CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`213051Orig1s000
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`SUMMARY REVIEW
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`Cross Discipline Team Leader Review
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`Cross-Discipline Team Leader Review
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`Date
`From
`Subject
`NDA/BLA # and Supplement#
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name
`Established or Proper Name
`Dosage Form(s)
`Applicant Proposed
`Indication(s)/Population(s)
`
`Applicant Proposed Dosing
`Regimen(s)
`
`Recommendation on Regulatory
`Action
`Recommended
`Indication(s)/Population(s) (if
`applicable)
`
`Recommended Dosing
`Regimen(s) (if applicable)
`
`September 19, 2019
`Mitra Rauschecker, MD
`Cross-Discipline Team Leader Review
`213051
`Novo Nordisk
`March 20, 2019
`September 20, 2019
`Rybelsus
`Semaglutide tablets
`Oral tablets
`as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus
`Start at 3 mg once daily for 30 days then increase the
`dose to 7 mg once daily. Dose may be increased to 14
`mg once daily if additional glycemic control is needed
`after at least 30 days on 7 mg
`Approval
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`as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus
`
`Start at 3 mg once daily for 30 days then increase the
`dose to 7 mg once daily. Dose may be increased to 14
`mg once daily if additional glycemic control is needed
`after at least 30 days on 7 mg
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`1. Benefit-Risk Assessment
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`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017 for all NDAs and BLAs
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`Cross Discipline Team Leader Review
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`Benefit-Risk Assessment Framework
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`Benefit-Risk Integrated Assessment
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`Type 2 diabetes mellitus (T2DM) is a serious, chronic medical condition, which has been increasing in prevalence in the US. It is characterized
`by insulin resistance with insufficient insulin production, and resulting hyperglycemia. Current approved therapies for T2DM include glucagon-
`like peptide 1 (GLP-1) receptor agonists, which acts to improve glucose dependent insulin secretion, slows gastric emptying, and reduces fasting
`and postprandial glucagon levels. Semaglutide is a GLP-1 receptor agonist, and the subcutaneous (sq) injectable formulation is currently
`approved as an adjunct to diet and exercise for the treatment of adults with T2DM. The applicant has developed an oral formulation of
`semaglutide, which would be the first oral GLP-1 receptor agonist, with the same proposed indication as the sq semaglutide formulation.
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`The clinical development program for semaglutide consisted of 33 studies, which included 7 multi-national, phase 3 controlled clinical studies in
`adults with T2DM, along with 2 studies conducted in Japan, and a pre-market CVOT to evaluate cardiovascular safety. Semaglutide
`demonstrated a dose-dependent reduction in HbA1c, and the maintenance doses (7 and 14 mg) were superior to placebo, and active controls
`(excluding liraglutide). While the reduction in HbA1c compared to placebo was somewhat less for oral semaglutide as compared to sq
`semaglutide based on historical data, oral semaglutide demonstrated substantial evidence of effectiveness for glycemic control from adequate and
`well controlled trials, and the oral formulation offers a therapeutic alternative from injectable therapies.
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`The safety findings for semaglutide were generally consistent with the known safety profile of sq semaglutide. There was a higher incidence of
`gastrointestinal adverse events versus placebo, specifically nausea and vomiting, which is expected with GLP-1 receptor agonists. In order to
`enhance oral absorption of semaglutide, the applicant used a novel excipient, salcaprozate sodium (SNAC). The nonclinical data demonstrated an
`increase in mortality with high dose administration of SNAC, attributed to inhibition of cellular respiration, associated with increased lactate
`levels. In the phase 3 clinical studies, there were few events of lactic acidosis overall, with no evidence of an imbalance between treatment
`groups. Similarly, serum lactate levels were evaluated in several of the trials, and there was no evidence of increased lactate levels. Overall, the
`data do not suggest an increased risk of lactic acidosis related to semaglutide/SNAC.
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`Nonclinical studies to evaluate the safety of the SNAC demonstrated that SNAC concentrated in the milk of lactating animals. Given there are
`alternative treatment options, including sq semaglutide, breastfeeding is not recommended for oral semaglutide. In addition, a post-marketing
`requirement (PMR) for a milk-only lactation study to assess concentration of semaglutide and SNAC in breast milk is recommended.
