Robert Morris is helming a biotech-focused stock newsletter that’s called Biotech Supertrader (modesty has no place in the world of newsletter promotions, of course), and I’ve never covered this letter before so I thought I ought to have a look at the latest teaser we’ve been asked about.
Morris, incidentally, has been featured in our pages before — but that was back when he was editor of China Stock Insider at the same publisher. That letter, like almost all China-focused investment newsletters, seems to have disappeared quietly into that good night … which probably tells you that it’s time to invest in China again, since the newsletter publishers are ignoring the Middle Kingdom and rushing out their pitches about biotech and tech stocks. At the time, Morris was teasing NQ Mobile (NQ), which has turned out to be pretty good if you bought it down there in the $6-8 neighborhood (though it’s been a wild ride).
So now what’s he pitching for his Biotech Supertrader?
Well, the destruction of “Man’s deadliest disease”, of course. Here’s how the teaser gets our attention:
“This Tiny, Unknown Biotech is About to Unleash Its ‘Holy Grail’ Drug on Man’s Deadliest Disease
“Their ‘Guided Missile Approach’ Could Save Thousands of Lives Each Year
“It’s about to become the most talked about advancement in cancer treatment in our lifetimes and you can lock in a life-transforming fortune if you act quickly….
“I’m urging my subscribers to load up on this stock NOW….
“I’ve just uncovered a tiny, unknown biotechnology company with a new cancer drug in phase 3 clinical trials which is showing remarkable success at treating several types of cancer.
“Their scientists have found an innovative approach to cancer care which involves a breakthrough in treatment. It goes deep inside the inner workings of our cells.
“Plus, this medicine looks to be many times more effective and with fewer side effects than the chemo, radiation, and drug therapies currently available.”
If there’s one thing that investors know can make them rich and make them feel good about themselves and the world, it’s a cure for cancer — we’ve seen that effective cancer treatments can and do (occasionally) turn little biotech stocks into gigantic successes, so the dream lives on that you’re going to catch one of these lottery tickets and own the next Genentech. Will we be so lucky? Well, let’s see which one he’s pitching:
“When this drug wins FDA approval – which I believe it will – this small company’s $4.16 stock price will go straight to the moon.
“And the market for this drug is absolutely huge!
“You see, this small biotech is targeting its new drug, let’s call it ‘drug S’, at cancers of the blood and bone marrow. And it is already in very promising phase 3 trials for these two types of cancer.
“But here’s where it gets really interesting. It looks like the drug this company is developing will also work on other types of cancer!
“There are positive signs it works on Non-Small Cell Lung Cancer (NSCLC) too. There are 1.1 million people with this type of malignancy. Just in the United States alone there are over 300,000 patients with this disease according to The American Cancer Society. Each desperate for a cure.
“Plus it looks like ‘drug S’ may turn out to be an effective treatment for ovarian Cancer. There are more than 204,000 new cases of ovarian cancer diagnosed worldwide each year with 22,280 of these in the United States according to the National Cancer Institute estimates.”
So … who is it? Thinkolator sez this is Cyclacel Pharmaceuticals (CYCC)
Cyclacel is indeed a little biotech around $4 (it closed at $4.35 yesterday), with a market capitalization of only about $80 million — so be careful, we’re a big enough group here that if just a small percentage of Stock Gumshoe readers got enthused about this stock it could drive the shares up, less than a million dollars worth of shares trade each day (Biotech Supertrader says they limited their readership to 750 people — I don’t know if that’s still their cap or if they’ve hit it, but we’ll have more folks than that reading this free article).
And like many biotech stocks, it’s got some impressive scientists and it’s been losing money for a long time as they’ve been searching for a viable drug (their current lead drug also was a big focus of theirs back when it was in Phase 1 trials five or more years ago, so that’s a good reminder of the time these things take, it’s just starting Phase 3 trials now). It looks like they must have gone public in 2004, when they were about eight years old, and a quick scan of ten years of their financials over at Morningstar indicates that they’ve never generated more than a token amount of revenue (meaning, they’ve probably had some research collaboration payments or partnership funding, but never got a product to market), and have accumulated more than $250 million in losses to date. And had two reverse splits to keep the price from sinking far into penny territory.
So that’s not unusual, but it means that — as with all developmental-stage biotechs — it’s not about the financials or the fundamentals, it’s about what’s going to happen in their clinical trials and whether things are going well enough that they can continue to finance the trials … which get much more expensive as you progress through Phase 2 and Phase 3.
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All I know about them so far is that they say they’ve got enough cash to get through enrollment in their key Phase 3 study for “drug S” (which is sapacitabine) as of September when they last updated their investor presentation, but I know nothing about the science or the competing cancer drugs that are out there or how fabulous this particular one might be, so I asked our favorite medical writer, Doc Gumshoe (who, yes, is not a doctor) to check them out quickly and chime in. Here’s what he could share after looking into them for a few minutes (he’s just looking at the medical stuff, not so much the “investor presentations”):
- Cyclacel’s Prospects
Cyclacel has three drugs in development at this time, and is involved in eight clinical trials with these drugs, not including two clinical trials that have been terminated. Their top contender is sapacitabine which targets the division of cancer cells. If you can prevent cancer cells from dividing and reproducing, you have the cancer whipped, so targeting cancer cell division (or mitosis, which is the technical term) is a highly promising avenue for treating cancer. However, we need to take note of the fact that sapacitabine is one of a large number of drugs that propose to fight cancer by this method.
