by DrKSSMDPhD | June 9, 2015 9:26 pm
[Ed. Note: Dr. KSS writes about medicine and biotech stocks for the Irregulars. He chooses his own topics, and his words and opinions are his own. He has agreed to our trading restrictions. You can see his previous articles here. Enjoy!]
Captain’s Log. Stardate 2015.06.09. The Enterprise has received a distress signal from planet Marus 4, a little-known class M planet on the outskirts of Federation territory. The subspace message we received spoke of an immediate, unknown threat to life on Marus 4. I have instructed Mr. Sulu to warp us into orbit around the planet, but have asked Ensign Chekhov to activate our cloaking mechanisms at the earliest possible moment as we near Marus 4, so that Mr. Spock and Dr. McCoy can examine sensor data about the nature of life there before we make our presence known. No Federation vessel has ever visited this planet.
Uhura: Captain Kirk, it’s Chief Engineer Scott. He’s requested that you join him immediately in crew living quarters on deck 9. A security team will meet you there.
Kirk: Mr. Sulu, you have the helm. Mr. Spock, with me, on the double.
(scene on Deck 9)
Scott: Aye, Captain. It’s engineer Ensign Cowan, one of my best men. He didn’t report for duty. When I used the ship’s intercom to hail into his room, he didn’t sound like himself. I came for a look….thought maybe he’d had too much Romulan ale. But I’ve never seen anything like it.
Kirk: Call Dr. McCoy in sick bay. Have him come here at once. (Kirk lightly slaps Cowan’s face). Ensign Cowan, can you address me?
(Cowan is sweaty, gray, gazing into middle distance with a thousand-yard stare).
Scott: Are ye all right, Cowan?
Kirk: Ensign, are you in pain?
(Cowan’s cabin door swooshes open).
McCoy: What the devil is going on here? Jim, I’ve got a sick bay full of junior officers sickened by eating spoiled Plomeek broth the Enterprise picked up during our shore leave on Vulcan.
Say, he looks bad….what happened?
Kirk: It’s Ensign Cowan. Mr. Scott found him this way when he didn’t report to his station in engineering.
(McCoy takes out tricorder, scans Cowan for several seconds.)
McCoy: Beats all I’ve ever seen Jim. Cowan’s cognitive function is down to a third of normal. He hasn’t had a stroke, but doesn’t even know his own name. His vital signs are all over the map, heart speeding up and then slowing down. His digestive system isn’t working but his liver has gone into overdrive. His tissues….well, they’re breaking down, almost like he’s starved. No evidence of infection, no toxins. And it looks like…hell…no, it cannot be…
Kirk: What, Bones?
McCoy: I’ve never seen anything like it, Jim. The tricorder indicates that this man doesn’t have one single molecule of cholesterol in his body, Jim! It’s all gone! His brain, his nerves, his tissues, his arteries, even his liver….none!
Spock: Cholesterol, fundamental building block of life in this galaxy. 97 percent of life forms catalogued in the Enterprise’s computers are themed around cholesterol. Vulcans have a special variety, dilithio-cholesterol, that confers upon us our exceptional powers of—-
Kirk: Thank you, Mr. Spock. Tricorder malfunction, Leonard?
McCoy: No Jim, it can’t be. Tricorder appears to be functioning normally.
(McCoy draws in close to Cowan, and gently raises his shirt. The onlooking guards recoil in horror.)
Kirk: Bizarre red circles all over his torso. Bones…
McCoy: Well, what do you want me to say, Jim? That some…some creature broke into Cowan’s room and just sucked all the cholesterol right out of him?
Spock: Do you have a better theory, doctor?
McCoy: I won’t know for sure til we get him to sick bay. Jim, this man’s critical. Guards, let’s hoist Cowan up and get him up to sick bay where I can work on him, pronto. Call Nurse Chapel, tell her we’re on the way!”
(Guards loop their arms beneath Cowan’s shoulders, and heave him to his feet. But Cowan’s head slumps fully forward, and his limp body slides to the floor. McCoy bends over Cowan, and tricorder-scans him again. McCoy rises slowly, and turns to face Kirk.)
McCoy: He’s dead, Jim.
