Merck Exhibit 2111, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`L-000224715
`DP-IV Inhibitor
` Update on Phase I Data
`
`RMC
`Jan 8, 2003
`
`Merck Exhibit 2111, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`a
`
`a
`
`Key points
`L-224715 generally safe & well tolerated
`no clear dose limiting toxicity identified
`,
`L-224715 lowers post-OGTT glucose in type 2
`diabetics
`greater reduction of glucose-AUC observed at higher
`,
`of 2 doses tested
`*
`optimal effect may require maximal DP-IV inhibition
`BID regimens may be required to maintain high DP-IV
`inhibition and optimize chances for best efficacy
`milder diabetics appear to respond better
`
`,
`
`,
`
`Merck Exhibit 2111, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Decisions Requested
`
`a
`a
`
`Support for Go decision to phase II
`Support for team recommendation to proceed to
`expanded Phase II program
`Define dose range
`,
`Assess QD vs. BID efficacy
`,
`Determine responder population
`,
`
`Merck Exhibit 2111, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`L-224715 generally well tolerated
`
`Exposure: single and multiple dose in healthy volunteers, single dose in
`obese male, in females, and in healthy elderly, single doses in patients
`with type 2 diabetes (134 volunteers, 53 patients with type 2 diabetes)
`
`a
`
`No dose limiting tolerability issues identified
`No trends for significant changes in lab, ECG or vital signs
`,
`parameters
`
`Merck Exhibit 2111, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`L-224715 Pharmacokinetics
`
`a
`a
`a
`
`Studied single doses from 1.5 to 600 mg, multiple doses of
`25-600 mg QD x 10 Days, 300 mg BID ongoing
`Half-life 8-14 hr
`Renally eliminated (> 80%)
`With single and multiple doses
`AUC increases ~linearly & dose proportionally
`,
`C 24 increases less than dose proportionally
`,
`Plasma concentrations increase ~20-25% at steady state
`,
`PK alterations
`AUC increases approximately 30% in the elderly
`,
`*
`may be explained by decreases in creatinine clearance
`Cmax ~30% higher in females
`,
`Phase I Capsule versus Phase II tablet
`AUC, C24 ~ equal, Cmax ~ 20% higher with tablets
`,
`
`a
`
`a
`
`Merck Exhibit 2111, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Phase IB Study: Single Doses in Type 2 Diabetes
`
`Randomized, Double-Blind, Placebo-Controlled 3- period
`crossover
`36-48 type 2 diabetics,
`21-60 years
`,
`HbA1c 6.5 to 11.0%, FPG 126 to 250 mg/dL
`,
`To insure broad spectrum: at least half of the pts with HbA1c > 7.5
`,
`Randomized to sequence of treatments- single doses of:
`Placebo
`,
`25 mg
`,
`200 mg
`,
`Fasted o/n, study drug at t=0, OGTT at 2 hr (~Tmax),
`standardized (~550 kcal) meals at 6, 24 hr post-dose
`Endpoints
`Primary: Post-OGTT incremental & total glucose AUC
`,
`PK, plasma DP-IV activity, active & total GLP-1
`,
`Insulin, C-peptide, glucagon, archive for GIP
`,
`Interim Analysis -- N=18
`
`a
`
`a
`
`a
`
`a
`
`a
`
`a
`
`Merck Exhibit 2111, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`L-224715 pharmacokinetics not appreciably different in type 2 diabetics
`
`200-mg (Young Males #001; N=6)
`200-mg (Diabetics #005; N=27)
`
`Trough
`~97nM
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`0
`
`L-000224715 Plasma Concentration (nM)
`
`Merck Exhibit 2111, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Phase IB study in type 2 diabetics: inhibition of plasma DP-IV activity (Periods 1-3)
`
`OGTT
`
`Plasma DP-IV Inhibition
`Percent Inhibition From Baseline
`
`Trough DP-IV
`Inhibition
`
`~80%
`
`~50%
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`-10
`
` From Baseline
`Percent Inhibition
`
`
`
`
`0 1 2
`
`4
`
`6
`
`8
`
`10 12 14 16 18 20 22 24
`Hour
`
` Placebo (n=18)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
` Back-transformed from the log scale
`
`Merck Exhibit 2111, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Post-OGTT glucose lowering following single doses of L-224715- greater reduction with 200 mg versus 25 mg