At present, all eight of Cyclacel’s clinical trials involve sapacitabine. Of these, at least one has been completed – a Phase 1 study of the safety and pharmacology of the drug. Four others are current, with no information about results. These are likely Phase 1 or small Phase 2 studies, to assess safety, determine what a correct dose might be, and evaluate whether the drug does what it’s supposed to do in human subjects with the target diseases, which in this case include acute myeloid leukemia (AML), cutaneous T-cell lymphoma, and some advanced solid tumors. Prior to the clinical trials, sapacitabine has demonstrated impressive results in delaying the spread of metastatic liver cancers in mice.
From what I can gather from public sources (i.e., the NIH Clinical Trials Registry), there is one Phase 3 trial, which started recruiting patients in February of 2013 and is expected to be completed in late 2015. The trial is in elderly patients with AML, and compares alternating cycles of sapacitabine and decitabine with decitabine alone. Decitabine (Dacogen) is FDA-approved for treating AML and also targets cancer cells’ replication by attacking their DNA.
It is possible that the Phase 3 trial by itself could lead to FDA approval for sapacitabine, depending on the strength of the results. However, that trial would not get the drug approved for use as monotherapy, since it is not being investigated as monotherapy. My guess is that Cyclacel is planning more trials of sapacitabine as monotherapy, perhaps in younger patients. And my further guess is that FDA approval is still quite a long way off.
Sapacitabine is also in a Phase 3 trial with cyclophosphamide and rituximab for the treatment of relapsed chronic lymphocytic leukemia. Cyclophosphamide (marketed under several trade names) is a well-established chemotherapy agent used in a number of cancers, and has led to remission in many cases; however, it is associated with truly harrowing adverse effects. Rituximab (Rituxan, Genentech) is used not only in cancers but in some autoimmune diseases. And sapacitabine is also being studied in patients with previously-treated non-small-cell lung cancers.
Although the piece from Biotech Supertrader said that the drug – identified as “drug S” –is also a promising treatment for ovarian cancer, I find no clue that it is being studied in such patients. [ed note: that’s because that “promise” is in the lab still, not in people — they had a press release about this in the Fall, “75% of Ovarian Cancer Patient Samples Highly Sensitive to Sapacitabine”, not studied in patients but on patient samples]
Cyclacel has two other drugs in development: selicilib and a drug designated as CYC116. One selicilib study has been terminated, and in a second Phase 1 study, selicilib is used with sapacitabine in patients with advanced solid tumors. Remember, however, that Phase 1 studies are many rungs of the ladder below what’s needed to gain FDA approval.
CYC116 is an aurora kinase inhibitor, meaning that it blocks the action of an intracellular enzyme that facilitates cancer cell mitosis. This is a promising avenue of cancer treatment, however, the traffic on this avenue is fairly heavy, and includes several other classes of drugs including tyrosine kinase inhibitors, and taxol based agents such as paclitaxel (Taxol, Bristol Myers Squibb); docetaxel (Taxotere, Sanofi-Aventis), Abraxane (a newer formulation of paclitaxel from Celgene) and others.
CYC116 supposedly also inhibits vascular endothelial growth factor (VEGF), which induces the growth of blood vessels that nourish cancer cells. Inhibiting VEGF is a well-established means of combating cancer, and CYC116 could hardly be characterized as a radically new departure in cancer treatment.
The one trial involving this agent has been terminated. That, of course, does not mean that development of CYC116 stops dead in its tracks – there are many reasons why a trial can be terminated, and ours is not to speculate without more information.
Beyond those three drugs, it’s hard to guess what Cyclacel may have up its corporate sleeve. It is certainly true that a successful cancer drug – even if only moderately successful– can be transformational for the biotech that develops the drug. But the drugs that Cyclacel has under development do not appear to this skeptical observer to be radically new departures in cancer treatment.
It’s important to remember, when trying to estimate the likelihood of a single drug demonstrating sufficient efficacy and safety to gain FDA approval and market share, that the competitive field is vast. As I mentioned earlier, Cyclacel has a total of 8 clinical trials in process at this time.
For the sake of perspective, it’s worth knowing that at present there are 41,445 cancer trials being conducted. So those are the odds.
So there you have it — it’s almost impossible to find a development-stage biotech whose financials look great or that makes your heart go pit-a-pat over their valuation, especially in a biotech bull market like we’ve seen over the past year or so, and Cyclacel doesn’t jump out as spectacular on that front either, not unless you’re a big believer in the promise of their specific drug. They’re a small stock and they don’t get much attention, other than from the analysts who probably helped them sell shares in secondary offerings in recent years, and there aren’t any major “skin in the game” insiders as far as I can tell (the CEO owns $1 million worth of shares, but he gets paid more than that every year), and there’s only one really focused owner on the institutional side that seems to have any kind of biotech focus (Eastern Capital owns about 7% of the shares, roughly $5 million worth … don’t know much about them).
