CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`
`
`APPLICATION NUMBER:
`22-044
`22-044
`
`
`PHARMACOLOGY REVIEW(S)
`PHARMACOLOGY REVIEWQS!
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`PRODUCT:
`
`22-044
`
`000
`
`31 May 2006
`Janumet
`
`(Sitagliptin/Metformin Fixed-Dose Combination)
`
`INTENDED CLINICAL POPULATION:
`SPONSOR:
`
`Type 2 Diabetics
`Merck
`
`DOCUMENTS REVIEWED:
`
`eCTD
`
`REVIEW DIVISION:
`
`Division of Metabolic and Endocrine Products
`
`PHARM/I‘OX SUPERVISOR:
`
`Todd Bourcier, Ph.D.
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`Mary Parks, M.D.
`
`Lina Aljuburi, Pharm. D., M.S.
`
`Date of review submission to Division File System (DFS):
`
`Appears This Way
`On Original
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`

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`TABLE OF CONTENTS
`
`........... 3
`EXECUTIVE SUMMARY
`I.
`Recommendations ........................'............................................................................................. 3
`II.
`Summary of non-clinical findings .......................
`............ 4
`A.
`Brief overview of non-clinical findings....................., ............................................................ 4
`B.
`Non-clinical safety issues relevant to clinical use .................................................................. 7
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW ................................................... 8
`
`INTRODUCTION AND DRUG HISTORY................................................................... 8
`2.6.1
`2.6.6.8
`Special toxicology studies
`............................................................................................... '10
`MK—0431 + Metformin: Combination Toxicity Studies in Dogs................................................. lO
`MK—0431 + Metformiu: 14 week oral toxicity study in dogs ...................................................... 10
`Exploratory 5-week oral tolerability' study with Metformin in female dogs ............................. 21
`MK—0431 + Metformin: 16 week oral toxicity in female dogs ..................................................... 25
`
`Appears This Way
`On Original
`
`

`

`Reviewer: Todd Bourcier= PhD.
`
`NDA No. 22-044
`
`EXECUTIVE SUMMARY
`
`1. Recommendations
`
`A. Recommendation on approvability
`AP A roval
`Pharmacology/Toxicology recommends approval of NDA 22-044 (Janumet)
`
`B. Recommendation for nonclinical studies
`
`No additional nonclinical studies are required.
`
`C. Recommendations on labeling
`The proposed labeling language relevant to phannacologY/toxicology has been
`accurately reproduced from the approved labels for Januvia and Glucophage. No
`further changes are recommended.
`
`Appears This Way
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`

`

`Reviewer: Todd Bourcier, PhD.
`
`NDA No. 22-044
`
`II. Summary of non-clinical findings
`
`A. Brief overview of non-clinical findings
`
`Non-clinical studies with the fixed-dose combination product were not performed.
`Potential toxicity unique to the combination of sitagliptin phosphate (MK-0431) and
`metformin was evaluatedin dogs co-administered each drug separately. The combination
`of MK-0431 and high-dose metformin (50 mg/kg) in dogs may have resulted in more
`numerous and earlier deaths than observed with metformin alone. The combination of
`MK-0431 and a lower dose of metformin (20 mg/kg) that better approximates human
`exposure of 2,500mg/day resulted in no deaths and yielded no evidence of exacerbated
`toxicity. Convincing evidence is provided that the deaths at 50 mg/kg are due to
`metformin toxicity and not to the combination. Nevertheless, there is a slight possibility
`of exacerbated toxicity in the setting of high metformin exposure (2 40011M*h AUC) and
`clinical exposure to MK—043l (~10uM*h AUC).
`
`The jbllowing summary is takenfrom the pharmacology/toxicology review for Januvia,
`NDA 21-995.
`
`Pharmacology
`MK-0431 (sitagliptin phosphate) is a competitive inhibitor of dipeptidyl peptidase 4
`(DPP4), an enzyme principally responsible for degrading incretin peptides, glucagon—like
`peptide-1 (GLP-1) and glucose-dependent insulinotropicpeptide (GIP). MK—043l
`prolongs incretin half-life and biological activity and thus potentiates glucose-dependent
`_ insulin release and delays gastric emptying. In non-clinical models of diabetes, MK-0431
`moderates glucose excursion and improves insulin release and islet cell function/mass
`without provoking hypoglycemia MK-043118 body weight-,neutral unlike marketed
`glitazones (weight gain) and GLP—1 analogues (weight loss).
`Immunomodulatory effects‘of DPP4 (aka CD26) are reportedly not altered by MK-
`0431, based on normal responses of murine T— and B-cells to antigens and mitogens.
`However, rodent DPP4/CD26 differs in some aspects from human DPP4/CD26 (e.g.,
`binding of adenosine deaminase) and Merck’s experiments did not directly test the T-
`helper memory function ascribed to CD26. Therefore, the non-clinical data do not
`adequately predict potential effects of MK-O431 on DPP4/CD26’s role in human
`immunity.
`
`Safety pharmacology assessment of neurological, renal, pulmonary, and
`gastrointestinal effects of MK-0431 did not identify any significant liabilities.
`
`Absorption, Distribution, Metabolism, and Excretion
`An oral dose of MK-0431 is rapidly absorbed and is 60-90% bioavailable in rats and
`dogs. MK-0431 distributes to most rat tissues with low amounts distributing to the brain,
`eyes, and bone. Plasma protein binding is moderate (30%). Metabolism of MK-0431 is
`minimal with 80% of unchanged parent compound being eliminated in the urine of rats,
`
`

