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Post by derek2 on Apr 10, 2017 15:31:32 GMT -5
I don't think this has ever been posted. MNKD never shared it, but it is available direct from the FDA. It's pretty fascinating. Starts off with CRL 2 and continues with CRL 1. www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000OtherActionLtrs.pdfMost of this info was shared in the FDA safety meeting briefing doc, but given everybody's interest here, and given that it's a publicly available document (and legally available, as published by the FDA), you may want to read them. Your money funded them, after all.
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Post by derek2 on Apr 10, 2017 16:17:48 GMT -5
Also - the main page for regulatory documents for Afrezza. The leadership review recommending approval has a lot of positive info, and the safety review is fascinating. (shows why pregnant women should not use Afrezza. I always thought it was because of the insulin. Nope. It's the FDKP.) www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000TOC.cfm
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Post by Deleted on Apr 10, 2017 18:40:19 GMT -5
derek2 I don't feel up to searching through a lengthy document to find something you claim; how about copying and posting? Cannot wait to read how an inert molecule can be harmful. But than sophie claimed nothing is inert!
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Post by Deleted on Apr 10, 2017 20:35:57 GMT -5
derek2 your silence is deafening!
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Post by mango on Apr 10, 2017 20:57:05 GMT -5
Afrezza is Pregnancy Category C which is the same as Lantus (insulin glargine). Let's compare. • AFREZZA Sourcewww.accessdata.fda.gov/drugsatfda_docs/label/2014/022472lbl.pdf• Lantus Sourcewww.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdfSo while Lantus might cause Ventriculomegaly and probably a skin tumor, Afrezza might decrease your balls. And, while Lantus killed such an excessive amount of female mice during the non-clinical carcinogenicity study—the results were rendered as "non-conclusive". Yikes! Anyways, the rats and mice in the Afrezza non-clinical carcinogenicity study lived, and NO signs of toxicity were observed. Afrezza also underwent a long-term study that demonstrated it causes NO amyloid deposits in any portion of the respiratory tract, however, there are numerous case reports and laboratory studies published that illustrates Lantus (insulin glargine) is amyloidogenic. If I was a pregnant woman, I'd rather chance it and let my kid have smaller balls than Down Syndrome, tumors and amyloidosis. Not sure what you were trying to prove with the CRLs and by mentioning pregnancy, but in the end, the facts show Lantus is toxic and Afrezza is not.
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Post by Deleted on Apr 10, 2017 21:25:51 GMT -5
mango "Not sure what you were trying to prove with the CRLs and by mentioning pregnancy, but in the end, the facts show Lantus is toxic and Afrezza is not" Thank you for writing what I was thinking!
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Post by sayhey24 on Apr 11, 2017 5:26:17 GMT -5
Mango - very interesting, similar to AspB10 development but this time Lantus killed the rats. I have been watching for long-term studies on the relationship between the increased cancer rates in PWD and the Analogs. There are a few mostly out of Europe pointing to the Analogs being the cause. It seems in the U.S. they are being suppressed or just not funded.
Based on this given metformin, afrezza or any of the analogs I would think a pregnant women should pick afrezza.
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Post by derek2 on Apr 11, 2017 5:34:50 GMT -5
derek2 your silence is deafening! Well, I was asleep. My wife wishes I was silent when I sleep! Personally, as a fan of data, not supposition, I was excited to find this. The info is there, you just have to read. And hey, since the drug got approved, it's overwhelmingly positive info. An example: Some posters hang on Al Mann's statement that Afrezza does not need refrigeration. Others accuse management if not doing their job by running a stability trial. Well, turns out both extremes are wrong. The Chemistry Review shows that MNKD ran stability tests over a 3-year period, and it was MNKD that proposed the 18 months refrigerated and 10 days at room temperature storage, and that the FDA agreed. (Chemistry Review, P 47, Other Reviews, page 22-24) So the reason that I find this fascinating is that it shows that all parties acted rationally and professionally and came to an agreement. No evil FDA, no stupid MNKD. Many people won't care, since the drug is approved, but it shows that those stating that Afrezza does not require refrigeration should take heed of the proof that there is degradation at room temp over longer time periods. Who showed that? MNKD. It's real-world data that can help patients get the best result.EDIT: EDIT: The fact that a 3-year stability study was already performed also acts as a signal that a change in storage instructions is probably not part of the requested label change. It's not like MNKD was bullied into this - they recommended it after 3 years of data collection. This gives you more information as an investor. I mean, you might still think that MNKD could have requested the storage instruction change, but you have more real-world data to base your opinion on, instead of just "it would be great if" positing. Now, what it says about how in-the-loop Al was when he was claiming "no refrigeration" since 2010 is another thing. Maybe he didn't talk to the chemists. Re: the pregnant women warning: The Medical review shows pregnant rabbits & mice having fetal malformations at VERY HIGH concentrations of FDKP. Concentrations that would never be seen in real life, but it acted as a rational basis for MNKD and the FDA to determine toxicity baselines and set a margin of safety.
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Post by derek2 on Apr 11, 2017 5:41:43 GMT -5
Afrezza is Pregnancy Category C which is the same as Lantus (insulin glargine). Let's compare. Wasn't trying to show anything, other than an example that the risk was assessed by both MNKD and the FDA before the label was agreed to, instead of the ridiculous "FDA forced a label on MNKD" narrative. Not trying to scaremonger or anything. How could I? Pregnant women don't use Afrezza. If I wanted to scaremonger I'd cherry pick data about some indicated population, but I don't do that kind of crap. I found this data - as anybody with the slightest interest could have - and shared it. Done.
