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Post by spiro on Mar 28, 2014 19:32:16 GMT -5
Liane, I am still around, just trying to digest today's events like a lot of other investors. I did weaken today and sell 25% of my share control. I truly believe that the MNKD team was expecting most of the FDA's response and I am fairly confident that they will be able to address the FDA questions with adequate answers. Since when does the FDA not approve drugs unless they can be effective with 100% of the patients. That's why they have endpoints. I think the FDA's missing data argument is weak at best. Numerous drugs are approved after having high dropout rates because they met their endpoints. I do have concerns about the dosing in type 1, but the FDA has let Afrezza advance to this stage without too much concern here. What happened to the concern about the withheld data from the 3rd arm? The FDA questions remind me of questions that would be asked in phase 1 trials. We are not going to see that light at the end of the tunnel until the FDA approves something. I think Jeff Eiseman has the best grip on this thing, actually his thoughts appear to be similar to yours. seekingalpha.com/article/2115243-what-the-fda-document-says-about-afrezza-implications-for-fda-approval?isDirectRoadblock=false&uprof=Spiro here, depressed in Miami, still battling. But what do I know?
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abwo
Newbie
Posts: 16
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Post by abwo on Mar 28, 2014 19:40:56 GMT -5
Heck, let me just say one thing about today as it seems fear is progressing into some people minds. It's quite amazing to see how people who seem to have perform their dd extensively can be so afraid and sell it all, even at a loss. For the old timers, the road has been bumpy already: just remember those days where the stock has lost over 50% intraday? When Exubera was said to cause cancer? When we did not partner in 2009? For both CRLs? Well despite all this, my MNKD portfolio is still up....Sure, it's been up over 300% in the past! As well as down close to 80%. So what? I never sold a share in over 7 years and I have kept investing money I can afford to loose, only buying shares as so many people got burnt playing around with options. And since then, no fundamental piece of data has changed. We have hundreds of evidence Afrezza is effective and will greatly benefit diabetics. Dilutive or not, financing ways have always been found....And to think years ago people were saying MNKD would never be able to find financing to last up until 2011... It doesn't seem to me there's anything very new in the adcom docs disclosed this morning. And people tend to say the bad stuff would be for T1 only? To think last time we submitted we were only applying for T1! Let me sign right here right now and buy more shares below $5 to get a massive vote in favor of approval in T2 and subsequent studies for T1 next Tuesday! I guess what I mean is: if you're not here to gamble for a fast return around the binary event happening right now, but in it for the long run, I can't see any reason to change your mind, in fact I can only think about nice progress. I'm happy we are where we're at, having a chance to have MNKD's best scientists explain years of study data at this adcom and have the FDA rule soon afterwards, be it 2 weeks or a little later. What's a few more months when you've been holding for years... And some should remember what was the share price when you were trying to build a position 7 or more years ago! Quite unbelievable to be able to buy so cheap today! We've been at those prices, and we'll get back up there, just hang on! Your worst enemy is Yourself, if you know the fundamentals, stop reading the FUD and get some fresh air And remember...MNKD people are doing their best to bring this drug to the market for years, it sure is no piece of cake but in the end it's going to happen! GLTAL, Abwo
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Post by babaoriley on Mar 28, 2014 21:32:02 GMT -5
Nice post abwo! As for options, they have been a huge winner for many on this board, that is selling puts over the many years. Going for long calls, well, I'd have to agree with you. "What's a few more months when you've been holding for years." I don't think you're going to hear much grousing over the time line at this point! LOL!
If they get the nod on Type 2 and direct further trials for Type 1, I'm certain we'll all be ecstatic. But, if they get zip, and are told to go back and keep trying, well, no matter how close the carrot would appear, all that means is much more dilution, and then the time-grousers will re-emerge with renewed energy and purpose.
"I never sold a share in over 7 years and I have kept investing money I can afford to loose." Sorry to say, not everyone here is in your enviable shoes in that respect, although they should be. You see, after reading on several boards posts from people that make perfectly good sense that this is a sure winner, some people actually begin to believe that.
