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  • Mannkind's Afrezza Seems Short of Breath [View article]
    I should add:
    "The two questions not addressed in their original submission was clinical utility (ie, how would this drug be utilized within the universe of existing diabetic therapies) and two, questions about the old inhaler. Neither of the issues had to do w/ safety issues related to Afrezza."

    The only concerns the FDA had stated with the original CRL for Bydureon were REMS and manufacturing concerns....and they issued a second CRL requiring additional safety data this time. Like I said, just because the FDA does/does not ask for specific things in no way means they are satisfied with everything else.
    Oct 20, 2010. 01:52 PM | 1 Like Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    This is not about what you, me, or Al Mann thinks. It is about what the FDA thinks. That is my bias- I am trying to view this from their perspective, you are clearly trying to view it from the opposite bias. You are entitled to your opinion, and pertaining to MNKD's strategy and potential market, it is well researched. But that is where it drops off a cliff; anything remotely scientific or related to the thought process behing FDA decision making you just have plain wrong.
    You say:
    "the company didn't need a single post CRL AFREZZA study in order to resubmit. Not one."
    You are mincing words. The FDA asked for more data, but fortunately for MNKD they had already ran the studies in anticipation.
    You also assume that just because the FDA "only" asked about clinical utility and the old inhaler, that they are satisfied with safety issue. From the outside, the FDA seems very fickle, but what the FDA really does is ensures that they have every single peice of data, from efficacy to labeling, in front of them when they make their final decision, so they can weigh all aspects. Don't interepret their actions as anything more.

    "Lung Impact. Sorry, Freddie. FDA disagrees with you. Wouldn't they have raised this safety issue if they were concerned?"
    See above comment.

    "As to the approaches the FDA is going to take. Are you really suggesting that the FDA would engage in post-approval study discussions with MNKD in which they asked them to lower the age of juveniles to 4 years old, then issue a CRL with no safety issues raised and then reject Afrezza because it's unsafe??? That's laughable.........."
    See above comment. No one trusts the FDA these days. Why has the FDA repeatedly re-reviewed and/or pulled products off the market? They are re-thinking their emphasis on safety, that is clear.

    "Why don't you tell people about the threshold for which it becomes a concern. I can't recall the parameter's name, but I do recall the threshold was a 1.2. Afrezza came in at 1.01 if i recall correctly, which basically means almost no impact."
    Here is the data you are looking for:

    The very large Phase III trials 102 and 103 showed that it is there, and it is statistically significant, and shows up relatively quickly in study . However, it magically dissapeared in the follow up study of patients (009) which only had 300 patients in each arm:
    So it shows up in large studies, but dissapears in smaller studies with less power...unnerving. Also, all these trials were very biased- look who they excluded- anyone who smoked, had any hint of lung disease or heart problems. These are not the "real world" patients used in 102 and 103- they were selected patients to attempt to show there was no change. Considering that inhaled insulin would be used chronically, I think the FDA is not viewing it lightly. The FDA looks at these kinds of details....

    "That's because it's human insulin they're using. Which is NOT what exubra was using."
    Better check you facts here!

    "It's completely different. it has a pH which when it hits the lungs is completely absorbed AND QUICKLY which is vastly different than Exubra's profile"
    Sure, but it is still insulin, which is well known to drive cancer in experimental models. Furthermore, the insulin is delivered at high concentration to the lung epithelium, and absorbed directly through the lung epithelium- which is the same tissue where lung cancer originates.

    "Further, lung impact doesn't mean lung impairment. It means lung impact and that doesn't equate to lung damage as you would have readers believe. How stupid can you possibly be??"
    Again, check you facts. They were "pulmonary function tests, including spirometry, lung volumes, and diffusion capacity." A change in outcome of these tests indicate impairment.
    You statement is like saying the engine doesnt run but the car is not broken....

    "The "potential cancer issue"? Who's potential cancer issue? What was the issue? Well, folks it was Exubra's potential cancer issue."
    The insulin-lung cancer connection is not clinically proven, but that is because there has never been lung administration of insulin before Exhubera, who's use strongly supported this concept i a very brief time. They pulled their product so quickly there are no epidemiologic follow up studies to prove or disprove it. But the scientific community as a whole believes it is there. Also, note that they specifically excluded smokers the MNKD study, the ones that got cancer in the Exhubera study were all smokers. As a cancer biologist studying lung cancer, this makes alot of sense to me- MNKD excludes the high risk subjects where the effect is likely to manifest. Clever..

