CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-995
`
`MEDICAL REVIEW
`
`

`

`ODE Decisional Review Memorandum
`
`
`Date
`Monday, October 16, 2006
`
`From
`Robert J. Meyer, MD
`
`Subject
`Summary Review, Office Director
`NDA/BLA #
`21-995
`
`
`Supp #
`Proprietary /
`Established
`
`Januvia (sitagliptin phosphate) Tablets from Merck Laboratories
`
`.
`
`
`
`
`(USAN) names
`25, 50 and 100 mg tablets (expressed as the sitagliptin base)
`Dosage forms /
`
`strength
`Proposed
`Indication(s)
`
`Januvia is indicated as an adjunct to diet and exercise to improve
`glycemic control in paitnets with type 2 diabetes. Januvia is indicated
`for:
`
`‘
`
`0 Monotherapy
`0 Combination therapy with metformin 0r PPARgamma agonists
`when diet and exercise plus the single agent do not provide
`adequate glycemic control
`[Notes This is very similar to other drugs more recently approvedfor
`use in type 2 DM]
`
`Approval
`
`1.
`
`Introduction to Memorandum
`
`This is the first cycle review for this first in class agent. Sitagliptin phosphate is from a
`drug class called dipeptidyl peptidase (or DPP)—4 inhibitors. Amongst other actions,
`DPP—4 breaks down incretins, which are short-lived intestinal peptides released in
`response to food ingestion, which have an inhibitory effect on glucagon (and hence on
`hepatic glucose synthesis) and an enhancing effect on insulin secretion when serum
`glucose iselevated (not when it is normal or low). Hence agents to augment incretin
`activity are of considerable interest in type 2 diabetes (DM), since both insulin and
`incretin secretion are disregulated in that disease, yet there are still clinically functional
`islet cells in type 2 DM to affect with this mechanism (as opposed to type 1 DM, where
`sitagliptin would be largely, if not entirely, ineffective). FDA recently approved a
`glucagon-like peptide—1 (GLP—l) analogue, exenatide [GLP-1 is one of the incretins
`prolonged by DPP-4 inhibition]. However, that agent is an injection and is more
`targeted in its actions than a DPP-4 inhibitor, which affects other incretins, including
`glucose—dependent insulinotropic polypeptide (GIP). Sitagliptin, therefore, represents a
`new means of treating type 2 DM, a disease with many currently available treatment
`options, but one that is expanding in prevalence and in which satisfactory glucose
`control still eludes many patients.
`
`There are relatively few controversies for this signatory review to address. The
`primary review team has recommended approval of this drug as safe and effective'for
`its proposed indications. The clinical efficacy and safety data are robust in amount and
`
`