So I don’t see a lot to make them stand out other than Robert Morris’ apparent enthusiasm for the shares (which certainly goes over the top, he calls his special report “The End of Cancer Worries Forever“), and I don’t know enough about the science to be a believer (though, to be fair, I almost never speculate on developmental biotechs because they’re so hit-driven and I’m not smart enough to be a hit-picker in the sector). It is at least encouraging that they are enrolling patients for Phase 3, and that they probably won’t have to raise more money before they have some indication of how the trial is going, but sometime in the next year or two they’re probably going to have to either get good results from this trial that let them raise cash at a good price, or have promising enough results that some big pharma company wants to jump in and help fund development of “drug S” (or just buy up the whole company, as happens with some regularity when a little biotech gets promising results).
Oh, and they are presenting at an investor conference next week, so maybe they’ll have something interesting to share then. As you can tell, this one doesn’t jump into my cup of tea … but these kinds of stocks almost never do. Sound interesting to you? Interested in the science or the lottery-ticket possibilities of $80-million developmental biotechs? Have any experience with Robert Morris or know whether or not we should consider him a biotech savant? Let us know with a comment below.
This thread has been first class and I want to thank Karmaswimswami for being so generous with his time and knowledge.
Karmaswimswami, if you have time I would love to know if you have an opinion on Nortwest Biotherapeutics?
NWBO are developing a Dendritic Cell Immunotherapy with several products in various stages of trials. DCVax-L for Blioblastoma multiforme, is the most advanced, now in a Phase III trial. This company has been much discussed on Seeking Alpha and some are absolutely downers on this company even though they’ve had some excellent Phase I/II results.
Karmaswimswami, are you familiar with this company?
Terje: In answer to your question about Northwest (NWBO), a longish answer but I will strive to keep it interesting and instructive. I do think NWBO carries a good chance of a huge upside surprise.
With any successful cancer, at least four things are going on. One cells are replicating like mad. The most basic, and rather antique I feel, approach to cancer is to give drugs that interfere with replication of all cells, and just are more harmful to rapidly dividing ones. This is why I am not keen on sapacitabine, which got this thread started.
Two, oncogenes get activated. Tumors have an oncogene expression signature. Drugs that nuke oncogene expression have marked anti-cancer effects. This is where RNAi may shake up cancer therapeutics, by silencing oncogenes.
Three and four are very interesting, and where the future lies for beating cancer. Three is the immune system. Any tumor that is thriving is doing so because it has somehow duped the immune system, lulled it into a state of neglect. Immunotherapies work to circumvent this. The archetypal company in this regard was Dendreon, and below I will review why Dendreon failed and what that lesson may teach us about immunotherapy. In fact, the way tumors fool the immune system may be via tolerance…that is, putting out so much of an offending antigen that the immune system is faced with either total expenditure of itself to fight the antigen, or simply regarding the offending protein with benign neglect.
Four, all tumors that are thriving have learned to evade and escape apoptosis. There are two fundamental ways cells die: they are killed (necrosis) or they commit suicide (apoptosis), (In fact there is a third way, pyroptosis, but save that for another time). An imperfect analogy, but imagine an al Qaeda safe house. Every terrorist in it is wearing an explosive vest. Every closet is stacked to the ceiling with TNT. The house is guarded round the clock, and if anything goes really amiss, it can obliterate itself quickly. Well, ALL cells are just like this. Cells are concerned with becoming immortal. They scan themselves constantly, and with the smallest sign that normal aging and death pathways have been subverted, they kill themselves (apoptosis). Imagine the trouble of actually making an al Qaeda safe house safe. You’d have to chloroform the guards, unprime the detonators, hose down the TNT. But all successful cancers have found sneaky, multiple ways to avert apoptosis. The hottest cancer therapies of the future, mark my words, will be drugs that restore apoptosis in cancer cells. They are coming.
Dendreon was doing what Northwest is now trying to do, and failed badly. What happened? Provenge was a technique in which patient white cells were leukapheresed off, and then subjected to ex vivo incubation with a fusion protein made of prostate acid phosphatase (PAP) and GM-CSF, a cytokine that can make tumor-killing cells mature. So where did they go wrong?
One, their choice of PAP was dumb. They chose it because PAP is made by nearly all prostate cells and no other organs. (And herein lies the proof that Provenge does NOTHING: if it did, 100% of the men receiving it would get clinical prostatitis. Did this happen? No, not at all. I have studied all the Provenge trials.) What Dendreon did not really realize, and maybe Northwest doesn’t, is that there are two big arms to the cellular immune system, Th1 and Th2. When you incubate immune cells with GMCSF as they did, frankly you are activating both arms, and that strafes one in the metatarsus. You want to turn on Th1. If you activate Th2, you turn things into an ineffective/autoimmune/non-tumorkilling phenotype, and frankly, Dendreon did not adequately exclude this in their preliminary studies (they showed that treated cells did not make IL-4, but did not check for, or report the results of, assays for IL-10, a more reliable Th2 marker). My point is, how do we know that Northwest’s method won’t do the same thing? Honestly I have searched and searched for details on their method, what specifically they do to make DCVax-L, and cannot find them. Why? It should be patent protected, so why it is secret?
There actually is another huge dark corner to the Dendreon saga. If you remember, in the pivotal NEJM trial that won Provenge FDA approval in 2010 after it had been denied twice, Provenge treated men lived 4.1 months longer than sham immunotherapy recipients. Many critics feel that was the problem. The latter had only a minority of their original leukapheresed cells reinjected. So it is not that Provenge treated men lived longer. It is that men in the control arm died sooner (which they did….much sooner than historical controls), because they were highly immune depleted by the sham technique.
