CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
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`
`
`
`APPLICATION NUMBER:
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`213051Orig1s000
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`
`NON-CLINICAL REVIEW(S)
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`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`
`
` CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`213051
`1
`03/20/2019
`03/20/2019
`Semaglutide, oral
`Type 2 diabetes
`
` Novo Nordisk
` Division of Metabolism and Endocrinology
`Products
`
` Elena Braithwaite, Ph.D.
`Reviewer:
` Federica Basso, Ph.D.
`
`Team Leader:
` Lisa Yanoff, MD
`
`Division Director:
`Peter Franks
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`
`
`Except as specifically identified, all data and information discussed below and
`
`
`necessary for approval of NDA 213051 are owned by Novo Nordisk Inc. or are data for
`
`
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`which Novo Nordisk Inc. has obtained a written right of reference.
`
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`Any information or data necessary for approval of NDA 213051 that Novo Nordisk Inc.
`
`
`does not own or have a written right to reference constitutes one of the following: (1)
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`
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`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug,
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`
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`as reflected in the drug’s approved labeling. Any data or information described or
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`referenced below from reviews or publicly available summaries of a previously approved
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`
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`application is for descriptive purposes only and is not relied upon for approval of NDA
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`213051.
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`
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`Reference ID: 4482035Reference ID: 4497378
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
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`TABLE OF CONTENTS
`
`
`1
` EXECUTIVE SUMMARY...........................................................................................5
`
`INTRODUCTION .....................................................................................................5
`
`1.1
`1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................5
`
`
`1.3 RECOMMENDATIONS .............................................................................................7
`
`2
` DRUG INFORMATION..............................................................................................8
`
`2.1 DRUG ..................................................................................................................8
`
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS............................................................9
`
`
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`2.3 DRUG FORMULATION ..........................................................................................10
`
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`2.4 COMMENTS ON NOVEL EXCIPIENTS ......................................................................10
`
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN........................................11
`
`2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .....................................11
`
`2.7 REGULATORY BACKGROUND ...............................................................................11
`
`3 STUDIES SUBMITTED...........................................................................................12
`
`3.1 STUDIES REVIEWED............................................................................................12
`
`4 PHARMACOLOGY .................................................................................................12
`
`4.1 PRIMARY PHARMACOLOGY ..................................................................................12
`
`4.2 SECONDARY PHARMACOLOGY .............................................................................13
`
`4.3 SAFETY PHARMACOLOGY ....................................................................................13
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS ...............................................14
`
`5.1 PK/ADME .........................................................................................................14
`
`TOXICOKINETICS.................................................................................................21
`
`5.2
`6 GENERAL TOXICOLOGY......................................................................................22
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`6.1 SINGLE-DOSE TOXICITY ......................................................................................22
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`6.2 REPEAT-DOSE TOXICITY .....................................................................................22
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`7 GENETIC TOXICOLOGY........................................................................................31
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`8 CARCINOGENICITY...............................................................................................31
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`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................31
`
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT................................................31
`
`9.1
`
`9.2 EMBRYONIC FETAL DEVELOPMENT.......................................................................32
`
`9.3 PRENATAL AND POSTNATAL DEVELOPMENT..........................................................32
`
`10
`SPECIAL TOXICOLOGY STUDIES....................................................................34
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`
`12
`
`APPENDIX/ATTACHMENTS ..............................................................................34
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`Reference ID: 4482035Reference ID: 4497378
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` Table of Tables
`
`
` Table 1: Composition of oral semaglutide used in the phase 3 clinical trial expressed as
`
`
`
`"per tablet" ......................................................................................................................10
`
`Table 2: Placental transfer and lacteal secretion of 14C-SNAC in the rat after an oral
`
`
`
`
`dose................................................................................................................................17
`
`Table 3: Percentage of Plasma Metabolites in Human and Rat.....................................19
`
`
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`Table 4: In vitro assessment of SNAC and metabolites as transporter substrates ........20
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`Table 5: Pharmacokinetics for SNAC in Sprague Dawley rats after oral gavage...........21
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`Table 6: Toxicokinetic parameters after oral administration of SNAC in Sprague Dawley
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`rats..................................................................................................................................21
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`Table 7: Pharmacokinetics for SNAC in Rhesus monkeys after oral gavage.................22
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`Table 8: SNAC exposure multiples at the NOAEL in pivotal toxicology studies.............23
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`Table 9: SNAC exposure multiples at the LOAEL in mechanistic studies......................29
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`Table 10: Summary of natural delivery observations - F0 generation female rats..........33
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`Table 11: SNAC exposure multiples at NOAEL in fertility and development studies .....34
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
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` Table of Figures
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` Figure 1: Semaglutide Chemical Structure.......................................................................9
`
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` Figure 2: Chemical Structure of SNAC...........................................................................11
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` Figure 3: Proposed metabolic pathways in mouse, rat, monkey and human .................19
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` Figure 4: Effect of SNAC on cellular respiration and the electron transport chain .........25
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`Figure 5: SNAC exposure (Cmax) and clinical chemistry changes following administration
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`of 75 to 1500 mg/kg in rats .............................................................................................27
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`Reference ID: 4482035
`Reference ID: 4497378
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`Elena Braithwaite, Ph.D.
