by DrKSSMDPhD | November 12, 2014 5:38 pm
In his tearjerker “Sisters of Mercy,” Leonard Cohen sings,
where you’re hanging
I can see
how you’re pinned.
Although I am less inclined to bash the FDA than many, it has recently let modern medical practice place many patients in an undesirable situation. What if there was a very powerful drug, one with a death-preventing effect, but also one for which there is literally no way out of its over-effect if you get too much in your system? Digoxin we can “undo” with anti-digoxin monoclonal antibodies. Acetaminophen overdose is mostly very effectively treated with N-acetylcysteine, and though one thinks of that overdose as lethal unless the patient gets a new liver, in fact it only uncommonly leads to liver transplant. Take too much OxyContin or methadone and Narcan saves you. Coumadin can be reversed with vitamin K or, in dire straits, with plasma.
But rather like a room with no door or a stairway to nowhere, therapy with one new class of medications can place patients in a life-threatening fix that doctors can do little about. It’s as if pharma companies and the FDA have given patients a one-way ticket: although treatment with these drugs can save lives, it can also leave patients dangling without a safety net.
Is there a way to profit from this mess? I believe there is.
Liver is my favorite organ and liver disease my favorite topic in medicine. But just by a nose. I love coagulation medicine, and would have become a specialist in it except that doing so would mean becoming a hematologist, and the rest of hematology holds no appeal for me. In fact, I mostly faint doing bone marrow biopsies. My PhD work was in the biochemistry of coagulation in the context of liver cells, which make most of the clotting factors. I browbeat my medical school dean into letting me spend a quarter of my final year doing coagulation consultations on inpatients with bleeding or clotting problems, as I wanted to graduate from medical school with genuine expertise in something rather than diffuse familiarity with a panoply of topics. Unexplained bleeding, unexplained clotting, unexplained abnormalities in clotting tests, I exult in fixing these issues by invoking a molecular understanding of their basis. During residency and fellowship, I was given the clout of an attending physician in managing coagulation issues, as the pharmacy and blood bank had learned painfully there was no point in arguing with me, that if they said no to me, they would shortly get an angry call from someone high in the foodchain.
I.F.G. Dunn is a friend and renowned photographer. He’s a master of so-called high-acutance Rodinal photography, using darkroom techniques and chemistry methods nearly a century old. As with the detail in this extraordinary picture, I want to bring to you a sense of granularity, of nuance, about clotting.
Factors II through XIII, kallikrein, protein C, protein S, kallikrein, kininogen, factor V Leiden, thrombomodulin, plasminogen, the plasminogen activators, the plasminogen activator inhibitors, antithrombin III, alpha-2-antiplasmin, tissue factor pathway inhibitor, protein C inhibitor, von Willebrand factor, fibrinogen and the dysfibrinogens, vitronectin, fibronectin, the mechanisms of platelet aggregation….these are the temple of my familiar. So are the exotic tests—the dilute Russell viper venom assay, the Reptilase time, the incubated mixes, the euglobulin lysis time, the serially-diluted factor assays— that baffle most hematologists but help a “clotter” doctor predict whether you will clot normally or bleed badly in surgery. And so are the agents we deploy: heparin; thrombin; desmopressin (ddAVP); recombinant factor VII (NovoSeven); warfarin (Coumadin); epsilon-aminocaproic acid (Amicar); the factor Xa inhibitors enoxaparin (Lovenox), rivaroxaban (Xarelto), and apixaban (Eliquis); the thrombin inhibitor dabigatran (Pradaxa); cryoprecipitate; prothrombin complex concentrates. These are friends and loved ones. I could take three full days of your time and explain all of this to you without stopping, but that would be merely the short version of things. (Disclosures: NovoSeven is from Novo Nordisk $NVO. Eliquis is from Pfizer $PFE and Bristol-Myers Squibb $BMY. I have long positions in $NVO and $PFE.) Catch that Oxford comma a half-mile back?
Snake venoms, which I once moved to Taiwan to study, have always fascinated me for one reason: most of the Asian vipers kill (and kill they do) by making venoms that violently shove the clotting system in the direction of either suddenly clotting or else becoming totally unable to clot. One viper venom protein called ancrod causes people to bleed to death because it clips fibrinogen, the precursor to clots, into an inactive form. Other venoms clot so aggressively that they can make the victim’s arteries and veins quickly become a cast, in clotted blood, of the vascular system. Venom of the Malayan pitviper Calloselasma rhodostoma contains rhodostomin, which completely blocks the ability of platelets to clump together, many times more effectively than Plavix does. In this graphic video watch what just a dollop of Russell’s viper venom quickly does to fresh blood.
When I was an intern, a highly-ill AIDS patient was randomly admitted to my team. The patient was a gay male who wasn’t taking antivirals. He had developed a massive oral Kaposi sarcoma (KS), a manifestation of AIDS now rarely seen. KS lesions are purple and blood-engorged, and in gay males prior to about 2000 commonly formed on sites of sexual contact, as KS is caused by a virus. The patient had called an ambulance because a KS lesion, a massive one that had taken over the hard palate of the roof of his mouth, had burst open. He was bleeding to death arterially. Paramedics found the ceiling at his apartment sprayed with and dripping HIV-infected blood. He was gagging on blood, inhaling it, and both expectorating and vomiting it back out.
