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Post by agedhippie on May 25, 2024 12:30:09 GMT -5
Thanks. I am not sure how I missed that! The trial doesn't seem to be registered on the Clinical Trials web site even if I manually look through all completed clofazimine trials which is a bit weird. They PR says detailed data findings will be presented in upcoming publications and scientific conferences, but it doesn't seem to have happened as far as I can see. That's not a big deal though as it would be superseded by the current trial results anyway.
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Post by agedhippie on May 24, 2024 23:07:08 GMT -5
It's not always down to the doctor or VDEX would always be able to prescribe Afrezza. It's often down to the payer, and especially for very expensive drugs. I don't see it as a huge problem since the probable progression would be multidrug -> oral Clofazamine -> 101. The initial multidrug step is likely to be a few months so the timescale is largely unaltered by the extra step as I expect the oral step would fail fast and they would move on to MNKD-101. Until there is an approved oral Clofazamine for NTM (Lamprene is not approved for NTM) the path would have to be multidrug -> MNKD-101 since an insurer cannot specify an off-label drug. Wouldn't oral use of Clofazimine that "fails" (doesn't cure) run the risk of developing resistance to Clofazimine? Seems if inhaled Clofazimine proves to be able to totally clear the infection, it should be step 2 after non-clofazimine multi-drug. Yes, I would expect it to be the step after multidrug. The insurer cannot specify an off-label drug so they cannot specify oral Clofazimine currently. I am not sure if inhaled Clofazimine has been studied in humans. All the work seems to have been in animals with this trial as a joint phase 2 and 3. That implies a phase 1 somewhere but I cannot find it and it is not listed in the clinical trials site.
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Post by agedhippie on May 24, 2024 8:33:14 GMT -5
Almost exactly that. This is the wording from the contract defining the roles: WHEREAS, Manufacturer is a pharmaceutical company engaged in the development, manufacture and sale of Active Pharmaceutical Ingredients (“API(s)”);WHEREAS, Supplier is a pharmaceutical company engaged in the marketing, distribution and sale of Active Pharmaceutical Ingredients (“API(s)”);WHEREAS, Supply Party is willing to manufacture and supply the API(s) to Purchaser upon the terms and conditions set forth herein.WHEREAS, Purchaser is a company that is engaged in the development, distribution and sale of certain pharmaceutical products utilizing the APIIt identifies Yonsung Fine Chemicals (aka. YS Lifesciences) as the manufacturer, LGM Pharma as the supplier, LQDA as the purchaser, and defines the supplier party as the combination of the manufacturer and the supplier. The testing and certification is the responsibility of the manufacturer, and the role of the supplier is to forward that paper work along with the drug. LQDA is also required to inspect the drug itself on delivery to ensure that it conforms to the specification. Aged, are you claiming that LGM never has possession (at any location) of the API treprostinil enroute to LQDA? I guess there's legal possession and physical possession so please break it down I am not a lawyer but it seems this would be a point that could cause a delay. Basically LGM performs the same role as FEDEX or UPS. They pick up a consignment, complete the paperwork, and deliver it. Think of this like shipping a FEDEX package internationally - you contract with FEDEX for them to move a package from point A to point B with all the attendant customs paperwork and package tracking. Once FEDEX accepts the package it is legally in their care from a liability standpoint but it does not become their property. This is why I think this petition gets dismissed out of hand - UTHR went after the mail man and not the company making the API. Going after YS Lifescience who make the API would be problematic for UTHR to say the least since they are one of UTHR's partners, a deal which, entertainingly, was set up by Roger Jeffs.
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Post by agedhippie on May 23, 2024 22:54:33 GMT -5
This doesn't go anywhere. The API is not manufactured by LGM, it's manufactured by YS Lifesciences in Korea. LGM just provide the shipping logistics so the drug cannot be tainted. The past history of LGM is irrelevant to approval of Yutrepia since LGM is in good standing with the FDA right now and that's what matters. This is why the share price didn't budge - nobody sees it as material. There was a BLaw article along with the Blaw document link that was posted that pretty much summed it up as "nothing to see here". So, they are an API supplier but did not supply the active ingredient for LQDA's Yutrepia. Gotcha. Almost exactly that. This is the wording from the contract defining the roles: WHEREAS, Manufacturer is a pharmaceutical company engaged in the development, manufacture and sale of Active Pharmaceutical Ingredients (“API(s)”);WHEREAS, Supplier is a pharmaceutical company engaged in the marketing, distribution and sale of Active Pharmaceutical Ingredients (“API(s)”);WHEREAS, Supply Party is willing to manufacture and supply the API(s) to Purchaser upon the terms and conditions set forth herein.WHEREAS, Purchaser is a company that is engaged in the development, distribution and sale of certain pharmaceutical products utilizing the APIIt identifies Yonsung Fine Chemicals (aka. YS Lifesciences) as the manufacturer, LGM Pharma as the supplier, LQDA as the purchaser, and defines the supplier party as the combination of the manufacturer and the supplier. The testing and certification is the responsibility of the manufacturer, and the role of the supplier is to forward that paper work along with the drug. LQDA is also required to inspect the drug itself on delivery to ensure that it conforms to the specification.
