Alagebrium
Larry Sharp
Alteon Inc. (ALT) announced today that data demonstrating the ability of
its lead A.G.E. Crosslink Breaker alagebrium to improve overall cardiac
function are being presented today at the American Heart Association
Scientific Sessions in Dallas, TX, by two independent research teams.
Data presented from the Phase 2a PEDESTAL trial in diastolic dysfunction
demonstrated the ability of alagebrium to improve measures of diastolic
function, including a significant reduction in left ventricular mass. A
second Phase 2a study found the compound to significantly improve
endothelial function. Both studies point to the importance of the
continued development of alagebrium and A.G.E. Crosslink Breakers as a
novel class of compounds that may help reduce cardiovascular risk.
The poster presentation "Improvements in Diastolic Function Among
Patients with Advanced Systolic Heart Failure Utilizing Alagebrium, an
Oral Advanced Glycation End-product Crosslink Breaker" describes the key
findings from Alteon's diastolic dysfunction trial, known as PEDESTAL
(Patients with Impaired Ejection Fraction and Diastolic Dysfunction:
Efficacy and Safety Trial of Alagebrium). Twenty-two patients were
treated in an open-label two dose (35 mg and 210 mg bid) regiment and
followed by echocardiography. The data revealed absolute improvements
from a combined analysis of both dose groups in Doppler measures of
diastolic function, including the early/late (E/A) atrial filling phase
ratio (3.3+/-1.4vs. 2.6+/-1.4) (p=0.18), deceleration time (DT)
(148+/-33 vs. 188+/-60), (p=0.04), isovolumetric relaxation time (IVRT)
(88+/-11.9 vs. 113.1+/-31) (p=0.04) and concomitant reduction of left
atrial pressure (25.0+/-8 vs. 19+/-8) (p=0.11). In addition, regression
of left ventricular mass (g) (297+/-57 vs. 246.+/-51) (p=0.002) and left
ventricular end-diastolic volume (ml) (297+/-57 vs. 246+/- 51) was
achieved.
Author Vinay Thohan, M.D., Assistant Professor of Medicine, Methodist
DeBakey Heart Center, Houston, TX, concluded, "Alagebrium had important
benefits among patients with systolic heart failure and diastolic
dysfunction. These benefits included improved measures of diastolic
function, hemodynamics and cardiac remodeling. Future investigations
aimed at evaluating the expected clinical improvements are warranted."
In the study, "Improved Flow-Mediated Arterial Vasodilation by Advanced
Glycation Crosslink Breaker, Alagebrium Chloride (ALT-711), in Older
Adults with Isolated Systolic Hypertension," conducted at Johns Hopkins
University School of Medicine under grants from the National Heart, Lung
and Blood Institute and the Society of Geriatric Cardiology, 13 adults
with isolated systolic hypertension on stable antihypertensive therapy
received a 2-week placebo run-in followed by 8 weeks of oral alagebrium
(210 mg bid). Data measurements were taken after placebo run-in and
after 8 weeks of therapy. Treatment with alagebrium reduced carotid
augmentation index (AI), a measure of arterial stiffness, by 37%
(0.3+/-0.04 to 0.2+/-0.05, p=0.007) and carotid augmented pressure from
16.4+/-10 to 9.6+/-9 mmHg (p<0.001), whereas pulse wave velocity (PWV)
was unaltered. Thus, overall arterial stiffening, as reflected by AI,
was markedly reduced by alagebrium therapy. Heart rate, brachial
arterial pressures and brachial artery distensibility measures were
unaltered by alagebrium therapy. However, alagebrium significantly
improved flow-mediated dilation, a measure of endothelial function, by
102% (4.6+/-1.1% to 7.1+/-1.1%, p<0.05). Alagebrium therapy improved
peripheral artery endothelial function, independent of changing local
arterial distensibility, suggesting a new mechanism through which
alagebrium may act on A.G.E.s which directly impair dynamic vascular
function in addition to its apparent effect on A.G.E.s impacting the
structural aspects of arteries.
Author Susan Zieman, M.D., Ph.D., Assistant Professor of Medicine, Johns
Hopkins University, noted that "these data support two potentially
separate and novel mechanisms for a vascular benefit that may help lower
cardiovascular risk in older adults: a decrease in overall arterial
stiffening and an improvement in endothelial function. This is
particularly exciting as both arterial stiffness and endothelial
dysfunction are risks for cardiovascular disease."
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