Kaposi sarcomas, such as this one on the hard palate, are terrifyingly vascular. Patients bleed to death from them.
Prior to his being admitted to the floor he had been transfused massively: 22 units of blood via the emergency room and in radiology! He had bled to death a few times over. And not only is 22 units of blood an enormous volume, he had lost all of it by coughing it out, spitting it out, or when too much had accumulated in his mouth, by swallowing. He now had tarry black urgent diarrhea from blood sluicing through his gut. He was being water-boarded with his own blood. He needed an ICU bed, but none were open. In radiology, a catheter had been threading into an artery feeding the KS lesion, and pro-clotting material squirted into it. This had shut down the bleeding for a time. But now he was bleeding again, profusely. No further radiology interventions were an option. Surgery was not an option….touching the lesion in any way would simply open the spigot of bleeding and kill the patient. Surgery had seen him, said they’d not touch him, and then said “Don’t call us again.” He had been placed in a room on a regular medical floor….to die. The nurses barricaded his door to keep people happening by, such as those delivering meals or drawing blood, from wandering in and getting blood-sprayed.
This patient would bleed to death soon unless I pulled a rabbit out of the hat. While what agents I gave him, in what doses and in what sequence by what route would be complicated to recount, I profoundly primed his system to clot and also defeated his body’s ability to dissolve clots. I gowned up in a hazmat suit, stood close enough to him (blood being coughed and vomited on my mask and suit) to irrigate his mouth with cannister after cannister of bovine thrombin. I then mixed up cups full of epsilon-aminocaproic acid powder in Kool-Aid, and stood over him and made him take mouthful after mouthful, swish it roughly in his mouth til he was exhausted, and then swallow….over and over, mouthful after mouthful. All bleeding stopped and he never re-bled. Knowing the clotting system intimately, how it works, how it falls short, how to jump start it, really can save lives. Word got back to my department chairman, a daunting person, that I had somehow stopped unstoppable bleeding. His secretary paged me to come to his office.
“How the hell did you do that?,” he asked.
After I explained it, he said, “Well, damn if I understand it. Glad you do. You didn’t ask for help, you didn’t consult anybody. You just up and did it….what balls!” I thought I was going to get yelled at for breaking chain of command, for not even talking to my supervising resident.
“You’re a class act, KSS. Don’t tell anybody I told you that.” I excused myself to answer a page.
I’ve always tried to keep a fishhook dangling in coagulation investment water. The last such—the R word—ended badly for shareholders including me, and came about because of the company’s reticence to just share data with shareholders, who were kept pinned and wriggling, as TS Eliot would have said. Some here retain shares in Regado ($RGDO) hoping for a reprieve, though I fear the company has the scent of death on it now and is too stigmatized by the biotechnology community to fetch a reprieve. In biotechnology, no news is bad news, and the mere two sentences of outcome information we got from Regado likely conceals very serious errors in company judgement. Since that debacle, I have reviewed scores of trials and companies trying to identify any instance in the history of biotech when a drug has failed not on efficacy but on safety concerns in phase 3, and even declares the safety issue early in phase 3. Remember, phase 1 is about safety and toxicity, usually in healthy people (chemotherapy phase 1’s are done only in cancer patients). Safety in phase 1 is no be-all guarantor of safety; in fact it just means that from a small sample, the drug is safe enough to graduate to phase 2. We’ve talked about how phase 2’s are the most variable in all of medicine: they range from small demonstrations of drug effect in affected patients without a control arm for comparison, all the way up to the randomized double-blind trial with placebo or active comparator arms. Safety is re-confirmed carefully in phase 2, and as such it’s rarely an issue in phase 3 (black swans all around on Regado).
But there is another biotech coagulation play worth knowing about.
In teaching medical students about medical problems involving abnormal bleeding and clotting, I often ask them: Which do you fear most? A medical problem on the basis of bleeding inappropriately, or one based on accidental clot formation? For me this is a no-brainer: I am nearly certain I have a mild form of von Willebrand disease, the commonest genetic disorder in man, affecting 1 per cent of all people regardless of race. I bleed distinctly more than I should, and that history is more reliable for making a diagnosis than the moody, finicky screening test for the ailment. Having it suits me fine, as it confers relative protection from a heart attack or a thrombotic stroke. The threat of accidentally clotting is ever-present in us. In the epic novel Midnight’s Children, Salman Rushdie’s protagonist is describing how all of his dead relatives seem to have succumbed to drowning or boating accidents. “Water claims us,” he writes wryly. Coagulation stalks and bedevils patients, and always is a threat to health. Far more often than bleeding does, clotting claims us.
Do you see why it must be so? If all of human history were compressed into one day, our species has only acquired the luxury of language in the last few minutes before midnight. Modern humans emerged perhaps 100,000 years ago, and for most of the interval since, we have mostly been grunting, hard-pressed hunter-gatherers on savannahs where losing blood, lots of it, from a lion attack, posed a daily greater risk to us than heart attacks or strokes did. We are programmed to clot exuberantly, and that has enabled us to make it to the 21st century. The tendency no longer serves us in good stead, however, and chances are that a whimsical—what physicians like to call “adventitious”—clotting event will be the thing that causes most of us to join the good ship earth.