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Post by mnkdfan on Mar 28, 2014 22:17:32 GMT -5
Great post ABWO. I am of the opinion that even in the worst case scenario, we would get Type II approval and may need additional testing for type I. Having said that, I still believe we get approval for type I with MNKD experts providing justification for the technical data glitch. It would also seem logical, like Liane said earlier, that Afrezza usage in real life setting would be easier to adjust for type I patients. Keep in mind that for many of the type I patients, they require and are used to making more insulin adjustments than those of type IIs anyway.
I also don't see a reason why type II would not be approved by the FDA when the 175 trial was designed by the FDA and met the Primary end point as agreed upon by the FDA. The FDA seems to be be content with Afrezza's safety and lung performance profile so safety is not a concern. After all they approved Exubera with pretty much the exact same small FEV lung performance degradation (Fev 50ml reduction for Exubera). As a matter of fact, MNKD have done more than Exubera in animal studies to demonstrate safety profile.
With all the drugs that the FDA have approved in the past with known cancer evidence in animals along with a rash of serious side effects, how can they not approve Afrezza!!. The FDA and panel also have a "CYA" option in that approving types I &II but require a post marketing follow up study as a semi-conditional approval anyway. This is one way to get the missing data for type I since it's deemed safe for use in type II patients. I can't imagine the FDA would reject a drug like Afrezza which is deemed safe and tremendously helpful for millions of diabetic patients. The credibility of the FDA would be in question if type II application is rejected when the primary end point in a trial designed by the FDA is met (as confirmed by FDA's own reviewer). After all, is it not also the FDA's responsibility to help bring innovation and treatment to help the people they serve.
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Post by alcc on Mar 28, 2014 23:08:05 GMT -5
Ok, I read the entire document. I am struck by the skeptical, almost gleeful tone of one reviewer in particular, including what I deem unprofessional editorializing. Examples: p. 77-78 -- "[...] an overall higher rate of subject discontinuation in the Afrezza groups [...] does not support a claim that patients prefer Afrezza over insulin aspart" P. 87 -- "[...] on its face, the magnitude of the effect size with Afrezza in comparison to these oral antidiabetic agents is surprisingly modest, especially in light of the fact that Afrezza can be titrated." Re the first comment, is the approval process now driven by subject preference? Besides, whereas it is true that the Afrezza Gen 2 dropout rate was a high 25.3%, compared to 11.2% for Insulin Aspart, they are not directly comparable. After all, many if not most of the subjects in the control arm have been on SC RAA for years as part of their treatment, whereas Afrezza was new to subjects in the Afrezza arm. I can look at it this way: in that arm, 25% dropped out, versus 75% stayed to the end. So I can say subjects preferred Afrezza 3:1! Come on. Re the second comment, I can accept the comment, but not with the editorial "surprisingly." Who is this guy, Adam F---stein? I note I am generally dismissive of conspiracies and am not inclined to paranoia. Still, this gives me pause for concern. What's going on? For comparison, I check the Exubera briefing doc. Imo, that doc is much more professional and respectful in tone, free of snide embedded reviewer comments. While I had the Exubera doc open, I decided to compare content, notably re some of the material negative points raised re Afrezza. (Note: I know Exubera failed in market, which is not reassuring. But I am making this comparison only in the context of the upcoming adcom.) In no particularly order: 1) T1 efficacy. I would say FDA expressed even greater concerns re Exubera. See attached excerpt: Attachment Deleted2) Bioavailability. Afrezza's is ~25%. Exubera ~10%. 3) Dosing non-linearity. Exubera has same non-linearity issue. However, author of the Exubera doc appended a fair qualifier that SC RAA can be equally non-linear. See attached: Attachment Deleted4) Dropouts. Exubera T1 PIII Efficacy trial had 12.4% dropout versus 8.9% for control arm, compared to Afrezza's 25.3% and 11.2%, respectively. But there was no name-calling Exubera's dropouts "missing data." And there was no sensitivity test done to account for the "missing data" using 3 methods of imputation. Why? Is Afrezza's 25% unusual and excessive for PIII? Subject dropout is not missing data! It ain't missing if it can't be found! WTF? 5) Exubera did better on A1c v. control than Afrezza. That is true. Other than that, Afrezza is superior v. Exubera by all other metric, notably hypo. 6) The Exubera doc respectfully presented sponsor's PK and PD and early trial data without attacking them as poorly conceived, improperly conducted, etc. I dunno what is going on. Maybe Pfizer simply has more clout. No idea what's going to happen on Fool's Day. Looks kinda uphill to me. Frustrating.