Glioblastoma multiforme patients in the phase II NWBO trial did have significantly improved survival and time to progression. NWBO seems to take tumor fragments, make lysates of them, and incubate patient cells ex vivo. I cannot find a specific recipe for what they do. My guess is that this will stunt GBM growth. My guess also, however, is that it will not prove curative, that it will just be temporizing/salvage. So the stock may rise a lot, but the agent may prove not to make a huge long-term difference. My concern is that as much as the agent may be activating Th1, it may also be turning on Th2. I would like to see data answering this. Dendreon could easily have made a successful agent, I feel, had they chosen GRP78 as a target rather than PAP. I wish NWBO had chosen one protein, one antigen, and then really cranked up the immune system to go after it. Instead they are going for a nonspecific gmish of antigens, and so I think patients will get “nonspecifically” but not spectacularly better. I think really smart tumor immunotherapy will be identifying antigens present just on the tumor surface, making antibodies and coupling those antibodies to cytotoxins. Certainly several companies are doing this, especially for breast cancer. I am concerned that while soluble/humoral immune approaches may be good, that the theoretical advantage of potentiating cell-mediated immunity is not quite at hand. We just do not know yet fully how to crank up that side of the immune system.
To James Franklin: Thanks for the kind words. They really mean a lot. I am nagging my Australian colleague for us to start a newsletter or website. She assesses the companies (cash flow, quick ratios, capital structure) and I assess the science and its applicability to the clinic.
I can tell you this: I firmly believe that there is not a single concept in medicine or biomedical science that a layperson cannot be helped to understand. This is critical, I feel. Company websites cannot help you do it. Doctors often lack the patience, scientists lack the vocabulary. The papers and studies and methods are often inaccessible to lay people, but if you assume that people are basically inteliigent and want to learn, there are ways to depict and present so that they can really grasp what is at issue and make informed decisions. In hepatology, I deal with patients with cirrhosis, quite honestly one of the most insanely complex diseases known to man, and one that even baffles most physicians, because so many pathophysiologic pathways are at work. Compared with cirrhosis, cancer and diabetes are cakewalks! And yet, over time, I have made patient after patient (mostly people with just high school diplomas) into people who really understand their disease process and know how to proactively manage themselves and keep themselves from ending up in an ICU. People are way smarter than most doctors and scientists give them credit for, I feel. If I explain something to a layperson and (s)he doesn’t get it, that is my fault, not theirs. All concepts in medicine and biology are accessible if they are spun and laid out the right way.
Sign me up! You’d have your first subscriber right here if/when you get set up.
Karmaswimswami, that is an awesome overview!
I too think that NWBO might surprise. I have little input with reference to the science, but I was impressed that the CEO bought almost 6.5 million shares about a year ago. This indicates a pretty high level of confidence imo!
I also like that they have added production facilities in Europe in addition to their existing set-up here in the USA. Again, reading ‘tea leaves’ here, but management must have based this decision on more than just a hunch!
From what I can understand they have a compassionate program that is run through CTCI in Israel.
Is there a way to get some feedback from CTCI? That would be most instructive.
As it were, I had the Provenge treatment about a year ago (PC detected 5 years ago at 54) There is of course no way to know if this is of any help. Currently on Zytiga / Xgeva which so far works great. Do you have any promising PC treatments on your radar?
Another company I might toss into the arena for consideration: Arena Pharm (ARNA). I have been long ARNA for 5 years, and will continue to hold. I felt its lorcaserin science was quite solid, and that it would be FDA approved despite all the setbacks, which finally it was. ARNA is down for three reasons, I believe: (1) the loosening everywhere of marijuana laws. This is upstaging the development of its CB-2 receptor agonist for pain. (2)the extreme short interest in the stock (30 per cent). This may be because of: (3) the fact that Belviq (lorcaserin) is something that keeps the weight off only as long as you are on it. Belviq’s big advantage over its main competitor Qsymia is that it isn’t a controlled substance and has no abuse potential. It has three solid drugs (in addition to the CB- agonist) in phase I: a prostacyclin receptor agonist for pulmonary hypertension (the pumonary HTN race is getting very interesting now!); a serotonin inverse agonist that could easily prove to be a better and safer agent than the awful hemorrhage-promoting drug Plavix (many downsides, I feel); and an agent for autoimmune illnesses, one I am still gathering data on. If any of its 4 candidates shine in phase II, it will suddenly start to look very very cheap, and paroxysmal short-squeeze buying could start. I’d watch for pullbacks and news and consider getting in, though I would not buy just yet. This is a company with grace and Olympian calm and poise. The FDA put them through abject hell on Belviq, and ARNA came out looking like a rose.