On 19 March 1996, Jethro Tull were performing in Lima, Peru, on a rickety wooden stage. Flautist frontman Ian Anderson, famed for performing flute solos with his left leg in the air, slammed his left foot onto the stage so as to leap to his right. That left foot went through the stage, however, and in pulling the leg out, he badly injured an anterior cruciate ligament. He was 48.
Anderson is known for being obedient of doctor orders, but apparently none of the South American doctors grasped the significance of the final sentence three paragraphs above. Two days later, as in this video of poor quality, Anderson was performing in a wheelchair at a La Paz, Bolivia, concert. His injured bundled leg is fulfilling the criteria of remarkable German physician Rudolf Virchow for accidental clotting, as the area is inflamed, there is injury, and blood is puddling, in stasis, from injury appliances. The leg became extremely painful, and upon arrival home in Blighty, a doctor immediately diagnosed Anderson with deep vein thrombosis (DVT). Anderson was immediately anticoagulated with warfarin. Lung scanning showed no evidence of pulmonary embolism, which would either have killed him or kept him from ever performing again. In 2002, Anderson did public service announcements for BBC Television about the dangers of DVT. I have digital clips of the silly outtakes and bloopers from this advert, but somehow they defy uploading to youtube.
Clotting when you shouldn’t is a serious thing. But to whom does it happen? It can happen in the legs of the injured, or in the legs or pelvis veins of those mostly lying in bed. If you have a family tendency to clot at inappropriate times, such as because of deficiency of antithrombin-III or plasminogen, or because of the presence of factor V Leiden (which protein C cannot inactivate), you need lifelong anticoagulation. The same is true if you have proteinuria from kidney disease. Oral factor Xa inhibitors can be used for most of these, as well as for many cases of atrial fibrillation. Patients chronically in atrial fibrillation have a tendency to hurl bits of clot into their arterial system, where such clots may block a coronary artery, an artery to a limb, or occasionally one to the brain. Most doctors still prefer warfarin, however, for valvular disease causing atrial fibrillation, the reason being that in such cases, the left atrium enlarges significantly and is a place where serious blood pooling, leading to clotting, is common. Warfarin is a more thoroughgoing anticoagulant that the factor Xa inhibitors.
Warfarin Is An Ornery Drug
No drug in the history of medicine has caused more doctors to curse more fitfully than warfarin (Coumadin), so named because Wisconsin Alumni Research Foundation dollars led to its discovery. I can’t provide a link to a study proving that warfarin provokes swearing, but warfarin gets a great nod for sheer cussedness: its pharmacokinetics, the relationship between dose size and timing and effect, could not possibly be more capricious. Its not that clinicians are not clever enough to divine warfarin’s mysteries. They have been divined, and the fact is, a 5 mg dose of warfarin will behave maddeningly differently in the same patient on a different day. Ascribe it to sunspots, to El Nino, to someone having not been sufficiently worshipful of ancestors… maybe it would help to lay in a supply of magic pixie dust to make warfarin therapy better-behaved. I once heard someone wish for a surplus atom bomb to blow up the factory where warfarin is made… that the severity of such a response was deserved because of the misery, angst, and expense warfarin causes.
Warfarin was intended to kill rodents. Warfarin interferes with the action on liver of vitamin K, a vitamin which though fat-soluble rarely achieves a body store in humans of more than one milligram. Spinach, broccoli and kale abound in vitamin K.
What’s vitamin K doing in the liver?
The blueprints for life are stored as code in long strands of DNA, which unfurls like scrolls in a medieval monastery to provide recipes for making each protein we need for life. DNA is transcribed into RNA. RNA is translated into protein. For most proteins, however, after they are made by translation, they skitter on foal legs for a few minutes as molecules called chaperonins assist them in folding into the proper three-dimensional configuration. Select proteins go on to be post-translationally modified, with bolt-on carbohydrate groups added. In particular, a subset of the clotting factors, specifically factor II, factor VII, factor IX, and factor X, as well as protein C and protein S, get gamma-carboxylated at certain glutamic acid sidechains. Imagine a suction cup being superglued at key points on those clotting factors by vitamin K. The suction cup is a COO- (carboxylate) moiety, and adding it onto glutamic acid residues allows the factors so modified to associate with cell membranes via the action of calcium. In the absence of vitamin K, or in the presence of warfarin, the carboxylation reaction cannot take place. The liver makes plenty of all factors, but none work for clotting at all in a warfarinized patient because they cannot hook up with membranes via calcium without gamma-carboxyl groups attached on glutamic acid sidechains.
If you share a bed with someone, you probably notice that (s)he shifts positions and even fidgets all night. Why is that? Why are all people this way with the exceptions of situations in which they are deeply drugged? Here’s a hint: shift your seating position. In fact, get up and stretch your legs, as you have been reading for a bit and we have a long way to go. Why? Because all of us all the time are forming small clots here and there all over our bodies. That we wriggle at night helps prevent each of us from forming deep vein thromboses nightly. Nature has selected for us to be this way when we sleep.
