Merck Exhibit 2158, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`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 study
`36-48 type 2 diabetics,
`21-60 years
`HbA1c 6.5 to 11.0%, FPG 126 to 250 mg/dL
`andomized to sequence of treatments
`Placebo
`25 mg
`200 mg
`Fasted o/n, study drug at t=0, OGTT at 2 hrs (~Tmax), meals at
`6, 24 hr postdose
`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
`
`*R
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Merck Exhibit 2158, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Mean Plasma Concentrations of L-000224715 in Type 2
`Diabetics
`
`200-mg (Young Males #001; N=6)
`200-mg (Diabetics #005; N=27)
`
`Trough
`~97nM in
`diabetics
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`0
`
`L-000224715 Plasma Concentration (nM)
`
`Merck Exhibit 2158, Page 3
`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)
`Plasma DP-IV Inhibition
`Percent Inhibition From Baseline
`
`Trough DP-IV
`Inhibition
`
`~80%
`
`~55%
`
`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 2158, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`PK/Plasma DP-IV for 25, 200 mg at Peak and
`Trough
`
`Dose
`
`C2hr
`[715]
`
`25 mg
`
`127 nM
`
`C2hr
`% DP-IV
`inhibition
`~80%
`
`C24
`[715]
`
`26 nM
`
`C24
`% DP-IV
`inhibition
`~55%
`
`200 mg
`
`1930 nM ~95%
`
`97 nM
`
`~80%
`
`Prediction: 200 mg at trough would generate similar or slightly lower
`active GLP-1 augmentation & glucose lowering as 25 mg at peak
`
`Merck Exhibit 2158, Page 5
`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)
`Log-transformed-geometric mean
`
`Merck Exhibit 2158, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`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)
`Log-transformed-geometric mean
`
`Merck Exhibit 2158, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Glucose Profile Following Single Oral Doses of
`L-000224715
`Figure X
`Plasma Glucose (mg/dL)
`
`Meal
`
`Meal
`
`330
`320
`310
`300
`290
`280
`270
`260
`250
`240
`230
`220
`210
`200
`190
`180
`170
`160
`150
`140
`
`Plasma Glucose (mg/dL)
`
`0 1 2 3 4 5 6 7 8 9 10 1112 1314 15 16 171819 20 2122 2324 25 26
`OGTT
`Hour
` Placebo (n=15)
` L-224715 25 mg (n=15)
` L-224715 200 mg (n=15)
`Back-transformed from the log scale for Mean ± SE
`
`Merck Exhibit 2158, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Post-OGTT Glucose Lowering Following Single
`Doses of L-000224715
`
`Post-OGTT Glucose Incremental AUC
`
`Group GMR* 95% CI p-value
`
`25mg
`vs. pbo 0.81
`
`200mg
`vs. pbo 0.68
`
`(.70,.94) 0.008
`
`(.59,.79) <0.001
`
`200mg
`vs 25mg 0.84
`
`(.72, 98) 0.024
`
`4
`
`5
`
`6
`
`Hour
`
`0
`
`1
`
`2
`
`3
`
`340
`
`300
`
`260
`
`220
`
`180
`
`140
`
`Plasma Glucose (mg/dL)
`
` Placebo (n=15)
` L-224715 25 mg (n=15)
` L-224715 200 mg (n=15)
`Back-transformed from the log scale for Mean ± SE
`* Geometric mean ratio based on least square mean (within-subject)
`(AUC over 240 min)
`
`Merck Exhibit 2158, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Plasma Glucose Following OGTT at 2 hr &
`Solid Meal at 6 hr Post-dose
`
`Post-Meal Glucose AUC*
`25 mg- 0.94
`(.88, 1.0)
`200mg- 0.93
`(.87, .99)
`
`Post-Meal Incr Glucose AUC*
`25 mg- 0.48
`(.18, 1.3)
`200 mg- 0.89
`(.31, 2.5)
`
`Meal
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`Hour
`
`6
`
`7
`
`8
`
`9
`
`10
`
`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)
`*GMR active/placebo (95% CI)
` L-224715 200 mg (n=18)
`Back-transformed from the log scale for Mean ± SE
`
`Merck Exhibit 2158, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Plasma Glucose Following Solid Meal at 24 hr
`Post-dose
