CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209803Orig1s000
`209805Orig1s000
`209806Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 209803 (ermgliflozin); NDA 209805 (mgliflom and sitagliptin); NDA 209806 (emigliflozin and metformin hydrochloride)
`Cross Discipline Tel- Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`(see electronic signature)
`William H. Chon '
`
`From
`
`Sub ' ect
`
`Cross-Disci o line Team Leader Review
`
`NDA/BLA #
`
`NDA 209803
`
`NDA 209805
`
`Supplement#
`NDA 209806
`
`Merck Sharp and Dohme Corp
`Applicant
`Date of Submission
`December 19, 2016
`
`PDUFA Goal Date
`
`December 19, 2017
`
`Dosage form(s) / Strength(s)
`
`glvcemic control in adults with tvpe 2 diabetes mellitus(m4)
`
`
`STEGLATRO (ertugliflozin)
`STEGLUJAN (ertugliflozin and sitagliptin)
`Proprietary Name / Non-
`SEGLUROMET (ertugliflozin and metformin
`Proprietary Name
`
`hydrochloride)
`NDA 209803: Once daily oral tablet (5 mg and 15 mg)
`NDA 2098E Once daily oral tablet
`(m4)
`5 mg/lOO mg, 15 mg/lOO mg
`[ertugliflozin/sitagliptinD
`NDA 209806: Twice daily oral tablet (2.5 mg/500 mg, 2.5
`mg/1000 mg, 7.5 mg/500 mg, 7.5 mg/ 1000 mg
`
`[eflugliflozin/metformin hydrochlorideD
`NDA 209803: adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`NDA 209805: adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`when treatment with both eitugliflozin and sitagliptin is
`appropriate
`NDA 209806: adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus(m4)
`
`Applicant Proposed
`
`Indication(s)/Population(s)
`
`
`
`
`
`Recommendation on
`
`
`Regulatory Action
`
`Recommended
`
`NDA 209803: Approval
`NDA 209805: Approval
`NDA 209806: Approval
`NDA 209803: adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`NDA 209805: adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`when treatment with both ertugliflozin and sitagliptin is
`
`Indication(s)/Population(s) (if
`applicable)
`
`appropriate
`NDA 209806: adjunct to diet and exercise to improve
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NMEloriginal BLA reviews)
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`Review Team:
`
`NDA 209803 (ertugliflozin):
`
`Drug Substance Reviewer
`Drug Product Reviewer
`Microbiology/Process Reviewer
`Biopharmaceutics Reviewer
`Facilities Reviewer
`Quality Technical Lead
`Pharmacology/Toxicology Reviewer
`QT-IRT
`Clinical Pharmacology Reviewers
`Efficacy Statistics Reviewer
`Safety Statistics Reviewer
`Clinical Reviewer
`Office of Scientific Investigations
`DPMH Reviewer
`OPDP Reviewer
`DMPP Reviewer
`DRISK Reviewer
`Project Manager
`
`Erika Englund
`Elise Luong
`Chaoying Ma
`Hansong Chen
`Allison Aldridge
`Suong Tran
`Jessica Hawes
`Moh Jee Ng
`Suryanarayana Sista and Lian Ma
`Alexander Cambon
`Elande Baro
`Frank Pucino
`Cynthia Kleppinger
`Carrie Ceresa
`Meena Ramachandra
`Sharon Williams
`Naomi Redd
`Elizabeth Godwin
`
`NDA 209805 (ertugliflozin and sitagliptin):
`
`Drug Substance Reviewer
`Drug Product Reviewer
`Microbiology/Process Reviewer
`Biopharmaceutics Reviewer
`Facilities Reviewer
`Environmental Assessment
`Reviewer
`Quality Technical Lead
`Pharmacology/Toxicology Reviewer
`Clinical Pharmacology Reviewer
`Efficacy Statistics Reviewer
`Safety Statistics Reviewer
`Clinical Reviewer
`Office of Scientific Investigations
`DPMH Reviewer
`OPDP Reviewer
`DMPP Reviewer
`DRISK Reviewer
`Project Manager
`
`Erika Englund
`Ravindra Kasliwal
`Haui Chang
`Peng Duan
`Krishna Ghosh
`James Laurenson
`
`Suong Tran
`Jessica Hawes
`Lei He
`Alexander Cambon
`Eland Baro
`Frank Pucino
`Cynthia Kleppinger
`Carrie Ceresa
`Meena Ramachandra
`Sharon Williams
`Naomi Redd
`Elizabeth Godwin
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`2
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`NDA 209806 (ertugliflozin and metformin):
`
`Drug Substance Reviewer
`Drug Product Reviewer
`Microbiology/Process Reviewer
`Biopharmaceutics Reviewer
`Facilities Reviewer
`Quality Technical Lead
