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Post by rrtzmd on Oct 19, 2015 20:08:17 GMT -5
I was speaking with Chad Smutney. He has quite a few patents to his name, so I'd argue he knows what he's talking about. Here's a list: patents.justia.com/inventor/chad-c-smutneyThe display at the ASM on this was enlightening. There was even a model that showed how the drug disbursed based on the breath taken / airway. I took a lot of things from this display. Ignorance from Chad and his team was definitely not one. I don't think anyone is going to bend over to inhale Afrezza, but I do think the shorts may have to do so...metaphorically...because of Afrezza. Mr. Chutney is a mechanical engineer who contributed to the inhaler design. I certainly wouldn't argue that he's ignorant, nevertheless the "aerodynamics" of the particle are minimally relevant to their lung distribution. Think snowflakes versus dust in a hurricane and you realize that shape, size, weight make little difference to how the hurricane disperses the particles. In the case of afrezza, you already lose 60% of the insulin to upper airway deposition due to turbulence slowing the particles down and allowing them to be "captured." The slower they get, the more that are trapped where they can't have any effect. And, yes, my "instructions" were "extreme," but they were meant to illustrate the idea that straightening the airway allows more time for vortex formation and raises the energy of the airstream. This is one reason why "spacers" are recommended for most inhaler devices -- see the link in my previous comment. |
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Post by rrtzmd on Oct 19, 2015 12:45:06 GMT -5
What I was trying to get at in my original post was more along the lines of trying to estimate the original expectations as to afrezza sales. I felt the requirement that the contract couldn't be cancelled without 2 years notice was pretty extreme, and MNKD agreeing to it meant it must have been pretty confident about its estimated need at the time. So I just wondered how many afrezza cartridges could be produced with 24 million euros worth of insulin and how that compares with the number of cartridges they are actually selling.
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Post by rrtzmd on Oct 19, 2015 11:42:16 GMT -5
Variation of pharmacokinetic profiles of some antidiabetic drugs from nanostructured formulations administered through pulmonary route benthamscience.com/journals/current-drug-metabolism/article/135824/Editor-in-Chief: Michael Sinz Bristol Myers Squibb Wallingford, CT USA Abstract Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. WHO projects that diabetes death will be double between 2005 and 2030, where 347 million people worldwide have diabetes as per the report of 2013. The increase in the prevalence of diabetes is due to three influences - lifestyle, ethnicity, and age. Current challenges in diabetes management include optimizing the use of the already available therapies to ensure adequate glycemic condition, blood pressure, lipid control and to reduce complications. At present, several pieces of research have been focusing on new management options for diabetes. Among these options, the use of nanomedicine is becoming an eye catching and most promising. Currently, nanoparticles and nanoliposomes are thrust areas of research to treat any deadly disease like diabetes. These drug delivery systems ultimately result in longer circulation half-lives, improved drug pharmacokinetics, reduced side effects of therapeutically active substances that may be insulin and non-insulin. Moreover, the pulmonary route is the most promising alternative route of drug delivery since it is non-invasive and lungs have a large surface area for absorption of drugs, richly supplied by capillary network. Thus, the present review summarizes the pharmacokinetic parameters and challenges in the field of nanoparticles and nanoliposomes of insulin and other antidiabetic drugs given through pulmonary route to treat diabetes effectively. Thanks, but I often wonder whether such articles are merely to pad curriculum vitae. Similar articles about nano-this and nano-that have come out multiple times a year for the past 15-20 years. They always seem to say the same things over and over, but rarely impart any real useful information. |
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Post by rrtzmd on Oct 19, 2015 11:35:06 GMT -5
