written by reader A Non-Statin Pill That Really Lowers Cholesterol, Blood Pressure and Inflammation without Side Effects Would be a Good Investment, Right?

Oh Yeah...It May Prevent Cancer, Too

By DrKSSMDPhD, August 2, 2014

[Ed. Note: Dr. KSS writes about medical topics and biotech stocks for the Irregulars. He has agreed to our trading restrictions, and his thoughts and words are his own. Enjoy!]

Any discussion of cholesterol immediately turns Brobdingnagian, such are the extremes in question.

Statins, which lower LDL cholesterol, are bombastically the best-selling drugs of all time. They’ve left a Paul Bunyan-size footprint in medicine. But they are hardly ancient and hoary. The prototype statin was discovered by Akira Endo, PhD, in 1970 while he worked for Japanese chemical giant Sankyo. Despite the Saganesque billions and billions of dollars, euros and yen his discoveries fetch every year, Endo has never seen even a nickel of the profits. Endo has been mildly honored, while those acting on principles he first introduced to the world, such as Brown and Goldstein, have gone on to Nobel notoriety.

Endo began with a hunch: cholesterol is an elemental life-cycle molecule for many organisms, and so maybe other organisms had stumbled onto ways to knock the cholesterol underpinnings out from potential invading pathogens as a safety measure. The fungi, for example, are famous sources of antibiotics that snuff bacteria. Maybe fungi had also devised a way to attack cholesterol production as a defense? Fungi have ergosterol rather than cholesterol in their cell membranes, and so could poison cholesterol-making machinery at no harm to themselves.

I’ve lived in Asia, and so have often searched for analogies to help Westerners understand how sharply Asian cultures differ from each other. One archetype is a thought exercise in which a representative of an Asian nation is given an uncut loaf of bread and asked to slice it in a way that reflects his/her culture. A Thai person, for example, would slice it ornately, lovingly, and so beautifully you’d be reluctant to eat it. A Vietnamese person would have it all sliced for you by the time you are finished explaining what you want. A Japanese person would devise a way to make bread slices that are but a few molecules thick. No culture has the fixity of purpose and ruthless attention to microscopic painstaking detail that the Japanese have. Endo went after this issue like a good Japanese scientist, and personally screened 6,000 individual compounds that had been purified from various fungi for one that could inhibit cholesterol synthesis. He didn’t have a high-throughput nanosensor-based microchip array to do it for him. He rolled up sleeves, told his wife not to wait up, and did it the old fashioned way.

akira endo-1

Dr. Akira Endo, discoverer of statins

Endo’s work led to identification of monacolin K, later dubbed lovastatin, the first such agent used as a drug, in certain oyster mushrooms and other species of fungi. To this day, many statins used as drugs are purified from fermenting yeast rather than synthesized. Although the fungus-derived statins are natural products, somehow patent protection on them was finagled (now lapsed). Meanwhile, in its most legendary abuse of power, the FDA in 1998 tried to ban red yeast rice because it naturally contains lovastatin, made by the yeast. All statins are inhibitors of a liver enzyme called hydroxymethylglutaryl CoA reductase. 85-90 per cent of the body’s total cholesterol burden is made in liver, which is why the weak anti-cholesterol agent ezetimibe, which only blocks absorption of dietary cholesterol, has little effect and really does not warrant clinical use as it is not cost-effective.

The Brobdingnagian thing, again: no topic incites more vigorous discussion, more one-off hyperbole, than statins. Character X emerges from stage left to say he knows someone who lived to be 100, ate bacon and fried eggs for breakfast every morning, and never took any pills. Mrs. Y flies out of stage right to say that one dose was all it took…..a statin nearly killed her husband and she can prove it. A chorus begins a strophe: “We’ll all get muscle aches anon!,” though perhaps only a fourth of statin users get meaningful muscle pain. Offstage a mournful basso begins a lacrimae about how his best friend took statins every day just like the doctor ordered and they didn’t save him from The Big One. I’ve posted commentaries on them, as has Michael Jorrin, and invariably the threads that follow become tempestuous. Many readers are angered by their doctors’ glib default recommendations that all should be on them and others assert their exceptional wellness in the absence of, or because of the absence of, a statin prescription. Statins are blockbuster drugs, and are so avidly believed in by both the medical and pharma establishments (which rarely are so aligned) that some only half-jokingly think statins should be in the water supply.

