`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`201280Orig1s000
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`SUMMARY REVIEW
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`Division Director Review
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`
`Date
`From
`Subject
`NDA/BLA #
`Supplement #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`Proposed Indication(s)
`
`Action/Recommended Action for
`NME:
`1. Introduction
`
`Division Director’s Memo
`
`May 2, 2011
`Mary H. Parks, M.D.
`Division Director Summary Review
`201280
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`July 2, 2010
`May 2, 2011
`Tradjenta/Linagliptin
`
`5 mg tablets
` To improve glycemic control in adults with T2DM as
`an adjunct to diet and exercise
`
`Approval
`
`
`Linagliptin is the 5th dipeptidyl peptidase-4 enzyme inhibitor (DPP4-inhibitor) to be submitted
`under an NDA for the treatment of T2DM. Two other DPP4-inhibitors are currently marketed
`in the United States. These are Januvia (sitagliptin) and Onglyza (saxagliptin), and their fixed-
`dosed combinations with metformin, Janumet or Kombiglyze XR, respectively.
`
`This is a relatively new class of anti-diabetic therapy whose mechanism of action targets the
`impaired release and availability of the incretin hormone, glucagon-like peptide-1 (GLP-1) in
`patients with type 2 diabetes. GLP-1 and another incretin hormone, glucose-dependent
`insulinotropic polypeptide (GIP), are released from the gastrointestinal tract in response to
`meals to further stimulate insulin release. Because GLP-1 is rapidly degraded by the serine
`protease, dipeptidyl peptidase 4, an inhibitor of this enzyme will prolong the half-life of this
`incretin hormone allowing for a more sustained effect on glucose control.
`
`Unlike other anti-diabetic therapies, which control hyperglycemia through stimulation of
`insulin release from the pancreas (e.g. sulfonylureas or glinides), incretin-based therapies
`control hyperglycemia through a glucose-dependent manner thereby mitigating the risk of
`hypoglycemia. GLP-1 receptor agonists are another class of incretin-based therapies. These
`agents are manufactured to avoid susceptibility to enzyme degradation while maintaining
`sufficient cross-reactivity with the GLP-1 receptor to impart similar effects on glucose control
`as the native hormone. Two GLP-1 receptor agonists are currently marketed: Byetta
`(exenatide) and Victoza (liraglutide).
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`2. Background
`
`
`The clinical development program for linagliptin was typical for most anti-diabetic therapies
`approved in the past 5 years. Monotherapy trials evaluated the drug’s safety and efficacy
`profile in treatment-naïve T2DM population or patients with fairly recent diagnosis of T2DM
`who could be controlled on a single drug regimen. In addition, combination therapy with
`linagliptin added to several approved anti-diabetic therapies was assessed in multiple trials and
`a single head-to-head trial comparing linagliptin to glimepiride was conducted. This latter trial
`provides the longest duration of controlled efficacy and safety data for linagliptin in this NDA.
`
`All new anti-diabetic therapies are now required to provide evidence to assure FDA that the
`new therapy is not associated with an adverse cardiovascular profile. Guidance for Industry
`outlining these recent changes to diabetes drug development programs was issued in December
`2008. As a result, several development programs that were in the midst of Phase 2/3 clinical
`trials were required to make adjustments to their CV risk assessment plans. Boehringer
`Ingelheim’s linagliptin was among these programs and the company presented to the FDA its
`proposal to evaluate CV risk from its ongoing Phase 2/3 trials. Although the inception of these
`trials was not with the recent guidance in mind, the trials were either early in initiation or not
`yet initiated such that a prospective plan for CV events adjudication and a meta-analytic plan
`could be implemented with FDA feedback/comments. Prior to submission of the NDA the
`applicant notified the FDA of its preliminary findings from its meta-analysis. Although the
`data appeared reassuring of CV safety, the limitations of the trials and the few CV events still
`required the conduct of a clinical trial prospectively designed to meet the standards set forth in
`the December 2008 Guidance.
