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Post by compound26 on Oct 26, 2016 9:00:48 GMT -5
aged and or all, isn't the fee for the EU to look at accepting afrezza something like a quarter million US dollars?
If you want to play, you have to pay. I'm not sure. There is also the downstream problem that once it is approved you have to get it adopted by each of the national health systems or you have a drug that can be sold but no customer. agree. For anything like a filing with EU for a new drug approval, it is far more than paying the filing fee and submit the application, I would imagine you will need a team of dedicated people to prepare the filing to the best you can and coordinate with the approval authority (EU central and then on a national level, as necessary) on many issues. Plus, more than likely, Mannkind will need additional clinical trials to support the filing. Even for the filing itself, if Mannkind decides to file, the filing must be vetted by the leadership team (Matt, Mike and Ray), technical and legal team many rounds to make sure they feel they got everything covered. So it likely is pretty time-consuming process. Right now, leaving aside the financial resources, I think everyone at Mannkind is tapped out. With the very tight financial resource, I think Matt is probably 100% focused on getting additional financing right now, while Mike is doing whatever he can to forge ahead on Afrezza re-launch and Ray on Epi-inhaler formulation and trial. So right now, Mannkind simply can not handle a separate new filing to EU, whether by its own choice or otherwise. peppy so an EU filing is probably not that simple as paying the filing fee and submit the filing. It is not like that Mannkind has already got the filing prepared and supporting data ready. I recall Matt talked about EU filing in a recent presentation. Do not remember the exact words, but my impression is that he basically said Mannkind hasn't looked the details about EU filing recently, but most likely to file in EU additional clinical trial will be needed. I also have the impression of that if they do file for a new application, they maybe thinking about getting the pediatric market approved first. |
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Post by compound26 on Oct 25, 2016 15:32:59 GMT -5
"Trial protocols required patients to dose Afrezza 15 minutes prior to the beginning of each meal. Had the trial required dosing at the time the meal began or five minutes into the meal, results would have been dramatically different. A1c improvement would have been off the chart, data published and NRx today north of 10,000 / week. But it wasn't and we are where we are." Exactly what I meant. All I was saying was that the trials were for the benefit of the FDA and NOT the drug. I would also not accept as final word, any hypos on patients with one or two other oral drugs as they are no longer valid in my mind. Those guys polluted the sample IMHO. I want Afrezza ONLY trials. Then, and only then, will we have proven the science effectively. That is when this thing "turns on a dime" generally agree with what you stated. However, the " Trial protocols required patients to dose Afrezza 15 minutes prior to the beginning of each meal" part does not appear to be accurate. Below is what Al Mann stated in an interview. www.diabetesincontrol.com/an-exclusive-interview-with-al-mann-founder-and-ceo-mannkind-corp/SF: Was that when you changed to the new device? AM: No, I think that a problem during the trials was that some patients took their dose of Afrezza even before starting to eat. The trial protocols called for Afrezza to be dosed “at the beginning of the meal,” but sometimes it was taken even before. We need to do additional trials to gain more experience with optimized dosing times. Actual ingestion of food in most meals in the United States except in restaurants takes only about 30 minutes, so I believe that the first Afrezza dose really ought to be taken ten or fifteen minutes after starting to eat. For a longer meal, which is not very common, a second dose might be taken fifty or sixty minutes after starting to eat. For a long feast that lasts for an hour and a half or more, I suggest a third dose be taken at maybe one and a half hours after start. Interestingly I believe the size of all those doses should probably be the same for most patients. Unfortunately the trial protocols called for dosing at the beginning of the meal so we will need to do more trials to be able to gain FDA label approval of optimized dosing. |