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Post by Deleted on Apr 11, 2017 6:46:09 GMT -5
derek2 "the pregnant women warning: The Medical review shows pregnant rabbits & mice having fetal malformations at VERY HIGH concentrations of FDKP. Concentrations that would never be seen in real life, but it acted as a rational basis for MNKD and the FDA to determine toxicity baselines and set a margin of safety." That is the definition of FUD: make some ludicrous remark that you claim to have found in a voluminous document and tell people go find the relevant data. Unfortunately for you mango did that and determined FDKP is NOT harmful as you claim in realistic dosages. Water and salt taken in large quantities are harmful, should they have black box warnings???
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Post by derek2 on Apr 11, 2017 7:27:22 GMT -5
derek2 "the pregnant women warning: The Medical review shows pregnant rabbits & mice having fetal malformations at VERY HIGH concentrations of FDKP. Concentrations that would never be seen in real life, but it acted as a rational basis for MNKD and the FDA to determine toxicity baselines and set a margin of safety." That is the definition of FUD: make some ludicrous remark that you claim to have found in a voluminous document and tell people go find the relevant data. Unfortunately for you mango did that and determined FDKP is NOT harmful as you claim in realistic dosages. I have no interest other than pointing to the document repository. Actually, the scientific reviews are far more interesting than the 2 CRL letters. Lots of detail showing that MNKD were not stumblebums that got hosed by the FDA. They did science with rigor and in concert with the FDA (other than ignoring the FDA regarding bioequivalency studies) Just forget I ever mentioned pregnant women. (Derek then proceeds to give more detail about pregnant women) Page 32 of the Cross Discipline Leader Review and detailed animal studies starting on page 9 of the Pharmacology Studies (section: Margin of Safety). I didn't see the mango stuff at first because I have him on ignore. (A great feature that people can take advantage of to mute me at any time. Hey look! No more Derek!) Once again - there's no FUD to spread about use by pregnant women. It's already out there. They are cautioned on the label: So some adverse effects at 6X - 20X real-world human equivalent doses in rats (paragraphs 1 & 3 and in real-world human equivalent doses in rabbits (paragraph 2). MNKD attested to this on the label. It's been available for years, out there front and center on the label. (Did I mention that it's on the label already?) I just stated that it was interesting to see the background and rationale as to why pregnant women are waned on the label. I get that I'm not your cup of tea. Discussion boards can sometimes breed division. If we met in real life, after you got over the urge to bop me in the nose, I bet we'd have a good convo over a beer or 2. Vive la difference!
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Post by slapshot on Apr 11, 2017 7:36:14 GMT -5
Some posters hang on Al Mann's statement that Afrezza does not need refrigeration. Others accuse management if not doing their job by running a stability trial. Well, turns out both extremes are wrong. The Chemistry Review shows that MNKD ran stability tests over a 3-year period, and it was MNKD that proposed the 18 months refrigerated and 10 days at room temperature storage, and that the FDA agreed. (Chemistry Review, P 47, Other Reviews, page 22-24 So the reason that I find this fascinating is that it shows that all parties acted rationally and professionally and came to an agreement. No evil FDA, no stupid MNKD. Many people won't care, since the drug is approved, but it shows that those stating that Afrezza does not require refrigeration should take heed of the proof that there is degradation at room temp over longer time periods. Who showed that? MNKD. It's real-world data that can help patients get the best result.Derek, from what I saw, you have misconstrued the data/results of the chemistry reviews. I agree that MNKD performed stability trials that prove the shelf life stability when refrigerated over long periods of time (actually up to 4 years), but i saw no data or evidence that suggested that they performed the same tests without refrigeration nor that any such conditions showed degradation. Thus, i believe you are jumping to (unsupported) conclusions when you say that because MNKD performed stability studies with refrigeration that proves refrigeration is required... What logic are you using that i am missing?
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Post by Deleted on Apr 11, 2017 7:43:31 GMT -5
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Post by derek2 on Apr 11, 2017 7:51:10 GMT -5
Some posters hang on Al Mann's statement that Afrezza does not need refrigeration. Others accuse management if not doing their job by running a stability trial. Well, turns out both extremes are wrong. The Chemistry Review shows that MNKD ran stability tests over a 3-year period, and it was MNKD that proposed the 18 months refrigerated and 10 days at room temperature storage, and that the FDA agreed. (Chemistry Review, P 47, Other Reviews, page 22-24 So the reason that I find this fascinating is that it shows that all parties acted rationally and professionally and came to an agreement. No evil FDA, no stupid MNKD. Many people won't care, since the drug is approved, but it shows that those stating that Afrezza does not require refrigeration should take heed of the proof that there is degradation at room temp over longer time periods. Who showed that? MNKD. It's real-world data that can help patients get the best result.Derek, from what I saw, you have misconstrued the data/results of the chemistry reviews. I agree that MNKD performed stability trials that prove the shelf life stability when refrigerated over long periods of time (actually up to 4 years), but i saw no data or evidence that suggested that they performed the same tests without refrigeration nor that any such conditions showed degradation. Thus, i believe you are jumping to (unsupported) conclusions when you say that because MNKD performed stability studies with refrigeration that proves refrigeration is required... What logic are you using that i am missing? I think you just missed 1 piece of data in the Chemistry review regarding the shorter term studies. My logic, however, is pinned on two items: #1 The company - who had run the stability trials - suggested both a 15 day room temperature excursion, then a 10 day time frame, know their compound. Page 47: Page 46 #2 - they did shorter term tests at room temperature. I misconstrued nothing. Hopefully that clarifies it.
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Post by mnkdfann on Apr 11, 2017 7:53:28 GMT -5
Tough room!
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