[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.
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.
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.
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.
I also echo tanglewood’s question (post 292) inquiring how to buy a low volume stock such as BIOZF in any meaningful amount. Lou L suggested buying in the Helsinki Exchange but can shares be purchased somehow in the US exchanges?
Dan: it’s easy…low volume doesn’t mean illiquid. When I bought shares, not a one had traded for 2 weeks. My order was filled within 15 minutes online. It’s not like they have to rouse some trader out of bed to execute.
Dan, I traded online with Fidelity for international stocks, if necessary, but seldom did it. The account has to be regular type, no IRA’s.
THis is somewhat repetitive, but perhaps worth it.
I trade the pink sheets (like BIOZF) on Fidelity a lot. While the volume may be low, the order is essentially a pass-through to the main exchange where it is traded, so it does not (usually) carry the same dangers as trading low volume stocks on other exchanges — as long as volume on the parent exchange is good enough to support your order without messing things too much.
The order goes through Fido’s trading desk, and then through a market maker on the parent exchange. If I think the stock is priced fairly or very attractively, I will put in a limit order that is 1 or 2 cents higher than the ask — this gives the market maker his edge, and I get the stock. If it is a very low priced stock like BIOZF, I’ll probably put in an order at the ask, and monitor it to see how things progress. Often it fills.
If’I then want to buy more of the stock, I’ll put in an order for a lower price, and let it run for a few days & see how it all works out. I have been pleased with the way Fido handles these orders, many times it fills for less than my limit. When I traded with Schwab, it never ever seemed to fill for less than my limit. Maybe it’s just the way it worked out for those trades, but I suspected that someone was pocketing the difference between my limit and the price they actually bought it at. I have no proof at all of that. I stopped trading with Schwab several years ago.
Thanks Tim for the tips. I seldom trade the pink sheets and always use day limit orders. Depending on the way the stock is trending and the gap between the bid and ask, I usually make an offer in the middle. I am also not too crazy about partial fills so I will sometimes specify ‘all or none’. It looks like I will have to change my strategy when dealing with pink sheet stocks.
Oregon tabled Sovaldi decision this afternoon. Disappointing as they have huge HCV problem per capita. Oregon MedicAid confided to someone I know that they “know they will have to come around and cover it.”
Chilling event in product liability today: an Alabama court has upheld a plaintiff’s right to sue PFE for harm done by a generic version of Reglan not made by PFE. This is psycho and deeply disquieting. The risks of Reglan are highly well-known, and to me it is the plaintiff’s fault for continuing to take it long after side effects had begun. With Reglan there is a period of time of months in which you can stop it and the neurologic effects abate.
GILD up, CTIX up, FOLD up, ESPR up, new Haruki Murakami novel out, Rick Perry indicted for well-known abuse of power…good weekend!
BTEBY up admirably hopefully another dose is achieved soon. A happy good weekend as well!
It was a good day for my portfolio yesterday, thanks in large part to you, Dr. K, GILD almost hit 100, yay! 1Q84 was a good read I’ll have to check out the new novel. Glad you mentioned it. Hope you have a great weekend 🙂
I think the only reason more people aren’t in GILD is that there really are some out there who think that its products are going to rapidly hoover up all the HCV and the moneymaker thing will be over. Well, guess what? There’s not the MD manpower in the US to get all those patients cured in 5 years. It will take 10. And by the time the HCV buzz abates, the company’s vast pipeline will be percolating, and replacing/supplanting all those revenues. It is purely speculative, but I just wonder if GILD is thinking about plucking CLDN. There are some sub rosa ties between the companies. It’s the kind of company GILD would like.
If you have Netflix, you might watch “Norwegian Wood,” based on Murakami’s novel of the same name. He collaborated with the makers, mainly Tranh Anh Hung, the director. For me personally, it is the most life-affirming film and novel I know of. Murakami’s short story “Thailand,” which appeared in the London quarterly Granta, issue 74, is my favorite short story of all time. Murakami, somehow by touching the mysterious, by letting you glimpse at the things that are otherwise ever darting away from the corner of your gaze, makes you shudder and thrill to be among the living. I have a galley proof of “Norwegian Wood” signed by Murakami, and it’ll have to be pried from my cold dead hands.
You can watch on you tube as well here.
https://www.youtube.com/watch?v=neK1yJAWyYs.
copy and paste the link above.