`
`Post-OGTT Glucose Incremental AUC
`
`Group GMR* 95% CI p-value
`
`25mg
`vs. pbo 0.79
`
`200mg
`vs. pbo 0.69
`
`200mg
`vs 25mg 0.87
`
`(.69,.90) <0.001
`
`(.60,.78) <0.001
`
`(.76, 99) 0.035
`
`0
`
`1
`
`2
`
`3
`
`Hour
`
`4
`
`5
`
`6
`
`330
`320
`310
`300
`290
`280
`270
`260
`250
`240
`230
`220
`210
`200
`190
`180
`170
`160
`150
`
`Plasma Glucose (mg/dL)
`
` Placebo (n=18)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
`Back-transformed from the log scale for Mean ± SE
`
`Merck Exhibit 2111, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Active GLP-1 levels following an OGTT at 2 hr post-dose- no detectable difference between 25, 200 mg
`
`Weighted Average GMR
` (active/placebo over 4 hr)
`
`25 mg: 2.09*
`200 mg: 1.93*
`
`* p < 0.001 (vs. placebo)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Hour
`
`18
`17
`16
`15
`14
`13
`12
`11
`10
`
`23456789
`
`Active GLP-1 (pM)
`
` Placebo (n=17)
` L-224715 25 mg (n=17)
` L-224715 200 mg (n=17)
`
`Merck Exhibit 2111, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Reduction in plasma glucose following solid meal at 24 hr post-dose not statistically significant
`
`Meal
`
`Post-Meal Glucose AUC
`25 mg- 0.96
`(.91, 1.0)
`200mg- 0.97
`(.92, 1.0)
`
`Post-Meal Incr Glucose AUC
`25 mg- 0.83
`(.60, 1.2)
`200 mg- 0.83
`(.59, 1.2)
`
`23
`
`24
`
`25
`Hour
`
`26
`
`27
`
`260
`250
`240
`230
`220
`210
`200
`190
`180
`170
`
`Plasma Glucose (mg/dL)
`
` Placebo (n=18)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
`Back-transformed from the log scale for Mean ± SE
`
`Merck Exhibit 2111, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`L-224715 increases active GLP-1 Levels following a meal at 24 hr post-dose
`
`Weighted Average GMR
` (active/placebo over 2 hr)
`
`25 mg: 1.88*
`200 mg: 2.34*
`
`* p < 0.001 vs. placebo
`
`23
`
`24
`
`25
`Hour
`
`26
`
`27
`
`14
`13
`12
`11
`10
`
`23456789
`
`Active GLP-1 (pM)
`
` Placebo (n=17)
` L-224715 25 mg (n=17)
` L-224715 200 mg (n=17)
`
`Merck Exhibit 2111, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Sub-Group Analysis: L-224715 demonstrates greater Post-OGTT glucose lowering in mild patients
`
`Parameter
`(post-challenge
`glucose AUC)
`Post- OGTT
`Incremental
`AUC
`(0-240min)
`
`Dose
`(mg)
`
`HbA1C < 7.5
`n=6
`
`HbA1C > 7.5
`n=12
`
`All
`n=18
`
`25
`
`200
`
`0.66 (.54,.81)
`
`0.86 (.75,1.00)
`
`0.79 (.69,.90)
`
`0.55 (.45,.67)
`
`0.77 (.66,.89)
`
`0.69 (.60,.78)
`
`Post-OGTT Incremental Glucose Lowering Stratified for HbA1C < or > 7.5%
`
`Merck Exhibit 2111, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Patients with HbA1c less than 8.5% also demonstrate good post-OGTT glucose reduction
`
`Parameter
`(post-challenge
`glucose AUC)
`Post- OGTT
`Incremental
`AUC
`(0-240min)
`
`Dose
`(mg)
`
`HbA1C < 8.5
`n=12
`
`HbA1C > 8.5
`n=6
`
`All
`n=18
`
`25
`
`200
`
`0.76 (.65,.88)
`
`0.85 (.69,1.05)
`
`0.79 (.69,.90)
`
`0.62 (.53,.72)
`
`0.83 (.67,1.03)
`
`0.69 (.60,.78)
`
`Post-OGTT Incremental Glucose Lowering Stratified for HbA1C < or > 8.5%
`
`Merck Exhibit 2111, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Baseline HbA1C versus post-OGTT incremental glucose lowering
`
`More responders with HbA1C < 9
`
`Non-responders (< 20% reduction)
`
`- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`Responders (> 20% reduction)
`
`6
`
`7
`
`8
`9
`10
`Baseline HbA1c (%)
`
`11
`
`12
`
`1.2
`1.1
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`
`Incre Glucose AUC Ratio over Placebo
`
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
`
`Merck Exhibit 2111, Page 16
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Active GLP-1 response is enhanced in milder patients
`
`HbA1c > 7.5%
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Hour
`
`45
`40
`35
`30
`25
`20
`15
`10
`
`05
`
`Active GLP-1 (pM)
`
`HbA1c < 7.5%
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Hour
`
