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Post by mnholdem on Nov 18, 2015 7:48:16 GMT -5
Curious...sorry.... off topic.. couldn't start a new thread.. Administrators .. thanks for all you do here.. Is there any way we can get the page numbers on the bottom of the page too.. would make it easier then to scroll all the way back to the top to go to the next page.. Thanks if you can. The page number location is not something we can alter. Yes, it would be nice to also have them at the bottom of the page. All I can say is that the numbers are visible all the way down to the reply box, but if you scroll to the very bottom of the page, they do disappear. If you are using a mobile device, you should see buttons along the bottom, one of which is "Top". Clicking this will move you instantly to the top of the current page, eliminating the need to scroll back up... |
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Post by cathode on Nov 18, 2015 9:24:31 GMT -5
Hakan Edstrom - Chief Executive Officer It’s very active way of discussion. People asked about Europe a lot. I mean, we did design our Phase 3 studies with European mind and based on discussions we have with them. So there is some hope that we could file there fairly quickly. That said, I mean, we asked them years ago about that and we all know things change in the regulatory agencies, so about to be approached and talk to. And I think there are these discussions like that going on to see what if anything might still be required to file in those kinds of jurisdictions. Read more: mnkd.proboards.com/thread/3776/evidence-maa-chmp-oct-agenda?page=7#ixzz3ro93dip9Yes, I saw this quote earlier. I am fairly confident MNKD management is aware of this "insulin Human" submission and the speculation it has caused. In my opinion, it would be very easy for Matt or Hakan to just come out and say, the EMA submission for "Insulin Human" is definetly NOT Afrezza. This would end all speculation, but they don't. The results of the EMA discussion on this "Insulin Human" will be released November 25th. We don't have long to wait. Good Luck to you. Who cares about the speculation of a few people. I certainly don't. I put my own DD ahead of whatever speculation other people make. This is very unlikely to be Afrezza, and I don't want management wasting their time addressing rumor and speculation that arises from the retail discussion boards. Beyond that, it is really the job of Sanofi to shed light on the approval status, not MannKind. |
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Post by peppy on Nov 18, 2015 9:39:56 GMT -5
I think there have been discussions on whether this is related to Afrezza. Argument against that this is Afrezza has been made (i.e., no name, biosimilar, etc.). I am not going to repeat them. I think there are also a few arguments for that this is related to Afrezza. 1. the timeline seems to match. It appears this application first generated a CHMP list of questions in October 2014. So this application was probably submitted anywhere between June 2014 to Sept. 2014. Given that Afrezza received affirmative Adcom vote in April 2014 and FDA approval in June 2014, it is not inconceivable that Mannkind had most of the documents ready to submit for EMA approval in the summer of 2014. Note that in this interview done in Sept. 2014, Al Mann said "The plan is to launch Afrezza in the first quarter of 2015. We will spend the next few months preparing for that launch. Sanofi had already done a great deal of work preparing for the launch — they started even before we had signed the agreement. They have set up an extensive team for the commercialization and that team is hard at work in planning the launch." It won't surprise among the work done by Sanofi before the signing of the partnership, there was coordination between the parties on EMA approval. Given the above, it won't surprise me that Mannkind prepared and submitted the EMA application in June/July 2014 and Sanofi took it over (or most part of it if the application was still in the name of Mannkind) after the partnership was signed, or alternatively, Sanofi had already discussed the EMA application with Mannkind before the partnership agreement was formally signed and then submitted the application right after the partnership agreement was signed. Also, since both Sanofi and Mannkind knew that the EMA approval was a lengthy process, there was no reason for them to wait. Rather, they probably wanted to submit an application as early as possible. Note that Toujeo received FDA approval on Feb. 25, 2015 and got the EMA CHMP opinion on Feb. 26, 2015 and EMA approval two months later. So for Toujeo, the FDA and EMA applications were carried out around the same timeline. 2. Mannkind and Sanofi have the incentive to keep the application underradar. So no reference to Afrezza or technoshere is understandable, if it is permitted.
3. the fact that the applicant actually extended the deadline to respond to the questions suggest that this is a major (and complex) application (not like a simple biosimilar product).
4. the fact that Sanofi has the clamp study done in Germany, instead of in US or some other developing countries (cheaper) suggests that the clamp study data may be used for the EMA application and approval.