I would argue that whoever you spoke to didn't know what they were talking about. Reaching the deepest alveoli requires maximizing airflow energy and minimizing turbulence. The lungs do this by effecting a vortex of the inhaled air as it moves through the upper airways. A vortex with high rotational velocity possesses enough energy to push the airflow into the extremely narrow distal tubes. The exubera "bong" effectively "extended" the upper airway allowing a better, stronger vortex to form. One reason that a "bong" is so effective at delivering smoke is the way it generates a strong vortex: bong gifAt each bifurcation of the lung "tube," turbulence is generated which results in a loss of energy and momentum. The large amount of energy imparted by the vortex rotation helps overcome the bifurcation effect. A second beneficial effect is that the rotation of the air forces the particles to the center of the stream -- sort of similar to the way a figure skater increases her rate of spin by pulling her arms except, in this case, it's the the increasing rotation speed forces the "arms" in. This prevents contact with the walls on the way to the alveoli. The energy of the afrezza particles themselves is so small relative to the air flow that their own aerodynamics are irrelevant. On the other hand, of primary importance is the method of inhaling. I suspect most afrezza users don't inhale properly. Most seem to think that exhaling as much as they can and then taking a sudden, huge breath is required. That is likely not the case. Indeed, it probably increases the amount of afrezza deposited in the upper airways. Taking a sudden huge breath imparts a great deal of turbulence to the powder which results in it being tossed about and collecting on the walls of the trachea. An analogous situation exists with other inhalers: inhaler difficulties
Arguably, the best way to use the afrezza inhaler -- although rather extreme -- would be first to bend over so that the torso is at 90 degrees to the legs, look forward parallel to the floor -- all this is to "straighten" out the airway as much as possible so as to reduce turbulence -- exhale normally, grip the inhaler with the lips, then slowly and steadily inhale, hold for a count of 5-10 and then slowly, steadily exhale -- particles are also deposited during the exhalation process. An alternative might be the use of a "spacer" where the extended tube effects are similar to the "bong." |
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Post by rrtzmd on Oct 18, 2015 23:06:35 GMT -5
From the most recent conference call by amphastar: So, right now, as you know, our biggest customer there is MannKind and they’re purchasing insulin for their Afrezza product. Now, they have an annual commitment. So, it’s not a quarterly commitment. And if you took their annual commitment and divided by four, you get something pretty close to that five million or so, a quarter that we had from them in the first quarter. However, they purchased less than that this quarter. And some of the timing of some of those sales are somewhat based on us, somewhat on their needs. So, but I will say that because they did purchase less in the first half of the year or less than half of their annual commitment, then they will be purchasing more than half the commitment in the second half of the year. The timing of that is not; there is no contractual obligation for them to take it, half of that remaining thing in the third and half and the fourth. So, the timing is variable. It could come in the third or the fourth. Mostly like it will not be all one quarter or the other quarter, most likely we will be shipping to them in both quarters. However it’s probably more likely that amount that was short in this quarter is more likely to be made up in the fourth quarter than the third quarter. Full transcript at www.seekingalpha.comThat definitely sounds like MNKD must buy 24 million euros worth a year one way or another. So, any guesses as to how much insulin that is? How much afrezza could be manufactured? |
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Post by rrtzmd on Oct 18, 2015 21:16:10 GMT -5
When Matt Pfeffer turned the 1st Quarter earnings conference call over to Al Mann, these were Al's first statements (note that SA may have transcript errors): "Thank you, Matt. After approval of Afrezza by the FDA on June 27, we've been preparing for the launch. In September, we finalized a partnership agreement with Sanofi, who will provide the commercialization with sales and marketing, and also responsible for further clinic and regulatory activities, and that launch was initiated in February."This next statement of Al's is what I find to be quite interesting: "We are getting reports, post-approval Sanofi results and early use of Afrezza that we like to share with you, but it is too soon to have publication of any such reports and peer review journal. Therefore, all we have at this time must be considered anecdotal and cannot be presented in the earnings call."
