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Post by lakers on Jan 15, 2016 20:07:03 GMT -5
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Post by anderson on Jan 15, 2016 20:50:25 GMT -5
Treprostinil is currently sold by United Therapeutics which was founded by Martine Rothblatt. Martine Rothblatt is an interesting person and was motivated to treat Pulmonary Arterial Hypertension when one of her daughters was diagnosed. Just like the movies Extraordinary Measures and Lorenzo's Oil. United Therapeutics has an inhaled version of Treprostinil called Tyvaso, but lets just say the bong for Tyvaso makes the Exubera bong look quite reasonable. Also United Therapeutics has a PDE-5 inhibitor drug called Adcirca which is tadalafil. Tadalafil is also marketed under another name as well, Cialis. I am hopeful that United Therapeutics is the partner.
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Deleted
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Post by Deleted on Jan 15, 2016 20:58:00 GMT -5
Treprostinil is currently sold by United Therapeutics which was founded by Martine Rothblatt. Martine Rothblatt is an interesting person and was motivated to treat Pulmonary Arterial Hypertension when one of her daughters was diagnosed. Just like the movies Extraordinary Measures and Lorenzo's Oil. United Therapeutics has an inhaled version of Treprostinil called Tyvaso, but lets just say the bong for Tyvaso makes the Exubera bong look quite reasonable. Also United Therapeutics has a PDE-5 inhibitor drug called Adcirca which is tadalafil. Tadalafil is also marketed under another name as well, Cialis. I am hopeful that United Therapeutics is the partner. lol openi.nlm.nih.gov/imgs/512/171/3267519/3267519_dddt-6-019f3.pngit comes with its own PCB board... |
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Post by lakon on Jan 19, 2016 13:08:47 GMT -5
I am surprised that no one has shown any excitement about the mention of PDE5 inhibitors. As it turns out, most people are probably familiar with the more common names of the marketed drugs: Viagra, Cialis, Levitra, and Stendra. Stendra is relatively new, but not the other three. I find it curious that two of three formulations are progressing. Concerns about Viagra on Technosphere go way back so it is no wonder that only two formulations are progressing. It might be a coincidence. The other candidate listed for PAH, Tacrolimus, is really an immunosuppressive drug for reducing the chance of rejection of a lung transplant in this case. I tend to think there is a lot more to the story here. It would be hard to deny that each has blockbuster potential in its own right. Sounds like the targeted pulmonary candidates are on the right track.
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Post by peppy on Jan 19, 2016 13:31:22 GMT -5
I am surprised that no one has shown any excitement about the mention of PDE5 inhibitors. As it turns out, most people are probably familiar with the more common names of the marketed drugs: Viagra, Cialis, Levitra, and Stendra. Stendra is relatively new, but not the other three. I find it curious that two of three formulations are progressing. Concerns about Viagra on Technosphere go way back so it is no wonder that only two formulations are progressing. It might be a coincidence. The other candidate listed for PAH, Tacrolimus, is really an immunosuppressive drug for reducing the chance of rejection of a lung transplant in this case. I tend to think there is a lot more to the story here. It would be hard to deny that each has blockbuster potential in its own right. Sounds like the targeted pulmonary candidates are on the right track.52. 6994851 Method of inducing a CTL response US 07.02.2006
A61K 39/00 09380534 MannKind Corporation Kundig Thomas M.
A method of inducing a cytotoxic T-lymphocyte (CTL) response to an antigen is disclosed. The method involves delivering the antigen to the lymphatic system of an animal regularly over a sustained period of time using, e.g., an osmotic pump. The method is advantageous over prior art methods for inducing a CTL response in that it does not require repetitive immunizations or the use of adjuvants. The method of the present invention can be used for the induction of CTLs in tumor or infectious disease immunotherapy.
- 67. 20080199485 Method for enhancing T cell response
screencast.com/t/wlqvltasM4
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Post by matt on Jan 19, 2016 17:12:52 GMT -5
I doubt you can get FDA to put any PDE-5 inhibitor in an inhaler due to the risk of hypotension. Dosing has to be very precise with these drugs and massive swings in blood pressure can cause all sorts of life threatening events. If you though insulin had a hard time at FDA . . .
