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Posted On: 01/06/2024 4:22:11 PM
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If you are bored and want to read about Cytodyn back when we had no short interest, the First part is boring, but it gets better.
$tock Gumshoe
SECRET TEASER STOCKS REVEALED. INVESTMENT NEWSLETTERS REVIEWED.
Cyto Who?
Posted on January 21, 2016 by Dr. KSS MD PhD
[Ed. Note: Dr. KSS is an MD and PhD who writes about medicine and biotech stocks for the Irregulars. He has agreed to our trading restrictions, and his words and opinions are his own. You can see his past articles and recent comments here.]
You’re probably getting it right by now—writing “2016” and not “2015.” The poster child for January could be a black labrador retriever draped in soporific splendor over a cushion in front of a blazing woodstove in an old country store. It’s a contemplative month. What will the year bring? And will it treat us well?
And you could be forgiven if the answers seem to demand a swig of Mylanta. China enables a North Korean dweeb to both detonate nuclear weapons of his own and to facilitate missile construction by Iran. Meanwhile, Iran, temporarily on good behavior, will use its new treaty with Washington to intensify glut pricing for a commodity whose cheapness, if sense made sense, would be liberating economies, causing airlines, automakers and transportation industries to surge in share price. Investors, finding no quarter in either energy or commodities, ought to be scouring the exchanges for businesses that will soon generate profit, creating a seller’s market. As such, biotech should be facing rosy times, especially as political tea leaves begin to suggest that we might have both Robert Califf, MD, in charge of the FDA and Donald Trump in the White House…. a shoot-the-moon situation for biotech.
If you’re seeing a patient who is psychotic, who is clinically crazy, it doesn’t help much to delve into the substance of their craziness. There’s no value in parsing it, in trying to legitimate it, in trying to make it make sense. The first thing you do is try to restore order with antipsychotics. Rationality always returns—it does—and shall return to markets. The smart money is not brooding and languishing over the present climate of awfulness; it’s stalking good stocks, laying plans, staying calm, maintaining the posture of a puma. Maybe we all now need to be performing five-minute mini-affirmations of each other in the thread, just as Paul Giamatti’s wife does in the new Showtime series Billions. Here, I improvise: “Yes, those biotech stocks are just waiting for you to buy them just so that they can swandive 30 percent the minute your order is filled! C’mon…do you really believe that? Is that RATIONAL?”
This morning, I got an email from Francis Collins, MD, director of NIH (you can get mail from him, too; just ask). According to Collins, 50,000 Americans will learn this year that they have HIV. That’s a different figure from the incidence of HIV, which is the number of true new cases, newly acquired, this year. And it’s different from the prevalence, which is the total number of cases out there. A sociological feature of the current HIV epidemic is still a fatalism that causes many not to be tested despite knowing they have compelling risks for having the virus. 50,000 Americans is a lot of people; we have Gumshoe Biotech readers who live in towns with fewer than 50,000 people. But views on treating it have changed sharply. For most of HIV’s duration among us, we have felt that treatment was necessary only when an AIDS-defining illness emerged in a patient with HIV. Younger loud voices, sometimes mine among them, argued that this approach was idiotic. For one thing, it is safe to assume that all infected with HIV will progress to AIDS. (Extremely rare people don’t.) But the destruction of the immune system is progressive and time-dependent and cumulative. Intervene early, why don’t we? It’s easier to salvage bedrock immune system than to spend years rebuilding it with pricey drugs. Collins makes the point that of those 50,000 people, beginning them as soon as possible on HIV therapy will allow them to live lifespans that are statistically no different from yours and mine. And because of this, HIV therapeutics will continue being a worthy space for us to study when new treatments rattle the landscape. Yet we’ve had no new HIV drugs in 15 years.
Penny Lane
For me as for many, a new year skittles on foal legs for its first few outings, after the repose and excess of the holidays. Let me convey with a literary seam I cannot hide that Alan Harris and I had a goodly discussion toward the end of last year about our forum. He made the point vigorously that I might be unwittingly depriving readers of great investment opportunities by being so reluctant to cover low-cost, low-market-cap, non-exchange-traded companies, ie, penny stocks.
His points, and I found them good ones, are below, to which I have woven in a few that occurred to me but that would not have occurred to me had he and I not thought and talked about it.
(1) We’ve seen a crazy period come through in which all biotechs have come down, all have succumbed to gravity. This tends to undermine any view that exchange-listed stocks are nobler.
(2) Penny stocks can and do rally. He pointed out many examples.
(3) The term “penny stock” gives existential short shrift to the nature of the stock in question. Some penny stocks were once exchange-listed dignified companies whose fortunes shifted. When this is the case, it’s fair to ask, Why they shifted? Might they unshift? Did this company become a penny stock because people walked away? Or was it born a penny stock because of blighted interest? Did it emerge as a penny stock as the result of a reverse merger as Arch Therapeutics ($ARTH) did? If it did, there’s no obvious shame in this, as debuting on a market via an IPO is a very expensive process.
(4) We cannot be fair to any class of stock if we say all its members are garbage. In fact during our last two years together, we have come across penny stocks with excellent science, diagnostics or proposed therapeutics ($ARTH is such a stock). Meanwhile, Alan was quick to point out that of exchange-listed biotechs, I regard 85 percent or so as being scientifically beneath consideration. If non-excellent stocks are already so prevalent among “pedigreed” names, is it not fair to honor consideration of the non-pedigreed? Indeed, should we not be judging all biotech plays ONLY on the basis of science quality? If so, then we are tossing aside occasional emerald, ruby, and sapphire penny stocks, and doing so as we treat most exchange-listed stocks as potential diamonds just because they’re exchange-listed.
(5) The reverse tractor-pull effect of six months of vexatious markets on the biotech space has created penny stocks (penny “opportunities”?) by shoving developing names out of the first-class cabin.
(6) It takes amazingly little coin to move the price of a penny stock. Who are we to tell our readers that they shouldn’t game these? I’ve made occasional serious money in penny plays.
(7) Alan made a heuristic point: our readers are not exactly the same people as when we began. We began with some sophisticated investors as readers, but have accrued many sophisticated investors out of “average” readers who have paid attention and gotten in the game. Readers don’t come here to be told where to invest. They come to get ideas and to have a vigorous discussion forum to backstop their thoughts.
Alan’s main point was that it’s better not to have an editorial policy of either not covering or being excessively reluctant to cover penny stocks. He persuaded me. Take every company case by case, each on its own merits. Let’s not parameterize. Let’s cover what’s worth covering.
Do you know the story of Teri Horton? Top up your mug with some fresh black Arabica and let me regale you. Horton was a 73-year-old retired Californian truck driver, and when she retired she missed the magic of the open road if not precisely the smell of diesel smoke in her hair. She became a wanderer, an itinerant denizen of roadside America, and particularly loved the allure of dusty, badly-lit junk shops in odd places. As a way of sharpening her claws for a weird painting she saw propped in picturesque disarray in a moldering corner, she asked the lady in the junk store for a cup of coffee. Then she began haggling. How much do you want for that picture? “Eight dollars,” was the answer.
“For that piece of junk?,” Teri asked, this being a junk shop. “I’ll give you five. I’m just gonna take it home, give it to a friend. We’ll throw darts at it while we drink beer.” Deal.
But the picture, which was unsigned, was too large to fit inside Teri’s friend’s trailer. Soon, the picture, a drip-painting, found itself at a yard-sale table in Horton’s community. That was when Teri was stopped by a local high-school art teacher. “I think that’s a Jackson Pollock,” the teacher said.
In so many words, Teri replied, “Jackson who?”….in so many words because what she actually said might not go over well in this fine family publication. But Horton became obsessed, and in subsequent years has vigorously sought consensus from Pollock experts. Some concur it is a Pollock, similar to work he was doing around 1948. Which is why Horton wants $50M for the painting, a figure some say she deserves. Her adventure is well-depicted in the fine 2006 documentary Who the #$&% is Jackson Pollock?, co-produced by Don Hewitt of 60 Minutes fame.
When the student is ready, the master appears. In the small hours this morning, by the dawn’s surly light, I made coffee and set about opening email. The first one was from my friend Jules. I’ve mentioned Jules here before: he has HIV, is medically healthy, and has devoted his life to being a radical HIV advocate. Rumor, bizarre treatment idea, secret drug in secret trials, straight dope on every pharma company: Jules never reveals his sources, but ah, what sources. Jules independently raises money so that he can personally attend every HIV meeting on the planet each year that matters, and he photographs every poster and presentation. Increasingly he’s being asked to lecture trainees: Jules is neither a physician nor a PhD, but he’s the ultimate insider. He has a way of showing up everywhere, seeing everything through the eyes of a jackdaw dressed to the nines.