`

`duration (though the systematic study of this drug with the full range of potential
`concomitant therapies is lacking, including concomitant use of insulin or sulfonylureas
`with sitagliptin), with acceptable dose-finding and a reasonable set of confirmatory
`studies. Note that there is some disagreement amongst the team on the optimal dosing
`of renally sufficient patients, and this will be discussed further. There is a broader
`issue in terms of toxicology of the DPP—4 agents under development that will be dealt
`with in the pharm/tox section of the memo (section 4).
`
`2. Background/Regulatory History/Previous Actions/Foreign Regulatory Actions/Status
`
`Per the primary MO review, the IND for this drug (65,495) was submitted August of
`2002. There was an EOP2 meeting on June 9, 2004 that I attended. At that meeting,
`the FDA encouraged the inclusion of a 50 mg dose in the pivotal studies, but in fact,
`the sponsor chose rather to study 100 and 200 mg. The reasoning for the FDA
`recommendation is that there was not much additional efficacy shown in the phase 2
`studies above 50 mg, yet there were dose-related tolerance issues. We felt, therefore,
`that if an important dose-related safety issue were to crop up in phase 3, it would be
`_ best for the company to have the data to support approval of the 50 mg dose. Merck
`chose not to follow this advice (more discussion on closing follows). Note that
`sitagliptin has not been approved previously in other markets, so there is no foreign
`post—marketing data available to inform FDA decision making.
`
`3. CMC/Microbiology/Device
`3.1.
`General product quality considerations
`This is a relatively straight forward, solid oral dosage form with immediate release
`characteristics. The drug has a chiral center, with no issues of chemical (or biologic)
`conversion. It is notable that the drug appears quite well—behaved
`pharmacokinetically, with all the clinical trials formulations being bioequivalent as
`subsequent formulations were developed, so the clinical trials results should be
`representative of those from the final, to—be-marketed formulation.
`Facilities review/inspection
`I
`The facilities review/inspections were all satisfactory and there is an overall
`recommendation for approval.
`Notable issues
`
`3.2.
`
`3.3.
`
`The only notable issue is a disagreement between OCP and ONDQA on whether the
`proposed disintegration method is adequate to assure the quality of the product as a
`part of batch testing. ONDQA has ultimately deferred to OCP’s recommendation for
`the need for dissolution testing and Merck has agreed to institute such testing post-
`approval.
`
`4. NonclinicalPharmacology/Toxicology
`4.1 . General nonclinical pharmacology/toxicology considerations
`The preclinical review was done by Dr. Bourcier, with Dr. Davis-Bruno doing the
`supervisory concurrence. The preclinical testing for this drug is relatively
`unremarkable. The drug does show kidney and liver damage/necrosis at very high
`chronic doses (at > 150 of times the human exposure) in rats, but dog studies did not
`
`

`

`show consistent toxicity patterns and 5—fold exposures in dogs for 1 year showed no
`significant toxicities.
`Carcinogenicity
`In rats, Sitagliptin led to hepatic adenomas/carcinomas at high doses (62 fold above
`human exposures). Since the drug is not genotoxic, but is hepatotoxic, the sponsor
`feels this may be due to chronic hepatotoxicity. The mouse studies showed no
`evidence of carcinogenicity. Given the lack of genetic toxicity, these rat findings at
`very high multiples of human exposure, are felt to be of no significant clinical
`consequence, but deserve mention in labeling.
`.
`Reproductive toxicology
`Reprotox studies were largely unremarkable, with only some resorption and post—
`implantation losses in rabbits at high human dose multiples (25x). At maternally non-
`toxic doses, no clear signal of teratogenicity emerged. The pregnancy category
`designation will therefore be category B. As with other NMEs, Merck plans to initiate
`a pregnancy registry to better assess matemal-fetal issues post—marketing.
`Notable issues
`
`4.2.
`
`4.3.
`
`4.4.
`
`Data from multiple DPP—4 programs, many of which are less selective to DPP—4 than
`sitagliptin, have shown the development of skin/vascular lesions in rhesus monkeys at
`relevant doses and durations of treatment. Merck has performed studies to assess this
`in Sitagliptin and did not find any such effects at doses up to 25 fold the human dose.
`Merck provided some mechanistic data to suggest these skin effects are related to
`agents affecting other DPP subtypes (e.g., 8 and/or 9). While this vascular effect of
`other DPP-4 agents would raise concern about clinical relevance for diabetics (who
`already have both microvascular and macrovascular complications of their disease),
`these effects do not appear to be an issue for sitagliptin.
`A second preclinical issue is that combination studies of Sitagliptin with
`metfonnin (done for the combination product NDA) showed excess deaths in high
`dose metforrnin and sitagliptin, which appears most clearly related to the metformin
`itself. There was no excess in deaths at more relevant doses of metforrnin.
`
`Lastly, it is notable that the preclinical pharmacology models for sitagliptin—
`mediated DPP—4 inhibition suggests that 80% inhibition of the DPP-4 enzyme is
`needed for a satisfactory pharmacodynamic effect. This information has relevance to
`the choice of dose discussed further in the next section.
`
`5. Clinical Pharmacology/Biopharmaceutics
`5.1.
`General — See Dr. Wei’s primary review for details (Dr. Ahn did the secondary
`review). Sitagliptin is highly bioavailable (87%) and excreted largely unchanged in
`the urine, so there is little metabolism of any note.
`It is a substrate for p—glycoprotein.
`The peak serum concentration occurs at approximately 1 — 4 hours post-dose and the
`terminal half—life is approximately 12 hours. There is no apparent food—effect in its
`absorption.
`Drug—drug interactions — noting that with cyclosporine (a p—glycoprotein inhibitor),
`there are increases in exposure to Sitagliptin by only 30%, there are no remarkable
`DDls, including other oral hypoglycemic agents, digoxin, warfarin and oral
`contraceptives.
`
`5.2.
`
`