    Again, your opinion is well thought out, but so is mine. Your opinion is shared by many MNKD longs. My opinion is shared by many as well. The difference between your bias and mine is that you are a shameless believer, and I am approaching it as a skeptic, as all investors should. And boy are the investors skeptical! Most investors won't even buy the Al Mann story , as MNKD has been 2/3 funded by Al Mann himself, and all recent capital raises have been done in a very very hedged manner (the last one is the most creative). You would think that such a great product would be embraced by the investment community, but it is not. It is simply too risky for most to invest in- Cramer had to emphasize that a dozen times- this is an obvious fact anyway. So here, "the street" is ignoring most of the data-walk-around MKND is touting, and is trying to anticipate the FDA, which is the only thing that really matters.
    Oct 20, 2010. 09:43 AM | 1 Like Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    ....because if you stand on the track and close your eyes and think positive thoughts the train wont hit you?
    Oct 19, 2010. 09:25 PM | 1 Like Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    "It's not my responsibility to do your work for you"
    No, but you need to support your claims.....which is what you are asking people with a counter-opinion to yours to do but wont do yourself. Your claims are that Afrezza is safe and that diabetics will embrace it. No one can prove that at this point until the FDA finishes its review and sales occur. So your claims are merlely hypotheses. Our claims about these concerns are based on observations that have already been made- we have the benefit of hindsight and you dont.

    "Show me the study that states people prefer needle therapies over non-needle therapies"
    That is not the question...of course no one loves needles....the question is if people really care enough about needles to switch formats given any real or percieved risk.
    Here is some data that might add a dose of reality:
    "Studies show that up to one-quarter of people with diabetes have needle anxiety (Diabetes Res. Clin. Pract. 1999;46:239-46), and that extreme needle phobia exists in about 1% of patients (J. Psychsom. Res. 2001;51:665-72)."
    So 1% of diabetics hate the needle so much it is detrimental, and less than 1/4 of diabetics have any stated concern about needles...a far cry from the 80% numbers MNKD keeps referring to in their surveys. I wonder how many of the 1/4 of diabetics that even are bothered by needles would use Afrezza if they new about the real or percieved link with cancer and pulmonary lung function?

    "FACT, no issues in years of trials on over 5000 people"
    Not true!!! Plenty of potential issues, triggering follow up sudies that have been delaying approval! I bet the FDA's version of the data looks much less favorable than the top line always does. You or I never get to see that data, but the FDA does.

    "FACT. Lung impairment is the difference between an 80 year old who turns 81. AND, FACT, they have proven through trials that stopping afrezza stops whatever "affect" it had on lungs. I'm sure you know the disease itself impacts lung function, but we'll set that aside for this charade."
    How ever so small you claim it to be, the fact is that it affects pulmonary function. The fact that the damage goes away when they stop using Afrezza only further solidifies the fact that Afrezza is the cause!!!! There is a scientific name for it- it is called a "washout" study! What diabetic is going to stop taking Afrezza for a 3 month pause every 6 months to let their lungs heal? The current SOC for diabetes does not cause lung impairment- and that is what Afrezza is being compared to. Sorry, Afrezza is a clear loser in this regard.

    Not to mention the potential cancer issue; the scientific rationale for insulin signaling promoting lung cancer is established- look at how many trials are using IGF1R antibodies which block IGF1R/IR signaling to treat lung cancer. The evidence for this biological mechanism is so overwhelming that MNKD must prove that Afrezza is absolutely not linked to lung cancer= the null hypothesis. The problem is that cancer does not develop over two years, it takes a study to date is powerful enough to invalidate this null hypothesis. Unfortunately for Exhubera, their study demonstrated that the null hypothesis was true rapidly.