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`Diabetic retinopathy was identified as a safety concern during the development program for sq semaglutide, with an increased risk of diabetic
`retinopathy complications seen in subjects treated with sq semaglutide during the cardiovascular outcomes trial (CVOT). The imbalance in
`diabetic retinopathy complications was attributed to the glucose lowering effect of sq semaglutide, with an early progression in diabetic
`retinopathy with improved glycemic control. For oral semaglutide, diabetic retinopathy events were collected by the applicant, and subjects also
`underwent baseline and end of treatment eye exams, including fundoscopy with dilation. Overall, the data do not suggest an imbalance in diabetic
`CDER Cross Discipline Team Leader Review Template
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`Cross Discipline Team Leader Review
`retinopathy events for oral semaglutide, although the trials were not designed to adequately assess the retinopathy risk, given the short duration of
`the trials, and the low risk population. For this reason, I recommend the risk of diabetic retinopathy is included in labeling for consistency with sq
`semaglutide.
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`The applicant also completed a CVOT to assess the cardiovascular safety of semaglutide designed to satisfy the 2008 guidance for industry on
`assessing cardiovascular safety for new therapies intended to treat type 2 diabetes. The trial was event-driven, and accrued a total of 137 first
`major adverse cardiovascular events (MACE). The data from this study ruled out a 1.3 risk margin and support that no additional post-marketing
`study should be required to assess the CV safety of semaglutide.
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`In summary, the clinical development program demonstrated semaglutide has a favorable benefit-risk profile. Semaglutide demonstrated the
`ability to improve glycemic control, and the safety profile is generally consistent with sq semaglutide and with other members of the GLP-1
`analog class. I recommend approval of semaglutide as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus.
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`Dimension
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`Analysis of
`Condition
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`Current
`Treatment
`Options
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`Benefit-Risk Dimensions
`Evidence and Uncertainties
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`• Type 2 diabetes mellitus (T2DM) is a disease characterized by
`hyperglycemia, insulin resistance, and relative impairment of insulin
`secretion.
`• It is a relatively common disease that is estimated to affect approximately
`30 million people in the United States as of the 2015 Center for Disease
`Control report.
`• T2DM is often associated with other metabolic derangements, such as
`dyslipidemia, hypertension, and obesity.
`• Chronic complications of T2DM include cardiovascular disease, retinopathy,
`nephropathy, and neuropathy.
`• Treatment options for T2DM includes lifestyle modifications, usually
`followed by the addition of one or multiple different medications.
`• There are currently multiple classes of pharmacologic treatments for T2DM,
`including biguanides, sulfonylureas, insulin and insulin analogs, glucagon-like
`peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP4) inhibitors, and
`sodium-glucose linked transporter (SGLT)-2 inhibitors.
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`Conclusions and Reasons
`T2DM is a serious, life-threatening condition that
`can lead to serious morbidity and mortality if left
`untreated.
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`There are multiple different classes of medication
`for patients with T2DM.
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`Cross Discipline Team Leader Review
`Dimension
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`Evidence and Uncertainties
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`Conclusions and Reasons
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`• Semaglutide is currently approved as a sq formulation.
`• There are no approved oral GLP-1 receptor agonists.
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`• Semaglutide demonstrated efficacy in reducing HbA1c in a dose-dependent
`manner, with an approximate reduction in HbA1c of 0.8-1.1% compared to
`placebo.
`• Semaglutide also resulted in weight loss of approximately -1 to -4 kg
`compared to placebo.
`• Semaglutide is an oral formulation, which would allow use in patients who
`cannot or prefer not to use injectable semaglutide.
`• The most common adverse events were gastrointestinal events.
`• Safety concerns common to all GLP-1 receptor agonists include pancreatitis,
`medullary thyroid tumors, and acute kidney injury. The development
`program for semaglutide did not change these concerns, or raise any new
`safety concerns.
`• There was no evidence of increased cardiovascular risk.
`• There was no evidence for increase in lactic acidosis events related to SNAC.
`Nonclinical studies demonstrated SNAC concentrated in the milk of lactating
`animals.
`• There was no evidence of increase in diabetic retinopathy complications.