`45
`40
`35
`30
`25
`20
`15
`10
`
`05
`
`Active GLP-1 (pM)
`
` Placebo (n= 5)
` L-224715 25 mg (n= 5)
` L-224715 200 mg (n= 5)
`
` Placebo (n=12)
` L-224715 25 mg (n=12)
` L-224715 200 mg (n=12)
`
`OGTT
`
`Merck Exhibit 2111, Page 17
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`C-peptide response (marker of newly released insulin) is enhanced in milder patients
`
`HbA1c > 7.5%
`
`
`
`60
`
`1
`
`2
`
`4
`
`3
`
`Hour
`
`5
`
`6
`
`11
`10
`
`123456789
`
`HbA1c < 7.5%
`
`asma C-Peptide (ng/mL)
`
`Pl
`
`0
`
`1
`
`2
`
`4
`
`3
`
`Hour
`
`5
`
`11
`10
`
`123456789
`
`asma C-Peptide (ng/mL)
`
`Pl
`
`
` Placebo (n= 6)
`
` L-224715 25 mg (n= 6)
`
` L-224715 200 mg (n= 5)
`
`
` Placebo (n=12)
`
` L-224715 25 mg (n=12)
`
` L-224715 200 mg (n=12)
`OGTT
`
`Merck Exhibit 2111, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

` Observations- IB Study
`
`a
`
`a
`
`a
`
`,
`
`,
`
`Extent of OGTT glucose-lowering generally comparable to
`other insulin secretagogues
`Superior OGTT glucose-lowering with 200 vs 25-mg dose
`Despite similar increment in active GLP-1 and achievement of ~
`,
`80% DP-IV inhibition with lower dose
`Suggests higher drug levels and greatest possible DP-IV
`inhibition may provide greater glucose-lowering
`PK/PD projections suggest that BID regimens will maximize DP-
`IV inhibition, especially evening and early AM time periods.
`Superior glucose-lowering in milder patients
`More responders with HbA1c < 8.5-9.0
`,
`Milder patients have greater stimulation of active GLP-1 and C-
`,
`Peptide Levels
`Additional subgroup analyses planned to understand non-
`responders-(T)-end Jan
`*
`e.g. PK, BMI, weight, HOMA, QUICK-I, age, race, gender
`
`,
`
`Merck Exhibit 2111, Page 19
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`200-mg bid (projection)
`100-mg bid (projection)
`400-mg qd (#004)
`200-mg qd (#004)
`25-mg qd (#004)
`
`Pharmacokinetic Projections of BID and QD Regimens
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`Plasma Concentration (nM)
`
`0
`
`0
`
`4
`
`8
`
`12
`Time (hr)
`400 mg is likely top daily dose (based on exposures and TK from SA studies)
`
`16
`
`20
`
`24
`
`Merck Exhibit 2111, Page 20
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Projections of Plasma DP-IV Inhibition with QD and BID Regimens
`
`200 BID
`
`400 QD
`
`200-mg bid (projection)
`100-mg bid (projection)
`400-mg qd (#004)
`200-mg qd (#004)
`25-mg qd (#004)
`
`0
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`Projected DP-IV Inhibition (%)
`
`Merck Exhibit 2111, Page 21
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Input from consultants
`
`a
`
`a
`
`a
`a
`
`Continued support for mechanism
`Proper selection of patients crucial to demonstrate efficacy
`,
`Upsides: effects on beta cells, use in prevention/halting
`,
`progression, potentially combinable with everything
`Efficacy with competitor DP-IV inhibitors modest
`Poor response with other DP-IV inhibitors when HbA1c > 8.5 to 9
`,
`Efforts of competitors may be slowed by modest efficacy and/or
`,
`safety issues
`*
`dose-limiting toxicities, inappropriate patient samples
`L-224715 safest DP-IV inhibitor
`Overall efficacy modest (similar to competitors)
`Efficacy good with HbA1c < 8.5: comparable to other insulin
`,
`secretagogues
`Incretins other than GLP-1 may be involved (e.g. GIP)
`
`,
`
`Merck Exhibit 2111, Page 22
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Input from consultants
`
`a
`
`a
`
`,
`
`Sustained inhibition (e.g. with BID dosing) may provide
`added efficacy
`Single-dose glucose response not likely to fully reflect
`potential efficacy:
`Time to maximal efficacy not known - could be days to
`,
`months
`chronic effects (e.g. on beta cells) not likely to be
`apparent for months
`Consultants
`Peter Butler, USC
`Dan Drucker, Univ. of Toronto
`Jens Holst, Univ. of Copenhagen
`Steve Kahn, Univ. of Washington
`Robert Rizza, Mayo Clinic
`Robert Sherwin, Yale Univ.