`
`This memo serves to highlight the key findings of the multiple disciplines involved in review
`of the NDA. In addition to evaluating the efficacy and safety of this new anti-diabetic therapy,
`with particular scrutiny of CV safety data, other disciplines have focused on the product
`manufacturing process and quality, nonclinical evaluation of known class safety concerns and
`to identify any unique toxicities of linagliptin, and clinical evaluation of the drug’s metabolism
`and pharmacokinetic profile under multiple scenarios of use. In addition, all such materials
`have been considered in the review of the drug product’s label and prescribing information.
`
`In each section of this memo, the reader is referred to specific discipline reviews for a detailed
`discussion of their findings.
`3. CMC/Device
`
`
`CMC reviewers have recommended approval of linagliptin. Please see the reviews of Drs.
`Markofsky and Al-Hakim dated 2 February and 7 March 2011 for details. An acceptable
`establishment inspection report of manufacturing and testing facilities was issued on 15
`February 2011.
`
`Linagliptin will be available as a 5-mg, immediate-release film coated tablet in the following
`package presentations: 60 cc HDPE bottles containing 30 or 90 tablets; 375 cc HDPE bottles
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`containing 1000 tablets; and physician samples as aluminum push-through blister packets
`containing 7 tablets. The commercial container systems have a 30-month expiry when stored
`at room temperature with excursions between 15-30oC permitted.
`
` being the predominant
`Linagliptin has one chiral center with the R-enantiomer
`enantiomer that is also considered the active ingredient. Linagliptin also exists as
`
`
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`.
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`The commercial formulation and investigational formulations differ only in the following:
`
` The biopharmaceutics review considered these to be Level 1 changes in
`accordance with SUPAC-IR guidance and no further comparative studies (dissolution testing
`or BE studies) were required.
`4. Nonclinical Pharmacology/Toxicology
`
`
`Please see Dr. David Carlson’s review dated 7 March 2011 which contains the details of the
`pharmacology/toxicology program for linagliptin. Dr. Todd Bourcier’s secondary review
`dated 10 March 2011 concurs with Dr. Carlson’s assessment and both have recommended
`approval from pharmacology/toxicology perspective.
`
`Linagliptin, its metabolite, and impurities were adequately studied in the nonclinical program.
`Pivotal repeat-dose toxicity studies were conducted in rats and monkeys and provided
`evidence of a wide safety margin. In the 6-month rat study, histopathology findings identified
`the kidney, liver, lung, stomach, and thyroid to be target organs of toxicity at doses ≥ 100
`mg/kg. The histopathology findings are summarized in a table on page 54 of Dr. Carlson’s
`review. In the 12-month monkey study there was one death of a female (1/4) at the highest
`dose tested 100 mg/kg/day. The cause of death was deemed kidney-related. Both males and
`females had evidence of delayed sexual maturation at this dose, as evidenced by decrease
`reproductive organ weights and decreased corpora lutea (females).
`
`Studies exceeding 6 months in rats, including the 2-year carcinogenicity study, provided safety
`margins exceeding 50-times clinical exposures. Three and 12-month studies in monkeys
`provided safety margins exceeding 40-times clinical exposures. The exposures corresponding
`to the above toxicities were ≥ 54,650 nM*h in the rat and 125,000 nM*h in the monkey. In
`contrast, clinical exposures at steady-state is approximately 158 nM*hr for the proposed daily
`dosing of 5 mg.
`
`Linagliptin is not mutagenic or clastogenic. Two impurities were identified positive on Ames
`testing (one was also clastogenic); however, Dr. Carlson noted that human exposure estimates
`for the impurities are below levels that which would pose a carcinogenic risk. Carcinogenicity
`studies established a NOAEL for neoplasms in male and female rats at 418x MRHD and 271x
`MRHD for male mice and 34x MRHD for female mice. No treatment difference in survival
`was noted in these studies. There were no statistically significant increases in tumor incidence
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`between treatment and control in the rat carcinogenicity study. There was a statistically
`significant increase in incidence of malignant lymphoma in female mice only at the highest
`dose (80 mg/kg/day ~ 287x MRHD). Given that no other drug-related tumors were observed
`in rats and male mice and the lymphoma finding was limited only in female mice at a 34-fold
`safety margin, this finding is unlikely to be of clinical relevance.