Cheers.
What a movie. Opens your eyes to how much love hurts.
More info on RGDO allergy halt.
http://seekingalpha.com/article/2426775-regado-biosciences-revolixys-kit-assessing-the-risks-of-allergic-reactions?uprof=46&dr=1
it’s lousy, Frank. He is trying to argue it is because the combo of pegnivacogin and anivamersen generates dsRNA. What a pseud. The event happens before anivamersen. dsRNA binds to TLRs to cause IFN release…..hours later! Save us from the SA “brain trust.”
DR thanks for science input,,,,I was more interested in description of allergy reactions,,#3 sounded non serious, In re Oregon medicaid ,,,OREGON ocare spent all the treatment money on a website that does not work,,,now they are looking in old suit pockets and under sofa cushions for spare change until they can raise taxes. IMHO
My browsers, both chrome and IE11, are infested with adware recently. McAfee I have doesn’t seem to help. Found a site with instructions to rid off the nuisance.
http://malwaretips.com/blogs/remove-adware-popup-ads/
Single enzyme is necessary for development of diabetes
An enzyme called 12-LO promotes the obesity-induced oxidative stress in the pancreatic cells that leads to pre-diabetes, and diabetes. 12-LO’s enzymatic action is the last step in the production of certain small molecules that harm the cell, according to a team from Indiana University School of Medicine, Indianapolis. The findings will enable the development of drugs that can interfere with this enzyme, preventing or even reversing diabetes. The research is published ahead of print in the journal Molecular and Cellular Biology.
http://medicalxpress.com/news/2014-08-enzyme-diabetes.html
Nice report.
The PR machine has tried to spin it into something bigger (I can assure you things are much more complex than involving a single enzyme…..100 is more like it), the underlying study is good and advances the field.
Some strategic entity, seemingly in Australia, picked up 260,000 shares of Benitec this week.
DR KSS, this would be BLT.AX ??
You may have missed this yesterday, someone picked up 39K @ .91 and 234K @ .92 shortly before the close yesterday.
Dr. Suhy responded to an e-mail I sent him a couple days ago. Seemed like a really good guy. “Took issue” with a couple things I brought up. Said Benitec has had a CRO for the last 18 months called Synteract-Hcr. According to him they were helping on the screening and recruitment process. He didn’t comment on the delays and whether they had other people on the sidelines for the second dose. (I think that means they didn’t, lol.) Asked for continued support and said Benitec’s goals are in line with shareholders. Enjoy the weekend everybody.
Tim: interesting, but doesn’t that really in fact make things all the weirder?
On one of Sonic Youth’s albums, “Murray Street,” I think, there’s a song I always think of lately when I think of Benitec:
“There are the words
But not the truth.”
So what did Synteract do for the first 12 months they were on retainer and nothing happened? Pat French on the rump reassuringly? Why have shareholders not been told of this? If they have been involved and things are as dilatory as they are, does not convey things are 10x more FUBAR than previously thought?
In medicine we often have to deal with the so-called “well-defended” patient…usually people with personality disorders who do not thrive, are not ever happy, and cause unhappiness in others….and continue to see you because they want YOU to change the world for them. They are well-defended in that regardless of whatever way you probe their role in their own problems, there’s an excuse, a reason, a basis for why they are as they are and why they have acted as they have. It’s never them….no. Benitec is so intensely like this. The problem with their defenses is that if the patient in question, or Benitec, did not exist, the problem would cease to exist. To Benitec there is no problem…only bloggers and pesky shareholders: they are the problem. To Benitec it is quite OK to have taken almost 5 months to dose a patient. ANY time a clinical trial takes more than one month to find and dose a patient, it means one thing: the criteria don’t fit the patients. Which means another thing: the trial is absolutely meaningless! Its outcome does not count because it was not done in people typically with the ailment.
For this reason, I feel there is absolutely no point in talking with the company anymore. Falcon cannot hear falconer. ALL my recent interactions have had one theme: I am mistaken, I am told, horribly in error. Benitec will find words, phrases, sentences and claims to plaster you with how you, the asker are wrong. Benitec does not errr, you do! You’ll get from them what Beavis and Butthead would call “uh…words…..words……words….blahblah….words.:
Interests aligned with shareholders??? What politician verbiage crap. “I stand for what’s good for everybody.”
