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The terms for debt financing have seldom been better if you take into account how companies like Microsoft and CREE have taken to the debt markets for the first time instead of raising money via equity offerings.
My experience is that biotechs do tend to rise after such debt offerings. I've seen it time and time again.
Still, disheartening to see the stock fall 6% or so, twice in a week, the first time on 3x normal volume and the second time at just above normal volume.
I hope that is all there is, is some angst and adjustment for an upcoming debt offering or a secondary offering.
With VRTX I have noticed that VRTX, almost as if it was planned, sold their secondary offerings at the very low that the share price would get within a 3 month period of or so. At one point they sold at $17 only to have the share price nearly double within weeks thereafter.
Many of these games go on well beyond our knowledge or view. The ones who get hurt are those who panic through them if nothing about the fundamentals have changed.
Tinker
MNTA - Just been pondering the ANDA process. It is my understanding that TEVA and Amphastar filed their ANDAs over 6 years ago. Six years!!!
Has anything changed from here to there on their ANDA's? Six years is more then enough time for even the Japanese lettuce inspection agency to let in American lettuce off the dock during a trade war.
One cannot really read too much into anything the FDA does. However, in 6 years there cannot be anything in those ANDAs that the FDA does not already know about, and that the FDA is not concerned enough about to not move the ANDAs forward.
MNTA's ANDA is about half the age of TEVA and Ampahstar's ANDAs. Does it mean anything that the FDA has done nothing with the competition ANDA's in 6 years? Does it mean anything that TEVA and Amphastar have taken no legal action to get the FDA moving on these applications?
Probably not, but I gotta think it means something in regard to the quality of the ANDAs that were submitted. CYA only goes so far.
Tinker
http://www.forbes.com/2009/05/21/isis-genzyme-mipomersen-business-health-care-cholesterol.html?partner=yahootix
This is how Forbes summarizes the topline data. I am interested in how many patients in this subset who were given mipomersen could otherwise be taken off the once weekly blood filtering process. The process costs about $100K a year (+ or -) and is very intrusive.
Have to see the data, but I would wager that a good proportion of patients who finished treatment had a reduction sufficient to remove the need for this weekly aphersis process. That would be quite the breakthrough for this indication and become the new standard of care for this tiny indication.
The big bucks are of course elsewhere as one moves up the disease ladder and I don't believe this clinical trial tells us much about these indications then we knew or speculated before.
Tinker
Dew,
I have tried to respond to your PM to me but for some reason my membership is not sufficient. I will need to get it straightened out and get back to you.
Thanks.
Tinker
From taking a quick look at the mipomersin results, the key issues are the 25% reduction (phase II was something like 40% reduction above and beyond statins) and of course the one phrase of "death" elevated liver enzymes. In one patient that is.
The 25% is on an ITT, and not on those who followed through with treatment. The drug works in a systematic matter and it reduces LDL over the course of time. I think the FDA can easily see through this. The complaint is that 25% reduction is not enough. 40% is enough. I think the data of completers will speak for itself. This is not the case, say with Elan's Bap where the completer analysis may be suspect. The completer analysis is quite relevant to this study.
The elevated enzyme in one patient does not appear to be a big deal to me.
This said, if ISIS's share price gets clobbered over this it may very well be a good looking share to get back into.
Tinker
<<<I seem to remember reading that the FDA itself feels that there is a definite benefit to consumers if the FDA approves more than one ANDA…>>>
There is no benefit if a defective generic is let on the market and the market loses confidence in all generics because of the one bad egg let onto the market.
Also, if entry into generics becomes too easy, then fewer companies will pursue the generic jackpot.
So the above statement would appear not to be true except in certain contexts that may involve more competition equals better pricing. But that only applies if the generics all work as a bioequivalent of the existing product.
If MNTA is the only approved drug then you have a real blockbuster as it not only creates tons of cash flow but validates the technology and look for a large multiple. If all 3 drugs are approved then MNTA is just another generic drug maker and look for a lower multiple based on revenues.
My confidence is, if it was so easy to replicate Lovenox then why would any large pharma company need to share the profits with MNTA in order to accomplish this goal?
Whether or not TEVA and Amphastar have accomplished this feat without having to partner with MNTA we will have to see, but we know at least one big monied player felt they had to pay the price to MNTA in order to accomplish the goal of a true generic lovenox.
Tinker
Funny how Victoza gets approved in Europe whereas Byetta has hardly ever been marketed in Europe (well not much by Lilly anyways). I don't see much point in trying to market the heck out of Byetta in Europe either if Victoza gets itself established. Victoza has better efficacy, more or less, 1x a day shot, vs. 2x a day Byetta BID.
Interesting how one drug may come to dominate one market and the other the other market. Byetta sold like pancakes for its first few years on the market, will not Victoza sell like pancakes in Europe in its first few years?
Tinker
I don't know ALKS cut off the top of my head. But it does seem clear that someone thinks there is value here with AMLN. Icahn has been buying from price levels much higher than today's price levels (indicating he thought it undervalued at more than double the current price) and continued to buy on the way down. Now he is spending a ton of money on a proxy battle. Proxy battles are not cheap. In fact it is one reason proxy battles are relatively rare, because they cost a lot of money.
I like to see smart people doing actions consistent with future higher stock prices. On the other hand they could just be fooling themselves as well. But I'll ignore this less likely, but possible, latter concern and just focus on the former for now because I own some shares.
Tinker
<<<Has DSCO set a record for Complete Response Letters on the same NDA? I think ENCY was the prior record holder.>>>
I don't know, but I do know that on the Investor Village board there was a guy who was long call options DSCO and short DNDN. Dang, what a hurting unit!
I would think that at some point DSCO has to get this thing right. They keep inching a little bit closer. Just that little bit.
But it does make you wonder as to the commercial viability of a product that they cannot get up to snuff production wise despite years of effort. Can they actually, and consistently, produce this stuff?
They are also going to need a real good marketing partner to sell this stuff. Looks like a good product, but I cannot see DNDN pushing this to market by themselves.
Tinker
Here is the relevant portion of the conference that describes, at least from the speakers information, the stark differences between Byetta and its more thyroid-cancerous prone peer:
Now, before I highlight the regulatory progress to the plan submission for exenatide once weekly, I want to provide perspective on the recent advisory panel for the liraglutide. Keep in mind that in Amylin, we are grounded in science, science is our strength. We have been investigating the GLP-1 area since 1996 and we established ourselves as leaders in 2005, when we launched BYETTA with our partner Eli Lilly.