    These are the approaches the FDA is going to take, as well as skeptical consumers. These are the battles Afrezza is fighting, and to date has not provided sufficient evidence that they have won.
    Oct 19, 2010. 01:15 PM | 1 Like Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    pacard, I still do not have any MNKD position.
    All those other responses were to call out Groucho on his asinine response...they have no context to our conversation, so don't twist my words. But OUR conversation is about the following:
    Show me the study that demonstrates non-compliance due to needles!!!!!!!!! That is central to your argument.
    Of course is intuitive that kids (and adults) dont like needles but they don't broccoli either. They don't like it when you clean their cuts and peel off band aids, they dont like to bathe, much less change their underwear, eat a balanced diet, and all the things that they dont like to do but are necessary for good health (and are also central to diabetes care). Go to diabetes forums and read the posts...very very few people talk about their kids crying with insulin needles...most complaints are about the glucose monitoring sticking their fingers. Many also say they would never let their kid use inhaled insulin. I have friends who kids are diabetic, cousins is all meaningless, these are all quit with the MNKD PRs and show me a scientific study that demonstrates non-compliance by diabetics due to needles.
    Apart from that, you are missing the central issue of FDA approval, which is what this debate is really about- not needles and secondary endpoints. So great- Afrezza is faster than existing insulins, reduces hypoglycemia, weight gain, less needles, but can the damn drug get approved?
    The FDA doesnt care if kids like needles or not- it has no bearing on Afrezza approval. Nor does titration, hypoglycemia, weight; it is a non-inferiority study.
    Lung cancer due to insulin receptor biology? Pulmonary function loss? I even saw claims of diketopiperazine being a potential carcinogen...sorry pacard, merits or not, it has alot of approval hurdles and that is the central discussion here.
    With SOC being as good as it is (needs improvement, yes, but RHI is meeting the medical need), what motivation does the FDA have to approve a drug like Afrezza, especially given the precedent?
    Oct 18, 2010. 04:32 PM | Likes Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    I have seen many claims that other forms of insulin (patch, inhaled, sublingual) etc WOULD increase compliance, but I have not seen one study that demonstrates lack of compliance for fear of needles is preventing diabetics from using insulin. Show me that data.
    Oct 17, 2010. 06:45 PM | Likes Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    Gaucho please answer the questions I asked, not some repetitive regurgitation of Al Mann quotes. Let me probe a little further:
    1)" About 1/3 of all diabetics REFUSE to take the needle"
    Really? So those diabetics REFUSE insulin? They would rather die within a few months than pokethemselves?.
    "and the market is still about 55 billion".
    So the insulin market is about $180 Billion (1/3 of market is $55 billion)? Wow...seems kind of high...most stats put the global insulin market it more like $25 billion.

    2) "Parents are tired of watching their children cry every time they inject."
    Show me a study that demonstrates this. Also, these kids wont need to use glucose monitors? Basal insulin?

    3) "We don’t have insulin that reduces the need for titration"
    So a 75kg person will use the same amount as a 25kg child?

    4) Afrezza prevents diabetics from "[stabbing themselves] around 1500 times a year"?
    Again, glucose monitors? Basal insulin? How does Afrezza elminate these?

    Oct 17, 2010. 06:39 PM | Likes Like |Link to Comment
  • Mannkind's Afrezza Seems Short of Breath [View article]
    Gaucho you should change your name to Groucho! Have some did endless hope and optimism in the face of real world doubt work for you in the case of ARNA? All situations have valid counteropinions, it would be best if you weighed it, at least as part of measuring your own opinion, lest MNKD turns into the debaucle ARNA was!
    Please provide links that support your claims:
    1) About 1/3 of all diabetics REFUSE to take the needle and the market is still about 55 billion.
    2) Parents are tired of watching their children cry every time they inject.
    3) We don’t have insulin that reduces the need for titration
    4) Do you really know what it is like to " stab yourself around 1500 times a year"??? Although not obviously ideal, what evidence do you have that the elimination of needles itself would "revolutionize" diabetes?

    Hopefully these points above are better supported than your wild claims about ARNA!
    Oct 17, 2010. 12:13 PM | 1 Like Like |Link to Comment
  • Incyte Pharmaceuticals’ JAK: Just Another Kinase? [View article]
    Nothing is perfectly selective, but mother nature designed protein affinities and selectivity well...using that always works better than small molecules for many of them being that protein-protein interactions have much larger interfaces, more opportunity for electrostatic and steric hinderences that regulate selectivity better than a small molecule with 5-6 points of affinity that determine its selectivity.
    All that aside, the data you mentioned are biochemical measurements. Protein-protein interactions under more biologically revelant conditions (for example the presence of serum proteins, different cations, endogenous antagonists and agonists) are usually more stringent and selective.

    Well, what a nerdy conversion! Cheers, Jason- keep up the interesting articles.
    Oct 17, 2010. 12:03 PM | Likes Like |Link to Comment
  • Incyte Pharmaceuticals’ JAK: Just Another Kinase? [View article]
    INCY has run RA trials through phase II. My point regarding Enebrel et al is that there is alot of space within the anti-inflammatory market for several drugs which all have identical mechanisms. Enebrel, Remicade, Humira all work by binding TNFa, seem to have equivalent potency and selectivity, yet all have a sizeable market share.