What rocket scientist at Benitec or Synteract decided to try TT-034 on only genotype 1’s first??? Was that possessed of the soundest of reason? No. In genotype 1, macrophages in and outside the liver are the reservoir and it is bloody hard to eradicate. You do NOT start out your trial, using shareholder precious capital, on the most difficult patients. You start small, with easy goals. They should have started in gt 2 and 3, easier to cure. See if it works there before going to 1’s. If you can’t cure a 2 or a 3, you have zero chance of curing a 1. But then hey WTF do I know? I am just an MD hepatologist with a PhD in hepatocyte biology. What I know sure as hell is not relevant to them.
Since he is so sure Benitec’s goals are aligned with shareholders, wonder what that means the goals are? My goal is one thing: share price rise. Shares will rise when one thing happens. Is it
(a) Yet another road show?
(b) yet another “deal” with another “company” trying to pretend to do something?
(c) another collaboration with another PhD who wants to advance his career and get tenure by dabbling in Malus Exoticus Raris?
(d) when they hire someone else?
(e) when Calimmune announces data?
(f) clinical trial data?
It is f and only f. Nothing else matters. Even so, there is no hurry, no rush, to get its one clinical trial done, a trial on which others wait, and the company is not even reporting all the data from its one dosed patient! What was his HCV RNA? His level of circulating shed exosomes? We as shareholders are funding this study and have a right to know that data.
I agree Suhy is a good guy. But William James wrote of how goodness is typically a very weak commodity. it doesn’t get stuff done. Evil is strong. He won’t stand up for anything in the company because he’s an odd-man-out American, and because he is thrilled to have a job that lets him do the bench science he likes without competing for grants. The Benitec train could be headed at full speed to a gap in the mountains where the bridge is out, and he might even know it, and he would be the last person to say anything.
Feb went by, then March, then April…and we are to believe that in none of that time it occurred to mgmt to open up a second site? That’s the problem: it DIDN’T occur to them! They are so out of touch!
Of mgmt I would say: You can lead a horse to water, but you can’t make him ski.
New verb for OED: Benitec: as in, “to Benitec a situation”…means taking issue with anyone not blithely and passively satisfied with mgmt, even when things aren’t going as planned.
Synonym: Captain of the Good Ship Lollipop scenario. In “Candide,” Voltaire had Dr Pangloss go on and on about how we are in the best of all possible worlds. “Everything’s FINE Dmitri…..F I N E…..You say you’re FINE, well I’m fine too Dmitri….Everything is fine!,” said President Merkin Muffley in “Dr Strangelove.”
Dr. KSS
I love reading your post and I like when you go off as I believe in your expertise. I’m trying to be positive as people can post down to me as I’m just an ordinary Joe investor and you probably forgot more science than I know. Thanks for your knowledge and I’ll try not to go off anymore.
I think his ‘niceness’ can be translated as stonewalling with a smile. I’m reminded of an inquiry in held in OZ where a British Civil Servant was being grilled. Later he was recalled and accused of lying coz he forgot to mention something crucial. ‘Certainly not! I was simply being economic with the truth……happens all the time in the Civil Service.’ 🙂
Doc Kss,what is your take on this patent granted to CTIX yesterday?Think this had something with movement up yesterday or just coincidence?
http://www.4-traders.com/CELLCEUTIX-1681790/news/Cellceutix–Assigned-Patent-18907220/ Here is the patent link.http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8,802,683.PN.&OS=PN/8,802,683&RS=PN/8,802,683
Cheers,Glenn
Glenn: I don’t think this is the reason for the price rise, but it does cover brilacidin-OM development and gives insight into company thinking. It acts as a “fright wig” in a way to other who might get in the space, as it creates a case for oral mucositis to be related to the sum total effects of the mouth biome (bacteria and fungI). It also does hint at the biggest impediment to systemic development of brilacidin….toxicity to the host. CTIX has said little about that. It’s quite unusual for an antimicrobial to be developed for both topical and systemic use. A good patent, though.
Thanks Doc for the great insight as usual.Exciting times to be a shareholder of this company right now.