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`Benefit
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`Risk and Risk
`Management
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`Semaglutide was effective in improving glycemic
`control, and also resulted in reduction in body
`weight.
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`The safety profile for oral semaglutide was
`generally consistent with sq semaglutide, and
`other GLP-1 receptor agonists. The risks associated
`with semaglutide can be adequately
`communicated with labeling. A lactation study is
`recommended to assess whether
`semaglutide/SNAC concentrates in milk.
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`2. Background
`Type 2 diabetes mellitus (T2DM) is a serious, chronic medical condition, which has been
`increasing in prevalence in the US. It is characterized by insulin resistance with insufficient
`insulin production, and resulting hyperglycemia. Patients with T2DM are at risk for secondary
`complications such as retinopathy, neuropathy, nephropathy, and cardiovascular disease,
`which are the result of chronic hyperglycemia. Current approved therapies for T2DM include
`glucagon-like peptide 1 (GLP-1) receptor agonists, which acts to improve glucose dependent
`insulin secretion, slows gastric emptying, and reduces fasting and postprandial glucagon
`levels.
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`Semaglutide is a GLP-1 receptor agonist, and the subcutaneous injectable formulation was first
`approved in the United States in 2017 as an adjunct to diet and exercise for the treatment of
`adults with T2DM. Novo Nordisk, hereafter referred to as the applicant, has submitted a new
`drug application (NDA) for an oral formulation of semaglutide. The proposed indication is as
`an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus. While there are multiple different approved injectable GLP-1 receptor agonists,
`semaglutide would be the first oral formulation.
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`The applicant has proposed two therapeutic doses for semaglutide, 7 mg and 14 mg, along
`with a titration dose of 3 mg, which is to be administered for the first four weeks, followed by
`an increase to the 7 mg dose. The dose can be increased to 14 mg if additional glycemic
`control is required.
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`In support of this NDA, the applicant conducted a total of 7 multi-national efficacy trials,
`along with 2 efficacy trials conducted in Japan, and a cardiovascular outcomes trial (CVOT) to
`rule out excess cardiovascular risk. The applicant has also submitted a separate application
`requesting an indication for the reduction in cardiovascular risk for both oral and sq
`semaglutide under NDA 213182, which is currently under review. For this reason, the data
`from the CVOT will only be discussed with respect to safety.
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`3. Product Quality
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`Drug Substance:
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`Semaglutide is a modified analog of the human GLP-1 peptide, which contains two amino acid
`substitutions, and a modification at the lysine 26 side chain. It binds to and acts at the native
`GLP-1 receptor. These amino acid substitutions and modifications protects semaglutide from
`degradation by the dipeptidyl peptidase 4 enzyme, and reduce renal clearance, thus prolonging
`its half-life. The structure of oral semaglutide drug substance is identical to that of sq
`semaglutide drug substance.
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`The molecular formula of semaglutide is shown below:
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`Figure 1: Chemical Structure of Semaglutide
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`Source: CMC review
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`Semaglutide is manufactured by
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`substance manufacturing process, see the Office of Pharmaceutical Quality (OPQ) review.
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`Drug Product:
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`Semaglutide tablets are available in three strengths, 3 mg, 7 mg, and 14 mg, and each tablet is
`formulated with 300 mg of salcaprozate sodium (SNAC), which is a novel excipient. SNAC
`works to enhance oral aborption, by transiently increasing transcellular permeability of the
`gastric epithelium to facilitate absorption. Other excipients, which are USP grade excipients,
`include micro-crystalline cellulose, Povidone
`and magnesium stearate. See Table 1.
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`Table 1: Composition of Semaglutide Drug Product
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`Source: Table 1 from Applicant’s eCTD 2.3.P.1
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`SNAC is manufactured by the applicant,
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`The
`excipients used in the manufacture of the drug product, including the manufacturing process
`for SNAC, were reviewed by Dr. Galliford, and found to be adequate.
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`The drug substance is manufactured usin
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`The drug product composition, process for manufacturing the
`drug product, and packaging system used for the phase 3 clinical studies is the same process
`proposed for commercial use. Dr. Galliford has found the manufacturing process and in-
`process controls to be adequate.