`

`5.3. Pathway of Elimination 4 being renally excreted, it is not surprising that renal
`impairment prolongs sitagliptin’s elimination and hence exposure. This is important,
`given the prevalence of renal impairment in long-term DM. Dose adjustments are
`needed for renal impairment/failure and have been appropriately addressed by the
`OCP reviewers and the labeling. Hepatic impairment does not seem to be clinically
`important in sitagliptin’s PK or dosing.
`5.4. Demographic interactions/special populations — no important issues identified.
`5.5. Thorough QT study or other QT assessment — Sitagliptin inhibits the hERG channel in
`vitro, though not at low, relevant levels. The IC50 is 147 microM (ICZO about 50 mM),
`with relevant human Cmax being approximately 1 microM. The canine safety
`pharmacology study did not show remarkable findings on cardiac intervals at many
`fold the human exposure, however. The sponsor did conduct a thorough QT study
`with a positive control of moxifloxacin 400 mg. The Sitagliptin doses were 100 mg
`and 800 mg per day (the clinical dose and 8 times the clinical dose). The clinical dose
`of sitagliptin had no significant effect on cardiac intervals/QT, while both
`moxifloxacin and, to a lesser degree, the high dose of Sitagliptin did prolong QT. The
`prolongation pattern with Sitagliptin 800 followed serum kinetics, with a peak mean
`effect at approximate Cmax of about 8 msec prolongation (compared to approximately
`14 seconds with moxifloxacin). While the QT effect of the 800 mg dose18
`approaching a level of some clinical concern, there are very few things outside of renal
`failure (which has modified dosing instructions in the label) that will appreciably raise
`drug levels with Sitagliptin. Severe renal failure only leads to about a 5 fold increase
`in exposure, an exposure still less than that expected from 800 mg given this drug’s
`linear dose—proportionality. These data support that QT prolongation should not be a
`concern with clinically recommended doses. Even if the drug were to be given to
`renally impaired patients at “normal doses” inadvertently or intentionally, the expected
`consequences on cardiac conduction are expected to be small.
`5.6. Notable issues — in multiple dose studies, 100 mg per day is needed to keep the
`percent DPP—4 inhibition above 80% throughout the 24—hour dosing interval, including
`at Cmin. This, combined with the preclinical data suggesting the importance of 80%
`inhibition to clinical effect, is a part of the sponsor’s rationale to focus on the 100 mg
`dose as the preferred dose. The OCP reviewer agrees with this assessment. Given the
`fact that a 100 mg dose is expected to maintain a level of drug that would lead to 80%
`or more inhibition of DPP—4 throughout the dosing interval and given the fact that the
`sponsor did not specifically instruct timing of the Sitagliptin dose to meals or to
`morning, the dosage and administration section will not recommend a specific time for
`dosing either.
`
`6. Clinical/Statistical
`
`6 1. General Discussion— This drug development program was quite complete, as
`mentioned above and there are no major issues related to deviation from expectations
`Please see Dr. Irony’ s primary review and Dr. Park’s summary memorandum fOr
`details of the clinical program. There is a “dispute” between the statistical team’s
`conclusions (see Drs. Pian’s and Sahlroot’s review) and the medical/OCP reviews on
`optimal dosing recommendations, but the statistical reviewer’s input is largely based
`on a statistical finding from the phase 2 study and does not take into account other
`
`