`
`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)
`
`260
`250
`240
`230
`220
`210
`200
`190
`180
`170
`
`Plasma Glucose (mg/dL)
`
`23
`
`24
`
`26
`
`27
`
`25
`Hour
` Placebo (n=18)
`*GMR active/placebo (95% CI)
` L-224715 25 mg (n=18)
` L-224715 200 mg (n=18)
`Back-transformed from the log scale for Mean ± SE
`
`Merck Exhibit 2158, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Sub-Group Analysis: L-000224715
`Demonstrates Greater Post-OGTT Glucose
`Lowering in Mild Patients
`
`Parameter
`(post-challenge
`glucose AUC)
`2 hr OGTT
`Inc. AUC
`(over 4 hr)
`24 hr meal
`Inc. AUC
`(over 2 hr)
`
`Dose
`(mg)
`
`All*
`n=18
`
`HbA1C < 7.5*
`n=6
`
`HbA1C 7.5*
`n=12
`
`25
`200
`
`25
`200
`
`0.79 (.69,.90)
`0.69 (.60,.78)
`
`0.66 (.54,.81)
`0.55 (.45,.67)
`
`0.86 (.75,1.00)
`0.77 (.66,.89)
`
`0.83 (.60,1.17)
`0.83 (.59,1.16)
`
`0.74 (.41, 1.35)
`0.74 (.40,1.34)
`
`0.88 (.58,1.35)
`0.88 (.57,1.34)
`
`* GMR active over placebo (95% CI)
`
`Merck Exhibit 2158, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Baseline HbA1C versus Post-OGTT Incremental
`Glucose Lowering
`
`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)
`Post-OGTT Incremental Glucose AUC (over 4 hr) GMR: active/placebo
`
`Merck Exhibit 2158, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`L-000224715 Suppresses Plasma Glucagon
`Levels Following an OGTT
`
`Post-OGTT Glucagon AUC GMR
` (active/placebo over 2 hr)
`
`25 mg: 0.90 (p = 0.140)
`200 mg: 0.81 (p= 0.002)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Hour
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`Plasma Glucagon (pg/mL)
`
` 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 2158, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`L-000224715 Slightly Increases
`C-Peptide Levels Following an OGTT
`
`Post-OGTT C-Peptide AUC GMR
` (active/placebo over 2 hr)
`
`25 mg: 1.09 (p = 0.151)
`200 mg: 1.14 (p= 0.034)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Hour
`
`23456789
`
`Plasma C-Peptide (ng/mL)
`
` 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 2158, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
` Issues- IB Study
`Difference in OGTT glucose-lowering with 25- and
`200-mg & modest effects on meal-glucose
`Suggests > 80% DP-IV inhibition required for maximal
`efficacy
`Would sustained and maximal (e.g. with BID dosing)
`DP-IV inhibition provide better control?
`Will overnight DP-IV inhibition lower fasting plasma glucose?
`Will there be greater safety issues with sustained DP-IV
`inhibition?
`Glucose-lowering appears greater in milder patients
`More responders with HbA1C < 8.5-9.0
`ifference in Post-OGTT Glucose Lowering Does Not
`Appear to Correlate With Stabilization of Active GLP-
`1
`
`*D
`
`Other incretins may be important in mediating effects
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Merck Exhibit 2158, Page 16
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Pharmacokinetic Projections of BID and
`QD Regimens
`
`200-mg bid
`100-mg bid
`400-mg qd
`200-mg qd
`25-mg qd
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`6000
`
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`0
`
`0
`
`Plasma Concentration (nM)
`
`Merck Exhibit 2158, Page 17
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Projections of Plasma DP-IV Inhibition with QD
`and BID Regimens
`
`200-mg bid
`100-mg bid
`400-mg qd
`200-mg qd
`25-mg qd
`
`0
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`Projected DP-IV Inhibition (%)
`
`Merck Exhibit 2158, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
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