. and
`human blood
`
`_
`
`Method of
`Administration
`In vltro direct
`contact
`
`.
`
`Human blood
`
`Hmn blood
`
`In vitro dlrect
`contact
`
`In vitro direct
`contact
`
`Doses
`5 mgmt. MG 073 Meeylate
`(50mM lactate, 190mm
`dexlmse, pH 420);
`- 1.33 mglrnLAMG 073 Hot (SOmM
`acetate, 222mm amuse, pH
`4.25); 5 mglml. AMG O73 Meeylale
`(50mm acelale. 187mM dextrose.
`. DH 4.20);
`.
`5 mghnL MG 073 Mosylale
`(SOmM eoelate. 4% Mt! elharlol,
`DH 4-27)
`
`ms 073 Meeylale and
`AMG 073 HCl at 0.005, 0.05, 0.5. ‘
`5.0. 50. 500. and 1000 :1me
`AMG 073 In the lollowlng vehicles:
`lntrallold-low shear. lnlralipld-hlgn
`shear: 10mM AcelaleJ278mM
`Dextrose: lOmM Acelaletz75mM
`Mannltol; 5% CapllsousomM
`Phosphate; 11.6% Capllsol’NaOH
`lo adiusl (pH~7.85); HCl lo adjust
`W440): 05% Tween 80/me
`Phosphate: OMSO. 15%
`Captlsol/10mM Phosphate, pH7.0
`All at 1 rug/ml. concentration
`and 815. 50. or 500% volume
`
`,
`
`Gender
`and No.
`Per Group
`Illa
`
`'
`
`Noteworthy Flndlngs
`All test articles and vehicle controls induced
`hemdysls in rat. non-human prime. and
`human blood.
`
`Study
`~ Number
`100359
`
`nla
`
`nla
`
`_
`
`Hemolysls observed in all test groups mm 3
`'
`general dose-response trend
`
`-
`
`lnooncluslve results for lntrallpld moles
`due lo opaque white appearance [modeling
`with optical density. The Mowing
`lormulalims were negative for producing
`hemolysas: 11.6% CaplisoUNaOl-l to 8133051
`and 15% Capllsollme Pbosphale,pH7.0.
`All remaining lest article lormulallons were
`positive tor producing hemolysls in human
`blood at 1 mgmL. Increasing nemolylic'
`index values occurred with higher volumes
`ol formulations used in the assays
`
`100399
`
`100482
`
`3
`3
`l
`I
`l
`;
`l
`’
`l
`é
`l
`,
`i
`;l
`
`Table 2.8.7.16b. Local Tolerance (In Vlvo)
`Test Article: Clnacelcet Hydrochloride (AMG 073)
`
`l il El
`
`100324
`
`New Zealand
`
`lnslllled into
`
`32 mg
`
`3 females
`
`WhileRabbi!
`
`6“?“ Pig
`
`theeye
`
`lnlrademal
`Topical.
`
`
`
`madame: 9,1 mljslte (0.5% m).
`Topical 0.3 mL'slle (25% wiv)
`.
`Challenge 0.2 mUslte (25% will)
`
`'
`
`Mild Smother (Grade u)
`
`102945
`
`.
`10 M a F
`(“’3‘ “Mel
`5 M 8: F
`(vehltle
`control)
`3M8F
`
`(posillve
`
`control) l
`
`
`
`Topical
`0,59! 1mL dlsfilled H20
`New Zealand
`MG 073 caused only a very slighl
`
`While Rabon
`erythema reaction In 18 anlmals at the 4-hr
`
`observation point No other dermal irritation
`.
`was observed
`
`AMG O73 caused corneal ooaclty, lrldel
`
`
`
`I ll ll ll
`
`all 3 animals. Corneal madly (313 animals)
`and nonlmolival inflation (1/3 me) were ,
`still present at day 21 alter (remnant
`
`lnltatlon.andsevereoonlunollvalmlalionIn
`
`Local tolerance studies showed that cinacalcet is a'severe eye irritant and a mild dermal
`contact irritant. In the guinea pig sensitization study, cinacalcet was a mild dermal sensitizcr.
`
`174
`
`

`

`' Lpagqs) have “been
`removed because it
` containstrade secret
`
`_
`
`_
`
`-
`
`*
`
`*
`
`and/or confidential
`information thatIS not
`diselosable .
`~
`
`M
`
`

