[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.
DBMD: my mantra on plazomicin from $AKAO is that it lacks all the usual aminoglycoside tox manifestations. Therefore you just pour it to the patient, at high doses n times MIC. It can thereby overwhelm AG resistance mechanisms.
understood, aminogylcosides always impressed me with their oto and nephrotoxicity, even while a medical student. Why wasn’t there something better? Nobody seems to get it! This is a long overdue drug.
Interesting news from Cubist(Glass found in their vials)
http://investors.cubist.com/file.aspx?IID=4093793&FID=24738832
Cheers,Glenn
proactive on their part, sounds like they are trying to do the right thing
This may have appeared earlier?
http://www.asia-insider-news.com/news/newsDetails/6278
It seems to show that CSIRO have no stake in Benitec while Peter French insists that they do ? Does Scorpio have a good point in post 69 concerning contacting RA Capital?, he received no reactions!
Peter French stated that they had not sold one share.
True as long as they sold zero or more than one.
The only record I can find about CSIRO is from BLT website. CSIRO % of holding changed due to private placement on 20140228. Its total holding 1,924,658 remains the same. Anyway, it’s interesting that RA sold shares at a loss, per your link. I still cannot find any record of Sabby.
http://www.benitec.com/documents/Ceasingtobeasubstantialholder.pdf
Tom, I think that link is wrong and found this one:
http://www.asia-insider-news.com/news/newsDetails/3591
DRTX: found this on Yahoo message board. Checked CMS site but can find nothing. Found http://www.appliedpolicy.com/2014/08/fy15-hospital-ipps-final-rule/
CMS denies DRTX NTAP coverage of dalbavancin
Durata Therapeutics—Denied–
Dalbavancin did not meet substantial clinical improvement criteria
WTF
There are some shorts on that board that will say anything. Yahoo’s message board reliability is pretty flimsy.
The link looks legit. What is CMS NTAP? Is that additional payment or CMS won’t pay the use of Dalbavancin?
Opposeable Thumb,
Thanks. The link you provided has a link in its first line, which goes to a CMS document. If it’s genuine, and it appears to be, apparently the Center for Medicare and Medicaid Services did deny dalbavancin’s application for add-on payments:
“in the case of this application, we do not believe that the technology meets the substantial clinical improvement criterion. Therefore, we are not approving new technology add-on payments for Dalbavancin for FY 2015.”
The CMS document is here: http://www.ofr.gov/OFRUpload/OFRData/2014-18545_PI.pdf
The passage regarding Durata (found by Control-F) takes you to their discussion on dalbavancin on pages 326 to 345. My quote above is from the last 2 lines of their discussion on p. 345.
An add-on payment is apparently an extra payment CMS would make for the use of a new technology, to cover its cost. Here’s a link to the CMS website covering “New Medical Services and New Technologies”: http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/newtech.html
A line from this says, “to receive special payment treatment, new technologies meeting this clinical definition must be demonstrated to be inadequately paid otherwise under the DRG system.” Not familiar with this field of govt. reimbursement, so am not sure if this means they won’t cover it or they won’t pay the extra add-on amount Durata requested.
Two articles (LA Times and WSJ) at link below concern use of experimental Ebola drug. Jiminy – looks like a “no-win” situation for the drug developers and governments alike. Hope it’s a win for the two missionaries, but, if they recover, we will never know. I’d like to think this might stimulate some innovative thinking about experimental drug availability in future public health emergencies (if only to articulate the reasons why it’s a bad idea under any circumstances, if that is the most reasonable conclusion), but what an ethical tangle it is.
http://www.kaiserhealthnews.org/Daily-Reports/2014/August/06/public-health-ebola-drug-concerns.aspx
Seems there is already some misinformation afoot about $DRTX.
Durata began pursuing CMS coverage for dalbavancin as early as last winter, and was on a March 2014 CMS meeting agenda to procure a new ICD-10 code as a New Technology Add-On Procedure. According to a June 2014 Forbes article, CMS was to decide on this at a mid-August meeting. A CMS denial of coverage for dalbavancin would make little sense, as despite the drug’s price for a one-gm dose, it is far cheaper than a 3-day hospitalization.