----- Perhaps more than anybody at MannKind Corporation, Al Mann would have inside knowledge of Sanofi's strategy concerning Afrezza. So what does it mean when he states, "it is too soon to have publication of such reports". What reports, what post-approval Sanofi results is he talking about? There are two questions I have that, in my opinion, haven't been thoroughly discussed in terms of feasibility. 1. Is it likely that Sanofi has been gathering patient data (this is allowed by HIPPA) from early prescribers for a peer review publication in a medical journal, and; 2. Is it mandated that such studies must be registered with the FDA before they commence? ----- This is not a shameless pump or speculation. Rather, I am making an honest inquiry. To date, we've only seen peer reviews of Afrezza Phase III trial results. Is it common after a drug launches for studies to be conducted by physicians, universities and BP which are outside the oversight of the FDA, but which can have an affect on prescriber adoption? Certainly, SNY can collect data from pretty much any source they wish as long as HIPPA guidelines aren't violated, and they are also free to publish pretty much anything anywhere. More relevant is whether any publication short of one clearly demonstrating afrezza is superior to lispro would be of any value at this point. Right now, afrezza needs third party payors, and they, in turn, "need" hard data such as that provided by clinical trials. Long term, user and physician experience might have an impact on their decisions, but the short term needs a high quality trial. |
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Post by rrtzmd on Oct 18, 2015 20:42:44 GMT -5
Thanks for link -- it's more detailed than the one I was using. The "cancellation fee" didn't make any sense but the way that Amphastar shareholder presentation was worded wasn't clear. I also noticed this in that presentation:
"Signed supply agreement with MannKind to supply RHI for Afrezza® − Agreement specifies minimum annual sales of 24 million euros annually for 5 years from 2015 - 2019"
I don't see anything corresponding to that in the link you provided. It just says:
"Each year during the term of this Agreement, no later than December 1st, MannKind shall provide to AFP a schedule for delivery of the following calendar year’s annual Product Purchase Commitment Quantities."
So is the Amphastar presentation correct in that MNKD must order 24 million euros worth of insulin next year whether they need it or not? They don't specify how much insulin that actually buys. Any idea how much afrezza that could make?
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Post by rrtzmd on Oct 18, 2015 11:24:43 GMT -5
Amphastar France Pharmaceuticals Investor Presentation September 2015 Recombinant Human Insulin (RHI) − Signed supply agreement with MannKind to supply RHI for Afrezza® − Agreement specifies minimum annual sales of 24 million euros annually for 5 years from 2015 - 2019 − Further amounts may be purchased − Several other customers currently purchasing R&D quantities for filings outside of the US − One customer buying production quantities outside of the US
− Signed Option Agreement to supply additional quantities in 2016-2019
− If MannKind chooses not to exercise its option, they pay a cancelation fee Lakers, the question is why would someone outside the US be buying production quantities? I think we all know the answer to that question. But do the Shorts? I think they know and the run down on the share price should end this year or the beginning of next. I hope that it is sooner then later. Indeed, I asked some questions about the Amphastar agreement earlier: questions about Amphastar deal
No one offered any answers, however. It seems to me that 120 million euros worth of insulin could make an awful lot of afrezza. Given the current level of sales in the US, why would Sanofi want to purchase quantities outside the US for more afrezza now, especially considering they haven't yet applied anywhere outside the US for approval? And your link brought up yet another question. It says: "-- [Mannkind?] Signed Option Agreement to supply additional quantities in 2016-2019 − If MannKind chooses not to exercise its option, they pay a cancelation fee" So, does that mean that if MNKD does not exercise its option to buy more insulin beyond what's already contracted, then they'll have to pay a cancellation fee on that option? Whoever heard of paying a cancellation fee for not exercising an option? The SEC document didn't mention any cancellation fees of any sort. |
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Post by rrtzmd on Oct 16, 2015 20:23:55 GMT -5
Did you read any of it? It was actually pretty funny. Although they never say it exactly, they imply that they can bypass the blood-brain barrier by accessing the exposed olfactory neurons at the top of the nasal cavity with this "sophisticated" device of theirs. But the only thing "special" appears to be that the device uses a gas cartridge -- similar to what's used in a pellet gun -- to impel the spray with added force. They claim that this forces the drug into the mucous coating the exposed neurons and that the neurons absorb the drug and transport it on into the brain. Unfortunately, although the idea behind the method has been discussed in the past, there is no good evidence to suggest that neurons can uptake and deliver drugs -- at least not in quantities sufficient to achieve therapeutic concentrations. However, the founders of the company did offer an abstract comparing their device's delivery to nose drop delivery of morphine in Sprague-Dawley rats. Of course, if you can imagine trying to apply nose drops to a rat, you'd have to wonder whether "operator error" may have had a role in achieving "significant" results. And that is basically all they have so far -- no human studies actually using a drug. But I'd almost be willing to bet that if you keep an eye out, you'll see their IPO coming to a broker near you. |