This thought experiment might help you understand why warfarin kills mice. You don’t necessarily think of them as being subjected to constant trauma, but warfarin causes their demise by making them bleed to death. How? Because you must have an intact clotting system at all times. Your injure joints and tendons when you walk. Because of the occasional rambunctiousness of formed feces being forced and squeezed through your colon, your colon normally bleeds at least one cc of blood each day. If you cannot clot your gums can bleed heavily. Too much warfarin kills, and in fact the most devastating way warfarin treatment can harm a human is a spontaneous intracranial hemorrhage. I have been present at a few of these….a patient with severely compromised ability to clot who breaks off in mid-sentence, loses all consciousness and dies a short time later as brain is forced down into spine by rising pressure from blood accumulating in the braincase.
Blood clotting absolutely transfixes many science students when they first study it. Why? Because as if by magic liquid turns solid. Because it is a neat trick: normal flowing blood with no particulates except for red cells, white cells, and platelets, has the ability on cue to go from being non-viscous with soluble proteins into a state where insoluble clumps form that plug holes and wounds exactly where they need plugging. Amazing! It can do so in an instant, and somehow manages this without a “cast” clot forming in all your blood vessels from runaway clotting. The system even has molecular tricks for gradually digesting away the clot so that in time, any blood-vessel roadblock caused by clot can be re-opened.
We now grasp this system well, but getting there has been hard-won. Sometimes my columns may digress into seance-like reposes in which we summon up names from the dim-and-distant past so as to rescue them from the fog-bank of history.
Marcello Malpighi (1628-1694)
The opening page of my doctoral dissertation thanks Malpighi for his greatness, for being a role model. Malpighi was born near Bologna to comfortable parents. Early in life, he cultivated what I consider the highest quality a person can have after empathy: Malpighi was an insolent doubter. The tradition in medical education is that because there is so much to be learned, that medical students accept volumes of material on faith and on the basis of endorsements of truth by their instructors. Many of my friends are physicians and fine folk, but I do not necessarily admire the tendency of many to believe everything the literature tells them and follow blindly what they were taught. The fact is, the cardinal canonical unshakable truths of medicine have half-lives of about seven years. Malpighi was known for scoffing at books and lecturers and accepting almost nothing as fact unless he had researched it himself. For many years, there hung in the Yale medical staff cafeteria a sign: “MANY THINGS YOU HEAR IN THIS ROOM ARE UNTRUE.” Sir Karl Popper famously said that in science, truth is transient. Science learns more from its failures than its successes. While if a physical law is “broken” (if e proves not to equal mass times the square of the speed of light) it simply ceases to exist, the pace of discovery in biological science, in which the sum total of all we know doubles about every 5 years, which means that all articles of faith in medicine will topple.
We’ve said that Malpighi “researched,” and this does not mean the lightweight process of Googling and PubMed-ing. He took out implements and microscope and researched for himself. While Galileo was using the inventions of optics to probe the outer world beyond earth, Malpighi was using them to look inward, to study the structures of life, and finding that much he saw for himself didn’t jive with prevailing dogma. Malpighi lived before a German physician romantically “devised” phrenology. However, speaking in phrenological terms, Malpighi’s “bump of veneration” for his elders was a dent.
In 1666, Malpighi was correct in feeling nothing was known about clotting, that someone needed to figure out what was going on when blood clotted. With patience, and sketchbooks, Malpighi looked at blood clots in tissue and described what he saw: a mixture of cells and fibers… fibers. Blood didn’t have visible fibers in it, no obvious wayward flotsam, and so he reasoned that somehow contents in blood were being instructed to create fibers and lay them down at sites of injury. He noted that clots extruded a transparent serum, which fed into an eventual concept that plasma was the liquid that blood cells flowed in, but that serum was what became of that liquid after clotting happened. Somehow, those fibers came from plasma.
In Aesopus Emendatus, Ambrose Bierce writes of a woman named Truth who says:
“I live in the desert in order to be near my worshippers when they are driven from among their fellows. They all come, sooner or later.”
Malpighi’s refusal to be a passive recipient of knowledge professed at institutions of higher learning in Pisa and Bologna, where he was known as doubting and disputative, led him to say of his life:
“I but see myself exalted by my own enemies, for in order to defeat some small works of mine, they try to make the whole rational medicine and anatomy fall, as if I were myself these noble disciplines” (translated from the Italian).
The end crowned all for Malpighi: his observations that flew in the face of dogma were again and again proved right, and by 1691, so great was his acclaim that Pope Innocent XII summoned him to Rome to become papal physician.
Orion Magazine, now mostly about the environment, has changed its editorial thrust over the years, and in the eighties was more about education, the academy, and philosophy. In an article from that era not available online, British education professor Dr. Peter Kelly wrote of his experiences in the British public school system. He noted a radical difference in how 7-year-olds and 14-year-olds learned about nature:
“The seven-year-olds looked at, smelled, handled, listened to, and even tasted the elements of their environment. They immersed themselves in their individual tasks and came out of their endeavors only occasionally, to inform and sometimes to show off their discoveries to their fellows_.