* * * * * *
When you sum-total all the things you’ve heard about cholesterol over the decades, you could be forgiven for regarding cholesterol as an evil substance, one that causes nothing but mischief, disease, and premature death. But cholesterol isn’t nearly so simple, and its presence in most forms of life on earth suggests it is indispensable for the recipes of life.
In my late twenties, when I completed my M.D. and Ph.D. degrees, I had a doomed, short-lived misadventure in the institution of marriage, a mysterious covenant on a good day. I was evaluated by another physician in order to be issued a marriage license. When blood was drawn for the state-mandated HIV test, I also asked that a wide array of routine tests be done, as I’d not had lab work in nearly in decade. I wasn’t quite prepared for one of the results: my non-fasting serum cholesterol was 120. In various clinical rotations during medical school, I’d heard anecdotes about the ominous significance of a really low cholesterol. But I decided to raid the literature, as nothing is more urgent to a physician than when (s)he’s the patient. What I found was disquieting.
Here, for the benefit of our many medical readers (who can realistically count this for a couple of hours of category 2 continuing education credit), as well as for the relentlessly curious, are some more modern studies corroborating what I saw. High serum cholesterol is deadly, but low serum cholesterol may not be much better. It’s been linked to violent crime, and more generally to violent behavior, It’s been strongly associated with aggression. It is a strong risk factor for violence that injures others and poor impulse control, and may underlie not only suicide, but suicide by particularly violent methods. These findings would appear to be supported by numerous instances in which patients placed on statins become newly hostile and irritable. A new study in JAMA Internal Medicine kvetches about the memory loss common among statin recipients during their first month of treatment.
But the problems incurred by cholesterol don’t end with behavior and the mind. Medicine does have a general theme that the commonest problems doctors see (97 percent of our case load) result from overnutrition, underactivity and self abuse; in keeping with that, high cholesterol, providing as it does raw ingredients for cell adventures, has a loose association with greater likelihood of cancer; indeed, in several specific cancer cell models, treatment with statins limits a tendency to cancer. But cholesterol is very much about having a Goldilocks number, a level that’s just right for health. Low cholesterol appears to impose a roughly 2.8-fold higher likelihood of death from cancer. This effect may prevail more in men than in women. An inverse relationship between serum cholesterol and death from cancer seems particularly true for hepatocellular carcinoma.
And there’s more. Low cholesterol seems to lead to greater likelihood of hemorrhagic, as opposed to thrombotic, strokes. A 2011 PLoS One study argues that lower cholesterol leads to telomere shortening, which could shorten life even while it provides some protection from cancer. Telomeres are the tear-off coupons at the end of each chromosome. Each of us is born with a certain endowment of them, and one telomere is shed each time a cell divides. When the telomeres are exhausted, a cell can no longer replicate, leading to cell death from the so-called Hayflick limit.
You may here wonder where I am leading you. I’m covering this material because medicine is about to embrace a class of drugs that will enable doctors to bring down cholesterol to a greater extent than ever possible, even into ranges where the outcomes will be unknown. We cannot go there without reviewing what is known about very low cholesterol levels. As we will come to, today is a red-letter day in deciding the fate of these new, terrifyingly powerful drugs.
I worry some readers will react to the above in the wrong way: “Dammit, that’s all I need to hear. I always thought my doctor didn’t know what he was talking about when he put me on those stupid statins. Hon, flush ’em!” We focus on cholesterol numbers because they are a big factor—admittedly not the only factor—in determining whether you get cardiovascular disease. And while cholesterol is not the only factor, it is among the most easily modified of factors. Here I speak not of diet. I never advise dietary cholesterol restriction as no evidence supports this. A completely fat-free diet would at most lower serum cholesterol by 10-15 percent, and yet this would lead to such a lack of sense of satiety, that you aren’t full, that you’d then overeat, probably feasting on carbohydrates.