Hi karmaswimswami;
A bit off topic, how do you feel about brand name drugs vs generics. I am always wary of generics. I was recently prescribed Azithromycin (brand name Zithromax) for Pneumonia. Here in Massachusetts, patients have no rights once they get to the pharmacist with prescription in hand and would like to get the brand name. Rather than make an issue of it, I accepted the generic. 60 Minutes recently did a program on Ranbaxy, a generic drug maker, that faked test results.
http://www.cbsnews.com/news/leading-generic-drug-maker-faked-test-results-for-fda-approval/
Hi Tanglewood. Thanks for asking. The Ranbaxy scandal was pretty awful, but I am not sure it can be generalized to other big generics makers such as Teva and Mylan, or even to other Indian generics makers. In the latter case, they pose a large threat to brand-name hegemony because many patents are ignored there and the knock-offs are quite good. There has always been a sense in medicine that for a certain (few) drugs, the brand name was always better. Lanoxin was always the preferred form of digoxin. In some cases, this perception was indoctrination: Boots/Knoll Pharmaceuticals tried for years to create the perception that Synthroid was the ONLY worthy form of levothyroxine. As evidence to the contrary grew, they paid (off) researchers to perform a study showing superiority in efficacy of Synthroid, only to get flummoxed when those researchers insisted the data showed no difference. Lawsuits resulted over publication. It was quite ugly. This was in 1997 I believe. Mostly generics are fine. Not to second-guess your doctor, but personally I never prescribe azithromycin, which is always given for a 5-day course because of its long half life. It has a pretty high failure rate for airspace disease because of this, and so if I am thinking macrolide, I generally go with 7-10 days of clarithromycin. You’ll probably be fine, but just be sure you get well. If you aren’t recovering, or if the infection appears to relapse, that’s an azithromycin failure, and you need further treatment,
Terje: I am truly sorry to hear you have prostate cancer. Really I am. It might be a good point of departure for a discussion in fact, because I see mostly male readers and the fact is ALL of us are going to be in your shoes at some point, Terje. And for ladies reading, someone close to you is going to get prostate cancer. It is not “likely,” I’m afraid; it is a given. Prostate cancer has been an intellectual hobby of mine for a long time because it is highly complex, and because it plays by a set of rules that apply to no other tumor type. It’s the only type of tumor diet can modulate, for example. But it is also a tumor type for which the most durable dogma, that testosterone is to blame, may be totally wrong. Explicating this may go on for a bit, but I will keep it relevant and interesting.
This is a link to a full PhD dissertation by a former student of mine regarding previously unrecognized ways that diet may attenuate prostate cancer. It is not light or easy reading, but the introduction is a fairly accessible summary of what is known.
http://dukespace.lib.duke.edu/dspace/bitstream/handle/10161/2263/D_Mavropoulos_JohnC_a_201005.pdf?sequence=1 In a nutshell, Seward buys Alaska from Russia. Alaska is populated by Eskimos, now called the Inuit. Academic physicians flock to Alaska to study them. They have different diets….lots of fish, lots of fat, both from fish and from blubber. Inuit men rarely get prostate cancer. What followed was an idea that would haunt and delude American medicine for two generations….that fish oil prevents prostate cancer, and that carbohydrate avoidance tames it or prevents it. Correlation does not prove cause, however. It never does. One of those ideas would prove to be wrong, and the other only partially true.
I have reviewed all the studies about fish oil and prostate cancer. One of the huge problems with nutrition science is that it lends itself to “confirmation bias.” Research an issue, and you can find 50 papers that corroborate and 50 that refute. Cite only the corroborating ones, and you look like a scholar and genius. But if you look at the totality of data for fish oil and prostate cancer, it’s fair to say there is just no link. Remember that in July 2013 there was a notorious J Natl Cancer Inst paper that argue fish oils CAUSE prostate cancer. That one had flawed methodology….basically one blood level followed by eons of surveillance. They didn’t assess intake. I am sure fish oil doesn’t cause prostate cancer, but neither does it prevent.
My former student got a little seduced by the intellectual romance of impugning Western diets (although no one can actually agree on precisely what a Western diet is, and although despite that awful Western diet, Western longevity is at an all time high and rising). And as I will discuss below, there is a critical reason that carbohydrate-restricted diets may help prostate cancer that he missed. Subsequent studies have borne out some of his findings, and undermined others. For mice implanted with human prostate cell lines, the best evidence now is that tumor growth is stunted not by ketogenic diets, but rather by diets significantly reduced in carbohydrate and fat. I can provide links easily for a dozen studies on this. It is somewhat dull reading. Mind you no one is saying these diets cure. They modulate.
We talked about why Dendreon’s Provenge failed. People criticized them: “Why not target your therapy against PSA?” Because that is intracellular, they claimed. And then they turned right around and targeted it against prostate acid phosphatase (also intracellular!). They should have chosen a cell-surface molecule that only malignant prostate cells make. There is such a molecule: GRP78. In normal prostate cells, GRP78 (which stands for glucose-regulated protein, 78 kiloDaltons), acts as a chaperone in the endoplasmic reticulum, In prostate cancer it is expressed on the surface. It has been clearly shown, recently, that antibodies directed against the carboxy-terminal portion of GRP78 help reconstitute apoptosis in prostate cancer cells in culture: http://www.ncbi.nlm.nih.gov/pubmed/20368692
We talked yesterday about immunotherapy and restoration of apoptosis being future ways of treating cancer. The approaches are not always mutually exclusive, as this paper shows. All cells are literally armed to the teeth with proteins that can kill the cell in just a few minutes (caspases). That was the al Qaeda analogy. All tumors MUST circumvent apoptosis to make it, because cells are always checking their checkpoints, and there is any hint they have become immortal, they apoptose without hesitation. (An entity in Australia recently devised a molecule that overrides the failed apoptosis that occurs in B-cell malignancies; that owes to a protein called bcl-2, for B-cell lymphoma. The new agent abrogates the antiapoptotic effect of bcl-2, and so with it, malignant B cells all quickly apoptose, which is much cleaner than necrosis by chemo. Apoptosis is tidy. That story is not ready for investment yet, but I am following it).