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Post by rrtzmd on Oct 15, 2015 19:01:55 GMT -5
Sanofi is best partner as they dont have competing meal time insulin..apidra doesnt have a major market while the others do... ( Novo and Lilly's - )... so these thoughts should be put to rest... Al owns 40% and knows whats best lol Yeah Al owns 40% and over 50% of shares are shorted. Not making any conclusions here, just saying, if Al wanted a squeeze, Al could get one. Likewise with Sanofi. We need to get Lizbeth Salander involved... Since Al does have such a large interest, would it be possible that he may have "shorted against the box" to reduce the risk of serious loss? |
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Post by rrtzmd on Oct 14, 2015 19:25:53 GMT -5
My own impression from reviewing the original prospectus is that the 9 million shares were part of a hedge established for some institution buying the convertible bond. The way it reads, it sounds like, once the bond came due, the convertible holder simply converted the bond, handed those shares over to BoA, who, in turn, returned them to MNKD. Has MNKD confirmed or denied that the shares have already been returned? Not returned YET! - confirmed Confirmed how? |
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Post by rrtzmd on Oct 13, 2015 23:24:53 GMT -5
From the SEC filing:
"On July 31, 2014, MannKind Corporation (“MannKind”) and Amphastar France Pharmaceuticals S.A.S., a French corporation (“Amphastar”), entered into a Supply Agreement, pursuant to which Amphastar will manufacture for and supply to MannKind certain quantities of recombinant human insulin (“Insulin”) for use in MannKind’s product AFREZZA®. Under the terms of the Supply Agreement, Amphastar will be responsible for manufacturing the Insulin in accordance with MannKind’s specifications and agreed-upon quality standards. MannKind has agreed to purchase annual minimum quantities of Insulin under the Supply Agreement of an aggregate of approximately €120.1 million in calendar years 2015 through 2019. MannKind may request to purchase additional quantities of Insulin over such annual minimum quantities.
Unless earlier terminated, the term of the Supply Agreement expires on December 31, 2019 and can be renewed for additional, successive two-year terms upon 12 months written notice, given prior to the end of the initial term or any additional two year term. MannKind and Amphastar each have normal and customary termination rights, including termination for material breach that is not cured within a specific time frame or in the event of liquidation, bankruptcy or insolvency of the other party. In addition, MannKind may terminate the Supply Agreement upon two years’ prior written notice to Amphastar without cause or upon 30 days prior written notice to Amphastar if a controlling regulatory authority withdraws approval for AFREZZA®, provided, however, in the event of a termination pursuant to either of these scenarios, the provisions of the Supply Agreement require MannKind to pay the full amount of all unpaid purchase commitments due over the initial term within 60 calendar days of the effective date of such termination."
A number of things stand out:
1) 120 million Euros seems like an awfully lot of insulin to contract ahead of a launch. How much afrezza would that produce?
2) MNKD can't terminate without two whole years written notice? Is that not an awfully long "lead time" for MNKD to anticipate its insulin needs -- especially ahead of the launch?
3) MNKD is required "to pay the full amount of all unpaid purchase commitments due over the initial term," but what are these "commitments." Is MNKD required to purchase so much per quarter? Have they bought any so far?
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Post by rrtzmd on Oct 13, 2015 21:58:40 GMT -5
How do you guys evaluate the financial situation of MNKD? Here is my take. Please feel free to correct me:
| Cash end 2nd qtr | 107 | | Debt settled cash | -50 | | Afrezza sales to SNY (at costs) 3 qtr | 5 | | ATM Facility | 50 | | Al Mann loan | 30 | | 3rd qtr cash burn | -20 | | restricted cash due to Deerfield | -25 | | cash or available loans (end 3rd qtr) | $97M |
Looking at your assessment, why was the convertible settlement such a "crisis"? Between the 107 million cash, the "ATM facility," and the "Al Mann loan," it appears as though they had enough "elbow room" to settle the debt outright. |
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Post by rrtzmd on Oct 13, 2015 21:47:18 GMT -5
My own impression from reviewing the original prospectus is that the 9 million shares were part of a hedge established for some institution buying the convertible bond. The way it reads, it sounds like, once the bond came due, the convertible holder simply converted the bond, handed those shares over to BoA, who, in turn, returned them to MNKD. Has MNKD confirmed or denied that the shares have already been returned?
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Post by rrtzmd on Oct 13, 2015 10:35:30 GMT -5
Does anyone know if Exubera ever got "Preferred status" insurance coverage? I don't believe exubera was around long enough to achieve "preferred status": example of exubera assessment |
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