Why do I mention 3 days? Well, let’s be clear: I love and am long $DRTX. BUT, DRTX mgmt is being quite disingenuous, I feel, with the rather nonsensical premise it is advancing that patients will get one dose a t-nought and then a second dose 7 days later. This is quite silly. One gives iv antibiotics to at tisk patients to establish control and get things under control. Almost never does initiation of therapy in iv form mean it must be completed in iv form. And as I think DBMD or any other MD reader with trench experience managing cellulitis and sepsis, the goal of dalbavancin is to get control, get ’em home, and provide a bridge to oral therapy. DRTX’s brass must be smoking Colorado’s Finest if they honestly think CMS and private insurers are going to cover a second dose a week later. That’s rather nutty. You would send these patients out, or at least I would, with an rx for an appropriate oral (cephalexin, dicloxacillin, linezolid) to begin about 5 days later and take for 5 days total. People deliberating about this around the idea of getting revenue for two doses per patient are just lacking in a sense of real world context and how infections are managed. Just because you start therapy iv in no way means that it must be iv for its entire duration. And frankly, while I think DRTX will get sNDA label changes to market 1.5 gm doses as that spikes plasma to have an adequate blood level for 10-14 days, payers may not cover this. Orals will always be cheaper, DRTX should not be greedy. A good 1 gm dose will tide people over til response can be assured and they can safely begin oral meds. But I see no evidence CMS has turned this down and would be quite surprised if they did. Keeping people OUT of hospital, where they only add to and are subject to the nasty-bug pool, is the theme of the times.
Thanks Dr. KSS. I did not sell as I found it strange with nothing on the CMS site. Would hope CMS would publish it before anyone else does. Earnings tomorrow, last minute short attempts a possibility?
Thanks! Strong work. Good to know.
Meant the above for Patrick.
Dr. Kss, I called Investor Relations @ Durata and was told the company did not view the CMS denial as a “negative” and that it would be addressed in tomorrows conference call.
Dr. Kss,
Thank you so much for taking the time to explain this. I appreciate you!
Dr. KSS: Although I have not studied and cross-checked this reference, it does appear that CMS denied the DRTX application for an ICD-10 code as a New Technology Add-On Procedure: http://www.appliedpolicy.com/2014/08/fy15-hospital-ipps-final-rule/
CMS Approves 3 of 5 New Technology Add-On Payments (NTAP); Denies Two for Failing to Meet Substantial Clinical Improvement Criteria
CMS received seven (7) applications for 2015 NTAPs. Two were withdrawn. The results of the remaining five are summarized in this table:
Product Company Result Rationale
— Dalbavancin Durata Therapeutics Denied Dalbavancin did not meet substantial clinical improvement criteria
— Heli-FX EndoAnchor System Aptus Endosystems, Inc. Denied Does not meet newness criteriaDoes not meet substantial clinical improvement criterion
— CardioMEMS HF Monitoring Systems CardioMEMS, Inc. Approved Meets all criterion
— MitraClip System Abbott Vascular Approved Meets all criterion
— Responsive Neurostimulator System NeuroPace, Inc. Approved Meets all criterion
In public comments on the proposed rule, AdvaMed and other organizations expressed concerns about the restrictive policies CMS uses for approving new technology add-on payments (NTAP). In particular, they commented about CMS’ position statement on the use of non-inferiority studies to demonstrate substantial clinical improvement. Most manufacturing companies believe that a policy to require superiority studies, or to question non-inferiority studies, could delay patient access to innovative treatments and improved health outcomes, curtail innovation, and discourage competition.
• CMS responded that it does not intend to have a blanket judgment as to whether non-inferiority studies are insufficient to demonstrate a substantial clinical improvement and that applicants can use data from non-inferiority studies to demonstrate superiority. Applicants can also demonstrate substantial clinical improvement by showing that:
• the treatment is the only option for a patient population unresponsive to, or ineligible for, currently available treatments; or
• the device offers the ability to diagnose a medical condition in a patient population where that medical condition is currently undetectable or offers the ability to diagnose a medical condition earlier in a patient population than is allowed by currently available methods.