So, is any company pursuing GRP78? Yes, one is. Patrys, in Australia. They are making monoclonal IgM’s against GRP78. The FDA has smiled on their clinical development of this antibody, which now they are studying in liquid malignancies. Patrys belongs on a watch list (PATZF) but is not a buy here: too many questions about management, capital structure too shaky, leadership a little too cloistered and reclusive.
One prostate cancer dogma will not die, but needs to: the idea that testosterone is to blame for the disease. I am not anti-establishment at all, but I just do not believe in belief. I believe only in data. Where is the data for that? In fact, testosterone supplementation is all the rage now, as men who are supplemented retain bone mass, muscle bulk and cognitive status. If testosterone caused prostate cancer, then testosterone supplementation, which is becoming wide spread, should be causing a huge uptick in prostate cancer incidence. It isn’t happening. The data suggest it is not testosterone at all, but rather what becomes of testosterone. Testosterone isn’t just a male hormone. Women make it too. It is responsible for libido in both genders. Woman aromatize it to estrogen….and so do men. Aromatase resides in fatty tissue. And this, in my view, is why carbohydrate-restricted ketogenic diets help prostate cancer: you lose weight. Less fat, less aromatase. And there are studies in men now showing that therapy with anastrozole (Arimidex), an aromatase inhibitor, both cuts prostate cancer risk and helps stem its progression. This helps explain why castration is of benefit in some men, but for a different reason. Without testes, there isn’t testosterone, and therefore there is nothing to aromatize into estrogen. My feeling is that this will get accepted more and more. Medicine has always had problems with what are known as mumpsimus ideas: customs obstinately adhered to no matter how wrong they are. I am sure I am guilty of some of them,
Terje, the medicines you are on are really state of the art for what you have. It is tragic you have it, and at such a young age too. The overwhelming majority of us are going to be in your shoes. And yet early detection and rectal exams are so controversial, so dodgy in efficacy that at present the US Preventive Services Task Force does NOT recommend PSA testing or exams. The SELECT trial, a huge multicenter multiyear undertaking found that taking vitamin E and selenium do not prevent it (and that in fact vitamin E alone raises the risk whilst selenium alone confers a diabetes risk). The best we can do is stay lean and shift our diets toward protein and away from carbohydrate and fat. And not smoke.
One thing I failed to mention in discussing Provenge yesterday was this: in men of African ancestry, prostate cancer is a somewhat different entity, Immune systems vary by ethnicity. There is much evidence that people of African extraction are relatively defective in Th1 immune responses. While I fear the Dendreon method stirs up both Th1 and Th2 responses, use of Provenge can correct a serious Th1 deficit in black men, and so Provenge actually really is of greater benefit there than in other races.
I am definitely always watching for new science and new agents as regards prostate cancer. I will post as I learn new things.
Thanks karmaswimswami for giving us the cancer 101 course and beyond. This has been the best thread ever especially for the biotechnical discoveries that are making this an exciting investment period.
I had Laparoscopic prostate cancer surgery in December 2007 (age 67 at the time). My PSA which was being closely monitored was 7.9 on 9/21/2007. It was stage 3, Gleason score 4 + 3 = 7/10, capsular penetration with negative surgical margins, negative seminal vesicles and negative lymph nodes. The pathology report sounds kind of scary, ‘extensively involving all four quadrants’. My doctor said my cancer was ‘fairly aggressive’. My PSA which had been zero for about 5 years after the operation, recently showed .11 and my doctor wants to do a re-test at the end of this month. Maybe I’m being too pessimistic but I hope that I don’t have to go onto hormonal deprivation therapy. I was thinking that surgical castration might be the better approach, less side effects. It’s funny that you mentioned that too.
This is kind of an old article but did anything ever happen with MDV3100?
http://www.medicalnewstoday.com/articles/185348.php
A friendly point of contention to the statement that, “[prostate cancer] is the only tumor [that] diet can modulate.” The work of Craig B. Thompson, MD, the CEO of Sloan Kettering, certainly offers strong evidence to the contrary–even in Glioblastoma, which is discussed previously on this page. His work on “Metabolic Reprogramming” of tumor cells, including those discussions in tumor metabolism at 2013 ASCO, completely contradict the idea that Prostate Cancer is the “only tumor” influenced by diet. Instead, he contends that all tumors are influenced by a patient’s diet. To claim otherwise, I believe, is misguided and dangerous–particularly in making those statements to patients.
If you’re an ASCO member, I’d encourage you to pull up his (and several other MD’s) discussions from the tumor metabolism sessions last year. In it, they discuss the influence of Medium Chain Triglycerides (MCT/highly-saturated fats), such as coconut oils, playing a major impact against many if not most tumor types. They also, of course, discussed the influence of glucose in tumor metabolism, as well as a particular subset of tumors that actually prefer to grow from l-glutamine. I have the audio mp3 of the session, should you like me to email it to you. There’s a powerful point in it, in which they mention the injustice being done to patients by the oncologist community turning a relative blind-eye to the influence of nutrition/tumor-metabolism.
Kind regards,
David
Swamiji!
This is most amazing! Not only you give extraordinary investment advice based on your knowledge of chemistry biology, etc, but also you give clinical advice, top of the top!
This is my personal thanks because I have a high PSA and your analysis give me a good direction in what I have to do!