At the recent FDA Advisory Committee meeting concern was raised regarding a preclinical cancer finding in the liraglutide development program particularly malignant C-cell carcinoma of the thyroid.
Let me first highlight, what we know. Currently, there is no clinical evidence that thyroid cancer of any type is a GLP-1 class effect. The discussions at the recent Advisory Committee meeting highlighted that risk benefit considerations are key for any potential therapeutic agents.
Drugs within the same class often have distinct efficacy and safety profiles due to differences in structure, mechanism of action and metabolism. Within the area of diabetes, we have three distinct examples. First, the biguinides where you can contrast phenformin with metformin, the thiozolidinedione class where you can contrast Actos with Avandia, and with resilient and the DPP-4 inhibitor class where you can contrast Januvia with [galvas].
Regarding efficacy, BYETTA and liraglutide appear to have similar results in terms of both glucose and late lowering FX. Yet BYETTA has no preclinical signals of cancer, but instead had established a well documented safety profile. BYETTA has been used in more than 1 million patients with over 7 million prescriptions written since introduction to the market. BYETTA and liraglutide are distinct molecules with significant differences in structure and metabolism.
BYETTA is not a GLP-1 analog instead BYETTA is a synthetic provision of a naturally occurring peptide that function as GLP-1 receptor agonists. BYETTA achieves clinical efficacy at much smaller doses of peptide and liraglutide. BYETTA is administered at low doses 5 or 10 micrograms and largely cleared intact through a well characterized renal elimination pathway. Liraglutide is administered at high milligram doses of peptide and circulates at high concentrations in the blood stream.
To achieve clinical outcomes similar to those achieved with BYETTA, first a patient must be exposed to approximately 90 to 100 or more liraglutide per day based on a weight basis of the drug. The drug substance that is administered the greater the potential for undesired for half target effects. The regulated bricks down into metabolite that circulate in the blood stream, the effects of these biologically active bi-products are not well characterized.
BYETTA has a different more typical peptide construct and is cleared largely intact by the kidneys and then fully eliminated from the body. In carcinogenicity studies, liraglutide was associated with increased malignant C-cell cancers in both males and females and rats and mice. In addition, the significant increases in malignant progress are commerce of the scan was seen in male mice.
Now, let’s focus on BYETTA. BYETTA is the only GLP-1 receptor agonist currently available for clinical use offering powerful sustained A1C reductions with weight loss. There is no limit association with evaluate C-cell carcinoma and BYETTA based upon preclinical trial data and post marketing surveillance data. Preclinical findings are outlined in the prescribing information for BYETTA.
To summarize, in BYETTA preclinical studies, beanie thyroid tumors were observed in female rats at all exenatide doses in a two year study. No tumors were observed in male rats or mice of either sex. For BYETTA, extensive clinical studies as well as post marketing data do not suggest an association of thyroid tumors of any type. As of 30 September, 2008 experience of BYETTA included more than 5500 subjects exposed in clinical trials with greater than 4600 total subject years of exposure.
Some advisory panel members questioned, there was a concern about thyroid cancer might apply to BYETTA. In response the questions of the post meeting press conference a senior FDA official stated that “the agency looked back at the clinical data for BYETTA and didn’t see any thyroid cancer risk and the agency so for hasn’t detected an increased risk and looking at post marketing data” but also said there are limited data to the preventively rollout it possible increased risk.
Now let me help you understand, what this data means to once we got. If approved exenatide once weekly will be the first once a week therapy for the treatment of type 2 diabetes. It has the potential of significantly advancing the treatment of type 2 diabetes as demonstrated by efficacy data from DURATION-1 and DURATION-2 studies and its novel once weekly administration.
In these comparative studies the exenatide once weekly as demonstrated a greater glucose lowering effect than three recently approved widely used medication for type 2 diabetes namely Actos, BYETTA and Januvia. In the preclinical program a two year study in rats employing three doses of exenatide once weekly demonstrating a finding similar to that seeing in the BYETTA program, an increase incidence of benign thyroid tumors called C-cell adenomas.
These tumors were observed in both males and females. In this study C-cell carcinoma a slow growing malignant tumor is also seen. While observe at all doses in both males and females the incidence of these malignant tumors was significantly increased only in female rats treated with the highest doses, the doses that provided tissue exposure approximately 30 times that seen with the intended human doses. Again I want to emphasis that the apples ability of these findings to human diseases has not been clearly established.
In addition no evidence of C-cell cancers received during exposure in primates in studies that extended over 11 months, that no time during either the BYETTA or exenatide once weekly program that malignant fibrosarcomas been seen this contrast to the liraglutide program.
Is it spin? Is it wishful thinking? Is it semantics? I am pleased to see management tackle this issue head on with confidence and information.
Tinker
Well, that is one strong opinion! I do like to see a brokerage take a strong, and what appears to be honestly held opinion instead of using the astrological model. This opinion is a risk and is obviously strongly believed by its proponent that provenge simply does not work.
The clock is ticking and we shall find out. Longs are presently making a killing and shorts may end up making a killing as well, just like last time around. I made a killing on the long-side last time, but alas, did not follow through on the short-side, or cover my butt either. Not that I knew the drug worked or did not work, but I thought the regulatory decision overwhelmingly called for conditional approval, which of course was not forthcoming back then.
Tinker
<<<Tinker, there are 2 sets of preclinical data: those of Byetta and those of the once-weekly version. As I posted here #msg-36816635, based on Byetta's preclinical data with regards to the c-cell growth, I thought AMLN could get away with the issue. However, LAR's 2 year rat data (note that AMLN didn't test in mice at all) are not so different from those of liraglutide as these two long acting GLP-1s showed stat-sig increase in c-cell adenomas in both sexes and a stat-sig increase in c-cell carcinomas only in one sex (only at the highest dose).>>>
I will have to look into this. I have reviewed the Lig briefing report and the discussion of byetta and the mouse and rat data that was presented. It is tough to separate out Byetta BID from Byetta LAR data as everyone continues to lump it together.