`

`Reviewer: Todd Bourcier, PhD.
`
`NDA No. 22-044
`
`dogs, and humans. Oxidative metabolism by CYP3A4 and 2C8 is a minor metabolic
`pathway. MK-0431 has a longer plasma half-life in humans (13hrs) than in rats and dogs
`(2-5hrs) probably due to different rates of renal elimination. MK-0431 slightly
`accumulates in humans but not in dogs or rats after multiple dosing.
`
`MK-0431 is a P-glycoprotein and hOAT3 substrate, but does not interfere in the
`shuttling of other substrates via these transporters in vitro. MK-O43l does not inhibit
`CYP450 enzymes or induce CYP3A4. The results predict a low probability for
`pharmacokinetic drug interactions via these pathways.
`
`General Toxicology (MRHD, Maximum Recommended Human Dose, or 100mg)
`
`Single dose studies identified minimum lethal doses of 2000mg/kg (200-400x lVRHD) in
`mice and 3000mg/kg (150-300x MRHD) in rats. Little other toxicological information
`was obtained in these studies.
`
`Repeat dose studies were conducted in Sprague—Dawley rats and Beagle dogs up to 6
`months and 12 months duration, respectively.
`
`A high—dose 3-month study in rats identified kidney and liver necrosis, myocardial
`degeneration, bone marrow necrosis, and death at 1500 and 2000mg/kg (150-200x
`MRHD). Kidney toxicity was also observed in mice at 500mg/kg. Note that exposure at
`these high doses is theoretically sufficient to inhibit off-target enzymes DPP8/9, proteases
`that are associated with these toxicities.
`
`Administration of doses up to 20x the MRHD for 6 months in rats did not elicit
`significant toxicity.
`
`Studies in dogs identified NOAEL doses based on clinical signs that consisted of
`reduced activity, hunched posture, ataxia, tremor, and sporadic emesis observed at
`50mg/kg (20x MRHD). Respiratory distress, described as audible and labored breathing
`and open-mouthed breathing, was also reported. Noconsistent target organs were
`identified in these studies.
`‘
`
`Administration ofdoses up to 5x the MRHD for up to 12 months in dogs did not elicit
`significant toxicity.
`
`Special Toxicology
`MK-O431 did not produce vascular/skin lesions in rhesus monkeys, as seen with some
`DPP4 inhibitors, after three months administration of doses up to 25x the MRHD.
`Mechanistic data provided by Merck suggests that inhibiting DPP4 activity alone is not
`sufficient to produce this toxicity.
`
`Reproductive Toxicology
`Exposure to MK-O43l in the definitive studies ranged from 12x to 90x MRHD in the
`rat and 6x to 50x in the rabbit. Resorptions and post—implantation losses increased in
`
`

`

`
`
`Reviewer: Todd Bourcier Ph.D. NDA No. 22-044
`
`females in a fertility study at ~25x MRHD; male fertility was not effected. MK—043l was
`not teratogenic but increased the incidence of skeletal malformations in rat pups at
`maternally toxic doses. At maternally non-toxic doses, a single rat pup had multiple
`skeletal abnormalities (incidence within historical range), and a single rabbit pup had
`multiple cardiovascular abnormalities, but a relationship to drug treatment is not
`conclusive. MK—0431 crosses the placenta in rats and rabbits and is excreted in maternal
`milk at a 4:1 ratio to plasma. As with other oral hypoglycemic agents, MK-0431 should
`not be given to pregnant or nursing mothers and Merck will maintain a pregnancy
`register. Pregnancy Category ‘B’ is recommended.
`
`There were no conclusive drug-related effects on embryoniC/post—natal development
`in rats at 125mg/kg (12x MRHD) or in rabbits at 125mg/kg (20x MRHD).
`
`Genetic Toxicology
`MK-O431 was not mutagenic or clastogenic in three in vitro assays (Ames,
`hepatocyte alkaline elution, and chromosome aberration) and one in vivo assay (murine
`micronucleus induction).
`
`.
`Carcinogenicity
`Carcinogenic potential of MK—043l was evaluated in 2 year studies in
`mice and rats. Both studies adequately assessed carcinogenesis. MK-0431 significantly
`increased the incidence of combined liver adenoma/carcinoma in male and female rats,
`and increased liver carcinomas in female rats at 500mg/kg (62x MRHD). Non-genotoxic,
`_ chronic hepatotoxicity is the suggested etiological event but this is based on weak
`correlative evidenceof liver toxicity. MK—043l did not produce any drug-related tumors
`in CD—1 mice up to 500mg/kg (72x MRHD). MK-0431 poses a minimal carcinogenic risk
`to humans.
`‘
`
`Appears This Way
`On Original
`
`