Wow, Lawrence. Thanks. That’s a bummer. Snagged on being merely non-inferior as opposed to superior perhaps. But dalba’s superiority is in cost, in overall cost to a payer. This is CMS being dunderheaded (which they wrote the book on, I think). It does not provide better outcomes bacteriologically, but is clinically better because patients do not have to go be admitted. This will have to be appealed and fought. I feel it can be won, but will take another year’s cycle. Most unfortunate. I think it is important to provide a little context on how improvident CMS is. The Greenlight photovaporization procedure for prostatism, keep in mind, was devised and ready to go clinically 20 years ago, and nearly disappeared as CMS would not cover it, even though it is safer and easier on the patient. It is now covered, but it took campaigning. I am not sure how many years it has been in use and covered, but it was on hiatus for many years. This may prove to be a situation where price-point becomes a basis for negotiation.
If I understand correctly what NTAP is (no guarantees that I do), it provides additional payments for new technologies for which the established prospective payment rate for a diagnosis does not adequately compensate the hospital. The Forbes article you cited somewhere above explained that hospitals would be disinclined to use the more expensive Dalbavancin over vancomycin in the absence of additional compensation via NTAP payments, which we now know they’re not going to get in 2015. However, as the Forbes article noted, one pertinent question is whether hospitals’ arithmetic would change if use of the more expensive Dalbavancin actually decreased their costs by shortening hospital stays. If, however, the chief advantage of Dalbavancin is that (some/many?) patients can be infused on an outpatient basis, it seems to me that NTAP eligibility of the drug would be irrelevant in those cases, and the Medicare Part D rate for the drug is what would be important. I will be very interested to hear what DRTX has to say about this.
Yes, well said and me too. If not in hospital and patients want to dodge the rigmarole of ERs (who wouldn’t?), then it needs to be givable in doctor’s offices. Many don’t routinely give iv’s, and don’t have pumps to meter flow rates, but this should be a bag set where one pushes 100 cc of saline in, dissolves the drug and lets it drip in over 30 minutes. So intellectually simple and appealing, made difficult and frustrating by our supervacaneous system.
The final rule cited in the article above was indeed filed with the Federal Register on Aug. 4. According to the Federal Register website, it will be officially published Aug. 22, but it is available for viewing now. The whole rule concerning the hospital prospective payment system (of which NTAP payments are just a small part) for 2015 is 2442 pages long and can be found at https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-18545.pdf. The discussion of Dalbavancin begins on page 326 and ends on page 345. Unhappily, the rule does indeed deny NTAP (New Technology Add-On Payments) for Dalbavancin. There is an explanation of NTAP in the rule beginning on page 278. A “WTF” moment, indeed.
As to the lack of clarity about CSIRO holdings in Benitec, again my Oz colleague and I shared a screen shot in March or thereabouts showing CSIRO dumping about a 10 per cent stake as of 28 Feb 2014. Possibly it was in error, but that is what it showed, as does the image in one of the links someone has posted today. Sabby dumped its position a while back, and I knew RA Capital had lightened up a while back.
If someone wants to give me a name and e-mail of the right go to person at RA CApital, I will be happy to make a strong case with them that they need to help us accomplish changes. Scorpio had a fine idea. Benitec considers Buchi to be the spokesman on its board for American investors, and I suspect he is in on the ego-syntonic groupthink dysfunction. The company is not being led, as mgmt only reacts, makes excuses, depicts itself ALWAYS as the victim…of bloggers, the FDA, and circumstances. I think people have often not understood my aims in taking the deliberative approach to Benitec I have, as some seem to think I am both long and trying to poison the well. I am trying to effect change there, so that my investment will reward me, and so that the investments of other irregulars will reward them. Mgmt has not made good on any of its aspirations it pitched last year, and seems not up to the task, and so now the only way for a long position in Benitec to come to fruition is for change in leadership. Readers here who think one should simply lie back, think of England (or Oz) and led mgmt have its way with investors do NOT understand biotech. The Peter Principle is in control at Benitec, as in Lawrence Peter. Biotech races are NOT won by going slowly.