`Pharmacology/Toxicology Reviewer
`Clinical Pharmacology Reviewers
`Efficacy Statistics Reviewer
`Clinical Reviewer
`Office of Scientific Investigations
`DPMH Reviewer
`OPDP Reviewer
`DMPP Reviewer
`DRISK Reviewer
`Project Manager
`
`Erika Englund
`Elise Luong
`Hong Yang
`Kalpana Paudel
`Michael Klapal
`Suong Tran
`Jessica Hawes
`Lei He and Lian Ma
`Alexander Cambon
`Frank Pucino
`Cynthia Kleppinger
`Carrie Ceresa
`Meena Ramachandra
`Sharon Williams
`Naomi Redd
`Elizabeth Godwin
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`3
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`1. Benefit-Risk Assessment
`
`Benefit-Risk Summary and Assessment
`
`Type 2 diabetes mellitus (T2DM) is a condition of chronic impaired glucose homeostasis that leads to chronic hyperglycemia and increases the
`risk for vascular complications (both microvascular and macrovascular). Therapies for T2DM have focused on improving glycemic control as
`assessed by change in hemoglobin A1c (HbA1c). While there are multiple drug products approved both as individual drugs and as fixed
`combination drug products (FCDP), many patients are unable to achieve glucose targets. While reasons for this are likely multi-factorial, one
`argument that has been made is that there are an insufficient number of available therapies to adequately allow for individualization of therapy.
`
`In these New Drug Applications (NDAs), Merck Sharp and Dohme (hereafter referred to as the applicant) is proposing to market three new
`antidiabetic drug products: ertugliflozin (a sodium glucose cotransporter-2 [SGLT2] inhibitor), ertugliflozin + sitagliptin (a combination of an
`SGLT2 inhibitor and a dipeptidyl peptidase-4 [DPP4] inhibitor), and ertugliflozin + immediate-release metformin (a combination of an SGLT2
`inhibitor and a biguanide). To support these three NDAs, the applicant has conducted seven phase 3 studies to demonstrate the glycemic
`lowering effect of ertugliflozin. From these studies, it can be concluded that ertugliflozin is better than placebo for improving glycemic control
`(as assessed using hemoglobin A1c [HbA1c]). This in turn should result in improved clinical outcomes (i.e., reduced risk for microvascular
`complications) for patients with T2DM. The fixed combination drug products (FCDPs) have similarly demonstrated the ability to improve
`glycemic control with each of the components showing a contribution to the glycemic lowering effect.
`
`Safety concerns for ertugliflozin include genital infections, urinary tract infections, hypoglycemia, volume depletion/hypotension, ketoacidosis,
`acute kidney injury, increases in hematocrit, increases in LDL-C, and lower limb amputations. Aside from lower limb amputations, these safety
`concerns are consistent with other members of the SGLT2 inhibitor class. One member of the SGLT2 inhibitor class currently includes lower
`limb amputations as a risk in the prescribing information and includes a Boxed Warning. The basis for that comes from findings of increased risk
`based on a larger database than is currently available for ertugliflozin. Though there are a limited number of events to consider in the
`ertugliflozin database, the signal of an increased risk for lower limb amputations that was seen is concerning. This potential risk should be
`communicated though I do not believe that the current data are sufficient to warrant a Boxed Warning for ertugliflozin. Additional data from the
`ongoing cardiovascular outcomes trial (CVOT) will inform whether further labeling would be appropriate in the future.
`
`The assessment of cardiovascular safety was performed using a meta-analysis of clinical trial and included interim data from an ongoing
`cardiovascular outcomes trial (CVOT). Based on this assessment, excess cardiovascular risk as discussed in the 2008 “Guidance for Industry:
`Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes” has been excluded.