`

`
`
`Reviewer: Todd Bourcier PhD. NDA No. 22-044 . I
`
`
`
`
`
`B. Non-clinical safety issues relevant to clinical use
`
`1. DPP4 cleaves several substrates in addition to GLP-l. Therefore, MK-O431 may
`have undesirable effects related to inhibiting cleavage of non-incretin substrates.
`Effects on human immunity, specifically recall responses to antigens and immune
`cell trafficking, may be adversely affected by DPP4 inhibition. This risk is an
`unavoidable characteristic of MK—0431 and the drug class. There is currently no
`clinical evidence of such effects with Januvia or with Janumet.
`
`I
`
`MK-0431 presents a marginal clinical risk of producing skin lesions with
`prolonged administration. This conclusion is based on the absence of skin
`findings in the 3-m0nth monkey study, on mechanistic data suggesting that
`inhibiting DPP4 activity alone is not sufficient to produce this toxicity, and on the
`high DPP4 selectivity of MK-043l at clinical exposure. Risk assessment for skin
`lesions must be done on a case—by-case basis and is not evidence of similar safety
`with other DPP4 inhibitors currently in clinical development.
`
`Issues specific for the combination of Januvia and metformin include the finding
`of excess deaths of dogs administered pharmacologically high doses of metformin
`and a clinically relevant dose of sitagliptin. Convincing evidence is provided that
`the deaths at 50 mg/kg are due to metformin toxicity and not to the combination.
`Nevertheless, there is a slight possibility of exacerbated toxicity in the setting of
`high metformin exposure (2 400uM*h AUC) and clinical exposure to MK-O43l
`(~10uM*h AUC).
`
`Appears This Way
`On Original
`
`

`

`
`Reviewer: Todd Bourcier PhD.
`
`NDA No. 22-044
`
`2.6 PHARMACOLOGY/TOXICOLOGYREVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`' NDA number: 22-044
`' Review number:
`1
`
`Sequence number/date/type of submission: SNOOO / 31 May 2006
`Information to sponsor: Yes (X) No ( )
`Sponsor and/or agent:
`, Merck Research Laboratories
`Manufacturer for drug substance: Merck Facilities
`Reviewer name: Todd Bourcier
`
`. Division name: Metabolic and Endocrine Products
`HFD #:
`510
`
`Review completion date: 28 Feb 2007
`
`Drug:
`
`Janumet
`Trade name:
`Generic name: Sitagliptin phosphate and Metformin HCl
`Fixed Dose Combination
`
`. Sitagliptinphosphate:
`Trade name: Januvia
`
`Code name: MK-0431, sitagliptin phosphate
`Chemical name: 7-[(3R)—3 -amin0—l-ox0-4-(2,4,S-trifluorophenyl)butyl]-5,6,7,8—
`tetrahydro-[3-(trifluoromethyl)—l,2,4-triazolo[4,3-a]pyrazine
`phosphate (1: l) monohydrate ‘
`CAS registry number: 654671-77-9
`Molecular formula/molecular weight: C16H15F5N50 ° H3PO4 ' H20 /523.32 MW
`Structure:
`
`RTIK a“ NH, 0
`/
`~‘k/u\“/"\V¢M\
`l\,'l I“ ~ H390,
`
`~ 3,0
`
`Metformin HCI:
`
`Chemical name: N,N-dimethylimidodicarbonimidic diamide hydrochloride
`CAS registry number:
`Molecular formula/molecular weight: C4H11N5~HCll 165.6 MW
`Structure:
`.
`9 ca:-
`>
`ti
`‘
`“J .
`
`2
`
`‘flCl
`
`ii
`
`HE
`
`14H
`
`Mi
`
`

