`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`$upplement
`
`
`
`N
`
`413-P
`
`Single Dose Treatment of Diabetic Patients by the DP IV Inhibitor
`P32/98
`HANS-U. DEMUTH, TORSTEN HOFFMANN, KONRAD
`GLUND, CHRISTOPHER H. S. MCINTOSH, RAYMOND A. PED-
`ERSON, KATJA FUECKER, SABINE FISCHER, MARKOLF
`HANEFELD,HaIIe (Saale), Germany,‘ Vancouver; Canada; Dresden,
`Germany
`The DP IV inhibitor Di-[3N-((2S,3S)-2-amino-3-methyl-pentanoyl) 1,3-
`thiazolidine] fumarate (P32/98) improves glucose tolerance (Gt) by an
`incretin-mediated enhanced insulin response in normal and diabetic
`rodents, as well as in human volunteers. Within the clinical program, a
`pilot study in diabetic patients on different therapies was designed. Goal of
`the open investigation was the evaluation of patients response to a single
`dose of 60 mg P32/98 15 min prior to an OGTT (75 g) after over-night
`fasting and 12 hour post-medication (diet, acarbose, metformin, gliben-
`clamide or insulin). Patients (n=20, men) were ‘allocated according to there
`current medication to 5 groups, each receiving placebo and OGTT at the
`beginning of the experiment. Seven days later, again after over-night fast-
`ing and 12 hours post-medication, 15 min prior OGTT one tablet contain-
`ing 60'mg P32/98 was administered. Glucose response was recorded every
`15 min in an interval of -15 to 300 min. Blood samples were taken to all
`that time points for determination of P32/98, glucose, insulin, proinsulin,
`C-peptide, GLP-l, glucagon, FFA and leptin. As expected, a profound Gt
`improvement caused by P32/98 was observed in patients being treated
`with acarbose or glibenclamide. In these cases the glucose tolerance
`improvement was 20.6% and 31.3%, respectively. These values parallel
`the elevated insulin responses observed after P32/98 treatment in these
`patients. In contrast, in diabetics on insulin therapy, the acute Gt improve-
`>ment afier a single dose of P32/98 was 8.8% only (assessed by area under
`the Gt curve). Whether insulin resistance can be reduced or islet respon-
`siveness will improve, mediated by DP IV inhibition, remains to be proven
`by longer term application of P32/98 in such patients.
`
`A numeral beside an author's name indicates a duality of interest. See page 93.
`
`Page 2 of 3
`
`A102
`
`~
`
`Merck Exhibit 2112, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`413-P
`Single Dose Treatment of Diabetic Patients by the DP IV Inhibitor
`P32/98
`HANS-U. DEMUTH, TORSTEN HOFFMANN, KONRAD
`GLUND, CHRISTOPHER H. S. MCINTOSH, RAYMOND A. PED-
`ERSON, KATJA FUECKER, SABINE FISCHER, MARKOLF
`HANEFELD,HaIIe (Saale), Germany,‘ Vancouver; Canada; Dresden,
`Germany
`The DP IV inhibitor Di-[3N-((2S,3S)-2-amino-3-methyl-pentanoyl) 1,3-
`thiazolidine] fumarate (P32/98) improves glucose tolerance (Gt) by an
`incretin-mediated enhanced insulin response in normal and diabetic
`rodents, as well as in human volunteers. Within the clinical program, a
`pilot study in diabetic patients on different therapies was designed. Goal of
`the open investigation was the evaluation of patients response to a single
`dose of 60 mg P32/98 15 min prior to an OGTT (75 g) after over-night
`fasting and 12 hour post-medication (diet, acarbose, metformin, gliben-
`clamide or insulin). Patients (n=20, men) were ‘allocated according to there
`current medication to 5 groups, each receiving placebo and OGTT at the
`beginning of the experiment. Seven days later, again after over-night fast-
`ing and 12 hours post-medication, 15 min prior OGTT one tablet contain-
`ing 60'mg P32/98 was administered. Glucose response was recorded every
`15 min in an interval of -15 to 300 min. Blood samples were taken to all
`that time points for determination of P32/98, glucose, insulin, proinsulin,
`C-peptide, GLP-l, glucagon, FFA and leptin. As expected, a profound Gt
`improvement caused by P32/98 was observed in patients being treated
`with acarbose or glibenclamide. In these cases the glucose tolerance
`improvement was 20.6% and 31.3%, respectively. These values parallel
`the elevated insulin responses observed after P32/98 treatment in these
`patients. In contrast, in diabetics on insulin therapy, the acute Gt improve-
`>ment afier a single dose of P32/98 was 8.8% only (assessed by area under
`the Gt curve)‘ Whether insulin resistance can be reduced or islet respon-
`siveness will improve, mediated by DP IV inhibition, remains to be proven
`by longer term application of P32/98 in such patients.
`
`Page 3 of 3
`
`Merck Exhibit 2112, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
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