The older children approached their work differently. They used their eyes, but rarely their other senses. They were very concerned with social approval. Were they doing what their fellows were doing? Would they make fools of themselves? When asked questions about their work, they called on the authenticity of the books they had read, television programs they had seen, or what they had been told by their teachers. They remained at a distance from the reality they were studying. The 7-year-olds tended to work themselves right into the reality.
This experience demonstrates what I believe to be a truth: that through the processes of formal education and social development, a young person is drawn away from the realities of his or her environment, away from other living things_.”
Kelly P. Understanding through empathy. Orion. 1983;2:12-16
As the days get shorter and colder, here’s a book that seriously warrants reading by the fire: The Necessity of Experience, by Edward Reed. Reed won a Guggenheim Fellowship to write this book, and in it he argues that Sir Francis Bacon and people following in his wake seriously messed up the Western mind. Why? Bacon was fond of inserting a pencil into a glass of water for students. Notice how it bends?, he’d ask. His point was: you cannot trust your senses. They deceive you, and you have to have cerebral types to make you grasp refraction. If you want to understand the world, you have to leave that to educated scientists to explain it to you. Your senses are no good. From this, it followed that first-hand experience, that doing, that seeing, that life lessons, also had little merit. What this mainly accomplished was a victory for the power of the academy and a diminution of worth for those lacking formal education but who were intelligent observers. What they claimed to see when they studied nature had no value, you see, because they lacked the theory to understand what their senses reported. Sound like nonsense? It does to me. Because of such nonsense, Reed argues quite successfully, we have needlessly empowered physicians and PhDs and dismissed the great value of learning by experience. Learning will always be necessary, but shouldn’t we also be teaching young minds that deep education in no way undercuts the importance and even divinity of doubt? That many questions are not as settled as they seem? The Janus face, the shadow self, of learning is its enormous dark capability of misleading, of short-circuiting thinking. About every five years, I buy another copy of Reed’s book, re-read it, then loan it to someone. I never get it back, as probably the borrower’s mind is so blown by it that (s)he insists to their friends that it needs reading by them too.
Rudolf Virchow (1821-1902)
It would take medicine more than two more centuries to pick up where Malpighi left off and advance the study of coagulation. The next set of insights were by Rudolf Virchow, born in Pomerania, Prussia (present-day Poland) in 1821.
Virchow entered German medicine to find it wallowing in a philosophical muskeg of romantic and mystical notions, eschewing science. As per our discussion of the life and times of the very clever and very cool Armand Trousseau, by this time English and French medicine had made remarkable strides and were firmly rooted in science. German doctors, meanwhile, still believed health was governed by “humors.” I thrill to studying the life of Johannes Brahms, who died of a mysterious jaundicing ailment not related to alcohol or virus hepatitis. A mere two years before he died, Brahms wrote to a friend of his plan to “take a cure” by spending time in the hot springs of Baden-Baden in the Black Forest of western Germany. Bubbling hot springs, life-giving minerals, good vibes from mountains with their air untainted by miasmas, an attitude adjustment and Bob’s your uncle: Brahms would be hunky dory. But Brahms was soon dead….so jaundiced that his eyes were not yellow but now green.
Virchow was mainly a pathologist, but also was enough of a polymath to make pioneering insights in anthropology, biology, public health, epidemiology and social medicine, then a new concept. Virchow was the first physician to establish a clear, causal connection between deep vein thrombosis and clots that fly off into a pulmonary artery (so-called pulmonary embolism). Virchow was the first person to recognize that the fibers in a clot, increasingly called fibrin, had to come from a soluble protein precursor, which Virchow dubbed fibrinogen. If you’ve ever seen an episode of NCIS in which Dr. “Ducky” Mallard inserts a liver probe into a murder victim to determine time of death, you are seeing an idea, technique and invention from Virchow. Most physicians and nurses are familiar with what’s called a Virchow node.
A highlight of any visit to Berlin, even for a non-medical person, is to stop by the Berlin Medizinhistoriches Museum der Charite, founded by Virchow in 1899. I’ve spent considerable time there rapt and in awe of some of the amazing examples of nature’s errors, and of disease, collected by Virchow. If you want a peek, do a Google image search of the museum.
Have you seen The African Queen? In a famous sequence, Katherine Hepburn helps Humphrey Bogart pluck leeches off himself. How do leeches suck blood without that blood clotting? By making, first, hirudin, a protein that inhibits thrombin. Hirudin was used as a template for the design of bivalirudin (Angiomax, from The Medicines Company $MDCO), used in cardiac catheterizations. Saliva of certain species of leech also have antistasin, first reported in this Journal of Biological Chemistry paper, the first discovered naturally-occurring factor Xa inhibitor.
Classically medicine’s two best anticoagulants have been heparin and warfarin. We have discussed how warfarin works, and by implication is the fact that warfarin overdosage can be remedied by vitamin K. However, large doses of vitamin K can make a patient highly resistant for weeks to become therapeutic on warfarin again. Warfarin doesn’t inhibit any clotting factors at all, but causes them to be made in a defective way. Which means that someone bleeding on warfarin can have their ability to clot restored by giving plasma.