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`The drug product is light sensitive, and is stored in blister packaging. The applicant conducted
`testing to evaluate long-term storage conditions, which included testing at 25°C/60% RH, and
`at the accelerated storage condition 40°C/75% RH. Based on the provided stability data, Dr.
`Galliford recommends an expiration period of 24 months when stored at 20-25°C in blister
`packaging. For detailed discussion of the drug product manufacturing process, see the OPQ
`review.
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`Facilities:
`The applicant’s manufacturing facility has an adequate inspection history for both manufacture
`of drug substance and drug product, and based on previous experience with the manufacture of
`other drug products that are considered equivalent to the proposed manufacturing operation in
`this application, no pre-approval inspections were recommended.
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`4. Nonclinical Pharmacology/Toxicology
`The nonclinical program was designed to assess the novel excipient, SNAC, as sq semaglutide
`is an approved product. While SNAC is present in a marketed “medical food”, at a maximum
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`dose of 200 mg in a vitamin B12 formulation, SNAC has not been used in an approved
`product, and it is present at a lower dose in the vitamin B12 formulation than that proposed for
`oral semaglutide (300 mg).
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`Nonclinical pharmacology studies were conducted with SNAC in in vitro studies, in rats, and
`in monkeys. After a single oral dose of SNAC, signs of CNS depression were exhibited,
`including decreased touch response, decreased respiration, and piloerection (which occurred at
`≥16-fold higher than clinical exposure based on BSA). Decreased respiration rates and
`mortality also occurred (which occurred at ≥32-fold higher than clinical exposure based on
`BSA) which were attributed to the inhibition of cellular respiration.
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`Following oral administration, the absorption of semaglutide co-formulated with SNAC
`demonstrated high inter-animal variability in rats, dogs, and monkeys, and was influenced by
`the fasting state of the animals. SNAC is highly bound to plasma proteins, with albumin being
`predominant. Pregnant rats treated orally with 14C-SNAC demonstrated SNAC-related
`radioactivity that crossed the placenta. SNAC was present in fetal tissues, and was also present
`in the milk of lactating rats when administered to rats 10 days post-partum. It was noted that
`SNAC and/or its metabolites appeared to accumulate the milk of lactating rats. The
`metabolism of SNAC is through β-oxidation and glucuronidation, mainly by UGT2B7 with
`additional contributions by UGT1A8 and UGT1A7. Metabolites resulting from β-oxidation
`also inhibit ATP synthesis in the mitochondria, but were noted to be 10-times less potent.
`SNAC is primarily excreted through the kidney, although metabolism is responsible for the
`majority of the clearance of SNAC.
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`Repeat dose toxicology studies were conducted in mice (up to 3 months), rats (up to 12
`months), and monkeys (up to 9 months). All species tested demonstrated adverse clinical
`signs, including sedation, ruffled fur, abnormal respiration, and increased salivation, and
`mortality at low multiples to the clinical exposure. However, there was considerable inter-
`individual variability for SNAC plasma concentrations with overlap of exposure between
`dosing groups, making it difficult to make correlations between SNAC exposure levels and
`clinical signs. For this reason, additional mechanistic studies were conducted to further
`evaluate SNAC-associated mortality in animals.
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`In the in vitro studies, SNAC demonstrated a concentration-dependent inhibition of ATP
`synthesis in the mitochondria, and human albumin increased the concentration of SNAC
`needed to inhibit cellular respiration. The in vivo studies conducted in rats demonstrated
`increases in plasma and CSF lactate levels, which generally occurred at ≥42X clinical Cmax,
`with a few animals showing increased lactate levels at lower exposures (3-30X clinical Cmax).
`The increases in lactate levels generally correlated with clinical signs and mortality.
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`The applicant conducted a 2-year carcinogenicity study in rats, and SNAC was not found to be
`carcinogenic. Developmental and reproductive toxicology studies were conducted in rats and
`rabbits. SNAC was not found to affect fertility in rats, and was not teratogenic in rats or
`rabbits. Prolonged gestation and increased incidence of stillbirths and early pup mortality was
`seen at 32X clinical exposure in pre- and post-natal development studies in rats.
