Sorry!! The article you are trying to read is not available now.
Thank you very much;
you're only a step away from
downloading your reports.

Next generation lipid science


RLT not HDL? Who knew!

The best-selling drugs in the world are for the treatment of lipid (cholesterol) disorders. Tens of billions of dollars are spent on these drugs each year with little end in sight to their rapid sales growth. Pfizer (PFE:NYSE) is probably the most visible beneficiary of this trend due to its ownership of the world's best-selling lipid drug, Lipitor.

Lipitor is member of a class of drugs called statins. Their job is to lower LDL (bad) cholesterol in the body. Statins are the primary treatment for lipid disorders. What science has realized over a couple of decades of statin use, however, is statins only reduce morbidity and mortality (medical problems and death, respectively) by about 30% even when the patient is able to achieve acceptable lipid targets.

While this is a significant decrease, researchers realized they needed to look for alternate solutions.

Reverse Lipid Transport

Most people who have had a cholesterol test are aware your lipid profile is made up of a number of substances. The most familiar to the lay person is LDL - bad cholesterol. The second most familiar is HDL - good cholesterol. When researchers realized there was a good cholesterol, drugs were developed to raise it in the hopes of finding the next Lipitor.

What they found was raising HDL was not necessarily a pathway to reductions in morbidity and mortality. Without reducing morbidity and mortality, you don't get FDA approval for your drug. The FDA will accept a reduction in LDL as de facto proof of efficacy since the relationship between a reduction in LDL and a reduction in morbidity and mortality is well established. The same is not true for HDL and, in our opinion, will never be true.

What we now understand is HDL is a key component of a process called Reverse Lipid Transport (RLT). What RLT does is remove fats deposited around your body - most importantly in your veins and arteries - and bring them back to the liver where they are processed and excreted.

It is easy to understand why researchers who discovered HDL thought all they needed to do was increase the number of HDL particles and they would hit a bonanza. The fact this didn't end up being the case was the cause for much puzzlement.

The HDL as a garbage bag

When Biotech Monthly came across Esperion (now a division of Pfizer) back in February 2002, it was eye opening. We'd been looking for a cardiology company to add to our coverage universe that was not developing the next me-too statin. After spending a considerable amount of time examining the import of RLT, it became crystal-clear Esperion had something special. Our challenge then became how to explain this company's science to our Subscribers in a way that made rather complex scientific principles readily understandable. What follows is the short version of what we came up with.

Think of HDL as a garbage bag. It travels around the body until it fills itself up with fat and then returns to the liver to offload that fat. Anyone who has raked leaves or grass clippings knows an empty garbage bag is far more useful than a full garbage bag.

The first drugs designed to boost HDL worked well enough to boost HDL levels. In the early short-term studies, HDL levels bloomed and LDL levels dropped slightly. All was good in the world.

What these drugs created, however, was a whole bunch of full HDL garbage bags floating around in the body. The drugs essentially blocked the process whereby full HDL bags were offloaded to the liver. The body responded by increasing the number of HDL particles, but this didn't do anything for decreasing morbidity and mortality because full HDL bags don't remove as much fat from arteries and veins. Unless you stimulate the entire RLT process, you simply aren't going to see the benefit of raising HDL.

In hindsight, this was pretty obvious. At the time, it seriously confused scientists. Until last November, the number of biotech investors who understood the crucial difference between boosting HDL and boosting RLT transport was a small club indeed.

RLT in action

What you want to do is create a whole bunch of empty HDL garbage bags. Last November, the world learned this was possible when the Journal of the American Medical Association (JAMA) published results of a small Phase II trial of ETC-216, a drug under development by Esperion.

Over a five-week period consisting of five short intravenous infusions, ETC-216 reduced the buildup of fatty plaque in the blood vessels of patients with lipid disorders by 4%. This was a real reduction of fatty plaque as determined by a scan of the inside of the target blood vessel. It was amazing news completely without precedent.