`
`The safety profile of the FCDPs reflects the combined safety profiles of the components, and no clear potentiation of identified safety concerns
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4194129
`
`4
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`for the components was seen.
`
`Overall, the data provided in support of these NDAs leads me to conclude that the benefits of improving glycemic control with ertugliflozin
`outweigh the risks associated with ertugliflozin. The risks associated with ertugliflozin can be adequately communicated through labeling.
`
`Dimension
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`Benefit
`
`Evidence and Uncertainties
`
` Type 2 diabetes mellitus (T2DM) is a condition of chronic impaired
`glucose homeostasis leading to chronic hyperglycemia and an
`increased risk for microvascular (e.g., retinopathy, nephropathy) and
`macrovascular (e.g., myocardial infarction, stroke) complications.
`The Center for Disease Control estimates that there are over 29
`million patients with type 2 diabetes mellitus in the United States.
` Based on the results of the Diabetes Control and Complication Trial
`and the United Kingdom Prospective Diabetes study, improved
`glycemic control (as measured using hemoglobin A1c [HbA1c]) is
`believed to result in improved clinical outcomes (i.e., reduced
`microvascular complications).
` There are currently 12 classes of medications (generally with
`multiple members in each class), approved to improve glycemic
`control in patients with T2DM. Many of these medications are also
`approved as fixed combination drug products (FCDPs).
` There are different safety concerns for each class. Metformin is
`often considered first-line therapy with the choice of subsequent
`therapies individualized by prescribers based on the patient.
` While all of the approved antidiabetic agents have been shown to
`improve glycemic control, data on the ability of individual agents to
`improve clinical outcomes is limited.
` Ertugliflozin has demonstrated an ability to improve glycemic
`control (as measured using HbA1c). This is in turn expected to result
`in improved clinical outcomes.
` Other findings that might be considered beneficial included changes
`in blood pressure, and changes in weight. Whether the small
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4194129
`
`Conclusions and Reasons
`Type 2 diabetes mellitus is a serious and life
`threatening condition that if left untreated leads
`an increased risk for morbidity and mortality.
`
`Despite the many available treatment options,
`many patients continue to have difficulty with
`achieving the desired degree of glycemic
`control. Further, T2DM is a progressive
`disorder and patients typically need additional
`agents added as the course of the disease
`progresses.
`
`Ertugliflozin has demonstrated the ability to
`improve glycemic control in adults with
`T2DM. It has been studied in a variety of use
`scenarios, and has been found to effective in all
`of them. Other findings that may be desirable
`for patients include a reduction in body weight
`
`5
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`Dimension
`
`Evidence and Uncertainties
`observed differences are clinically meaningful is unknown.
`
`Conclusions and Reasons
`and in blood pressure.
`
` Safety findings for the class that would be considered applicable to
`ertugliflozin include genital infections, urinary tract infections,
`hypotension, hypoglycemia, acute kidney injury, and ketoacidosis.
` The most common adverse reaction was genital mycotic infections.
` An increased risk for amputations has been included in the label for
`another member of the class. The available data suggest a similar
`risk with ertugliflozin though there remains some uncertainty due to
`the small number of events.
` Consistent with the 2008 Guidance on evaluating cardiovascular risk
`with new antidiabetic drugs, excess cardiovascular risk (i.e., the 1.8
`upper bound) has been excluded.
` There remains uncertainty with regards to exclusion of the 1.3 upper
`bound.
`
`Risk
`
`Risk
`Management
`
` The risk associated with ertugliflozin can be adequately managed
`through labeling.
` Labeling for the risk of genital infections, urinary tract infections,
`ketoacidosis, and hypoglycemia should be similar to other SGLT2
`inhibitors.
` The findings for a potential increased risk for lower limb amputations
`should also be included in the prescribing information.
`
`The safety profile of ertugliflozin is generally
`consistent with other SGLT2 inhibitors.
`Genital mycotic infections were seen more
`frequently in ertugliflozin treated subjects.
`Other safety concerns include urinary tract
`infections, hypoglycemia, acute kidney injury,
`hypotension/volume depletion, ketoacidosis,
`and lower limb amputations. The increased
`risk for lower limb amputations is based on a
`small number of events, but this observation is
`particularly concerning given the finding of
`increased risk for these events with another
`member of the class. Hopefully the ongoing
`CVOT will be able to provide additional
`information to consider in evaluating this safety
`concern.