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`1
`
`Executive Summary
`
`Introduction
`1.1
`
`
`Rybelsus® (semaglutide tablet) for oral administration is a glucagon-like peptide (GLP­
`
`1) analog co-formulated with salcaprozate sodium (SNAC), a novel absorption enhancer
`that transiently increases the permeability of the gastric epithelium to promote
`
`
`absorption of semaglutide in a size-selective manner. It is indicated as an adjunct to diet
`and exercise to improve glycemic control in adults with type 2 diabetes.
`1.2 Brief Discussion of Nonclinical Findings
`
`
`Semaglutide for subcutaneous injection was approved in 2017; therefore, the nonclinical
`
`
`
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`program for oral semaglutide focused mainly on SNAC. As a novel excipient, SNAC
`
`was qualified in a full toxicology program.
`
`Pharmacology
`
`Semaglutide lowers fasting and postprandial blood glucose and reduces body weight by
`
`
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`stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent
`
`manner. In Rybelsus® (semaglutide tablet), semaglutide is co-formulated with the novel
`
`
`absorption enhancer SNAC. SNAC is a small fatty acid derivative that interacts with
`plasma membranes to promote transcellular absorption of semaglutide and facilitates
`localized decreases in pH to protect semaglutide from degradation by gastric enzymes.
`
`
`Safety pharmacology studies were conducted with SNAC in vitro, in rats and in
`monkeys. Acute SNAC exposure in rats resulted in decreased touch response (≥16­
`
`
`fold higher than clinical exposure based on BSA), piloerection, decreased mean
`respiration rates and mortality (≥32-fold higher than clinical exposure based on BSA)
`
`
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`which were due to inhibition of cellular respiration through inhibition of complex I in the
`
`electron transport chain.
`
`Absorption, Distribution, Metabolism and Excretion
`After oral administration, SNAC is rapidly absorbed and eliminated, with a Cmax typically
`
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`reached within 2 hours and a T1/2 ranging between 1-3 hours. When SNAC is co-
`
`formulated with semaglutide, both products are absorbed due to a transient increase in
`
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`permeability of the gastrointestinal epithelium in a highly localized area around the
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`immediate vicinity of the tablet. SNAC-facilitated absorption of semaglutide showed
`
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`very high inter-animal variability in rats, dogs, and monkeys and was influenced by the
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`
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`fasting state of the animals.
`
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`SNAC is highly bound to plasma proteins, predominantly albumin. The free fraction in
`
`animals is slightly higher than in humans. Radiolabeled SNAC rapidly distributes to all
`
`tissues at levels below plasma levels, except in the excretory system (kidney and
`urinary bladder wall and contents) and gastrointestinal system (cecum mucosa, small
`
`intestine mucosa, and stomach mucosa). Very low levels were observed in the CNS
`
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`(~2%). Drug-related radioactivity was rapidly eliminated from most tissues within 24
`
`hours, with quantifiable radioactivity limited to adipose tissue and skin at 168 hours
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` post-dose. SNAC crosses the placenta, distributes to all fetal tissues reaching peak
`
`
`
` levels at 4 hours and persists in the gastrointestinal tract up to 24 hours. SNAC is
` secreted into breast milk with a mean milk/plasma ratio that ranges between 7 and 12 in
`
` the 4 to 24 hour time frame following a single administration.