The various rapamycin derivatives might be interesting. Tacrolimus is an older drug and not as effective as sirolimus (Pfizer) or everolimus (Novartis). Sirolimus went off patent in the last year or 18 months so I am not sure Pfizer would invest more in a generic, but everolimus is a very good drug that remains on patent. It is more specific for mTOR-2 than sirolimus or tacrolimus which means that it does what it is supposed to do with fewer off-target side effects. It is a possibility, although it works pretty well in pill form.
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Post by peppy on Jan 19, 2016 17:34:54 GMT -5
I doubt you can get FDA to put any PDE-5 inhibitor in an inhaler due to the risk of hypotension. Dosing has to be very precise with these drugs and massive swings in blood pressure can cause all sorts of life threatening events. If you though insulin had a hard time at FDA . . . The various rapamycin derivatives might be interesting. Tacrolimus is an older drug and not as effective as sirolimus (Pfizer) or everolimus (Novartis). Sirolimus went off patent in the last year or 18 months so I am not sure Pfizer would invest more in a generic, but everolimus is a very good drug that remains on patent. It is more specific for mTOR-2 than sirolimus or tacrolimus which means that it does what it is supposed to do with fewer off-target side effects. It is a possibility, although it works pretty well in pill form.
DOSAGE AND ADMINISTRATION AFINITOR is available in two dosage forms: tablets (AFINITOR Tablets) and tablets for oral suspension (AFINITOR DISPERZ). AFINITOR Tablets may be used for all approved indications. AFINITOR DISPERZ is approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC).
www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf
reading about technosphere; I got the impression that the medications most useful to use in technosphere formulations were peptides (proteins) that had to be injected because they could not be absorbed in gastrointestinal (oral) delivery. with my limited understanding, it that because the protein is sent to the liver to have the nitrogen cleaved...... only on nitrogen molecule on this drug The molecular formula is C53H83NO14 and the molecular weight is 958.2.
www.google.com/search?q=proteins+definition&rlz=1T4GGHP_enUS620US620&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiQzt319bbKAhWBkoMKHXHWCJMQ_AUIBygB&biw=1352&bih=558#tbm=isch&q=nucleic+acids+structure
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Post by matt on Jan 19, 2016 17:56:07 GMT -5
You digest a lot of protein, like the meat you are going to have for dinner, and those proteins get absorbed into the circulatory system just fine thank you very much. The problem with drug delivery is that the stomach juices cannot tell the difference between your hamburger and a very expensive protein therapeutic, so the drug might get digested too (rendering it useless). Encapsulation technologies have come a long way and can often protect drugs from premature digestion until the drug has passed into the intestines, but very large molecules cannot be absorbed in the intestine.
The lung is good for small drugs (peptides are just small pieces of protein) and those that need to work locally, like epinephrine for bronchospasm.
Cleavage in the liver doesn't have much to do with it. The mesenteric artery (which feeds the digestive organs) takes about 25% of the output of the heart so there is a lot of blood flowing through the liver. If you get the drug absorbed, it will get to the liver just fine. The trick for any systemic drug is to get the drug into the blood stream and let the heart do the rest.
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Post by peppy on Jan 19, 2016 20:12:53 GMT -5
I doubt you can get FDA to put any PDE-5 inhibitor in an inhaler due to the risk of hypotension. Dosing has to be very precise with these drugs and massive swings in blood pressure can cause all sorts of life threatening events. If you though insulin had a hard time at FDA . . . The various rapamycin derivatives might be interesting. Tacrolimus is an older drug and not as effective as sirolimus (Pfizer) or everolimus (Novartis). Sirolimus went off patent in the last year or 18 months so I am not sure Pfizer would invest more in a generic, but everolimus is a very good drug that remains on patent. It is more specific for mTOR-2 than sirolimus or tacrolimus which means that it does what it is supposed to do with fewer off-target side effects. It is a possibility, although it works pretty well in pill form. I know mnkd can not have technosphere PDE-5 inhibitor. However at this age, it would be fun to watch.