Even so, statins have their vigorous detractors, many of whom are quite learned. The International Network of Cholesterol Skeptics makes interesting if insufficient arguments. Every major medical credo always has passionate critics; Peter Duesberg, PhD, of UC-Berkeley has actively, savagely denied for 30 years that HIV causes AIDS. Duesberg is a member of the National Academy of Sciences. Statins are roundly bashed by abominations like Dr. Joseph Mercola at his appalling website, and commonly if people do quite the opposite of what Mercola asserts they should, they will be far better off and healthier. Mercola’s interests are not, of course, in health; they’re—-you guessed it!—-pecuniary! He tells you that health comes only from what he sells you, from his special nostrums that the establishment denies exist.

Where cooler heads prevail about vascular disease,  the following large tenets usually emerge, on the basis of large numbers of studies of large numbers of people for large numbers of years:

(1) there is great merit to linking cholesterol with vascular disease. It is not the only factor, as insulin resistance, blood pressure and inflammation play roles too, but it is a major factor.

(2) statins are poorly tolerated in some patients, but by no means all. Most can muddle through, especially if they dose their statins at night and sleep through the muscle-ache interval.

(3) statins may not provide be-all-end-all vascular disease prevention because they address only the cholesterol aspect, but they do play a vital role, as the overpowering evidence is that cholesterol contributes to vascular disease and is easily modified.

(4) statins are definitively, overwhelmingly helpful in secondary prevention: preventing a second MI or CVA after a patient has had a first one. For primary prevention, helping a patient never have an initial event, their merit is debated still. The bulk of data shows them helpful in primary prevention, but that data is not as stark as for secondary prevention.

(5) statins do have other effects: they may worsen insulin resistance in some patients,  intensify dementia in others (cholesterol is the most abundant substance in brain), though they clearly have mild anti-cancer effects. Occasionally statins can trigger a syndrome called rhabdomyolysis. I have managed several people through it: rhabdo is ugly, painful (it is a breakdown and profound inflammation of muscle tissue), leads to renal failure. Not only are statins not ideal, but the potential for significant problems from them is always just on the other side of the door.

Many people rightfully wonder: if cholesterol is so deleterious for humans, why has nature endowed us with so much of it? I would respond to this by stealing a line from Baruch Spinoza, that nature does not work with the end in view. Natural selection caters mostly to reproductive fitness, and so rigs us to be at our best until such time as we can reproduce. In slightly balder terms, nature may not care about what becomes of us beyond the age of 18 or so. We are configured and calibrated in fact so that two systems tend to get us into trouble: the clotting system and the lipid system. Both may be teed up to favor survival advantages for hunter-gatherers. If being attacked by a lion or cheetah is a daily threat, then you need to be able to clot your wounds quickly, and also channel to them ingredients needed to rebuild flesh. These abilities to clot and generate flesh become maladaptive for us as we age. An unfortunate additional feature of cholesterol metabolism has to do with how it interdigitates with other metabolic pathways, and somehow, the factors that drive weight gain, high blood pressure and inflammation all tend to make blood more coagulable and cholesterol more abundant in it.

Blood from a patient with profound familial hypercholesterolemia

Blood from a patient with profound familial hyper-cholesterolemia

In November 2013, the American Heart Association and American College of Cardiology issued new guidelines for prevention of MI and stroke. Their guidelines were that there is no longer a role for niacin, fibric acid derivatives (ie, clofibrate), bile acid sequestrants (ie, colesevelam), ezetimibe or fish oils. The reasoning was that even if any of these latter agents modify cholesterol parameters favorably, they do not lead to better outcomes for patients. This observation calls into question the whole cholesterol model of vascular disease, of course, and caused some to speculate that perhaps statins have effects beyond their role in lowering cholesterol. At any rate, the councils recommended statins for all, and this immediately led to cries of outrage in some circles, as there were claims of conflicts of interest: many members of the committee advancing statins had consulting and investigative ties to Big Pharma. There’s just one problem with that theory, however: with the exception of Astra-Zeneca’s (AZN) Crestor, statins are largely no longer patent-protected.