`
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`SNAC is rapidly metabolized via β-oxidation and glucuronidation mainly by UGT2B7
`with additional contributions by UGT1A8 and UGT1A7. No unique metabolites were
`detected in humans. The primary route of excretion is the kidney, with negligible
`
`
`
`amounts recovered as unchanged SNAC. Metabolism is responsible for the majority of
`SNAC clearance in animals and humans.
`
`General Toxicology
`
`Pivotal repeat dose studies were conducted in mice up to 3 months, rats up to 12
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`
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`
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`months, and monkeys up to 9 months. Adverse clinical signs and mortality occurred in
`all species tested starting at low multiples to the clinical exposure. Generally, mortalities
`
`occurred within 3 hours after dosing and were not associated with histopathological or
`
`
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`standard clinical chemistry findings. Some common clinical signs observed before death
`
`
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`in animals included sedation/decreased activity, ruffled fur, abnormal respiration and
`salivation. Considerable inter-individual variability was observed for SNAC plasma
`concentrations with overlap of exposure between different dosing groups, making
`meaningful correlations between mean exposure levels and clinical signs challenging.
`Therefore, a series of mechanistic studies were performed where the onset of clinical
`
`
`
`signs was evaluated concurrently with SNAC plasma concentrations. The in vivo studies
`
`
`were conducted under fasting conditions to minimize variability in SNAC exposure, and
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`mostly in female rats, as they appear to be more sensitive than males to SNAC effects.
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`
`Mechanistic Studies
`SNAC caused a concentration-dependent inhibition of ATP biosynthesis in isolated
`mitochondria and submitochondrial particles and inhibited cellular respiration in several
`
`
`cell types with IC50 values that ranged between 175 and 1214 mcM. SNAC metabolites
`
`
`were at least 10-times less potent inhibitors of ATP biosynthesis in mitochondria
`
`indicating that metabolism could be important for detoxification of the parent compound.
`When human serum albumin was added in in vitro studies, the concentration of SNAC
`
`
`
`needed to inhibit cellular respiration increased indicating that albumin can sequester
`SNAC and prevent it from entering the inner mitochondrial membrane where it interacts
`
`
`with complex I and inhibits cellular respiration.
`
`Following single high doses of SNAC (>900 mg/kg), a dose-dependent increase in
`
`
`
`
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`adverse clinical signs (e.g. apathy, abnormal respiration, reduced alertness and startle
`
`response, abnormal body carriage, abnormal gait, passivity, reduced body tone,
`
`salivation and convulsions) and mortality were observed at approximately >100-fold the
`clinical Cmax. SNAC exposure also resulted in changes in clinical chemistry parameters
`including decreased blood and CSF glucose, and increases in plasma and
`
`
`cerebrospinal fluid (CSF) lactate levels. Decreases in blood pH, pO2, sO2, and HCO3
`
`-
` were also seen consistent with an effect of SNAC on cellular respiration. These findings
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`
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`generally occurred above 45-fold the clinical Cmax, with only few animals showing
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`changes in lactate levels without obvious clinical signs at lower exposures (between 3 to
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`Elena Braithwaite, Ph.D.
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` 30-fold the clinical Cmax). In an investigative 13-week study, small but significant
`
`
`
`
` increases in CSF lactate levels (~ 25%) were observed at the clinical exposure in few
`animals.
`
`Genetic Toxicology and Carcinogenicity
`SNAC was not mutagenic or clastogenic in a standard battery of GLP-compliant in vitro
`
`and in vivo genetic toxicology studies and was not carcinogenic in a 2-year Sprague
`
`
`Dawley rat or 6-month rasH2 transgenic mouse study.
`
`Reproductive and Developmental Toxicology
`
`Fertility, early embryonic development and pre- and post-natal development was
`
`assessed in rats and rabbits at once daily dosing of 1,000 mg/kg. SNAC had no effect
`
`on mating, or male and female fertility indices in rats, and was not teratogenic in rats or
`
`rabbits at doses 32- or 65-fold clinical exposure, respectively (based on BSA). In a pre-
`
`
`and post-natal development study in rats, prolonged gestation, and an increased
`incidence of stillbirths and early pup mortality was observed at 32-fold clinical exposure
`(based on BSA). A NOAEL for maternal toxicity and postnatal mortality was not
`
`
`determined in this study. No remarkable effects on neurobehavioral development or on
`
`fertility and reproductive performance of the F1 generation were observed.