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Post by agedhippie on May 23, 2024 22:31:29 GMT -5
Oral Clofazamine has toxic side effects due to the amount administered to have a positive effect. The goal for 101 is to lower dosage and remove most of the toxic side effects and possibly increase clofazamine benefits by only administering directly to the lungs. How will the old form be a competitor? If I have an oral with crappy side effects and a reduced benefit but is cheep, so what? That would be one inept doctor. It's not always down to the doctor or VDEX would always be able to prescribe Afrezza. It's often down to the payer, and especially for very expensive drugs. I don't see it as a huge problem since the probable progression would be multidrug -> oral Clofazamine -> 101. The initial multidrug step is likely to be a few months so the timescale is largely unaltered by the extra step as I expect the oral step would fail fast and they would move on to MNKD-101. Until there is an approved oral Clofazamine for NTM (Lamprene is not approved for NTM) the path would have to be multidrug -> MNKD-101 since an insurer cannot specify an off-label drug.
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Post by agedhippie on May 23, 2024 16:05:58 GMT -5
"Find out if ARIKAYCE is right for you On treatment but still testing positive for MAC? FDA Approved MAC (Mycobacterium avium complex) can be hard to treat. If you are still testing positive for MAC, you are not alone. For 1 in 3 people, a multidrug treatment alone may not be enough to test MAC-negative. That’s where ARIKAYCE comes in. Learn about adding the first and only FDA-approved treatment used in combination with multidrug therapy for adults who still test positive for MAC after at least 6 months on multidrug treatment alone. ARIKAYCE was approved by FDA using the Limited Population pathway. This means FDA has approved this drug for a limited and specific patient population, and studies on the drug may have only answered focused questions about its safety and effectiveness." www.arikayce.com/is-arikayce-right-for-you/That is what I meant by payers requiring a step therapy. The multidrug treatment could work and the payer wants the cheapest viable option first.
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Post by agedhippie on May 23, 2024 15:59:45 GMT -5
The initial readout is to decide it the trial can continue and is usually around the halfway mark. They are looking to see if there is a significant number of problems with the protocol and if they need to restart. Results from the read out are considered interesting, but not significant as only part of the cohort will have completed the trial (the bad outcomes may all be lurking in the second half). Good color. Thank you agedhippie. I think you're confirming that if the halfway mark is about 7 to 9 months from now, then the trial could be completed in 2025 assuming 100% enrollment is by the halfway mark. Yes? Mannkind say that the Primary Completion date is 2026-08-01 based on their filing. Expect six months beyond that for QC. There is a second date out in 2028 which I suspect covers the extended trial.
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Post by agedhippie on May 23, 2024 13:41:00 GMT -5
^This They extension is because they want to see the percentages of cases where NTM reoccurs because that is a current problem. This is the problem you see where the infection drops to low levels, but is not eliminated and reoccurs over time. There are existing oral versions of clofazimine that would be the competition for 101 and will probably limit the price that can be charged at scale (there are always corner cases where the oral absolutely cannot be used for which a high price can be supported.) If 101 is approved for NTM, would oral clofazimine be competition? It was approved in the US for leprosy as Lamprene, but was discontinued in 2004. It is also available for NTM under an expanded access program Once there is an FDA approved drug for NTM, I would think that patients would be prescribed the approved drug (MNKD-101), rather than doctors putting in a SPIND request. It is still approved, it's just that nobody sells it. If 101 turned out to be a success then Novartis may consider turning in the results from their expanded access trial and get Lamprene approved for NTM. They could just start selling it again and doctors could prescribe it off-label, but I suspect they would wait for approval.
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Post by agedhippie on May 23, 2024 13:31:56 GMT -5
Best case for approval is 6 months (shorter review period) after Estimated Primary Completion Date of August 1, 2026? I assume 8/1/26 is on the paperwork, but I also thought MC said during the most recent EC, initial readout could be Q1 2025 (because they’re supposed to begin enrolling patients in June) and that it is possible 100% enrollment would be achieved by the time of the readout. (Would love to have that confirmed without having to listen to the EC again). I think the treatment lasts about 6 months. So maybe mid-2026 for FDA approval (if they use all of their permitted “Fast Track” 6 months). I’m not very knowledgeable of the process and timelines so caveat emptor. The initial readout is to decide it the trial can continue and is usually around the halfway mark. They are looking to see if there is a significant number of problems with the protocol and if they need to restart. Results from the read out are considered interesting, but not significant as only part of the cohort will have completed the trial (the bad outcomes may all be lurking in the second half).