`

`
`Reviewer: Todd Bourcier, PhD.
`
`NDA No. 22-044
`
`Relevant INDs/NDAs/DMFS:
`
`1. NDA 21-995 (Januvia)
`2. NDA 20-357 (Glucophage)
`
`Drug class: Oral antihyperglycemic agents
`
`Intended clinical population: Type II diabetics
`
`Clinical formulation: Film-coated tablets containing 50 mg sitgliptin phosphate and 500
`mg metformin hydrochloride (Janumet 50/500) or 1000 mg metformin hydrochloride
`(Janumet 50/1000). Inactive ingredients include microcrystalline cellulose,
`polyvinylpyroolidone, sodium lauryl slfate, and sodium stearyl fumarate.
`
`Route of administration: Oral
`
`'Maxim um Recommended Human Dose: Twice daily dosing of Janumet 50/1000 will
`provide 100mg sitagliptin phosphate and a maximum of 2000mg metformin.
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`Studies reviewed within this submission:
`
`MK-0431 + Metformin: Combination Toxicity Studies in Dogs
`MK-0431 + Metformin: 14 week oral toxicity study in dogs
`Exploratory 5-week oral tolerability study with Metformin in female dogs .
`MK-0431 + Metformin: 16 week oral toxicity in female dogs
`
`Studiesn_ot reviewed within this submission:
`
`All other pharmacology/toxicology studies relevant to evaluation of Janumet have been
`reviewed previously and are publicly available under NDA 21,995 for Januvia
`(sitagliptin) and under NDA 20,357 for Glucophage (metformin).
`
`09.06013: Thlg
`.
`W?“
`0“ OFianelé W
`
`

`

`
`
`Reviewer: Todd Bourcier PhD. NDA No. 22-044
`
`2.6.6.8 Special toxicology studies
`
`MK—0431 + Metformin: Combination Toxicity Studies in Dogs
`
`_
`Summary
`A series of studies evaluated the potential toxicity of MK—043l administered in
`combination with metformin to dogs. The combination of MK-043l and high-dose
`metformin (50 mg/kg) in dogs may have resulted in more numerous and earlier deaths
`than observed with metformin alone (Study #TT 06-6000). The combination of MK-O431
`and a lower dose of metformin (20 mg/kg) that better approximates human expOsure
`resulted in no deaths and yielded no evidence of exacerbated toxicity (Study #TT 06-
`6017). Convincing. evidence is provided that the deaths at 50 mg/kg are due to metformin
`toxicity and not to the combination (Study #TT 06-6018) . Nevertheless, there is a slight,
`possibility of exacerbated toxicity in the setting of high exposure to metformin (Z
`400uM*h AUC) and clinical exposure to MK-043l (Z lOuM*h AUC). ’
`
`MK-0431 + Metformin: 14 week oral toxicity study in dogs
`50 mg/kg Metformin and 2, 10, 50 mg/kg MK-O43l
`
`Key study findings:
`
`0 Mortality occurred in females of all combination groups and the metformin-alone
`group. Deaths with the combination appear more numerous and occur earlier than
`with the metformin-alone group.
`
`0 Mortality occurred in females only; all males survived to termination.
`
`o The metformin-alone death may be due to lactic acidosis, indicated by high
`plasma lactate and low bicarbonate.
`
`- Earlier deaths with the combination are not adequately explained.
`
`i
`0 Three deaths in the MI) and HD combination groups showed vacuolation in the
`brain with one of the three also showing neuronal. necrosis; degenerative changes
`in brain are reported in dogs administered metformin (NDA 20-537).
`
`0 Exposure to MK-O43l is not altered by co-administration of metformin.
`
`0 Exposure to Metformin tends to be 50% higher in females co-administered MK-
`0431 than. metformin alone. However, TK comes from a single female in the MD
`and HD groups, so only tentative conclusions can be drawn. There is no
`difference in males.
`
`10
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`

`

`Reviewer: Todd Bourcier, PhD.
`
`‘
`
`. INDA No. 22-044
`
`Reviewer Comments
`
`Merck concludes that all deaths are related to metformin toxicity and not to exacerbated
`toxicity with the combination The data1n this study do not support that conclusion
`because earlier deaths with the combination are not adequately explained To the
`contrary, the death of one female given metformin alone was associated with a 50%
`higher metformin AUC than the females given the combination, yet deaths were observed
`in all groups except control.
`
`Nevertheless, it is feasible that the deaths are related to metformin toxicity for the
`following reasons:
`
`1. Plasma lactate tended to be higher in surviving dogs and was clearly higher in 2
`dogs in the HD combination group, though this may be related to morbidity.
`
`2. The minimally toxic dose of metformin in dogs is. 50mg/kg, with death1n 50% to
`100% of animals at > 100mg/kg (IND 5934, NBA 20357), indicating a sharp
`dose response curve.
`
`3. Metformin exposure in females was higher in this study (2 500pg*h/ml) than
`reported in the metformin NDA (~300 pg*h/ml). Exposure in males was similar
`to females on day l but decreased by week 8.
`
`Exacerbated toxicity of the MK-0431/Metformin combination cannot be excluded based
`on this data, but neither can it be confirmed.
`
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`11
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`