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Post by compound26 on Oct 25, 2016 12:48:14 GMT -5
Actually, I'm mostly in agreement with what you have written. I also think that Al was speaking about severe hypo and simply mis-spoke. And then Matt failed to correct him. And then it spawned this whole "no hypo" misunderstanding - that's what I was speaking to. The reality, as you lay out quite nicely, is more down to earth. I buy into the view that in the trials the participants were exposed to less insulin when using Afrezza due to the dosing rules, leading to: 1. Slightly lower efficacy (barely proved non-inferiority (but yes did prove it) and surprised management, who had been expectiung approximately twice the effect on HbA1c) 2. Lower side effect (weight gain, hypo). There's nothing magical about Afrezza. It's insulin. Take a bigger dose, get a bigger primary effect and side effect. Take a smaller dose (as many have argued the trial design forced participants into) get a smaller primary effect and fewer side effects. , I generally agree with you are saying. However, IMHO, Afrezza significant reduces the risk of hypo events mainly because its unique PK/PD profile, not because of whether ones used less insulin or arrived at a slightly higher A1C. Yes, Afrezza is insulin, however, because of its unique PK/PD profile, it is entirely a difference class of insulin, in many respects very different from RAAs. According to this study of Yale University ( www.medpagetoday.com/Endocrinology/Diabetes/40764), compared to a baseline HbA1c of 7% to 7.9%, no level of HbA1c -- ranging from less than 6% to 9% or higher -- had a significantly different relative risk of hypoglycemia in a model fully adjusted for age, diabetes duration, and category of diabetes medication, they wrote online in Diabetes Care. So based on the above article, significant difference in A1C actually does not automatically lead to significant difference in hypo events. Given the marginal difference between Afrezza and RAAs in A1C results, the significant difference in hypo rate between the two arms can not be explained by the slightly higher A1Cs of the Afrezza arm (as the FDA reviewer obviously has concluded, without any study supporting his/her conclusion). The FDA reviewer obviously did not think through this issue or did much research on this issue. Most likely, he/she just does not want to find out the real explanation why Afrezza causes less hypos. |
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Post by compound26 on Oct 25, 2016 11:21:30 GMT -5
Here's what Al actually said. "There was one patient that had almost half of the hypoglycemic incidents" Simply not possible. 171 - number of subjects: 174 Number of Gen2 subjects with hypoglycemic events: 167 (96%) Number of events: 7919 Incidence per subject month: .48 175 - different metric quoted: Incidence Rate Analyses The exposure adjusted incidence of ‘any hypoglycemic’ event was 1.63 per subject year vs. 0.78 per subject year exposure, for Afrezza TI and placebo, respectively. To get an incidence per subject month for Gen 2: just divide by 12 = .135 Since the subject population is the same as 171, we can derive the number of hypos in the Gen2 arm of 175: = 7919 * (.135 / .48) = 2227 hypo events So it strains credulity to believe that in a 90-day study one patient either had 3960 hypos (study 171) or 1113 hypos (study 175) - that would be 44 hypos per day (171) or 12 hypos per day (175) when blood glucose was not even being measured that often.
Afrezza has lower hypo events and incidences in every category as compared with RAAs. See pages 124-126 of the document (the version I looked has 248 pages as noted on the document itself). And when we are discussing hypo rate, we are mainly look at study 171 (the study for Type ones), i.e., a comparison with RAAs. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM390864.pdfAs for what Al Mann was referring to, even though he did not specify, IMHO, he was referring to severe hypos events. For Afrezza (on Generation 2 device), there were only 65 severe hypo events (as compared to 7979 total hypo events). It is quite possible that one or two subjects accounted for a significant percentage of these severe hypo events. And if one looks at the severe hype events, which I believe is the most important to the PWDs, Afrezza ((on Generation 2 device, i.e. dreamboat) beats RAAs hands down.
Number of severe hypo events 65 vs 130 and event rate 8.05% vs 14.45%.
Hypo events with Glucose <= 36 mg/dl 94 vs 230 and event rate 11.64% vs 25.57%.