Why is it, by the way, that serum cholesterol rises as we age? I’ve needled many physician friends with that over the years, and never gotten what I believe the correct answer is. The answer appears to be that insulin sensitivity, how hard insulin has to knock on the door of the insulin receptor in order to mediate glucose uptake into cells, rises inexorably as we age. Metabolic syndrome is that state many of us drift into as we age, comprised of belly fat, hypertension, dyslipidemia (high cholesterol) and insulin resistance. Remember, diabetes mellitus type II is merely endstage insulin resistance. By very complex mechanisms, resistance to the action of insulin causes more cholesterol to be made and less to be cleared from the body. GenFit’s ($GNFTF) new agent for insulin resistance and NASH has been shown, by the way, markedly to lower cholesterol. A fat-free diet would cause more carbohydrate intake, leading to more insulin resistance, leading to higher cholesterol despite the absence of cholesterol ingestion. The best diet will always be a balanced one, consisting of calories equally divided among fats, carbohydrates and proteins. The doctor who tells you to avoid eggs, to avoid the occasional bacon for breakfast if it’s in balance with your diet, is not, I am afraid paying attention to the data. Facts are pesky things. 85 percent of your body cholesterol is made in your body (about a fourth of it in liver), and so diet modifications, except to the extent they limit insulin resistance, literally make no sense.
The astute skeptical reader will here pipe up and point out the single biggest charge that can be leveled against the statins, which is that they cause insulin resistance in all and in some, intensify insulin resistance to the point that patients, especially women, develop type II diabetes. A direct hit, of course. As you read this column, you will see that I am only a partial defender of statins, and that I come here more today to bury them rather than to praise them. Statins do cause reductions in cholesterol by poisoning one of two main enzymes, hydroxymethylglutaryl CoA reductase, that make cholesterol (the other enzyme is ATP citrate lyase). Statins help you by modifying one cardiovascular risk, at the expense of worsening another risk factor, insulin resistance.
On 2 August 2014, Gumshoe Biotech introduced readers to Esperion Therapeutics ($ESPR) as a compelling lipid management play. We discussed the humble origins of statins in the work of Japanese biochemist Akira Endo, Ph.D., who discovered them among fungi, who had seemingly evolved them as an antimicrobial tool to choke out competing organisms (cholesterol is a building block of life). Prior to Esperion, the field had barely nudged beyond finding and devising yet more statins.
Esperion and its founder, Roger Newton, Ph.D., were roundly celebrated in our Gumshoe 2015 Biotech Awards Show. Newton was named our biotech entrepreneur of the year for inventing a small-molecule inhibitor, ETC-1002 (proprietary name: bempedoic acid), that inhibits ATP citrate lyase. In very high quality trials to date, this agent had demonstrated a powerful ability to lower cholesterol while also conferring other favorable properties on patients that include a tendency to weight loss, a reduction in systolic blood pressure, and the promotion of sensitivity to insulin.
As I write this, an FDA advisory committee is reviewing documents that may affect $ESPR shares as an investment. Since $ESPR represents a major holding for many Gumshoe Biotech readers including me, it’s vital that you know the issues at hand before the FDA. It is not discussing Esperion. It is reviewing phase III data for alirocumab, an anti-PCSK9 monoclonal antibody developed by Sanofi ($SNYNF) and Regeneron ($REGN). Alirocumab competes with a similar agent, evolocumab, from Amgen ($AMGN), which has been given a PDUFA date of 27 August 2015 and will be discussed by the FDA tomorrow. What the FDA’s advisors recommend today will have major implications both for the field of cholesterol management and for investing in cholesterol therapies.
The FDA briefing documents can be found at this link. I’ve read them in their entirety. As such briefing documents go, this is very well written. It describes the outcomes from 10 phase 3 alirocumab trials.
Let’s review some more pharmacology, and provide some context. In the 1970’s, doctors were not routinely checking cholesterol levels. However, two luminary physicians we’ve discussed before, Tom Starzl, M.D., Ph.D., and David Van Thiel, M.D. (Van Thiel is a personal friend and I regard him as the greatest hepatologist who has ever lived), were performing the first human liver transplantations in Pittsburgh. People with endstage liver disease severe enough to warrant transplantations generally have remarkably low cholesterol levels. Not only is the liver, a key site of cholesterol synthesis, ailing, but badly cirrhotic patients are in a state of consummate malnutrition that they cannot overcome regardless of how well they eat. To the extent that data were available, Van Thiel began to notice that transplant survivors, once their liver was well-engrafted and functioning adequately, began to take on blood cholesterol levels that were those of the liver donor. This was one of medicine’s first major lines of evidence about the overwhelming role of liver in cholesterol homeostasis.