`
`Reproductive/fertility studies also established wide safety margins for linagliptin and both Drs.
`Carlson and Bourcier support pregnancy category B labeling. Linagliptin crosses the placenta
`and is secreted in breast milk. These findings will also be reflected in labeling.
`
`Safety findings of special interest for the class of DPP4-inhibitors include: pancreatitis (signal
`arising from AERS reports for Januvia and a GLP-1 analog, Byetta); cutaneous lesions (from
`nonclinical program of vildagliptin, a DPP4 inhibitor marketed outside the U.S.); and
`hypersensitivity reactions which will be further discussed under the Clinical Safety section of
`this memo.
`
`Overall, the nonclinical findings have identified toxicities that occur at very high exposures
`yielding a wide clinical safety margin. As noted by Dr. Bourcier, these safety margins would
`also cover the susceptible patient population that may have higher than expected drug
`exposures. I concur with their assessment that nonclinical findings support approval and no
`nonclinical postmarketing required studies are needed at this time.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`There were 24 Phase 1 (20 in healthy, 2 in T2DM, 1 in renal impaired, 1 in hepatic impaired),
`four Phase 2, and 9 Phase 3 clinical trials and several in vitro ADME studies conducted in
`support of this NDA.
`
` with Cmax ranging between 0.5 and 3 hrs
`Absorption of linagliptin occurs
`post-dosing. The extent of absorption was unaffected by food but the Cmax had a clinically
`insignificant 14% reduction. Linagliptin is not metabolized extensively with approximately
`90% excreted unchanged in the feces and 5% excreted unchanged in the urine. Non-linear
`pharmacokinetics is displayed with less than dose-proportional increase in exposure at doses
`of 1 to 10 mg and dose-proportional increase in exposure at doses exceeding 25 mg.
`
`Dose-Response/Dose-Selection
`Several doses of linagliptin were tested in Phase 1 and 2 trials resulting in the selection of the
`single daily dose of 5 mg for Phase 3 development and proposed marketing. In particular, two
`12-week, Phase 2 studies compared linagliptin across doses of 0.5 mg, 1.0 mg, 2.5 mg, 5 mg
`and 10 mg to placebo. These two studies also included active comparisons to metformin or
`glyburide.
`
`Study 1218.5 was a 12-wk, randomized, double-blind, placebo-controlled trial in 302 T2DM
`patients who were drug-naïve or were treated with one or two oral agents and who had HbA1c
`7.5-10% at screening. Patients were randomized to linagliptin 0.5, 2.5, 5 mg, placebo, or
`metformin. The objective of this study was to compare efficacy and safety of several doses of
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`linagliptin to placebo. Based on a hierarchical testing procedure, a power of 85% was planned
`to show superiority of the highest dose of linagliptin to placebo. The metformin treatment arm
`was open-label and intended for sensitivity assessment. The following table summarizes only
`the descriptive statistics at Week 12 in the Full Analysis Set
`
`Table 1. Mean Change from Baseline in HbA1c at Week 12 in FAS from Study 1218.5
`
`Placebo
`Lina 0.5
`Lina 2.5
`Lina 5
`Metformin
`N=63
`N=57
`N=55
`N=54
`N=65
`8.3
`8.2
`8.4
`8.4
`8.3
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`Baseline
`HbA1c
`Mean change
`(SD)
`
`Both the 2.5 and 5 mg dose had statistically significant reductions in HbA1c from baseline
`relative to placebo. The adjusted mean difference was -0.5% for the linagliptin 5 mg dose and
`-0.4% for the linagliptin 2.5 mg dose, with accompanying p-value of 0.0012 and 0.0032,
`respectively. The adjusted mean difference for linagliptin 0.5 mg was -0.1%, which was not
`statistically significantly different compared to placebo. Interestingly, the descriptive statistics
`summarized by the applicant show that metformin achieves greater glycemic control than all
`doses of linagliptin. The mean change in HbA1c at Week 12 in the metformin group was -
`0.7%, approximately twice the reduction achieved with linagliptin 5 mg.