Too bad that FDA does not allow Mannkind to include less hypo in the label. FDA reviewer had the following comment reagrding this. (Reviewer’s comment: For the T1DM trial, conclusions regarding hypoglycemia are confounded by the difference in efficacy observed between the two study arms and are entirely consistent with the fact that Afrezza was demonstrated to be less effective than comparator. For the T2DM trial, the result of greater hypoglycemia risk vs. placebo is expected.) If this is FDA's reason or excuse for not allowing Mannkind to include less hypo in the label, I personally found it to be less than persuasive. This because the Afrezza trial was designed and approved by FDA to show non-inferior and the trial did show non-inferior. I.e., FDA is acknowledging that Afrezza is non-inferior to RAAs in terms of reducing A1Cs. If so, how can FDA ignore the significant reduction in hypo events and incidence rates? Other than BP influence embedded in the FDA review process, I personally cannot find any other explanation.
IMHO, the choice of words there "entirely consistent" clearly reflects FDA reviewer's bias. Afrezza is shown to be "non-interior" to RAAs (i.e., if less effectively, only marginally so, in terms of reducing A1Cs), why is this "entirely consistent" with Afrezza's significant reduction in hypo events and incidence rates (especially severe hypo events and incidence rates)?
Did the FDA reviewer cite any study backing up his/her conclusion or showing how he/she arrives with such "entirely consistent" conclusion? At least I did not find any!
(There is no reason to look at the hypo rates for study 172, as study 172 is Afrezza vs placebo. So that is insulin vs no-insulin. Afrezza is expected to have higher hypo rates in study 172. If you add insulin to the system, you are increasing the possibility for hypo events. The FDA briefing document made that clear.) Because of this, even though Al Mann did not specify, when he was speaking about Hypo events, IMHO, he must be referring to the 171 study, not the 172 study. |
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Post by compound26 on Oct 21, 2016 9:42:23 GMT -5
Mannkind just needs one catalyst, whether it is a cash settlement, a deal with upfront fee or a buy-out, or any other positive development. For example, if Matt P. can ink a Epi deal with $250 million milestone payments in total (say first payment upon signing the deal, with the rest of the milestone payments expected to be received in every 6 months or so based on clinical and commercial developments), plus a 10% royalty in the net sales, then Mannkind's market cap will increase many fold overnight. In such a case, if Epi inhalers get an annual sales of a billion dollar worldwide, then Mannkind will be worth 2 billion based on such Epi license deal alone. If Epi inhalers get an annual sales of half a billion dollar worldwide, then Mannkind will be worth one billion based on such Epi license deal alone. And Mannkind will have enough cash to ramp up the Afrezza sales just based on such Epi license. Based on the above, Mylan will make a good deal if they buys out Mannkind for 2-4 billion in all and save that $250 million milestone payments and use it to market Afrezza. With another two years' marketing, Afrezza should be able to establish itself in the market. Thus, for 2-4 billion in all, Mylan will have got Afrezza + Epi inhales + future income from the RLS deal + other TS technology/pipeline + tax credits worth one billion plus. That will be a good deal. Does it make sense to speculate about all that stuff when it looks like Mannkind can't figure out to sell insulin to over 30 million diabetics? One of the main reasons (of course not the only reason) that Mannkind is having difficulty in selling Afrezza is that people (and Endos in particular, as medicine is a very conservative industry where doctors are constantly threatened by malpractice suits) have reservations in using lung as a drug delivery channel for concern of lung function deterioration or increased likelihood of lung cancer. Though there is no clinical/trial data supporting such a concern, however, it is also very difficult to persuade them out of such concern. I think this is currently the elephant in the room among all the barriers to entry for Afrezza. As amply noted in the posts of agedhippie , mannmade and others when they had discussions with the endos. On the other end, we do not have this problem with an Epi-inhaler as it is used only very occasionally. Therefore, once it is proved effective and approved by FDA, the barrier for marketing will be much less than Afrezza. And of course, once it is approved, to fully realize its potential, we will need an experienced partner like Mylan to market it. In hindsight, maybe Mannkind would have a much better time if they had an Epi-inhaler as their first approved product instead of Afrezza. |
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Post by compound26 on Oct 21, 2016 9:27:23 GMT -5
Mannkind just needs one catalyst, whether it is a cash settlement, a deal with upfront fee or a buy-out, or any other positive development.