Soon Michael S. Brown, M.D. and Joseph L. Goldstein, M.D., were beginning their pioneering work in lipidology at University of Texas-Southwestern that would lead to their sharing the 1985 Nobel Prize for Medicine or Physiology. A general theory was emerging that cholesterol was mostly carried from A to B in the body in microscopic wheelbarrows called lipoprotein particles. Strong data suggested that high-density lipoprotein particles (HDL) shuttle cholesterol from arterial blockages back to liver. Low-density lipoprotein particles (LDL) transport cholesterol from liver out into vessel, when trouble emerges. Cholesterol piles up in aggregates called plaque, creating both restriction to blood flow and also a local inflammatory, irritative process in the vessel wall. Normal healthy endothelium, by nature smooth and tended to prevent clot, gets masked. Severe plaque can fissure and rupture, creating a trap door effect within a vessel that shuts down flow. When clot forms atop this fresh wound, a heart attack or thrombotic stroke begins.
When NBC News anchor Tim Russert experienced ventricular fibrillation cardiac arrest at his desk in Washington on 13 June 2008, he had just returned from a physically vigorous trip to Italy with wife Maureen Orth. She had warned him during the trip that he probably shouldn’t be personally lugging so many of their bags, as she feared this possibility. Russert had type II diabetes, and Orth knew this might make him unable to feel angina pains if he were overexerting. Russert’s physical strain likely fractured a plaque in a coronary artery that set into motion the final lethal coronary event.
Working in Dallas, Brown and Goldstein used genetic methods advanced for their time to demonstrate that liver expresses a receptor for LDL, and that the binding of LDL to this receptor leads to ingestion of the LDL particle and degradation by the hepatocyte. Their work led to a spate of fine publications, well-synopsized in this 1986 Science paper. Brown and Goldstein showed that patients with severe familial hypercholesterolemia, unfortunate patients prone to early vascular events, had their disease because of missing or defective liver LDL receptor.
Further characterization of liver LDL receptor regulation revealed that a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9) has a major role. PCSK9 is a proteinase, or proteolytic enzyme, that has a way of chewing on one edge of the LDL receptor and making it far less active in removing LDL particles from blood. Many readers have become modestly sophisticated drug developers, and so obvious ways of turning down PCSK9 so as to turn up LDL activity and lower cholesterol come to mind: one could clone and infuse soluble LDL receptors with no activity to bind and occupy PCSK9; one could design a molecule that inhibits the proteolytic function of PCSK9, though it would have to not inhibit other proteinases, and this is tricky; one could use RNAi to dial back PCSK9 expression, an approach being pursued by Alnylam ($ALNY); or one could make a monoclonal antibody that sticks to PCSK9 and sumps it away so that it leaves the LDL receptor alone. Monoclonals these days are a good first line approach.
The FDA briefing documents for alirocumab disclose consummate reductions of LDL cholesterol. Sanofi and Regeneron are pursuing two-pronged approval: they’d like to see alirocumab approved for use in the statin-intolerant (defined as having tried entry-level doses of at least two statins and having had symptoms, generally muscular or neuropsychiatric, that cause the patient to deem them unacceptable). They also want approval for patients with profound hypercholesterolemia who have not achieved at least a 50 percent reduction in LDL cholesterol by means of statin therapy.
In earlier threads, we have voiced concerns about the possible emergence of a class of so-called PCSK9 zombies. In fact, why does this theme of brain side effects keep coming up in cholesterol discussions? If you took a high school or college physics course, or have studied electricity and magnetism, you may know the answers. Nerves are little more than wires, wires made of protein, that carry electrical impulses. As with real-world wires, insulation is needed to avoid the bleeding off of current, and to avoid short-circuiting. Nerves accomplish this by means of their so-called myelin sheath, which is carefully arranged tissue that refuses to bear charge. The main ingredient in the myelin sheath? Cholesterol: this is why certain dishes made from animal brain (human brain if you are Hannibal Lecter) are so pleasing to the palate. Absent cholesterol, brain and nerve function is disorderly and undependable, and Ensign Cowan loses two-thirds of his IQ.