`

`3.5 REFERENCES
`
`Blankenship KA, Williams JJ, Lawrence MS, McLeish KR, Dean WL, McArthur JM: The
`calcium--sensing receptor regulates calcium absorptionin MDCK cells by inhibition of
`PMCA. Am J Renal Physiol 280:F815-F822 2001
`
`Bronsky D, Dubin A, Kushner DS, Waldstein SS: Calcium and the electrocardogram. III The
`relationship of the intervals of the electrocardiogram to the level of serum calcium. Am J
`Cardiology, 840-843 (1961)
`
`Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor 0, Sun A, Hediger MA,
`Lytton J, Hebert SC: Cloning and characterization of an extracellular
`Ca(2+)-sensing receptor from bovine parathyroid. Nature. 366:575-580, I993.
`
`Brown EM, MacLeod RJ: Extracellular calcium sensing and extracellular calcium
`signaling. Physiol Rev. 81:239-297, 2001.
`
`Brown EM, Chattopadhyay , Vassilev PM, Hebert SC: The calcium-sensing receptor (CaR)
`permits Ca2+ to function as a versatile extracellular first messenger. Recent Prog Horm Res:
`257l280, 1998.
`
`Davis TM, Singh B, Choo‘KE, Ibrahim J, Spencer JL, StJohn A: Dynamic asessment of the
`electrocardiographic QT interval due to citrate infiision in healthy volunteers. Br Heart J
`73(6): 523-526 (1995)
`
`Delamere NA, Paterson CA, Holmes DL: Hypocalcemic cataract. I. An animal model and
`cation distribution study. Metabol Pediatr Ophthalmol 5: 77-82, 1981.
`
`Fox J. Lowe SH. Petty BA. Neineth EF. NPS R-568: A type II calcimimetic compound
`that acts on parathyroid cell calcium receptor of rats to reduce plasma levels of
`parathyroid hormone and calcium. Journal ofPharmacology & Experimental
`Therapeutics. 290(2):473—479, 1999a.
`
`Fox J, Lowe SH, Conklin RL, Petty BA, Nemeth EF. Calciinimetic compound NPS R-568
`stimulates calcitonin secretion but selectively, targets parathyroid gland Ca2+
`*
`receptor in rats. Journal ofPharmacology & Experimental Therapeutics.
`290(2):480-486, 1999b.
`
`Hauache OM, Hu JX, Ray K, Spiegel AM: Functional interactions between the
`extracellular domain and the seven—transmembrane domain in Ca2+ receptor
`activation. Endocrine. 13:63-70, 2000
`
`Hu J, Reyes-Cruz G, Chen W, Jacobson KA & Spiegel AM. Identification of acidic
`residues in‘ the extracellular loops of the seven--transmembrane domain of the
`human Ca2+ receptor critical for response to Ca2+ and a positive allosteric
`modulator. (2002) J. Biol Chem. 277, 46622—46631.
`
`I79
`
`

`

`Ishii H, Wada M, Furuya Y Daily intermittent decreases in‘serum levels ofparathyroid
`hormone have an anabolic-like action on the bones of uremic rats with
`
`low-turnover bone and osteomalacia. Bone (2000) 26: 175-182.
`
`Li YC, Amling M, Pirro AE, Priemel M,‘ Meusve J, Baron R, Delling G, Demay MB.
`Normalization of mineral ion homeostasis by dietary means prevents
`hyperparathyroidism, rickets and osteomalacia, but not alopecia in vitamin D
`receptor-ablated mice. Endocrinology (1998); 139: 4391-4396.
`
`’
`
`Marban, E: The surprising role of vascular KATP channels in vasospastic angina J.Clin
`Invest. 110: 153—154, 2002
`
`‘ Nemeth EF, Steffey ME, Hammerl'and LG, Hung BCP, VanWagenen BC, DelMar EG,
`Balandrin MF: Calcimimetics with potent and selective activity on the parathyroid
`calcium receptor. Proc Natl Acad Sci USA 95:4040—4045, 1998
`
`'
`
`Suzuki, M, Sasaki, N., Mild, T, Sakamoto, N, Ohmoto—Sekine, Y, Tamagawa, M, Seino, S,
`Marban, E and Nakaya, H: Role of sarcolemmal K(ATP) channels in cardioprotection against
`ischemia/reperfusion injury in mice. J.Clin.1nvest. 109: 509-516, 2002
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`180
`
`

`

`3.6 OVERALL CONCLUSIONS AND RECOMMENDATIONS
`
`Conclusions: Pending agreement on the label, this NDA can be approved (AP)
`
`Recommendations: Based on in vitro and in vivo nonclinical data, thorough evaluation of
`clinical trial data for any events related to cardiac conduction abnormalies under
`resting or stress conditions (EKG), myocardial and coronary artery disease, and CNS
`excitation (seizures)1s recommended. A
`m
`
`Suggested labeling: Labeling changes for the “PRECAUTIONS” section relating to
`carcinogenicity and reproductive study results are appended (Team Leader Memo, K.
`Davis-Bruno, February 10,2004)
`
`Signatures (optional):
`
`Reviewer Signature
`
`Supervisor Signature
`
`ISI I
`
`I g,
`
`Concurrence Yes _ No_
`
`18l
`
`

`

`3.7 APPENDIX/ATTACHMENTS
`
`INITIAL IND REVIEW
`
`ECAC MEETING MINUTES -
`
`PROPOSED LABEL
`
`’
`
`SUGGESTED LABELING CHANGES (Team LeaderMemo, K Davis-Bruno, February
`
`_,10 2004)
`
`182-
`
`

`

`IND 56,010
`
`Reviewer:
`Review Date:
`
`‘ Gemma Kuijpers
`June 19, 1998
`
`PHARMACOLOGY REVIEW OF ORIGINAL IND
`
`'
`
`Amgen Inc.
`May 21, 199
`000
`'
`
`AMG 073
`Calcimimetic
`Treatment of secondary hyperparathyroidism
`
`'
`Sponsor.
`Submission:
`Serial NL:
`
`Drug:
`Category:
`Indication:
`
`Contents Page
`
`........................ 2
`A. Clinical Plans
`B. Chemistry...:........'. ..................................................................
`3
`C. Pharmacology ......................................................................... 4
`D. Toxicology ............................................................................. 4
`E. Toxicokinetics ............................................'........‘.................... 6
`
`8
`F. Genotoxicity ...........................................................................
`8
`' G. Summary and Evaluation .......................................................
`H. Recommendation .................................................................... 10
`
`Gemma A. Kuijpers, PhD.
`
`.
`
`cc:
`‘
`
`IND Arch
`HFD—SlO
`
`4
`
`HFD—SlO/Steigerwalt/Kuijpers/Lutwak/Hedin
`c:\my documents\ind56010\original ind review
`
`183
`
`