Jules was writing to beat a company to the punch…..he was telling me what announcement they’d be making this morning, about two hours before they announced it. And now, same day (I am writing this on 19 January 2016), I am letting you know. In order to enhance my objectivity, I’ve not invested in this company yet. If you visit Bali, Indonesia, you get the best price of the day on any object you buy in a store if you’re the first customer who shows up that day. Maybe by analogy, this can be a first buy of the year for readers, one that affords serious profit. I’ve scoured the science of the company, and I like what I have found. The company may be an unrecognized masterpiece.
Make a note of it: CytoDyn ($CYDY), a company for which your due diligence will immediately reveal a share price of under $1 and a market cap of under $100M. $CYDY shares trade over the counter, and both institutional and short interest stand at zero. Like the possibly-Pollock painting, discerning biotech eyes, which many of you now have, can find plenty about this stock that could catapult shares well past a dollar.
Early this morning, CytoDyn, which is headquartered in Vancouver (Washington, not BC), announced that HIV patients receiving its lead drug PRO140 as monotherapy for their illness have no detectable serum HIV RNA out to 17 months, the longest any patient has yet been treated. You can peruse the study protocol here. This study, which began enrolling in November 2014, seeks to take 28 HIV patients at a single site in San Francisco, and treat them with once-weekly 350 mg subcutaneous doses of PRO140. The study will end with a maximum duration of 24 weeks of treatment, and following this many happy patients will no doubt ask fervently to remain on it by compassionate release. To service the interested clientele, the company has two phase 3 trials planned, and is keen on having this drug to market in 2017.
PRO140 is a monoclonal antibody directed against chemokine receptor 5 (CCR5…which rings some bells, I hope). The significance of the study, though now only with one site, may be apparent to some readers: San Francisco has a large gay male population and is a hotbed of HIV, particularly of stubborn, resistant forms. CytoDyn decided not to dance around the edges of whether its drug works. Rather, they chose to roadtest it in probably the toughest patient population in the US. The FDA likes what it sees: it has bestowed fast track designation on PRO140.
We’ll review the highlights of CCR5 and HIV, but first allow me to dispel one objection you may already have to this story, especially if you have HIV or know someone who does. Big whoop, perhaps you are thinking. Combination cocktails of antiretroviral drugs have long been known to drive HIV serum viral loads to undetectability. In that case, does PRO140 matter? Or is it just a fancy, cynical (because it might be high-priced) pharma ploy to achieve a kind of zero-sum objective?
I treat a lot of HIV and know others who do as well, and can tell you that if you study large numbers of stable patients on combination anti-HIV therapy, what you generally see is an overall prevalence of about 25 percent of them at any given time having no detectable HIV RNA. Some of this owes to human imperfection: none of us doses our oral meds perfectly. If there’s a pill you take daily, admit it: you forget it now and again. Moreover, for reasons we don’t fully get, HIV is like HCV and HBV in that sometimes we see eruptions in serum virus burden despite the fact that nothing seems to have changed for the patient in question. But already with PRO140, we see the drug achieving clinical goals superior to the best HIV oral drug combos out there. (Gilead ($GILD), maker of best-of-breed fixed-dose-combos for HIV, has no doubt taken notice.)
A hand is raised, and its owner looks skeptical. “KSS, aren’t you just baiting us with a straw-man scenario? Does it really make a difference if the HIV viral load is zero as opposed to being significantly lowered by antiviral therapy?” But you’re all beginning to think like pharmacologists, which primarily means recognizing that when an agent is acting on a living system, the extent of the action is related mathematically to the dose. No measurable virus means nothing to confound all the players in the immune system. The immune system is thus free to fully engage against infectious pathogens and cancer, and drive them out. No cell can harbor HIV and function normally, and while PRO140’s resulting absence of serum HIV RNA does not mean no cell is HIV-infected (many have latent infection) it does mean the body has significantly more physiological agility. Zero is better than non-zero. Zero virus means greatly reduced risk of transmission of HIV to another person, though that comes with caveats, as zero serum virus can’t be presumed to result in absence of virus in semen (the testes are an HIV reservoir). It’s very easy by a Google search to pull up scores of published studies showing that in HIV, the higher the virus level in a tissue, the worse the pathology is in that tissue. But tissue is in equilibrium with blood, so when virus can’t be found in blood, it’s clearly less abundant in tissue too.
Don’t be confused by this if you have dealt with virus hepatitis and are trying to draw analogies. The HCV-infected are often preoccupied with serum virus burden, but the relationship between serum HCV RNA level and disease severity is bizarre. In some collections of patients, a near inverse relationship between virus burden and pathology is seen, seemingly because reduced virus level implies more vigorous immune attack on one’s own organs. Patients with HBV or HCV with astoundingly high virus burdens are often amazingly free of liver disease on biopsy because their immune system is mostly ignoring the virus (generally because it has mutated).
You’ve got the picture: a single drug that, given beneath the skin once a week at home, can completely control HIV infection. Let’s round out meditating on that by making one more point of discussion, which is that if you could choose treating a condition with a single highly effective medicine versus a cocktail of highly effective medicines, which would you choose? The essence of HIV infection is just like bacterial infection: the infecting agents mutate to resist drugs being used to treat them. Combination therapy might be better, in some cases, at deterring mutation, but make no mistake: resistant “escape” mutations WILL occur, and when they occur as a result of drug combinations, the result is often a much more virulent virus. I think it’s important that we not draw too easy a conclusion that resistance comes earlier and easier as a result of monotherapy. Every antimicrobial agent comes with a mathematically defined “barrier to resistance” based on how effectively it kills and based on how cardinal or resistance-proof the killing mechanism is. All drugs have side effects, and the HIV platter of pills is no exception, and meanwhile PRO140 is well-tolerated. In this case, if I had to choose between the one drug and the combination of many, I’d choose the single-agent approach, with this in mind: HIV mutates rapidly when it chooses to, and yet CytoDyn’s present study has patients treated for 17 months and counting without breakthrough mutations. 17 months is a long time for HIV.
A Crash Course on Antibodies
Suppose that elephants were small enough to dissolve in water, draw up in a syringe, and inject into a person. The elephant is a totally different creature from people, a “foreign” organism, and so immediately after you are injected with an elephant solution, your body gets to work on producing polyclonal anti-elephant antibodies. A clone is a line of cells or organisms that are identical, and have identical DNA. Antibodies (which come in fiveclasses: IgG, IgA, IgE, IgM, IgD) are made by B-lymphocytes. If you’re discussing antibodies and the class isn’t specified, it’s safe to assume you’re speaking of IgG.
Monoclonal anybodies
Here I am trying to lead you into potential confusion so you’re not confused in the future. “Polyclonal” does NOT mean containing different classesof antibodies. A polyclonal antibody, rather, is of a single class, usually IgG, and recognizes a diversity of epitopeson a molecule of interest. What’s an epitope?
Epitopes Indeed
When I’m trying to explain epitopes to students, I always think of the mashed potato sequence in Close Encounters of the Third Kind. Take a couple of minutes and watch it at the link. Richard Dreyfus’s character has come under the spell of a haunting rock formation, one that will soon be the site where he makes contact with extraterrestrial life. He broods about the place by sculpting it on a dinner plate in mashed potatoes, gently conferring on it ridges, lumps, and escarpments. You could think of each of these structural features as being like an epitope on the rock formation. Each is a locus in three dimensions with unique structure. Every object is a collection of epitopes, of unique sites on its surface, and two objects that share precisely the same set of epitopes in the same spatial relationship are the same (are clones of each other).
Our polyclonal anti-elephant antibodies recognize multiple epitopes on the dissolved elephants. We’ve got anti-tusk antibody and anti-trunk antibody. We’ve got anti-floppy ears antibody. You may realize we’re here stumbling onto the famed story of the elephant and the blind men. All of the individual antibodies in our polyclonal mix of can be correctly called “anti-elephant antibodies” but each represents one and only one site on the elephant, a different site from every other specific type of antibody in our polyclonal mix. Each clonal type of antibody in our polyclonal mix recognizes a different part of the elephant from each other subtype, and yet all are anti-elephant antibodies.
Think of how dogs socially sniff one another. When a mammal encounters a foreign protein, the immune system sniffs the nooks and crannies of that molecule, and makes a different antibody to everything it recognizes as an epitope. Our miniature injectable elephants are nothing more than proteins, and most invading pathogens drag proteins with them that trigger an antibody response. A protein is a string, extending in one dimension, that has a unique sequence of amino acids. Each amino acid has an average molecular weight of about 110 grams/mole, and so a common plasma protein weighing, say 55,000 daltons would consist of about 500 amino acids.