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Post by jpg on Mar 28, 2014 23:54:17 GMT -5
I am finished reading the documents almost twice and am mostly struct by the tone of some of the reviewers. It almost seems personal with a lot of editorializing as if the reviewers wanted to challenge the adcom panel participants into a 'deep reflection'? Or they hate Afrezza... Or they just don't get that HbA1c is not that great a tool to measure everything there is to measure about diabetic therapy. One number soves it all... If it were that simple! Imagine Lantus going up against any of the meal time insulins and saying the rapid acting insulins suck because they have lower A1c's then Lantus and not looking at the granularity of the diabetic management? This is in essence what some of these reviewers are saying when comparing a very short acting insulin to an medium duration insulin (that is what the prandials really are).
Does anyone kniw of any other past briefing document that had this kind of tone? And ideally came out with a positive outcome... I tried finding some past briefing documents but keep getting held up by an extremely slow Internet connection. I'd love to read one but can't download and look at one easily. The pleasures of being on vacation in an exotic country during all this...
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Post by alcc on Mar 29, 2014 0:48:33 GMT -5
Confounding editorials abound. On P. 127, the reviewer attributes the data on T1 hypo events (in Afrezza's favor, for a change) to be "entirely consistent with the fact that Afrezza was less effective than the comparator." !!
Less effective -> fewer hypo. Ergo, more hypo -> more effective !
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Post by jpg on Mar 29, 2014 1:07:01 GMT -5
Confounding editorials abound. On P. 127, the reviewer attributes the data on T1 hypo events (in Afrezza's favor, for a change) to be "entirely consistent with the fact that Afrezza was less effective than the comparator." !! Less effective -> fewer hypo. Ergo, more hypo -> more effective ! Agree. Same with the weight gain issue and a bunch of other issues. It's as if they were stuck in this rigid mindset where the realities of diabetic management are defined by non alterable dogma and their interpretation of Afrezza has to fit into this somehow. Problem is they write these things. Not us... Hopefully the panel participants will be a bit more sophisticated... I haven't done my DD on the panel members yet and hope to have a bit of time to do a bit before Tuesday.
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Post by chmith27 on Mar 29, 2014 1:28:23 GMT -5
Confounding editorials abound. On P. 127, the reviewer attributes the data on T1 hypo events (in Afrezza's favor, for a change) to be "entirely consistent with the fact that Afrezza was less effective than the comparator." !! Less effective -> fewer hypo. Ergo, more hypo -> more effective ! you might be thinking about this point incorrectly. an ineffective insulin (a very bad thing) will have essentially no hypo events (a good thing, right) and an insulin that works appropriately (a very good thing) will have a higher rate of hypos (a bad thing). which one do you want to use? i can treat your DM with a wave of my wand, which will have no hypos(a good thing)- but is that going to be good for your diabetes? the primary goal of an insulin is to move glucose into the cell- if it doesn't do that then you have to call it ineffective. the reviewer should have said, "entirely consistent with the possibility that Afrezza was less effective..." i agree there seems to be some editorializing but i also have never dealt with a briefing doc so i don't know the true context and acceptable tone that is allowed for these things.
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Post by alcc on Mar 29, 2014 4:12:13 GMT -5
chmith27,
By this point, most of us longs here do not need a lecture about glycemic control. Otoh, you may need a lesson in logic. Yes, less effective may imply fewer hypos. That's obvious. However, fewer hypos does not imply less effective. That, too, should be obvious.
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Post by jpg on Mar 29, 2014 4:40:19 GMT -5
I would think that the fact Afrezza has less hypoglycemia could be seen as a maker of a smart prandial insulin without a fat tail as Mannkind claims and the way I interpret the data.. Afrezza could get punished for doing something for which it was designed to do and do it better then the other prandials (the 'cost' of not having any basal component as the sc prandials all have with their fat tails)..