`
`,
`,
`,
`,
`,
`,
`
`Merck Exhibit 2111, Page 23
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Key issues for phase II
`
`a
`
`a
`a
`
`Need to examine BID and QD regimens
`PK/PD BID regimens may provide better efficacy versus QD
`,
`Per Marketing
`,
`*
`Efficacy (HbA1c reduction) is primary consideration
`*
`Convenience of QD also important
`Need to identify T2DM responder populations
`Need to evaluate combination efficacy
`e.g. monotherapy failure patients
`,
`
`Merck Exhibit 2111, Page 24
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Phase II plans: recommendations
`
`a
`
`Accelerated Phase II Program
`Initiate BID dose-range finding study to support dose
`,
`selection for phase III
`Determine responder population
`Assess efficacy of QD vs. BID
`
`,
`,
`
`a
`
`PLUS
`Phase I studies to support (Jan)
`200 mg BID x 28 days in middle-aged obese
`,
`volunteers
`
`Merck Exhibit 2111, Page 25
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Phase II timelines
`
`a
`
`Initiate phase II studies in 4/03
`Interim analysis to support Go-No Go decision to
`,
`Phase III in 4Q03
`Supports continued accelerated development
`program for L-224715 with earliest possible WMA
`filing date
`
`,
`
`Merck Exhibit 2111, Page 26
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`
`D R A F T M E M O
`TO:P. Kim; D. Greene; B. Gertz; K. Gottesdiener; P. Deutsch; J. Wagner; K.
`Kaufman; P. Stein; E. Stoner; R. Bain; L. Oppenheimer; J. Zhang
`
`CC: DP-IV PDT
`FROM: Peng-Liang Zhao, Gary Herman
`DATE: January 3, 2002
`SUBJECT:Preliminary Interim Analysis Results: Protocol 005- A Randomized,
`Multicenter, Placebo-Controlled 3-Period, Crossover Study to Assess the
`Glucose-Lowering Activity, Pharmacokinetics, and Safety and Tolerability
`of Single Oral Doses of L-000224715 (Dipeptidyl-peptidase-IV inhibitor) in
`Patients With Type 2 Diabetes
`
`EXECUTIVE SUMMARY
`
`1.
`2.
`
`3.
`
`4.
`
`5.
`
`Single doses of 25- and 200-mg of L-224715 were generally well tolerated.
`The 25-mg and 200-mg doses of L-224715 were associated with dose-dependent
`inhibition of plasma DP-IV activity. For the 200-mg dose, ~95% inhibition of plasma
`DP-IV activity was maintained through 12 hours, falling to approximately 78%
`inhibition at 24 hours. For the 25-mg dose, ~70-84% inhibition was maintained
`through 12 hours, falling to ~50% inhibition at 24 hours.
`Single dose administration of both 25 and 200-mg L-224715 resulted in significant
`reductions in incremental glucose AUC following an oral glucose tolerance test
`(OGTT): at 2 hours post-dose, the 200 mg dose resulted in a 31% reduction compared
`to placebo (p<0.001), and the 25 mg dose resulted in a 21% reduction compared to
`placebo (p<0.001). The 200 mg dose provided significantly greater reduction in the
`incremental glucose AUC compared to the 25 mg dose (p= 0.035) suggesting that
`optimal glucose lowering efficacy requires near maximal DP-IV inhibition.