`
`
`1.3 Recommendations
`1.3.1 Approvability
`The nonclinical data support market approval of Rybelsus® (semaglutide tablet).
`
`
`
`1.3.2 Additional Nonclinical Recommendations
`SNAC has been shown to inhibit cellular respiration in animals at high concentrations.
`
`
`Though SNAC exposure associated with toxicity in animals was not achieved in Phase
`
`3 studies with semaglutide/SNAC, a risk for higher exposure to SNAC and/or its
`
`
`
`
`metabolites is plausible for individuals with weak UGT2B7activity (an enzyme involved
`in SNAC metabolism) or with compromised hepatic function. Similarly, pediatric patients
`and lactating infants may be at greater risk given the immaturity of UGT2B7 in this
`
` population and because it is unknown if SNAC and or its metabolites accumulate in
`milk.
`
`1.3.3 Labeling
` Pharm/Tox labeling recommendations for SNAC are shown below in red.
`
`
`
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`
`
` Animal data
` Salcaprozate sodium (SNAC), an absorption enhancer in TRADENAME, crosses the
`
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` placenta and reaches fetal tissues in rats. In a pre- and postnatal development study in
` pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/day
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`Elena Braithwaite, Ph.D.
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` (exposure levels were not measured) on gestation day 7 through lactation day 20. An
`
`
`
`
` increase in gestation length, an increase in the number of stillbirths and a decrease in
`pup viability were observed.
`
`Lactation
`8.2
`Risk Summary
`
`
`
`
`There are no data on the presence of semaglutide in human milk, the effects on the
`breastfed infant, or the effects on milk production. Semaglutide was present in the milk
`
`of lactating rats. SNAC and/or its metabolites concentrated in the milk of lactating rats.
`When a substance is present in animal milk, it is likely that the drug will be present in
`human milk. (see Data). Higher SNAC plasma levels may occur in neonates and
`
`
`infants,
`
`
`ecause of the potential for serious adverse reactions in
`
`the breastfed infant due to the possible concentration of SNAC
`advise
`
`
`patients that breastfeeding is not recommended during treatment with TRADENAME.
`
`Data
`
`
`In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than in
`
`maternal plasma. SNAC and/or its metabolites were detected in milk of lactating rats
`following a single maternal administration on lactation day 10. Levels of SNAC and/or its
`
`metabolites in milk were approximately 12-fold higher than those found in maternal
`blood based on Cmax.
`
`13.2 Animal Toxicology and/or Pharmacology
`Increases in lactate levels and decrease in glucose levels in the plasma and
`
`cerebrospinal fluid (CSF) were observed in mechanistic studies with SNAC in rats.
`
`Small but statistically significant increases in lactate levels (up to 2-fold) were observed
`
`in a few animals at approximately the clinical exposure. At higher exposures (≥45-times
`
`
` clinical Cmax) these findings were associated with moderate to marked adverse clinical
`
` signs (lethargy, abnormal respiration, ataxia, and reduced activity, body tone and
`
` reflexes) and marked decreases in plasma and CSF glucose levels. These findings are
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`
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` consistent with inhibition of cellular respiration and lead to mortality at SNAC
`
`concentrations >100-times the clinical Cmax.
`2 Drug Information
`
`2.1 Drug
`CAS Registry Number (Optional): RN910463-68-2
`
`Generic Name: Semaglutide
`
`
`Code Name: NNC 0113-0217; NNC 0113-0000-0217; 0217; NN9535
`
`
`Chemical Name: Nε26 [(S)-(22,40-dicarboxy-10,19,24-trioxo-3,6,12,15­
`tetraoxa-9,18,23-triazatetracontan-1-oyl)] [Aib8, Arg34] GLP-1-(7-37) peptide
`
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`(b) (4)
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
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`Molecular Formula/Molecular Weight: C187 H291 N45 O59 / 4,113.6 g/mole
`
`
`
`Structure or Biochemical Description
`Figure 1: Semaglutide chemical structure
`
`Pharmacologic Class: Long acting GLP-1 receptor agonist
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`Semaglutide
`
` NDA # Drug Name
`209637 Ozempic
`(Semagllutide)
`
`Sponsor
`Novo
`Nordisk Inc
`
`Indication
` Adjunct to diet and exercise to improve
`
`glycemic control in adults with type 2
`diabetes mellitus
`
`Status
`Approved
`
`SNAC
`IND # Drug Name Sponsor
`
`Indication
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`Status
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
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`2.3 Drug Formulation
`
`
`
`Table 1: Composition of oral semaglutide used in the phase 3 clinical trial
`expressed as "per tablet"
`
`2.4 Comments on Novel Excipients
`
`Salcaprozate sodium (SNAC) is a novel excipient and will be the focus of this NDA
`
`
`
`review. It is a fatty acid derivative that is used as an absorption enhancer.