`

`
`Reviewer: Todd Bourcier PhD.
`
`.
`
`NDA No. 22-044
`
`Study no.1 TT 06-6000
`Volume #, and page #: eCTD
`Conducting laboratory and location: MRL, Chibret, France
`GLP compliance: French Ministry of Health GLP standard
`QA report: yes ( x ) no ( )
`'
`Drug, lot #, and % purity:
`MK-0431, lot L-000224715-010X029
`Metformin, lot L-000282095-001L012, from
`Wpurity by HPLC (manufacturer’s data)
`
`
`
`Methods
`
`
`
`
` cmmmgmc c515; -_ _ '
`
`
`
`
`MIC-0431 éPJlttet'fofiiiih
`
`
`0 + 50.xnwgfdayh.
`
`.3i3
`2 +50 mgfkg’dhyc
`l
`
`z-~
`5. no+svmgzk§¢aw
`Wigwam
`:..__:.w~1.m.,_i,_._m§..m
`
`l
`5‘ Control animals received fink-kg of acidified deionized water followed by
`
`S luLékg of0;5% (my) methyleellulofise in deionized \mter daily.
`.
`'g *3 Animals: received Smulrgof acidified deimrized “ale: filllowcd by S nil/kg
`
`¥
`{
`ofMetthrmajndosing {emulationdaily.
`V
`'
`
`%
`‘3 Animals received 5 man of mums! dosing fommlmion tbllowcd by
`i
`< 11:]:le ofzvletfonuin dosing fomiulnlionjdail >1
`'-
`’
`
`
`
`
`
`
`'
`40-42 weeks
`Age:
`
`
` Weight:
`
`
`
`
`
`
`Blood collected after the first dose and in drug week 8
`
`‘ Recoveg groups: No recovery
`
`
`
`ll
`
`
`
`
`Route formulation
`
`
`dose volume
`
`
`
`Oral gavage of both drugs, MK-0431 first, then metformin
`MK—0431 in acidified water
`Metformin in 0.5% meth [cellulose in water
`
`
`
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`
`1Reviewer: Todd Bourcier PhD. NBA No. 22-044
`
`Observation and Times:
`
`'
`
`Clinical Findings: Daily observations
`
`Body weights: Pretest and then weekly
`
`
`
`Ophthalmoscopy Pretest, drug weeks 6 and 12
`
`Pretest, drug weeks 6 and 12
`
`Hematology: Pretest, drug weeks 4, 9, and 12, fasted state
`
`
`
`
`
`-
`
` ‘
`
`Clinical chemistry:
`
`~
`Pretest, drug weeks 4, 9, and 12
`Lactate and bicarbonate done on week 6, 9, and 12
`
`
`
`' Some frozen samples from week 4 analyzed in week 6 for
`bicarbonate and serum electrol
`es
`
`
`
`
`
`ysis: Overnight urmes collected in drug weeks 9 and 12
`
`Gross pathology: Complete necropsrcs on all scheduled/unscheduled deaths
`
`prostate, spleen, testes, thyroid
`From control, metformin alone, and high dose MK-
`.
`. Histopathology. 0431/metformin
`Also from found dead/earl
`
`sacrifice animals
`
`yes ( X): “0 ()
`
`
`
`
` Adequate Battery:
`yeSO, n0 (X) Peer review:
`
`Appears This Way
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`Reviewer: Todd Bourcier, PhD.
`
`i
`
`NDA No. 22-044
`
`Results:
`
`Mortality: Deaths occurred in all treated groups including metformin alone (Table 1).
`There was one death each in the metformin alone group and the low dese MK-
`043 l/metformin group, and two deaths each in the m-id- and high-dose MK-
`0431/metformin groups. Deaths in the combination groups occurred earlier (1-4 weeks)
`than the metformin alone group (week 6).
`
`Note that only females were effected; mortality did not occur in males.
`
`Females 05-0121 and 05-0l43 showed severe physical signs, including lateral
`recumbency, limb paddling, rigidity, labored breathing and prostration.
`
`'
`
`Females 05-0133 and 05-0137 showed body weight loss, markedly reduCed food intake,
`and anorexia
`
`
`
`Table 1: Mortality in female dogs administered MK-0431 andMetformin
`.
`Group
`Animal
`Drug Week
`Found Deadlor' 'V H '
`V
`(Dose in mg/kg/day)
`Number
`of Death
`Early Sacrifice Death/R asonKilled
`
`'V Metformin (50)
`05-0133‘F
`6
`__ES'
`‘
`' Bod" weightless
`
`-."MK-04%i+
`'- 05-0137F
`
`
`
`f 05:01:}: '_'_’
`‘
`g
`__
`V
`'V
`"
`054012351?
`'25
`050143F -
`Animal diedprior to euthanasia:for earlySacrifice
`17—.EarlyiSacrificed
`
`etermin'edi'
`VUndthennined“
`.--.':“..-i:;;Undet’erinined .
`'
`'
`.
`'
`~
`
`'
`
`'
`
`’
`
`=Fo_un‘d Dead.
`
`Histological changes in early sacrifice females #05-0121, ~01 l l, and -0143 included
`vacuolation of the brain in all three and neuronal necrosis in #05-0143. NOte that two of
`these dogs are in the MD combo group and the one with vacuolation and neuronal
`necrosis is in the HD combo group. Hemorrhage was not reported in these individuals.
`No other early death or surviving dogs showed histological changes in brain. Metformin
`administration to dogs has been associated with degenerative changes in the brain, among
`otherorgans (ref. NDA ."'~
`
`Other histological changes found only in early sacrifice females include lymphoid
`depletion of Peyer’s patch, lymph nodes, and thymus, and adrenal vacuolation (If).
`
`I Merck concludes that the deaths are related to metformin alone and not to co-treatment
`with MK-0431, citing lactic acidosis as a likely mechanism. As evidence, the metformin-
`
`l4
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`
`Reviewer: Todd Bourcier PhD. ‘ NDA No. 22-044
`
`alone death was associated with high plasma lactate and low bicarbonate prior to sacrifice
`in week 6 compared to the control group. Unfortunately, plasma lactate was not measured
`in 3 other combination-group deaths where frozen samples were available from week 4.
`Bicarbonate tended to be lower in those samples, but not substantially. Changes in
`lactate/bicarbonate in surviving animals is discussed under the clinical chemistry section.
`
`The data indicate lactic acidosis as a possible cause of death in the metformin-alone
`group, but is not conclusive as to the cause of deaths in the combination groups.
`
`I?
`
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`
`Egg.r
`Dog number
`
`asmmmesw
`Plasma Lactate
`a.r
`
`Bicarbonate (mM)
`
`CONTROL
`
`‘
`
`group average
`
`23.9
`
`
`
`LD MK-043 l/metformin
`
`05-0137F
`
`MD MK-043 l/metformin
`
`.
`HD MK-043 l/metformin
`
`05-0121F
`
`05-01 1 IF
`
`'
`
`05-01st
`
`05 -0 143F
`
`nd = sample not taken (05-0137 & -0121) or not analyzed (05-0111, —0125, & -0143)
`
`Clinical signs:
`
`Males and females in all treatment groups (excluding control) showed physical signs
`starting in drug weeks 1/2. Signs included salivation and occasional emeSis shortly afier
`dosing, and an increased incidence of unformed stools. There was no difference noted
`between the dose groups relative to these clinical signs.
`
`In the high dose MK-O431/metformin group, ataxia and. tremors were observed in 2
`females and 1 male shortly after dosing but the signs subsided within 4-6 hours. The
`transient ataxia/tremors associated with dosing were observed from drug weeks 1 to 3.
`This CNS effect has been identified in several previous toxicity studies in beagle dogs
`administered 50 mg/kg.
`'
`
`15
`
`