`Statistically significant reductions in glucose were not observed following the
`administration of a standardized meal at 24 hours post-dose.
`The L-224715 plasma concentration-time profile and other pharmacokinetic
`parameters in the type 2 diabetics participating in this study were generally similar to
`that previously observed in healthy young male subjects.
`The 25- and 200-mg doses of L-224715 were both associated with approximately 2-
`fold increases in active GLP-1 levels following an OGTT at 2 hr post-dose and a
`standardized meal at 24 hours, as compared to placebo (p<0.001).
`
` 1
`
`Merck Exhibit 2111, Page 27
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`DRAFT
`
`6.
`
`A preliminary subgroup analysis assessing treatment responses in patients with
`varying degrees of baseline hyperglycemia was performed:
`Post-OGTT glucose lowering appears greater in patients with milder baseline
`hyperglycemia (e.g. baseline HbA1c less than 9%). The degree of glucose
`lowering in patients with milder baseline hyperglycemia is generally comparable
`to that reported with other insulin secretagogues.
`Stimulation of active GLP-1 and C-peptide (a marker of newly-secreted insulin)
`levels was greater in patients with milder baseline hyperglycemia as compared to
`more severely hyperglycemic patients.
`Note that the subgroup results are based on limited data and final more definitive
`conclusions should await the complete study results.
`
`BACKGROUND
`
`Protocol 005 is a randomized, multicenter, placebo-controlled, 3-period, crossover study
`to assess the glucose-lowering activity, pharmacokinetics, and safety and tolerability of
`single oral doses of L-224715 in patients with type 2 diabetes. The primary objective of
`this Phase IB study is to assess the effects of single doses of L-224715 on post-challenge
`glucose levels following the administration of an oral glucose tolerance test (OGTT) in
`patients with type 2 diabetes. The secondary objectives are (1) to assess the effects of
`single doses of L-224715 on post-challenge glucose levels following the administration
`of standardized meals; (2) to obtain preliminary plasma pharmacokinetic data in patients
`with type 2 diabetes; (3) to assess the effects over time of single doses of L-224715 on
`plasma dipeptidyl peptidase IV (DP-IV) activity in patients with type 2 diabetes; and (4)
`to assess the effects over time of single doses of L-224715 on active and total GLP-1
`levels.
`
`An additional exploratory objective addressed in this memo is to preliminarily assess the
`relationship between baseline HbA1c (i.e., pre-study) and the treatment-related effects of
`L-224715 on post-challenge glucose. To insure that patients with a broad spectrum of
`disease were studied, it was planned that at least half of the patients recruited into the
`study would have a baseline HbA1C that was greater than 7.5%.
`In this 3-period crossover study, patients were randomized to 1 of 6 treatment sequences
`where they received single oral doses of 25 mg L-224715 or 200 mg L-224715 or
`placebo in each of the three treatment periods, separated by at least a 7-day washout
`interval. Patients fasted for 10 hours prior to each period, had study drug administered
`and underwent an OGTT at 2 hours post-dose and standardized meal challenges (solid
`meal, ~ 550 kcal) at 6 and 24 hours post-dose. Plasma was sampled for glucose, L-
`224715 levels, plasma DP-IV activity, active and total GLP-1, insulin, C-peptide and
`glucagon (samples were also archived for GIP and other incretins).
`
`This document describes the interim analysis results of the first 18 patients completing
`the study (through November 25, 2002).
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`2
`
`Merck Exhibit 2111, Page 28
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`DRAFT
`
`STATISTICAL METHODS
`
`Post-OGTT and post-meal glucose AUC were analyzed in the log scale using an
`appropriate analysis of variance (ANOVA) model for a complete 3-period, crossover
`design. Back-transformed summary statistics, geometric mean ratio (GMR) over placebo
`(with each subject serving as his/her own control) with 95% confidence interval (CI), and
`p-values for the L-224715 doses versus placebo comparisons were provided. The
`weighted average inhibition (WAI) of plasma DP-IV activity (through 12 and 24 hours
`post-dose) from baseline was compared between L-224715 and placebo using the same
`ANOVA model. Similar analyses for the weighted average and peak active GLP-1 levels
`through 2 and 4 hours post-OGTT and following each meal challenge were also
`performed. The L-224715 pharmacokinetic parameters following single doses of L-
`224715 were summarized.
`
`RESULTS
`
`1.