`
`
`CAS Registry Number (Optional): 203787-91-1
`
`Generic Name: Salcaprozate sodium (SNAC)
`
`Code Name: SNAC, N-(salicyloyl)-8-aminooctanoic acid monosodium salt, monosodium
`
`
`N-{8-(2-phenoxybenzoyl)amino} octanoate, sodium N-[8-(2­
`hydroxybenzoyl)amino]caprylate E414 monosodium salt, EMIS000414 monosodium salt
`
`
`Chemical Name: Sodium 8-[(2-hydroxybenzoyl)amino]octanoate
`
`Molecular Formula/Molecular Weight: C15H20NNaO4/301.32 g/mol
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA # 213051
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`Structure or Biochemical Description
`Figure 2: Chemical structure of SNAC
`
` 2.5 Comments on Impurities/Degradants of Concern
`
`While semaglutide for oral administration is structurally identical to injectable
`
`
`
`
`semaglutide (Ozempic®), a different
`and optimized production
`
`process was introduced between Phase 2 and 3
`
`
`
` The major semaglutide-related impurities in the degraded
`
`
`semaglutide drug product have been identified and found to be
`
`
`. All of the mentioned semaglutide-related
`impurities have been observed in nonclinical batches during development.
`
`
`All impurities/degradants present in SNAC batches were qualified in toxicology studies
`or were present at levels below the reporting threshold described in ICH Q3A.
`
`
`
`
`2.6 Proposed Clinical Population and Dosing Regimen
`
`Rybelsus® is indicated as an adjunct to diet and exercise to improve glycemic control in
`
`
`
`adults with type 2 diabetes mellitus. Rybelsus® has not been studied in patients with a
`
`
`history of pancreatitis and is not indicated for use in patients with type 1 diabetes
`mellitus or for the treatment of diabetic ketoacidosis.
`
`
`
`
`Three, 7 or 14 mg of Rybelsus® is administered daily (dose escalation occurs at one-
`
`month intervals if additional benefits are needed).
`
`2.7 Regulatory Background
`Semaglutide is an FDA approved long acting GLP-1 analog with a high degree of
`
`
`
`
`
`homology to human GLP-1. Semaglutide injection was approved under NDA 209637
`
`Ozempic® (semaglutide) on December 5, 2017. To facilitate long-term glycemic control
`using a convenient oral formulation, semaglutide was co-formulated with a novel
`
`
`absorption enhancer, salcaprozate sodium or SNAC. A full nonclinical program was
`
`
`completed to qualify this novel excipient under IND 114464 (submitted on September
`
`
`
`
`26, 2013). On March 20, 2019, Novo Nordisk Inc. filed NDA 213051 to seek approval
`for Rybelsus® as an adjunct to diet and exercise to improve glycemic control in adults
`
`
`with type 2 diabetes. On the same day, Novo Nordisk also filed NDA 213182 to seek
`
`approval for Rybelsus® to reduce the risk of major adverse cardiovascular events
`(cardiovascular death, nonfatal myocardial infarction or non-fatal stroke) in adults with
`
`
`type 2 diabetes mellitus and established cardiovascular disease
`
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`(b) (4)
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
`
`3
`
`Studies Submitted
`
`3.1 Studies Reviewed
`
`
`Pivotal nonclinical studies addressing pharmacology, general toxicology, genotoxicity
`
`
`and carcinogenicity, and reproductive and developmental toxicology of SNAC were
`
`reviewed under IND 114464 and are summarized in this NDA review.