`

`I believe 100 mg once daily is an appropriate recommended dose.
`information.
`Whether 50 mg would have worked as well in replicate studies is an unknown, but
`with no overriding safety issues to limit dosing and with theoretic reasons (based on
`PD assessments) for the 100 mg dose, I believe the sponsor has provided adequate
`support for this proposed dosing.
`6.2. Efficacy
`6.2.1.
`Dose identification/selection and limitations — as above, this area of sitagliptin
`has led to disparate recommendations of the review team. There were two main
`phase 2 studies (P010 and P014). P010 was a 12 week study of 5, 12.5, 25 and
`50 mg BID (total daily doses of 10, 25, 50 and 100) of sitagliptin with a
`positive control of glipizide. P014 examined 12 weeks of therapy with 25, 50,
`100 mg QD and 50 mg BID. These data show a dose related increase in effects
`on HgbAlc up to 50 mg QD, with no further gain in efficacy at 100 mg QD or
`50 mg BID. Therefore, there is not a clear statistical rationale for dosing higher
`and in fact, this was noted by FDA at the EOP2 meeting. Merck was warned
`that if untoward dose—related safety issues were found, their strategy of only
`examining 100 mg and 200 mg daily in phase 3 could be risky. However,
`Merck went forward with these doses, in part presumably based on modeling of
`DPP—4 inhibition and serum concentrations, and no untoward events are seen.
`
`6.2.2.
`
`The clinical team and OCP team feels the 100 mg daily dose for patients with
`full renal function is appropriate and I agree with them.
`Phase 3/essentia1 clinical studies, including design and analytic features
`The sponsor conducted 4 phase 3 trials, 2 as monotherapy (one 24 weeks, one
`12 weeks — both examining 100 and 200 mg) and 2 trials as add—on therapy, one
`for metformin and one for pioglitizone (as a demonstration for coadministration
`with PPARs in general), both add—on studies were of 100 mg only. The details
`of these studies can be found in the medical officer’s and stastical reviewer’s
`
`reviews, but these studies showed consistentefficacy for the 100 mg dose with
`approximately 0.5 — 0.6 % mean absolute lowering of HgbAlc irrespective of
`monotherapy or add—on. (Note that glipizide showed a mean effect of about
`1.0% lowering in the phase 2 study.) The 200 mg dose did not show a clinical
`advantage on this endpoint. Secondary endpoints also supported evidence of
`efficacy.
`Secondary assessments in the efficacy trials were numerous and typical
`of agents for type 2 DM, including effects on fasting plasma glucose, post—
`prandial glucose excursions, serum fructosamine and need for rescue glycemic
`therapy. These secondary endpoints generally supported efficacy in a pattern
`not inconsistent with the primary endpoint.
`Given the clinically advantageous effects of the GLP—l analogue —
`exenatide — on weight and appetite, these parameters were assessed in the
`clinical trials for sitagliptin. However, unlike exenatide, there does not seem to
`be a meaningful effect of sitagliptin on either satiety and weight. On the other
`hand, since some agents for type 2 DM appear to increase weight (irrespective
`of effects in some in causing edema), a neutral effect is not itself a negative, as
`further weight gain in type 2 DM is not helpful in controlling the underlying
`pathophysiology.
`'
`
`