`
`Table 2. HbA1c in Study 1218.5 for All Treatment Groups
`
`0.2 (0.8)
`
`0.1 (0.8)
`
`-0.2 (0.8)
`
`-0.3 (0.7)
`
`-0.7 (0. 8)
`
`
`
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`Study 1218.6 was a 12-wk, double-blind, placebo-controlled trial in 669 T2DM patients who
`had inadequate glycemic control (HbA1c 7-10%, dependent on background therapy) on
`metformin therapy who were then randomized to placebo, linagliptin 1 mg, 5 mg, or 10 mg
`once daily, or glimepiride 1-3 mg once daily. Similar to Study 1218.5, there was a
`hierarchical testing procedure to show superiority of at least the highest dose of linagliptin to
`placebo. Glimepiride was an open-label treatment arm for sensitivity analysis.
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`Table 3. Glycemic Efficacy Results from Study 1218.6
`
`
`All doses of linagliptin tested showed significant reductions in HbA1c relative to placebo.
`Study 1218.6 also showed greater efficacy with glimepiride over placebo and the treatment
`difference exceeded the findings observed with all doses of linagliptin.
`
`Table 4. Efficacy of Glimepiride vs Placebo in Phase Trial 1218.6.
`
`
`The findings in the active control arms of Studies 1218.5 and 1218.6 reveal that while
`linagliptin can reduce HbA1c, its efficacy is less than that of two commonly prescribed anti-
`diabetic therapies, metformin and glimepiride, at least for the 12-week duration of these
`studies.
`
`DPP4-inhibitory activity was assessed in these trials and was noted to be consistently greater
`than 80% at doses above 5 mg. Despite the higher DPP4 inhibition at the 10 mg dose, there
`was no additional reduction in HbA1c achieved with the 10 mg dose over the 5 mg dose
`observed in Study 1218.6. The minimal additional benefit of glycemic control was noted in
`another trial conducted in Japanese patients, which evaluated the 5 and 10 mg doses of
`linagliptin relative to placebo. After 12 weeks, the mean change from baseline in HbA1c at
`the 5 and 10 mg dose was identical.
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`Figure 1. Efficacy of Linagliptin 5 and 10 mg at 12 weeks. Figure from Dr. Lokesh Jain’s
`review.
`
`
`
`Overall, the dose-response studies support the proposed maximal dose of linagliptin 5 mg.
`Although lower doses of linagliptin provided statistically greater reductions in HbA1c relative
`to placebo, the mean treatment differences of 0.2% and 0.4% are modest. Provided the 5 mg
`dose is a safe and effective dose and no vulnerable patient population has been identified
`necessitating a lower marketed dose, I concur that the 5 mg dose provides the maximal benefit-
`risk response.
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`Drug-Drug Interactions
`DDI studies evaluated the effect of potent inducers and inhibitors and likely co-administered
`drugs on the PK of linagliptin. Conversely, the effect of linagliptin on the PK of likely co-
`administered drugs and drugs with narrow therapeutic indices was studied in several DDI
`studies. Please see the review of Drs. Jain and Choe, dated 8 March 2011 for the detailed
`summaries of these studies. A brief summary is provided below.
`
`Linagliptin is a CYP3A4 and P-gp substrate. The effect of CYP3A4 and P-gp inhibition on
`linagliptin pharmacokinetics was evaluated in a DDI study evaluating the relative
`bioavailability of a single dose of linagliptin 5 mg after co-administration with ritonavir 200
`mg bid for 3 days compared to the bioavailability of a single dose of linagliptin 5 mg alone in
`a healthy male patient population. AUC and Cmax of linagliptin increased by about 2 and 3-
`fold, respectively. Conversely, the effect of the CYP3A4 and P-gp inducer, rifampicin, on
`linagliptin pharmacokinetics was evaluated and significant reduction in linagliptin exposure
`was noted. The bioavailability of linagliptin 5 mg daily doses was reduced to approximately
`the exposure expected with a 1 mg daily dosing regimen when co-administered with
`rifampicin.