The amino acids are everything from glutamic acid (which agitates you if it’s loose in your brain) to tryptophan (precursor of the happy hormone serotonin) to cysteine (whose sulfur thiol sidechain acts as an entering nucleophile for the cysteine proteinases). Each amino acid has an identical three-atom backbone that allows it to be a bolt-on part for a protein strand. Then, jutting off the second atom of the backbone, each amino acid has a unique sidechain, a sidechain responsible for most of the amino acid’s properties, and that has spatial structural features (with or without electrical charge) that make it distinct to all the other amino acids.
Gummies, I know this is dry to many of you, but medical biochemistry is best learned in bolus feedings.
When a protein is out and about, it doesn’t travel like a string or strand. It has long since folded itself into a blob, a blob like a jumble of twine. Although the twine may look random and haphazard, if you challenge a protein to unfolding, it will generally refold itself in exactly the same three-dimensional way. This is because all the amino acid sidechains find an energy-ideal most-overall-comfort way to sidle up next to each other, making the conformation of each protein unique and non-negotiable.
Amino acid side chains can be near to each other in a protein from either of two influences. First they may be nearby in the sequence of amino acids on the primary protein strand. But second, depending on how they jut out into space, they may have sidechain neighbors that occur literally anywhere else in the primary amino acid sequence. This is because the protein folds, forms helices, and builds sheets.
As the immune system scans the protein, looking to reckon it in epitopes, it is looking for clusters of amino acid sidechains, usually between 5 and 12 amino acids altogether, that have spatial uniqueness. These amino acids can either be adjacent on the protein backbone, or else side-by-side in space because adjacent strands of protein are lining up next to each other in space. Nature conserves, and everything in a protein structure counts for something. Thus antibodies recognizing different protein epitopes (such as an enzymic active site, such as a transmembrane channel, such as an allosteric modulator binding domain, such as an ion binding site) can have stunningly disparate effects on protein behavior.
Polyclonal antibodies are great, don’t you see, for subduing or neutralizing a questionable protein. They do this by sticking to it at every conceivable epitope. The protein travels through the bloodstream having incurred a gang of miffed polyclonals atop it, and is plucked out of circulation in the liver and spleen, where antigen-antibody complexes are destroyed. “Antigen” has a similar meaning to “epitope” in that both draw the attention of immune antibodies, but each antigen generally has several epitopes, while an epitope is the smallest unit to which you can reduce something attracting the immune system.
When we speaking of antibody binding to epitope, it’s important to consider how tight the binding in question is. All chemical reactions proceed in forward and reverse directions at once, and what favors the progress in either direction has to do with kinetics (are there impediments to the reaction?) and thermodynamics (is the overall energy of the state we seek the lowest that is available?). In general antibodies bind so tightly to epitopes that the only way to dissociate them is to boil them in denaturing detergents. Because of this, antibodies could be a weapon against disease if we could harness them, direct them to exactly the epitopes we want, and make them on demand.
Those very requirements, however, tend to leave out polyclonals. Why? Because when an animal is exposed to a new protein for the first time, the polyclonal antibody it makes tends to fade in titer and specificity over time. Moreover, if you rechallenge the animal with the protein, though it will still crank out polyclonals, some polyclonals will be enhanced and others will begin to fade from the mixture.
Make Mine a Monoclonal
A monoclonal antibody is usually a laboratory-generated IgG that binds to one, and only one, epitope. It was usually generated as part of an array of monoclonals against a protein, but has been separated and set aside for its ability to stick to precisely one three-dimensional spot on the target protein’s surface. Do monoclonals ever occur naturally? They do….but when they do, they represent an underlying malignant process. Remember, all antibodies are made in B-lymphocytes, and within each of us are countless clones of B-lymphocytes. If one such clone expands in a brakeless way, monoclonal antibody begins accumulating in the serum, and can be detected by so-called SPEP (serum protein electrophoresis). Multiple myeloma, for example, is diagnosed in part by SPEP.
How to Make a Monoclonal Antibody
Because each monoclonal sticks to but one epitope, and because most targets have scads of epitopes, it stands to reason that different monoclonals to the same target protein are binding to unique microregions in that protein. Two companies can have monoclonals directed against the same target protein, and yet have agents that have little in common how they behave clinically. The picture schematic below maps out the steps in making a monoclonal antibody.
OncoDyn has devised a monoclonal against CCR5 that doesn’t block or shut down the entire molecule. CCR5 has many roles, including some we don’t grasp well yet, and we’re in an important age of discovery right now for the members of the chemokine receptor class (see our 7 Jul7 2015 column introducing ChemoCentryx ($CCXI) and the chemokine receptors). You may recall from discussions during the summer of 2014 how CCR5 behaves as an entry portal on lymphocytes for HIV, in addition to having several other immune system roles. OncoDyn has designed a monoclonal antibody that sticks only to the epitope on CCR5 that enables HIV entry into a CCR5-bearing T-lymphocyte. As such, CCR5 still binds chemokines, and can thus still participate in other healthy immune-defensive processes. Its mechanism is depicted with enormous clarity in this cartoon, which I strongly encourage you to watch. What comes to mind for me is an old credit card commercial: “MAKING A CUSTOM MONOCLONAL ANTIBODY: $4,500. MAKING A CUSTOM MONOCLONAL ANTIBODY TO JUST THE RIGHT EPITOPE: PRICELESS.”
Some readers may be aware of the GlaxoSmithKline ($GSK) drug maraviroc (Selzentry), which also adheres to CCR5. Maraviroc was designed years ago with the hope that it would accomplish what PRO140 does. Its problem, however, is its more diffuse, less-finely directed binding at CCR5. Patients on anti-HIV cocktails containing maraviroc generally have somewhat lower HIV RNA loads than those on cocktails without maraviroc, but the results aren’t stunning. Their viral loads don’t go to zero, and in terms of quality of life, maraviroc seems to add nothing. Its sales are about $220M/year worldwide, but it hasn’t been the magic bullet that PRO140 is, and it seems to be gradually fading from use. Maraviroc has been on the market for 15 years.
CCR5 Saga Redux
In 2006, Timothy Ray Brown, a gay white man from Seattle, underwent a special hematopoietic stem cell transplant in Berlin. His HIV had been well-controlled for some time, but he experienced medical bad luck not related to his HIV infection: he was diagnosed with AML. His German oncologist was quite familiar with HIV elite controllers, patient with risk factors for HIV acquisition who seroconvert and show HIV RNA in serum. Over the following months after the initial infection, however, HIV virus burden declines to undetectable levels in elite controllers, and stays there. And it stays gone after they are weaned from HIV cocktails. Moreover, their anti-HIV antibody titer, the quantity of HIV antibody in their blood, subsides with time, strongly suggesting they are no longer battling the virus.
Elite controllers have a mutation in their gene for CCR5. CCR5 isn’t missing, mind you, but a fragment of gene is missing; they have the so-called CCR5del32 mutation. About 10 percent of Western Europeans have a copy of the CCR5del32 gene at either of their two alleles for it. The deleted part of their gene encodes for a segment of CCR5 receptor protein needed for HIV entry into helper T-lymphocytes. Brown was stem-cell transplanted using donor cells from a patient with two copies of the CCR5del32 gene. After an appropriate window of time, his HIV burden began to fall. Finally, it clocked zero. His anti-HIV regimen was slowly tapered. He remains HIV-free and in good health.
The simplicity of Brown’s scenario belies what may have really happened, and immunologists still debate whether mutant CCR5 was the whole story (see, for example,this fine 2014 discussion appearing in Science, the US’s answer to the UK’s inestimableNature). Many feel that graft-versus-host disease incurred by the stem cell transplant helped purge Brown’s body of HIV. Other oncologists have tried replicating the protocol used for Brown and have had mixed results as regards HIV; no one doubts the integrity of his care, but Brown may bear other exceptional, unknown features in his physiology that favor HIV clearance. One potential reason for failure is that while most strains of HIV have a strong tropism for entering T-cells via the CCR5 receptor, a minority of strains enter via the nearby CXCR4 receptor. Whether one such strain can mutate into the other in the context of drug-mediated virus suppression isn’t known yet. CytoDyn’s study protocols have excluded non-CCR5-tropic strains.
It’s worth emphasizing that we don’t know what we don’t know, especially with a virus capable of as much legerdemain as HIV is. For example, an Argentinian woman known to have contracted HIV took anti-viral drugs for a time…..and then stopped taking them for 22 years. When she next surfaced in the health care system, she had neither virus nor antibody. She does not have mutant CCR5 receptor, and the fact that no published case report yet appears on her suggests she still baffles medical science. Paris’s famed Pasteur Institute has a cohort functionally cured of HIV. By functional cure, doctors there mean that the patients can stop HIV drugs, still present with low level virus in serum, but that viral load never escalates and they never progress to AIDS. HIV mysteriousness cuts both ways, moreover: it’s now clear that about 1 percent of humans are genuinely immune to it: that they engaged in risky behavior, been found to have anti-HIV antibody, but never (unlike elite controllers) have virus found in them. Why they are this way still befuddles us, and may owe to more than one biological reason.