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`Pediatric patients may be at risk for higher SNAC exposures given that UGT2B7, one of the
`enzymes responsible for the metabolism of SNAC, operates only at 3-10% of its maximal
`activity in adults. However, β-oxidation is the primary mechanism of metabolism, which is
`present in pediatric patients. Given the findings of SNAC which was concentrated in the milk
`of lactating animals, and due to alternative treatment options, including sq semaglutide,
`breastfeeding is not recommended for oral semaglutide. In addition, a post-marketing
`requirement (PMR) for a milk-only lactation study to assess concentration of semaglutide and
`SNAC in breast milk is recommended.
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`The nonclinical data for semaglutide co-formulated with SNAC support approval of
`semaglutide. Based on the data reviewed, Dr. Elena Braithwaite recommends approval.
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`5. Clinical Pharmacology
`Semaglutide is a long-acting recombinant analog of human GLP-1, an incretin hormone which
`acts to stimulate glucose-dependent insulin secretion and inhibit glucagon secretion. In order
`to enhance oral aborption, semaglutide has been co-formulated with SNAC for the tablet
`formulation. SNAC works to transiently increase transcellular permeability of the gastric
`epithelium to facilitate absorption, by increasing the pH in the localized environment in the
`stomach directly beneath the tablet, to prevent degradation of the semaglutide tablet by gastric
`enzymes. Following absorption, oral semaglutide is distributed, metabolized, and eliminated in
`the same way as sq semaglutide.
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`The clinical pharmacology data was reviewed by the Office of Clinical Pharmacology (OCP)
`reviewers, Dr. Suryanarayana Sista, Dr. Mohammad Absar, Dr. Justin Penzenstadler, Dr.
`Justin Earp, and Dr. Manoj Khurana. The clinical pharmacokinetics of oral semaglutide are
`summarized in Figure 2 below.
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`Figure 2: Clinical Pharmacokinetics of Oral Semaglutide
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`Source: Clinical Pharmacology Review
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`The clinical development program for oral semaglutide consisted of 33 trials, which included
`10 Phase 3 studies, of which 2 studies were conducted in Japan, and one study was a CVOT.
`See Appendix 1 for further details. The Applicant conducted a modeling-based comparison of
`exposure-response data in the Phase 3 trials comparing sq semaglutide (SUSTAIN) with oral
`semaglutide (PIONEER). The comparative exposures demonstrated that the exposure after
`administration of oral semaglutide were comparable to exposures following sq semaglutide
`administration.
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`Figure 3: Semaglutide Exposures- oral (PIONEER) and sq (SUSTAIN)
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`Source: Figure 3-2 from Applicant’s Clinical Overview
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`In order to evaluate oral semaglutide dose selection, the Applicant conducted a randomized,
`dose escalation, dose ranging study with 9 treatment arms, which included 7 oral semaglutide
`groups, 1 oral placebo group, and 1 sq semaglutide group (Study 3790). Mean steady-state
`exposures after administration of 2.5-40 mg of oral semaglutide were in the range of 2-50
`mmol/L, while sq semaglutide dosed once weekly had a mean steady-state exposure of 30
`mmol/L. A dose-response relationship for change in HbA1c for oral semaglutide and body
`weight was supportive of the selected doses for oral semaglutide of 3 mg, 7 mg, and 14 mg,
`which demonstrated similar exposure and efficacy parameters in comparison to approved
`doses of sq semaglutide.
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`The Applicant has formulated all three strengths of oral semaglutide (3 mg, 7 mg, and 14 mg)
`with a fixed amount of SNAC (300 mg). The dose of SNAC was selected based on the results
`of Study 3691, which demonstrated plasma semaglutide concentration increased with
`increasing SNAC concentration (150 mg to 300 mg), however, increasing SNAC content
`further (from 300 mg to 600 mg) did not increase semaglutide exposure. The exposure of
`semaglutide appeared to be lower with 600 mg of SNAC in comparison to 300 mg of SNAC,
`although the data was highly variable and there was missing data. As a result, it is not clear if
`increasing SNAC concentrations to 600 mg would result in similar systemic exposure in
`comparison to 300 mg of SNAC. The clinical pharmacology reviewers conclude that product
`labeling should clearly state patients should not take two 7 mg tablets in place of one 14 mg
`tablet, as this may result in different semaglutide exposures, and I agree with their assessment.