5. the fact that Sanofi completed the study ahead of schedule (I understand that it was originally supposed to complete in December 2015) in September 2015 suggests that Sanofi needs the data for use at sometime after September. This seems to match the October oral presentation date set by the CHMP.
6. EMA formal approval is generally given two months after CHMP opinion.
If this is related to Afrezza, then Afrezza will get formal EMA approval in Jan. 2016. If that is the case, this seems to explain why Matt used the cash to paid off the debt as he probably was pretty certain that he would get $30/35 million milestone payment for EMA approval in another quarter. (If there is EMA approval, then perhaps also the rumored $25 million milestone payment for the Sanofi insulin certification).
7. If there is going to be EMA approval and global expansion, this also seems to explain the subzone application recently done by Mannkind.
8. This also seems to explain why the JV's expenses have been pretty high. If we just for argument's sake, take out $10 million of expenses per quarter for EMA application activities (there probably is team working on the application and approval), then the expenses will look much reasonable.
Anyway, the above are just my wild speculations. Just for your entertainment.  I would give it a 50% chance that this is Afrezza-related.
I have been away for a bit and just now reviewed this. I think your logic is reasonable and many of of your comments seems possible. I cant wait till then, we need a break!!!! Jay, thank you. Well thought out, well written. I believe there is a fine chance you nailed it. (I looked hard at compounds time line yesterday) So many super intelligent and well written people on this board. Thank you for every one of your thoughts.
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Post by gamblerjag on Nov 18, 2015 12:02:30 GMT -5
Mnholdem.. thanks for your reply..
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Post by compound26 on Nov 18, 2015 12:12:01 GMT -5
Just FYI, Arena Pharmaceuticals's and Vivus's FDA and EU filing timeline: On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes. On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who "have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol. en.wikipedia.org/wiki/LorcaserinArena receives Day 180 List of Outstanding Issues from CHMPtheflyonthewall.com January 22, 2013 9:41 AM finance.yahoo.com/news/arena-receives-day-180-list-144128647.htmlArena Pharmaceuticals disclosed earlier that it received the Day 180 List of Outstanding Issues from the EMA's Committee for Medicinal Products for Human Use, or CHMP. The issues will need to be addressed before the CHMP can recommend BELVIQ for marketing approval in the EU, the company said. The major objections relate to previously identified non-clinical and clinical issues, including tumors in rats, valvulopathy and psychiatric events, and the CHMP requests that the company further justify BELVIQ’s overall benefit-risk balance taking these issues into consideration. Arena has been asked to address the issues in writing. The CHMP also plans to consult with independent experts who will provide recommendations on the outstanding issues. The CHMP is expected to reach its final opinion on the BELVIQ MAA by Day 210, which Arena continues to expect in the first half of 2013.____________________________________________________________________________________ EU Rejects Obesity Drug Qsiva for the Second Time
Lisa Nainggolan February 26, 2013
www.medscape.com/viewarticle/779897The European Medicines Agency (EMA) has again refused to grant approval for the new obesity treatment phentermine/extended-release (ER) topiramate (Qsiva, Vivus) in the European Union. The EMA's Committee for Medicinal Products for Human Use (CHMP) first rejected the product in October but was asked by the company to reexamine the decision. Defending its second rebuttal, the CHMP said it "has concerns about the medicine’s long-term effects on the heart and blood vessels, particularly due to the effects of phentermine, which is known to increase the heart rate but whose long-term effects are not clear." Second, there are "concerns about the long-term psychiatric effects and cognitive effects related to the topiramate component of Qsiva," it noted. The EMA noted that there was a high probability that, if approved, "the medicine would not be used strictly for the intended patients. The applicant did propose measures to reduce this risk, but the measures were considered difficult to implement in practice," so it concluded that "the benefits of Qsiva did not outweigh its risks." Vivus says the European agency would also require a cardiovascular-outcomes trial to establish long-term safety before the product could be approved. US Approved Product Under REMS Last July