Heparin is an iv medicine that has the ability to prevent clotting strongly. In the column on Regado we discussed the clotting cascades, which are mostly of enzymes that activate a subsequent enzyme. Factor IXa, in the presence of factor VIIIa, activates factor Xa. In turn, factor Xa, in the presence of factor Va, activates prothrombin to thrombin, which acts on fibrinogen and lays down clot. Factors IXa and Xa as well as thrombin (factor IIa) are inhibited by antithrombin-III. However, heparin has the ability to associate with antithrombin III and “supercharge” it, make it a much more avid inhibitor. In the presence of heparin, antithrombin III keeps factors IXa, Xa, and thrombin from working at all.
Starting about 25 years ago, coagulation scientists realized that they could use certain chemicals to “crack” or fragment heparin. The product, so-called low-molecular-weight heparin, was observed to have the unique property of being able to make antithrombin-III act only high up in the clotting cascades. It would block factor IXa and Xa, but not act on thrombin.
Heparin has always had a downside of causing immune reactions in people for odd reasons, often immune reactions that cause platelet counts to nosedive. Low-molecular-weight heparins successfully thin the blood but leave platelet counts alone. Moreover, physicians realized than enoxaparin, a low-molecular-weight heparin, had the virtue of not only preventing accidental clotting such as DVT in hospitalized patients, but that also on rare occasions when those patients were challenged by unexpected bleeding (from a stomach ulcer, for example), they’d do OK….they’d not bleed massively. Enoxaparin was providing “just right” Goldilocks anticoagulation.
The ability of enoxaparin (an injection), mainly a factor Xa inhibitor, safely to prevent accidental clotting without making patients a lot more likely to bleed made drug designers mull the possibility of devising an oral agent that could inhibit factor Xa. Around 1990, Asian scientists had devised and advanced argatroban, an inhibitor of thrombin (factor IIa), one that works like Pradaxa (dabigatran) does, but that had an excessive accompanying tendency to cause serious bleeding because it acted so low down in the clotting cascade. A very recent paper shows that Pradaxa is even likelier than warfarin to lead to accidental bleeding, particularly from the GI tract. Pradaxa is by privately-held Boehringer Ingelheim, and has a murky future. Meanwhile, the great issue with warfarin has always been the risk of intracranial bleeding that goes with treatment using it. This risk is the great way in which oral direct factor Xa inhibitors shine as compared with warfarin…they rarely make patients bleed into their heads.
Drug design and trials led first to rivaroxaban (Xarelto) marketed by Janssen (a unit of Johnson and Johnson, $JNJ) in the United States and soon after to apixaban (Eliquis) from $PFE and $BMY. Similar agents darexaban (from Astellas, $ALPMY), edoxaban (from DaiIchi Sankyo, $DSNKY), eribaxaban (from Pfizer, $PFE) and betrixaban (from today’s featured company) are in late-stage clinical trials. Clearly all these drugs cause less accidental bleeding than warfarin does, but “less” does not mean they don’t cause it. Biotech and medicine are about numbers, those things invented way back when by the Arabs, and we need to use them. At least once a week I get an advert in my email trumpeting the tremendous virtues of the new boron-based cream from Anacor ($ANAC), the billion-buck boron boondoggle… trumpet-worthy because it is merely better than placebo. Tavaborole made it past the FDA because it cures nine percent of all toenail fungus cases while only one percent remit on placebo. Make no mistake!, the ads claim; this drug (which fails 91 percent of the time!) is topshelf medicine.
If a doctor places you on a drug like Xarelto or Eliquis, that drug will alter your clotting tests. But there are problems:
(1) unlike the situation with warfarin where specific INR targets are known on the basis of huge studies, no one knows how to correlate desired factor Xa inhibitor effect with INR or aPTT blood tests.
(2) there ARE assays that would allow a doctor to monitor your therapy on factor Xa inhibitor, but though they are not super-arcane, hospitals not attached to academic laboratories mostly don’t have the ability to run them.
(3) those specialized tests to monitor factor Xa inhibition have not been validated in large populations of treated patients, which means they may not be reimbursed by payers.
As a result of this, here is how doctors monitor you on drugs like Xarelto and Eliquis:
Do patients on Xarelto or Eliquis ever get into trouble, ever bleed when they shouldn’t? The drugs are still relatively new enough that comprehensive data on this is hard to find, but most of us in gastroenterology definitely see it and deal with it, often in the wee hours. And in fact an unpublished company-sponsored study I am aware of suggests that in 2014 in the US, about 7000 patients per month present to hospitals with acute bleeding while on a oral direct factor Xa inhibitor. Patient on Xarelto strains back, takes ibuprofen for a few days because of low back pain following a brisk session of yard work. Begins vomiting blood from a stomach ulcer, which can emerge in mere days from NSAIDs. At emergency endoscopy, we find an ulcer crater with a pumping, visible arteriole. We inject some epinephrine and do a little char-and-scorch routine with endoscopic devices…..but the fact is that patient is at high risk of rebleeding when the clotting system can’t be depended on.
Imagine yourself as a drug developer. Someone approaches you with a clinical problem: some people get too much direct factor Xa inhibitor in their systems and have acute bleeding. Can you make a agent to fix this? How would you do it? The first idea that comes to mind for many is to make a monoclonal antibody to the drug. All chemical reactions are in equilibrium, as factor Xa inhibitors do not bind covalently to factor Xa. The drug pops on and off factor Xa, and during a nanosecond when the drug is free, the antibody can bind to it. Easy, right? Perhaps, but it’s not the outcome you want. Antibodies given as drugs stay around and are active in the body for weeks, while nearly all people on factor Xa inhibitors were placed on those for good reasons, and will need to go back on them, perhaps at lower doses.