Scenario: Pfizer (PFE) loses patent protection on bestseller statin Lipitor. It has seemingly only one flagship product, Viagra, which is amazingly patent-protected til 2020, though Teva (TEVA) is allowed to launch a rival in 2017. PFE makes overture to buy AZN for the benefits of tax inversion. And because AZN’s Crestor is still on patent til mid-2016, it gets rebuffed. PFE’s R&D pipeline is fallow, and PFE is smarting from a fall off a patent cliff. What can it do to right its ship? In fact, what can Big Pharma do to put shareholders back on the gravy strain of dividends and profits to rival the statin golden years?

And what can medicine devise to really prevent heart attacks and strokes in people in such an effective and safe way that people no longer quibble over the cholesterol hypothesis and the imperfectness of statins?

A company I’ve found may hold the answer to these issues. And that may provide a surprise, an upset, to what many will think is a refutation of my thesis. But I will get to that shortly.

Statins mainly work by lowering LDL cholesterol. They inhibit the hepatocyte cholesterol synthesis enzyme HMG CoA reductase. Other present agents reduce LDL to a much lesser degree, raise HDL somewhat, lower triglycerides…..but do nothing to prevent cardiac and cerebrovascular events. And yet HMG CoA reductase is by no means the only enzyme pivotal for cholesterol synthesis. Why has no biotech entity tried some other means of blocking the production of cholesterol in liver?

Enter Esperion Therapeutics (ESPR) of Ann Arbor, Michigan. Esperanza is “hope” in Spanish, in which esperar means “to wait.” ESPR has many investors waiting hopefully for what may be some very nice news during the next six months regarding its main pipeline agent ETC-1002. Esperion had its IPO debut in mid-2013, when 17 insiders bought 3.4 million shares.

Aisling Capital (an investor in Durata (DRTX)), Domain Associates (investors in DRTX, Achaogen (AKAO) and Regado (RGDO)) and Alta Partners each own 2.1 million shares of ESPR. Roger Newton, PhD, Esperion’s founder and Chief Scientific Officer, owns 629,700 shares, the largest position of any company insider; Newton is also on ESPR’s board. Newton has chops and street cred: he co-discovered atorvastatin (PFE’s Lipitor, which PFE acquired Warner-Lambert for), and led its clinical development. Newton was once Brobdingnagianly called “The Luckiest Guy in the Drug Business” by Forbes Magazine

roger newton, PhD-1

Dr. Roger Newton, founder of Esperion

Esperion’s float is 13.5 million shares, 81 per cent of which are owned by institutions,  and 93 per cent of which are owned by large-block holders. Its recent market capitalization is just under $250 million. Pfizer owns nearly 6 per cent of Esperion, and no other pharmaceutical company has a position in it. Pfizer has some history with Esperion, which I will discuss.

ETC-1002 is being developed because it inhibits ATP citrate lyase, a fundamental step in cholesterol biosynthesis. Curiously, however, ETC-1002, which is an oral small molecule, also strongly activates 5′-adenosine monophosphate-activated protein kinase (AMPK). AMPK has important roles, or seems to, in insulin sensitivity, inflammation, weight, and even blood pressure. ESPR has preliminary clinical evidence of improvement in all four of those parameters in ETC-1002-treated patients.

The primary basis of statin-intolerance is that a minority of patients unpredictably have defects or mutations in an anionic transporter molecule that is responsible for uptake of statins into liver cells. In patients so afflicted, muscle tissue sees undue burdens of statin, which is toxic to muscle tissue. ETC-1002 is taken up into liver by a different mechanism, and in fact in a sizable cluster of phase 1 and phase 2 trials has yet to cause any serious adverse events and only rarely leads to minor instances of side effects.

ATP citrate lyase is an enzyme that merits some technical attention. It is found in cell cytosol, as opposed to nucleus, mitochondria, endoplasmic reticulum or lysosome. As described in this helpful recent review article, which has an excellent diagram of reactions on page 2, ATP citrate lyase generates acetyl CoA from citrate, which then has one of three fates: it feeds into cholesterol synthesis (HMG CoA reductase, inhibited by statins, is the very next step), or fatty acid synthesis (which means inhibiting the enzyme could result in triglyceride reduction), or else into acetylation reactions, such as those of histones, which bind DNA. Histone deacetylase modulators are a “hot” area in cancer therapeutics, and in fact an abundance of evidence shows that inhibiting ATP citrate lyase blocks tumorigenesis.