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`The Applicant has proposed that oral semaglutide be administered on an empty stomach, and
`should be swallowed with 120 mL of water, following which patients should wait at least 30
`minutes before the first meal or drink, and before taking other medications. These proposed
`dosing administration instructions were based on two clinical pharmacology studies in which
`the exposure of semaglutide (Cmax and AUC0-24h) was decreased following dosing with 240 mL
`of water, in comparison to either 50 mL or 120 mL of water. Additional clinical pharmacology
`studies evaluated the effect of the absorption of semaglutide after post-dose food intake. These
`studies demonstrated that post-dose food intake and stomach contents, along with the volume
`of water, affected the absorption of oral semaglutide. As a result, the dosing conditions were
`stipulated in the Phase 3 trials.
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`In the drug-drug interactions studies, semaglutide and SNAC did not affect the absorption of
`orally administered medications to any clinically relevant degree, although when a single dose
`of levothyroxine was administered concurrently with semaglutide, the total exposure (AUC)
`was increased for levothyroxine. This can be communicated in labeling.
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` A
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` thorough QT study did not identify any significant prolongation of QT interval. Studies in
`patients with renal impairment did not demonstrate any relationship between creatinine
`clearance and exposure across the range of renal function studies. Exposure of SNAC
`metabolites increased with increasing degree of renal impairment, but the level remained well
`below the safety margin established from non-clinical studies, and is therefore not considered
`to pose a safety concern.
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`Immunogenicity data was collected in three Phase 1 trials, along with 1 Phase 2 trial, and six
`of the Phase 3 trials (PIONEER 1-5, and 9). There were only 14 of 2924 subjects (0.5%) who
`tested positive for anti-semaglutide antibodies at any time point post-baseline. However, anti-
`semaglutide in vitro neutralizing antibodies, or anti-semaglutide antibodies with an in vitro
`neutralizing effect on endogenous GLP-1 were not found in any subject. Additionally, all
`antibody responses were transient, and none of the subjects had positive antibody titers at
`follow-up. The formation of anti-semaglutide antibodies did not affect either plasma
`semaglutide levels or the efficacy of semaglutide as measured by reduction in HbA1c levels.
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`The OCP reviewers, Dr. Suryanarayana Sista, Dr. Mohammad Absar, Justin Penzenstadler,
`Justin Earp, and Manoj Khurana recommend approval of oral semaglutide based on the
`reviewed clinical pharmacology data. The Office of Study Integrity and Surveillance (OSIS)
`determined that an inspection was not warranted.
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`6. Clinical Microbiology
`Not applicable.
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`7. Clinical/Statistical- Efficacy
`The efficacy discussion will focus on six randomized controlled efficacy trials conducted by
`the Applicant in support of this NDA, and include PIONEER 1-5, and PIONEER 8. Due to
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`differences in trial design and study population, PIONEER 9-10 (studies conducted in Japan),
`PIONEER 7 in which a flexible dosing design was utilized, and PIONEER 6, which was a
`CVOT, will not be discussed further in the efficacy review. PIONEER 6 was conducted to
`evaluate cardiovascular safety, and efficacy data for this trial will be discussed in the review
`for NDA 213182. See Table 2 for a list of the key efficacy trials.