Despite this argument, an important fact is that cholesterol in the brain doesn’t get there via LDL. In fact, neither LDL nor HDL cross the blood-brain barrier. There are, however, esterification reactions that allow swapping of cholesterol among lipoproteins. In studies by Sanofi and Regeneron to date, which largely look at alirocumab therapy limited to two years, investigators are not yet describing dementia. My contention is that this is too short an observation period, and that a negative cholesterol equilibrium will in fact draw cholesterol from the central nervous system. While monoclonal antibodies do not cross the blood brain barrier, the FDA states politely in its documents that present studies are insufficient to exclude the chance that alirocumab will interfere with brain function.
This isn’t to say investigators did not observe neurological side effects. Several patients had symptoms consistent with so-called demyelinating neuropathy. Guillain-Barre syndrome would be an example of a demyelinating polyneuropathy, but patients could also present with cranial nerve palsies, autonomic dysregulation, paresthesias and burning sensations, and possibly problems with bowel or bladder control. That alirocumab can cause such processes is of concern, and patients would require monitoring for them throughout therapy. How reversible they are with discontinuation of treatment isn’t known. My contention is that the longer one is on a PCSK9 inhibitor, the likelier these are to occur.
Alirocumab, as well as evolocumab, to be discussed tomorrow, are foreign proteins. Small numbers of treated patients have developed hypersensitivity reactions and presence of neutralizing antibodies to alirocumab. These issues appear to abate either with steroid therapy or time.
But here is the most important result that will come of today’s deliberations, and it could affect $ESPR shareholders. It involves the sometimes annoying branch of clinical science called evidence-based medicine (EBM). EBM, you may say…..isn’t all medicine evidence-based? It’s not, and this has much to do with the style of thinking used for EBM.
Human papilloma virus is the leading cause of cervical cancer. Vaccines now exist to prevent the HPV strains most often implicated in cervical cancer. Those vaccines have been shown to boost the immune response against HPV. Ergo, vaccinating against HPV prevents cervical cancer, right? Not so fast. That hasn’t been shown yet.
A low blood level, or a high level, is associated with a disease. For decades, pharma reasoning has been to devise an agent that fixes the level, and that it’s then safe to assume that prevents the disease. But often it doesn’t, and that’s EBM-style thinking. It may well be that the altered blood level and the disease are related to a third thing not yet identified, and that medicine has deceived itself yet again. EBM studies are often dubbed “nihilistic” because time and again, they have shown some of medicine’s most hallowed practices to be utterly pointless. Colon cancer starts in polyps. Colonoscopy can easily remove polyps before they become cancer. But does colonoscopy actually prevent colon cancer? We know now that it does, based on highly broad and systematic studies, but even as of 10 years ago, gastroenterologists were accused of merely running up a bill to perform an intervention not linked to a better outcome. It’s been an article of faith for decades that patients about to undergo cardiac surgery should be pre-operatively hydrated with iv fluid, that doing so makes kidney injury and failure associated with the surgery less likely. In the last month, two excellent studies have shown that pre-op fluid in these patients actually makes renal failure more likely, not less. The premise had never been tested.
This was precisely the thinking that was behind the perplexing guidelines for cholesterol management issue by the American College of Cardiology and American Heart Association in 2013 (summarized here). Although the cholesterol theory of vascular disease is not perfect, and though some assert controversially that it is size distribution of LDL particles and underlying inflammation that really matter, the fact is that long-term sustained therapy with statins has been clearly and strongly shown to reduce the likelihood of a second heart attack or stroke if you have had a first one (the primary prevention case, for using statins to prevent a first event, is far weaker).
Other agents also reduced LDL cholesterol: namely niacin and fibric acid derivatives. The problem is that good EBM studies show clearly that treatment with these agents makes no difference whatsoever in cardiovascular risk, and that treatment with them thus no longer has a justifiable place in medicine. They lower LDL, yes, but fail on EBM grounds because they don’t prevent the disease that LDL reduction intends to prevent. (This has led some in cardiology to concede that statins may be working in ways other than LDL reduction to prevent vascular events). Puzzlingly, ezetimibe, which only blocks enteric absorption of cholesterol and so should make little difference in cardiovascular outcomes, does appear to reduce risk. Ezetimibe has been speculated to be modulating more in cholesterol regulation than merely dietary uptake.
Based on the theme set forth at the ACC/AHA 2013, alirocumab should be required by the FDA to fulfill EBM guidelines for road-test-proven ability to prevent strokes and heart attacks. In fact, a large 80,000-patient study is in progress to demonstrate this. Based on precedent, such studies generally need to be at least five years long to ”capture” enough cardiovascular events to provide interpretable data.