From the briefing report I found this possible concern: http://www.investorvillage.com/smbd.asp?mb=2885&mn=57873&pt=msg&mid=7032274
I will have to review through here more carefully to try to unmix the BID and LAR animal study information. The FDA itself did not necessarily do a good job of that either. Probably because it is Lig and LAR that is up for review here, but they make little distinction in this briefing between BID and LAR.
Tinker
<<<"Mary Parks, director of the FDA's division of metabolism and endocrinology products, said the agency looked back at Byetta's clinical data and didn't see any thyroid-cancer risk. She also said the agency hasn't detected an increased risk when looking at post-marketing data but also said there are limited data to definitively rule out a possible increased risk.">>>
That is because there is none other then at the highest dose in one species of rodent, in one gender, and if I recall correctly those cells were non-malignant. Not a single person has died from thyroid cancer despite nearly a million people having tried the drug. Not a single person in a byetta or LAR clinical trial has shown any such sign. I have to double check this data, but I believe there was something like 5 in the LIR trial of clinical trial participants.
The data on the two drugs is quite divergent in regard to safety profile. This did come out of left field for most people for NVO so who the heck knows what is in the small print with Byetta. The top line data is not pointing to this generalized class concern. I think more accurately that Lir creates a heightened scrutiny for GLP-1s.
In fact, an AMLN scientific executive was quoted today as stating that the FDA asked for thyroid information on Byetta (and I assume he was speaking of LAR) about a year ago and this executive was puzzled as to why. After the last few days the reason was became crystal clear. It had to do with the scrutiny for LIR, to see if the data on LIR was abberational, or if this might be a class issue. So far the data is pointing to it being a LIR issue and not a drug class issue.
But as always in biotech investing, there is never a moment without worry and fear and doubt and uncertainty so stay tuned.
Tinker
<<<"Exenatide and liraglutide are distinct molecules, so it is not scientifically sound to assume that what is seen with one molecule will automatically be seen with the other," Amylin Vice President Dr. Orville Kolterman said in an interview with The Associated Press.[But the FDA considers c-cell carcinomas a class effect of the long acting GLP-1’s!]>>>
I am not really sure where you are getting this commentary from. In one article the FDA representative was quoting as stating that they looked back at Byetta and saw no signs or indications of any such issue with Byetta.
The animal studies on Byetta LAR are in total contrast to those conducted on liraglutide. Liraglutide showed tumors at every dosage level, in each gender, in each species. Also, you can look at other types of cancers and liraglutide also showed potential signs as well. Where LAR's only c-cell carcinoma in the mouse and rat studies was at the highest dosage level tested, and was considered to be statistically insignificant.
The science is in opposition to the above supposition. Doesn't mean the FDA won't be very suspicious that it might be a drug class problem but the data between Lir and Lar do not back up that supposition.
It is in NVO's interest though, if Lir is to be rejected or delayed for there to be a perception of a drug class link. Lar is a direct threat to not only Lir but also NVO's franchise in diabetes.
Show me the science where the above supposition is supported.
Thanks.
Tinker
ITMN-191's promise were as follows: BID dosing (ie, 2x a day vs. 3 x a day), fewer side effects due to more specific action of the drug vs. telaprevir, and greater efficacy. In addition, Roche has started plans to test ITMN-191 without interferon, beating VRTX to the punch (VRTX's acquisition probably has to do with the fact that companies like Roche and IDIX were not going to partner their polymerase and VRTX needed to keep up).
However, based upon the current treatment paradigm, it remains to be seen as BID dosing and fewer, less severe side effects. The latter is particularly important because if ITMN-191, all things being equal, is equally as effective as telaprevir and boceprevir, the SVR rate will be much higher for ITMN-191 if the side effects are less frequent and less severe due to the intent to treat (ITT) framework used in the trials.
Fewer side effects, less severe side effects, equal efficacy equals greater SVR numbers as there will be fewer dropouts.
Too early to tell if ITMN-191 will have fewer side effects. Its efficacy so far is comparable to telaprevir.
Tinker
ooops - Make that 10-15 years later - EOM
Fair enough Wallstarb, fair enough.
The two most important take aways to me are that ISIS can have its cash tossed into the valuation equation which is unlike most biotechs who burn through their cash too quickly for it to make any sense to put any cash into their marketcap, and second that ISIS is at least largely self-financing for the next several years, if not indefinitely. Which is a very rare biotech. Large secondary offerings may be a thing of the past for ISIS.
Now for the upside, we will have to watch their drug pipeline continue to grow and mature. See if some of the enthusiasm of Worth magazine can really start to play out, just 20-25 years after the fact, as is fitting, and maybe just about right, given the pace of drug development.
Tinker
http://www.bloggingstocks.com/2009/03/20/two-experts-eye-isis-isis-as-biotech-bet/
$175 million is not yet counted on the books. According to these analysts they expect $550 million in cash at end of 2009.
Presently, from the latest from YHOO at end of Q4 2008, $490 million cash, plus $175 million from the IBIX transaction, brings present cash to $665 million less $172 million long-term debt, bring net cash to just shy of $500 million, with ISIS, and at least by these analysts, and by company projections at their Q4 conference call, ISIS is not anticipating any material net cash burn for all of 2009.
Which, unlike say VRTX, who may have more pure cash, that cash is illusionary as VRTX will burn through it in no time. ISIS is now at the stage where it is starting to keep and even starting building its cash without dilutive secondaries or other debt offerings.
It is a rarity. I am high on mipomersen, and a phase I type II diabetes drug that is not yet appreciated (not that it should be quite yet at that early stage). ISIS also has an enormous pipeline of partnered and to soon be partnered drugs in mid and late stage development. Somewhat like what MEDX and ABGX use to be like but with more substance to it.
If one wants to hold to the analogy, second generation antisense drugs are a new drug platform that ISIS dominates just as MEDX and ABGX dominated with their transgenic mice, except that ISIS has more meat to it, at least that is my sense of it.
In any event, it is a biotech that I have grown interested in. The market once thought very big things about it as evidenced by a 1996 cover story on Worth magazine proclaiming "the next Microsoft" which they indicated was ISIS. The problem was that ISIS's first generation antisense technology did not hold up very well. The drug would not stay together long enough to reach its target, although the underlying foundation of the technology was otherwise sound.