`
`The following forest plots provide a nice summary of the different DDI studies which
`evaluated the effects of selected drugs on linagliptin PK and vice versa.
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`Figures 2 and 3. From OCP review, page 10
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`• There is no clinically meaningful effect of metformin, pioglitazone, and glyburide on
`linagiptin PK. The oral anti-diabetics were also co-administered with linagliptin in
`several of the Phase 3 trials.
`• Co-administration with potent CYP3A4 and P-gp inhibitors is expected to increase
`linagliptin exposures; however, OCP reviewers are not recommending any dose
`adjustments based on acceptable safety data at these higher drug levels obtained in a
`Phase 3 trial which tested the 10 mg dose of linagliptin. I would further add that the
`wide safety margin identified in pharmacology/toxicology studies provide additional
`reassurance.
`• Linagliptin drug levels will likely be reduced significantly when co-administered with
`a potent CYP3A4 and P-gp inducer. Given the availability of other anti-diabetic
`therapies including two other DPP4-inhibitors that are unaffected by 3A4 and P-gp
`induction, I concur with OCP recommendations that labeling should recommend the
`use of alternative anti-diabetic therapies in patients requiring therapies with a 3A4/P-gp
`inducer.
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`Linagliptin co-administered with simvastatin (a CYP3A4 substrate) did not result in a
`clinically meaningful increase in simvastatin/simvastatin acid exposures. A 30% increase in
`AUC is not expected to result in simvastatin exposures posing a marked increased risk for
`rhabdomyolysis. Linagliptin did not result in clinically meaningful increase or decreases in
`digoxin or warfarin. Although exposures of pioglitazone and glyburide were lowered by the
`co-administration with linagliptin, this should not adversely impact clinical efficacy as
`supported by data from several Phase 3 trials where these drugs were studied in combination.
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`Special Populations
`This section will only summarize findings in the renal impaired patient population. The OCP
`review provides detailed analyses on drug exposure by gender, BMI/weight, age, race, and
`hepatic impairment. Overall, no clinically meaningful difference in exposures was observed
`by those intrinsic factors although data were sparse in certain subgroups (e.g., racial/ethnic
`subgroups).
`
`Study 1218.26 was a PK study evaluating linagliptin pharmacokinetics in diabetic and non-
`diabetic patients with normal renal function and varying degrees of renal impairment. The
`study had multiple and single-dose treatment groups as summarized below:
`
`Group 1: non-DM with normal renal function (multiple dosing; 7 days)
`Group 2: non-DM with mild renal impairment (multiple dosing; 7 days)
`Group 3: non-DM with moderate renal impairment (multiple dosing; 7 days)
`Group 4: non-DM with severe renal impairment (single dosing)
`Group 5: non-DM with ESRD (single dosing)
`Group 6: T2DM with severe renal impairment (multiple dosing; 10 days)
`Group 7: T2DM with normal renal function (multiple dosing; 10 days)
`
`Sample size in each treatment group was small (n=6 except in Groups 6 and 7 which enrolled
`10 and 11 patients, respectively). Across the varying degrees of renal impairment in both the
`non-DM and T2DM population, average linagliptin exposure was increased from 41% to 71%
`compared to patients with normal renal function. Cmax in all comparisons increased by 36-
`50%. The following scatter plot displays the individual steady state AUCs in Study 1218.26.
`Except for one outlier, steady state AUCs fall within the range of 100-350 nmol-hr/L.
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`Clinical pharmacology reviewers are not recommending any dose adjustments based on renal
`function, citing the wide safety margin from nonclinical program, reassuring safety findings
`from a clinical trial in Japanese patients which studied linagliptin 10 mg out to 52 weeks, and
`the 12-week interim analysis of a 52-week trial in patients with renal impairment.
`
`Overall, the clinical pharmacology of linagliptin has been adequately evaluated in this NDA.
