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  • Arena's Weight Loss Drug Faces Relatively Easy Path to Approval [View article]
    Micheal, it is obviously not as black and white as you state.
    People say "25X dose is never acheived" and it "meets the guidelines" and that the wieght loss "met the FDA's criteria". But people forget that the FDA is an ever-changing regulatory agency and can basically do what the hell they want. What is clear is that the FDA is extremely risk-averse these days, and especially critical of new diet drugs and existing ones it has already approved. So the old rules don't apply.
    What remains constant about the FDA is that they will approve a drug if there is sufficient data to establish a risk-benefit profile. If this can be established, and the FDA agrees the benefit outwieghs the risks, they approve the drug. Lorcaserin is too light on the benefit side and too heavy on the risk side, so the balance is clearly not there. I am not sure how they could shift this balance in either direction. So you can hide behind implied FDA "policy" about safety and efficacy standards all you want, but the fact is there is no strict policy- just opinion. Every NDA is judged in an ever changing context of FDA opinion. The FDA has made their opinion loud and clear- will not approve new diet drugs that aren't completely safe miracle benefit pills- and lorc is definetely not that.

    As far as the rat data, all the toxicologists are right- these exposure levels have nothing to do with reasonable human multiples. But the toxicologists are forgetting their pharmacology and biology:
    1. Pharmacology 101: Exposure-AUC= dose over time. A small dose over a long time has the same exposure as a big dose over a small time. So overdosed rats in a short study should emulate low dosed rats over a long time.
    2. Biology 101: Cancer takes 10 or more years to develop in humans as a result of multiple mutations and epigentic changes which are influenced by extrinsic non-genetic factors that promote the cancer. It will never show up in a 2 year clinical trial (if it does- look out!) and if they can get it to show up in an experimental model like rats it presents a huge risk that it will show up in humans in 10 years. Especially in a drug that is to be used chronically, like a diet pill.

    So although black-and-white toxicology arguments hold ground, more "fuzzy" pharmacology and biology arguments far outwiegh them. Again, there is nothing ARNA can do to convince the FDA that these other arguments are not valid. All ARNA can potentially do is convince them that there is a large enough benefit to outwiegh this potential risk- and they cannot do that either. The BLOOM-DM study is not likely to show any additional benefit (as diabetics suffer with wieght gain) and certainly not enough benefit to outwiegh the "muddy" cancer risk (and other unkonwn potential risks). That is the only thing black and white about this situation.
    Oct 26 12:33 PM | Likes Like |Link to Comment
  • Arena's Weight Loss Drug Faces Relatively Easy Path to Approval [View article]
    The Meridia For example, in the SEQUAL study:
    Categorical Weight Loss (ITT-LOCF)

    Top-dose
    79%* of patients lost 5%
    54%* of patients lost 10%
    32%* of patients lost 15%

    Mid-dose
    75%* of patients lost 5%
    50%* of patients lost 10%
    24%* of patients lost 15%

    Placebo
    30% of patients lost 5%
    12% of patients lost 10%
    7% of patients lost 15%

    In the Qnexa trial, the placebo lost an average of 2.5%. This is similar to the Meridia, and Xenical trials, where placebo lost about 3% also.
    The primary difference is that Qnexa was used in obese patients (BMI of 36); Meridia also (BMI of 34); Xenical (greater than 30). In the case of lorcaserin, the accepted patients with a BM1 as low as 27. If more overwieght patients can lose more percent body weight easier, this could explain the difference.
    Oct 26 10:54 AM | Likes Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    I agree with your thoughts and that is my strategy as well. But I definitely am holding some for a "surprise" approval.
    Oct 26 08:52 AM | Likes Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    As we all know, what is holding BIOD back is the data issue. Even if the FDA buys their arguments, the thoughts are that the whole NDA is "sloppy" and the FDA will issue a CRL asking for more data or clarification about several issues. This may be the case, but a CRL issued with easily fixed problems would actually be good news here.
    As far as safety, the last fast insulin approved was Aprida, through the more difficult 505b1 mechanism. Their study had about 750 patients in each arm compared to BIODs 300ish patients. The NDA was accepted, and during the review process things went well but the FDA had alot of questions about hypoglycemia, and only one question about the HbA1c level data. Aprida is NDA 21-629. Correspondence during FDA evaluation can be found here:
    www.accessdata.fda.gov...
    In particular, see pages 15-16 46-47.
    Also see page 46, comment 1:
    Aprida study 3001 had problems with the HbA1c levels- what they called an "imbalance" at baseline. The FDA asked for an explanation of the data.
    Also see page 18- Aprida had twice as many hypoglycemia events as control!