You’re bound to be wondering: does ETC-1002 work? Does it lower LDL cholesterol?

Esperion presented a fine poster at the 2014 National Lipid Association that meta-analyzed 4 phase 2a studies of ETC-1002: placebo-controlled dose escalation studies of the drug in patients with dyslipidemia, with dyslipidemia and type II DM, and dyslipidemia with statin intolerance, and in addition to atorvastatin. You can review the data here. But the key summary points are that LDL lowering was dose-dependent, was much more prominent in patients with diabetes, was well-tolerated, and above all else, achieved LDL reductions comparable to what statins can achieve. Bear in mind: this effect is additive to statins and possibly synergistic. In fact, one can envision a future in which a patient might not be placed on either a statin or ETC-1002, but on both, and with a reduced dose of statin so that side effects are milder. A common goal of statin therapy is reduction of LDL to 100 mg/dL or less, and from these studies it appears this is easily accomplished in a brief time with 240 mg ETC-1002 once daily. Some patients on ETC-1002 have achieved 80 per cent diminutions in LDL cholesterol.

Among the most interesting findings in these studies is that ETC-1002 therapy afforded reductions in hsCRP, a marker of inflammation, of 40 per cent or more as compared with placebo. This is a striking and statistically significant finding. While statins do lower hsCRP to a degree, this effect in them has been less comprehensively studied. In these trials, ETC-1002 was no likelier than placebo to lead to any adverse event, something statins can never claim.

In another pooled analysis, Esperion has demonstrated that ETC-1002 establishes a nearly 7 mm Hg reduction in blood pressure with statistical significance. The mechanism of this is not yet known, but the effect is additive to other anti-hypertensives, and is certainly a physiological benefit none of the statins can boast. The links to the posters provide ample graphics supporting the data.

Esperion is now enrolling in two phase 2b studies. One examines ETC-1002 as an add-on to ongoing statin therapy. It is placebo-controlled, and compares two doses of ETC-1002, and seeks 132 patients among 27 U.S. study locations. The other examines ETC-1002 in 144 patients with both hypercholesterolemia and hypertension at 35 U.S. centers. This latter study will of course examine achievement of blood pressure reduction goals. Both studies have a mix of urban and rural, private and academic study sites. Both will also look at effects on LDL particle size, number and distribution, apolipoprotein B, and HDL cholesterol, as some evidence has suggested Esperion’s drug may slightly lower HDL.

For would-be investors in Esperion, as for the company, the main question is not whether to proceed to a large phase 3 trial, but rather what sort of phase 3 should be run. Here Esperion is feeling its way. The goals of such a trial must be clearly decided in advance: is ETC-1002 to be studied as a stand-alone lipid-lowering agent, in which case it might be compared with placebo? Or would the FDA deem statins to be standard of care and so insist on a head-to-head trial against statins? Or does the company wish to pursue an add-on, adjunctive indication in which the drug can be used in addition to statins, recognizing that some physicians will prescribe it as stand-alone therapy? This will take careful decision analysis, and deft negotiation with the FDA. No single class of drug has been as comprehensively studied in human trials as the statins have. The tenor and expectations of such negotiations, however, may be strongly affected by the fact we are now nearly in a post-brand-name statin era. Since ETC-1002 works by a route completely untouched by statins, the FDA may well endorse development along two paths (both as single-agent therapy and as adjunctive therapy).

At the same time, Esperion does face a serious obstacle in that statins have been so thoroughly studied. In fact statins appear to have vascular protective effects that may be unrelated to either their lipid-lowering or inflammation-lowering abilities. The most cited and best study in this regard is the 20,000-patient 5-year study that appeared in The Lancet in 2011. Patients lacking elevations in LDL and hsCRP were just as likely as patients with elevations to be protected from MI and CVA. The ability of statins to lower hsCRP is not related to their effects on cholesterol, and meanwhile many antihypertensive agents have anti-inflammatory effects. My feeling is that it would be most unfortunate if the FDA required Esperion to compare ETC-1002 in a head-to-head way with statins, as it could shine nicely as monotherapy in the statin-intolerant, and as add-on treatment in those with an insufficient statin response. My sense is that ETC-1002 more potently lowers hsCRP than statins do, but I cannot prove that, and the two have never been directly compared.