<---- so inappropriate.
PDE5 selective inhibitors[edit]
Main article: PDE5 inhibitor
Sildenafil, tadalafil, vardenafil, and the newer udenafil and avanafil selectively inhibit PDE5, which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used primarily as remedies for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension.
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Post by agedhippie on Jan 19, 2016 22:59:11 GMT -5
If you want a suggestion I would say glucagon. Type 1 diabetics especially get into hypos that it's very difficult to get out of. They are not life threatening but you can sit in the 30s and 40s for a long time. Even in hospital there can be problems getting people to maintain high enough levels to get discharged.
Today glucagon is cumbersome. You need to mix a powder with the saline solution and then inject the resulting cocktail in an intramuscular injection. You blood sugar rises into the stratosphere leaving you to deal with the rather nasty side effects (a lot of nausea and vomiting). You don't normally give glucagon to someone who is not unconscious, not least because it is so expensive (around $250 a shot), and so complex to use (there is a huge error rate). Most people just phone 911 and let the EMT do it, that's not the market as you will never replace rescue kits because unconscious patients cannot inhale.
Whenever people here talk about the artificial pancreas they fixate on the insulin, but the AP has two pumps, one insulin and one glucagon. The system corrects lows with glucagon and highs with insulin. It avoid the problem of the side effect of glucagon rescue kits because it only uses small doses (you cannot overdose on glucagon so the rescue kit gives a huge shot to make sure it has an effect). There is a market for small glucagon doses to counter bad, but not life threatening, lows and persistent lows. You can use sugar, but that takes 15 minutes or so and can be fairly unpredictable depending on what you have eaten recently. Inhaled glucagon may be an interesting proposition.
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Post by anderson on Jan 20, 2016 10:52:12 GMT -5
Those saying you cant inhale a PDE5 inhibitor must of just skipped the combo therapy "Treprostinil+PDE5 inhibitor" on slide 9 of MNKD's presentation at the JP Morgan Healthcare conference.
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Post by mnholdem on Jan 20, 2016 11:38:07 GMT -5
I am surprised that no one has shown any excitement about the mention of PDE5 inhibitors. As it turns out, most people are probably familiar with the more common names of the marketed drugs: Viagra, Cialis, Levitra, and Stendra. Stendra is relatively new, but not the other three. I find it curious that two of three formulations are progressing. Concerns about Viagra on Technosphere go way back so it is no wonder that only two formulations are progressing. It might be a coincidence. The other candidate listed for PAH, Tacrolimus, is really an immunosuppressive drug for reducing the chance of rejection of a lung transplant in this case. I tend to think there is a lot more to the story here. It would be hard to deny that each has blockbuster potential in its own right. Sounds like the targeted pulmonary candidates are on the right track. PDE5 inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are clinically indicated for the treatment of erectile dysfunction.
PDE5 inhibitors Sildenafil and tadalafil are also indicated for the treatment of pulmonary hypertension.
It's likely that in the slide that listed:
- Drug Candidate: Treprostinil + PDE5 Inhibitor
- Therapy: Pulmonary Arterial Hypertension (PAH)
...that one of the PDE5 inhibitors indicated for PAH will be used in combination with the Treprostinil, one of which is marketed under the trade name Tyvaso and is administered via inhalation.
---
In a recent article in the Expert Opinion of Orphan Drugs, Dr Peter Norman states, “The treatment of PAH is viewed as a commercially attractive option by several companies. This is highlighted by the value of this market segment, producing revenues of ~ $4.5 billion in 2013.”
In total, there are 28 orphan drugs approved or designated for the treatment of PAH.