`The Office of Clinical Pharmacology has recommended approval in its review dated 7 March
`2011 without additional studies/trials required postmarketing.
`6. Clinical Microbiology
`
`
`
`
`Not applicable
`
`
`7. Clinical/Statistical-Efficacy
` for
`There were 9 Phase 3 trials submitted with this NDA; 7 of these were
`efficacy and will be discussed under this section of the memo. The other two studies were
`reviewed in more detail by FDA for safety, including CV safety. The primary efficacy
`endpoint in all trials was percent change in HbA1c from baseline. Among the multiple
`secondary efficacy parameters were post-prandial glucose levels after meal tolerance tests
`(MTT) and fasting plasma glucose levels, which have been summarized in the primary reviews
`and will not be noted here. Please see Dr. Wei Liu’s statistical review dated 11 March 2011
`for a detailed discussion of trial design, statistical analysis plan, and results. I will summarize
`the efficacy findings of linagliptin when used as monotherapy and add-on therapy, compared
`to placebo or to other anti-diabetic therapies.
`
`Linagliptin Monotherapy
`The efficacy of linagliptin as a single agent for the treatment of T2DM was compared to
`placebo in two Phase 3 trials. Its efficacy relative to placebo was also evaluated in two dose-
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`response studies described under Section 5 of this memo. The Phase 3 trials included a 24-
`week trial in which T2DM patients who were drug-naïve or previously treated but could be
`washed off therapy to assess linagliptin monotherapy (Study 1218.16) and a 18-week trial in
`patients similar to those in Study 1218.16 plus patients who could not tolerate metformin or
`had contraindications to its use (Study 1218.50). This latter trial had a 2nd active-controlled,
`double-blind portion which will not be discussed here as it is ongoing.
`
`Study 1218.16 was a randomized, double-blind, placebo-controlled trial in 503 T2DM patients
`with mean baseline HbA1c of 8%. Slightly more than half were drug-naïve (57.5%).
`Randomization was 2:1 (linagliptin:placebo) and stratified by HbA1c at start of run-in (< or ≥
`8.5%). The majority had HbA1c < 8.5% (70.8%). 36.1% of patients had diagnosis of T2DM
`of < 1 yr duration; 36.7% for 1-5 yrs; and 25.2% > 5 yrs. The short duration of disease is not
`unexpected for a monotherapy trial as most patients with diabetes for longer duration are on
`multiple drug therapy and are more appropriate candidates for add-on trials.
`
`Different analyses were performed on the primary endpoint measure. Overall the findings
`across these different analyses and sensitivity analyses support the conclusion that linagliptin 5
`mg daily dosing was superior to placebo in reducing HbA1c from baseline. The following
`table summarizes the sponsor’s and FDA’s primary analysis.
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`Table 5. Study 1218.16 Primary Efficacy Results
`
`Sponsor’s Analysis*
`Number of patients
`Baseline mean HbA1c
`Adjusted mean chg from baseline (SE)
`
`Placebo
`
`Linagliptin 5 mg
`
`163
`8%
`+0.25 (0.07)
`
`
`
`167
`8%
`+0.26 (0.08)
`
`
`
`333
`8%
`-0.44 (0.05)
`
`
`-0.69 (-0.85,-0.53)
`
`336
`8%
`-0.45 (0.05)
`
`
`-0.71 (-0.89,-0.53)
`
`Adjusted mean treatment difference
`(linagliptin-pbo) 95% CI
`
`FDA’s Analysis**
`Number of patients
`Baseline mean HbA1c
`Adjusted mean chg from baseline (SE)
`
`Adjusted mean treatment difference
`(linagliptin-pbo) 95% CI
`
`*Analysis of covariance method w/ treatment and prior anti-DM as fixed effects and baseline HbA1c as linear covariate on
`full analysis set
`**mixed model repeated measures method with visit week as an additional fixed effect on the observed completers population
`
` A
`
` consistent finding of greater HbA1c reduction in linagliptin compared to placebo was
`observed across all subgroups analyzed (e.g., baseline HbA1c, prior anti-DM therapy, gender,
`BMI, etc.)