`

`IND 56,010
`
`Sponsor:
`Drug:
`
`_
`
`Category:
`Indication:
`Dosage formulation:
`Dosage route:
`Clinical Status:
`Memos:
`Related IND's:
`
`Amgen Inc.
`‘
`AMG 073
`(N-[l -(R)-( l -naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]— l -
`aminopropane
`'
`' Calcimimetic
`Treatment of secondary hyperparathyroidism (HPT)
`\N
`'
`Oral
`PhaseI/Il
`Pre-IND meeting: May 6, 1998
`
`
`-
`
`'
`
`INTRODUCTION
`
`Secondary hyperparathyroidism (HPT) is characterized by parathyroid gland hyperplasia and eleveated
`circulating PTH levels. The disease is a consequence of chronic renal failure (CRF) and/or end’stage renal
`disease (ESRD). Prevalence of CRF is 250,000 in US. The bone of HPT patients has a fibrotic marrow space,
`and there is a predisposition to fractures and impaired erythropoiesis. Excess PTH may also affect various other
`tissues (heart,- neurons, muscle, vessels). Hypercalcemia can develop in severe cases. Together with
`hyperphosphatemia this can lead to sofi tissue calcification. Primary HPT is associated with persistently elevated
`seium calcium and PTH levels. Most cases are dye to parathyroid gland adenoma. It is frequently asymptomatic,
`but can lead to high bone tumover, osteolysis, marrow fibrosis and sofi tissue calcification.
`Current therapy for secondary HPT includes oral phosphate binders, dietary P restriction, Ca supplementation
`and vitamin D therapy. Calcimimetic compounds such as AMGO73 are compounds that mimic or potentiate the
`effects of extracellular calcium, and offer an alternative therapeutic approach for the treatment of HPT. AMG
`acts in an 'agonistic manner on the PT gland Ca receptor to increasevthe sensitivity of parathyroid cells to
`extracellular ionized calcium. Calcimimetics also act on parafollicular cells of the thyroid gland to increase
`calcitonin secretion. AMG has been shown to suppress PTH secretion and increase calcitonin release. A
`
`reduction in serum PTH is expected to lead to improvement of renal osteodystrophy and bone pathology. C
`'Wm
`
`:3
`,
`
`A. CLINICAL PLANS
`
`The initial clinical trial (Amgen Protocol 980126) is a phase II double-blind, randomized, placebo-controlled, ,
`multicenter study to assess safety, tolerability, pharmacokinetics and clinicalleffects of single and multiple doses
`' of AMGO73. Measurements will be laboratory tests, ECGs, adverse events, physical examination, AMGO73
`pharmacokinetics, and plasma PTH, total serum Ca concentrations and serum calcitonin concentrations. Trial
`will be done in patients with secondary HPT.
`.
`Study will consist of a single dose phase, 72h follow up phase and washout phase of minimal 4 weeks, followed
`by a multiple dose phase of 8 days, plus 72h follow up phase. Five (5) single dose cohorts will consist of 10
`subjects each'(2 placebo, 8 on drug) for 5, 10, 25, 50, 75 mg doses. Cohorts will be sequential (ascending dose
`regimen), and SMC will evaluate whether it is safe to advance to next dose. Three (3) multiple dose cohorts will
`consist of 10 subjects each (2 placebo, 8 on drug) for 3 doses selected from 5, 10, 25, 50 and 75 mg. Fifty
`subjects will be in single-dose phase,'thirty subjects will continue to multiple-dose phase. The latter will receive
`the same study medication as they received in the single-dose phase.
`‘
`Previous human experience has been obtained in a double blind phase I study in normal volunteers. Single doses
`of l, 5, 25, 50, 100 mg , and multiple doses of‘25, 50, 100 mg daily for 8 consecutive days were administered did
`not cause serious adverse events. AMG caused a decrease in plasma PTH at single and multiple doses of 25, 50,
`
`184
`
`