`

`Reviewer: Todd Bourcier, PhD.
`
`NDA No. 22-044
`
`Body weights:
`
`Death of females #05-0133 and 05-0137 from the metformin-alone and LD MK-
`0431/metformin group was associated with a 1 to 2 kg loss in body weight by drug week
`2 and' 5, respectively, consistent with reduced food intake and anorexia in these
`individuals.
`'
`
`Treated females generally gained less weight than the control females except for the
`individual in the HD MK-043 l/metformin group. Males administered the combination
`tended to gain less weight than the control of metformin—alone males, but the data is
`variable and not dose-dependent.
`‘
`
`The data are not conclusiveas to an effect on BW in surviving dogs, though the data in
`males suggests some effect with combination treatment.
`
`
`
`‘
`
`Females
`
`I
`
`i
`
`I
`
`H Males
`
`043 l/metformin
`
`0.5
`
`0.5
`
`Metformin
`
`LD MK-
`043 1/metformin
`
`MD MK-
`043 1/metforrnin
`HD MK-
`
`Food consumption: Aside from reduced food consumption in the moribund females
`described above, there was no difference in food intake between the treated and control
`groups.
`
`Ophthalmoscopy: There were no treatment-related changes reported.
`
`
`. EKG: There were no treatment-related changes reported. Note that primary data was not
`submitted.
`
`Hematology: There were no treatment-related changes relative to RBC, WBC, and
`coagulation variables.
`
`16
`
`