One tricky aspect of ETC-1002’s development may be that the FDA will want data not only of LDL reduction, but also of event risk reduction too. We now know that non-statins that improve lipoprotein profiles make no difference in MI and stroke risk. ETC-1002’s case is strongly enhanced by the fact that it sharply lower hsCRP, a great bonus. But evidence-based medicine insists on evidence, and the fact is that these markers are imperfect surrogates for risk reduction. Accordingly, it is very possible that Esperion will be placed into performing risk-reduction phase 3 trials to support an NDA for ETC-1002. Such trials would be quite expensive, and unless the company is acquired, will warrant dilutive capital-raising. Pfizer may be looking for acquisitions to bulk up its pipeline, and would be a good fit with Esperion, but at the same time may wish to devote energy to bigger transformative steps than acquiring a microcap company.

Some company history is worth mentioning. Before the present Esperion was formed in 2008, there was a prior incarnation of Esperion, which developed ETC-1002 in 2004. That Esperion was acquired totally by Pfizer. ESPR in current form broke away from Pfizer, and purchased from Pfizer worldwide rights to ETC-1002, and does not have to pay licensing fees or royalties to Pfizer in any form. Esperion’s relationship with Pfizer is amicable, and Pfizer owns ESPR shares. Is Pfizer actively thinking of buying out Esperion? That’s hard to know. Pfizer seems more concerned right now with a grandiose deal, such as a tax inversion, to reinvent itself. Even so, Esperion would be a diminutive company for it to acquire, and this would not confound larger plans. An Esperion acquisition however would fly in the face of the development resources Pfizer has placed behind its PCSK9 agent. Accordingly, a suitor might take the form of a another traditional pharma house, not a biotech.

The potential refutation to any investor interest in Esperion may be the coming of the PCSK9-acting agents.

Let’s discuss them.

It would be difficult for me to convey fully the extent to which I regard the advent of the PCSK9 inhibitors with boredom. Although Regeneron (REGN) and Sanofi (SNY) unveiled awaited data on 30 July that their new PCSK9-inhibiting monoclonal antibody alirocumab not only lowers cholesterol potently but also reduces cardiovascular event risk, investors seem to be forgetting key things about this class of drug, which includes Amgen (AMGN)‘s evolocumab and PFE‘s bococizumab (which lags the other two in development):

(1) these are injected drugs

(2) these drugs are not yet approved

(3) these drugs lower LDL cholesterol to such a stark degree that dementia may prove to a be a serious consequence of them. Make no mistake about it: “fuzzy thinking” is already pegged as a serious issue in PCSK9-antibody treated patients.

(4) therapy with these drugs will likely be priced at $10,000 or more per annum, which will create a third-party payer cost apocalypse that will make the everybody-can-recite $84,000 for 12 weeks of Gilead‘s (GILD) Sovaldi seem penny-ante. Although only 9 per cent of HCV-infected Americans have been cured, the fact is that they are cured by treatment, and do not require chronic intervention. And their numbers (“only” 3.2 million Americans have HCV) are utterly dwarfed by the number of Americans with dyslipidemia.

(5) the PCSK9 inhibitors will not replace statins, but will be used as add-ons. They will replace statin therapy only in those who have experienced clinical catastrophes on statins, which are rare.

Because of these considerations, drug companies expecting a register-ringing Hemingwayesque Moveable Feast of revenues from the PCSK9 inhibitors may be misguided. Your insurance company is not going to let you receive them just because you don’t like statins. And if the cognitive side effects are as bad as some suggest, you may not want to take them.

While the biochemistry of PCSK9 is complex, the Cliff’s Notes version is that it suppresses expression of the LDL receptor on the surface of hepatocytes. When PCSK9 is blocked by antibodies, LDL receptors are more abundant in liver, and so better able to soak up LDL from circulation. LDL is generally regarded as the entity that carries cholesterol to the arteries, while HDL is regarded as the conduit of cholesterol from arteries back to liver.