For example, if Matt P. can ink a Epi deal with $250 million milestone payments in total (say first payment upon signing the deal, with the rest of the milestone payments expected to be received in every 6 months or so based on clinical and commercial developments), plus a 10% royalty in the net sales, then Mannkind's market cap will increase many fold overnight.
In such a case, if Epi inhalers get an annual sales of a billion dollar worldwide, then Mannkind will be worth 2 billion based on such Epi license deal alone.
If Epi inhalers get an annual sales of half a billion dollar worldwide, then Mannkind will be worth one billion based on such Epi license deal alone.
Mylan was able to ramp up the Epi-Pen sales from $200 million to a billion dollar in less than 10 years. I would think that will be very successful in marketing Epi-inhalers. They can even offer a combo of Epi-pen + Epi-inhaler with a discount.
And Mannkind will have enough cash to ramp up the Afrezza sales just based on such Epi license.
Based on the above, Mylan will make a good deal if they buy out Mannkind for 2-4 billion in all and save that $250 million milestone payments and use it to market Afrezza. With another two years' marketing, Afrezza should be able to firmly establish itself in the market.
Thus, for 2-4 billion in all, Mylan will have got Afrezza + Epi inhales + future income from the RLS deal + other TS technology/pipeline + tax credits worth one billion plus. That will be a good deal for Mylan.
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Post by compound26 on Oct 19, 2016 14:49:35 GMT -5
It was not ruined by the doctor IMO. That's what this thread is all about. Tell that to Laura who has had tons of people calling her! And read Mike's post^. It's going out to other stations. @sportsrancho Agree. I think the doctor did ok. OK he is not super excited about Afrezza, but that's just the reality, otherwise our scripts wouldn't be at the current levels. Additionally, the video says he has less than 5% of his patients on Afrezza, which suggests he has some of his patients on Afrezza. Even if at less than 5%, say 3-4%, he is still doing better than most Endos in terms of supporting Afrezza. There are about 1.2-1.4 million T1s in the US. If we capture 3-4% of the T1s, that will be 40,000 to 50,000 T1s on Afrezza, probably 10 times the current users base of Afrezza, which translates to around 3,000 to 4,000 weekly refills. At that level, we are pretty close to break even. In other words, if every Endo prescribes Afrezza to 5% of his patients, we will break even. |
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Post by compound26 on Oct 19, 2016 8:42:00 GMT -5
Anyone knows what is the status of this trial? It is supposed to end by March 2017. Efficacy and Safety of Alirocumab Versus Placebo on Top of Maximally Tolerated Lipid Lowering Therapy in Patients With Hypercholesterolemia Who Have Type 1 or Type 2 Diabetes and Are Treated With Insulin (ODYSSEY DM - Insulin) www.clinicaltrials.gov/ct2/show/NCT02585778Estimated Enrollment: 500 Study Start Date: October 2015 Estimated Study Completion Date: March 2017 Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure) Drug: ALIROCUMAB SAR236553 (REGN727) Pharmaceutical form:solution for injection Route of administration: subcutaneous Other Name: Praluent
Drug: insulin Pharmaceutical form:solution for injection Route of administration: subcutaneous Other Name: Lantus (insulin glargine) Drug: insulin Pharmaceutical form:powder Route of administration: inhalation Other Name: Afrezza (insulin human) Drug: statin Pharmaceutical form:tablet Route of administration: oral Drug: lipid modifying therapy Pharmaceutical form:tablet Route of administration: oral |
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Post by compound26 on Oct 18, 2016 18:46:26 GMT -5
What disappoints me is that Al Mann was mentor to so many successful/influential people in the diabetic business, e.g., the current CEO of Dexcom. Many said very nice words about Al Mann in the Al Mann Gala. However, at this critical juncture, so far none of them has offered a help hand to Mannkind, Al Mann's last baby.