Peter Y. Tam, president of Vivus, said in a statement that the company "is disappointed with the CHMP decision. We have worked diligently throughout Europe with key opinion leaders and regulatory and risk management experts to highlight the favorable safety and efficacy profile of Qsiva. Despite the positive recommendation of CHMP's own Scientific Advisory Group (SAG) and the high unmet medical need in obese patients, a majority of CHMP members have failed to recognize the importance of making this treatment option available, particularly for patients whose only effective intervention is surgery." The EMA's decision runs counter to that of the US Food and Drug Administration (FDA), which approvedphentermine/topiramate ER, which acts as an appetite suppressant, in July last year. It is marketed as Qsymia in the United States under the risk evaluation and mitigation strategy (REMS), which includes guidance for safe prescription — the drug will be dispensed only through specially certified pharmacies — and use. In addition to this safety measure, the manufacturer will conduct postmarketing studies, including the long-term CV outcomes trial suggested by the FDA's advisory panel in February 2012 to investigate the effect of phentermine/topiramate ER on risk for major adverse CV events, such as myocardial infarction and stroke. It took 2 attempts to get Qsymia approved in the US: the product was rejected the first time it went in front of an FDA advisory panel in 2010, and the agency subsequently turned it down. |
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Post by mnholdem on Nov 18, 2015 19:02:17 GMT -5
EMA
Product-specific biosimilar guidelinesReference no. EMEA/CHMP/BMWP/32775/2005 Rev.1 Revision of the guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues. PDF documents: - Overview of comments
- Adopted guideline
- Second draft guideline
- First draft guideline
- Concept paper
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp--- I dug up this EMA site today. Perhaps someone can read through these to report what the EMA actually considers in determining whether to classify an insulin application as a biosimilar. I have grandkids over tonight so I'll be very occupied for the evening. NOTE: ...as in occupying army.   
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Post by james on Nov 18, 2015 19:52:55 GMT -5
I don't think there's anyway that Afrezza could be considered biosimilar to other substances already approved in the EEA, even if certain characteristics match other approved substances. The fact that Exubera was previously approved means that the inhalation characteristic was already approved, but the composition of the powder, basic molecular structures of the active compound, pharmacokinetics, etc. are entirely different. There isn't anything else like Afrezza in the EEA, so I would be shocked if it could meet that criteria. A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the EEA.
Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established.
Here are a couple of official documents that put this 'insulin human' application under the biosimilar indication: www.ema.europa.eu/docs/en_GB/document_library/Report/2015/09/WC500193281.pdf EMA Applications under evaluation Sept 2015 www.ema.europa.eu/docs/en_GB/document_library/Agenda/2015/06/WC500187793.pdf PRAC Agenda for June 2015 It's mystifying, however, why a biosimilar insulin should take over a year to achieve approval. At one point the clock was stopped on 120 day questions. Also, what is this then? There was some speculation that this is for an update to Insuman, but this does not seem likely to me. |
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Post by cathode on Nov 18, 2015 19:55:23 GMT -5
EMA
Product-specific biosimilar guidelinesReference no. EMEA/CHMP/BMWP/32775/2005 Rev.1 Revision of the guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues. PDF documents: - Overview of comments
- Adopted guideline
- Second draft guideline
- First draft guideline
- Concept paper
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp--- I dug up this EMA site today. Perhaps someone can read through these to report what the EMA actually considers in determining whether to classify an insulin application as a biosimilar. I have grandkids over tonight so I'll be very occupied for the evening. NOTE: ...as in occupying army. Skimmed the 'Adopted Guidelines' and read what seemed like the important parts. Copied the obvious bits here. It doesn't say broadly what a biosimilar is, but it does define insulin and RAA molecules. I didn't see anything that stated where the line was drawn between biosimilar and new medication. This document is a FAQ on biosimilars and answers "What is a biosimilar" on the first page. www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdfFrom what I read, I am further convinced that SNY would not submit Afrezza as a biosimilar. It is not a copy of an existing drug which has been on the market. It probably has a different efficacy than existing drugs. Of course, I am waiting like everyone else on the results of the Afrezza clamp study to see whether that is the case. |
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Post by slugworth008 on Nov 18, 2015 19:57:20 GMT -5
It seems that anything involving Afrezza, MNKD, SNY-MNKD is an enigma, wrapped in a mystery shrouded by clouds, however,
Chief inspector Clouseau is currently investigating this matter.
Here is his recent quote regarding the investigation: "With MNKD, surprises are rarely unexpected."
(If I've used this in another post - forgive me - it's been a long week already)
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Post by lakers on Nov 18, 2015 20:38:27 GMT -5
Oversea-version, German-insulin Afrezza is bio similar to U.S. Version, French-insulin Afrezza. One stone kills Two birds.
