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Post by mango on Nov 16, 2018 15:29:26 GMT -5
Ralinepag is a selective prostacyclin receptor agonist. Treprostinil is a prostaglandin I2 analog. 1. Why take puffs throughout the day when you can simply take 1 pill? Treprostinil Technosphere is ancipated to allow people with PAH to achieve at or beyond the current recommended total daily dose of treprostinil (216mcg) in a single inhalation, as already evidenced by Mike Castagna's slides on Science Day. TreT was tolerated in healthy volunteers up through 150mcg. For comparison, Arena's results from their single-dose escalation study involving healthy volunteers showed Ralinepag was tolerated up to 0.1 mg. That's 100mcg. TreT was tolerated up through 150mcg, far exceeding Ralinepag's tolerability already in healthy volunteers. Dose escalation for Ralinepag was discontinued at 0.2 mg due to treatment-emergent AEs (vomiting, headache, and nausea). There is no anticipation, nor evidence indicating, that people with PAH will potentially require taking "puffs throughout the day" with TreT, as Spencer so incorrectly stated. 2. Why would United have any desire to pay Mannkind $40 million plus royalties to put Ralinepag on technosphere? Ralinepag is a selective IP agonist and is different from the analog Treprostinil. If Ralinepag demonstrates promising therapeutic potential, beyond what Treprostinil can provide, or would be a great combo, etc...but shows drawbacks and limitations mainly due to its ROA &/or formulation, then United Therapeutics could get MannKind to formulate it onto Technosphere to overcome those barriers. You cannot compare mcg TreT to mcg Ralinepag. 2 different drugs, different molecular wts, different effects. Thank you for pointing that out. Could a therapeutically equivalent dose be figured out then or no? |
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Post by liane on Nov 16, 2018 15:34:02 GMT -5
No - trial and error.
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Post by porkini on Nov 16, 2018 15:59:53 GMT -5
Not a nurse or doctor here but... isn't there almost always a concern about liver/kidney function when taking an ingested medication?
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Post by agedhippie on Nov 16, 2018 16:34:05 GMT -5
Not a nurse or doctor here but... isn't there almost always a concern about liver/kidney function when taking an ingested medication? You have to think that if the XR pill works better than the IR pill you want a slow even uptake rather than a very fast spiky uptake. Like the difference between basal insulin like Lantus or Tresiba, and bolus insulin like Afrezza. The $250M milestone is the table stakes should UTHR ever wish to make an inhaled version, there is no commitment there. It's quite an incentive not to make an inhaled version and to rely on pills instead for as long as possible. |
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Post by lakers on Nov 16, 2018 16:41:02 GMT -5
Investigational Extended-Release Ralinepag for PAH Treatment Shows Favorable Results in Phase 1 Trials www.google.com/amp/s/pulmonaryhypertensionnews.com/2018/08/30/extended-release-ralinepag-pah-treatment-shows-positive-phase-1-results/%3fampRalinepag, also known as APD811, is a next-generation, selective prostacyclin receptor agonist designed to be taken orally. Prostacyclin is a hormone produced by cells lining the walls of blood vessels, with known vasodilator — blood vessel widening — and anti-inflammatory effects. It also is a potent inhibitor of platelet clumping and the growth of blood vessel muscle cells. Ralinepag’s extended-release tablet is intended to allow for once-daily dosing. Prior research showed that its immediate-release capsule had an extended half-life (nearly 24 hours) over Arena’s Uptravi (up to 2.5 hours) and its active molecule MRE-269 (up to 13.5 hours). Half-life refers to the time required for the amount of a compound in the body to be reduced by half, an indicator of how long it has an effect. Results showed that, as expected, the once-daily extended-release formulation led to a lower plasma level of ralinepag than the immediate-release capsules. However, the extended-release tablets had a superior half-life of 28-29 hours and maintained low peak-trough fluctuation, which means there was little variability in ralinepag’s plasma levels within each dosing. “The ralinepag XR tablet formulation offers improved PK performance over both ralinepag and selexipag IR formulations,” the scientists wrote. “With an extended half-life and low peak-to-trough fluctuation, the ralinepag XR tablet closely approximates the PK profile of continuously infused IV [intravenous]-prostacyclin,” Preston Klassen, MD, Arena’s chief medical officer, [ DPI Ralinepag may address an acute attack episode when one forgets to take XR Pill daily, or XR doesn’t provide sufficient dosage, or XR alone is not foolproof, or sufficient for everyone. XR is analogous to basal. DPI is analogous to prandial. Prandial supplements basal. Ying and Yang. Does that sound familiar?] |