`

`Finally, the assessment of efficacy by demographic subpopulations,
`while not always definitive due to low numbers of some ethnic groups, does not
`suggest any notable differences in response by gender, age or race for
`sitagliptin either as monotherapy or in combination.
`6.2.3. Other efficacy studies — a study of reduced dosing strategies in renally impaired
`patients showed similar magnitude reductions in HgbAlc compared to renally
`sufficient patients given 100 mg daily. This study, along with the PK data in
`the impaired population, establishes the support for the proposed dosing
`recommendations for renal impairment in the labeling.
`6.2.4. Both the medical and statistical team support approval based on robust data
`showing evidence of efficacy with sitagliptin and 1 agree with their
`recommendations.
`
`6.2.5. Pediatric use/PREA waivers/deferrals
`
`Pediatric studies were, appropriately, not initially done with sitagliptin until
`safety and efficacy were better examined in adults. The population down to age
`11 will need to be studied clinically. Ages 10 and’below are generally waived
`for drugs targeting type 2 DM due to the relatively few numbers of children
`with type 2 DM in this age range. The conduct of the studies in 11 to 17 year
`olds will be a required phase 4 commitment under PREA.
`6.2.6. Notable issues — no additional issues, other than those discussed above.
`6.3. Safety
`6.3.1. General safety considerations
`The safety database was reasonably sized, with over 2650 patients exposed in
`total, and approximately 2400 patients exposed to 100 mg or higher in phase 3
`studies. For longer term exposures, 444 subjects were treated with sitagliptin at
`100 mg or higher for at least 365 days, with some data out to beyond two years
`(164 patients). With this database, there is no clear signal of concern.
`Common AEs that were numerically higher with sitagliptin compared to
`placebo include nasopharyngitis, nausea, vomiting, diarrhea and arthralgias.
`lmportantly, the rate of hypoglycemia, which one would predict would be low
`given the incretin’s glucose dependant effects on the beta cells, was indeed low
`with only a mild increase relative to placebo (1.2% overall compared to 0.9%
`with placebo).
`Twelve deaths were seen in phase 2 and 3 studies, with 10 of these
`being cardiovascular deaths. Of these 10, 7 patients were receiving sitagliptin,
`3 were not on drug but in the run—in period, and 2 were on glipizide. Factoring
`in time of exposure and numbers of patients exposed to sitagliptin vs. controls,
`there is no clear signal of concern here. The rate of serious cardiac AEs in the
`long—term safety data showed the number of patients experiencing such AEs
`being numerically lower with sitagliptin than the non—exposed patients (1.2%
`vs. 2.6%). Otherwise, the safety findings were relatively benign.
`One notable issue is the effect of sitagliptin on serum creatinine levels.
`There is a small, dose—related mean increase in serum creatinine out to week 24
`in subjects given sitagliptin that seems isolated (i.e., not reflected by other
`indicators of renal disease). These changes amount to very small deviations
`(about 0.01 to 0.03 mg/dL above placebo), but are fairly consistent. The
`
`

`

`sponsor feels that this is not a result of toxicity, but rather due to altered
`creatinine excretion due to the tubular handling of the drug, similar to what is
`seen with cimetidine. This supposition seems plausible and consistent with the
`observations and pharmacology (and the preclinical renal toxicity, which only
`showed pathologic renal changes at very high multiples above human exposure
`in a single species). While there is no signal of overt clinical renal toxicity and
`many patients with prespecified “notable” creatinine rises spontaneously
`resolved while continuing on drugs, the sponsor has not rigorously established
`this purported mechanism to explain the small, dose related changes in
`creatinine either. Specifically, direct assessment of GFR has not been
`conducted. The character of all the available renal data does not suggest a
`significant cause for concern, nonetheless, this issue will deserve some tracking
`and further assessment post—approval.
`6.3.2. Discussion of primary and secondary revieWers’ comments and conclusions
`The primary and secondary reviewers feel the safety database is adequate and
`the findings allow for a favorable risk—benefit determination. I agree with this
`assessment.
`
`6.3.3. Notable issues — none
`
`6.4. Clinical Microbiology (where relevant)
`Not relevant
`
`7. Advisory Committee Meeting
`No AC was scheduled or held due to the fact that, while this is an NME of a
`new class, this mechanism of action has in fact been the target of therapy
`(exenatide) and this drug present no daunting efficacy or safety issues requiring
`advisory committee deliberation, considering the resources needed to conduct
`such a meeting.
`
`8. Risk Minimization Action Plan (where relevant)
`8.1. No specific RiskMAP is needed for Januvia at this time, since no outstanding risks
`necessitating specific management have been identified in the pre—marketing database.
`
`9. Other Regulatory Issues
`9.]. Application Integrity Policy (AIP) ,— no outstanding issues
`9.2. Exclusivity/patent issues — no outstanding issues
`
`10. Financial Disclosure — No issues, see Dr. Irony’s review for details.
`
`1 1. Labeling
`11.1.
`
`.
`Proprietary name — The division has disagreed with the DMETs assessment that
`Januvia represents a substantial risk for confusion with Tarceva when written
`out in script ( these two drugs do have overlapping dosage strengths). The
`division feels that the likelihood of confusion is low, since the directions for use
`differ and due to inherent differences in the spelling and therefore find Januvia
`acceptable.
`I agree with the Division on this.
`I would note further that the
`likely extreme differential in price (Tarceva is very expensive) and indication
`would make the chances of Tarceva being dispensed for a Januvia prescription
`
`