DR KSS I agree,,,,in the case of a newly planted field/garden and in startup companies it is a case of grow or die. Beni should be working on getting clearance to get a product to market or sell out and let someone do it who is capable.
Doc, Thanks for volunteering. Looks like Amanda Daniels is the one to approach.
P: 617.778.2509
F: 617.778.2510
adaniels@racap.com
You can find other names from their website: http://www.racap.com/team/
I’d almost think kroy@racap.com (if you are a healthcare or life science company – gumshoe biotech startup) might the one to contact. Probably the best guy to get a hold of would be Peter Kolchinsky, Ph.D, but no email is found on racap.com. He does have a linkedin profile, so he might be contacted that way if you have a premium linkedin account. Certainly, Amanda Daniels would know who to direct the letter to, but not sure it would necessarily get past her filtering process.
About $CLDN, I am afraid I did not remember verse and note everything I had written about it, but it’s quite right about CUPID-2b having SPA, and possibly being a springboard into direct FDA approval with phase 3. This would be a likely situation for that to happen. Even though final data are not in and won’t be for months, I can assure people that BY NOW, based on the tempo of CHF and how often those patients customarily need readmission for inotropes and diuresis, CLDN does have a sense of what the overall outcome likely will be. I feel they are acting on that data by seeking new funds, as the aim is to get Mydicar to market. It is hard for me to envision another reason for such fiscal action at this stage. It implies however that buyout is not imminent.
Opposable: still now word on oritavancin. PDUFA is today. If the outcome is announced, I cannot find it. People need to keep in mind, DRTX is still a company with an approved drug for a broad indication. Regardless of CMS, it is an undervalued company here.
Opposable: still no word on oritavancin. PDUFA is today. If the outcome is announced, I cannot find it. People need to keep in mind, DRTX is still a company with an approved drug for a broad indication. Regardless of CMS, it is an undervalued company here.
For Dr. KSS re Post 107 above pertaining to DRTX versus CMS:
In a Quorum Consulting letter dated May 12, 2014, it was noted (at page 10) that “CMS expressed concern with the details of the (Dalvance) trial design and the primary efficacy endpoints used within those trials that were used to provide the clinical data supplied by the applicant.”
[Note also that the NTAP applications cited in the Quorum Consulting letter essentially track the applications cited in the secondary reference cited in my previous post].
http://www.quorumconsulting.com/docs/Summary_of_FY2015_IPPS_Proposed_Rule.pdf
The following reference consists of an AHIMA letter dated April 17, 2014 which discusses issues addressed during a March 19th ICD Committee meeting:
http://library.ahima.org/xpedio/groups/public/documents/ahima/bok1_050664.pdf
Remember that I am just the messenger here – but if the issue is confirmed and remains unresolved (highly likely), having to do battle with CMS (charitably called dunderheads by Dr. KSS) would appear to put DRTX / Dalvance at a substantial competitive disadvantage vis-a-vis oritavancin / MDCO. [additional separate comments via subsequent email].
Oritavancin suspense is killing me. Is the late notice going to be a no?
Hopefully! Doc if you had to guess how much do you think the CMS issue hurts Durata?
Matt: it ‘s not small, as the patients who tend to get cellulitis and to fall under the eerie rubric where the treating MD feels they need iv antibiotics (?elderly, ?diabetic, ?chronically ill, ?decreased physiologic reserve) are often public-paid patients. But I admit I am still not sure if what we know about the CMS stance means they don’t pay at all, or if they don’t pay an add-on fee such as reimbursement of a tech fee for an outpatient infusion? I truly don’t know. When I try to grasp these reimbursement arcana and realize how little they have to do with taking care of people, I just want to grab heaps of my scalp and pull. The goal is to make it complex so as to trip people up and ensnare them.