    My point here is that Aprida was approved even in the face of these potential safety and even data issues. In contrast, Linjenta reduced hypoglycemia...so compared to Aprida the FDA should
    be comforted. The FDA is even more agressive about safety now, but I cannot think of any other safety issues other than hypoglycemia, which are common to all insulins.
    The EDTA stuff is absolute nonsense.
    Oct 25 10:58 PM | 2 Likes Like |Link to Comment
  • Arena's Weight Loss Drug Faces Relatively Easy Path to Approval [View article]
    Michael, I believe you are missing the forest through the trees.
    The rat cancer "problem" wont go away, no matter how close they analyze the results. Fortunately, the FDA understands that cancer in rats (risk) has its caveats and can be overlooked if there is sufficient benefit (reward). Unfortunately, Lorc could not demonstrate any benefit significant enough to overlook the rat "problem". Nor will it ever be able to- the BLOOM-DM study is likely to be worse than the BLOSSOM/BLOOM studies as its population is harder to treat.
    So it is a dead end for Lorc unless they can prove benefit worth the risk....and thousands more patients and hundreds more rats just won't do it. If Lorc showed the efficacy of Qnexa it might have a fighting chance.
    Oct 25 10:51 PM | 1 Like Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    "Insulin antibodies: mean endpoint (LOCF) change from baseline was -0.82 U/mLin the Viaject group and -0.30 U/mLin the RHI group"

    files.shareholder.com/...
    Oct 25 08:26 PM | Likes Like |Link to Comment
  • Vivus, Arena and Orexigen Investors All Worried About Qnexa FDA Panel Review [View article]
    When I wrote this article I said:
    "However, a little further out I would expect ARNA not to recover (due to the safety concerns) but a rally in OREX could occur"
    Right now, almost two months later, after the dust has settled, ARNA is $1.50 and OREX is almost $6.
    Oct 23 10:42 AM | 1 Like Like |Link to Comment
  • Avanir Pharma's Pending FDA Approval: The Upside Potential [View article]
    The news I missed is that the FDA voted to keep dextromethorphan on the market...they were proposing to pull it- I thought it was a done deal, but I was wrong. The fact that it went on an intensive re-review after being on the market for a decade or more demonstrates that it has risks. Increasing the exposure by preventing its metabolism will surely increase the risk.
    Oct 23 10:22 AM | Likes Like |Link to Comment
  • Avanir Pharma's Pending FDA Approval: The Upside Potential [View article]
    If there is a CRL don't think it will affect AVNR stock price too much anyway. They have revenue, although not profitable. An approval would help them be profitable, and that may boost the stock price. Given the current price action, the risk/reward here may in fact be a long position, if you think it has a decent shot at approval. I don't, but frankly the decision isnt pivotal enough to be exciting!
    Oct 22 01:48 PM | Likes Like |Link to Comment
  • Avanir Pharma's Pending FDA Approval: The Upside Potential [View article]
    Unfortunately AVNR didnt run up sufficiently to make buying put options worthwhile, given the premium. I think it will be rejected for many reasons, with the primary being the small follow up trial size and the secondary the safety risk of treating someone with a CYP2D6 inhibitor: It is always a bad idea to have any CYP inhibition because it increases toxicity and especially drug-drug interactions (of course they want this, in this case, but would be bad in every other case). Also CYP2D6 is one of the most polymorphic CYPs and their could be extreme variability among patients...when treating with dextromethorpan that could be a major problem. The second safety reason being the problem with having a NMDA antagonist with long exposure. Their trials just were not large enough to show these wouldnt be problems.
    I had intended to write an article about this put ran out of time.
    Oct 22 12:43 PM | Likes Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    The follow up study you mentioned should demonstrate that; at least in concept. However, the study was not designed specifically to show that; and no one has any idea how many patients were in that study. Management has not released that data, although they stated they provided interim data to the FDA with the NDA. Investors would sure like to hear about that study, but I get the sense that management wants to keep in the their back pocket as part of a quick re-submission if a CRL is issued asking for more data.
    Oct 22 08:56 AM | 1 Like Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    I have to admit that the FDA's actions for ALXA, AMLN, and JAZZ all shook my confidence in "easy" 505b2 approvals. However, the one common denominator between all of these others was safety. This is is not so much a problem with Linjeta, as it is insulin...a well study, safe, efficacious, and widely used natural hormone. As well, 3 other fast acting insulins have been "easily" approved before it.
    But, the take home message is that the FDA is clearly on a hostile mission to banish all safety issues- so many re-reviews and denials this year based on safety. Although Linjeta seems to be somewhat exempt (in concept) from this, the FDA is clearly scrutinizing drugs to an almost unreasonable level. At this point, I would not be surprised for the FDA to ask for more data...just because they can. Clearly the street is pricing in a CRL.
    However, whatever the FDA does decide apart from approval, it should provide a clear path towards eventual approval within a short amount of time (6-12 months). If a CRL is issued, I am waiting with cash reserves to buy more BIOD depending on what the CRL says.
    That being said, I am still holding BIOD through PDUFA, but like most people (based on the money flow in BIOD), I am reducing my position to half of what I originally planned. Due to the FDA's (horrid) behavior these last couple months, the risk/reward ratio has been reduced since when I wrote an article on BIOD a couple months ago, in my opinion. Options are expensive but will pay off tremendously on a "surprise" approval. They also limit your loss to the option price, so it may be a good way to hold a stake in BIOD going into PDUFA with a defined risk.
    Oct 21 06:31 PM | 2 Likes Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    Keep in mind the three recent denials of 505b2 applications this month alone. It is not a slam dunk.
    Oct 21 01:28 PM | Likes Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    Like I said 10 times already, my problems with Afrezza relate primarily to:

    1) The well accepted role of insulin receptor-IGF receptor signaling in lung cancer. Here is a nice review that explains how insulin receptors are overexpressed in lung and other cancers, and how they work through the "IGFR axis" to promote cancer:
    cigjournals.metapress....
    Afrezza (like Exhubera) exposes the lung epithelium to high concentrations of insulin...a known cancer promoting agent. The scientific community knows about it; it is no secret. There is no direct clinical evidence between inhaling insulin and lung cancer besides Exhubera (which proved it quite well from a statistical standpoint), but there is plenty of clinical evidence demonstrating a link between IR/IGFR signaling and lung cancer- see how many IGF1R based therpaies are in clinical trials for lung cancer right now! Don't be surprised if the FDA brings this up, even if they havent before- any comments regarding "the FDA never asked" are nonsense- see what just happend to Byuredeon and so many before it.
    BTW, I personally am not really worried about diketopiperazine; but it's link to brain cancer in rats is well publicized; but the official stance of the FDA and NCI is that it does not cause cancer.

    2) The FDA: The follow up study was quite small compared to the original phase III studies that did in fact show decreased pulmonary function. It was a well designed study, but hardly abates these concerns....I feel the FDA will take that stance. First the trials which showed a decrease in lung function are extremely well powered...on top of that when removing the cause (Afrezza), then lung function returns to normal. To follow up, they use a study with much less statistical power to claim it has no effect? I dont think this will satisfy the FDA- a company has to use much larger studies to disprove what a study already demonstrated. Look at Meridia-they ran a huge follow up study to disprove cardiac toxicity, and they only proved it more!

    Obviously no MNKD sponsored data is going to convince me- I am relying on outside sources of data and interpretation of precedent to weigh my stance. Your willing acceptance of biased company sponsored PRs should be weighed against outside research, precedent (regarding the role of insulin and also the precedents of clinical trial design and FDA responses to such situations), and the now ever-so-clear pessimism of the FDA regarding safety.
    Look at the evidence outside of MNKD sponsored data- the fear and doubt is there for a reason. Will the risk averse FDA support a new drug with real or percieved risks? Probably not- they have proven this about 8 times this year. This is why Al Mann has to fund the company with his own money and any PIPES are well hedged through strange financing terms. .
    If you can't see why there is so much fear and doubt about Afrezza, you are blind. The risk/reward is not there for most.
    Oct 21 01:26 PM | 2 Likes Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    You are missing the forest through the trees, plain and simple.
    Oct 20 02:59 PM | 1 Like Like |Link to Comment
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