`
`Demographic Summary
`
`This interim analysis included 18 patients. Of the 18 patients, 6 (33%) were women and
`12 (66.7%) were men. Ten patients were white and the other 8 patients were Hispanic.
`The age was between 37 and 55 years. Table 1 lists the summary statistics for other
`demographic information, baseline HbA1c, and baseline fasting glucose, C-peptide, and
`insulin levels. The baseline HbA1c and fasting glucose were the values at the screening
`visit. The baseline fasting C-peptide and insulin were the predose values in the first
`period. Twelve (66%) of the patients included in this analysis had a baseline HbA1c
`greater than 7.5%.
`
`Table 1
`Summary of Demographics
`
`Variable
`Gender
`Female
`Male
`Race
`Hispanic
`White
`Variable
`Age (year)
`Height (cm)
`Weight (kg)
`Body Mass Index (kg/m2)
`Baseline HbA1c (%)
`Baseline Fasting Glucose (mg/dL)
`Baseline Fasting C-peptide (ng/mL)
`Baseline Fasting Insulin (mcIU/mL)
`
`Frequency
`
`Percent (%)
`
` 6/ 18
`12/ 18
`
` 8/ 18
`10/ 18
`Mean
`47
`172.9
`87.9
`29.5
`8.3
`178.6
`2.9
`8.6
`
`SD
`4.9
`9.3
`13.5
`4.6
`1.3
`44.8
`1.1
`5.1
`
`N
`18
`18
`18
`18
`18
`18
`18
`18
`
`33.3
`66.7
`
`44.4
`55.6
`Range
`to
`37
`155.4 to
`64.2
`to
`22.0
`to
`6.9
`to
`115.0 to
`1.1
`to
`0.8
`to
`
`55
`188.0
`115.0
`39.7
`11.7
`264.0
`5.3
`17.5
`
`Median
`47
`171.0
`86.5
`29.5
`8.0
`159.0
`2.6
`8.0
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`3
`
`Merck Exhibit 2111, Page 29
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`DRAFT
`
`2.
`
`Glucose
`
`Figure 1
`Geometric Mean Glucose Over 26 Hours Postdose
`(Periods 1-3)
`
`0 1 2 3 4 5 6 7 8
`
`10 12 14 16 18 20 22 24 26
`Hour
`
`330
`320
`310
`300
`290
`280
`270
`260
`250
`240
`230
`220
`210
`200
`190
`180
`170
`160
`150
`
`Plasma Glucose (mg/dL)
`
` Placebo (n=18)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
`Back-transformed from the log scale for Mean ± SE
`
`The mean plasma glucose profile over 26-hours post-dose for the three treatment groups
`is shown in Figure 1. The oral glucose tolerance test (OGTT) was given at 2-hours post-
`dose. Standardized meals were given at 6 and 24-hours post-dose. The post-OGTT and
`post-meal glucose data are discussed below. Since glucose levels did not return to
`baseline following the OGTT (at the time the 6-hour meal was administered), and given
`the variability of the glucose measurements during the post-meal challenge period, the
`ability to assess change in glucose-AUC with treatment is very limited.
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`4
`
`Merck Exhibit 2111, Page 30
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`DRAFT
`
`Post-OGTT Glucose
`
`Figure 2
`Geometric Mean Glucose Over 6 Hours
`(OGTT at 2 Hours Post-dose)
`(Periods 1-3)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Hour
`
`330
`320
`310
`300
`290
`280
`270
`260
`250
`240
`230
`220
`210
`200
`190
`180
`170
`160
`150
`
`Plasma Glucose (mg/dL)
`
` Placebo (n=18)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
`Back-transformed from the log scale for Mean ± SE
`
`Mean glucose values prior to and following the OGTT (administered at 2-hours post-
`dose) are indicated in Figure 2 above. A statistical analysis using an ANOVA model for
`a crossover design was performed (using a within-subject comparison). Both total and
`incremental glucose AUC were analyzed over the 4-hour interval following the OGTT
`(similar results were also obtained over a 2-hour interval). The incremental glucose AUC
`measures the glucose excursion over the baseline pre-challenge glucose level following
`the OGTT and is thus useful to assess the treatment-related reduction in glucose
`excursion. Both the 25- and 200-mg doses of L-224715 were associated with significant
`reductions in both total and incremental glucose AUC as compared to placebo (p 0.006
`for the 25 mg dose; p<0.001 for the 200 mg dose). For total glucose AUC, the GMR
`over placebo was 0.92 (95% CI, 0.87 to 0.98) for the 25 mg dose and 0.88 (95% CI, 0.83
`to 0.93) for the 200 mg dose. For incremental glucose AUC, the GMR over placebo was
`0.79 (95% CI, 0.69 to 0.90) for the 25 mg dose and 0.69 (95% CI, 0.60 to 0.78) for the
`200 mg dose.