Science constantly goes astray when it thinks it understands data: biological data is complex, and its truths can be like a mind-numbing Escher painting, where every facet of it emerges only after long stares. Brown’s case led a Nobel laureate, David Baltimore, PhD, and his once-promising company, CalImmune, to attempt curing HIV by silencing expression of CCR5 using ddRNAi from Benitec ($BNTC). That didn’t work and wasn’t good: oops, they forgot to account for HIV strains that don’t use CCR5 to enter T-cells (Brown was lucky because he had one non-diverging strain on board that exclusively used CCR5). They also forgot to account for the fact that evolution conserves what it needs and that CCR5 is not just a protein tchotchke that you can tear off and toss away. It has roles in normal immune function, which probably explains some of the clinical problems their CCR5-silenced patients began having. CalImmune is now trying to transplant HIV patients using stem cells transfected to express CCR5-silencing ddRNAi and a full-length lentivirus-borne gene for an HIV fusion inhibitor. I once had some optimism this would work, but in light of new science since 2014, cannot see how it possibly will work in any reliable way. And in fact, next to what CytoDyn has produced, CalImmune’s efforts look Rube Goldbergian.
E
As I mull CytoDyn’s prospects, I have to admit that a certain E-word comes to mind:Esperion ($ESPR). Like Esperion it has a highly effective drug for a common condition in the clinical context of good drugs for that same condition already being in use, already being things MDs are highly familiar and comfortable with. Let’s not equivocate: patients who stay under the care of a physician with HIV competency who tracks their virus for emergence of resistance mutations and rotates drugs in the HIV cocktail in appropriate ways can now expect to have two things: (1) a normal lifespan, and (2) death from the same things with the same overhang of likelihood that you and I will die from: congestive heart failure, stroke, myocardial infarction, cancer, and “diabesity” and its setpiece of complications.
Khrushchev Pounding
When my mind turns to Esperion it quickly starts doing what Nikita Khrushchev famously did to desks and podiums at the UN (see photo). After reviewing CytoDyn’s prospects for several hours, I am frankly in table-pounding mode about it, too. In the clinic, it’s always better to have multiple therapeutic strategies that can achieve the same end. “Innocent catastrophes,” patient who have medical disasters from seemingly idiot-proof regimens, are common in clinical practice; the happy housewife to whom you casually prescribe Septra (same as Bactrim) for a UTI without a warning that 1 in 40,000 patients get Stevens-Johnson syndrome will be sloughing her skin in 3 days and in the ICU dying by the weekend.
Anyone not grasping the glory of bempedoic acid has a mind that dwells in toshy sordor because physicians cringe when prescribing statins. Your administrator will breathe down your throat if you spend more than seven minutes with a patient, and during that time, you’ve got to have with them “the chat”…about statin side effects. You’ve got to address ALL their concerns and their neighbors’ concerns about going on statins. If you’re an honest MD—you are an honest MD, aren’t you?—you MUST advise them that the statin will cause or worsen insulin resistance…..which will pour gas on the fire of the condition that’s the very reason you’re prescribing a statin! Bempedoic acid is being studied in combination with statins and ezetimibe for only one reason: though many question the primacy and hegemony of statins, few are ready to endure the heckling they’d get were they to advocate overthrow of the statin edifice. But FDA approval is FDA approval….after 2018, you’ll be able to prescribe bempedoic acid as you see fit. Watch the number of prescriptions start to do an Orville Redenbacher, blowing the lid right off the container.
It will be the same with CytoDyn. You can prescribe a cocktail, and then spend the next 10 minutes in catechism recitation with the patient, about which component will cause jaundice, about which will cause nausea, about which will cause headache, about which will cause diarrhea. PRO140 has none of those side effects in phase 1 and phase 2. Maxims that state drug compliance is best with once daily regimens are primarily speaking of single-pill regimens; no such truth holds for daily cocktails of pills. Nearly all HIV patients miss their cocktails on a regular basis because some days they can’t face all the swallowing and side effects. With both Esperion and CytoDyn, clinical trials being done now will establish the role of new drugs in the context of existing satisfactory and reckon guidelines for their use.
Let’s admit something: it’s early in the game for CytoDyn. It’s only wrapping phase 2 and starting 3. We’ve just now gotten an interim analysis showing 17 months of control, but 17 months is as far as treatment has gone thus far. There may be a point at which patients breakthrough and virus re-emerges. The drug could induce resistance in a few. We’ve not seen the full breakout of topline data: number treated, AE’s, SAE’s if any. Possibly management has glossed over a problem….not that I distrust them, but we’ve seen management do that.
CytoDyn will soon start phase 3 work, and the protocol design has an Esperion vs statins flavor. The company is still recruiting for a phase 2 trial that will add PRO140 to injection-drug-using HIV patients who are already on oral regimens and have had those regimens optimized, but who are non-adherent. This trial began enrolling in late 2013, seeks 79 patients, and is at a single center (Drexel University in Pennsylvania). It’s not exactly progressing at warpspeed (the trial record was update 11/15) and could benefit from another center enrolling, though that will add costs. The company is not yet recruiting, per clinicaltrials.gov, for a phase 2/3 trial that will take patients with an optimized background oral regimen, continue that regimen, and randomize them to either placebo or PRO140 (350 mg SQ once weekly) in double-blind fashion. The trial seeks 300 patients, and the trial record has not been updated since 6/15: possibly it is underway. The primary outcome measures will be sophisticated mathematical analysis of how HIV RNA burden falls in response to PRO140, and the extent to which CD4 T-lymphocyte count rises.
Imagine a hedge maze, like the one in Kubrick’s The Shining. Every alley, every turn, every blind end in that maze represents some facet of human disease: infectious, vascular, autoimmune, genetic, diseases from toxicity, coagulation disorders, nutritional deficiencies, cancer, kidney disease, psychiatric illness….stay in the maze long enough and you will encounter all. HIV has been a disease whose study has led us down every inch of that maze, bypassing nothing. As cruel as HIV is, it has taught us more about the human body in health and disease than any other planetary event could have. In the era since its advent, it has produced 27 approved medicines, even though the last of these, maraviroc, was 15 years ago. (Here I am not counting TAF from Gilead, as it’s a refinement of an older tenofovir formulation). HIV hasn’t gone away, and won’t, but after a long wait, medical science has afforded a real knockout punch HIV drug, PRO140, that works solo or in combination and completely suppresses virus. It has essentially no side effects, excellent compliance, and no toxicity issues. PRO140 in fact is the only HIV drug that has no drug interactions with ANY other medicines; drug-drug interactions are the bane of the HIV-treating physician. There will be avid market uptake of PRO140. I can easily project $1B in annual revenues during its first year on the market, which may be next year, based on simplistic and lean base-case assumptions: PRO140 priced at $1000/month (it will be higher) given to 100,000 patients (1.2M Americans have HIV).
Things aren’t perfect at CytoDyn. It faces the bete noire of all start-up biotechs: cash deficiency. It has no revenue, about $2M in assets on hand, and a burn rate of about $20M per year, though most of the burn is paid via NIH grants to the company. Its trials to date have mostly been financed by a collective $28M in NIH grants, proof that powers that be love PRO140 and are amazed by its prospects. Whether it can stay funded or will need to private-place for funds is unclear now. The company has excellent governance in place, and with a reverse stock split could NASDAQ uplist and execute an IPO. Certainly it may now have the data firepower, the promise of its drug sufficient to pull this off.
But my favorite thing about $CYDY is that it is performing well on the basis of one clear idea, a lucid, straightforward one that any member of the Gummune paying attention could have come up with: instead of going to the moon with gene silencing, ddRNAi, gene therapy, and hematopoietic stem cell transplants (which have serious morbidity and mortality), why not just run around the corner, make a monoclonal that tweaks CCR5 function, and see what happens? They’ve accomplished this with thrift. They also recognize that given newly identified roles for CCR5 in graft-versus-host (GVH) disease (a complication of stem cell transplant in which new cells attack the skin, liver and GI tract), PRO140 may work nicely for GVH. A trial is planned.
Denis R. Burger, PhD
CytoDyn has appointed, today, Denis R. Burger, PhD, as its chief science officer. Burger does not come cheap but has a great track record of wealth creation in biotech, as your due diligence will show. With his hire, CytoDyn is telegraphing it will take no prisoners in getting PRO140 to market. As you delve into CytoDyn, which I know you’ll do before you buy a single share, spend about 10 minutes looking over this corporate slide deck from August 2015. CytoDyn will probably update it soon.