`I believe that the risks associated with
`ertugliflozin can be adequately handled through
`labeling. Lower limb amputations should be
`included as a Warning & Precaution for
`ertugliflozin containing products, though I do
`not believe the available data are sufficient to
`warrant a Boxed Warning. This can be
`addressed in the future once more data are
`available.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4194129
`
`6
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`2. Background
`Diabetes mellitus is a disease of impaired glucose homeostasis that results in chronic
`hyperglycemia. There are two main types of diabetes mellitus: type 1 diabetes mellitus (T1DM;
`characterized by autoimmune destruction of pancreatic β-cells and loss of insulin secretion) and
`type 2 diabetes mellitus (T2DM; characterized by resistance to insulin activity with inadequate
`insulin production to maintain euglycemia). Chronic hyperglycemia in turn leads to an increased
`risk for microvascular (e.g., retinopathy, nephropathy) and macrovascular (e.g., myocardial
`infarction, stroke) complications. Based on the results of the Diabetes Control and Complication
`Trial (DCCT) 1 and the United Kingdom Prospective Diabetes study (UKPDS) 2, improved
`glycemic control (as measured using hemoglobin A1c [HbA1c]) is believed to result in improved
`clinical outcomes.
`
`The development of therapies to treat T2DM has focused on developing agents that can improve
`glycemic control as assessed by the ability to reduce HbA1c, and this has served as the basis for
`approval of antidiabetic agents. Recently, studies of some antidiabetic drugs have reported
`improved clinical outcomes in patients with T2DM. These findings are limited to a few drug
`products 3, 4 and were conducted in a population with high cardiovascular risk. Whether these
`findings can be generalized to the entire population of patients with T2DM is unknown.
`
`There are currently 11 classes of antidiabetic drugs with most classes having multiple members
`(Table 1). Many of these drug products are also available as FCDPs.
`
`Biguanides
`
`Table 1: Summary of FDA approved drugs to improve glycemic control in diabetes
`Drug Class
`Drug Products
`Insulin and insulin analogs
`Multiple products including basal, prandial, and mixed insulin
`products
`Metformin (as an immediate release and an extended release
`formulation)
`Chlorpropamide, Glimepiride, Glipizide, Glyburide
`Rosiglitazone, Pioglitazone
`Repaglinide, Nateglinide
`Acarbose, Miglitol
`Sitagliptin, Saxagliptin, Alogliptin, Linagliptin
`Exenatide (as a twice daily and as a once weekly), Liraglutide,
`Albiglutide, Dulaglutide, Lixisenatide, Semaglutide
`Canagliflozin, Dapagliflozin, Empagliflozin
`
`Sulfonylureas
`Thiazolidinediones
`Meglitinides
`Alpha glucosidase inhibitors
`Dipeptidyl peptidase-4 (DPP4) inhibitors
`Glucagon-like peptide-1 (GLP1) receptor
`agonists
`Sodium glucose cotransporter-2
`(SGLT2) inhibitors
`Amylin analogs
`
`Pramlintide
`
`1 The Diabetes Control and Complications Trial Research Group. “The effect of intensive treatment of diabetes on
`the development and progression of long-term complications in insulin-dependent diabetes mellitus”. NEJM, 1993;
`329 (14): 977-986.
`2 UK Prospective Study Group. “Intensive blood-glucose control with sulphonylureas or insulin compared with
`conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)”. Lancet, 1998; 352
`(9131): 837-853.
`3 Zinman B, et al. “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes”. NEJM, 2015;
`373: 2117-2128.
`4 Marso SP, et al. “Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes”. NEJM, 2016; 375: 311-322.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`7
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`Drug Class
`Bile acid sequestrants
`Dopamine agonists
`
`Drug Products
`Colesevelam
`Bromocriptine
`
`Despite the number of available therapies, many patients with T2DM continue to have difficulty
`in achieving glycemic targets. While reasons for this are likely multifactorial, it has been
`suggested that more therapeutic options are needed to allow for better individualization of
`therapy.