`
`Study 1218.50 was a randomized, double-blind, placebo-controlled trial in 227 T2DM patients
`with mean baseline HbA1c of 8%. Slightly more than half were drug-naïve (54.1%).
`Randomization was 2:1 (linagliptin:placebo) and stratified by HbA1c at start of run-in (< or ≥
`8.5%), previous use of anti-DM therapies; and reason for metformin ineligibility. The
`majority had HbA1c < 8.5% (70.8%). 22.7% of patients had diagnosis of T2DM of < 1 yr
`duration; 52.3% for 1-5 yrs; and 25% > 5 yrs.
`
`Similar to Study 1218.16, different methods of analyses were performed by the applicant and
`FDA; however, the primary analyses and sensitivity analyses all revealed a consistent finding
`of linagliptin 5 mg being superior to placebo.
`
`Table 6. Study 1218.50 Primary Efficacy Results (FDA analysis)
`
`Placebo
`Number of patients
`76
`Baseline mean HbA1c
`8.09%
`Adjusted mean chg from baseline (SE)
`+0.25 (0.13)
`
`
`
`Linagliptin 5 mg
`155
`8.12%
`-0.33 (0.09)
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`-0.57 (-0.89,-0.26)
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`Adjusted mean treatment difference
`(linagliptin-pbo) 95% CI
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`Dr. Wei presented efficacy results by subgroups in a forest plot in his review in Figure 3.1.8.
`Across all subgroups a numerically greater HbA1c reduction was observed with linagliptin
`although not all were statistically significant with the obvious limitation being small sample
`sizes in some subgroups. Metformin is considered 1st line therapy for most patients with
`T2DM. This study specifically enrolled patients who were ineligible or intolerant to
`metformin, so it of interest to see that in the subgroup of metformin ineligibles there was a
`mean HbA1c reduction of 0.55-0.89% relative to placebo.
`
`In conclusion, Studies 1218.16 and 1218.50 confirm the effectiveness of linagliptin 5 mg daily
`dosing noted in Phase 2 trials of shorter duration. Although these Phase 3 trials would support
`labeling for use of linagliptin as monotherapy in T2DM, I would emphasize the observation
`that metformin and glimepiride provided greater glycemic control in the two Phase 2 dose-
`response trials over linagliptin monotherapy.
`
`Linagliptin Add-on Therapy
`Five Phase 3 trials evaluated the addition of linagliptin to other anti-diabetic therapies. Four of
`these trials compared linagliptin add-on to placebo add-on in patients who had not achieved
`adequate glycemic control on other anti-diabetic therapies or as initial therapy in a drug-naïve
`population. These studies were designed to show superiority of linagliptin over placebo in
`different add-on scenarios. There was one head-to-head comparison of linagliptin to
`glimepiride. The trial was designed to show non-inferiority between the two drugs.
`
`The placebo-controlled, add-on trials all supported a conclusion of superiority of linagliptin 5
`mg over placebo. This is not an unexpected finding as it is generally observed across
`numerous development programs that the addition of an anti-diabetic therapy of a different
`class to current therapies will result in better glycemic control than continuing therapy with the
`current regimen. The following table summarizes the findings from these four trials using
`FDA’s analysis.