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Post by agedhippie on Nov 16, 2018 17:05:58 GMT -5
... [DPI Ralinepag may address an acute attack episode when one forgets to take XR Pill daily, which is orthogonal to the XR which is analogous to basal. Prandial complements basal. Ying and Yang. Does that sound familiar.] It's an interesting question, but why not just take an IR pill for short quick action, and then continue with the XR pills again? Is the IR pill fast enough to make that work? |
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Post by goyocafe on Nov 16, 2018 17:19:48 GMT -5
... [DPI Ralinepag may address an acute attack episode when one forgets to take XR Pill daily, which is orthogonal to the XR which is analogous to basal. Prandial complements basal. Ying and Yang. Does that sound familiar.] It's an interesting question, but why not just take an IR pill for short quick action, and then continue with the XR pills again? Is the IR pill fast enough to make that work? And which drug actually works best, Treprostinil or Ralinepag? Fewer side effects, tolerability? |
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Post by Omega on Nov 16, 2018 23:37:44 GMT -5
Not a nurse or doctor here but... isn't there almost always a concern about liver/kidney function when taking an ingested medication? You have to think that if the XR pill works better than the IR pill you want a slow even uptake rather than a very fast spiky uptake. Like the difference between basal insulin like Lantus or Tresiba, and bolus insulin like Afrezza. The $250M milestone is the table stakes should UTHR ever wish to make an inhaled version, there is no commitment there. It's quite an incentive not to make an inhaled version and to rely on pills instead for as long as possible. So you believe someone decided to specifically put mention of bringing the drug to inhale form on the contract so that they will NOT want to go that route? |
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Post by traderdennis on Nov 17, 2018 0:50:53 GMT -5
You have to think that if the XR pill works better than the IR pill you want a slow even uptake rather than a very fast spiky uptake. Like the difference between basal insulin like Lantus or Tresiba, and bolus insulin like Afrezza. The $250M milestone is the table stakes should UTHR ever wish to make an inhaled version, there is no commitment there. It's quite an incentive not to make an inhaled version and to rely on pills instead for as long as possible. So you believe someone decided to specifically put mention of bringing the drug to inhale form on the contract so that they will NOT want to go that route? Yes it is mentioned for ARNA to protect their drug. |
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Post by agedhippie on Nov 17, 2018 10:39:37 GMT -5
It's an interesting question, but why not just take an IR pill for short quick action, and then continue with the XR pills again? Is the IR pill fast enough to make that work? And which drug actually works best, Treprostinil or Ralinepag? Fewer side effects, tolerability? At this point I don't think anyone really knows for certain, but after the phase 3 trials it should be clear. I would say that UTHR expects Ralinepag to be better or they would not have spent close on a billion dollars for the rights. A failure of that magnitude is not a survivable experience for the executives involved so self-interest says it is is almost certain to be better. |
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Post by agedhippie on Nov 17, 2018 10:50:49 GMT -5
You have to think that if the XR pill works better than the IR pill you want a slow even uptake rather than a very fast spiky uptake. Like the difference between basal insulin like Lantus or Tresiba, and bolus insulin like Afrezza. The $250M milestone is the table stakes should UTHR ever wish to make an inhaled version, there is no commitment there. It's quite an incentive not to make an inhaled version and to rely on pills instead for as long as possible. So you believe someone decided to specifically put mention of bringing the drug to inhale form on the contract so that they will NOT want to go that route? Absolutely, it's good risk management. If you are purchasing the rights to a drug you want to make sure the contract ties up the drug in all forms regardless of whether or not you intend at the time to use them. Not doing so would be negligent. In this case it costs UTHR nothing to get that particular right unless they exercise it so they would be crazy not to take it since it locks out everyone else at zero cost. If they went down the route of making an inhaled version there is a big upfront cost, and royalties and milestones to both Arena and Mannkind. It's hard to see why they would do it since speed of onset is not important in this case as the focus is on maintaining a level of the drug in the blood at all times which XR formulations are specifically designed for. |
