Alteon, Alagebrium, ALT-711

Alagebrium - or ALT-711 - is one of the better known compounds discovered and developed with the intent of repairing a type of accumulated damage that leads to age-related degeneration. In this case, the damage is the buildup of extracellular protein crosslinks, and amongst them the type known as advanced glycation endproducts. Aubrey de Grey gives a good explanation of this topic and the level of interest one should have in ALT-711 at the SENS website:

Luckily, it happens that a lot of the cross-links that accumulate in this way have very unusual chemical structures, not found in proteins or other molecules that the body makes on purpose. This means that it is theoretically possible to identify chemicals that can react with the cross-links and break them, without reacting with anything that we don't want to break. And indeed, several years ago a group of chemists found such a molecule, which has now been tested in many different animals and also in humans and seems to lower blood pressure quite substantially. These chemists formed a company (named Alteon) to market the drug (named ALT-711), but it is still in clinical trials.

We need more work in this area. There are plenty of other types of cross-link that ALT-711 doesn't break, so we need other chemicals that will complement what ALT-711 does.

Another good introduction, with an emphasis on development for use as treatment for specific age-related conditions, can be found at the Alteon website:

Alagebrium is the only A.G.E. Crosslink Breaker in advanced human testing. The compound has demonstrated promising results in several Phase 2 human clinical trials and is being developed initially for cardiovascular and vascular diseases. Results to date suggest that alagebrium may be a novel therapy for a number of conditions that occur as a result of myocardial or vascular alterations associated with aging or diabetes. Preliminary evidence suggests that the compound is able to modify both the structure and function of the left ventricle (main pumping chamber of the heart) consistent with a partial reversal of pathology. Similarly, alagebrium has been shown to improve the reactivity and function of the arterial system. In addition, in all clinical testing to date, the compound has demonstrated a clean safety profile.

Alteon has gone through many of the reshapings common to young pharmaceutical development companies; the latest would seem to place them more in line for financial viability - and thus continuing development of ALT-711 for modest goals relating to the treatment of specific conditions. This is the sort of profile that maximizes the chance of attracting funding and clearing sufficient regulatory hurdles to make it to profitability.

The new management of Alteon Inc. (Amex: ALT), to further validate the Company's newly focused development of alagebrium on diastolic heart failure, highlights the recent publication of several articles that illustrate the medical community's increasing recognition of this form of heart failure. "A strong body of preclinical and clinical evidence supports our advancement of alagebrium's clinical development in diastolic heart failure," said Malcolm MacNab, M.D., Ph.D., Vice President, Clinical Development of Alteon. "The recent focus on this patient population by key opinion leaders further encourages our aggressive pursuit of this disease characterized by an unmet medical need."

It is unfortunate that the modern wasteful, useless regulatory burden so narrows and slows all medical development - but this is the inevitable consequence of overbearing, invasive government. When government employees dictact whether your business is permitted to succeed, venture funding will only be obtained by those who demonstrate the greatest ability to please government employees. Merits and goals are demoted to secondary concerns, and we all know where that leads.

Not that we should be surprised. Plausible solutions and their enactment are the province of the free market and people who work to create and build - something that policians cannot do. The only results you'll obtain from the insertion of big government and central control into any arena of human endeavor are shoddy goods, higher costs, and slow progress. One would hope that most people understand what happens when you attempt to centrally control complex systems - the fate of those who lived through the Soviet Union should spring to mind. As centralization grows, progress, efficiency and quality die; this is an iron law of our time, and one that - sadly - seems to have to be relearned again and again.

Back to the alagebrium. My attention was drawn to a recent study suggesting that ALT-711 might have merit in the treatment of progressive kidney failure in diabetes, or diabetic nephropathy. There's an Alteon press release out there also, for those who don't enjoy reading scientific abstracts.

The renal morphological parameters characteristic of [diabetic nephropathy] decreased in treated compared with untreated mice. Conclusion: Alagebrium may prevent, delay, and/or reverse established [diabetic nephropathy] in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.

This sort of investigation is fairly standard practice. Because it is so enormously hard to gain government approval for any compound, it makes economic sense to test it for other uses once you have or are close to having approval. Once again, regulation becomes the primary motivator for the practice of science and research, rather than efficiency, speed, merits and goals.

One might view Alteon and the development of ALT-711 as something of a transition from the old to the new in the community of folk seeking to extend the healthy human life span. It has its roots in the old school drug development pipeline and firm focus on supplements and things you can put in a pill. The aims, however, are well within the Strategies for Engineered Negligible Senescence (SENS), in that Alteon's founders and employees seek to effectively and deliberately repair a small portion of the cellular damage that cause age-related degeneration.