Having worked in government bureaucratic double speak for the past 8 years, it sounds like it wont pay an additional “add on fee.” That doesn’t mean that it wont pay for Dalvance, it just means they wont pay extra. That’s my read, so it looks like fairly minor bad news. Correct me if I am wrong as it’s quite possible. Bureacratic double speak is meant to confuse so the bureaucrats can pretend like they have the inside scoop and are smarter than everyone else (obviously not the case–true only in their delusional world).
I found a 2010 study on NTAP for a dissertation.
http://conservancy.umn.edu/bitstream/93750/1/Bockstedt_umn_0130E_11164.pdf
Bottom line was that the NTAP had a small effect on the utilization of a particular medication/technology. One of the reasons was that the doctors choose what to prescribe. Hospitals were not particularly good at capturing value from the NTAP.
Found this explanation of NTAP
http://content.healthaffairs.org/content/27/6/1632.full
If it helps, I replied to Opposeablethumb’s post #104 with a link to the CMS’s discussion of dalbavancin, if anyone wants to read it. However, I was slow, and the thread has kind of left it in the dust. Trying to contribute something here.
I just did, too, replying to post 107. You beat me to it, and I’d have saved myself some work if I’d seen it – thanks!
To D Brown: I meant to answer your follow-on question about HCV last night. As far as screening now, I really think it is going on at an intense pace, especially since some providers can get their knuckles rapped by insurance panels if they do not screen. Based on prevalence, rate of ID of new cases, the CDC believes that 72 per cent or so of cases have not yet been identified. I can say personally, from my vantage, I feel that figure is high, as mostly what I am dealing with is not new diagnoses, but this large morass of patients who either failed prior IFN-based tx, or else who never were candidates for it. These patients are just everywhere in large numbers. One thing to keep in mind is that there was a point in our cultural history when HCV was very much “out there” and being passed, before people knew it was out there and being passed. They now know ways to avoid getting it. But the period of time when it was actively being passed around was long enough ago that those patients, by the mere nature of biology, are mostly now of an age that they are in the healthcare system: they are not young anymore. Standards of care are pretty much calling for testing everybody once for HCV and HIV now. I personally think that’s low yield and costly, because overwhelmingly people with these have definable risks. Some may not want to say what their risk is, as they may not want it charted, but they will tell their doctors they have risks. People can now also use Orasure test-at-home kits too. But mostly I am not on the front lines but rather am taking care of people with established disease. For HCV newly acquired cases are not at a zero pace, as we have a minor booming heroin problem, but most cases are chronic and long-established. Companies like Gilead poll MD’s constantly (online studies where the MD gets paid for completing a questionnaire…and the software is slick enough to be sure your answers are self-consistent, that you are not padding) to gage numbers under care, numbers being treated now, numbers warehoused, numbers who failed prior rx. Industry estimates are based on these and over the long-term they are quite accurate I feel.
Interesting and helpful…thank you.
It’s very odd indeed….in biotech the no-news-is-good-news does not apply. But still no news on oritavancin from $MDCO. This drug has been sent back a couple of times by the FDA. It had completed a phase 3 trial better evaluating MRSA efficacy and seemed destined to get the nod.
By the way, one of orita’s virtues is that it kills anthrax. I did some checking: actually dalbavancin does also, and at fairly low doses as well. So dalba does this and has the advantage over oritavancin that dalba also is effective against plague (Y pestis). Dalbavancin is the better drug. Whether MDCO gets approval or not, this event should clear some lingering uncertainty out of the way for DRTX. If dalbavancin is not CMS-covered, neither will oritavancin be covered.
From my (limited) understanding we are here talking only about New Technology Add-On (NTAP) which is only one component of the reimbursement package.
I think you are correct Terje–see my post above re. bureaucratic double speak meant to confuse : )
Yes, and for more detail see also my response to post 105 above.
No news is now news – MDCO received their approval.