`

`quite low. Since the drug does not cause hypoglycemia in normal patients,
`Januvia dispensed for Tarceva would not be of important short—term
`consequence (although clearly an oncologic patient prescribed Tarceva would
`need their drug properly dispensed in the long—run).
`.
`Physician labeling — No major issues. The sponsor was requested to submit in
`PLR format and they did so.
`Carton and immediate container labels
`
`One issue that arose with the labeling, particularly for these portions of
`labeling, is how to represent the milligram strength. The established name of
`the product is sitagliptin phosphate, so the dosage strength would most
`correctly be in total milligrams of the drug substance as the salt (not as the base,
`which is the case for the 100 mg designation). Ibelieve there are a number of
`ways to address this, but clearly the labeling of Januvia Tablets (sitagliptin
`phosphate) 100 mg is incorrect and should not be allowed without some
`clarification. This will be resolved with ONDQA taking the lead.
`Patient labeling/Medication guide — none planned
`
`11.2.
`
`11.3.
`
`11.4.
`
`12. DSI Audits
`
`These audits were done and showed no evidence of data integrity issues or
`systematic study conduct issues (see Dr. Irony’s review and DSI report for
`details).
`
`13. Conclusibns and Recommendations
`13.1.
`
`Regulatory action
`Like most recent therapies for DM, this drug will be approved on the basis of a
`very well accepted and characterized surrogate for improved outcomes — the
`HgbAlc. This endpoint essentially integrates glycemic control over time and
`lowering of HgbAlc has been shown repeatedly to predict better outcomes of
`microvascular and even macrovascular complications in DM, both type 1 and 2.
`However, as it is a surrogate,it is incumbent on the FDA to assure that the
`. safety database is robust and relatively clean of seIious concerns that would
`make the value of this surrogate questionable.
`I believe that Merck has
`presented such a safety database for sitagliptin (both preclinical and clinical).
`While the drug has a fairly modest effect on HgbAlc lowering, it is additive to
`metphormin or a PPAR agent and the drug does not appear to have significant
`adverse effects of concern, including weight gain. Overall, 1 find the efficacy
`and safety data compelling for approval without a specific Risk MAP being
`needed.
`
`13.2.
`
`Safety concerns to be followed postmarketing
`The one concern that deserves some monitoring post-approval, but not an active
`intervention, is the issue of the creatinine rise seen in the clinical studies.
`I
`
`understand the sponsor’s argument that this is likely related to tubular secretion
`alterations, but I don’t think we can definitively say there is no reason to give
`this further attention or thought.
`.The sponsor does have ongoing studies that
`will further clarify this effect. It is important to realize, however, that periodic
`monitoring of renal function is recommended in patients on sitagliptin because
`
`