`
`4
`Pharmacology
`Semaglutide binds the human GLP-1 receptor and is thought to lower blood glucose by
`
`
`
`stimulating glucose-dependent insulin secretion and insulin biosynthesis, inhibiting
`glucagon secretion and decreasing gastric emptying. Salcaprozate sodium (SNAC) is a
`
`small fatty acid derivative and absorption enhancer that facilitates the absorption of
`
`
`semaglutide across the gastrointestinal epithelium.
`
`SNAC is currently available in a marketed ‘medical food’ in the US where 1,000 mcg
`vitamin B12 is formulated with 100 mg SNAC1. The amount of SNAC present at the
`
`
`
`maximum recommended dose for this product is 200 mg, which is less than the 300
`
`
`
`
`
`mg/day dose proposed in Rybelsus®; therefore, SNAC has not been used in a
`
`
`
`marketed product at the proposed level.
`
`
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`4.1 Primary Pharmacology
`In vitro and in vivo studies show that when SNAC is co-formulated with peptides it
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`transiently increases the fluidity and permeability of cellular membranes to facilitate
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`intracellular transport of peptides in a concentration-dependent and size-selective
`manner. In vitro studies with cell membranes and monolayers show that SNAC’s ability
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`to facilitate transport of compounds increased with increasing concentrations,
`decreased as the molecular weight of the compound increased over 4 kDa (absorption
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`of compounds greater than 150 kDa is minimal) and occurred over a period of 20-90
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`minutes after SNAC was removed. Nuclear magnetic resonance studies show that
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`SNAC does not associate with semaglutide in solution; therefore, increased absorption
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`does not occur through an interaction between these two compounds. To demonstrate
`that semaglutide is pharmacologically active when administered orally and co-
`formulated with SNAC, male db/db rats were given a single oral dose of vehicle,
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`semaglutide, SNAC, or semaglutide co-formulated with SNAC. When administered
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`orally in an intraperitoneal glucose tolerance test, reduced glucose levels were
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`observed when SNAC was co-formulated with semaglutide but not with semaglutide
`alone. These findings show that orally administered semaglutide co-formulated with
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`SNAC can enter the blood stream and produce a pharmacological effect.
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` 1 https://eligenb12.com/wp-content/themes/eligen/pdfs/cccPC4745C_3c2.pdf
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`Reference ID: 4482035Reference ID: 4497378
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
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`4.2 Secondary Pharmacology
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`Using an in vitro radioligand binding assay, SNAC was shown to inhibit human
`prostanoid DP and prostanoid EP4 (49 and 34% at 30 mcM SNAC, respectively) and
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`serotonin 5-HT2B (>30% at 100 mcM SNAC) receptors. Additionally, SNAC caused
`reduction of spontaneous tone in a tracheal relaxation assay (21% at 10 mcM and 70%
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`at 30 mcM) and inhibition of arachidonate-induced platelet aggregation (100% at 30
`mcM), which may account for the moderate relaxation of spontaneous tone in guinea
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`pig trachea (48% at 30 mcM). Since the highest recorded Cmax value for SNAC after an
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`oral dose of 300 mg in humans was 9,300 ng/mL or 31 mcM and albumin-mediated
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`SNAC-binding will reduce the amount of free SNAC available to interact with these
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`receptors in vivo, no significant inhibitory effects would be expected in humans.
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`4.3 Safety Pharmacology
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`Safety pharmacology studies were conducted in vitro, in rats and in monkeys to
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`investigate the effect of SNAC on central nervous, cardiovascular and respiratory
`systems.
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`CNS
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`After a single oral dose of SNAC, male Sprague Dawley rats experienced generalized
`signs of CNS depression including a slight decrease in touch response (≥500 mg/kg),
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`and decreased respiration and piloerection (>1,000 mg/kg) that were transient in
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`surviving rats. Transient decreases in mean body temperature from baseline were seen
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`in female rats given a single 900 or 1,500 mg/kg dose of SNAC. Mortalities also
`occurred at doses ≤1,000 mg/kg.
