Chemistry Reference
In-Depth Information
The potential for formulation-related challenges with saxagliptin also spur-
red the application of a unique formulation strategy which may ultimately
translate into a significant advantage for the development of future single-tablet
saxagliptin drug combinations. It was discovered that in the process of com-
pressing the saxagliptin API salt together with excipients to develop a standard
tablet formulation, unacceptably high levels (2%) of the undesired cyclization
products were produced. A pharmaceutics solution to the problem, made
possible by the low dose (2.5-10mg) of saxagliptin required to effect maximal
HbA1c lowering in humans, was realized by spray coating the drug substance
(sandwiched between two polymeric vapor barrier layers) onto an inert tablet
core. This formulation is currently used in the marketed brand of saxagliptin,
Onglyza
t
. It is anticipated that the spray coating technique, a procedurally
simple technology, will greatly facilitate the development of future fixed-dose
combinations of saxagliptin with other OADs.
55
As proof, saxagliptin has been
readily formulated with extended-release metformin, leading to the most
clinically advanced once-daily DPP4/metformin single-tablet combination.
This innovative combination was submitted for FDA regulatory review in
December 2009.
1.10 In vivo Ecacy of Saxagliptin
As SAR within the series developed, a simple ex vivo plasma DPP4 inhibition
assay was used to eciently differentiate among the growing number of potent
compounds. To further understand particularly promising compounds, a
clinically relevant pharmacodynamic assay (an oGTT in Zucker
fa/fa
rats or ob/
ob mice) was also utilized. These models served as an ecient means to phe-
notypically stratify compounds without the need for prior, time-consuming PK
assessments, thereby reducing cycle times. In these models, saxagliptin afforded
quite robust effects on glucose excursion and insulin release at doses as low as
0.3-1 mmol kg
1
.
6
However, preclinical demonstration of reduced fasting
plasma glucose and/or HbA1c in subacute or chronic disease models proved to
be elusive. In-house experience gained in earlier discovery programs targeting
PPARa agonists led the team to evaluate the chronic dosing of saxagliptin in a
variety of genetic models of type-2 diabetes, such as in ZDF and Zucker
fa/fa
rats. Despite numerous attempts to optimize these models, the group was
unable to demonstrate statistically significant, dose-dependent ecacy (fasting
plasma glucose lowering), irrespective of the model or dosing duration. Despite
this lack of validation in pre-clinical disease models, timely disclosures of
clinical data by Novartis helped to bolster internal confidence in the mechan-
ism. Novartis scientists had recently reported promising reductions in HbA1c
for DPP-728 (12) in a 12-week Phase IIa trial in diabetic subjects.
56
Based on
our belief that saxagliptin exhibited superior potency and pharmacokinetic
profiles compared to DPP-728, the decision was made to forego further efforts
to develop chronic in vivo ecacy models and to move forward into clinical
development. Despite more than 10 years of pre-clinical testing of DPP4
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