The way I read the briefing docs the reviewers are simply following a predesigned pattern of evaluation and asking the panel to think this through. Hopefully panel members will have a more modern vision of insulin and diabetics then simply A1C...
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Post by alcc on Mar 29, 2014 4:58:22 GMT -5
Correct. But imo this is one bald-faced biased, overreaching reviewer. Let's parse this comment: "[fewer hypos is]... entirely consistent with the fact that Afrezza was less effective than the comparator."
1) Fewer hypos is equally consistent with the "fact" that Afrezza was superior to the comparator re post prandial glycemic control.
2) What fact was he referring to? That the data shows Afrezza was less effective re A1c control? Fine, let's stipulate that. But how does an informed, unbiased reviewer stretch that "fact" to speculate that that is the reason why Afrezza had fewer hypos? A1c and hypo events are loosely correlated, if at all.
In the end, I don't give a rat's a-- about one crappy reviewer, unless he has input into, or ends up influencing, the outcome.
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Post by liane on Mar 29, 2014 6:11:44 GMT -5
I would think that the fact Afrezza has less hypoglycemia could be seen as a maker of a smart prandial insulin without a fat tail as Mannkind claims and the way I interpret the data.. Afrezza could get punished for doing something for which it was designed to do and do it better then the other prandials (the 'cost' of not having any basal component as the sc prandials all have with their fat tails).. The way I read the briefing docs the reviewers are simply following a predesigned pattern of evaluation and asking the panel to think this through. Hopefully panel members will have a more modern vision of insulin and diabetics then simply A1C... jpg, You hit the nail on the head, and this is what I was alluding to earlier in this thread. Afrezza is a whole new way of thinking. It is not a fair to evaluate based solely on A1c. TI is in the body for maybe 6 hours of the day (give or take). Basal insulin - for 24 hours. So far more of the burden for controlling the A1c should come from the basal. In utilizing TI, we need to adjust our thinking as to how much basal is used. Is TI less effective or "gentler" - No! It gets in and gets out. It's very effective during its time in the body. This is the paradigm shift. I'm still working on my full read-through of the docs (about 50% done). I've bounced around focusing on some of the juicy parts. Probably will have more to say this afternoon. Appreciate all of you that have made it all the way through already!
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Post by chmith27 on Mar 29, 2014 14:23:55 GMT -5
chmith27, By this point, most of us longs here do not need a lecture about glycemic control. Otoh, you may need a lesson in logic. Yes, less effective may imply fewer hypos. That's obvious. However, fewer hypos does not imply less effective. That, too, should be obvious. here's my argument: an ineffective insulin (let's say placebo sugar pill haha) = less hypos afrezza could be an ineffective insulin and therefore = less hypos. that is a coherent argument, right? it may not describe afrezza, and i sure hope it does not otw i lose an illogical amount of money on this. i never said less hypos means poor efficacy. less hypos could be a result of poor efficacy, which is how i said the reviewer should have worded it. less hypos could also be a result of a better insulin as well, as in the following: endogenous insulin = less hypos afrezza could mimic endogenous insulin and therefore = less hypos tell me where my logic is incorrect? otw, kindly watch your tone.
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Post by alcc on Mar 29, 2014 16:07:00 GMT -5
you might be thinking about this point incorrectly. an ineffective insulin (a very bad thing) will have essentially no hypo events (a good thing, right) and an insulin that works appropriately (a very good thing) will have a higher rate of hypos (a bad thing). which one do you want to use? i can treat your DM with a wave of my wand, which will have no hypos(a good thing)- but is that going to be good for your diabetes? the primary goal of an insulin is to move glucose into the cell- if it doesn't do that then you have to call it ineffective. the reviewer should have said, "entirely consistent with the possibility that Afrezza was less effective..." i agree there seems to be some editorializing but i also have never dealt with a briefing doc so i don't know the true context and acceptable tone that is allowed for these things. You should think again about your construction: " Proposition A is entirely consistent with the possibility that Proposition B [is true]" It is a tautology, therefore meaningless. otw, kindly watch your logic.
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