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Post by compound26 on Oct 17, 2016 16:21:56 GMT -5
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Cash
Oct 14, 2016 11:21:18 GMT -5
Post by compound26 on Oct 14, 2016 11:21:18 GMT -5
I think the label has already been submitted for change. I think mnkd cares is handling all insurance issues now. I think mann foundation is another option to help financially. I think scripts need to continue to increase so we can get another partner. I think No to dilution. I think no to R/S. I think time is running out!! about the label change, "I think the label has already been submitted for change". This is just your guess, correct? I want to see if you have any source of information on that. |
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Post by compound26 on Oct 13, 2016 18:16:05 GMT -5
Wow this is an absolute bombshell. I cannot believe that anybody still uses the 2013 version of Microsoft Word. I think based on this, it is time to sell. It's been a long time since there was a compelling reason to move to a new version of Word. (Which is kind of an awful word processor to begin with, but I digress.) I am an attorney in a major us law firm and we are still using Word 2010.  |
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Post by compound26 on Oct 13, 2016 13:21:02 GMT -5
I think the biggest problem to prescription growth is that doctors and PWD remain fearful of the long-term health implications related to the respiratory system. This is in part tainted by the exubera recall/abandonment and misinformation swirling around that. Two of my partner's endos have explicitly stated this concern. One had actively turned down samples during the early Sanofi launch period, and the other hasn't prescribed Afrezza. The second (current) endo was instrumental in getting her a CGM and is aware of the diversity of treatment options. He stated that he wouldn't prescribe Afrezza until his colleagues had vetted it and there was sufficient data on its long-term safety, so maybe 2+ years down the road. He did think it would be a good option for the extremely needle-phobic who have associated poor glucose control. We could debate the validity of their concerns and their motives, but these are the anecdotal facts I have encountered in the past 1.5 years. These are concerns that will exist regardless of who is doing the marketing and education. Exubera has left a bad taste in people's mouths and Afrezza is being hurt by it. You can't point all the blame to Exubera, but there is certainly a predisposition now. That sounds rights. The following comments following Haynes'a Afrezza video illustrate this: Roy L Flush 10 months ago Why is the stock so low? I would have thought by now it would have soared. Who turned you on to this drug? Hayes Fejer 6 months ago My husband's endocrinologist actually mentioned it, but I had to ask my endo for it. Since it is so new I think many endocrinologists are hesitant to suggest it because of the lack of data published on it. I just got my second lung function tests done in order to get the prior approval my insurance requires. Roy L Flush 6 months ago It's really not that new. At least 5 years I think. Hayes Fejer 6 months ago It's my understanding that Afrezza didn't receive FDA approval until mid 2014 and wasn't widely distributed until January 2015. |
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Post by compound26 on Oct 13, 2016 12:51:40 GMT -5
The sound of inhaling afrezza was noticed by early users long time ago. See this video at around 4:30". But it is a very minor issue (as the video indicates, only if you want to inhale Afrezza during a meeting or lecture and you want to be discreet, then that may be an issue, but imagine you want to inject yourself during such occasion). www.youtube.com/watch?v=CbixFksNU48 |
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Post by compound26 on Oct 11, 2016 13:11:45 GMT -5
Wow, saxcmann, I assume you facilitated that? Or was it mere coincidence? Nope, not me. They reached out to him. that's great. I assume you are talking about the same "friend" you mentioned before. "To confirm what sports said mnkd is targeting currently prescribing endos first. Dr Combs will probably be hit soon. Mnkd has already met with my endo friend and it was very positive. They will meet again in late August. He is prescribing 2-4 afrezza PTs per week. mnkd has also reached out for him to speak. So things are moving well. Hope my feedback helps." Read more: mnkd.proboards.com/user/363/recent#ixzz4MnkazNtd |
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