`

`100 mg. A single 100 mg doses caused a decrease in serum Ca. In the multiple dosing study, 5 subjects receiving
`daily 100 mg doses were withdrawn due to mild hypocalcemia or related symptoms (section 9 of IND).
`AMG is a second generation derivative of the parent compound R-568 1 \— _. R-568 has low
`bioavailability due to liver metabolism, and1n humans thereIS large inter— and intrapatient variabilityin drug
`blood levels. Sponsor projects from chemistry and preclinical data that, compared to R-568, AMG-073 will have
`higher bioavailability and less blood level variability
`
`B. CHEMISTRY
`
`Chemical name for AMG 073.HCl1s (N—[-1-(R)-(l-naphthyllethyl]-3-[3-(trifluoromethyl)phenyl]-aminopropane.
`AMGrs registered as AMG 099073-011n Amgen Chemical Registration File. AMG 073is a calcimimetic
`intended to reduce plasma levels of PTH.
`
`Empirical formula:
`Molecular weight:
`Empirical formula free base:
`Molecular weight free base:
`Appearance:
`Solubility:
`Drug product:
`Strength:
`
`CanFJN-HC]
`394
`CquzF3N
`357
`White to off-white powder
`1 Methanol or95% ethanol, slightly soluble1n water
`\ . ~——f__.=__
`. 5 or 25 mg
`
`_C_._ PHARMACOLOGY
`
`Efficacy Pharmacology
`In normal and hyperparathyroid rats, single oral doses of AMG (0.4-36 mg/kg) decreased serum PTH and Ca
`levels, and increased calcitonin. The effect was dose-dependent.
`
`Safety Pharmacology
`In guinea pigs, a single 20 mg/kg iv dose produceda transient increase in airway resistance and
`bronchoconstriction, leading to death in 1 animal. At a single oral dose of 200mg/kg, AMG increased gastric
`motility in mice by 35%.
`AMG did not antagonize ACh, BaCl, orhistidine-induced contractions of the guinea pig ileum at concentrations
`of 10 ug/ml. In mice, single oral doses of up to 200 mg/kg had no neurologic, analgesic, anti-convulsive,
`proconvulsive effects. In rats, single oral doses of up to 200 mg/kg had no effect on diuresis or body temperature.
`
`D. TOXICOLOGY
`
`Toxicity Studies
`
`Sin - 1e or escalatin dose studies
`
`Study
`Number
`
`Specie Dosing
`schedul
`
`gDosin Doses N/sex
`(mg/kg)
`lgrp
`Route
`
`Parameters
`
`Findings
`
`970151
`
`single
`dose ‘
`
`oral
`gavage
`
`0, 10,
`100,
`
`500
`
`Mortality: 500 mk: 1f dead on Day 4, cause
`BW, FC,
`unclear'
`signs,
`
`
`
`
`BW/FC: 500 Ink: BWG and FC sli_
`or_an
`
`
`
`
`
`185
`
`
`
`
`
`

`

`'
`
`'
`
`'
`
`,
`
`_
`
`'.
`'
`
`.
`
`'
`
`'
`
`,
`
`,
`
`,
`
`-
`oral
`gavage
`
`,
`
`,
`
`,
`
`I .
`'
`'
`
`'
`
`,
`
`,
`
`,
`
`,
`
`weights,
`gross path,
`
`during week 1 post-dosing
`
`y
`
`'
`
`‘
`
`'
`
`'
`
`gross path,
`histopath
`
`BW: 20 mk: BWG reduced in in during week 1
`post dose.
`Pathology: 5, 20 mk: adhesion of liver lobes,
`white discoloration of liver and/or spleen,
`capsulitis and capsule fibrosis of liver and spleen
`in several animals
`
`Mortality and signs: 10, 100 mk: 1 f dead in each
`group on Day 8, with distended, air-filled
`inteStines and stomach. 500 mk: 1m dead on Day
`12, with decreased activity, abnormal signs and
`air-filled intestines and stomach. 1m with
`decreased activity on Day 8- 10.
`BW/FC 500 mk: BWG and FC reducedin m on
`Da 8.
`
`signs,
`organ '
`weights,
`gross path,
`histopath
`
`‘
`
`' Mortality and signs: 20 ink: 1m and 1f dead on
`Day 3 and 6, with decreased activity, abnormal
`signs, and distended dark red (in) or air~filled (f)
`intestines or stomach. 20 mk: signs in all animals
`on Day 1, in a few during week 1: decreased
`activity, abnormal gait and stance, body
`quiver/prostation.
`Pathology; 0, l, 5,20 (all groups): liver areas of
`~ ca usulitis and/0r causule fibrosis.
`
`970152
`
`970153
`~
`
`‘
`
`970154
`
`,
`
`970060
`
`.
`
`
`
`'
`
`escalati
`ng dose
`schedul
`e (4-day
`multiple
`dosing
`
`oral
`gavage
`
`_
`
`,
`,
`
`,
`,
`
`,
`,
`
`_
`
`signs,
`plasma
`ionized
`calcium
`and pH,
`PK
`'
`
`Signs: emesis (216mk), salivation (Z32mk),
`nonformed feces (216mk), tremors (264mk).
`Serum Ca: All doses: Calcium levels reduced
`(22% at 200 mkd, at 2-8h postdose).
`PK 200 mkd Cmax r/f‘ AUC- 77o
`‘ ng.h/ml,
`Tm 4.7h
`
`970142
`
`monke
`y
`'
`
`.
`
`escalati
`ng
`doses '
`on days
`1 3,5
`
`intrana
`sal
`gastric
`gavage
`
`A
`
`,
`
`,
`
`'
`
`,
`
`,
`
`_
`
`'
`
`_
`
`.
`
`,
`
`Signs: >32 mk: suppressed appetite
`Serum Ca: All doses: ionized calcium suppressed
`by 25-30% (16 ink, 4h-12h postdose), 35-25% (32
`, mk, 6h postdose), 35-40% (48h, 12h postdose).
`No effects on plasma pH.
`
`Multi - 1e dose studies
`
` Mortality; 250 mkd 1f, 500 mkd Sf, 3m.
`
`Signs: 250, 500 mkd: stained fur, abnormal breathing,
`salivation, sneezing, eyes closed, pallor, weakness, tremors,
`dehydration, cold, thin, hunched posture, distention of abdomen,
`sofi feces, reduced feces, reduced activity.
`BW, FC: reduced at all doses
`0 h_ta1molo : 250, 500mkd: cataracts in all survivin
`
`186
`
`