Early SENS research presently funded by the Methuselah Foundation and generous donors takes a somewhat different approach to the problem. Rather than drug discovery, they are working on bioremediation and bacterial enzyme discovery:

So how is LysoSENS supposed to work? In brief, we are looking for enzymes capable of selectively degrading the respective target material in the environment. This idea is heavily inspired by the field of environmental bioremediation (using microbes to degrade environmental contaminants). We are working in the lab of Bruce Rittmann, a well-known environmental engineer, as he has the expertise to find microbes that degrade weird stuff. We hope that we can isolate enzymes from these microbes and deliver them in a manner similar to current FDA-approved treatments for heritable lysosome storage diseases, where the missing enzyme is tagged with certain sugars for targeting and then injected into the bloodstrem. You can learn more about the LysoSENS strategy from its originator and Methuselah Foundation chairperson Aubrey de Grey here (quick and easy) or here (detailed and technical).

May the best science win, to the benefit of all.

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Comments

ALT-711 was one of the most promising products for the same type of long-term, low-dose usage that seligilene (trade name Deprynl, a parkinsons medication with a 70 year history of medical use) and Metformin (a medication often given for Type II diabetes. Rather than working on insulin release, it works to maintain glucose tolerance, diabetes being a case of extreme glucose intolerance.)that became popular amongst anti-aging aficianados.

In the case of these two other meds, both the diseases they are used upon are among the groups that we all get eventually. Some of us die before we manifest symptoms, some of us manifest symptoms before we die. In either case, the oxidation of glial brain cells (parkinson's) and progressive glucose intolerance (diabetes) are inevitable. In both cases, these meds, formerly used for treatment, have proven useful as prophylactics against the diseases. They are both off-patent, and available inexpensively. Good.

In the case of ALT-711, the chemical compound had been discovered many years ago, and had traveled a circuitous route through academia, research firms, and finally, Alteon. There are two prominent attributes to Alagebrium (as Alteon renamed it). The first is that it is not a difficult compound to sysnthesize. An active black market rose very quickly after the early Phase I and II tests came in. Independent, lab-tested, certified for purity product was available for a short time on the grey market at about $3 per gram.

Now the issues for these small pharma-development firms are a)can they bring a blockbuster medication through the approval process with proven efficacy and safety in a time frame short enough to keep drawing venture capital until they have an approved product. Alteon, having a huge amount of convertible preferred stock hanging over it's head (held by Genentech), had increasing difficulty raising subsequent levels of venture capital until finally, it was unavailable at any price. At that time, Alteon was essentially bought for it's corporate shell by a three-man operation developing another medication that needed a corporate shell in order to move fast. The company now has perhaps three employees here in the states, and outsources it's research, (probably non of it on ALT-711, despite the websits assertions).

A central issue to the difficulty of approving the medication was that the patents were of questionable worth. First, the molecule is not difficult to replicate, and that's a negative vis-a-vis obtaining approval and also satisfying investors that they are buying into an exclusivively owned product. According to some, and I though I have read parts of the patent application, I am no expert on that subject, the patent was only a "use" patent. For treatment of severe heart failure. And the medication had dramatic positive results in the tests for efficacy in that field. But again, lack of patent protection, and ease of replication by others, obviously made the venture investment community lose faith before an approved product arrived.

Counterintuitively, this end result may be the optimal outcome for those interested in anti-aging compounds that reverse some of the inevitable processes associated with aging.

The early interest in, and black market for Alagebrium was based on the perception, probably accurate, that at lower long-term dosing, the medication would prove not only restorative of an earlier state regarding heart health, but would also act, again in low doses, as a prophylactic against glcoslylation, or cross-linking of cells, wherein they become stiff and cease to function well vis-a-vis water and nutrient exchange and other functions. One conclusion that could easily be derived from the published research was that Alagebrium worked first and fastest on those areas with the most blood-to-surface coverage and that were constantly in a state of higher levels of hemodynamic pressure. I.E. the large and small chambers of the heart, as well as the atriums, and potentially, the valves. Because testing for approval such as Alteon engaged in, looks for quick answers for severe problems in order to meet the "need" hurdles of the FDA, and the impatience of the venture capital markets, Alteon never engaged in long-term tests seeking FDA approval of the medication for other conditions. Given the relationship between surface-area coverage under pressure and short-terms results, testing for conditions such as diabetic neuropathy, or long-term low-dose prohylactic use for aging hearts, which would have taken years, was never an option for Alteon.

For those who read such research regularly, and are agressive about finding answers to their anti-aging goals, the failure of Alteon is not all bad. One can find small chemical labs and chemists who can replicate the molecule using existing, readily available information. Production of such medications for personal use does not violate any patents or laws (excluding of course, scheduled substances). Third party testing of the end product is also avialable.

So, while the drug industry environment in this country failed to produce a good product, readily available, probably at high cost, the news is not all bad for the knowledgeable and determined.

Although I have not seen Alagebrium available on the "grey market" since the Alteon became an obvious near-term casualty, those who seek, will find. And probably much, much cheaper than if the medication had been approved.

The research is there. The results were excellent. One could draw reasonable conclusions about long-term low dose usage. And the mechanisms are out there to obtain the product.

Not a perfect outcome, but not a disaster, either.

Posted by: frank at April 20th, 2007 6:21 AM

Please tell me.. If one wanted to find this product somewhere, or on how to formulate it, have it formulated...where would one find that information, or product??

Posted by: Victoria Smith at April 10th, 2014 12:27 PM

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