Their second generation drugs seem to be living more up to the promise as mipomersen demonstrates along with several other ISIS drugs are now demonstrating.
Anyway, I like the story, ISIS has paid its dues to develop and grow this technology, and the next several years look exciting to me for the company. I therefore bought some shares.
I don't know if anyone else has had a chance to follow ISIS or has any comments, but on topic with this thread, for a biotech of this size, with a pipeline as large as ISIS has, that is a lot of cash and that is a very small cash burn projected going forward. And all this before ISIS even commercializes a single commercially successful drug (yes they have one drug they did commercialize from its first generation technology, but it was not a commercial success).
Tinker
You left out perhaps the most cash rich small biotech of all (at least near the top) and that would be ISIS. I will have to go back and look at the latest statements as all the proceeds from the sale of their IBIS product are not yet accounted for on the books, but I believe that ISIS, net of long-term debt, will have a cash balance of $500 million or more. ISIS is also looking to be perhaps moving to sustainably profitable, and at least to minimal cash burn (for a developmental biotech that is anyways).
Anyone have an opinion on this second generation antisense? Their lead anti-cholesterol drug clearly works, and works better then anything else out there. The FDA put up an outcome based hurdle for wider adoption that did not use to exist, but the EU has yet to put up such a hurdle. $1.9 billion buy-in price by Genzyme speaks at least to its full market potential, as GENZ still thinks it would be profitable even after it pays all the milestones, its share of developmental costs, and pays its sliding rate 30-50% split with ISIS on this particular drug.
Anyways, ISIS is a cash rich biotech with a low to vastly diminishing cash burn.
Tinker
Here I am thinking that Biib's presentation and the news on tysabri about neurologist confidence increasing, the lower PML rate articulated, and the entire facts/spin, however you want to phrase BIIB's presentation on tysabri, along with the recent presentations in other forums on alzheimer, were all working to bring ELN shares back into favor.
Turns out, at least the most likely explanation for recent the share rise, is new rumors of ELN being bought out at 8 euros by a Danish pharma company Lundbeck.
Deja vu to about 2-3 months ago, but then I believe Pfizer was the rumored bidder.
Tinker
<<<A possible reason they may not: Doctors would prescribe the regime for treatment-naive patients, already knowing the efficacy blasts SoC.>>>
Which is no reason not to approve the drug for second line. What you are going to end up having is more patients in need of second line treatment, that would not have needed second line treatment, had they been treated with telaprevir to begin with.
This is one of those logically absurd situations that screams out for the FDA sticking to its mandate of (1) does it work as indicated, (2) is it reasonably safe. Yes, yes, and we can say both with a very high degree of confidence in both the first and second line setting. This is not a provenge where the efficacy data is ambiguous. This is an in your face, the drug works, the drug works very well, the drug is reasonably safe, so lets get it out there and let the phase III continue as a de-facto phase IV post marketing study.
Makes too much sense, I'm sure this to be the inevitable result. It is situations like this where the FDA has to lighten up, and free up some resources to deal with the more problematic issues for more problematic drugs.
The FDA of the last two years however will not allow a filing on the Prove 3. The FDA prior to this, okay maybe going back a little further to pre-Vioxx, would have allowed just this result.
The good thing with VRTX is even if you don't feel lucky, you may just have to wait another year to get satisfaction, and being satisfied earlier would be a nice upside surprise.
I see peak telaprevir sales of up to $3.5 billion a year. I would put the range on a low end of $1.5 billion to a high end of $3.5 billion. VRTX obviously feels the threat of future generations of interferon free treatment options such as Roche is attempting with ITMN-191. VRTX felt it strongly enough that they went out and made a speculative acquisition to acquire their own potential non-interferon cocktail drug additions that may or may not actually work as they would like. Indicating that VRTX does not presently have such a capacity in house either. So there is risk down the road, maybe 5 years or so with this new cocktail. But from here to there at 6x $1.5 billion you get about a double from here. At 6x $3.5 billion a triple to quadruple or thereabouts. Good upside, limited downside (assuming some unforseen catastrophe does not strike telaprevir). In biotech, that is rather "risk-adverse" as things go.
No, it does not presently have the potential upside of say a MNTA. But MNTA is a crapshoot in regard to how many generics are approved. We really have no way of knowing. We just hope. VRTX does not have any large follow-up programs yet. It has a drug that has performed well in a very limited market with cystic fibrosis, that maybe can be expanded into a larger market. Whereas MNTA does have other potential blockbusters at present. But that would be my only concern for VRTX at present. But from here to there is a long way.
Anyways, that is my take on the present issue. The old FDA approves it second line and uses the on-going phase III as essentially a post-marketing study. The new FDA leans towards waiting for all the data to come in, even if we pretty much know what it is.
Did I forget to mention boceprevir? Sorry. Schering (who just bought them, sorry I forgot) is a much better marketing and sales company, they can try to bundle boceprevir, play with reimbursements etc to take marketshare, but head to head, on an even playing field, even though the data is arguably very similar, I just don't see boceprevir being anything but a distant #2, absent some very creative and seriously successful marketing and sales campaign that deals with issues that get around the head to head issues, and plays more on reimbursement and bundling issues.
Anyone feel any different about this?
Tinker
<<<"accelerate access to make affordable generic biologic drugs available through the establishment of a working regulatory, scientific and legal pathway.">>>
This one has me puzzled. MNTA is a pure play on this very issue. Yet MNTA stock has been anything but a pillar since this proposal became public.
Anyone have any insight as to why?
It may be totally unrelated, perhaps to information leaking fro the FDA on the current outstanding ANDA. Who the heck knows. But absent this, this is shaping up to play into MNTA's hands long-term, unless people are reading between the lines, and like much in the Obama budget, it is the details and not the platitudes that count in regard.
Tinker
I used yesterday's stock crash to load up on MNTA like I should have done last year when it crashed but was otherwise pre-occupied. Buy this morning, come back after lunch, and dang nab it! Up 13% as I speak! I guess it must be the label expansion for Copaxone.
I do have to say that it is much more comfortable owning an interest in the success of glatiramer acetate then it is in owning an interest in tysabri. I still do not think much of copaxone as a drug, but as a marketing success it lives up to its billing. Clearly those who make a living prescribing it and paying for it do think a lot of it.