`

`Hematology/din path: 50600 mkd (m), 250 mkd (1): reduced
`Hb, RBC, Hct, WBC, elevated protrombin time, increase in -
`BUN, increase in cholesterol.
`Ca, PTH: All doses: dose-related reduction in serum calcium,
`with reduced predose levels. Reduction in PTH similar at all
`doses, with normal predose levels
`’
`Urine: 250, 500 mkd: WBC in urine in m and f
`Organ weights: thymus reduced (250, 500), uterus reduced
`(250)
`Gross findings: emaciation (>250), dilatation of GI (500)
`Histopathology:
`250,500 mkd: myocardial degeneration, adrenal degeneration,
`kidney necrosis of cortical tubules, ovarian degeneration, uterine
`atrophy, lymphoid tissue necrosis/atrophy, salivary gland acinar
`hypertrophy , bone marrow hypocellularity
`500 mkd: prostate atrophy, mucosal hyperplasia of colon/rectum
`PK: non-linear absorption with relative decrease at higher doses
`Values: 500 mkd (Day 14): Cmax = —‘
`AUC = 14700
`ugh/ml, Tm=12h
`NOAEL <50 mkd
`
`'
`
`Mortality: 1 control, lLD, lHD.
`Signs: 50, 125 mkd: stained fur, abnormal breathing,
`dehydration.
`BW, FC: 50, 125 mkd: slightly reduced in f.
`Ophtalmology: 50, 125mkd: cataracts.
`Hematology/01in path: 50, 125 mkd: elevated protrombin time in
`f, elevated BUN, triglycerides at 125 mkd.
`Ca, PTH: 50, 125 mkd: reduction in serum calcium >30 min
`postdose. Reduction in PTH at all doses.
`Urine: 50, 125 mkd: increased Ca, decreased Na
`Organ weights: uterus reduced (all doses)
`Histopathology:
`125mkd: myocardial inflammation
`50, 125mkd: mucosa! hyperplasia of cecum/colon
`PK: Cmax and AUC increased less than proportional to dose.
`Ratio 125/5 mkd, Day 1: Cmax 10~fold, AUC 19-fold, Day 28:
`Cmax 11-fold, AUC 76-fold.
`Values: 125 mkd (Day 28): Cmax = . -'
`ugh/ml, Tm = 18h
`NOAEL <5 mkd
`
`AUC = 6180
`-
`I
`
`,
`
`.
`
`
`
`Signs: Emesis in MD, HD. Tremor and hypoactivity in HD.
`Hematology: mild anemia in MD, HI).
`Ca, PTH: decreased serum Ca in MD, HD, decreased ionized Ca
`in all treated, reduced PTH levels in all treated.
`Urine: Urine volume increased in MD, HD, specific gravity
`decreased, pH decreased. Decreased Na, K, C]. Increased Ca, or
`increased Ca excretion in all treated. After recovery urine
`volume remained increased and specific gravity decreased in
`HD.
`
`
`
`Pathology: no remarkable findings
`PK Values: 100 mkd (Day 28): Cmax-— “"
`AUC=503n .h/ml, Tm=6h
`Signs: Drug-related suppression of appetite at all doses. Emesis
`at 96 mkd in 2/2 animals.
`
`
`
`
`No clear effects on hematology, clin path, urinalysis.
`All doses: ionized calcium decreased
`
`
`
`
`
`187j
`
`oral
`
`gavage
`
`
`
`oral
`gavage
`
`0,5,50,
`100
`
` 1 m
`
`onth,
`daily, 2
`weeks
`recover
`
`Y
`
`rat
`
`970070
`
`970078
`
`dog
`
`970147
`
`monke
`
`.
`
`7 days,
`
`intrana
`sal
`
`gastric
`
`daily
`
`0,24,
`48,96
`
`(mon
`keys
`not
`
`

`

`960128
`
`Novasc
`reen
`
`ug/ml
`
`vuitro
`
`AMG was active (>50% inhibition of binding) in following
`receptbr systems:
`alpha] -adrenergic, muscarinic, dopaminergic, sigma, sodium
`
`site 2, NK2 and dopamine and serotonine sites on transporter
`
`decrease). Levels were back to near-normal1n 48h. No clear
`dose-relationshipin calcium effect.
`PK: Cmax and AUC increased less than proportional to dose
`(absorption less at high dose). Absorption erratic over time. BA
`estimated at 10%. Tm 5-15h. Cmax (day 8) < Cmax (day I) at
`MD, HD. No gender effects on PK.
`.
`Values: 96 mkd (Day 8)} Cmax= ""
`, AUC 1330 ugh/ml,
`1“,,2 10h
`‘
`
`APPEARS nus WAY *
`0N ORIGINAL
`
`188
`
`