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Post by cathode on Nov 18, 2015 21:24:20 GMT -5
Oversea-version, German-insulin Afrezza is bio similar to U.S. Version, French-insulin Afrezza. One stone kills Two birds. Page 2 of www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf"How are biosimilar medicines evaluated in the EU? Because the reference medicine has been authorised in the EU for several years and its clinical benefit is established, some studies carried out with the reference medicine may not need to be reproduced." US version is not yet approved in EU. |
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Post by mnholdem on Nov 18, 2015 22:03:59 GMT -5
Personally, I would be astounded if this mystery EMEA Case No. 005838 is Afrezza, but I continue to dig, since I typically don't like to leave any stone unturned, whether it kills two birds or not.
Besides, I am curious who the applicant is for this insulin human that appears to be on the verge of approval by EMA. I'm even more curious how any pharmaceutical company can get the kind of confidential treatment that surrounds this case.
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Post by rrtzmd on Nov 18, 2015 22:14:41 GMT -5
EMA
Product-specific biosimilar guidelinesReference no. EMEA/CHMP/BMWP/32775/2005 Rev.1 Revision of the guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues. PDF documents: - Overview of comments
- Adopted guideline
- Second draft guideline
- First draft guideline
- Concept paper
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp--- I dug up this EMA site today. Perhaps someone can read through these to report what the EMA actually considers in determining whether to classify an insulin application as a biosimilar. I have grandkids over tonight so I'll be very occupied for the evening. NOTE: ...as in occupying army. I posted yesterday: "There is really nothing mysterious that I can see. The October meeting lists one application for insulin under "Non-orphan generic and biosimilar medicinal products." Obviously, afrezza is not a generic. If you look at how the agency defines "biosimilar": defining biosimilar...and look under "Application of the biosimilar approach" on pages 4 and 5, it should be obvious that afrezza does not qualify. Although several of the details would likely disallow it, perhaps the most relevant is probably this one: "The posology and route of administration of the biosimilar must be the same as those of the reference medicinal product." While "route of administration" could make afrezza similar to exubera, posology -- referring to dosing -- is completely different than any other product -- at least I can think of no other drug that doses by blue and green cartridges. Hence, whatever insulin is being referred to as having an application under "generic and biosimilar" extremely unlikely to be afrezza." The link is to a pdf that gives a full description of how they view "biosimilar." As I pointed out, there are several things that would likely exclude afrezza from being biosimilar to anything. The most relevant one -- in my opinion -- was "posology," since afrezza is dosed in various colors of "cartridges." |
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Post by mnholdem on Nov 18, 2015 23:18:51 GMT -5
I'm inclined to agree. In addition, this section of the new EMA guideline should rule out Afrezza being considered as a biosimilar:
EMEA/CHMP/BMWP/32775/2005_Rev. 1 Effective date: 01 September 2015
5. Clinical studies
Pharmacology studies
In addition to similar physicochemical and functional characteristics, demonstration of similar pharmacokinetic (PK) and pharmacodynamic (PD) profiles is considered the mainstay of proof of similar efficacy of the biosimilar and the reference insulin. For this purpose, cross-over, preferably double-blind hyperinsulinaemic euglycaemic clamp studies using single subcutaneous doses of the test and reference agents are considered most suitable. The wash-out phase between study periods should take into account the duration of action of the investigated insulin preparation to avoid carry-over effects. The time-concentration and time-action profiles should preferably be studied simultaneously (in the same clamp study). Additional pharmacology studies for intravenous use, if applicable, are not required.
www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500184161.pdf.
We've been hearing for years how Afrezza PK/PD profile is significantly different than RAA insulin. Although, I don't think I've ever seen a PK/PD profile comparing Afrezza and the other human insulin brands Humalin or Novolin, which are not analogues like Humalog and Novolog. |
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Post by Deleted on Nov 19, 2015 20:22:53 GMT -5
www.ema.europa.eu/docs/en_GB/document_library/Minutes/2015/03/WC500183844.pdffeast on the above to keep the forum bz.. cant even decipher PKWP position paper on specific questions: 1. Evaluation of orally inhaled medicinal products: For adoption 2. Clarifications on the “Evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function” guideline: For adoption
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I would give it a 50% chance that this is Afrezza-related. 