`
`Merck Sharp and Dohme (hereafter referred to as the applicant) has submitted three New Drug
`Applications (NDAs) for three new antidiabetic drug products containing ertugliflozin, a sodium
`glucose cotransporter-2 (SGLT2) inhibitor. The three drug products consist of ertugliflozin
`alone (NDA 209803), ertugliflozin + sitagliptin (NDA 209805), and ertugliflozin + immediate-
`release metformin (NDA 209806).
`
`As an SGLT2 inhibitor, ertugliflozin blocks glucose reabsorption by the kidney. This in turn
`lowers plasma glucose levels. This approach has been shown to improve glycemic control, and
`there are already several members of this drug class approved to improve glycemic control in
`adults with type 2 diabetes mellitus (T2DM).
`
`In addition to developing ertugliflozin, the applicant has developed fixed combination drug
`products (FCDPs) combining ertugliflozin with other antidiabetic drugs.
`
`Ertugliflozin has been combined with sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor. By
`inhibiting DPP4, sitagliptin prevents the breakdown of endogenous incretin hormones (e.g.,
`glucagon-like peptide-1 [GLP1]). This in turn leads to increased and prolonged levels of these
`hormones which play a role in glucose homeostasis through enhanced glucose-dependent insulin
`production and secretion, and reduction of glucagon.
`
`Ertugliflozin has also been combined with immediate-release metformin. The mechanisms by
`which metformin exerts its antidiabetic effects are not completely understood, but it is believed
`to decrease hepatic gluconeogenesis and to improve insulin sensitivity.
`
`The applicant has proposed the following indications for these NDAs:
`
` NDA 209803 (ertugliflozin): adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus
`
` NDA 209805 (ertugliflozin and sitagliptin): adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus when treatment with both
`ertugliflozin and sitagliptin is appropriate
`
` NDA 209806 (ertugliflozin and immediate-release metformin): adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus
`
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`8
`
`Reference ID: 4194129
`
`(b) (4)
`
`

`

`NDA 209803 (caugliflou'n); NDA 209805 (crtugliflozin and singliptin); NDA 209806 (ermgliflozin and metformin hydrochloride)
`Cross Discipline Tel- Leader Review
`
`3.
`
`Product Quality
`
`a. Drug Substance
`
`The focus in the discussion of drug substances will be on ertugliflozin. Details on the chemistry,
`manufacturing, and controls (CMC) information for the other components of the FCDPs (i.e.,
`sitagliptin and metformin) can be found in the previous NDA reviews and approved prescribing
`information for these drug products.
`
`Ertugliflozin is an unstable amorphous material. The active ertugliflozin moiety is manufactured
`in a co-crystal form with L-pyroglutamic acid (L-PGA) to achieve better physical and chemical
`properties including stability (Figure 1).
`
`Figure 1: Structure of ertugliflozin and ertugliflozin L-PGA co-crystal
`
`0
`
`\_
`
`HO‘
`
` H0
`
`.,
`
`HN
`
`Ertugliflozin L-PGA
`Ertugliflozin
`Source: Excerpted from Figure 2.3.8.1-1 of the General Information provided in module 2.3.8 of NDA 209803
`
`The ertugliflozin L-PGA
`is manufactured as a white to off-white powder.
`
`W4)
`M“)
`
`The commercial manufacturing process is the same as that used for the phase 3 clinical batches
`and the primary stability batches. The to-be-marketed drug substance will be manufactured by
`Pfizer Ireland Pharmaceuticals.
`
`b. Drug Products
`
`NDA 209803 (ertugliflozinl:
`
`The ertugliflozin drug product will be manufactured as a 5 mg or 15 mg immediate release oral
`tablet. There are no novel excipients or human/animal-derived excipients.
`M“)
`
`The manufacturing process and evaluation of drug product
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NMEu’original BLA reviews)
`
`9
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflou'n); NDA 209805 (ertugliflozin and Sitagliptin); NDA 209806 (ermgliflozin and metfonnin hydrochloride)
`Cross Discipline Tel- Leader Review
`
`specifications, degradants and stability data were found to be adequate and supportive of the
`proposed 24 month shelf-life at room temperature.
`
`
`NDA 209805 (ertugliflozin and Sitagliptin):
`
`The ertugliflozin and Sitagliptin drug product will be manufactured as an immediate—releasemm
`film-coated oral tablet in four dosage strengths (mg of ertugliflozin/mg of Sitagliptin:
`"”“’ 5 mg/lOO mg, and 15 mg/100 mg).