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Post by agedhippie on May 23, 2024 13:26:46 GMT -5
^This They extension is because they want to see the percentages of cases where NTM reoccurs because that is a current problem. This is the problem you see where the infection drops to low levels, but is not eliminated and reoccurs over time. There are existing oral versions of clofazimine that would be the competition for 101 and will probably limit the price that can be charged at scale (there are always corner cases where the oral absolutely cannot be used for which a high price can be supported.) Curious what role the current SAE's being mentioned by Mike are included with the oral versions? Was it 101 that was once used for leprosy and has many reported side affects? Mike feels with the new intervention lasting only six months, this reduces the systemic tox levels and thus, he expects more patient levels of compliance? If so, who will champion 101 as better than orals? MNKD? Clofazimine is already a treatment for NTM, just not a favored one as it is off-label. There are established antibiotics that are currently the first line drugs, but as the NTM variants become drug resistant they are less effective. The idea is that clofazimine is a newer line of attack that will encounter less drug resistance but at the price point that is being talked about I can see payers wanting it to be a step therapy. The issue for 101 is going to be that if MNKD establishes clofazimine as a viable option then the oral version of clofazimine will be considered again and that will create price pressure. There are also trials ongoing for new oral drugs like omadacycline although their timeline is beyond 101.
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Post by agedhippie on May 23, 2024 9:23:34 GMT -5
If you look at the primary and secondary outcome measures they’re all from baseline to end of 6 months. I’m pretty sure the trial is only 6 months long and I think Mike has said that before. Also, the Arms and Interventions states: “…Study drug will be inhaled using the PARI breath-enhanced jet nebulizer system daily for 28 days in Cycle 1. Cycle 2 will commence after 56 days off treatment and resume daily for 28 days.” That’s all they’re doing so the trial will not be lasting 4 1/2 years. It’ll be 6 months. There’s an extension phase too I believe, for certain participants. So it says right there in the intervention description how long this trial will last and in the outcomes. Outcomes say end of 6 months. The intervention will last: 28 days ON, 56 days OFF, 28 days ON. That’s it, that’s the trial. ^This They extension is because they want to see the percentages of cases where NTM reoccurs because that is a current problem. This is the problem you see where the infection drops to low levels, but is not eliminated and reoccurs over time. There are existing oral versions of clofazimine that would be the competition for 101 and will probably limit the price that can be charged at scale (there are always corner cases where the oral absolutely cannot be used for which a high price can be supported.)
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Post by agedhippie on May 23, 2024 8:35:01 GMT -5
They did it to UTHR. Why not pay them back. I don't support that case either. I want patients to get drugs and not get stalled by spurious lawsuits. The vast majority of Citizens Petitions are drug conmpanies going after each other for delays, and the majority of those are incumbents trying to delay generics. This process has never worked as intended, but BP likes it so it's here to stay.
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Post by agedhippie on May 22, 2024 16:20:59 GMT -5
Wow, you bring about a very sound point with Liquidia providing evidence of certified CGMP materials to be used in their clinical trials. FDA would never allow a company to do a clinical trial with tainted API. The questions then becomes, did Liquidia know about this and if so, did they inform FDA? I would think it would be impossible for Liquidia to not know, IMO. Also, from the petition we learn that the API manufacturer whom Liquidia relies on for Yutrepia has a long and sordid history of noncompliance with regulations and its inspections dating back to 2010 show Liquidia’s API manufacturer has been plagued by repeated drug quality and misbranding vilations. Dig deeper and one has to ask why would LQDA continue using this vendor if they knew a Permanent Injunction was in place for these substantive issues? My guess LQDA knew after they had already been supplied with enough trial inventory of DPI and after the trials had concluded (I didn't look at clinical trials site but think the trials were complete) and either neglected it or, just as noteworthy, got a free pass on this one from the FDA. Any other trials, wherein LGM was a supplier, called into question? Therein would be a possible answer. This doesn't go anywhere. The API is not manufactured by LGM, it's manufactured by YS Lifesciences in Korea. LGM just provide the shipping logistics so the drug cannot be tainted. The past history of LGM is irrelevant to approval of Yutrepia since LGM is in good standing with the FDA right now and that's what matters. This is why the share price didn't budge - nobody sees it as material. There was a BLaw article along with the Blaw document link that was posted that pretty much summed it up as "nothing to see here".
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Post by agedhippie on May 22, 2024 15:57:39 GMT -5
... Just because I am shocked does not mean hospital insurance companies won’t pay. I do not know what is possible or customary. (Note: agedhippie is who suggested coverage may be via hospital insurance. I didn’t even know there was such a thing.) ... In Medicare terms it's the difference between Part B and Part D.
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Post by agedhippie on May 21, 2024 16:27:42 GMT -5
Go to LGM Pharma website. Look up treprostinil. You get the comment, "LGM Pharma is an API distributor. LGM Pharma supplies APIs as per CGMP with DMF support, subject to availability and manufacturer requirements." LGM asserts their importance as part of supply chain. I don't see UTHR "winning the case". But there is enough going on here to cause a delay. That's interesting but irrelevant since LQDA buy their API from YS Lifesciences. LGM handles the importation. This will not affect the approval timeline.
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