I assume from the stock price reaction that this label expansion is materially significant to copaxone's already substantial market.
Tinker
http://uk.reuters.com/article/healthNewsMolt/idUKTRE5216V020090302
Spoke about this FDA issue before with Dew. FDA delays drug that is already given out on a compassionate use basis and utilized in 40 other countries.
I cannot say I know the full details here, but the FDA is saying that the drug is not identical. From the discussion it does not sound like there can be too much of a discernible difference, and the drug will continue to go to patients on a compassionate use only basis anyways.
Just more evidence of the current FDAs stance on drug approval.
I am looking at a drug like exantide LAR from Amlyn. This is a drug that works, works very well, with no evidence at all of a pancreatitis link. All it is is rumor and innuendo, yet given the current FDA stance, how many here think the FDA will approve LAR within the next year?
I welcome anyone's well thought out opinion. A few months ago I thought it was a no brainer. Now though I am leaning more towards the idea that the FDA will require any new drug to disprove any perceived material side effect, even if there is no other evidence out there that it has such an issue other then some mass media rumors and whispers.
Hands, who thinks LAR gets approved within the next year? I cannot see byetta getting a black label, and there should not be any problem with the monotherapy label for byetta, but dang, with the current FDA that is some real risky money betting on approvals like this that had to be considered near no-brainers for eventual approval.
Tinker
<<<Considering the world wide situation right now do you foresee any ramifications when our government tries to borrow around $3 to $5 Trillion dollars of the next two years?
Interest, Inflation, Weak Currency are all possible problems. Also keep in mind the world just might say NO!>>.
I did write a big long and detailed response, but thought this not the forum. Suffice to say, there is some big problems here. The good side is all that money has to go somewhere, and right now it is going under the pillow. It comes out from under the pillow, and boooommmm! Perhaps like 1999/2000 again if we ever get our optimism back.
When this is done however I anticipate, for a variety of factors, a 20% reduction in our real standards of living after the devaluation of our currency, the flight of capital to more tax friendly, entrepreneurial friendly venues, and the higher cost of energy due to carbon tax issues, and unemployment that is stuck back in the levels of 6-8% in perpetuity. I remember that full employment in the mid-80s was considered to be 6%, now we consider 6% unemployment to be very high unemployment. Not anymore. And the risk of stagflation...if one is to follow the fiscal and tax policies of the 1970s, one can expect a return to the 1970s. If the rest of the world won't buy our debt, we will monetize our debt. We print the money anyways.
Also, one has to wonder how stupid it is to spend so much money so inefficiently. Not one person can make the argument that this money will have any measure of economic efficiency behind it. And there is certainly no incentive in this money to cause private enterprise to increase their efficiency.
Anyways, don't want to go too long on this topic on this forum.
Regardless, biotechs, if they get their drugs approved, are still one of the few investment vehicles that can still be a systematic homerun in this environment. Know the drugs you are buying, wait for the huge volatility to kill the stock, load up, ride the waves of volatility, sell when all the good news is priced in. Still gotta pay for drugs, well, urgghh, unless the FDA continues its present stance of no drug is ever too safe or efficacious enough stance. Then we can also see the center of drug creation in the world move to Europe and Asia (if that is not already happening).
Tinker
<<<I was saying that it's not all about one man in today's complex world. Many IHUB posters seem convinced that it is.
It took a long time to construct this complex crisis in which we find ourselves, it can't be solved in a month. At least I'm willing to give this administration a fair chance.>>>
I agree. What has me troubled are the things that are being done. there is nothing on the supply side to encourage production, even in the housing issue, Obama's plan calls for reducing the deductibility of home mortgages for those who make more than $250K. Just one example of multiple contrary policies.
I actually ignore what comes out of Washington as for the most part we tend to adjust and get over it all. But day after day it is something new that just makes one not want to invest. it is turning into a culture of malaise as well. This has to bottom out somewhere. I am looking for that point as I am not seeing it in any policy initiatives, and I'm not seeing it out of any rhetoric from Washington. Where else do we turn to try to ascertain this "malaise" or lack of confidence bottoming?
Until it does I would not mind seeing a company like VRTX fall back into the teens, or a copany like Genzyme or ISIS moving to attractive levels. If nothing is wrong with MNTA what is it with that 20% crash today.
All in all, it takes a hell of a lot to move me to cash. Been through multiple crashes and too stupid to move to cash. What I am seeing now is the first incident where I've actually moved to cash. And that is reflected in the record savings rate reported today, and what I am seeing as this culture of malaise which is much more then the financial crisis, or at least has grown into much more than this. That is at least my perception. As such, the use of the bully pulpit and policy initiatives is a powerful force to attempt to assert some optimism and change the culture back to we can instead of we can't "help us".
Hoping others out there can ascertain how we find the bottom of this psychological malaise, loss of confidence, so we can start putting money back to work. I may perhaps be too close to it now to see through it. But I presently do not see anything coming from Washington to remedy the situation either financially or culturally. Just the opposite. And that is where my malaise has started coming from and I'd like to find something to give me a bit of optimism.
Tinker
<<<Exactly. The entire concept of "root causes" seems to be conveniently escaping many people, as if this was a totally unpredictable astronomical phenomenon akin to a giant asteroid hitting Earth!
Or better yet: one evil, all-controlling "Other" has suddenly seized control of the universe and he's the one who sent this asteroid crashing down on our poor, fiscally responsible, undeserving heads.>>>
The financial crisis will in the end take care of itself one way or another. It will crash down, reach bottom, etc., and is in the process of doing that.
The real issue regarding this crisis of confidence is what happens thereafter? As an investor I am investing in the future. What exactly from a forward looking basis is happening to give on confidence in the future?
As an example, today, with the market crashing, Obama's answer was "we must reform healthcare" to help fix the economy. Admittedly healthcare needs some fixing and I don't wish to debate the merits of it. But this is clearly not a solution to provide confidence in the future. Neither are higher taxes, neither is the carbon tax, neither are annual deficits approach $2 billion per year (when one looks at the assumptions one understands that the projected deficits in the budget are understated).
Bush suck! I agree. So what. Bush is out of office.
What is being done to reinstate confidence in the markets, and what should we be looking for to ascertain that this crisis of confidence is coming to some sort of crescendo? Is there something I'm missing in the Obama proposals that should make me more confident?