One other thing about the Dendreon debate is that it does have object lessons for all of us about the differences between how the smart money, the really smart money, and the naive money invest in biotech.
The smart money sat out Dendreon. Too many efficacy questions. Serious clouds over the research. The fact that in 2007 and 2009 the FDA turned it down for lack of benefit.
But the really smart money realized that it was likely to be approved on the basis it caused no harm, and that there would be great hoopla and fanfare to the approval. They bought in with a readiness to bail out as soon as Dendreon ran up. It did, quickly from $20 to $40 in 2010. It is now of course in single digits and is a dead stock.
But the NAIVE money said, Hmmm, this is bad science. People are SMART. People will see that this is bad science and the company will falter. Let’s short Dendreon. People are not always smart in what they invest in, and many went in on Dendreon. Marie Huber was an analyst at the New York hedge fund Schoenfeld. She asserted that people would be smart and not buy the Dendreon hype. When the stock was at $20, solely on her advice, the firm shorted a million shares. When the FDA approved Provenge, Dendreon soared to $40, and her firm panic-sold fearing further appreciation. (Huber also advised Schoenfeld to short OSI Pharma….a brilliant company I was long on. It was bought by Astellas, and I made money. Huber’s short cost Schoenfeld $3.5 million).
On 4 December 2013, the SEC fined Huber $25,000 for her actions in Dendreon. Her claims about the science being bogus were accurate (she has started an antiProvenge website, and it is quite smart, really). But she disseminated an unsigned memo dissing Provenge and did not disclose her interest in the Dendreon failing. That is what the SEC nabbed her for. She spent $1 million defending herself against the SEC. She is scientifically a really bright woman with a Cambridge degree, but she is totally naive about investing, and about what makes a biotech investment successful (even if only temporarily). A good object lesson, I feel.
That was stunning. Not the usual ‘I think this is headed for the moon….’ crap. A well composed, considered piece of education about the highs an low styles of investing. More than $49 worth in a paragraph or two. I think I just saw a door open in my investment world. Stunning !
Alan: it is sobering if you think about it really. It is wrong to predicate an investment on the idea that people are dumb, but equally wrong to base it on the idea that they are brilliant. Somehow one must factor in clinical sex appeal, even if one thinks it will be transient and that people will soon think better of it.
Huber’s events just shock me. Very intelligent woman who just does not understand markets at all. Based exclusively on her advice, just on her whim, Schoenfeld short-sold 1 miilion Dendreon shares at $20 that they had to panic-cover at $40. $20 million lost on this and $3.5 million lost shorting OSI Pharma (shorting OSI was incredibly stupid…..brilliant company). Even in the NY hedge fund world squandering $23.5 million in 2 weeks is serious coin. Huber is now completely unemployable. She gave both awful investing advice and also committed securities fraud by falsely trying to cause selling in Dendreon. No one will go near her.
Wow. Just joined as an irregular. This comment section itself was worth the membership fee. Thanks Travis for pointing this out as I usually never bother to look at the comment sections however with this level of education I will not fail to look it over.
I think there are some longs here in Galena (GALE). Because it is on subject, let me say this: what they are doing may be a recapitulation of Dendreon. There has been feverish runup in GALE shares in the last 2-3 weeks, and I am not sure I see a solid basis for it. Their NeuVax methodology is incubating E75 ex vivo with leukapheresed cells and GMCSF, just like Dendreon did with PAP-GMCSF. E75 is expressed on many breast, ovarian and prostate tumors. But as I have argued before, this method may stoke Th2 responses just as much as it does Th1 responses. E75 is just a peptide derivative of the HER-2 antigen, and yet for their NeuVax breast cancer recurrence prevention trial, they are looking only at HER-2-negative tumors. This does not make any sense at all.
Galena acquired Mills to get sustained release anagrelide to treat essential thrombocytosis. (ET)Anagrelide is a phosphodiesterase inhibitor that blunts megakaryocyte maturation into platelets (ET is a disease in which platelets are grossly overabundant). Anagrelide is already approved. Extended release anagrelide? So what? Who cares? Anagrelide itself isn’t even first choice for ET; hydroxyurea is.
They have only one profitable approved product: sublingual fentanyl. Doesn’t appeal to me in the least. In the current exaggerated regulatory climate over narcotics, fentanyl is an agent that physicians are avoiding prescribing in droves because it is highly abused and sets off red flags at pharmacies when you write for it.
People may make money in GALE, but I will not touch it. People who have made money in it need to think about taking some profits and getting out.
Thanks Karmaswimswarmi, you have expressed, much more eloquently and much more intelligently, some thoughts I have had for a long time, especially in regards to Provenge. The market is so irrational sometimes, and it’s difficult to understand why some stocks keep going up on hype, even when results are so poor. One company in Australia, Prima Biomed (who are also listed on the NASDAQ) who have an ovarian cancer immunotherapy C-Vac (not unlike Provenge) has just gone up 44% on an announcement regarding an amendment to overall survival from progression free survival in one of their PII studies. The results from preliminary PII were not good and ended early. No significant difference in PFS. In fact, in one treatment group, they appeared worse off than controls. But still, people just pile on in. There was, however, perhaps a lot of short covering. I noticed the US listing went up just 7%. So I guess those Aussie investors who bought in on hype on Friday will take a bath on Monday. I guess this is what you talked about earlier. They may be approved because of this amendment to clinical trial protocol, even if their results are only as good as Provenge and, as it is an infusion, will be covered completely by Medicare (who cannot negotiate a better price) for the over 65s, which probably make up a large percentage of patients, meaning much more pressure on the public health system. There is something morally wrong with developing $100,000 drugs that do nothing except provide false hope and, possibly extend patients’ suffering for a couple of extra months. To top it all off, some family members who have had to give up their paying jobs to help care for these poor patients, are left with nothing, and in some cases, a huge debt, whilst the pharma executives send their kids off to Harvard et. al to learn how to keep transferring the wealth from Joe Public to themselves via million dollar Christmas bonus. Thanks for all your advice and quality information Karmaswimswarmi. I agree with others here, you really should consider your own blog.