The whole PCSK9 monoclonal field had its legitimacy undermined when CNBC reporter Meg Tirrell broke a story on 30 July that Biomarin (BMRN) sold, for $67.5 million, a rare disease drug development voucher to Regeneron that will cut 4 months from its approval review cycle for alirocumab. This distasteful event reminds one of the ridiculousness of the sale of indulgences by the Catholic Church in the run-up to the Protestant Reformation. Drugs should be advanced on scientific merits, not certificated bribes. At fault here is neither REGN nor BMRN, but Margaret Hamburg’s FDA, which is quite OK with this abusive non-meritocratic practice, one it will likely make haste to place fig leaves over. It is because of kleptocratic practices like these that Sovaldi costs $1000 per pill. When I contemplate the drug development business in the US, “arch” and “turgid” and “epic” come to mind.

Most Irregulars who follow these biotech threads are now streetwise enough to realize that any time a drug works by blunting the effect of a protein, the same pharmaceutical effect can be achieved by using RNA silencing to suppress expression of the protein in question. To this end, Alnylam (ALNY) has already done phase I trials in the UK of a siRNA that silences expression of PCSK9. It’s unclear, however, that complete obliteration of PCSK9 is a good thing or a worthy goal, and Alnylam may be wishing to position itself to see how monoclonals to bind up PCSK9 fare before it advances itself into the lipid management arena. Alnylam has not presented phase I results, and most of its work in PCSK9 silencing is still preclinical.

Does Esperion have other attributes, other assets? It reports having acquired worldwide rights to an agent known as 4WF from Cleveland Clinic in 2011. 4WF is said to be an HDL mimetic, something that would channel lipid from areas of vascular disease back to liver, and the CSO has had an interest in these. Both 4WF and a second agent that seems to ameliorate hyperglycemia and weight in overfed mice, however, are strictly preclinical. Try as I might, I have been unable to glean any information about the molecular nature of these entities.

Then comes a question: is ETC-1002 something akin to a Second Coming of statins? I don’t know. What I can say for sure is that the PCSK9 inhibitors are not an event of eschatological significance, though Big Pharma wants us to believe that they are. ETC-1002 clearly has two strong effects in vivo, and sharply lowers both LDL cholesterol and inflammation as measured by hsCRP. It has few or minimal side effects, is compatible with other drugs and is far safer even at this stage of development than statins were ever known to be. Without resorting to hyperbole, ETC-1002 is a lot like a global metabolic tonic, one that tames the bundle of manifestations of syndrome X’s high cholesterol, high inflammation, high triglycerides, insulin resistance and high blood pressure. ETC-1002 could likely stand in the marketplace as either first- or second-line treatment for hypercholesterolemia. A vigorous search through the drug development literature suggests that no other viable oral-drug candidates for safe lowering of cholesterol are being trialled anywhere, and confirms that Esperion is in fact working along a unique mechanism and unique pathway (ATP citrate lyase), one that few know of, and one in which it has no competition at all. This is a drug indication littered with failures, and Esperion has made it past the worst of its hurdles, in my view. The architect of the strategy is the same person who brought the world Lipitor, the single best-selling cholesterol agent in history. He may be crafting another lipid home run.

ETC-1002 has completed 7 clinical trials now and done famously in all. Two new trials are underway, and the trial in patients with both high cholesterol and high blood pressure has just dosed its first patient. Data from both trials should be at hand no later than 2Q15, during which time, I suspect ESPR shares are likely to become less and less undervalued. Esperion isn’t the sort of recondite company trawling in sophisticated science that I usually delve into here, but it has a simple pill—one that works—-for mankind’s worst and most prevalent ailment, one that is likely to be sought after in an age where the best other pills no longer offer big profits. It is likely to be able to do so at prices that, unlike the costs of PCSK9 inhibitors, will not outrage pharmacy benefits managers. It’s an opportunity all the more compelling because of stealth. Seemingly no one knows of Esperion: no one has heard of it, and no one is familiar with the enzymic pathway it is acting on and the striking potency of its lead drug. We’ll be hearing more about ETC-1002 from Esperion and it’s likely to be good.

Is Esperion vulnerable to competition? Are others pursuing ATP citrate lyase inhibitors? I explored this in detail. A number of naturally-occurring molecules from fruits and vegetables, presumably not patentable, do inhibit ATP citrate lyase. Many other inhibitors exist as well, including halogen- and sulfur-substituted citric acid derivatives, the bile salt deoxycholic acid, vanadium, and even polychlorinated biphenyls. These moieties seem invariably to have one or more of the following issues: (1) severe toxicity, (2) severe side effects (e.g., radicicol is a good inhibitor, but a potent sedative), (3) unfavorable thermodynamics such that doses required would be enormous. These have been comprehensively reviewed in a 2012 paper by Zu and colleagues, and full pdf versions of this manuscript can be freely downloaded at researchgate.net. Above all else, none are even to clinical trials yet, and so Esperion has several years of lead time now.