Up 14% after hours. On Sept 24 they are holding an Infectious Disease Care Investor and Analyst Meeting at their New Jersey headquarters.
Yes. . .
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm408475.htm
I am quite concerned now about how Ebola is playing itself out. I may be repeating myself, but as a virus propagates, it tends to lose virulence. The fewer it kills and the longer it takes to kill them, the likelier it is to keep itself going, passing from host to host. When one considers it now is in Lagos, Nigeria, which has millions living in sub-par conditions, and when we consider the virus may be in a natural reservoir of arthropods and rodents, the makings are at hand for a perfect storm. I am glad the Americans brought home are turning for the better, but I also feel that the PTB were cardinally unfair to Sheikh Umar Khan….nice guy, risked his life to get hundreds of people through acute Ebola, and the world stood by and let him die. While the mortality is down to 55 per cent now with the present strain, the number of people ensnared by it is picking up pace, not abating. It won’t be an issue here or outside Africa because of reservoir issues, but the carnage there may just be getting warmed up. $SRPT may dust off its mothballed agent.
From Bloomberg:
Ebola Drug Panel Set by WHO to Weigh Unproven Drugs Use
By Makiko Kitamura Aug 6, 2014 10:36 AM PT
Aug. 5 — Bloomberg’s Yang Yang reports on U.S. Ebola patients treated with Zmapp experimental drug from Mapp Pharmaceuticals in San Diego. She speaks with Betty Liu on “In The Loop.” (Source: Bloomberg)
The World Health Organization will convene a panel of medical ethicists next week to explore the use of experimental treatments for Ebola amid the worst outbreak of the disease on record.
An experimental antibody cocktail developed by Mapp Biopharmaceutical Inc. was used to treat two infected American health workers whose conditions have improved. The WHO’s announcement came after Nigeria’s health ministry said it has written to the director of the U.S. Centers for Disease Control and Prevention to request access to the drug.
Use of the drug, called ZMapp, is raising questions about whether a medicine that hasn’t been shown as safe in humans should be distributed more widely during the outbreak and, given the limited amount of medicine available, who should get it, the WHO said in a statement.
“We have a disease with a high fatality rate without any proven treatment or vaccine,” said Marie-Paule Kieny, assistant director-general at the World Health Organization, in the statement. “We need to ask the medical ethicists to give us guidance on what the responsible thing to do is.”
While Tekmira Pharmaceuticals Corp. (TKMR) was conducting early-stage tests of its Ebola therapy in humans, the FDA in July placed the trial on hold due to safety concerns. Other companies developing drugs for the deadly disease include Fujifilm Holdings Corp. (4901), BioCryst Pharmaceuticals Inc. (BCRX) and Sarepta Therapeutics Inc. (SRPT)
Separately, the U.S. Food and Drug Administration said today it has authorized use of a “real-time” diagnostic test developed by the U.S. Department of Defense to help detect the Ebola virus in Africa. A positive result from the test should be be considered “presumptive” rather than conclusive, according to a fact sheet provided by the defense department.
‘Continued Improvement’
Nancy Writebol and Kent Brantly, American aid workers who contracted Ebola in Liberia, have been given doses of ZMapp. Writebol, 59, was showing “continued improvement” yesterday as she arrived in the U.S. for treatment, said Bruce Johnson, the president of SIM USA, the charity that sponsored her work in Liberia.
As of Aug. 4, the outbreak of the Ebola virus had killed 932 people, the WHO said today. Most of the cases are in Guinea, Liberia and Sierra Leone in West Africa. Two deaths have been reported in Nigeria.
John: the thing here is that for the type of agent in question, the pre-test probability of it being harmful to people is essentially nil. THis is the context these commentators are ignoring. Yes, under ideal circumstances, phase I it in normals. But life in wartime is different. I would be rendered speechless if ZMapp’s agent were harmful in the slightest to people, and I say let it roll. Cheaper for them to prove it this way that in a proper phase I trial. I think they should get aliquots of it off to W Africa and dole it out, and do a makeshift trial that way. Just amazing how officials and reporters and the like posture around this and sound learned. it’s an antibody. Not coupled to a toxin, not directed against any self antigen. There is no reason for it to be dangerous in and of itself. Formalism in drug trials can be excessive.