`

`
`
`Reviewer: Todd Bourcier PhD. NDA No. 22-044
`
`
` — A—M———
`
`———
`_——-
`
`
`
`—-m-m
`
`
`*Plasma lactatein dog #05-0138 was 37 and 31 mg/dL at weeks 9,12 respectively, skewing the
`mean upward.
`
`Historical Control Values for Dogs, Plasma Lactate and Bicarbonate
`
`
`
`Hiatocicall‘ongrotxraluw (or Dag {§6~?Bbf2606 to zo-gebazoos}
`'Aqe-v
`3
`'.
`V'
`-
`,
`'
`Nc.- of Ho; iaf
`mmn '
`Range of
`"
`Tenth
`333335319
`Value
`Actual Value:
`Qicarbwte Micki-L
`.
`7. 4
`18 . .7
`23
`, 23a:
`13.7
`
`73
`73
`.
`74
`74
`
`-
`
`'
`
`24.0
`24,0
`
`20.")
`20.7
`
`,
`
`V
`
`2.5!
`
`19.5
`1.9.5
`
`'
`
`26 .
`s
`9.5.6
`
`27.7
`27.7
`
`27.7
`27;?
`
`30.9
`20.9
`
`20.0
`min
`
`95% Spread
`97.5!
`
`25.4
`24;»;
`
`37.2:
`r7 2
`
`16.9
`24.9
`
`“”me
`22.9
`28.8
`
`w“
`5.5
`5.5
`
`”m" M“ "MM
`2.5.7
`28.7
`
`33,4
`33,4
`
`’32.:
`33.4
`
`418
`4.8
`
`33...
`33.2
`
`5.4 .
`5:4" »
`
`g
`
`,‘
`
`.
`
`13.21
`' 32.1
`
`'
`
`Female
`26 to 39 Weeks
`Cambium ages
`mm
`264:6 39 Make
`memes Agar.
`Both Sexes
`26 to 39 weeks
`Cambineé-Agei:
`
`
`'73
`‘73
`
`74
`‘M
`
`147
`14‘:
`
`.
`
`I i“
`Female
`.
`es tu_ 39' make
`.
`
`I
`
`“WWW“
`
`‘
`
`“
`_53
`53
`
`147
`'u‘l
`
`18.7
`23.5
`123.3
`18.7
`
`W m ma‘fie mgVBL
`.
`[53‘
`'
`~
`.12.).
`5‘3
`gig-.4.
`
`"m
`.59:
`5.4
`
`
`
`Urinalysis: Treated and control groups showed no difference in urinary volume, specific
`gravity, urobilinogen, glucose, protein, blood, ketones, or sediments.
`
`Gross pathology: Treated and control groups showed no difference. (scheduled
`sacrifices)
`
`Organ weights: Treated and control groups showed no difference. (scheduled sacrifices)
`
`18
`
`

`

`
`Reviewer: Todd Bourcier PhDi
`
`'
`
`NDA No. 22-044
`
`Histopathology:
`
`Histological changes were present onlyin early sacrifice females, and are described
`under the ‘Mortality’ section above
`
`To summarize, females #0540121 and -0111 had brain vacuolation and female 05-0143
`showed brain vacuolation and neuronal necrosis. Although these dogs are in the MD and
`HD combo groups, such changes in brain have been previously described in dogs
`following administration of metformin (ref. NDA "f'_‘_
`
`Other histological changes found only in early sacrifice females include lymphoid
`depletion of Peyer’s patch, lymph nodes, and thymus, and adrenal vacuolation (1t).
`
`Appears This Way
`On Original
`
`19
`
`