Cheers,Glenn
To Frank Archambeau and Dr KSS regarding RGDO allergic rxn according to SA braintrust:
“Three patients had allergic-like reactions shortly after pegnivacogin administration; two of these reactions were serious. The first patient had a history of allergic urticaria treated with corticosteroids and antihistamines 1 month prior to enrolment. She developed nausea, pruritus, and shortness of breath 5 min after pegnivacogin administration and was treated with corticosteroids, antihistamines, and short-term vasopressor support with resolution of all symptoms within 2 h of onset. The second patient had a history of allergy to radiographic contrast and multiple other allergies. She developed generalized urticaria without respiratory or haemodynamic changes, and was treated with steroids and antihistamines with resolution within 25 min. The third patient had listed allergies to beta-blockers and steroids. After receiving pegnivacogin, she developed dyspnoea and cutaneous tingling. She was treated with corticosteroids, antihistamines, and haemodynamic support after developing tachycardia prompting cardioversion.”(sic)
All of these may not be serious at all, and may not even be related to pegnivacogin or RNA. Without seeing the actual chart and what was done and how the patient looked, I can’t say if this was really even life threatening. Cardioversion is a broad term, and may just be SVT and carotid massage or Adenocard, but it could be pull out the paddles and blast them for V-Tach. Even the rhythms could be misread and not needed that aggressive of treatment. Some people have neurotic reactions with hives or may have some c1 esterase or some undiagnosed immunological response with hives. I’ve never seen this report in this detail, maybe not accurate, but I don’t think it is anyway related to TKMR’s cytokine storm. I suspect this will blow over, but RGDO should see if those with adverse reactions to contrast, multiple allergies or history of unexplained hives could be excluded.
The drug is a polyanion, and probably does an alternative pathway activation of complement. I don’t feel it is a true cytokine event, as such would take more than a couple of hours, usually, to set into motion. Many of these are peri-MI patients who can already be subject to “cardiac asthma” on that basis also. “Nausea, pruritus and shortness of breath” have one thing in common: they are subjective, not objective. For many people, if you say “I’m giving you The Compound now,” this is exactly what will happen and it in no way means anything is wrong.
Many thanks to you, DBMD, for your post, and to Dr. KSS and all of the Irregurlars contributing to this site. You all are greatly appreciated.
Rumors flying in blogosphere today that $GILD getting ready to acquire. Wouldn’t a $GILD takeover of $ACHN—-just to make its drugs go away—be interesting?
What will keep GILD shares growing is revenue stream…which means new sources of revenue, or else protecting the revenue stream you have. ACHN’s drugs could impart to JNJ an ability to run at GILD’s share of pie.
Gregg Alton, the powerful person at GILD who priced a pill of Sovaldi at $1000, is a CLDN director. CLDN wouldn’t make GILD money immediately, but is poised to really bring in bucks in 2 years.
Sounds like things could heat up with ACHN this week Doc.
Cheers,Glenn
Hmm….ACHN up 10% to its high of the year. Looks like you’re not the only one to spot this opportunity. Thanx for bringing it to our attention.
Long KSS
I would throw another wild card – BLT.
Doc. I have one for you to look at if you get chance please. Their financials do not look great but they just completed a offering for 2 million dollars,which may get them through phase 1. Science looks very interesting especially their breast cancer vaccine.The company is TapImmune(TPIV) and they sit at 1.25 and have coverage on them with a 6.97 price target.They just hired Dr. Knutson to their scientific board who has a nice background.
http://finance.yahoo.com/news/tapimmune-appoints-leading-immunotherapy-researcher-211600548.html
Here is a fact sheet. http://www.tapimmune.com/_resources/One_pager_April_2014.pdf
This is the research report back in May. http://www.wsav.com/story/25618581/seethruequity-initiates-research-coverage-on-tapimmune-with-target-price-of-697
Cheers,Glenn
Glenn: let me study it. I am not sure why…I thought TapImmune had been phagocytosed into Abbott. Maybe I am thinking about TAP…different co?
Doc KSS, I have one for you to look at if you get chance please. Their financials do not look great but they just completed a offering for 2 million dollars,which may get them through phase 1. Science looks very interesting especially their breast cancer vaccine.The company is TapImmune(TPIV) and they sit at 1.25 and have coverage on them with a 6.97 price target.They just hired Dr. Knutson to their scientific board who has a nice background.
http://finance.yahoo.com/news/tapimmune-appoints-leading-immunotherapy-researcher-211600548.html
Here is a fact sheet. http://www.tapimmune.com/_resources/One_pager_April_2014.pdf
This is the research report back in May. http://www.wsav.com/story/25618581/seethruequity-initiates-research-coverage-on-tapimmune-with-target-price-of-697
Cheers,Glenn
Glenn: I would avoid TPIV for the following reasons:
(1) you might want to take a look at who else SeeThroughEquity has “buy” ratings on: AtheroNova, Tonix, ISCO…….real “choice” companies. If you were buying a house, don’t think you’d want STE for your realtor.