What else might you do? Dialyze away excess drug? That won’t work, as the drug is stuck mostly to factor Xa, and proteins that size don’t come off at dialysis. Could you override the effects of the drug, maybe by loading the patient with proteins or drugs that favor clotting? That probably won’t work: factor Xa activity is a “final common pathway” for both the intrinsic and extrinsic clotting routes. Some doctors have tried giving thrombin in the form of prothrombin complex concentrates, to bypass the factor Xa blockade, but doing this in people with an underlying tendency to clot, such as atrial fibrillation, can be very risky. Could you somehow give recombinant factor Xa? Well, it doesn’t exist as a drug, but moreover, in settings where people on factor Xa inhibitors are bleeding, those inhibitors are present in gross excess compared with factor Xa, such that all the new factor Xa you give just gets inhibited too.
This problem needed the smartest scientific solution biotech could devise.
A New Company for Your Consideration
The company being contemplated here today is Portola Pharmaceuticals ($PTLA), a riotously smart South San Francisco firm that can beat bleeding caused by factor Xa inhibitors. What’s in a name here? I suppose it depends on where you place the accent when you pronounce “Portola.” The name may imply use of the Italian verb portare, to carry, and Portola seems to be “bring it (on)!” What also comes to mind is Potala Palace in Lhasa, Tibet, where the Dalai Lama lived until his self-exile to India upon the Chinese anti-Tibet crackdown of 1959. You can be forgiven if Potala Palace conjures Shangri-La. Portola may merely have named itself for the tiny unincorporated town of Portola Valley, between San Mateo and San Jose, close to corporate headquarters.
Portola began trading on the NASDAQ by IPO in mid-2013. Its present market capitalization is about $1.3B on 41.4 million shares outstanding, 39.4 million of which float. Institutions own about 80 per cent of the shares, and large block owners control another four per cent. The single largest shareholder, a Maxwell party in Mauritius (?), owns 5.8 million shares, 1.6 million of which were added on 8 October 2014. Temasek, Wellington Management and Fidelity each control more than five percent of the outstanding shares, and Alta Partners, whose biotech investments I track from time to time, owns a large position. Fierce Biotech editor John Carroll deemed Portola one of the top 10 biotech IPOs of 2013, a designation mainly based on the price fetched at IPO versus the price sought (shares were in heavy demand) as well as durable share price uptick following the IPO.
Portola is a coagulation therapeutics company. When I was “unwrapping the package” of it by perusing its website, I came to the portion where advisers were listed. Before I clicked on that, I made a mental short list of my top five most admired living experts in clotting, and wondered whether Portola had snared any of them. Amazingly, four of those on my list work with Portola: Charles Esmon, PhD, of the Oklahoma Medical Research Foundation; Robert Califf, MD, of Duke; Eric Topol, MD, of the Scripps Research Institute; and Shaun Coughlin, MD, PhD, of UCSF. Califf is on PTLA’s board of directors.
Esmon trained someone subsequently involved in training me, and is regarded as the intellectual dean of American coagulation medicine. His work led directly to the development of two major life-saving drugs, Xigris (from Eli Lilly, $LLY) and Ceprotin (from Baxter $BAX). He’s a member of the Howard Hughes Medical Institute and of the National Academy of Sciences. An Oklahoma newspaper praised him last summer.
Portola has engineered a designer version of factor Xa with the following properties:
Portola manufactures this in cultured Chinese hamster ovary cells transfected with a vector that expresses the gene for its designer protein, called andexanet alfa. In fact, this drug is being made for Portola by highly-regarded contract manufacturer Lonza ($LZAGY) of Switzerland at its facility near Heathrow Airport, about a half hour west of our man Alan Harris, who can always check on things if we need to get Portola in line.
Andexanet alfa is deep in phase 3 trials of its antidote for factor Xa inhibitors, and has recently reiterated that it is on track for a NDA for andexanet alfa in 2015 with product launch in 2016. The FDA has granted Portola breakthrough therapy designation for this agent, and in pre-clinical studies, it is highly effective against all the oral factor Xa inhibitors, even those not yet approved or marketed. Portola also recently provided insight into its recentest negotiations with the FDA that suggest the FDA is exceptionally willing to provide accelerated approval for andexanet alfa.
Is andexanet alfa a shoo-in? Hey, TIB and nothing is a shoo-in. Immune or allergic reactions to it are possible, as is the possibility of developing antibody to it. My feeling clinically, however, is that even if antibodies to the agent emerge, there is a reasonable chance it could be used again in a given patient without harm and with some expectation of efficacy. The agent should not be highly immunogenic, as its main structural differences are in the cleft of the active site, the “naughty bits” of factor Xa not usually accessible to antibodies. Anytime you reverse an anticoagulant you always worry a bit about making a patient transiently hypercoagulable. Neither this phenomenon nor adverse reactions have been issues in Portola’s trials of andexanet alfa.