Global Orphan Drug Sales (2013)
Tracleer $1,711 Million
Letairis $520 Million
Remodulin $491 Million
Tyvaso $439 Million
Revatio $307 Million
Volibris $231 Million
Adcrica $177 Million
Flolan $162 Million
Ventavis $123 Million
Opsumit $6 Million
[information in table adapted from Norman (2014)]
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Post by lakon on Jan 20, 2016 12:26:31 GMT -5
Exactly what I assess to be the case, but I think MNKD is looking at multiple options for PDE5 inhibitors to treat PAH as a combination therapy, based on their use of word choices, such as drug candidates versus drug formulations, during discussions. It's somewhat subtle. There are two very important aspects here that are somewhat newly revealed. For some time, I thought that it should be possible to delivery combination therapies. This pairing of Treprostinil+PDE5 inhibitor is the first time that I have seen MNKD admit to working on a combination. That's huge in my opinion. The second is that it is possible to view the combination therapy as two separate drugs that can be delivered separately or together. If one of the PDE5 inhibitors proves safe and effective for inhalation with a fast onset of action, well, you get the idea. Cialis is safe to take daily, and it is known as the "weekend drug" after all. Another treatment for ED may be possible, unlike many have derided without any hard data, just a hypothesis. Al Mann said that it would not likely be Viagra, but left open other possibilities. I think we are starting to see early signs of the possibilities. As anderson wrote, United Therapeutics would be an ideal partner. They have been a darling of Wall St. They have personal and professional interests in better treatments for PAH and organ transplantation. The former being discussed already, and the latter being mentioned with regard to Tacrolimus. The founder of UTHR was involved with satellites, like Al. Sirius XM Holdings Inc. has had its share of short interest battles. More research and analysis along this train of thought could be fruitful. www.unither.com/www.adcirca.com/patient/index.aspxwww.lilly.com/home.aspx |
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Post by sluggobear on Jan 21, 2016 16:48:16 GMT -5
Exactly what I assess to be the case, but I think MNKD is looking at multiple options for PDE5 inhibitors to treat PAH as a combination therapy, based on their use of word choices, such as drug candidates versus drug formulations, during discussions. It's somewhat subtle. There are two very important aspects here that are somewhat newly revealed. For some time, I thought that it should be possible to delivery combination therapies. This pairing of Treprostinil+PDE5 inhibitor is the first time that I have seen MNKD admit to working on a combination. That's huge in my opinion. The second is that it is possible to view the combination therapy as two separate drugs that can be delivered separately or together. If one of the PDE5 inhibitors proves safe and effective for inhalation with a fast onset of action, well, you get the idea. Cialis is safe to take daily, and it is known as the "weekend drug" after all. Another treatment for ED may be possible, unlike many have derided without any hard data, just a hypothesis. Al Mann said that it would not likely be Viagra, but left open other possibilities. I think we are starting to see early signs of the possibilities. As anderson wrote, United Therapeutics would be an ideal partner. They have been a darling of Wall St. They have personal and professional interests in better treatments for PAH and organ transplantation. The former being discussed already, and the latter being mentioned with regard to Tacrolimus. The founder of UTHR was involved with satellites, like Al. Sirius XM Holdings Inc. has had its share of short interest battles. More research and analysis along this train of thought could be fruitful. www.unither.com/www.adcirca.com/patient/index.aspxwww.lilly.com/home.aspxI doubt whether there is an application for ED in the MNKD candidate "pipeline". But we know they have mentioned PAH as a target for next API. Excerpts from Matt's comments at the Aegis presentation on Oct. 8 2015 (these were my key takeaways): • Looking at drugs which take advantage of TS features besides just obviating the injection. • Not practical to develop new chemical entities so working for next product to be a known drug. Occasionally look at NCE’s but 10 year process. • Spent a lot of time and money on the consulting process to put forward 2 new application candidates. • First indication would be pulmonary hypertension. • This is a serious effort on the company’s behalf. The R&D activities are fully staffed and preclinical work has been done. We can look forward to hearing more news about this soon but not at the moment. • Licensing tech to other companies - have to be careful and not create