`

`Reviewer: Todd Bourcier, PhD,
`
`NDA No. 22-044
`
`Toxicokinetics:
`
`MK-0_431: Exposure as AUC at all dose groups is consistent with TK from prior studies.
`.There is no sex difference, and exposure slightly decreases by drug week 8. Co-
`administration of metformin did not alter TK of MK-0431.
`
`Metformin: Exposure as AUC was ~50% higher in females given metformin alone
`compared to females given the combination, which may suggest some PK interaction in
`females. This was not seen in males. In addition, exposure in females tends to be higher
`than in males by drug week 8, though not substantially. Note that TK comes from a single
`female in the MD and HD groups, so only tentative conclusions can be drawn.
`
`Exposure to MK-0431
`
`" AUCum-m (axiom)
`
`
`501 e 50‘?
`
`
`22:30
`
`
`
`
`1 he s 1.6:
`' ChurxiWM}
`59.2; x 9,55
`2.2+: :.
`
`
`L3 .i 1.02
`
`
`71.0 $4.35
`36$ : 30.9 ,e
`1.1.6 20.5%.: i 53.7 i0.6;: g
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`
`
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`
`¥
`
`Mean Plasma MKJMM Texicokincxic annmersm Drug week 3
`
`M16043! *Mctfanhiu (in :‘k lduv)
`
`
`
`- Females
`
`
`108+ 506
`2n 4 50‘»
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`9.12 z (D
`:\UCQ.34 hr (”M-hr]
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`
`
`Males!
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`
`71:4 $2.20
`42.9mm
`313.229.!
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`AUCog: 1.; (“M01")
`
`
`
`
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`
`
`Cnmx (WM)
`i
`mum ‘ as“:
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`
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`2933255
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`Mm: Plum bow:$2095 (Mdt‘mni’a) Toxicakiaaic bran-arm » pm; week 1;
`MK-Mfi rkmfmmin fwd *
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`
`'50.“: [D
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`
`g
`‘3 Dose ekauhnuiu
`
`SEMM.
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`mean
`
`
`[Jun
`
`Exposure to Metformin
`
`
`
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`592 2593’
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`» .154 i 1.1.2
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`
`
`
`
`20
`
`

`

`
`Reviewer: Todd Bourcier, PhD.
`
`‘
`
`NDA No. 22-044
`
` a;
`
`a9.
`Control and 50mg/kg
`
`Key study findings:
`
`0 One female was found dead on day l6 following body weight loss and reduced
`food intake.
`
`0 One female was sacrificed on day 23 for physical signs; plasma lactate was
`markedly elevated and bicarbonate reduced just prior to sacrifice, likely an effect
`of morbidity than true drug-related lactic acidosis.
`
`o The timing of deaths is similar to deaths in response to the combination with MK-
`0431 in study #TT 06-6000.
`
`0 Mean plasma lactate increased 5 2 fold in metformin-treated females (high end of '
`historical range), but bicarbonate was unchanged.
`
`Reviewer Comments:
`
`This study shows that 50mg/kg metformin is not well-tolerated in dogs, with 2 of 5
`females dying by drug day 23. Merck suggests that metformin—induced lactic acidosis
`underlies morbidity/mortality in the dogs, but the reviewer concludes that morbidity in
`
`the dogs may be responsible for elevations in plasma lactate. The NDA '
`(Glucophage) review states that animal (rodent) studies have provided conflicting results
`relative to lactate prOduction, and that death of dogs administered metformin are
`associated with symptoms of GI distress, vascular lesions, and degenerative changes in
`the brain, heart, kidney, and skeletal muscle (NDA W ), which are reasonable
`alternative explanations for the deaths.
`
`The mechanism of metformin-related death is less important than the occurrence of
`death; a 50mg/kg dose with an exposure of 2 400 uM*h appears too high for combination
`toxicity studies in dogs.
`
`The reviewer concludes that the deaths of female dogs given the combination of MK—
`0431 and metformin may be due to metformin toxicity rather than exacerbated toxicity of
`the combination.
`
`21
`
`

`

`
`Reviewer: Todd Bourcier PhD.
`.
`*
`NDA No. 22-044
`
`Study no.2 TT—06—6018
`Volume #, and page #:
`Conducting laboratory and location: MRL, Chibret, France
`GLP compliance: No
`QA report: yes (. ) no ( x)
`Drug, lot #, and % purity:
`Metformin, lot L—000282095-001L012, fromW
`
`Methods
`
`
`
`Control and 50 mg/kg groups
`
`'
`
`
`
`
`
`
`
`
`
`
`
`
`C
`
`
`
`
`Route formulation
`Oral gavage of drug in 0.5% methylcellulose/water
`
`dose volume
`
`
`
`Number/sex/ rou :
`{main study!
`
`5 females
`
`After first dose and drug week 3
`
`Results:
`
`Mortaligl: Two females died during the study. One female (#05-0277) was found dead
`before dosing on drug day 16, and the other (#06-0047) was sacrificed after dosing on
`drug day 23 due to marked physical signs.
`
`Female 05-02 77: This female lost 1.2 kg body weight and food intake decreased
`markedly before death. Plasma lactate was elevated, but not substantially.
`
`Female 06—004 7: This female had labored breathing and lateral recumbency prior to
`sacrifice. Plasma lactate was markedly increased (177 mg/dL), bicarbonate decreased
`(l3mM), and glucose, potassium, and chlo