`
`"’""
`The
`
`manufacturing process and evaluation of drug product specifications, degradants and stability
`data were found to be adequate and supportive of the proposed 24 month shelf-life at room
`temperature.
`
`
`NDA 209806 (ertugliflozin and mey‘ormin hvdrochloride):
`
`The ertugliflozin and metfonnin hydrochloride drug product Will be manufactured as an
`immediate—release, fihn—coated oral tablet in four dosage strengths (mg of ertugliflozin/mg of
`metformin: 2.5 mg/500 mg, 2.5 mg/lOOO mg, 7.5 mg/SOO mg, and 7.5 mg/lOOO mg).
`8}
`
`manufacturing process and evaluation of drug product specifications, degradants and stability
`data were found to be adequate and supportive of the proposed 24 month shelf-life at room
`temperature.
`
`The
`
`4. Nonclinical Pharmacology/Toxicology
`
`The discussion here will focus on the nonclinical data for ertugliflozin. Sitagliptin and
`metformin are both approved drug products and the nonclinical data for these components of the
`fixed combination drug products has been discussed in other reviews and is described in the
`currently approved labeling of those products.
`
`In vitro studies of ertugliflozin demonstrate that it is a potent and selective inhibitor of SGLT2
`with a low probability of sodium glucose co—transporter—l (SGLTl) inhibition at clinical
`exposures. Metabolism of ertugliflozin is primarily through glucuronidation, and there are two
`main metabolites (MSa and M5c). Neither metabolite is likely to inhibit SGLT2 or SGLTl at
`clinical exposures, and the nonclinical program has adequately qualified these metabolites (i.e.,
`no significant toxicological concern at clinical exposures).
`
`In the nonclinical studies, adverse findings were observed in the kidney and urinary tract. These
`findings included renal pelvic and tubule dilatation, mineral deposits, and
`hypertrophy/hyperplasia of the organs of the urinary tract. These findings were felt to be
`secondary to the pharmacodynamic effects of SGLT2 inhibition (i.e., glucosuria).
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NMEu’original BLA reviews)
`
`10
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`Adverse findings were also observed in the digestive tract. These included GI dilatation,
`stomach erosions/ulcers, and increased intestinal villi height. These findings were felt to be
`secondary to SGLT1 inhibition.
`
`Hypercalciuria was observed in the nonclinical studies, and this was accompanied by decreases
`in parathyroid hormone and calcium levels as well as with increases in trabecular bone and
`hyperostosis.
`
`All of these findings were seen at large multiples of the clinical exposure.
`
`Carcinogenicity studies showed a drug-related increase in adrenal medulla pheochromocytoma.
`This was observed in male rats at a dosage of 15 mg/kg/day (safety margin of 18x maximum
`recommended human dose).
`
`Juvenile rats exposed to ertugliflozin during the period of renal development had adverse renal
`findings similar to that seen in adult animals. Reversibility was not assessed. Other findings
`(e.g., decreased weights, decreased growth) were felt to be secondary to the glucosuric effect and
`subsequent caloric loss.
`
`In reproductive toxicity studies, adverse fetal effects were attributed to maternal toxicity.
`
`Studies of ertugliflozin in combination with sitagliptin and in combination with metformin did
`not raise any concerns for significant toxicities. Combination therapy was generally well
`tolerated and the safety margins were felt to be adequate.
`
`The observed adverse findings are consistent with effects seen with other SGLT2 inhibitors and
`they generally occur at high multiples of the clinical exposure. Similar to other SGLT2
`inhibitors, Dr. Hawes has concerns with respect to the use of ertugliflozin in the 2nd and 3rd
`trimester due to adverse renal effects in the developing kidney.
`
`Based on review of the nonclinical data, Dr. Hawes recommends approval of ertugliflozin and of
`the ertugliflozin fixed combination drug products.
`
`5. Clinical Pharmacology
`The discussion here will focus on the clinical pharmacology data for ertugliflozin. Sitagliptin
`and metformin are both approved drug products and the clinical pharmacology data for these
`components of the fixed combination drug products has been discussed in other reviews and is
`described in the currently approved labeling of those products.