Me? I am merely waiting for an entry point in a stormy market that may pull share price down yet.
$tock Gumshoe
SECRET TEASER STOCKS REVEALED. INVESTMENT NEWSLETTERS REVIEWED.
Cyto Who?
Posted on January 21, 2016 by Dr. KSS MD PhD
[Ed. Note: Dr. KSS is an MD and PhD who writes about medicine and biotech stocks for the Irregulars. He has agreed to our trading restrictions, and his words and opinions are his own. You can see his past articles and recent comments here.]
You’re probably getting it right by now—writing “2016” and not “2015.” The poster child for January could be a black labrador retriever draped in soporific splendor over a cushion in front of a blazing woodstove in an old country store. It’s a contemplative month. What will the year bring? And will it treat us well?
And you could be forgiven if the answers seem to demand a swig of Mylanta. China enables a North Korean dweeb to both detonate nuclear weapons of his own and to facilitate missile construction by Iran. Meanwhile, Iran, temporarily on good behavior, will use its new treaty with Washington to intensify glut pricing for a commodity whose cheapness, if sense made sense, would be liberating economies, causing airlines, automakers and transportation industries to surge in share price. Investors, finding no quarter in either energy or commodities, ought to be scouring the exchanges for businesses that will soon generate profit, creating a seller’s market. As such, biotech should be facing rosy times, especially as political tea leaves begin to suggest that we might have both Robert Califf, MD, in charge of the FDA and Donald Trump in the White House…. a shoot-the-moon situation for biotech.
If you’re seeing a patient who is psychotic, who is clinically crazy, it doesn’t help much to delve into the substance of their craziness. There’s no value in parsing it, in trying to legitimate it, in trying to make it make sense. The first thing you do is try to restore order with antipsychotics. Rationality always returns—it does—and shall return to markets. The smart money is not brooding and languishing over the present climate of awfulness; it’s stalking good stocks, laying plans, staying calm, maintaining the posture of a puma. Maybe we all now need to be performing five-minute mini-affirmations of each other in the thread, just as Paul Giamatti’s wife does in the new Showtime series Billions. Here, I improvise: “Yes, those biotech stocks are just waiting for you to buy them just so that they can swandive 30 percent the minute your order is filled! C’mon…do you really believe that? Is that RATIONAL?”
This morning, I got an email from Francis Collins, MD, director of NIH (you can get mail from him, too; just ask). According to Collins, 50,000 Americans will learn this year that they have HIV. That’s a different figure from the incidence of HIV, which is the number of true new cases, newly acquired, this year. And it’s different from the prevalence, which is the total number of cases out there. A sociological feature of the current HIV epidemic is still a fatalism that causes many not to be tested despite knowing they have compelling risks for having the virus. 50,000 Americans is a lot of people; we have Gumshoe Biotech readers who live in towns with fewer than 50,000 people. But views on treating it have changed sharply. For most of HIV’s duration among us, we have felt that treatment was necessary only when an AIDS-defining illness emerged in a patient with HIV. Younger loud voices, sometimes mine among them, argued that this approach was idiotic. For one thing, it is safe to assume that all infected with HIV will progress to AIDS. (Extremely rare people don’t.) But the destruction of the immune system is progressive and time-dependent and cumulative. Intervene early, why don’t we? It’s easier to salvage bedrock immune system than to spend years rebuilding it with pricey drugs. Collins makes the point that of those 50,000 people, beginning them as soon as possible on HIV therapy will allow them to live lifespans that are statistically no different from yours and mine. And because of this, HIV therapeutics will continue being a worthy space for us to study when new treatments rattle the landscape. Yet we’ve had no new HIV drugs in 15 years.
Penny Lane
For me as for many, a new year skittles on foal legs for its first few outings, after the repose and excess of the holidays. Let me convey with a literary seam I cannot hide that Alan Harris and I had a goodly discussion toward the end of last year about our forum. He made the point vigorously that I might be unwittingly depriving readers of great investment opportunities by being so reluctant to cover low-cost, low-market-cap, non-exchange-traded companies, ie, penny stocks.
His points, and I found them good ones, are below, to which I have woven in a few that occurred to me but that would not have occurred to me had he and I not thought and talked about it.
(1) We’ve seen a crazy period come through in which all biotechs have come down, all have succumbed to gravity. This tends to undermine any view that exchange-listed stocks are nobler.
(2) Penny stocks can and do rally. He pointed out many examples.
(3) The term “penny stock” gives existential short shrift to the nature of the stock in question. Some penny stocks were once exchange-listed dignified companies whose fortunes shifted. When this is the case, it’s fair to ask, Why they shifted? Might they unshift? Did this company become a penny stock because people walked away? Or was it born a penny stock because of blighted interest? Did it emerge as a penny stock as the result of a reverse merger as Arch Therapeutics ($ARTH) did? If it did, there’s no obvious shame in this, as debuting on a market via an IPO is a very expensive process.
(4) We cannot be fair to any class of stock if we say all its members are garbage. In fact during our last two years together, we have come across penny stocks with excellent science, diagnostics or proposed therapeutics ($ARTH is such a stock). Meanwhile, Alan was quick to point out that of exchange-listed biotechs, I regard 85 percent or so as being scientifically beneath consideration. If non-excellent stocks are already so prevalent among “pedigreed” names, is it not fair to honor consideration of the non-pedigreed? Indeed, should we not be judging all biotech plays ONLY on the basis of science quality? If so, then we are tossing aside occasional emerald, ruby, and sapphire penny stocks, and doing so as we treat most exchange-listed stocks as potential diamonds just because they’re exchange-listed.
(5) The reverse tractor-pull effect of six months of vexatious markets on the biotech space has created penny stocks (penny “opportunities”?) by shoving developing names out of the first-class cabin.
(6) It takes amazingly little coin to move the price of a penny stock. Who are we to tell our readers that they shouldn’t game these? I’ve made occasional serious money in penny plays.
(7) Alan made a heuristic point: our readers are not exactly the same people as when we began. We began with some sophisticated investors as readers, but have accrued many sophisticated investors out of “average” readers who have paid attention and gotten in the game. Readers don’t come here to be told where to invest. They come to get ideas and to have a vigorous discussion forum to backstop their thoughts.
Alan’s main point was that it’s better not to have an editorial policy of either not covering or being excessively reluctant to cover penny stocks. He persuaded me. Take every company case by case, each on its own merits. Let’s not parameterize. Let’s cover what’s worth covering.
Do you know the story of Teri Horton? Top up your mug with some fresh black Arabica and let me regale you. Horton was a 73-year-old retired Californian truck driver, and when she retired she missed the magic of the open road if not precisely the smell of diesel smoke in her hair. She became a wanderer, an itinerant denizen of roadside America, and particularly loved the allure of dusty, badly-lit junk shops in odd places. As a way of sharpening her claws for a weird painting she saw propped in picturesque disarray in a moldering corner, she asked the lady in the junk store for a cup of coffee. Then she began haggling. How much do you want for that picture? “Eight dollars,” was the answer.
“For that piece of junk?,” Teri asked, this being a junk shop. “I’ll give you five. I’m just gonna take it home, give it to a friend. We’ll throw darts at it while we drink beer.” Deal.
But the picture, which was unsigned, was too large to fit inside Teri’s friend’s trailer. Soon, the picture, a drip-painting, found itself at a yard-sale table in Horton’s community. That was when Teri was stopped by a local high-school art teacher. “I think that’s a Jackson Pollock,” the teacher said.
In so many words, Teri replied, “Jackson who?”….in so many words because what she actually said might not go over well in this fine family publication. But Horton became obsessed, and in subsequent years has vigorously sought consensus from Pollock experts. Some concur it is a Pollock, similar to work he was doing around 1948. Which is why Horton wants $50M for the painting, a figure some say she deserves. Her adventure is well-depicted in the fine 2006 documentary Who the #$&% is Jackson Pollock?, co-produced by Don Hewitt of 60 Minutes fame.
When the student is ready, the master appears. In the small hours this morning, by the dawn’s surly light, I made coffee and set about opening email. The first one was from my friend Jules. I’ve mentioned Jules here before: he has HIV, is medically healthy, and has devoted his life to being a radical HIV advocate. Rumor, bizarre treatment idea, secret drug in secret trials, straight dope on every pharma company: Jules never reveals his sources, but ah, what sources. Jules independently raises money so that he can personally attend every HIV meeting on the planet each year that matters, and he photographs every poster and presentation. Increasingly he’s being asked to lecture trainees: Jules is neither a physician nor a PhD, but he’s the ultimate insider. He has a way of showing up everywhere, seeing everything through the eyes of a jackdaw dressed to the nines.
