Alagebrium 'reverses' ED

Alteon, from Parsippany, NJ, has said that its lead AGE crosslink breaker compound alagebrium (formerly known as ALT-711) has demonstrated an ability to reverse erectile dysfunction (ED) in a preclinical model of diabetes.

The preclinical study, entitled: 'Delayed Administration of ALT-711, but not of Aminoguanidine, improves erectile function in streptozotocin diabetic rats: Curative versus preventive medicine,' concluded that alagebrium - through what appears to be a unique mechanism of action - offers significant potential for the treatment of diabetic erectile dysfunction.

According to the investigative team, these data are unlike results for existing ED drugs in similar experiments, particularly due to a beneficial effect on the function of the corpus cavernosum. 'Alagebrium appears to have significant therapeutic potential for the treatment of diabetic erectile dysfunction, with a unique mechanism of action,' said Dr Wayne Hellstrom, an author of this study and many of the seminal studies in ED.

An estimated 30-40% of diabetic and aged patients with ED do not receive benefit from currently available drugs, and patients with diabetes or severe vascular disease are among the most refractory to such treatment. This occurs, in part, because the corpus cavernosum, the structure that acts as an expandable reservoir for blood, has become significantly glycated and fibrotic, unable to properly dilate due to the accumulation and crosslinking of pathological structures called advanced glycation end-products (AGEs). AGEs have been implicated in the fibrosis and stiffening of tissues and organs throughout the body and have been shown to contribute to many inflammatory processes. They have been demonstrated to impair erectile function in diabetes by affecting the functional capabilities of the corpus cavernosum and by interfering with the production of natural penile vasodilating agents, endothelial and neuronal nitric oxide (NO).

The study authors investigated the effect of delayed administration of alagebrium, a crosslink breaker of AGEs, as compared with aminoguanidine (pimagedine), an inhibitor of AGEs, in a well-established ED animal model. In previous preclinical and clinical testing, alagebrium has demonstrated the ability to cleave advanced glycation end-product crosslinks as well as diminish deleterious inflammatory responses caused by AGEs. Aminoguanidine has previously been shown to prevent ED in diabetic animals if given immediately after the induction of diabetes. In the current study, both aminoguanidine and alagebrium were initiated at the 6th week of diabetes and the two treated groups were compared with a group of age-matched controls and a group of untreated diabetic animals. Twelve weeks after diabetes induction, in vivo intracavernosal pressure measurements were assessed, as well as serum and penile AGE levels. The diabetic rats had a significant decrease in erectile function as assessed by the level of intracavernosal pressure obtained after cavernosal nerve stimulation and elevated AGE levels when compared with the control rats.

The administration of alagebrium resulted in a significant improvement in erectile function, as well as a decrease in serum and tissue AGE levels, while the delayed administration of aminoguanidine did not correct either AGE levels or erectile dysfunction. In addition, alagebrium normalised other diabetes-induced pathologies associated with ED, an effect unlike any currently marketed therapies used to treat symptoms of the condition. The results of the preclinical study have been submitted for publication in a peer-reviewed medical journal.

In prior clinical and preclinical studies, alagebrium has been shown to have a remodeling effect on the cardiovascular system¹ as well a positive effect on systolic hypertension² and vascular compliance³. The drug is currently in Phase II studies in patients with hypertension and heart failure. In addition, it is being studied for its effect in endothelial dysfunction, a condition also linked to erectile dysfunction.

'We are actively evaluating a clinical development pathway for the ED indication,' said Kenneth Moch, president and ceo. 'Because ED is an early indicator of vascular disease, this exciting research by world-renowned ED investigators is fully consistent with, and supportive of, our ongoing clinical development programs for alagebrium in hypertension and heart failure. Should alagebrium's therapeutic effect be seen in human studies in ED, this would not only represent a breakthrough for ED, but would also be indicative of alagebrium's potential to reverse pathologies in a number of other human vascular diseases.'

ED and vascular disease

Erectile dysfunction is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual intercourse. ED has been reported to affect as many as 20-30m men in the United States and 152m men worldwide, according to the National Institutes on Health. The risk for ED increases progressively with advancing age, with an estimated 54% of men ages 65-70 reporting some degree of impotence (Nicolosi, 2003). It is believed that 85-90% of ED cases are related to a physical or medical condition, while 10-15% is due to psychological causes. Many studies have identified ED as an early indicator of cardiovascular diseases, including hypertension, heart attack and stroke, and point to the underlying dysfunction of the arteries and vascular system as a principal cause. ED is commonly associated with a number of other conditions frequently occurring in aging men, including prostatic hypertrophy, arterial hypertension, ischemic heart disease, peripheral vascular disease, atherosclerosis, hyperlipidemia, and diabetes mellitus.