`

`General
`
`E. TOXICOKINETICS ~
`
`Assay of AMG073 was done by HPLC. In rats, dogs and monkeys, oral clearance [(dose/AUC)x(l/F)] was very
`high indicating low oral bioavailability. This may be due to high first-pass metabolism Mean Tl/2in all three
`species was less than 24h
`.
`In rats, excretion and tissue distribution were similar following oral and1.v. dosing. Excretion of radioactively-
`labeled AMG was: 40%in feces, 20-25%in breathed C02, 20-27%In urine. Dose was largely cleared after 96h
`Afler 96h tissuezblood ratio’s varied between 1 and 7.6. Largest tissuezblood radioactivity ratios were seen in
`adrenal gland (7 .6)>liver (4.6)>adipose (4.5)>ovaries (3.3)> kidney (3), lowest one in muscle (1.01). In dogs,
`excretion of radiolabeled test substance was again similar afler oral and i.v. dosing, andwas 40%-70% in feces,
`'and 12-32% in urine, consistent with high biliary excretion of radiolabelled drug and/or metabolites. Dose was
`largely cleared in 72h. Tl/2(elim) of radioactivity was long: 58-162h. Plasma protein binding was large: 98-99%
`in mice, rats, dogs, monkeys and humans.
`AMG 073 is predicted to be cleared mostly by oxidative hepatic metabolism by P450 enzymes. Microsomal
`clearance was high in mouse, rat, dog, monkey (>500 ul/min/mg) and in humans it was 93 ul/min/mg. One major
`metabolite -as yet unidentified- was seen in HPLC assay. AMG was a potent inhibitor of CYP2D6 (IC50<0.1
`uM), and could thus slow the metabolism of other drugs.
`
`PK parameters
`
`1. Rat studies
`PK l4-da multile dose stud
`
`Dose (mg)
`
`Day
`
`Cmax
`n- ml
`
`AUC (0-24h)
`n_ .h/ml
`
`Tl/2 (h)
`
`Accumulation Ratio(AUC
`Da 14/AUC Da 1
`
`PK 28-da multile dose stud
`
`2. Dog studies
`
`1189
`
`

`

` 6
`
`-
`1.34 .
`_
`0.86
`-
`0.90
`
`J
`
`.
`
`5
`7
`9
`l 5
`10
`
`Comment:
`
`In rats and monkeys nominal AUC values are roughly 10x Cm, values, while in dogs this factor is much lower
`(2-4x).
`
`F. GENOTOXICITY
`
`Four mutagenicity assays were performed. .
`I. Ames assay in S. typhimurium TA98, TAIOO, TA1535, TA1537 and E.Coli WP2 uvrA in presence and
`absence of 8—9
`
`2.
`3.
`4.
`
`In vitro mammalian cell gene mutation assay (CHO cells, HGPRT) in absence and presence of 8-9
`In vitro mammalian chromosomal aberration test using CHO cells in absence and presence of 8-9
`In vivo mouse erythrocyte micronucleus test
`
`AMG 073 was negative in all 4 assays.
`
`G. SUMMARY AND EVALUATION
`
`.
`Pharmacology
`AMG-073 appears to suppress PTH secretion and serum calcium levels. This effect can be attributed to its
`calcimimetic action at the parathyroid gland calcium receptor. There are potential safety issues involving
`bronchoconstriction and GI motility.
`
`,
`
`'
`'
`'
`_ Toxicology
`In single dose studies, death occurred in rats at 500 mg/kg (oral). In mice, death occurred at 10, 100 and 500
`mg/kg (oral), and at 20 rug/kg i.p. Clinical signs in mice that died included decreased activity and distended, air-
`filled or dark-red stomach and intestines. Decreased body weight gain or food consumption was seen in rats (500
`mg/kg oral, 20 mg/kg ip), and monkeys (doses 2 32 mg/kg). Dogs experienced emesis and non-formed feces
`(216 nag/kg), salivation (232 mg/kg), and tremors (264 mg/kg).
`.
`'
`
`In multiple dose studies in rats, death occurred at 250 mkd. Body weight wasreduced at doses 250 mkd in both
`14- and 28-day studies, and hematology parameters were abnormal at 50 mkd in 14-day study. Various other
`toxicities were observed at doses 2 250 mkd (14 days) or 250 mkd (28 days), including cataracts, increased BUN
`values, increased cholesterol, reduced uterus and thymus weights, emaciation and GI dilatation, myocardial
`abnormality, hyperplasia of GI mucosa, kidney cortex necrosis, bone marrow hypocellularity, lymphoid tissue
`necrosis. The decreases in serum Ca and PTH that occurred at all doses were the expected pharmacological effect
`of the compound.
`In the 28-day multiple dose dog study, emesis, tremor and hypoactivity, and hematological and fluid homeostasis
`abnormalities were seen at doses 250 mkd.
`
`I90
`
`