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`5
`
`Merck Exhibit 2111, Page 31
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`DRAFT
`
`The reduction in glucose excursion associated with the 25 mg dose (21% based on the
`GMR) was significantly lower than that associated with the 200 mg dose (31%)
`[p=0.035]. Based upon predictions from pre-clinical rodent data, it had been expected
`that > 70-80% DP-IV inhibition would be associated with maximal glucose-lowering. In
`contrast, these preliminary results (see also Figure 5 below) suggest that for optimal post-
`challenge glucose lowering, higher DP-IV inhibition is required.
`
`Post-meal Glucose
`
`Figure 3
`Geometric Mean Glucose From 24 to 26 Hours
`(Meal at 24 Hours Postdose)
`(Periods 1-3)
`
`23
`
`24
`
`25
`Hour
`
`26
`
`27
`
`260
`250
`240
`230
`220
`210
`200
`190
`180
`170
`
`Plasma Glucose (mg/dL)
`
` Placebo (n=18)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
`Back-transformed from the log scale for Mean ± SE
`
`Mean glucose values prior to and following the administration of a standardized meal at
`24 hours post-dose are indicated in Figure 3 above. A similar statistical analysis was
`conducted as was performed for the post-OGTT glucose values. Both the 25- and 200-mg
`doses of L-224715 showed a small numerical (but not statistically significant) reduction
`in the total and incremental glucose AUC as compared to placebo. The GMR over
`placebo for total glucose AUC was 0.96 (95% CI, 0.91 to 1.01) for the 25 mg dose and
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`6
`
`Merck Exhibit 2111, Page 32
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`DRAFT
`
`0.97 (95% CI, 0.92 to 1.02) for the 200 mg dose. For incremental glucose AUC, the
`GMR over placebo was 0.83 (95% CI, 0.59 to 1.17) for both the 25 and 200 mg doses.
`For both doses, plasma L-224715 levels were relatively low (less than 100 nM at trough,
`see Figure 4 and Table 2 below), and the responses in glucose lowering may be indicative
`of inadequate DP-IV inhibition at trough. The trough (24-hr) DP-IV inhibition for the
`200 mg dose was similar to the 2-hr DP-IV inhibition achieved with the 25-mg dosea
`level of DP-IV inhibition shown during the OGTT challenge to not provide the full
`glucose-lowering efficacy possible with this mechanism. In addition, the incremental
`glucose-AUC was highly variable, possibly due to two large outliers. In light of this
`variability, and the small number of patients analyzed, the post-meal results at 24 hours
`should be interpreted with caution.
`
`Due to the observed variability of the meal challenge, the protocol was amended to
`change the meal challenge at 24 hours to an OGTT. The last 20 patients completing the
`study will receive an OGTT at 2 and 24 hours post-dose, which should provide a clearer
`signal for treatment-related reduction in glucose excursion at trough. These results will
`be available as part of the final study analysis.
`
`3.
`
`Pharmacokinetics of L-224715
`
`Following each dose of 25- and 200-mg L-224715, a limited plasma sampling scheme for
`24 hours post-dose was used for characterization of the pharmacokinetics of L-224715 in
`diabetic patients. In a subset of patients, samples were collected up to 72-hours for a
`more complete determination of the apparent elimination kinetics of L-224715. The
`available plasma pharmacokinetic data in this study included the results from 23 patients
`for the 25-mg dose and 27 patients for the 200-mg dose. Only two patients for each dose
`underwent the extended 72-hr sampling scheme (but additional patients will be available
`as part of the final analysis memo).
`
`The mean plasma concentration profiles for the 25-mg and 200-mg doses are shown in
`Figure 4. The mean pharmacokinetic parameters are listed in Table 2.