That is the issue that I see, and it is even now tearing down the once recession resistant biotech and pharmaceutical sector as well.
Tinker
<<<Today may be the proverbial day of capitulation when hordes of people decide they don’t want to own any stocks and sell everything.>>>
I do not think so. Looking at the macro numbers today. Consumer spending was slightly up, but savings rates hit all time highs.
What this means is that there is an utter lack of confidence in the market. Instead of putting money to work, people are putting money under their bed, despite deciding to spend some more money.
this lack of confidence is forward looking. When does one get confidence to invest back in the market? Obama is giving us none. He has promised us a substantial capital gain and income tax increase. He gave us absolutely nothing as an incentive in the "stimulus" bill or in the 2010 budget. We are looking at nearly $2 trillion a year in deficits per year. Producers in the world are bad mouthed, and the entrepreneurial class is shamed in his rhetoric. He for example says he wants to increase home sales, proposes a $250 billion + program on this issue, and then proposes to cut the deductibility of interest for upper income taxpayers, who just happen to buy the majority of homes (on a dollar basis).
I am not making this political, but I do challenge someone to come forward and let us know what is being put forward to reduce this CRISIS OF CONFIDENCE?
Consumers decide to spend more, but at the same time they also decide to keep their money under their pillows. All this money sitting on the sideline, so many stocks on "sale", what else is it at this point in time but a crisis of confidence.
If so, let me know what is being done to resolve this issue? We will not bottom until a complete wipeout with this crisis of confidence IMO. A one day sell off, is likely to be followed by a small rebound and a new wipeout until this crisis of confidence is resolved.
Tinker
<<<SOMX was down 80% today on the FDA rejection of Silenor (low-dose doxepin) for insomnia. As mentioned in #msg-35915183, this is no great loss for patients. However, the rejection is the best example I know of the FDA’s bunker-down mindset on drug approvals.>>>
I do not think that we are going to see any new sleep inducing drugs on the market for years to come, if ever. I am still pissed about indiplon. I did not own any NBIX stock, I had no financial interest in it, but my wife has the very problem this drug was designed to treat, and did treat, without all the other side effects of the other drugs that one could use. Drowsiness, rebound effect, etc. That is getting back to sleep at 3 a.m. type insomnia. But no, FDA denies people a drug like this that clearly would enhance not just her quality of life but mine as well (as grouchiness is a side effect of sleeplessness).
Hmm, I wonder, what is the bigger health hazard, indiplon. or someone driving a car, in a grouchy move, after having a fight with their spouse, because they were grouchy, etc., go down the list of all the reprecussions of lost sleep, etc. There is no doubt that indiplon is the safer alternative.
FDA killed indiplon off like the Japanese kill imported lettuse off at the port.
It is not going to get any better. The government's new focus on cost is going to create a lot of pretextual reasons for delaying or denying drug approvals in the U.S. I do believe, and I believe that Dew you linked to such an article a while back, that it will be the EU and Asia where new and better drugs will be targeted, and we will have to travel abroad or illegally import said drugs if we want to improve our lot in life from such drugs.
I thought the FDA stuck their neck out on tysabri and did the right thing. That appears to have been the last decision based upon science and cost/benefit analysis that the FDA has made.
If there is a drug, it had dang well better address a clear unmet need, with overwhelming efficacy superior to the existing standard of care, otherwise, even a perfectly safe drug is not likely to make it to market. We often use the example of aspirin, but lets face it, aspirin would not be approved for use today for any condition. It is absurd, and it will get worse, not better going forward with marginal cost for benefit becoming an implicit function of the FDA's judgments as well.
Tinker
Thanks Dew. Very interesting. That would mean that tysabri for example, if they move to the high-titre production method, would also have similar scrutiny (were ELN and BIIB to ever get so lucky to actually need to increase production in this manner).
Tinker
Dew,
I have a question. With the Genzyme thing, maybe I missed something, but if the FDA is taking such a strict stand that the same drug, produced by the same company, with the same process, but only at a different facility is treated as a "biosimilar" and not a "biogeneric" then what hope does such a drug, even if identical in every way hope to have when it is manufactured not only in a different facility, but also by a different company to be a true biogeneric?
Thanks.
Tinker
This blood washing is old news. It was something we all knew worked but Biogen had to pay to get a study done so they could get it published in a journal and use it for marketing purposes.
It does make a difference in the real world as neurologists and patients can now point to the same thing that investors have been pointing to, and whether justified or not, take comfort that a peer reviewed journal says it is so. It is how the urban myths of medicine spread and become reality.
So a positive for ELN and Biogen, although the IRIS issue still comes into play.
But in the end 3 out of 50,000 patients who have taken tysabri have died. One can cull that further to how long they've been on it, etc., but all 3 have been either combo or had a immune modifying drug treatment, an any statitical analysis you take finds the PML risk result at much less than 1 in 1000 and the death chances even less then that.
So if the risk of tysabri can be overblown, why not allow the mitigating factors to be overblown as well as the information get disseminated.
Tinker
I thought I was hallucinating when I saw that press release.
P value of .501!!! That would be grounds for summary judgment at trial as the chances of the results be do to something other than random chance are less than 50/50!
Then Capacity 2 comes through with a p value of .001. 1 in 1000!
Hold on here. These two clinical trials were identical except as to location of the testing centers.
What do we do. Say we have confidence in our clinical trial system but ignore the result that says that the minor improvement results seen were most likely by random chance but take the word of the clinical trial that says otherwise?
I actually liked the DNDN data better then this. At least they had multiple consistent clinical trial data.
I have no idea how the FDA handles this one. It also brings to the front how it appears to be more of a game when you try to measure small clinical benefit and dress it up with the rigor of statistics.
Tinker
<<<NOTHING that I have seen suggests that the PML cases are "manageable" as I would use that word. I would use it to signify that with intervention serious injury to the patient was avoided. I do not think that has been the case in any of the PML cases. Perhaps, I have that wrong. If so I would be interested to read something that would correct my perception that serious permanent injury is probably/certain for these PML cases.>>>
No, the term manageable is the correct term. I have not saved or indexed links to the issue and I do not have time to go dig up research on the issue, but that is indeed the proper term.