`

`In the 8-day multiple dose monkey study, suppressed appetite was seen at doses 224 mkd.
`
`14-day study (50,
`250, 500 mkd)
`
`
`
`
`
`
`
`
`
`28-day study (5,
`50, 125 mkd)
`
`
`
`‘
`
`
`
`
`Target organs
`
`-
`
`CNS, eye, thymus, uterus,
`ovary, GI tract, heart,
`kidney,
`lymphoid tissue,
`bone marrow
`'
`
`
`
`'
`
`NOAEL
`
`LOAEL Adverse effects at
`LOAEL
`
`Cmax, AUC at
`LOAEL
`
`<50 mkd
`
`50 mkd
`
`‘
`
`BW loss,
`hematological effects
`
`94]
`
`'
`
`.
`
`'
`
`50 mkd
`
`CNS, eye, uterus, GI tract,
`heart
`
`5 mkd
`
`.
`
`.
`
`,
`
`1400
`,
`
`
`
`
`
`
`
`BW loss,
`hematology effects,
`cataracts, BUN
`increase, cholesterol
`increase, GI
`dilatation,
`
`uterus/thymusweight
`
`decrease, GI mucosa
`
`hyperplasia,
`-
`
`myocardial
`
`abnormality, kidney
`
`cortex necrosis, bone
`
`marrow
`
`hypocellularity,
`
`lymphoid tissue
`
`necrosis
`
`Dog
`
`’ 28-day study (0, 5,
`50, 100 mkd)
`
`Target organs
`'
`CNS, GI tract (bone
`marrow?)
`
`NOAEL
`
`,
`
`5 mkd
`
`50 mkd
`
`A
`
`'
`
`'
`
`.
`
`'
`
`.
`
`LOAEL
`
`8-day study (24, 48,
`96 mkd
`
`CNS, GI tract
`
`<24 mkd
`
`24 mkd
`
`suppressed appetite
`
`LOAEL Adverse effects at
`
`LOAEL
`Emesis, anemia,
`
`increased urine
`
`volume, decreased
`urine Na, K, Cl,
`
`increased urinary ca
`
`excretion
`
`
`Cmax, A-UC at
`
`
`LOAEL
`
`
`
`
`LOAEL
`
`,
`
`
`
`
`Carcinogenicig and reproductive toxicity studies are planned buthave not been carried out.
`
`Genotoxicig
`AMG 073 had no genotoxic' activity in the Arnes test, the mammalian cell gene mutation test, a chromosomal
`aberration test, and the mouse micronucleus test.
`
`Clinical PK data
`
`1. Single dose study
`,
`Doses: l, 5, 25, 50, 100 mg
`Doses of 5mg and above caused a transient, dose-dependent suppression of plasma PTH, with dose-dependent
`suppression duration. Baseline PTH averaged 20-25 pg/ml. Suppressed values at nadir (ca. 2h post-dose) ranged
`from R“ ' dose. Nadir level was%———(BLQ) at doses >50 mg. A
`transient rebound above baseline occurred. Doses of 50 and 100 mg caused a reduction in serum Ca (maximum
`decrease -5% and -8% at 12-18h post-dose).
`
`191
`
`

`

`Dose (mg)
`
`Cmax (ng/ml)
`
`AMG plasma concentration (0-24h
`avera_e
`n /_ml
`
`AUCM“, (ng.h/ml)
`
`.
`
`2.3
`
`2. Multiple dose study
`Doses; 25, 50, 100 mg
`Duration: 8 consecutive days
`
`Plasma PTH was suppressed dose-dependently for up to 12h following dose. At 100 mg nadir value was below
`BLQ. There was a rebound in PTH above baseline at ca 12h post-dose. 25 and 50 mg daily caused small
`reductions in serum Ca of 1-2%. At 100 mg daily dosing, a marked 15-20% reduction in semm calcium was
`obtained afier ca 72h (mild hypocalcemia). Serum Ca returned to normal afler 48h of dose discontinuation.
`
`PK multi .le dose stud
`
`AUCmmng.h/ml
`
`Tm (h)
`
`Accumulation Ratio(AUC
`
`Dose (mg)
`
`Day
`
`Cmax
`n_ ml
`
`Da 7/Da 1
`
`'
`Evaluation of clinical plans
`The clinical protocol prOposed in the IND is a phase II study in patients with secondary HPT. The largest single
`and multiple dose to be used is 75 mg. To estimate the human plasma levels PK data from previous phase I
`' clinical studies with AMG are available. From these data (see above), it can be extrapolated that at
`single/multiple doses of 75 mg the plasma levels (AUC) in humans are expected to average approximately 150
`- ng.h/ml. This suggests a safety margin of 6x, 1x, 4x, based on texicity data from rats, dogs and monkeys,
`respectively. Based on Cmax values the safety margin for the 75 mg dose is 6x, 2x, 4x.
`
`safety margin based on safety margin based on
`animal data (rat, dog, monkey) at
`. human data at 75
`Cmax
`AUC
`_ LOAEL
`mg dose
`.
`Cmax ___——
`
`
`
`
`'~ 941C152,556 _—
`
`w
`
`In conclusion, the highest dose to be used (75 mg) appears to be reasonably safe. Main toxicities to be expected
`on the basis of the animal studies are nausea, vomiting, anemia. Other toxicities suggested by animal studies are
`GI tract, kidney, heart, eye, hematopoietic tissue, reproductive organ toxicities. In the initial and future clinical
`studies these toxicities should be kept in mind, and appropriate monitoring should be conducted.
`
`H. RECOMMENDATION
`
`l92
`
`

`

`Pharmacology has no objection to initiation. of the clinical protocol described in this IND.
`
`4
`
`/$/
`
`
`
`~
`
`Gemma A. Kuijpers
`
`\
`
`193
`
`