`
`The mean plasma concentration time profile and pharmacokinetic parameters in diabetic
`patients enrolled in this study were generally similar to that observed in healthy young
`male subjects (PN 001). One possible exception was the apparent terminal elimination
`half-life in the diabetic patients which was calculated to be 5.9 hours following the 200-
`mg dose, notably lower than that observed in healthy male volunteers. However, this
`preliminary observation may be an artifact due to the limited sampling scheme available
`for most of the patients included in this analysis. A more definitive assessment will await
`the analysis of samples from patients undergoing the extended sampling scheme.
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`7
`
`Merck Exhibit 2111, Page 33
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Figure 4
`Mean (± SE) Plasma Concentrations of L-224715
`
`0 1 2
`
`4
`
`6
`
`8
`
`10 12 14 16 18 20 22 24
`Hour
`
`DRAFT
`
`1800
`1600
`1400
`1200
`1000
`800
`600
`400
`200
`0
`
`Plasma Concentration (nM)
`
` L-224715 25 mg (n= 23)
` L-224715 200 mg (n= 27)
`
`Table 2
`Summary Statistics for Pharmacokinetics of L-224715
`
`25 mg
`(N=23)
`1802* (399§)
`123* (33§)
`3.6 (1.4)
`8.9* (1.9¶)
`26.1 (15.0)
`
`AUC(0-inf) (nM* hr)
`Cmax (nM)
`Tmax (hour)
`t1/2 (hour)
`C24 hr (nM)
`* SD = Standard Deviation.
`* Geometric Mean. §Standard Deviation back-transformed from log scale.
`* Harmonic Mean. ¶Standard Deviation from Jackknife.
`
`Mean (SD* )
`
`200 mg
`(N=27)
`14376* (3262§)
`1887* (633§)
`2.3 (1.3)
`5.9* (1.2¶)
`96.5 (40.4)
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`8
`
`Merck Exhibit 2111, Page 34
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`DRAFT
`
`4.
`
`Plasma DP-IV Activity
`Figure 5
`Plasma DP-IV Inhibition
`Percent Inhibition From Baseline
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`-10
`
` From Baseline
`Percent Inhibition
`
`
`
`
`0 1 2
`
`4
`
`6
`
`8
`
`10 12 14 16 18 20 22 24
`Hour
`
` Placebo (n=18)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
` Back-transformed from the log scale
`
`The profile of mean inhibition of plasma DP-IV activity from baseline for the three
`treatment groups is shown in Figure 5 above. The 25-mg dose was associated with
`approximately 70 to 84% inhibition through 12 hours falling to approximately 50%
`inhibition at 24 hours post-dose. The 200-mg dose was associated with approximately
`95% inhibition (or higher) through 12 hours falling to approximately 78% inhibition at
`24 hours post-dose.
`
`The weighted average inhibition (WAI) of plasma DP-IV activity (through 12 and 24
`hours) from baseline following 25- and 200-mg L-224715 was significantly higher than
`that with the placebo (p<0.001 for both doses). The WAI of DP-IV activity through 24
`hours was 68.2% (95% CI, 57.7 to 78.8%) for the 25 mg dose and 90.4% (95% CI, 79.9
`to 100.9%) for the 200 mg dose.
`
`The WAI of plasma DP-IV activity (through 12 and 24 hours) with the 200 mg dose was
`
`L-000224715 Protocol 005 DRAFT Interim Analysis Memo
`9
`
`Merck Exhibit 2111, Page 35
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`5.
`
`Active GLP-1
`
`Figure 6
`Geometric Mean Active GLP-1 Levels Over 26 Hours Post-dose
`(Periods 1-3)
`
`0 1 2 3 4 5 6 7 8
`
`10 12 14 16 18 20 22 24 26
`Hour
`
`18
`17
`16
`15
`14
`13
`12
`11
`10
`
`23456789
`
`Active GLP-1 (pM)
`
` Placebo (n=17)
` L-224715 25 mg (n=17)
` L-224715 200 mg (n=17)
`
`The mean plasma active GLP-1 profile over 26 hours post-dose for the three treatment
`groups is shown in Figure 6 above. The post-OGTT and post-meal active GLP-1 data are
`discussed below.
`
`
`
`10
`
`Merck Exhibit 2111, Page 36
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Post-OGTT Active GLP-1
`
`Figure 7
`Geometric Mean Active GLP-1 Over 6 Hours
`(OGTT at 2 Hours Postdose)
`(Periods 1-3)
`
`18
`17
`16
`15
`14
`13
`12
`11
`10
`
`23456789
`
`Active GLP-1 (pM)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`Hou