competitors to ourselves. What is Receptor then? Of the 2 new application candidates, Matt said the API furthest along was a PAH drug. Added to that, we have the JPM slides with 2 drugs for PAH listed on the MNKD 2.0 Drug Candidates slide: 1. Treprostenil + PDE5 inhibitor Pulmonary Arterial Hypertension 2. Tacrolimus Lung transplant, PAH Do they already have a partner in mind for PAH or do they intend to find a partner who will compete with United Therapeutics? For treprostenil-containing PAH drugs, Tyvaso and Remodulin are produced by United Therapeutics. Remodulin is injected, Tyvaso is inhaled and was approved in 2009. www.tyvaso.com/dtcThe PDE5 addition with treprostenil might be a new improved PAH drug that United would like in a TS/Dreamboat format? I am sure they are aware of the potentiation by PDE5 and could afford their own development. But as mentioned previously Tyvaso uses a very large inhalation device so maybe there is a potential next gen PAH product there? Even asthma (fluticasone) or COPD might be a reasonable opportunity. If the TS "simply inhale" platform is fairly easily applicable to such drugs - the market is huge. There is enormous competition in this space but the TS/Dreamboat tech could provide the generic drugs in a much more consumer-friendly and environmentally-friendly way, and possibly? be very cheap. |
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Post by lakers on Sept 4, 2018 23:32:18 GMT -5
I am surprised that no one has shown any excitement about the mention of PDE5 inhibitors. As it turns out, most people are probably familiar with the more common names of the marketed drugs: Viagra, Cialis, Levitra, and Stendra. Stendra is relatively new, but not the other three. I find it curious that two of three formulations are progressing. Concerns about Viagra on Technosphere go way back so it is no wonder that only two formulations are progressing. It might be a coincidence. The other candidate listed for PAH, Tacrolimus, is really an immunosuppressive drug for reducing the chance of rejection of a lung transplant in this case. I tend to think there is a lot more to the story here. It would be hard to deny that each has blockbuster potential in its own right. Sounds like the targeted pulmonary candidates are on the right track. PDE5 inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are clinically indicated for the treatment of erectile dysfunction.
PDE5 inhibitors Sildenafil and tadalafil are also indicated for the treatment of pulmonary hypertension.
It's likely that in the slide that listed:
- Drug Candidate: Treprostinil + PDE5 Inhibitor
- Therapy: Pulmonary Arterial Hypertension (PAH)
...that one of the PDE5 inhibitors indicated for PAH will be used in combination with the Treprostinil, one of which is marketed under the trade name Tyvaso and is administered via inhalation.
---
In a recent article in the Expert Opinion of Orphan Drugs, Dr Peter Norman states, “The treatment of PAH is viewed as a commercially attractive option by several companies. This is highlighted by the value of this market segment, producing revenues of ~ $4.5 billion in 2013.”
In total, there are 28 orphan drugs approved or designated for the treatment of PAH.
Global Orphan Drug Sales (2013)
Tracleer $1,711 Million
Letairis $520 Million
Remodulin $491 Million
Tyvaso $439 Million
Revatio $307 Million
Volibris $231 Million
Adcrica $177 Million
Flolan $162 Million
Ventavis $123 Million
Opsumit $6 Million
[information in table adapted from Norman (2014)]
Could Mnkd and UTHR split the Orphan pediatric voucher which could be worth several hundred millions? Rare Pediatric Disease Priority Review Voucher Program www.fda.gov/forindustry/developingproductsforrarediseasesconditions/rarepediatricdiseasepriorityvoucherprogram/default.htmThe Office of Orphan Products Development (OOPD) Food and Drug Administration Tuesday’s deal will be a boost for MannKind and the region’s biotech industry, he said. “It shows the viability of the platform and the ability to do different things with it,” Enany said of MannKind’s technology. Under the deal, United Therapeutics will be responsible for global development, commercialization and regulatory approvals for the inhalable version of treprostinil and receive exclusive worldwide licensing rights. There is an inhalable version of treprostinil now, but it requires use of an electronic nebulizer that must be plugged in. MannKind’s version is delivered through a portable inhaler that can be used anywhere. MannKind will manufacture the supplies of the drug for clinical trials and initial commercialization at its Danbury, Conn., facility. United Therapeutics will manufacture the long-term commercial supplies. United Therapeutics also has the option to expand the exclusive licensing deal to other MannKind treatments for pulmonary hypertension. |
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