PML in the AIDS setting is mostly fatal, although there are many incidents of PML in AIDS reversing itself when the patients immune system is strengthened with treatments for AIDS. It is all through the literature.
Drug induced PML is simpler to treat, because unlike the AIDS patient, drug induced PML can be quickly reversed (relatively speaking) and the immune system takes over again.
The patient that is recovering in Europe is one such example. There is literature out there that suggests just such manageability has indeed occurred with this patient. I have read one source that indicates the patient may have suffered some minor disability (forget what it was, but it was minor in the scheme of things) and all other sources have pointed to a near complete recovery.
The present patient in the U.S. appears to be similarly situated in that the PML outbreak was discovered early and aggressive intervention to flush tysabri from the system was given (aplasmapheresis) and use of mefloquine appears to be the present treatment protocol. Given how rare PML has been with tysabri, there has not been a lot of opportunity to test this protocol, but it worked in the first patient, and appears (from the initial description) to be working with this latest patient.
The patient who did not do so well was diagnosed late and misdiagnosed as his doctor thought he suffered from a stroke, was maintained on tysabri 2 months after PML evidenced itself, and was actually given heavy steroid treatments to boot after PML manifested itself. This patient could not have been more mismanaged had mismanagement been planned ahead of time. To make matters worse, this patient had been long-term on an immune depressing agent. There appears to have been a flushing period (6 months or so from use of that drug, but this patients immune system, to make matters worse, may never have been normal to begin with).
In any event, the numbers are too small (as there have only been 3 patients treated with this protocol, and now only 2 of them have been quickly identified and properly treated) but this treatment protocol has created comfort and the buzz of "manageability" amongst neurologists, and investment analysts.
At least 2 analysts have stated similar things in their reports today on commenting on this 3rd incident. Comfort level amongst neurologists has been widely reported both because tysabri has been less dangerous than the label, and the treatment protocol appeared to them to be reasonable, albeit, still needed more proof.
In any event, time will tell as it usually does. This 3rd patient may have a similar recovery as the first European patient. Making it 2 for 2 with this new protocol for patients identified early and then aggressively treated.
Without doubt that would create increased buzz and confidence in the neurologically community (whether justified or not), as it will probably magnify in neurologists minds that PML can be reversed and managed utilizing this protocol. Yes, just 2 cases, but the 1st case alone created a closely watched buzz.
Tysabri is just that much more efficacious then any other MS drug on the market. Patients taking tysabri have failed the CRABS, or are aware of the cumulative damage caused by MS that the CRABS do not address, and there are no real alternatives. They weigh this against the much smaller risk of PML. As such, patients and neurologists are not waiting years for clinical proof of this PML protocol. They are taking it case by case, and 2 for 2 would be very substantial, in my opinion, in this market. At some point it may just become part of using the drug, like the dangerous side effects of many effective drugs used today.
But lets see how this current patient does. Her status will be closely watched over the coming weeks and months without question. But there is literature out there on the subject. I was quite surprised myself to find that it is far from unknown for even an AIDS induced PML case to be reversed, at least as long as the patients immune system could be reconstituted.
Which is why I think that PML is thought to be an irrevocable disease even if first arrested. In AIDS, the immune system eventually breaks down and PML reasserts itself. In drug induced PML the healthy immune system permanently reasserts itself.
Or so is the present working hypothesis that is being tested cases by case in the real world because taking tysabri is that valuable to these patients.
Tinker
Look at ELN's chart since 2000. It makes the Tour de France look like a race conducted in a swimming pool in regard to flatness.
ELN has risen to very high levels on multiple occasions, just off the top of my head 4x in the last 8 years. It first hit $60 or something then crashed on AN-1792 withdrawal in phase III, then rose again on tysabri, only to crash on business debt and organization issues (ie,. the Enron of the biotech world), it then rose again to high levels when it looked certain tysabri would be approved, it then crashed again when tysabri was removed from the market, it then rose high again when tysabri was put back on the market, rising even higher in anticipation of Bap, and it has crashed again.
The reason it may not be so irrational to have some emotional attachment to the drug is because the drug really works, it works extremely well, to many it really is a miracle drug, and there is no true competitive drug approved on market that comes even close to it as present. Looking at the drugs coming up the pipeline, fingolimod will not as efficacious, but it will be a pill. However, it has some serious adverse event issues to deal with. Campath, we discussed recently may or not demonstrate equal or better efficacy (and if so, it may be in a more limited patient set, and the duration of benefit may not be enduring) and has its own very serious adverse event issues.
If this PML case turns out to be manageable as was one of the two cases in Europe (and the one patient in Europe that is having problems was treated in a manner that would be textbook for the worse possible way to treat such a patient and hope for a positive outcome) then suddenly tysabri's primary adverse event issue has become a known and manageable issue, that will materially decrease its risk profile. By the time competitive drugs come to market, 10s of thousands will have been on tysabri for years, with the PML issue now manageable, no other material (marketing wise) adverse events, against new comers to market with unresolved and serious adverse events that may or may not stack up to tysabri efficacy wise, with little market experience which will be stacked up against large numbers of patients with 5-7 years of history on the drug, demonstrating what will probably ever increasing efficacy over time vs. CRABS as MS is progressive, and as one neurologist explained it is like compound interest, the difference gets bigger the further down the road you go.
Then again desperate patients may decide that they are more afraid of a less than 1 in 1000 risk of PML, that appears very likely to be a manageable condition for most, then they are about the inevitable decline that MS will produce for them.
That is the choice from the patient perspective. Over a period of 5 yeard 50% or more patients on CRABS will fail on their treatment.
In any event, that is the rational argument for the confidence in the product long-term and what some would call an emotional attachment to the product.
Put that in combination with the world's leading alzheimer pipeline, including 2 drugs now in phase III, and multiple drugs in phase II, and you get soem very rational attachment to Elan. Ie, high risk and probably the most volatile stock on the stock market, and perhaps that has ever been on the stock market.
Losing 85% of value for ELN is an occurrence that occurs practically every 18 months, if not with greater frequency.
Of course, this time after the hair cut, the hair may not grow back. Tysabri may really die this time around. The alzheimer program may utterly strike out, and there could be an awful lot of emotionally attached Elan investors who do become bagholders this time around for good.