`
`Table 7. Glycemic Control Efficacy Results in Linagliptin Add-on, Placebo-controlled Trials
`Placebo
`Linagliptin
`
`
`
`130
`259
`8.6 (0.08)
`8.6 (0.05)
`-0.85 (0.09)
`-1.30 (0.06)
`
`-0.46 (-0.67, -0.24)
`
` N
`
`
`Mean baseline HbA1c (SE)
`Adjusted mean chg from baseline (SE)
`Adjusted mean treatment diff (95% CI)
`
`
`Study 1218.15 (24 wks)
`Compared lina+pio to
`pbo+pio in drug-naïve or
`patients wash-out of
`current anti-DM therapies
`24-wk trial
`
`Study 1218.17 (24 wks)
`Compared
`lina+metformin to
`pbo+metformin in patient
`inadequately controlled
`on metformin
`
`Study 1218.18 (24 wks)
`Compared lina + met/su
`to pbo + met/su in
`
`
`523
`8.1 (0.04)
`-0.58 (0.04)
`-0.66 (-0.82,-0.50)
`
`
`792
`8.2 (0.03)
`
`
`177
`8.0 (0.07)
`0.08 (0.07)
`
`
`
`263
`8.1 (0.05)
`
` N
`
`
`Mean baseline HbA1c (SE)
`Adjusted mean chg from baseline (SE)
`Adjusted mean treatment diff (95% CI)
`
` N
`
`
`Mean baseline HbA1c (SE)
`
`
`
`Reference ID: 2940523
`
`13
`
`

`

`-0.11 (0.05)
`
`
`
`84
`8.6 (0.08)
`-0.13 (0.10)
`
`-0.72 (0.03)
`-0.61 (-0.73, -0.49)
`
`
`161
`8.6 (0.07)
`-0.60 (0.07)
`-0.47 (-0.71,-0.22)
`
`Division Director Review
`
`Adjusted mean chg from baseline (SE)
`Adjusted mean treatment diff (95% CI)
`
`patients inadequately
`controlled on met/su
`
`Study 1218.35 (18 wks)
`Compared lina+SU to
`pbo+SU in patients
`inadequately controlled
`on SU
`
` N
`
`
`Mean baseline HbA1c (SE)
`Adjusted mean chg from baseline (SE)
`Adjusted mean treatment diff (95% CI)
`
`
`
`
`Study 1218.20 is a long-term, active-controlled trial comparing linagliptin 5 mg daily dosing
`to glimepiride in T2DM previously treated with metformin or metformin plus one other oral
`anti-diabetic drug without changes to dosing within 10 weeks prior. Patients treated with anti-
`diabetic drugs other than metformin entered a 6-week washout period. In effect, this trial
`randomized patients in a 1:1 fashion to linagliptin + metformin vs glimepiride + metformin.
`Glimepiride was initiated at 1 mg. Over the course of the first 12 weeks, glimepiride could be
`titrated stepwise to the next dose up to 4 mg daily every 4 weeks if the home BG monitoring
`was > 110 mg/dL.
`
`This trial was designed to be a 104-wk (2-yr) trial but only the interim results are presented in
`this NDA (52 wk data). The primary hypothesis is that linagliptin is non-inferior to
`glimepiride. In addition, the trial tested the superiority of linagliptin versus glimepiride with
`respect to body weight change and hypoglycemia. This trial is of relevance to this NDA for
`the following reasons:
`
`
`•
`It contains controlled data for the longest duration of all trials reviewed in the NDA
`• Long-term glycemic control of linagliptin relative to glimepiride from this trial support
`the observation of lower efficacy with linagliptin from a 12-wk Phase 2 trial
`It is the largest controlled trial, in terms of number of patients randomized, of all trials
`reviewed in the NDA
`It is an active controlled trial using the same comparator proposed in the postmarketing
`required trial to assess long-term CV safety
`• The majority of CV events from the CV safety meta-analysis came from this trial
`
`•
`
`•
`
`
`
`Mean baseline HbA1c was 7.8% in this patient population. This is in contrast to other Phase 2
`and 3 trials summarized above in which the average baseline HbA1c values were 8% or
`higher. Approximately 53% of the population had a diagnosis of T2DM for more than 5 years
`and 33% of the population was ≥ 65 years of age. From Table 3.1.8 in Dr. Liu’s review, one
`will note that other add-on trials tended to enroll fewer patient within this age category (17-
`27%).
`
`The non-inferiority of linagliptin to glimepiride with regard to HbA1c reduction applied a non-
`inferiority margin of 0.35% as the upper bound of the 97.5% CI.
`
`The trial randomized 1560 patients in a 1:1 fashion to linagliptin (779) and glimepiride (781)
`with stratificatio