The absence of a credible safety concern would significantly alter my opinion on this matter. Important point. It seems that manufacturing quickly may be a problem – limited by how fast tobacco leaves grow (a tobacco product, albeit highly modified, curing Ebola – what an ironic concept).
Dr I have heard of fruit bats being a possible reservoir species,,,has evidence now been found to implicate, say , rats and fleas, etc or are those groups just now being looked at?
Do we have any knowledge of how long the virus is viable outside a host? Is there any evidence yet of air borne transmission,,,sneezing etc & if it can be transmitted on clothing, surfaces etc.. Can a mosquito carry a large enough virus load to infect a human? I ask all this with Lagos in mind.
Frank I am going to do some more digging because the move into Lagos, which I somehow picture as being an even more massive version of the slums of Rio, has me on edge. My understanding is that rodents carry it….many succumb to it, but then devour one another. That arthropods can propagate it but mostly are not sickened by it, since their immune system is so primitive (they have Toll-like receptors, in common with us, but no white cells and systemic inflamm responses). I am not sure about bats, but they should be vulnerable. This is a naked simple small RNA virus that should not in any way be hardy outside the body. I also need to find the name of the company that has the Niemann Pick protein blocker. NP protein is how it gets into cells. It is a cholesterol transporter and if you block it you are immune. I am also wondering: these who have survived it should be now immune to this (Zaire?) strain. Wonder if they will go back and tend to the ailing?
Maybe help?
http://connection.ebscohost.com/c/articles/84603202/ezetimibe-inhibitor-niemann-pick-c1-like-1-protein-decreases-cholesteryl-ester-transfer-protein-type-2-diabetes-mellitus
thatsbasicscience.blogspot.com/2011/11/ebola-blocker.html
http://thatsbasicscience.blogspot.com/2011/11/ebola-blocker.html
Got cut off
Just chatting with Michael Fitzhugh of Bioworld Today. Great guy! His report will run tomorrow:
By Michael Fitzhugh, Staff Writer
The FDA approved The Medicines Co.’s antibiotic Orbactiv (oritavancin) after the market close Wednesday, making the acute care specialist the latest player to market a product to treat acute bacterial skin and skin structure infections (ABSSSIs) outside hospitals, where multi-day stays can lead to big bills for both patients and payers.
The therapy is approved to treat ABSSSIs caused by gram positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). Its label includes a warning regarding interference with coagulation tests and interaction with warfarin, a drug used to prevent blood clots.
“The approval of several new antibacterial drugs this year demonstrates that we are making progress in increasing the availability of treatment options for patients and physicians,” said Edward Cox, director of the FDA’s Office of Antimicrobial Products. “However, more work is needed in this area, and the FDA remains a committed partner to help promote the development of antibacterial drugs.”
With the FDA’s favor, Orbactiv becomes the second long-acting antibiotic approved to treat ABSSSI following the FDA’s May 23 approval of Dalvance (dalbavancin), developed by Durata Therapeutics Inc., and the third qualified infectious disease product (QIDP) to win approval following Cubist’s Sivextro (tedizolid phosphate) in June. (See BioWorld Today, May 27 and June 24, 2014.)
Medicines CEO Clive Meanwell told investors July 23 that manufacturing and supply chain resources for Orbactiv are in place, but that it might take some time to drive adoption of the product, conceding that after numerous hospital launches during his career, “it is probably best not to assume speed at the beginning.”
The company has yet to set pricing for Orbactiv, but Medicines Co. Meanwell noted on the company’s July 23 earnings call that his company is paying close attention to Cubist and Durata’s strategies. Dalvance is priced at a premium to Cubicin, while Sivextro is priced roughly in line with Pfizer Inc.’s oxazolidinone drug Zyvox (linezolid), noted Bank of America analyst Steve Byrne. Picking the right price for Orbactiv will take a little time, Meanwell said.