Jules was writing to beat a company to the punch…..he was telling me what announcement they’d be making this morning, about two hours before they announced it. And now, same day (I am writing this on 19 January 2016), I am letting you know. In order to enhance my objectivity, I’ve not invested in this company yet. If you visit Bali, Indonesia, you get the best price of the day on any object you buy in a store if you’re the first customer who shows up that day. Maybe by analogy, this can be a first buy of the year for readers, one that affords serious profit. I’ve scoured the science of the company, and I like what I have found. The company may be an unrecognized masterpiece.
Make a note of it: CytoDyn ($CYDY), a company for which your due diligence will immediately reveal a share price of under $1 and a market cap of under $100M. $CYDY shares trade over the counter, and both institutional and short interest stand at zero. Like the possibly-Pollock painting, discerning biotech eyes, which many of you now have, can find plenty about this stock that could catapult shares well past a dollar.
Early this morning, CytoDyn, which is headquartered in Vancouver (Washington, not BC), announced that HIV patients receiving its lead drug PRO140 as monotherapy for their illness have no detectable serum HIV RNA out to 17 months, the longest any patient has yet been treated. You can peruse the study protocol here. This study, which began enrolling in November 2014, seeks to take 28 HIV patients at a single site in San Francisco, and treat them with once-weekly 350 mg subcutaneous doses of PRO140. The study will end with a maximum duration of 24 weeks of treatment, and following this many happy patients will no doubt ask fervently to remain on it by compassionate release. To service the interested clientele, the company has two phase 3 trials planned, and is keen on having this drug to market in 2017.
PRO140 is a monoclonal antibody directed against chemokine receptor 5 (CCR5…which rings some bells, I hope). The significance of the study, though now only with one site, may be apparent to some readers: San Francisco has a large gay male population and is a hotbed of HIV, particularly of stubborn, resistant forms. CytoDyn decided not to dance around the edges of whether its drug works. Rather, they chose to roadtest it in probably the toughest patient population in the US. The FDA likes what it sees: it has bestowed fast track designation on PRO140.
We’ll review the highlights of CCR5 and HIV, but first allow me to dispel one objection you may already have to this story, especially if you have HIV or know someone who does. Big whoop, perhaps you are thinking. Combination cocktails of antiretroviral drugs have long been known to drive HIV serum viral loads to undetectability. In that case, does PRO140 matter? Or is it just a fancy, cynical (because it might be high-priced) pharma ploy to achieve a kind of zero-sum objective?
I treat a lot of HIV and know others who do as well, and can tell you that if you study large numbers of stable patients on combination anti-HIV therapy, what you generally see is an overall prevalence of about 25 percent of them at any given time having no detectable HIV RNA. Some of this owes to human imperfection: none of us doses our oral meds perfectly. If there’s a pill you take daily, admit it: you forget it now and again. Moreover, for reasons we don’t fully get, HIV is like HCV and HBV in that sometimes we see eruptions in serum virus burden despite the fact that nothing seems to have changed for the patient in question. But already with PRO140, we see the drug achieving clinical goals superior to the best HIV oral drug combos out there. (Gilead ($GILD), maker of best-of-breed fixed-dose-combos for HIV, has no doubt taken notice.)
A hand is raised, and its owner looks skeptical. “KSS, aren’t you just baiting us with a straw-man scenario? Does it really make a difference if the HIV viral load is zero as opposed to being significantly lowered by antiviral therapy?” But you’re all beginning to think like pharmacologists, which primarily means recognizing that when an agent is acting on a living system, the extent of the action is related mathematically to the dose. No measurable virus means nothing to confound all the players in the immune system. The immune system is thus free to fully engage against infectious pathogens and cancer, and drive them out. No cell can harbor HIV and function normally, and while PRO140’s resulting absence of serum HIV RNA does not mean no cell is HIV-infected (many have latent infection) it does mean the body has significantly more physiological agility. Zero is better than non-zero. Zero virus means greatly reduced risk of transmission of HIV to another person, though that comes with caveats, as zero serum virus can’t be presumed to result in absence of virus in semen (the testes are an HIV reservoir). It’s very easy by a Google search to pull up scores of published studies showing that in HIV, the higher the virus level in a tissue, the worse the pathology is in that tissue. But tissue is in equilibrium with blood, so when virus can’t be found in blood, it’s clearly less abundant in tissue too.
Don’t be confused by this if you have dealt with virus hepatitis and are trying to draw analogies. The HCV-infected are often preoccupied with serum virus burden, but the relationship between serum HCV RNA level and disease severity is bizarre. In some collections of patients, a near inverse relationship between virus burden and pathology is seen, seemingly because reduced virus level implies more vigorous immune attack on one’s own organs. Patients with HBV or HCV with astoundingly high virus burdens are often amazingly free of liver disease on biopsy because their immune system is mostly ignoring the virus (generally because it has mutated).
You’ve got the picture: a single drug that, given beneath the skin once a week at home, can completely control HIV infection. Let’s round out meditating on that by making one more point of discussion, which is that if you could choose treating a condition with a single highly effective medicine versus a cocktail of highly effective medicines, which would you choose? The essence of HIV infection is just like bacterial infection: the infecting agents mutate to resist drugs being used to treat them. Combination therapy might be better, in some cases, at deterring mutation, but make no mistake: resistant “escape” mutations WILL occur, and when they occur as a result of drug combinations, the result is often a much more virulent virus. I think it’s important that we not draw too easy a conclusion that resistance comes earlier and easier as a result of monotherapy. Every antimicrobial agent comes with a mathematically defined “barrier to resistance” based on how effectively it kills and based on how cardinal or resistance-proof the killing mechanism is. All drugs have side effects, and the HIV platter of pills is no exception, and meanwhile PRO140 is well-tolerated. In this case, if I had to choose between the one drug and the combination of many, I’d choose the single-agent approach, with this in mind: HIV mutates rapidly when it chooses to, and yet CytoDyn’s present study has patients treated for 17 months and counting without breakthrough mutations. 17 months is a long time for HIV.
A Crash Course on Antibodies
Suppose that elephants were small enough to dissolve in water, draw up in a syringe, and inject into a person. The elephant is a totally different creature from people, a “foreign” organism, and so immediately after you are injected with an elephant solution, your body gets to work on producing polyclonal anti-elephant antibodies. A clone is a line of cells or organisms that are identical, and have identical DNA. Antibodies (which come in fiveclasses: IgG, IgA, IgE, IgM, IgD) are made by B-lymphocytes. If you’re discussing antibodies and the class isn’t specified, it’s safe to assume you’re speaking of IgG.
Monoclonal anybodies
Here I am trying to lead you into potential confusion so you’re not confused in the future. “Polyclonal” does NOT mean containing different classesof antibodies. A polyclonal antibody, rather, is of a single class, usually IgG, and recognizes a diversity of epitopeson a molecule of interest. What’s an epitope?
Epitopes Indeed
When I’m trying to explain epitopes to students, I always think of the mashed potato sequence in Close Encounters of the Third Kind. Take a couple of minutes and watch it at the link. Richard Dreyfus’s character has come under the spell of a haunting rock formation, one that will soon be the site where he makes contact with extraterrestrial life. He broods about the place by sculpting it on a dinner plate in mashed potatoes, gently conferring on it ridges, lumps, and escarpments. You could think of each of these structural features as being like an epitope on the rock formation. Each is a locus in three dimensions with unique structure. Every object is a collection of epitopes, of unique sites on its surface, and two objects that share precisely the same set of epitopes in the same spatial relationship are the same (are clones of each other).
Our polyclonal anti-elephant antibodies recognize multiple epitopes on the dissolved elephants. We’ve got anti-tusk antibody and anti-trunk antibody. We’ve got anti-floppy ears antibody. You may realize we’re here stumbling onto the famed story of the elephant and the blind men. All of the individual antibodies in our polyclonal mix of can be correctly called “anti-elephant antibodies” but each represents one and only one site on the elephant, a different site from every other specific type of antibody in our polyclonal mix. Each clonal type of antibody in our polyclonal mix recognizes a different part of the elephant from each other subtype, and yet all are anti-elephant antibodies.
Think of how dogs socially sniff one another. When a mammal encounters a foreign protein, the immune system sniffs the nooks and crannies of that molecule, and makes a different antibody to everything it recognizes as an epitope. Our miniature injectable elephants are nothing more than proteins, and most invading pathogens drag proteins with them that trigger an antibody response. A protein is a string, extending in one dimension, that has a unique sequence of amino acids. Each amino acid has an average molecular weight of about 110 grams/mole, and so a common plasma protein weighing, say 55,000 daltons would consist of about 500 amino acids.