While 4% might not seem like much, realize the best-selling statins in the world manage about a 0.5% decrease over three years. This finding revolutionized how cardiologists thought about fats and placed the concept of RLT directly on the front page for scientists and investors.
ETC-214 is essentially synthetic HDL - or at least that's the best way to explain it in this short space. It boosts the number of empty HDL garbage bags and their ability to attract fat to such a high degree that they rapidly and dramatically remove fat from blood vessels via the RLT pathway. This was a key scientific breakthrough that proved boosting HDL was an effective treatment, as long as you boosted the level of empty garbage bags.

Why the science lesson?

The impetus behind this science lesson is the release of an early Phase II trial in the current issue of The New England Journal of Medicine (NEJM). This article is about a 19-patient study of torcetrapib, a drug under the development by Pfizer. This drug is very important to Pfizer because it is designed to be combined with Lipitor to extend Lipitor's patent, which would otherwise expire in 2010/11.

One of the interesting things about HDL is that it most often empties its fat to the liver directly. Other times, a certain set of molecules encourages HDL to empty its fat "prematurely" so the fat is recaptured by LDL molecules and redeposited in the body. This is rather counterproductive.

Torcetrapib is a member of a class of drugs called CETP-inhibitors. CETP (pronounced see-tep) is a molecule involved in the RLT process that can remove fats from the HDL garbage bag. This would be good except CETP is one of those molecules that removes fat from the garbage bag prematurely, transferring it to LDL molecules.

By blocking CETP, torcetrapib removes four of the five ways HDL can offload its fat. Three of these ways are not beneficial, but the fourth is one of the primary ways HDL empties its garbage bag to the liver as part of the beneficial RLT process. The final remaining way HDL offloads its fat fits the RLT process and is unaffected by torcetrapib.

CETP-inhibition is not without controversy. While blocking CETP always boosts the number of HDL particles, animal studies show the complete absence of CETP causes serious cardiac disease due to a build-up of fat. Exactly how complete the block of CETP is can be critical to whether the drug helps or hurts the patient.

The NEJM study confirms that torcetrapib increases HDL and decreases LDL, especially when used with Lipitor. It also causes the size of the HDL particles to move towards the larger end of the scale - full(er) garbage bags, in our analogy.

Studies that have gone the months/years necessary to determine whether torcetrapib or other CETP-inhibitors can reduce morbidity and mortality have not yet been completed. ETC-216 made it crystal clear it is not about increasing HDL, but about stimulating RLT. This makes the results of longer studies of CETP-inhibitors like torcetrapib all the more critical.

RLT as the future of lipid treatment

Pfizer had the right of first refusal to inlicense Esperion's ETC-216. We think the fact Pfizer bought Esperion - whose whole pipeline was focused on RLT drugs - for $1.3B cash six weeks after the JAMA article made such an enormous splash is indicative of the importance of the RLT concept to the future treatment of lipid disorders. When you are evaluating an investment into a cardiology company focused on treating lipid disorders, you'll find many treatment types put forth that theoretically will result in scientific and financial success. Keep the concept of RLT in the back of your head, however, and it may help you find winners and avoid losers.

< Previous
  • 1
Next >
No positions in stocks mentioned.

The information on this website solely reflects the analysis of or opinion about the performance of securities and financial markets by the writers whose articles appear on the site. The views expressed by the writers are not necessarily the views of Minyanville Media, Inc. or members of its management. Nothing contained on the website is intended to constitute a recommendation or advice addressed to an individual investor or category of investors to purchase, sell or hold any security, or to take any action with respect to the prospective movement of the securities markets or to solicit the purchase or sale of any security. Any investment decisions must be made by the reader either individually or in consultation with his or her investment professional. Minyanville writers and staff may trade or hold positions in securities that are discussed in articles appearing on the website. Writers of articles are required to disclose whether they have a position in any stock or fund discussed in an article, but are not permitted to disclose the size or direction of the position. Nothing on this website is intended to solicit business of any kind for a writer's business or fund. Minyanville management and staff as well as contributing writers will not respond to emails or other communications requesting investment advice.

Copyright 2011 Minyanville Media, Inc. All Rights Reserved.

Featured Videos