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Post by goyocafe on Nov 17, 2018 11:25:32 GMT -5
And which drug actually works best, Treprostinil or Ralinepag? Fewer side effects, tolerability? At this point I don't think anyone really knows for certain, but after the phase 3 trials it should be clear. I would say that UTHR expects Ralinepag to be better or they would not have spent close on a billion dollars for the rights. A failure of that magnitude is not a survivable experience for the executives involved so self-interest says it is is almost certain to be better. So if it all goes as "planned" by UTHR, MNKD just sold their Trep-T drug for 100 million + 2 to 3 years of low double digit royalties? I hope they do a better deal next time. Granted, it bought them needed time, but, damn. |
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Post by agedhippie on Nov 17, 2018 11:35:10 GMT -5
At this point I don't think anyone really knows for certain, but after the phase 3 trials it should be clear. I would say that UTHR expects Ralinepag to be better or they would not have spent close on a billion dollars for the rights. A failure of that magnitude is not a survivable experience for the executives involved so self-interest says it is is almost certain to be better. So if it all goes as "planned" by UTHR, MNKD just sold their Trep-T drug for 100 million + 2 to 3 years of low double digit royalties? I hope they do a better deal next time. Granted, it bought them needed time, but, damn. I could see UTHR pitching Trep-T at a tier below Ralinepag in price. An analogy would be statins where you had simvastatin as the base generic, the XR version of simvastatin as the next tier, and then the non-generic statins. They could slot Trep-T into the mid-tier XR equivalent. |
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Post by mango on Nov 17, 2018 11:58:20 GMT -5
At this point I don't think anyone really knows for certain, but after the phase 3 trials it should be clear. I would say that UTHR expects Ralinepag to be better or they would not have spent close on a billion dollars for the rights. A failure of that magnitude is not a survivable experience for the executives involved so self-interest says it is is almost certain to be better. So if it all goes as "planned" by UTHR, MNKD just sold their Trep-T drug for 100 million + 2 to 3 years of low double digit royalties? I hope they do a better deal next time. Granted, it bought them needed time, but, damn. Comparing the Arena and MannKind deals is really like comparing apples to mangos. TreT and the Phase 1 study cost MannKind very little. Arena discovered and developed Ralinepag themselves so they are really two entirely different scenarios. However, Rothblatt stated that it is an honor to be working with MannKind, and that they are fully integrated with an UT R&D team at their Research Triangle Park location in North Carolina. MannKind has a long-term future with United, and this is merely the beginning. From Rothblatt: "And the team at MannKind is one of the absolute best groups of people that we've ever had the honor to work with. They are now fully integrated into our Clinical Drug Development Group over in Research Triangle Park. And I'm confident that once the MannKind device is approved that that will augur yet additional thousands of patients..." |
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Post by goyocafe on Nov 17, 2018 12:42:51 GMT -5
So if it all goes as "planned" by UTHR, MNKD just sold their Trep-T drug for 100 million + 2 to 3 years of low double digit royalties? I hope they do a better deal next time. Granted, it bought them needed time, but, damn. Comparing the Arena and MannKind deals is really like comparing apples to mangos. TreT and the Phase 1 study cost MannKind very little. Arena discovered and developed Ralinepag themselves so they are really two entirely different scenarios. However, Rothblatt stated that it is an honor to be working with MannKind, and that they are fully integrated with an UT R&D team at their Research Triangle Park location in North Carolina. MannKind has a long-term future with United, and this is merely the beginning. From Rothblatt: "And the team at MannKind is one of the absolute best groups of people that we've ever had the honor to work with. They are now fully integrated into our Clinical Drug Development Group over in Research Triangle Park. And I'm confident that once the MannKind device is approved that that will augur yet additional thousands of patients..." I wasn't trying to compare the deals, just trying to see the reality of the deal in terms of the revenue stream Trep-T will have in light of the new deal between UTHR and ARNA. Time will tell. Hopefully by then we'll have more streams to focus on that have a greater impact on the bottom line and the SP. |
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