`

`of the need to dose titrate for any significant reductions in renal function, which
`is, unfortunately, a common consequence of advancing DM. So, presumably, if
`this labeling advice is followed (and good care of DM patients would argue for
`periodic monitoring of kidney function), there may be additional sensitivity to
`detect any unanticipated untoward effects of sitagliptin on renal function in the
`larger population of use.
`Risk Minimization Action Plan, if any - None
`Postmarketing studies (rationale, questions to be addressed)
`Required studies — Pediatric safety and efficacy studies in ages 11 and above
`will be needed to fulfill PREA. These may be conducted under a written
`request, as appropriate.
`Commitments (PMCs)
`The sponsor will need to commit to study this drug with other likely
`concomitant antidiabetic agents in type 2 patients, including insulin and insulin
`secretagogues, including the sulfonylurea agents. The main concern here
`would be to demonstrate safety (e. g., no unreasonable potentiation of
`hypoglycemic effects), as well as to demonstrate added efficacy from such
`combination therapy. A study of concomitant sulfonylurea treatment with
`sitagliptin has been recently completed and the commitment for this
`combination therefore will really be a commitment fer timely reporting of these
`data (as an efficacy supplement).
`'
`Other agreements
`None
`
`13.3.
`13.4.
`
`13.4.1.
`
`13.4.2.
`
`13.4.3.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Robert Meyer_
`10/16/2006 09:18:05 AM
`MEDICAL OFFICER
`
`

`

`“or him “1“.”
`c
`.3
`
`. _/ DEPARTMENT OF HEALTH & HUMAN SERVICES
`\HIAUH“
`ar4.
`a.)‘3‘*4m
`
`PUb'iC Health Service
`
`Food and Drug Administration
`Silver Spring, MD 20993-002
`
`NDA #
`
`Drug name
`
`DIVISION DIRECTOR’S MEMO
`
`21-995
`
`Januvia® (sitagliptin phosphate) - dipeptidyl peptidase
`IV inhibitor
`
`Formulation and Dosage Strengths
`
`25, 50, and 100 mg tablets
`
`Sponsor
`
`Indication
`
`Merck Laboratories
`
`Treatment of Type 2 diabetes mellitus as monotherapy
`as combination therapy with metformin or a PPAR—
`gamma agonist
`
`Date of submission
`
`December 16, 2005
`
`Date review completed
`
`October 13, 2006
`
`' Primary medical reviewer
`
`Ilan Irony, MD
`
`I. CLINICAL SUMMARY
`
`A. Background and Product Description
`Januvia® (sitagliptin phosphate), hereafter referred to as sitagliptin in this memo, is an inhibitor of the
`serine protease, dipeptidyl peptidase IV (DPP-IV), which is the enzyme responsible for the metabolism of
`the incretin hormones, glucagon—like peptide—l (GLP-1) and glucose—dependent insulinotropic
`polypeptide (GIP).
`
`Incretin hormones are gastrointestinal hormones which increase insulin secretion in response to food
`ingestion. These hormones contribute to the control of postprandial glucose excursions, and their actions
`are dependent upon the level of plasma glucose. As opposed to other anti-diabetic therapies that stimulate
`pancreatic insulin release regardless of plasma glucose levels, this glucose-dependent effect of incretin
`hormones provides an internal safeguard against hypoglycemia. The release of incretin hormones in
`response to meal ingestion is illustrated in studies comparing insulin secretion after an oral glucose load
`versus an intravenous glucose load, with a larger insulin response observed in the fOrmer study condition.
`Studies comparing the incretin-mediated release of pancreatic hormones in Type 2 diabetics versus non—
`diabetics show a decreased incretin effect in patients with T2DM suggesting a deficiency or defective
`incretin effect contributing to the poor glycemic control over time in these patients.
`
`In addition to enhanced postprandial insulin release, incretin hormones reduce glucagon release from
`pancreatic alpha cells thereby reducing hepatic glucose production. Again, this effect of incretin
`,
`hormones is glucose-dependent such that under normoglycemic or more importantly, hypoglycemic
`conditions, the counter—regulatory response of glucagon release is not impaired. ‘Finally, GLP—l has
`
`

