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post-prandial antihyperglycemic effects to a registrational Phase IIb clinical trial
would require more detailed dose-ranging efforts early on. Because the majority
of the preclinical ecacy data generated for saxagliptin was in an acute setting,
accurately projecting an ecacious human clinical dose was somewhat chal-
lenging. Saxagliptin was very well tolerated in Phase I/II single and multiple
ascending dose studies ranging up to 100mg and exhibited 24 h maximal inhi-
bition of plasma DPP4 activity at steady state, beginning with the 5mg dose.
Additional higher dose panels (up to 600mg) were added at a later date to
examine the possibility of achieving greater e
cacy. As the top marketed dose of
saxagliptin is only 5 mg once-daily, the high doses tested in the Phase I clinical
program provided the development team with a deeper understanding of and
confidence in the compound's safety margin. Dose ranging proof-of-concept
studies with saxagliptin followed a standard randomized, double-blind, placebo-
controlled Phase IIb protocol in drug naı
¨
ve type-2 diabetic patients measuring
HbA1c reductions.
66
Five doses of saxagliptin were studied (2.5, 5, 10, 20, and
40mg, q.d.) and compared with placebo in an active 12-week treatment period.
All doses of saxagliptin significantly lowered HbA1c from baseline (mean
baseline HbA1c 7.9%) compared with placebo, and placebo-subtracted adjusted
mean changes from baseline ranged from
0.45 to
0.63%, with no apparent
statistically significant dose-relationship in this study. These results supported
saxagliptin's advancement to Phase III, where additional ecacy and safety
data were generated in 43000 drug-treated patients to support the registra-
tional package.
67
In January of 2007, BMS entered into a co-development and
co-marketing agreement with Astra-Zeneca encompassing saxagliptin and the
SGLT2 inhibitor dapagliflozin, as well as the back-ups for each. This partner-
ship was established in order to share in the late-stage development costs/risks
and to broaden the sales and marketing capacity required to effectively reach the
target clinical population, generally served by primary care physicians. Ulti-
mately, the BMS/Astra-Zeneca collaboration was successful in obtaining reg-
ulatory approval from both the FDA (July 2009) and the EMEA (October 2009)
for the use of saxagliptin, either as monotherapy or in combination with met-
formin,
68,69
sulfonylureas,
70
or TZDs, in the treatment of type-2 diabetes. The
retrospective CV safety package generated to support the filing indicated an
acceptable CV safety risk in the patient population studied, though further
prospective post-marketing studies will be conducted in other patient popula-
tions to more comprehensively assess the impact of chronic saxagliptin treat-
ment on CV outcomes. Interestingly, trends towards reduced events in this
analysis have prompted BMS and Astra-Zeneca to initiate larger, more exten-
sive CV safety trials, with the hope of demonstrating a statistically significant
and meaningful reduction in CV morbidity and mortality in diabetic patients.
1.14 Summary
In the late 1960's, the pioneering team of Miguel Ondetti and David Cushman
gave birth to the concept of rational drug design with the invention of
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