The amino acids are everything from glutamic acid (which agitates you if it’s loose in your brain) to tryptophan (precursor of the happy hormone serotonin) to cysteine (whose sulfur thiol sidechain acts as an entering nucleophile for the cysteine proteinases). Each amino acid has an identical three-atom backbone that allows it to be a bolt-on part for a protein strand. Then, jutting off the second atom of the backbone, each amino acid has a unique sidechain, a sidechain responsible for most of the amino acid’s properties, and that has spatial structural features (with or without electrical charge) that make it distinct to all the other amino acids.
Gummies, I know this is dry to many of you, but medical biochemistry is best learned in bolus feedings.
When a protein is out and about, it doesn’t travel like a string or strand. It has long since folded itself into a blob, a blob like a jumble of twine. Although the twine may look random and haphazard, if you challenge a protein to unfolding, it will generally refold itself in exactly the same three-dimensional way. This is because all the amino acid sidechains find an energy-ideal most-overall-comfort way to sidle up next to each other, making the conformation of each protein unique and non-negotiable.
Amino acid side chains can be near to each other in a protein from either of two influences. First they may be nearby in the sequence of amino acids on the primary protein strand. But second, depending on how they jut out into space, they may have sidechain neighbors that occur literally anywhere else in the primary amino acid sequence. This is because the protein folds, forms helices, and builds sheets.
As the immune system scans the protein, looking to reckon it in epitopes, it is looking for clusters of amino acid sidechains, usually between 5 and 12 amino acids altogether, that have spatial uniqueness. These amino acids can either be adjacent on the protein backbone, or else side-by-side in space because adjacent strands of protein are lining up next to each other in space. Nature conserves, and everything in a protein structure counts for something. Thus antibodies recognizing different protein epitopes (such as an enzymic active site, such as a transmembrane channel, such as an allosteric modulator binding domain, such as an ion binding site) can have stunningly disparate effects on protein behavior.
Polyclonal antibodies are great, don’t you see, for subduing or neutralizing a questionable protein. They do this by sticking to it at every conceivable epitope. The protein travels through the bloodstream having incurred a gang of miffed polyclonals atop it, and is plucked out of circulation in the liver and spleen, where antigen-antibody complexes are destroyed. “Antigen” has a similar meaning to “epitope” in that both draw the attention of immune antibodies, but each antigen generally has several epitopes, while an epitope is the smallest unit to which you can reduce something attracting the immune system.
When we speaking of antibody binding to epitope, it’s important to consider how tight the binding in question is. All chemical reactions proceed in forward and reverse directions at once, and what favors the progress in either direction has to do with kinetics (are there impediments to the reaction?) and thermodynamics (is the overall energy of the state we seek the lowest that is available?). In general antibodies bind so tightly to epitopes that the only way to dissociate them is to boil them in denaturing detergents. Because of this, antibodies could be a weapon against disease if we could harness them, direct them to exactly the epitopes we want, and make them on demand.
Those very requirements, however, tend to leave out polyclonals. Why? Because when an animal is exposed to a new protein for the first time, the polyclonal antibody it makes tends to fade in titer and specificity over time. Moreover, if you rechallenge the animal with the protein, though it will still crank out polyclonals, some polyclonals will be enhanced and others will begin to fade from the mixture.
Make Mine a Monoclonal
A monoclonal antibody is usually a laboratory-generated IgG that binds to one, and only one, epitope. It was usually generated as part of an array of monoclonals against a protein, but has been separated and set aside for its ability to stick to precisely one three-dimensional spot on the target protein’s surface. Do monoclonals ever occur naturally? They do….but when they do, they represent an underlying malignant process. Remember, all antibodies are made in B-lymphocytes, and within each of us are countless clones of B-lymphocytes. If one such clone expands in a brakeless way, monoclonal antibody begins accumulating in the serum, and can be detected by so-called SPEP (serum protein electrophoresis). Multiple myeloma, for example, is diagnosed in part by SPEP.
How to Make a Monoclonal Antibody
Because each monoclonal sticks to but one epitope, and because most targets have scads of epitopes, it stands to reason that different monoclonals to the same target protein are binding to unique microregions in that protein. Two companies can have monoclonals directed against the same target protein, and yet have agents that have little in common how they behave clinically. The picture schematic below maps out the steps in making a monoclonal antibody.
OncoDyn has devised a monoclonal against CCR5 that doesn’t block or shut down the entire molecule. CCR5 has many roles, including some we don’t grasp well yet, and we’re in an important age of discovery right now for the members of the chemokine receptor class (see our 7 Jul7 2015 column introducing ChemoCentryx ($CCXI) and the chemokine receptors). You may recall from discussions during the summer of 2014 how CCR5 behaves as an entry portal on lymphocytes for HIV, in addition to having several other immune system roles. OncoDyn has designed a monoclonal antibody that sticks only to the epitope on CCR5 that enables HIV entry into a CCR5-bearing T-lymphocyte. As such, CCR5 still binds chemokines, and can thus still participate in other healthy immune-defensive processes. Its mechanism is depicted with enormous clarity in this cartoon, which I strongly encourage you to watch. What comes to mind for me is an old credit card commercial: “MAKING A CUSTOM MONOCLONAL ANTIBODY: $4,500. MAKING A CUSTOM MONOCLONAL ANTIBODY TO JUST THE RIGHT EPITOPE: PRICELESS.”
Some readers may be aware of the GlaxoSmithKline ($GSK) drug maraviroc (Selzentry), which also adheres to CCR5. Maraviroc was designed years ago with the hope that it would accomplish what PRO140 does. Its problem, however, is its more diffuse, less-finely directed binding at CCR5. Patients on anti-HIV cocktails containing maraviroc generally have somewhat lower HIV RNA loads than those on cocktails without maraviroc, but the results aren’t stunning. Their viral loads don’t go to zero, and in terms of quality of life, maraviroc seems to add nothing. Its sales are about $220M/year worldwide, but it hasn’t been the magic bullet that PRO140 is, and it seems to be gradually fading from use. Maraviroc has been on the market for 15 years.
CCR5 Saga Redux
In 2006, Timothy Ray Brown, a gay white man from Seattle, underwent a special hematopoietic stem cell transplant in Berlin. His HIV had been well-controlled for some time, but he experienced medical bad luck not related to his HIV infection: he was diagnosed with AML. His German oncologist was quite familiar with HIV elite controllers, patient with risk factors for HIV acquisition who seroconvert and show HIV RNA in serum. Over the following months after the initial infection, however, HIV virus burden declines to undetectable levels in elite controllers, and stays there. And it stays gone after they are weaned from HIV cocktails. Moreover, their anti-HIV antibody titer, the quantity of HIV antibody in their blood, subsides with time, strongly suggesting they are no longer battling the virus.
Elite controllers have a mutation in their gene for CCR5. CCR5 isn’t missing, mind you, but a fragment of gene is missing; they have the so-called CCR5del32 mutation. About 10 percent of Western Europeans have a copy of the CCR5del32 gene at either of their two alleles for it. The deleted part of their gene encodes for a segment of CCR5 receptor protein needed for HIV entry into helper T-lymphocytes. Brown was stem-cell transplanted using donor cells from a patient with two copies of the CCR5del32 gene. After an appropriate window of time, his HIV burden began to fall. Finally, it clocked zero. His anti-HIV regimen was slowly tapered. He remains HIV-free and in good health.
The simplicity of Brown’s scenario belies what may have really happened, and immunologists still debate whether mutant CCR5 was the whole story (see, for example,this fine 2014 discussion appearing in Science, the US’s answer to the UK’s inestimableNature). Many feel that graft-versus-host disease incurred by the stem cell transplant helped purge Brown’s body of HIV. Other oncologists have tried replicating the protocol used for Brown and have had mixed results as regards HIV; no one doubts the integrity of his care, but Brown may bear other exceptional, unknown features in his physiology that favor HIV clearance. One potential reason for failure is that while most strains of HIV have a strong tropism for entering T-cells via the CCR5 receptor, a minority of strains enter via the nearby CXCR4 receptor. Whether one such strain can mutate into the other in the context of drug-mediated virus suppression isn’t known yet. CytoDyn’s study protocols have excluded non-CCR5-tropic strains.
It’s worth emphasizing that we don’t know what we don’t know, especially with a virus capable of as much legerdemain as HIV is. For example, an Argentinian woman known to have contracted HIV took anti-viral drugs for a time…..and then stopped taking them for 22 years. When she next surfaced in the health care system, she had neither virus nor antibody. She does not have mutant CCR5 receptor, and the fact that no published case report yet appears on her suggests she still baffles medical science. Paris’s famed Pasteur Institute has a cohort functionally cured of HIV. By functional cure, doctors there mean that the patients can stop HIV drugs, still present with low level virus in serum, but that viral load never escalates and they never progress to AIDS. HIV mysteriousness cuts both ways, moreover: it’s now clear that about 1 percent of humans are genuinely immune to it: that they engaged in risky behavior, been found to have anti-HIV antibody, but never (unlike elite controllers) have virus found in them. Why they are this way still befuddles us, and may owe to more than one biological reason.