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`Cardiovascular system
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`SNAC had no clear effects on the hERG tail current at doses up to 1 mM and other
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`cardiac ion channels at concentrations up to 200 mcM. In female Sprague Dawley rats
`implanted with telemetry radiotransmitters that were administered 900 or 1,500 mg/kg
`SNAC orally on Day 1 and Day 8, transient increases in mean heart rate were
`observed. Consistent with increased heart rates, RR interval time decreased and QT
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`and corrected QT interval times increased. Additionally, increases in atrial (pause and
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`premature beat) and junctional (salvo) arrhythmias were observed at 900 mg/kg and
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`increases in atrial (premature beat), ventricular (beat), junctional (beat), and other
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`arrhythmias were observed at 1,500 mg/kg/day. Ultimately, 2/8 rats in the 900
`mg/kg/day group (Cmax values ranged between 240,593 - 445,346 ng/mL or 26- to 48­
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`fold higher than clinical Cmax) and 3/8 rats in the 1500 mg/kg/day group (Cmax values
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`ranged between 211,430 – 539,136 ng/mL or 23- to 58-fold higher than clinical Cmax)
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`died after experiencing marked decreases in diastolic arterial pressure. High levels of
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`exposure found in this study would indicate that mortalities occurred due to SNAC
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`inhibition of complex I in the electron transport chain and subsequent inhibition of
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`cellular respiration; therefore, cardiovascular findings observed in this study may be a
`secondary response. Conscious monkeys instrumented with a telemetry transmitter did
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`Reference ID: 4482035Reference ID: 4497378
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
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` not experience any treatment-related effects on cardiovascular parameters at doses up
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`to 600 mg/kg for 6 months at 6 to 7-fold the clinical exposure based on Cmax.
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`Respiratory system
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`A mechanistic study where female Sprague Dawley rats were given 900 or 1,500 mg/kg
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`SNAC orally on Day 1 and Day 8 had increased mean respiration rates. Mortality also
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`occurred at doses >1,000 mg/kg, with the lungs of decedent rats showing reddening
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`with small hemorrhagic areas. A safety pharmacology study in male rats showed no
`statistically significant effects on mean respiration rates or tidal volumes at doses up to
`1,000 mg/kg (32-fold clinical exposure based on BSA).
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`5
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`Pharmacokinetics/ADME/Toxicokinetics
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`5.1 PK/ADME
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`SNAC Absorption
`SNAC absorption was evaluated after oral administration in mice, rats, and monkeys. In
`all test species examined, SNAC was rapidly absorbed, typically reached Cmax in under
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`2 hours and had a half-life that ranged between 1-3 hours. Although systemic exposure
`was highly variable, AUC and Cmax values generally increased with increasing dose and
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`female rodents tended to have a higher systemic exposure when compared to male
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`rodents. In dogs and monkeys, the relative oral bioavailability of semaglutide in the
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`presence of SNAC was estimated to range from 0.04 – 4.04%. SNAC absorption was
`influenced by the fasting state of the animal. Fasted Sprague Dawley rats given a
`single oral dose of 14C-SNAC had AUC(0-6h) values 1.4 to 3-fold greater than unfasted
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`rats.
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`Semaglutide Absorption After Co-formulation with SNAC
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`Absorption of semaglutide after co-formulation with SNAC has been investigated both in
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`vitro and in vivo (rats, dogs and monkeys). In vitro, SNAC promoted trans-epithelial
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`permeation of semaglutide across Caco-2 (human epithelial colorectal adenocarcinoma
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`cell line) monolayers where increasing concentrations of SNAC (up to 80 mM) resulted
`in increased transport of semaglutide. Consistent with in vitro studies, a single oral
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`administration of semaglutide co-formulated with SNAC to fasting beagle dogs resulted
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`in absorption of semaglutide through the stomach. Systemic exposure to semaglutide
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`over a 1-hour period was comparable between anesthetized dogs treated
`intragastrically after pyloric ligation and conscious dogs treated orally without pyloric
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`ligation. Plasma levels of semaglutide were higher in the splenic vein 30 minutes after
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`dosing when compared to the portal vein in anesthetized dogs dosed intragastrically
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`with oral semaglutide. Optimal absorption of semaglutide occurred in the presence of
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`300 mg SNAC (higher levels of SNAC resulted in decreased bioavailability of
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`semaglutide). Additionally, semaglutide exposure increased in a greater than dose
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`proportional manner with increasing dose when administered with 300 mg SNAC.
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`Reference ID: 4482035Reference ID: 4497378
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`14
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`NDA # 213051
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`Elena Braithwaite, Ph.D.
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` Similar to SNAC absorption, SNAC-facilitated absorption of semaglutide showed very