    Being biologicals, the above drugs have perfect selectivity, but a TKI will never be perfect. INCY "favors" JAK1/2 specifically more than the PFE drug; but both have activity towards JAK3. The basis for the 80X claims of selectivity is based on biochemical profiles, not cell mechanistic or much less real world data. There is an awful lot of promiscuity in the JAK/STAT pathway and a biochemically "perfect" JAK1/2 inhibitor still modulates the same STATS that a JAK2/3 inhibitor does.
    Some light reading for you:
    There is scientific rationale for a JAK1/2 vs JAK1/2/3 inhibitor to reduce undesired bone marrow suppression, but it is not clear if there is any real world clinical benefit- only phase III trials can confirm that. No one has seen any of these claims come to fruition yet.
    Oct 16, 2010. 10:22 AM | Likes Like |Link to Comment
  • Incyte Pharmaceuticals’ JAK: Just Another Kinase? [View article]
    INCY's compounds seem to be in the middle of the pack as far as development progress, with Pfizer in the lead. However CP 690,550 may have its drawbacks; first in class usually has a marketing advantage, although is rarely best in class. Without dissecting each JAK TKI in the "slew", it is hard to know if these will truly be better than CP, 690, 550. But entering the market second may be an advantage in this case, as drawbacks from one may provide a window for others. Or the market may just be big enought to fit many- look at how many players are in the anti-TNFa market ; Enebrel was first- long before Remicade and others- and they all seem to be doing well.
    Oct 15, 2010. 09:12 AM | Likes Like |Link to Comment
  • Incyte Pharmaceuticals’ JAK: Just Another Kinase? [View article]
    To my knowledge, their are a slew of JAK TKIs coming on the market from the major players you mentioned as well as several smaller companies. What makes INCB18424 better than the rest? Broad myelosupression is a direct effect of all these drugs, so what is a differentiation strategy from eachother...or even from methotrexate for that matter?
    Oct 13, 2010. 04:45 PM | Likes Like |Link to Comment
  • Avanir Pharma's Pending FDA Approval: The Upside Potential [View article]
    Dextropmethorphan is a NMDA antagonist, and is somewhat dangerous because of these effects (note that you cant buy cough syrup it anymore due to abuse and deaths related to abuse). What allows its use is that its effects only last 4 hours. However, Quinidine prevents metabolism of it so the effects last longer- making it even more dangerous.

    If you read the trial study data, its effects are good but they seem wear off significantly after 3 months use. Also NMDA antagonists could potentiate depression, and may counteract any anti-depressants that PBA patients are on (current treatment).

    Although the reasons for a CRL were addressed (Potential for QT interval prolongation, Rate of AEs in ALS population, Potential for increased risk of falls, Potential for respiratory depression in ALS) I dont think the number of patients needed to prove this are there.

    I think there is alot of muddy water in this river....but I havent passed judgement yet.
    Oct 12, 2010. 05:20 PM | Likes Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    patrick I think those are all valid points and investors need to consider their appetite for risk and invest accordingly. In the case of ARNA, investors were absolutely convinced that their was almost no risk, and the market was pricing that in. In the case of BIOD investors are aware of the risks, and the market is pricing that in also. The difference is that the opinions are somewhat skewed- BIOD investors have much more to gain and far less to lose than ARNA investors percentage wise depending on the outcome. So in my opinion the risk/reward favors an hold-through PDUFA investment of some type, even if with hesitation. Just don't bet the farm on it....
    Oct 1, 2010. 04:57 PM | Likes Like |Link to Comment
  • Biodel: Upside from Potential Linjeta Approval [View article]
    I think the real answer may be that the warmed samples, in the absence of oxygen, fermented. Red blood cells can use anaerobic glycolosis to produce energy. The product of anaerobic glycolysis followed by fermentation is acetaldehyde! Hemoglobin can be acetylated by a wide variety of contaminants other than glucose- including asprin. But the key here is acetaldehyde, which accumulated when the samples were allowed to ferment and caused the high levels of HbA1c. It makes more chemical sense than speeding the a reaction of glucose with hemoglobin that is typically very slow.
    Oct 1, 2010. 09:59 AM | 2 Likes Like |Link to Comment