KRP-104, a uniquely prandial-targeted DPP4 inhibitor (EASD 2012) - Jul 5, 2012 - Publication-only abstract: P2, N=403; NCT00525330, NCT00995345; P1b KRP vs Sita. Group1: KRP at 80mg twice daily produced Con-inh of ~90-95% and glycemic efficacy similar to sita at =>80% Con-inh assessed by fasting plasma glucose (FPG), 7 point glucose (G), or Con G monitoring; No increase in glycemic effect was seen with higher inh; Group2: Prand-only inhibition by KRP (70mg) achieved comparable glycemic efficacy to sita; P2a Diurnal Profile Assessment: KRP 120mg once daily (prand-inh); 60mg twice daily (=>80% Con-inh).
P2 data • Diabetes
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48th EASD Annual Meeting, 1-5 Oct 2012
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Abstract: Background and aims: Dipeptidyl peptidase4 inhibitors (DPP4i) used to treat hyperglycemia exhibit differential potency depending on incretin release stimulated by glucose intake. Unlike currently available DPP4i that are continuous inhibitors of DPP4 due to their PK/PD profiles, in Phase (P)1, KRP-104 (KRP) had a PK/PD profile with a unique dose by duration response enabling either continuous or daytime, i.e. prandial-specific, DPP4 inhibition depending on dose. The aim of the KRP P1-P2 clinical development program was to test and compare the glycemic effects of these contrasting inh profiles.
Materials and methods: Glycemic efficacy of continuous (Con) vs prandial (prand) only DPP4 inh was assessed in 3 studies in type 2 diabetics. P1b: 2-period open-label, balanced cross-over, 7days/period, KRP vs 100mg daily sitagliptin (sita), 14 pts/group. Group 1, KRP 80mg twice daily; Group 2, KRP 70mg daily (60mg in AM, 10mg with dinner). P2a: 12 week (wk) randomized (R), double-blind (DB), KRP 120mg once daily, 60mg twice daily, or placebo (PBO)(1:1:1) on stable metformin, n=213. P2b: 24 wk R, DB, KRP 20/120mg (dose up titrated at wk 12), 40mg, 80mg, 100mg or PBO once daily (1:1:1:1:1) on stable metformin, n=403.
Results: P1b KRP vs Sita. Group1: KRP at 80mg twice daily produced Con-inh of ~90-95% and glycemic efficacy similar to sita at =>80% Con-inh assessed by fasting plasma glucose (FPG), 7 point glucose (G), or Con G monitoring. No increase in glycemic effect was seen with higher inh (Table). Group2: Prand-only inhibition by KRP (70mg) achieved comparable glycemic efficacy to sita (Table). P2a Diurnal Profile Assessment: KRP 120mg once daily (prand-inh); 60mg twice daily (=>80% Con-inh). After 12 wks, there was a statistically significant change from baseline compared to PBO for both KRP groups for HbA1c and FPG, but no significant difference between KRP groups (Table). Safety parameters were comparable among all 3 groups. P2b Dose Finding. As predicted by PK/PD modeling, after 12 and 24 wks treatment, 80mg was the lowest dose that achieved the maximum HbA1c reduction (LS mean, LOCF, -0.7% 24 wk) (Table).
Conclusion: In all 3 studies, KRP was well tolerated with a safety profile similar to controls. KRP demonstrated similar glycemic efficacy when dosed to inhibit DPP4 continuously or only during prandial hrs, and had comparable efficacy to sita even when dosed for only prand-inh or at higher levels of Con-inh. Thus, clinical studies with KRP demonstrated that the clinically meaningful glycemic benefit of DPP4i is mediated primarily during the prandial hours and inh =>80% is sufficient for maximal effect. Thus the KRP development dose of 80 mg once daily provides a diurnal on/off inh cycle; inh DPP4 during daytime for maximal glycemic control but releases DPP4 for other functions at night (when the impact on glycemic efficacy was negligible) to potentially boost chronic safety.
KRP-104 Diurnal Effects on Glycemic Response
P1b: KRP-104 vs Sitagliptin
Group 1: 7-point Mean Daily Glucose (mg/dL)
Test: 90-95 vs >80% Con Inh
-26.8
3.9 (p=0.5730)
Group 2: FPG (mg/dL)
Test: Con-Inh vs Prand-Inh
-11.7
0.1 (p=0.9797)
P2a: KRP-104 120mg Once Daily (Prand-Inh) vs 60mg Twice Daily (Con-Inh)
HbA1c (%)
n
LS Mean Change vs Placebo2
FPG (mg/dL)
n
LS Mean Change vs Placebo2
P2b: KRP-104 20/120, 40, 80, 100mg Once Daily (Prand-Inh, Dose Finding)
100mg
HbA1c (%)
n
79
79
LS Mean Change vs Placebo3
-0.61
(p
-0.64
(p
1. LS=least squares; From linear model to analyze crossover data 2. Adjusted for baseline HbA1c
3. Adjusted for screening metformin use and baseline HbA1c 4. 20 mg for 12 wks followed by 120 mg for 12 wks
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