“As a general rule, we like to look at the value of the products that we launch in absolute terms for the hospital,” Meanwell said. “Before we really can comment on our pricing strategy, I think we would really like to see the outcome of the FDA process and make sure we know what is on the label, so that we can do the right thing for our customers.”
Orbactiv was approved based on data from two trials in which showed that a single 1,200 mg dose of Orbactiv was non-inferior to twice daily intravenous dosing of vancomycin given for seven to 10 days in patients with acute bacterial skin and skin structure infections caused or suspected to be caused by such gram positive bacteria including MRSA.
Big need, crowded market
Medicines, of Parsippany, N.J., added Orbactiv to its portfolio in February 2009 when it acquired Targanta Therapeutics Corp. for about $42 million. At the time, Medicines cited 2007 data pegging the U.S. hospital market for gram positive infections at $1.1 billion and growing.
An estimated 5.2 million patients in the U.S. and Western Europe are admitted to hospitals with ABSSSIs annually, Medicines found. Patients often receive intravenous therapies that require hospital admission and multi-day dosing, according to Pharmerit International researchers who joined colleagues in evaluating recent trends in U.S. hospital admissions.
Given the need and opportunity, Medicines’ efforts put it in good company. In addition to Dalvance and Sivextro, it will be facing down Cubist’s Cubicin (daptomycin); quinupristin/dalfopristin; Theravance Inc.’s Vibativ (telavancin); Sanofi-Aventis’ teicoplanin, ceftaroline, which is marketed by Forest, Astrazeneca plc and Dainippon Sumitomo Pharma Co. Ltd.; and Pfizer Inc.’s tigecycline.
Despite the crowded field, Medicines’ expects that Orbactiv’s single 1,200 mg dose regimen will give it an edge, by helping “eliminate the need for daily infusions and potentially reduce the need for patient hospitalization, outpatient infusion services or central intravenous access,” it noted in a recent regulatory filing. By contrast, Dalvance is given in a two-dose regimen, first in a 1000 mg injection followed one week later by 500 mg injection. Sivextro is administered once daily for six days.
Research Assistant in Molecular Biology (hayward / castro valley) Required —
Tacere Therapeutics Inc. is currently seeking a highly-motivated candidate to fill a Research Assistant position in Molecular Biology.
http://sfbay.craigslist.org/eby/sci/4606339119.html
“Tacere is a rapidly growing……”
Check.
Doc, Perhaps someone is pulling Benitec’s leg?
🙂
A RA search from craigslist? LOL.
Seriously?
Craigslist?
Again, no doctor’s need apply.
Some of the best molecular biologists in the world can be found on craigslist. Nothing to be concerned about, stop complaining and be patient.
Sincerely,
The Hot Copper brainwashed
I like this guy tim fris!
Thanks, like you too!
I wish I had more to contribute than smart ass comments but I hope Benitec realizes shareholders (not the Hot Coppers) deserve answers when HIS timelines are so off and progress is revoltingly slow. His answer seems to be like Animal House: Road trip!! On the companies dime no doubt. Doing any good? Not if you look at the share price. Don’t like to take shots at people or groups but have a lot of respect for you and didn’t like Dr. French responding to your posts so condescendingly. It was as if he was trying to shut you up and put you in your place. How dare you question me?? If he was going to take the time to respond to your views on Benitec, he could of shown some appreciation and acknowledgement of your efforts and expertise. You’re not just some dill weed full of crap blogger like he treated you. As a group we own thousands upon thousands of shares. Probably millions. Maybe show some communication skills and pretend to appreciate his shareholders? After all, his stock is in free fall mode at the moment.
Hot Copper, what can I say, you try to impart some knowledge for them and they treat you rudely for even questioning their wizard of oz, Dr. French. I raised some questions pretty politely, I got some jerky responses too. Oh well. Still got a lot of hope for Benitec and if we do strike it rich I’ll put a THANXKISS license plate on a new corvette for my wife. Thanks for all the people that contribute to this forum, really appreciate you all.