Could Esperion be sideswiped by an RNAi company suppressing ATP citrate lyase expression? Others may try this, but bear in mind that this enzyme is life-critical, and that complete abrogation of it would likely be harmful. Also, Esperion’s drug acts by turning on the activity of the enzyme AMPK, something RNAi cannot do. Esperion’s drug candidate is a once daily pill that is well-tolerated, and since it appears to work well, it’s not likely to be supplanted by any form of injectable drug.

For more than a decade, cardiovascular disease researchers have conjectured widely about  a “polypill”….a single tablet that might contain, for example, aspirin, a statin, a beta-blocker and an ACE inhibitor. The theory has been that compliance would be so good—all agents dosed once daily in one tablet; side effects minimal as the dose of each agent would be reduced; synergistic benefits among the drugs—that such a preparation could cut cardiovascular event risk by 75 per cent. ETC-1002 has so many health-positive actions (simultaneously lowering blood pressure, lipids, inflammation and cancer risk) that one cannot help but speculatively regard it as like a single-agent polypill: one drug, poly in its effects. Esperion knows this, and continues with phase 2b studies to limn and define the drug’s actions. As explored in this 2014 peer-reviewed study, ETC-1002’s metabolically favorable effects appear to shine in patients with type II DM. Phase 3 trials of ETC-1002 are unlikely to be underway until 3Q2015 at the earliest, but meanwhile my starter position in Esperion compels me to follow the company, track drug development, and be poised to add in anticipation of good news. The drug will probably never see an indication as a cancer preventive, of course, but Esperion can leverage the ample data on ATP citrate lyase inhibition’s anti-neoplastic effects as a means of currying favorable bias among patients.

In your due diligence, you’ll come across the company’s 2014 annual report, which confirms the fiscal health of Esperion. Analysts from Citi, Stifel Nicolaus, JMP Securities and Credit Suisse cover Esperion and all have “buy” or “strong buy” ratings on it.

Stock Gumshoe, of course, is not a tipsheet. For the many PhD and MD readers who now participate in this forum, I would encourage spending 1-2 hours to read over studies I have provided in hyperlinks, as you will find the content quite gratifying. It is intellectually sexy. Biopharma investing entails consummate risks, as although the body works along fixed principles, biology is bewilderingly complicated. Even so, if ever there were a biotech insider capable of pulling off a great second act in lipid drugs, Roger Newton is probably that person. Esperion is his company.

Addendum: The author owns shares in ESPR, PFE, GILD, AKAO, RGDO and DRTX, has no positions in any other mentioned company, and no plans to trade in any mentioned company for 7 days after publication.

This is a discussion topic or guest posting submitted by a Stock Gumshoe reader. The content has not been edited or reviewed by Stock Gumshoe, and any opinions expressed are those of the author alone.



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August 18, 2014 1:11 am

For the PVCT’s fans another similar approach using Clostridium Novyi. There is tumor necrosis and abscess formation the company involved is BioMed Valley Discoveries, not public. http://clinicaltrials.gov/ct2/show/NCT01924689?term=biomed+valley&rank=2
Not one I would invest in if I could , but interesting using Clostridium. A palliative treatment probably not curative for solid tumors.

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August 18, 2014 8:30 am

Moving to the new thread!

👍 1313
August 18, 2014 9:42 am

Which thread is the “new thread”?

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June 2, 2016 5:19 pm


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April 15, 2020 11:49 pm

I feel compelled to add to Dr. KSS’s post. I am a retired physician who was treated on and off with statins for high cholesterol for many years. On one occasion, I tore two tendons in my right rotator cuff, unrelated to any physical exertion. A few years later I experienced severe pain and limitation of motion in my left shoulder (I am left-handed). I was found to have four torn tendons in my left rotator cuff. The radiologist indicated in her report that this occurred after extreme exertion. There was no extreme exertion, as I have fibromyalg