From Charles Uray, Jr.
Just completed reading the above 64 “chapters” of this biomedical discussion in which Dr. Karmaswimswami was the primary “answer man”. WOW !! Very impressed !! If he and his collegue in Australia (I believe) ever publish a newsletter, please include me on your mailing list !!
Charles Uray, Jr., P.E., P.S.
curayjr@yahoo.com
Just renewed as an irregular. Heartily agree with comments above. Thanks to all, for the extended watch list! A special thanks to karmaswimswami for your incredible imput!
A couple of people have asked about or are long PSTI. I have been tracking it for a while actually. Will cobble together some thoughts on it for tomorrow.
Any one here know any thing on RGLS
Regulus (RGLS) is a collaboration between Alnylam and ISIS. They combined their microRNA intellectual property and created a new company. Like Benitec (BNIKF) discussed here, they are working on an RNAi HCV drug. They aim to be in the clinic later this year, but more likely next year. Comparing the two companies, Regulus is at least a year behind Benitec, but they are in a much better cash position, so the threat of dilution is diminished. However their market cap is $330m compared to BNIKF’s $30m. shRNA is a much more mature science compared to microRNA. The drug Regulus is working on would need to be injected several times if their clinical trials replicated their pre-cinical results. I’m not sure that this would be considered an improvement over Sofosbuvir.
I’ve been watching Regulus. They are a different play on gene silencing, going after microRNA (which is different from mRNA). In this way, they are fellow travelers with Santaris (different from Santarus), which isn’t publicly traded yet, but which has miraversen in development for HCV (with good phase II data). Frankly, they are very late to the HCV party. I will try to cobble together some commentary on Regulus. If you are in it, I would hold, Personally, I would not buy yet. This is a new issue, and frankly I think a lot of people are still sussing out this company. I am a long way from convinced that massaging microRNA is the way forward. There are a lot of hardcore RNAi fans out there (I am one) that think RNAi needs to play itself out for gene silencing first before we pile in on anti-microRNA. Insiders are selling RGLS lately, and it is way way off its high.
I missed saying it above but meant to: Santaris’s lead drug candidate (miravirsen) goes after exactly the same microRNA target (miR-122) as Regulus’s lead candidate. Santaris is way ahead in this race.
I agree with Charles and Brian, just read through the complete conversation and really enjoyed it. I too would be interested in any newsletter that karmaswimswami might create. Thanks for a great evening.
The only way to get notified of new comments is to comment. Here is my useless comment so I can get further comments. Go figure????
Hi All,
I just put in a limit order with Ameritrade to buy some NKIF. May it and we do well. Thanks Karmaswimswami for so freely and kindly sharing your knowledge with us.
I know this is kind of off topic,but for those who have high PSA levels, be careful about too readily agreeing to prostate biopsies. For the second time, after my recent one, I am now suffering from a UTI that won’t respond to any antibiotics.
I will have to undergo another cystoscopy and have it flushed as in the past to clear it up. I never had these until the biopsies, so I am sure they are related.
Don
I’m sure they are related too. You might wanna look into Nascent Iodine as a dietary supplement to up your iodine levels. Often times, we don’t get enough good iodine intake which is critical to Prostate health. Just a thought. It’s good for fighting infections too.
Thanks Sean; will do.
Don: Sorry to be slow responding. Hard to keep up. What is amazing about prostate biopsies is that they do not leading to raging UTIs more often than they do. Generally these should respond, however, either to trimethoprim-sulfamethoxazole or to ciprofloxacin. It would not be unreasonable to acidify your urine with vitamin C (vitamin C does NOT have any antimicrobial effect intrinsically, but just by dropping urine pH, bacteria get quite unhappy).
Many thanks; will definitely do the vitamin C; how many MG would you suggest?
Sorry all this is off topic, but one last question please to Karmaswimswami. Kind of desperate to know.
Urologist says I need a green light laser treatment to reduce urethral blockage by middle prostate lobe. Is this standard, safe, and wise?
Thank you.
Don
Karma, you have really done your homework. Great discussion (lecture), thanks to you. Would you care to share why BNIKE went from a penny to over 30 cents last July and then almost to 70 cents in October? Thanks.
Leo S: it was because of the reverse 25 to 1 split that Peter French the CEO effected. Australian capital structures are rather a lot different from here. Billions of shares for pennies there are normative. It’s a Down Under peccadillo. That was done specifically to make shares more attractive to American capital markets.
Karma, thank you for your kind answer to such a mundane question. I figured it out by reading a few of the company reports. Thanks again.
Yes, thanks Louis, I forgot to check the box.