Discovery of Pyridorin™
Mesangial expansion and capillary basal lamina thickening are the characteristic
lesions of glomerular damage caused by diabetes, and are the hallmark
of diabetic kidney disease (nephropathy). The glomerular basal lamina
thickening that develops in diabetic patients
is due in part to the formation of advanced glycation
end-products (A.G.E.s) in both circulating serum proteins
and vascular basal lamina proteins. A.G.E.s are caused
by non-enzymatic glycation and ensuing glycoxidative chemical reactions
that arise in the diabetic patient due
to chronically high blood glucose concentrations. The deleterious effects
of A.G.E.s are believed to be a major causative factor in glomerular basal
lamina thickening and the resulting break-down of the kidney's filtration
barrier, which leads to proteinuria and ultimately kidney failure.
Mechanistic studies of A.G.E. formation conducted by BioStratum scientists
led to the isolation of a stable
protein intermediate from the cascade of non-enzymatic reactions that
produce A.G.E.s. This product, termed the post-Amadori intermediate, was
subsequently used in a screening system to identify drug candidates that
specifically inhibit the conversion of Amadori intermediates to A.G.E.s.
The Company believes that most A.G.E.s
that form in vivo do so via the Amadori intermediate pathway, and thus,
this screening procedure potentially provides for a dramatic improvement
over previously used approaches to identify A.G.E. inhibitors. This screening
system has identified pyridoxamine (Pyridorin™) as a potent post-Amadori
inhibitor of A.G.E. formation.
We have evaluated Pyridorin™ in several animal models
of diabetic kidney disease, a disease for which there are,
to our knowledge, very few drugs available or under development. The two
commonly studied parameters
of kidney disease are, albuminuria and plasma creatinine,
as well as glomerular histopathology. In a streptozotocin (STZ) induced
animal model of diabetes, Pyridorin™ inhibited the development of albuminuria
compared to untreated diabetic animals (P=0.0001). It also inhibited the
elevation of plasma creatinine levels compared to untreated animals (P=0.0001).
Pyridorin™ exhibited a significant therapeutic improvement over aminoguanidine,
a well studied AGE inhibitor, in both of these indicators of diabetic
kidney disease. Pyridorin™ also reduced the plasma levels of triglycerides
and cholesterol in the diabetic animals, another indication of improved
performance over aminoguanidine.
The Company believes the specific post-Amadori mechanism of action exhibited
by Pyridorin™ is in large measure responsible for the improved performance
of this drug candidate over aminoguanidine. The Company also believes
that a successful therapeutic approach to preventing the development of
diabetic kidney disease
or its progression must have minimal side effects,
because this therapy will likely require daily dosing
for many years. Pyridorin™ exhibits a very favorable
preclinical toxicity profile, and exhibited no severe
adverse effects in Phase I trials.
The Company believes Pyridorin™ might also prove effective against other
complications of diabetes including retinopathy (eye disease) and neuropathy
(nerve disease). We plan additional animal studies to examine the efficacy
of Pyridorin™ against these diabetic complications.
Phase I clinical trials on Pyridorin™ are completed. Single and multi-dose
administration of Pyridorin™ at escalating doses, which in some cases
were well above the anticipated therapeutic dose, showed that Pyridorin™
is well tolerated. No serious adverse events were reported.
Phase II clinical trials are ongoing to evaluate the efficacy
of Pyridorin™ in inhibiting the progression of albuminuria in patients
with early stage diabetic kidney disease. The trials are also monitoring
plasma triglyceride and cholesterol levels and several other parameters
relevant to diabetes
and kidney function.
We are currently developing protocols for Phase III
trials in collaboration with a team of clinical experts in diabetic kidney
disease. The Company is seeking to establish a trial endpoint that will
enable Pyridorin™ to be evaluated in diabetic patients who have early
stage kidney disease, where the Company believes the prospects for demonstrating
an efficacious treatment are the greatest, and where the largest number
of patients will benefit from Pyridorin™'s potential efficacy in significantly
retarding the development of diabetic kidney disease.
There are approximately 1 million individuals in the United States with
Type 1 diabetes, and an estimated 15 million with Type 2 diabetes. Up
to 40% of patients with Type 1 diabetes and 15% of patients with Type
2 diabetes will develop diabetic kidney disease over the course of their
lives. We expect that Pyridorin™ will be administrated daily at an estimated
annual drug cost of approximately $1,200 per patient.
The size of the European market for Pyridorin™ is approximately equal
to that of the United States, and the market for Japan is approximately