`

`.
`Executive CAC
`Date of Meeting: December 16, 2003
`
`4 Committee: David Jacobson—Kram, Ph.D., HFD-024, Chair
`Joseph Contrera, Ph.D., HFD—90l, Member
`Abby Jacobs, Ph.D., HFD—024, Member
`Robert Osterberg, Ph.D., HFD-520, Alternate Member
`Karen Davis-Bruno, Ph.D., Team Leader
`
`Germna Kuijpers, Ph.D., Presenting Reviewer
`
`Author of Draft: Gemma Kuijpers
`
`The following information reflects a brief summary of the Committee discussion and its
`recommendations. Detailed study information can be found in the individual review.
`
`NDA #:
`21-688
`Drug Name: Cinacalcet HCl (Sensiparm)
`Sponsor:
`Amgen Inc.
`
`BackgrOund: Cinacalcet HCl (AMG—073) is a calcimimetic that binds to the calcium receptor
`on the parathyroid gland. Its pharmacologic effect is a suppression of PTH secretion and
`reduction of serum calcium levels. The proposed indication is treatment of secondary
`hyperparathyroidism in patients with end stage renal disease and treatment of primary
`hyperparathyroidism. The compound is not genotoxic.
`
`-
`Mouse Carcinogenicity Study
`A lO4—week carcinogenicity study was carried out in CD-1 mice at doses of 0, 0, 15, 50, 125
`mg/kg/day (males), and 0, O, 15, 70, 200 mg/kg/day (females) (N=60/sex/grp, two control
`groups), by the dietary route. Doses were selected based on data from a 3-month dietary study
`in which a dose—related decrease in body weight gain was observed. In the lO4-week study, a
`dose-related decrease in body weight was observed in both sexes of up to 35% (males) and
`40% (females). There was no significant effect on survival. Exposure was dose-related with
`metabolite levels (M7) 10 to 20 times higher than those of parent drug. Effects related to the
`pharmacodynamic action of the drug (hypocalcemia, hyperphospatemia, soft tissue
`mineralization) were seen in the'treated groups.
`In high dose males, there was an increased incidence of kidney tubular adenoma (Ctrle—LD?
`MD-HD: 0-0-0—2). The finding was not statistically significant according to Sponsor’s
`analysis (pairwise‘comparison: Ctrl-HD), or‘CDER Biometrics’ analysis (trend test).
`Historical control incidences for tubular cell adenoma in males ranged from 0-5.1%.
`In high dose females there were increased incidences of erythroid leukemia (Ctrle-LD-MD-
`HD: 0-0-0-2) and pituitary adenoma (intermediate lobe) (Ctrlm-LD—MD-HD: 0-0-0—2), not
`statistically significant according to Sponsor’s pairwise comparison or CDER Biometrics’
`trend test. The incidence of pituitary (intermediate lobe) hyperplasia was also increased in a
`dose-related and statistically significant manner. Uterine stromal sarcoma incidence was non-
`statistically significantly increased in mid dose females (Ctrlm-LD-MD—HD: 3-1-4-1).
`Historical control incidences for pituitary adenoma intermediate lobe in females ranged from
`
`194
`
`

`

`0-0.9% (average 0.1%), and for uterine strornal sarcoma from 0-25% (average 1.8%).
`Erythroid leukemia was not observedin the historical control database (0/959). However, it
`was also observed1n 1/60 low dose malesin the current study.
`_
`
`Rat Carcinogenicity Study
`A 104—week study was carried out in Sprague Dawley rats at doses of 0, 0, 5, 15, 35
`' mg/kg/day (males), and 0, O, 5, 20, 50/35 mg/kg/day (females) (N=60/sex/grp, 2 control
`groups), by the dietary route. Doses were selected based on data from a 3—month dietary study
`in which a dose-related decrease in body weight gain was observed. In the lO4-week
`carcinogenicity study, a dose-related decrease in body weight was observed in both sexes of
`up to 25% (males) and 35% (females). The female high dose had been lowered from 50
`mg/kg/day to 35 mg/kg/day in Week 63 due to excessive body weight effects. There was no
`significant effect on survival. Exposure was dose-related with metabolite levels (M7)_at least
`20 times higher than those of parent drug. Effects related to the pharmacodynarnic action of
`the drug (hypocalcemia, hyperphospatemia, soft tissue mineralization) were seen in the treated
`groups.
`In high dose males, there was an increased incidence of combined malignant lymphoma
`(Ctr11+2-LD-MD-HD: l-l-1-3) and an increased incidence of lung bronchio-alveolar
`carcinoma (Ctrlm—LD-MD-HD: 0-0-0—2), The findings were not statistically significant
`according to Sponsor’s analysis (pairwise comparison: Ctrl-HD), or CDER Biometrics’
`analysis (trend test). There was also an increase in bronchio-alveolar hyperplasia in the mid
`dose males. Historical control incidences for lung bronchio-alveolar carcinoma in males
`ranged from 0—1 .7%, and for combined lymphoma from 0-8%. There was a single incidence
`of ependymoma in HD males, a tumor not observed in the historical control database
`(n=1224).
`.
`In high dose females therewas an increased incidence of combined malignant lymphoma
`(Ctrlm-LD-MD—HD: 0-1-0-3), which was not statistically significant according to Sponsor’s
`p