(2) TPIV has produced no papers in 7 years
(3) TPIV has been in existence since 1998 and yet has only now gotten one trial to the phase 1 stage. Very troubling.
(4) trials company claims it is doing are discrepant with what it IS doing
(5) its one trial is single center…..disquieting.
(6) the science is unsettling….they make verbal claims for their method increasing Th1 activity, but their papers suggest it only reduces Th2 activity. If your shower is running a mix of cold and hot water, and you turn off the cold, it will get hotter…but not hotter than the intrinsic hot water stream! This is what the company wants you to believe.
(7) the chart is absolutely wretched. Multiple reverse splits. This stock has gone forever down for most of its existence.
(8) current breast cancer phase 1 began in summer 2012…and still no interim reports.
If it ever makes it to 6.97, it will be after Hillary has finished her second term in the WH and we are living on Mars and Putin has been canonized by the Russian Orthodox church.
Thanks Doc Kss for taking the time looking at this one.You cracked me up Doc with the statement after number 8.Sorry for wasting your time on this one.
Cheers,Glenn
A discussion about tramadol. Very problematic drug, one I don’t rx. Causes real problems for pts,, and gives little benefit.
http://www.cmaj.ca/content/185/8/E352.long
Many of us wish it would be withdrawn.
Given the geologic time scale that its current trial is following, would it be:
a. scientifically valid
b. economically feasible
c. FDA appropriate
for Beni to initiate a second trial with more realistic parameters of exclusion that would go after the lower hanging fruit of the type 2’s and 3’s? They could maintain their overblown bravado surrounding the current approach, admitting nothing, while concurrently moving the bar forward and potentially realizing the hopes of all concerned. Just a random Sunday thought.
Yes, Jim, it really would be and that’s brilliant thinking! The current trial is a phase 1/2a. The first two patients, they’re the phase 1 part. So they could go after gt 2 and gt 3 patients after the second patient is dosed and “does not do” a Gelsinger.
What everybody in hepatology knows, and they seem to want to ignore us and the literature, is that gt 1 is different not in degree but in kind. Same virus overall, but very structurally divergent from ALL other strains. It is sort of like gt 4 in clinical behavior. HCV-1 is cardinally very macrophagotropic. A common mistake people make is thinking one kind is more pathogenic than another…not true (although 3 may be the worst). If you breathe on gt 2, it goes away. So, if TT-034 cannot cure a 2, what good is trialling it in the toughest patient?. Gt 3 to be sure is harder to cure than 2, but is still a difference in degree, not kind, from 2’s difficulty to cure as compared with gt 1.
Since they are already talking about it in their deliberations publicly I won’t keep quiet about it any longer. When cells are transfected with ddRNAi-expressing vectors, those cells shed exosomes bearing shRNA. So, if TT-034 is to work, it will do so by hepatocytes giving off shRNA blebs of membrane that fuse with other cells. In a sense, the liver here is the stone in the soup. They could just as easily put the same 3 shRNA-encoding DNA strands into an AAV-1 transfecting muscle and bung it in systemically, and let muscle shed the exosomes. Muscle does not get toxic very easily the way liver cells can! Again, a cardinal point that has to be made here is that HBV AIN’T HCV….it is in only 1/10 hepatocytes….hardly hepatotropic, I’d say. HCV is somatitis C.
To Don Barrett: a friend who has scouted and tried many probiotic strains tells me that this is the one with that is highest in both biodiversity and organism count. It isn’t cheap.
http://www.renewlife.com/ultimate-flora-probiotics/ultimate-flora-mega-potent-150-billion.html
I will say most of the preparations have pitifully few species, 5-8 at most.
Very kind Doc; thank you!!
A stirring is occurring down under….nice volume in first half hour with shares markedly higher.
BLT down under is $1.07…up 12.63%……..475,023 shrs so far today.
Dr. KSS;
Patrys seems to be on a move; are you still a fan?
Watching BLT down under — rise