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`Table 2: Clinical Efficacy Trials
`
`Trial Background
`
`
`
`P1
`(4233)
`
`Blinding
`
`Inclusion
`HbA1c
`7.0-9.5% DB
`
`P2
`(4223)
`P3
`(4222)
`
`Met
`
`Met
`SU±Met
`
`7.0-10.5% OL
`
`7.0-10.5% DB
`
`7.0-9.5% DB
`DD
`
`7.0-9.5% DB
`
`renal imp
`
`
`
`7.0-9.5% DB
`
`P4
`(4224)
`
`Met±SGLT2i
`
`P5 Met±SU
`(4234) SU±Met
`BasIns
`BasIns±Met
`Ins±Met
`
`P8
`(4280)
`
`
`
`Japan: Met
`w/BasIns only
`
`Duration
`(Weeks)
`26
`
`Treatments
`
`N
`
`S3
`S7
`S14
`Pbo
`S14
`SGLT2i (E)
`S3
`S7
`S14
`DPP-4i (Si)
`S14
`GLP1 RA (L1.8)
`Pbo
`S14
`Pbo
`
`175
`175
`175
`178
`411
`410
`466
`465
`465
`467
`284
`283
`142
`163 26
`161
`
`52
`
`78
`
`52
`
`S3
`S7
`S14
`Pbo
`
`52
`
`184
`182
`181
`184
`
`
`Met metformin, SU sulfonylurea, SGLT2i sodium-glucose co-transporter 2 inhibitor, BasIns basal insulin, Ins
`basal with or without bolus, or premixed insulin, OAD oral anti-diabetic drug using any of the above therapies,
`plus thiazolidinedione with or without metformin, renal imp moderate renal impairment, DB double-blind, OL
`label, DD double-dummy, S3 S7 S14 semaglutide maintenance doses 3 mg, 7 mg, or 14 mg qd po, Pbo
`open-
`placebo, DPP-4i dipeptidyl peptidase-4 inhibitor, Si sitagliptin 100 mg qd po, E empagliflozin 25 mg qd po, L1.8
`liraglutide injection qd escalated to 1.8 mg, DPP-4i (Si)
`Source: Table 1 from Statistical Review
`
`The primary efficacy endpoint in all the trials was the change from baseline in HbA1c at week
`26. Four of the trials were placebo-controlled trials (PIONEER 1,4,5, and 8), with one trial
`(PIONEER 4) including both a placebo and an active-control arm (liraglutide 1.8 mg), and two
`other trials which were active-comparator trials (PIONEER 2, vs. empagliflozin, and
`PIONEER 3, vs. sitagliptin). The dose of semaglutide was escalated every four weeks from 3
`mg to 7 mg to 14 mg. Multiple doses of semaglutide were evaluated in PIONEER 1, 3, and 8,
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017 for all NDAs and BLAs
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`13
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`Reference ID: 4494322Reference ID: 4497378
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`

`

`Cross Discipline Team Leader Review
`
`while only the highest dose of semaglutide was evaluated in PIONEER 2, 4, and 5. All the
`trials were double-blinded, except for PIONEER 2, due to the infeasibility of producing a
`placebo tablet to match empagliflozin.
`
`The primary and secondary endpoints (continuous variables) were analyzed by the Applicant
`using a pattern mixture model with ANCOVA-based multiple imputation to impute missing
`data. Missing data was imputed using a regression based on data collected from other subjects
`in the same group. Following imputation, an ANCOVA model was used with categorical fixed
`effects of treatment, stratification, and region, and baseline value as a covariate. Binary
`endpoints were evaluated using logistic regression after accounting for missing data using the
`same approach as for continuous variables. A pre-defined, weighted Bonferroni closed testing
`strategy was used for hypothesis testing, in which non-inferiority in the active-controlled trials,
`and superiority in the placebo-controlled trials for HbA1c was first demonstrated, followed by
`testing for secondary endpoints. For non-inferiority, a margin of 0.4% was used to compare the
`upper bound of the 95% confidence interval (CI). For trials with multiple doses, testing
`occurred first for 14 mg, followed by 7 mg, and then 3 mg doses.
`
`Subject disposition is displayed in Table 3, Table 4, and Table 5. Overall, the number and
`percent of patients with missing HbA1c was less than 10% for all studies. In the placebo-
`controlled studies, there was a dose-dependent trend in the semaglutide groups for increase in
`treatment discontinuation due to adverse events. The use of rescue medication was lower in
`the semaglutide groups vs. placebo, and was comparable to the liraglutide group in PIONEER
`4. See Table 3 and Table 4.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017 for all NDAs and BLAs
`
`
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`14
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`Reference ID: 4494322Reference ID: 4497378
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`

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`Cross Discipline Team Leader Review
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`
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`Table 3: Subject Disposition for Placebo-Controlled Efficacy Trials PIONEER 1 (4223)
`and 4 (4224)
`Trial
`
`
`
`4233
`S7
`S3
`175
`175
`(100)
`(100)
`18
`12
`(10.3)
`(6.9)
`7
`4
`(4)
`(2.3)
`1
`2
`