My contention is that alirocumab should be held to this same standard as statins. The PCSK9 inhibitors may cost as much as $12,000 per year for therapy, a very dear cost for a drug not proven to change an outcome. FDA advisory committee members are selected from experts without conflicts of interest, and yet such conflicts are often very opaque in academic medicine. An FDA vote to require EBM evaluation of alirocumab would add about three years to its approval timeline and introduce a genuine possibility of failure. It would likely boost $ESPR shares markedly.
How the FDA acts here will set tremendous precedent for the industry, and though it could burden Esperion with the inevitable need to achieve the same data (a five-year multicenter international study that compares a large number of patients randomized to either bempedoic acid or statin to prove non-inferiority to statins), Roger Newton has said he is prepared to move in that direction and anticipates it. The FDA could vote to allow marketing authorization for alirocumab with the caveat that its ongoing 80,000-patient trial will be reviewed intently when its data emerge and that these could cause restrictions in label indications for alirocumab.
My feeling is that a longer period of observation of patients on alirocumab, however, may also serve the phase 4 trial-like purpose of allowing more extensive surveillance of the effects of deep cholesterol depletion on patients. Agents like alirocumab combined with a statin may lower LDL cholesterol by 75 percent, an extent so significant it would likely cause disappearance of plaque over time. That’s a good thing, but only if it is not being offset by premature dementia, by hemorrhagic strokes, by violence, aggression and suicide, or by a change in cancer risk profile. As I see it, answers to that are as of now completely unknown.
Statins are no longer patent-protected, and the advent of PCSK9 inhibitors will add another Gilead ($GILD) HCV-drug style shock to pharmacy benefits manager budgets. While the retail price of Esperion’s drug isn’t yet known, perceptions are it will be considerably cheaper, and favored because oral. Esperion’s drug may prove to be additive to statins as well as beneficial without or with ezetimibe. We await with keen interest fuller sets of data from Esperion that may reveal genuine benefits from its agent as regards weight and blood pressure reduction, a probable reduced risk of cancer, as well as no risk of intensified insulin resistance. While none of these will find their way onto label indications for bempedoic acid, representatives marketing the agent can easily chat up these features of the drug, with the clear message that the agent attacks metabolic syndrome in a unified way.
My feeling is that there is still a three in five chance the FDA adcom will vote to approve alirocumab for marketing based on the present data package. Such a move will exert a temporary downward pressure on $ESPR shares until cooler heads prevail and smart money gets clear again that at the level of the clinic, at the level of patient management, doctors will favor Esperion’s drug over a PCSK9 inhibitor. Esperion’s approach will require no persuasion to go to an injectible medicine, and no teaching how to inject. We feel that formulary guidelines are likely to strongly favor Esperion’s drug, and worse, will require the agony of prior authorization, probably with peer-to-peer review on the telephone in order to place a patient on a PCSK9. For me, “bad” news tonight will merely be another opportunity to buy $ESPR shares at sale prices.
When Kirk and Spock beamed down to Marus 4, they discovered a race of humanoids that, because of a genetic experiment gone awry, had lost all enzymic machinery to make cholesterol. They had learned to subsist by ingesting massive quantities of cholesterol from their agricultural sources. The ruler of Marus 4, however, and his tribe, had been separated from reasonable food supplies brought on by a planetary war. The ruler had stolen aboard the Enterprise and killed Cowan by draining all cholesterol from his body so that he could stay alive long enough to convey his plight to Star Fleet. In an unusual example of interspecies amity, Spock and McCoy took cDNA constructs for ATP citrate lyase and HMG CoA reductase from ship repositories, cloned them into an adeno-associated virus, and transfected all the Marutians to be able to make their own endogenous cholesterol.
Disclosures: My columns are journalism leavened by opinion, not personal investing advice. Of companies presented today, I have long positions in $ESPR, $GNFTF and $GILD. I have no short positions or options. I will trade in no named security for 7 days after this column appears. I have neither sought nor accepted anything of pecuniary value from any person or company named by me at Stock Gumshoe or in other media. Questions may be forwarded to me via email@example.com, but pleased be advised I will give no personal investing opinions outside this forum. Follow me on Twitter @KSSMDPhD.
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