Science constantly goes astray when it thinks it understands data: biological data is complex, and its truths can be like a mind-numbing Escher painting, where every facet of it emerges only after long stares. Brown’s case led a Nobel laureate, David Baltimore, PhD, and his once-promising company, CalImmune, to attempt curing HIV by silencing expression of CCR5 using ddRNAi from Benitec ($BNTC). That didn’t work and wasn’t good: oops, they forgot to account for HIV strains that don’t use CCR5 to enter T-cells (Brown was lucky because he had one non-diverging strain on board that exclusively used CCR5). They also forgot to account for the fact that evolution conserves what it needs and that CCR5 is not just a protein tchotchke that you can tear off and toss away. It has roles in normal immune function, which probably explains some of the clinical problems their CCR5-silenced patients began having. CalImmune is now trying to transplant HIV patients using stem cells transfected to express CCR5-silencing ddRNAi and a full-length lentivirus-borne gene for an HIV fusion inhibitor. I once had some optimism this would work, but in light of new science since 2014, cannot see how it possibly will work in any reliable way. And in fact, next to what CytoDyn has produced, CalImmune’s efforts look Rube Goldbergian.
E
As I mull CytoDyn’s prospects, I have to admit that a certain E-word comes to mind:Esperion ($ESPR). Like Esperion it has a highly effective drug for a common condition in the clinical context of good drugs for that same condition already being in use, already being things MDs are highly familiar and comfortable with. Let’s not equivocate: patients who stay under the care of a physician with HIV competency who tracks their virus for emergence of resistance mutations and rotates drugs in the HIV cocktail in appropriate ways can now expect to have two things: (1) a normal lifespan, and (2) death from the same things with the same overhang of likelihood that you and I will die from: congestive heart failure, stroke, myocardial infarction, cancer, and “diabesity” and its setpiece of complications.
Khrushchev Pounding
When my mind turns to Esperion it quickly starts doing what Nikita Khrushchev famously did to desks and podiums at the UN (see photo). After reviewing CytoDyn’s prospects for several hours, I am frankly in table-pounding mode about it, too. In the clinic, it’s always better to have multiple therapeutic strategies that can achieve the same end. “Innocent catastrophes,” patient who have medical disasters from seemingly idiot-proof regimens, are common in clinical practice; the happy housewife to whom you casually prescribe Septra (same as Bactrim) for a UTI without a warning that 1 in 40,000 patients get Stevens-Johnson syndrome will be sloughing her skin in 3 days and in the ICU dying by the weekend.
Anyone not grasping the glory of bempedoic acid has a mind that dwells in toshy sordor because physicians cringe when prescribing statins. Your administrator will breathe down your throat if you spend more than seven minutes with a patient, and during that time, you’ve got to have with them “the chat”…about statin side effects. You’ve got to address ALL their concerns and their neighbors’ concerns about going on statins. If you’re an honest MD—you are an honest MD, aren’t you?—you MUST advise them that the statin will cause or worsen insulin resistance…..which will pour gas on the fire of the condition that’s the very reason you’re prescribing a statin! Bempedoic acid is being studied in combination with statins and ezetimibe for only one reason: though many question the primacy and hegemony of statins, few are ready to endure the heckling they’d get were they to advocate overthrow of the statin edifice. But FDA approval is FDA approval….after 2018, you’ll be able to prescribe bempedoic acid as you see fit. Watch the number of prescriptions start to do an Orville Redenbacher, blowing the lid right off the container.
It will be the same with CytoDyn. You can prescribe a cocktail, and then spend the next 10 minutes in catechism recitation with the patient, about which component will cause jaundice, about which will cause nausea, about which will cause headache, about which will cause diarrhea. PRO140 has none of those side effects in phase 1 and phase 2. Maxims that state drug compliance is best with once daily regimens are primarily speaking of single-pill regimens; no such truth holds for daily cocktails of pills. Nearly all HIV patients miss their cocktails on a regular basis because some days they can’t face all the swallowing and side effects. With both Esperion and CytoDyn, clinical trials being done now will establish the role of new drugs in the context of existing satisfactory and reckon guidelines for their use.
Let’s admit something: it’s early in the game for CytoDyn. It’s only wrapping phase 2 and starting 3. We’ve just now gotten an interim analysis showing 17 months of control, but 17 months is as far as treatment has gone thus far. There may be a point at which patients breakthrough and virus re-emerges. The drug could induce resistance in a few. We’ve not seen the full breakout of topline data: number treated, AE’s, SAE’s if any. Possibly management has glossed over a problem….not that I distrust them, but we’ve seen management do that.
CytoDyn will soon start phase 3 work, and the protocol design has an Esperion vs statins flavor. The company is still recruiting for a phase 2 trial that will add PRO140 to injection-drug-using HIV patients who are already on oral regimens and have had those regimens optimized, but who are non-adherent. This trial began enrolling in late 2013, seeks 79 patients, and is at a single center (Drexel University in Pennsylvania). It’s not exactly progressing at warpspeed (the trial record was update 11/15) and could benefit from another center enrolling, though that will add costs. The company is not yet recruiting, per clinicaltrials.gov, for a phase 2/3 trial that will take patients with an optimized background oral regimen, continue that regimen, and randomize them to either placebo or PRO140 (350 mg SQ once weekly) in double-blind fashion. The trial seeks 300 patients, and the trial record has not been updated since 6/15: possibly it is underway. The primary outcome measures will be sophisticated mathematical analysis of how HIV RNA burden falls in response to PRO140, and the extent to which CD4 T-lymphocyte count rises.
Imagine a hedge maze, like the one in Kubrick’s The Shining. Every alley, every turn, every blind end in that maze represents some facet of human disease: infectious, vascular, autoimmune, genetic, diseases from toxicity, coagulation disorders, nutritional deficiencies, cancer, kidney disease, psychiatric illness….stay in the maze long enough and you will encounter all. HIV has been a disease whose study has led us down every inch of that maze, bypassing nothing. As cruel as HIV is, it has taught us more about the human body in health and disease than any other planetary event could have. In the era since its advent, it has produced 27 approved medicines, even though the last of these, maraviroc, was 15 years ago. (Here I am not counting TAF from Gilead, as it’s a refinement of an older tenofovir formulation). HIV hasn’t gone away, and won’t, but after a long wait, medical science has afforded a real knockout punch HIV drug, PRO140, that works solo or in combination and completely suppresses virus. It has essentially no side effects, excellent compliance, and no toxicity issues. PRO140 in fact is the only HIV drug that has no drug interactions with ANY other medicines; drug-drug interactions are the bane of the HIV-treating physician. There will be avid market uptake of PRO140. I can easily project $1B in annual revenues during its first year on the market, which may be next year, based on simplistic and lean base-case assumptions: PRO140 priced at $1000/month (it will be higher) given to 100,000 patients (1.2M Americans have HIV).
Things aren’t perfect at CytoDyn. It faces the bete noire of all start-up biotechs: cash deficiency. It has no revenue, about $2M in assets on hand, and a burn rate of about $20M per year, though most of the burn is paid via NIH grants to the company. Its trials to date have mostly been financed by a collective $28M in NIH grants, proof that powers that be love PRO140 and are amazed by its prospects. Whether it can stay funded or will need to private-place for funds is unclear now. The company has excellent governance in place, and with a reverse stock split could NASDAQ uplist and execute an IPO. Certainly it may now have the data firepower, the promise of its drug sufficient to pull this off.
But my favorite thing about $CYDY is that it is performing well on the basis of one clear idea, a lucid, straightforward one that any member of the Gummune paying attention could have come up with: instead of going to the moon with gene silencing, ddRNAi, gene therapy, and hematopoietic stem cell transplants (which have serious morbidity and mortality), why not just run around the corner, make a monoclonal that tweaks CCR5 function, and see what happens? They’ve accomplished this with thrift. They also recognize that given newly identified roles for CCR5 in graft-versus-host (GVH) disease (a complication of stem cell transplant in which new cells attack the skin, liver and GI tract), PRO140 may work nicely for GVH. A trial is planned.
Denis R. Burger, PhD
CytoDyn has appointed, today, Denis R. Burger, PhD, as its chief science officer. Burger does not come cheap but has a great track record of wealth creation in biotech, as your due diligence will show. With his hire, CytoDyn is telegraphing it will take no prisoners in getting PRO140 to market. As you delve into CytoDyn, which I know you’ll do before you buy a single share, spend about 10 minutes looking over this corporate slide deck from August 2015. CytoDyn will probably update it soon.
Me? I am merely waiting for an entry point in a stormy market that may pull share price down yet.
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