`

`Januvia (sitagliptin phosphate) tablets
`
`NDA 21-995
`
`effects on food intake and gastric emptying as observed in clinical studies in which intravenous infusions
`of GLP—1 have shown reduced appetite and enhanced satiety.
`
`GLP-l is a product of the glucagon gene, expressed both in pancreatic alpha cells and in specialized
`intestinal endocrine cells called L cells, located in the lower small intestine and colon. Proglucagon is
`cleaved primarily to glucagon in alpha cells and to GLP—l in the L cells. GIP is produced by K cells from
`the upper small intestine. Both these hormones are rapidly metabolized by DPP-lV, resulting in a half-
`life of only 1 to 2 minutes. Therapeutic use of native incretin hormones would therefore require
`continuous infusion or frequent injections, presenting practical challenges to their clinical use. The
`recently approved exenatide or Byetta® is a 34-amino acid GLP-l analogue produced in the saliva of the
`Gila monster lizard. Exenatide has 53% homology with human GLP-l but retains agonistic activity at the
`GLP-1 receptor.
`It is naturally resistant to DPP-IV allowing for a half—life of approximately 4 hrs. It is
`approved for the treatment of Type 2 diabetes in combination with metformin or sulfonylureas and is
`available as twice daily subcutaneous injections.
`
`Inhibiting DPP—IV represents another measure in which to improve glycemic control through prolonging
`the half—life of endogenous incretin hormones and their effects. In the sitagliptin clinical development
`program, the applicant investigated whether prolonging the effect of endogenous GLP—1 and GIP activity
`through DPP—IV inhibition would enable its use as monotherapy or in combination with a PPAR—gamma
`agonist or metformin in the treatment of Type 2 diabetes mellitus.
`
`B. Summary of Clinical Development Program
`Please see Tables 5 and 6 from Dr. Irony’s review for a summary of the Clinical Studies conducted in
`support of this NDA.
`
`Bl. Phase 1 and 2 Programs
`Phase 1 studies have been reviewed by Drs. Wei and Bhattaram from the Office of Clinical
`Pharmacology. Key findings from these studies are summarized under the Clinical Pharmacology section
`of this memo.
`
`Three Phase 2 dose—finding studies were conducted which evaluated sitagliptin 5, 12.5, 25, 50, and 100
`mg administered as single or divided doses. These studies were placebo-controlled (one study included
`glipizide as an active control group) and were 12 weeks in duration; two of them have a 40-week
`extension period that is currently on-going. The results of these studies are discussed under Section 5.3 of
`Dr. lrony’s review and Section 3.1.5 of Dr. Pian’s statistical review. These studies demonstrated that
`there was no difference in efficacy with bid versus qd dosing of sitagliptin thereby supporting the
`applicant’s recommendation for once—daily dosing. Daily doses of 25, 50, and 100 mg lowered HbAl c
`significantly compared to placebo.
`
`Dr. Pian noted that there did not appear to be significant differences in efficacy between the 50 mg and
`100 mg daily doses as illustrated in the following figure obtained from her review.
`
`

`

`Januvia (sitagliptin phosphate) tablets
`
`NDA 21-995
`
`Figure. 34 LSYVI Difference from Piacebo (95% CI} — Phase 2 Studies
`
`Study 1301C}
`
`Study P014
`
`gh'pizide
`
`5 nag bid
`
`'
`
`33.5 mgAbid
`25ragbid
`3? lug bid
`
`0.0 —0.3 43.4 43.6 -9.3 4.0 -1.2
`
`0
`
`25 lug qd
`
`59 nag qd
`
`109 ang qd
`
`513 mg bid
`
`I
`I
`-
`-0.2 —0,4 43.6 -0.8 J 4.2
`
`Nevertheless, the applicant evaluated only the 100 mg and 200 mg once daily doses in their Phase 3
`program, despite advice at the EOP2 meeting that they focus on the 100 mg and 50 mg dosing in phase 3,
`due to theoretic concerns over potential dose-related serious toxicities.
`
`The applicant conducted one study in a special population of type 2 diabetic patients with varying degrees
`of chronic renal impairment. Study 028 was a 12-week, double—blind, placebo—controlled study
`evaluating two lower doses of sitagliptin in patients with moderate (CrCl 230 to <50 mL/min), severe
`(<30 mL/min), or ESRD (on dialysis). Patients were eligible if they had the following basel