You needn’t tab over to your trading platform and frantically put in a buy order for $PTLA. I haven’t yet. I am eyeing it and feel favorable on it. One of our goals at Stock Gumshoe is not to be a tip sheet for biotech but rather to provide a buffet of quality stocks for your consideration. Many roads lead to Rome. You can choose from among them based on your risk tolerance, based on the specific variety of biotech that appeals to you, even based on which sort of clinical issues you enjoy following… all persuasions, no brutality. I’d characterize PTLA as a high-quality biotech midcap that is a relatively asymmetric upside opportunity. PTLA shares are unlikely to catapult right away, but when you make a high-tech drug that, for medical-legal reasons, every hospital in the US and EU must stock so as to manage liability risk, and that drug is likely to be priced at more than $25,000 per adult dose, profits will be made. Especially when 84,000 patients per year may need the agent. Get out your calculator.
In medicine, when we want to describe a clinical situation in which something is lacking, we use the suffix “-openic.” Platelets are “thrombocytes,” and if you are thrombocytopenic, your platelet count is low. Cash is always an issue for development stage biotechs, but some of them we’re fond of here are deeply vexed by chronic cashopenia. Arch Therapeutics ($ARTH), for example, is so cashopenic right now it probably can’t afford to give each employee a $50 Christmas bonus, even though Arch really could soon become a 10+ bagger. It’s thus refreshing to come upon Portola, which as of 30 September 2014, had $252 million in cash or cash equivalents. Because of a large capital raise by a secondary offering in October 2014, the company is now sitting on $437 million. Its annual research and development costs, up somewhat from last year, now run at about $150 million per year.
Portola has other things going for it as well. Its in-house oral factor Xa inhibitor, betrixaban, is about 60 per cent of the way through phase 3. Portola have asserted that betrixaban has several properties that may make it theoretically superior to present factor Xa inhibitors. I reached out to the company for clarification on this, asking if they could provide some color on betrixaban as compared with other agents, and have not yet heard back from them.
Recent clinical evidence suggests that not only are patients prone to DVTs during hospitalization, but that those who are hospitalized for prolonged periods are at increased for an accidental clotting event for up to a month after they go home, for incompletely understood reasons. Portola is seeking a novel indication for betrixaban as comparably safe and easier to take (oral not injection) than enoxaparin in this setting. Betrixaban is less dependent on clearance by the kidney than other factor Xa inhibitors, which may make it preferred for renally-insufficient patients. The company asserts that betrixaban is less likely to cause accidental bleeding than any other oral factor Xa inhibitor, and while I have no reason to doubt Portola, I regard proof as lacking for that claim.
Portola will have new data to present at both the American Heart Association meeting on 17 November 2014 and at the American Society of Hematology meeting in early December, and either event could conceivably move shares.
Though not a specific reason to invest now in PTLA the company also offers investors the omake (where Japanese merchants toss in a bonus gift after your purchase if they like you) of cerdulatinib, an oral drug that inhibits both spleen tyrosine kinase and Janus kinase (JAK). This agent is still in phase 1, but may have a role in treating diffuse large B-cell lymphoma.
Short interest in Portola is limited at only about five percent, and the quality of the company’s data probably confer on it a protective effect against badmouthing by shortsellers wanting to game share price. A comprehensive search for competition, for other approaches to managing people who bleed acutely on oral factor Xa inhibitors, suggests that Portola is utterly alone in this space; the competition is nil. Meanwhile, Portola has good relationships with all the other manufacturers of oral factor Xa agents, all of whom are likely to implicitly promote andexanet alfa from Portola for emergencies caused by their drug. Most will likely have the FDA modify the label instructions and package insert for their products. Beyond that, it would be rather unsurprising to me if Portola placed itself up for sale to a large pharmaceutical company merely because of the efficiencies of scale to be had from combining sales forces, with those who promote the house brand oral factor Xa inhibitor also promoting Portola’s antidote.
Biotechnology investing, as you are learning, is both science and dark art. Large cap biotechs offer safety, downside protection, but may do so at the expense of share appreciation potential. Smaller cap biotechs may each offer the lure of possible bombastic returns, but the truth is most will fail. You have to kiss a lot of frogs to find a prince in biotech companies of market capitalization less than $500 million. Portola may exist in a biotech midcap sweet spot of having earned its way on quality and esteem to a market cap of $1 billion while also offering potential several-fold upside in the event that its phase 3 trials, coming down home stretch in 2015, succeed. Portola owns all global rights to both andexanet alfa and betrixaban, and in my view, the likelihood of any competitor being able to devise another antidote for factor Xa inhibitors that does not violate Portola IP is nil. I have looked at intellectual problem posed by factor Xa inhibitors, and Portola is in the catbird seat.
By most prognostications, including mine, Portola will succeed in phase 3, and $PTLA shares may belong in your portfolio.
Disclosures: of companies mentioned, I have long positions in $LLY, $NVO and $PFE. I have no short positions or options, and will not trade in any mentioned company for 7 days after publication. This discussion of biotechnology securities is not intended as personal investment advice, and while in any discussion of a company I endeavor to present everything of relevance in making a decision about investing in said company, I may know facts about such companies not presented in the text.
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