`
`Following oral administration of ertugliflozin tablets in the fasted condition, there is rapid
`absorption of ertugliflozin with nearly 100% bioavailability. The time to maximum
`concentration (Tmax) was 1 hour. Administration of ertugliflozin with a high-fat and high-calorie
`meal reduced the maximum concentration (Cmax) by 29% and prolonged the Tmax by 1 hour. The
`area under the curve (AUC), however, remained unchanged. Thus, the observed effect of food
`on ertugliflozin pharmacokinetics is not considered clinically relevant.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`11
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`Based on a population PK analysis, the elimination half-life of ertugliflozin in patients with
`T2DM and normal renal function is approximately 16.6 hours.
`
`No meaningful differences in the pharmacokinetic findings for ertugliflozin were seen when
`ertugliflozin was co-administered with metformin or sitagliptin.
`
`In patients with renal impairment, mean increases in AUC of ertugliflozin were 1.6x, 1.7x, and
`1.6x (mild, moderate, and severe, respectively) that of patients with normal renal impairment.
`Exposure to ertugliflozin was not increased in patients with moderate hepatic impairment. The
`AUC and Cmax of ertugliflozin decreased by ~13% and ~ 21%, respectively, compared to patients
`with normal hepatic function. Neither of these findings was felt to be clinically meaningful.
`
`In a thorough QT study, no significant prolongation of the QTc was seen with ertugliflozin 100
`mg.
`
`Additional clinical pharmacology studies were conducted to support the final formulation of
`ertugliflozin and the two FCDPs.
`
`In the phase 3 clinical trials, patients randomized to ertugliflozin 15 mg were administered one
`10 mg tablet and one 5 mg tablet. The to-be-marketed product consists of a 5 mg dosage
`strength and a 15 mg dosage strength. To support the 15 mg dosage strength, the applicant has
`compared the pharmacokinetic profile of the 15 mg tablet with that of administration of one 10
`mg tablet and one 5 mg tablets. No meaningful difference was seen.
`
`To support the ertugliflozin + sitagliptin FCDP (NDA 209805), the applicant conducted single-
`dose bioequivalence studies to bridge the to-be-marketed tablets to co-administration of the
`individual components. The geometric mean ratios for Cmax, AUCo-t, and AUC0-∞ were all within
`the 80-125% range used to demonstrate bioequivalence. No clinically meaningful drug-drug
`interaction was observed with co-administration of ertugliflozin and sitagliptin.
`
`To support the ertugliflozin + metformin FCDP (NDA 209806), the applicant conducted
`bridging studies to bridge once daily dosing of ertugliflozin with split/twice daily dosing of
`ertugliflozin. At steady-state (i.e., after 6 days of administration), exposure to ertugliflozin was
`similar between once daily and twice daily administration (as measured by AUC0-24h). The
`pharmacodynamic effect ((i.e., UGE0-24h) was also similar. Thus, split/twice daily dosing is
`expected to yield a clinical response similar to once daily dosing. Additional bioequivalence
`studies were conducted to bridge the to-be-marketed FDCP with co-administration of the
`individual components. These studies indicate that exposure with the FDCP is similar to that of
`co-administration of the individual components. No clinically meaningful drug-drug interaction
`was observed with co-administration of ertugliflozin and metformin.
`
`Based on the review of the submitted data, the reviewers from the Office of Clinical
`Pharmacology recommend approval of ertugliflozin, the ertugliflozin + sitagliptin FDCP, and the
`ertugliflozin + metformin FDCP. The clinical pharmacology reviewers recommend approval of
`both the 5 mg and the 15 mg dose of ertugliflozin.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`12
`
`Reference ID: 4194129
`
`

`

`NDA 209803 (ertugliflozin); NDA 209805 (ertugliflozin and sitagliptin); NDA 209806 (ertugliflozin and metformin hydrochloride)
`Cross Discipline Team Leader Review
`
`6. Clinical Microbiology
`Not applicable
`
`7. Clinical/Statistical- Efficacy
`The statistical assessment of the efficacy of ertugliflozin and the ertugliflozin fixed combination
`drug products (FCDPs) was reviewed by Dr. Alexander Cambon. I will summarize findings
`from the statistical review in th