Up until now however, the only bagholder Elan shareholders have been those that sold out at the bottom following such incidents like this PML incident that has been far over done by the market.
Tinker
P.S. Again, I am just setting out the rational case for attachment, based upon history, and based upon the present potential long-term strength of tysabri and the pipeline. Elan has frequently been here before, and this time may or may not be the final death knell. Time will tell.
But also consider, as I think I addressed above, if this PML case becomes manageable as well (and my understanding is that this patient is not hospitalized but being treated by her physician similar to the less sick patient in Europe) then WHAT DOES THAT DO LONG-TERM FOR THE PML CONCERN? And if that does materially reduce the fear revolving around the PML scare, then does that not make tysabri the safest of any disease modifying MS drug that is in the relevant universe for years and years to come?
All conjecture of course, but that is what Elan investors are presently considering along with Elan's unprecedently volatile stock history - at least for the last 8 years.
Question on MDVN.
If Dimebon turns patients blue, does this mean that in the clinical trial that placebo patients will need to be given placebo pills that will also make them turn blue?
If not, then how do you run a legitimate placebo arm?
Tinker
<<<However, to suggest as you did that business writers as a whole have become the pawns of naked shortsellers is carrying healthy skepticism into the realm of InvestorVillage paranoia, IMO.>>>
Dew point taken. Clearly, most business journalists are not such pawns. But I will say that there are selected journalists who clearly are. Going back to Rambus when the leading industry journalist (whose name I forget now) actually admitted to being on the payroll of Micron et al. He was the sought after first opinion on the DRAM industry. Admittedly, I made a lot of money as this journalist helped push the share price down despite the objective evidence in front of us.
Similarly, there are those in the biotech press. Primarily however, I believe it is just lazy journalists. I've been a journalist, and it is very tempting to take stories that are easy to write, without much research, when supposes objective experts in the field come to you with story ideas and quotations.
Here you have doctors working on campath that I am sure were put up by Bayer (tacitly that is) or that intern who I am sure was put up (tacitly again) by Schering Plough. I find it all over the place, and they seem to focus primarily on pieces that make the Internet for quick hitting effect.
Some are more blatant than others, like Teva's use of a journal to put out there that tysabri was the equivalent of drug induced AIDS. Others are just a combination of lazy journalists, and journalists who are tacitly cooperating with industry leading companies, and sometimes both.
In this case, the article itself appears to be so misleading that it is worthless. I think we need to read the NEJM article to know for sure as the information that has been presented by the actual NEJM article on campath describes a drug that is totally divorced from the one presented in the article, much less a drug that can be said to be clearly more effective and safer than tysabri.
It is part of the business I guess. There is money to be made from such articles for investors, and small biotech companies are not real good at utilizing such "marketing" channels, but larger companies appear to be very good at it for whatever reason.
Tinker
<<<I would submit that your views have been colored by spending too much time on InvestorVillage.>>>
Dew, I am amazed that you find nothing wrong with the blatant statement, leaving out all that material information about safety issues and duration of efficacy, and that the drug appears to work well only in very early stage MS, that campath is more effective and safer than tysabri.
That is not a statement that you find objectionable both scientifically, ethically, and as a marketing message that I'm sure if the FDA cared they would find it an illegal marketing statement as well?
In regard to the Schering article that we discussed about 6 months ago regarding telaprevir quoting the "intern" you found that a valid and reliable source in regard to how desperate and dangerous telaprevir was in comparison to Schering's drug?
I guess I might as well just leave my political reading to the Daily Kos, or just to the Wall Street Journal. No sense trying to get the objective truth on the matter if that is the case.
Tinker
<<<"The researchers did not compare the drug directly to Tysabri but based on existing data said they believe alemtuzumab is a more effective and safer treatment."
I suppose the NEJM authors compared data from Tysabri's
trials (such as SENTINEL) to Campath's and stated the above. We know the limitation of comparing different trials but I think we can agree that Campath appears to be a potent agent for MS and the issue is side effects. I think that if there's even one ITP related death in Campath's Phase III trials, it would end its chance to compete in the MS market.>>>
A balanced article? Okay, if you ignore all scientific method, and avoid the fact that the statement is put out their purposely as a marketing statement that the drug is better than tysabri.
Campath has some very good efficacy, at least in the context that Bayer lets us know about. But what about the limited duration of efficacy that was reported in the NEJM? One might have thought that important. What about the need to catch the very early stage of MS for efficacy? That would have been very valuable to know. Heck, since MS is generally such a slow moving disease, it is quite possible that much of the great efficacy is simply due to the natural course of MS taking its time to move forward. Although I doubt that is the case, it is possible.
The authors also very much downplay the adverse events.
This might as well have been the New York Times discussing Palin's wardrobe (no political opinion meant by this, just explaining what the biasness of the report appears to me).
If the article had stuck to the great results of campath, then dang, more power to Bayer for getting some good PR interest in the drug. But push it so far as to say it is better than tysabri in such a clear cut statement, and fail to articulate those extremely material missing bits of information, then you might as well describe tysabri as an utterly and completely safe drug, omitting of course people on combination treatment or with deprived immune system in making that statement.
It reminds me very much of Schering Ploughs "objective" news story that Dew posted about 6 months ago or so which cited an "internist" that telaprevir needed to back and re-do the phase II and making it sound dire for telaprevir. No, that also was nothing but a fluff piece.
Good, unbiased business journalism is tough to find these days, and the naked short issues and the rise of hedge funds has made it even harder.
Tinker
In regard to the Campath article. This was posted in response on the Investor Village board. It is taken from the NEJM article and contrasts strongly with the positive words from the Reuters article which has to be considered, at least partially, a fluff piece. Particularly the portion of that article that states "although no clinical data to support it, Campath is more effective, and safer than tysabri".
In some situations campath has good efficacy that may or not be greater than tysabri, although the duration of this efficacy is in dispute. But campath is most definitely not safer than tysabri. But it is a Reuters piece, so such fluff is to be expected.
In any event, the contrast between the article and what was actually stated in the NEJM article appears to be miles apart (again, as is not unusual for a Reuters piece, and in particular this author (isn't she the same author who said that 35,000 patients was a drop off from 31,000 patients last quarter)?
http://www.investorvillage.com/smbd.asp?mb=160&mn=295128&pt=msg&mid=5944430
Tinker