|
|
Post by mango on Aug 30, 2019 22:16:53 GMT -5
I would approach GSK with a proposal to develop Imitrex(TS). They are in the same situation with their migraine drug as United Therapeutics is with PAH. With competition from generics and patent life issues, a rapid-acting inhaled TS-Sumatriptan would breathe new life into their portfolio. I don't see a whole lot of opportunity there. The 5-HT agonists are pretty crowded. I'd prefer they go after the new CGRP class like Aimovig. Those need to be injected IM, like epipens. There is a far greater market for these, especially because they are new. I think a yearly supply runs close to $5k per patient. But insurance companies are happy to pay for it because it keeps migraine sufferers out of the ED. There is also research going on that show IV CGRP's can safely abort status migrainosus, or intractable migraines. Previously they required other neurological medications that typically took a couple days to break the headache. So there will be opportunity for a long time with these medications. The only side effect with them so far has been injection site reactions, meaning they are extremely safe and have essentially no side effects other than what's caused by the needle. Truly, this is one market I hope MC is targeting. MNKD should have a legitimate shot at landing a good partner. I totally disagree. The CGRP antagonists are very new and lack robust safety data, especially long-term safety data. There also has not been any carcinogenesis and mutagenesis studies conducted with Aimovig. I'll assume the same is true for the others like it. It would be extremely high risk for MannKind to go this route. There simply has not been enough research and studies done with these etc... I don't see them taking this route this early on, and while there is more questions and unknowns that still remains with this new class. By the way, constipation is a common side effect, as well as pain from the injection. Cramps and muscle spasms was also experienced in participants during trials. |
|
paul
Researcher
Posts: 134
|
Post by paul on Aug 30, 2019 22:37:09 GMT -5
I would approach GSK with a proposal to develop Imitrex(TS). They are in the same situation with their migraine drug as United Therapeutics is with PAH. With competition from generics and patent life issues, a rapid-acting inhaled TS-Sumatriptan would breathe new life into their portfolio. I don't see a whole lot of opportunity there. The 5-HT agonists are pretty crowded. I'd prefer they go after the new CGRP class like Aimovig. Those need to be injected IM, like epipens. There is a far greater market for these, especially because they are new. I think a yearly supply runs close to $5k per patient. But insurance companies are happy to pay for it because it keeps migraine sufferers out of the ED. There is also research going on that show IV CGRP's can safely abort status migrainosus, or intractable migraines. Previously they required other neurological medications that typically took a couple days to break the headache. So there will be opportunity for a long time with these medications. The only side effect with them so far has been injection site reactions, meaning they are extremely safe and have essentially no side effects other than what's caused by the needle. Truly, this is one market I hope MC is targeting. MNKD should have a legitimate shot at landing a good partner. Aimovig's insert says it is administered subcutaneously once a month. I don't see that inhalation would offer much advantage. Also, it's a monoclonal antibody and best I can tell from google those are not well absorbed via lung inhalation. As far as insurance coverage, it would run into the same problem as afrezza in that the trials would need to show superiority, otherwise Amgen's financial muscle would keep it on the lower tiers. |
|
|
|
Post by letitride on Aug 30, 2019 23:32:20 GMT -5
Im not sure what ya all are thinking but as for me I have rising expectations!
|
|
|
|
Post by uvula on Aug 31, 2019 9:12:41 GMT -5
Im not sure what ya all are thinking but as for me I have rising expectations! If they last longer than 4 hours see a doctor. |
|
|
|
Post by stevil on Aug 31, 2019 18:08:10 GMT -5
I totally disagree. The CGRP antagonists are very new and lack robust safety data, especially long-term safety data. There also has not been any carcinogenesis and mutagenesis studies conducted with Aimovig. I'll assume the same is true for the others like it. It would be extremely high risk for MannKind to go this route. There simply has not been enough research and studies done with these etc... I don't see them taking this route this early on, and while there is more questions and unknowns that still remains with this new class. By the way, constipation is a common side effect, as well as pain from the injection. Cramps and muscle spasms was also experienced in participants during trials. Every novel drug that comes to market runs the risk of serious adverse effects. That's a given. However, doctors look at the whole picture when deciding whether to prescribe or not. How serious are the adverse reactions vs the benefits of therapy. You are correct about constipation. I forgot about that because, if memory serves, it was very insignificant- something like low single digits vs placebo. Doctors will consider it for people with GI illnesses like gastroparesis or other diseases and opioid dependence, but for the other millions of people, they won't bat an eyelash at constipation (or cramps and muscle spasms- btw, these will disappear if it is inhaled). There are calcitonin receptors in the GI system that cause the constipation, so this would likely remain even if inhaled. I'm not sure I'd take my patient seriously about their migraines if they told me they didn't want to prevent a migraine due to constipation. You're comparing what you know about Afrezza with other drugs. That is not how perception of other drugs work. Sure, there will be slow adopters with all things new, but this is different than Afrezza because there have already been multiple thousands of people on CGRPs without any serious events, and there hasn't been another drug in its class that already has red flags. You might see slow adoption with GP's, but if you're a neurologist, there is added pressure to make your patient's better. It is not unethical to reach for the biggest gun in your arsenal if it has proven to be safe over many patient years. There is a very large therapeutic index and it does not interact with other drugs. There are many other prophylactic regimens, but outside of botox, GPs generally know how to prescribe them. By the time referrals go to a neurologist, they have tried and failed all of those other medications and are seeking relief from their conditions. For many migraine sufferers, the risk is well worth it. Their quality of life is greatly diminished because their headaches are completely debilitating. |
|
|
|
Post by stevil on Aug 31, 2019 18:16:27 GMT -5
Aimovig's insert says it is administered subcutaneously once a month. I don't see that inhalation would offer much advantage. Also, it's a monoclonal antibody and best I can tell from google those are not well absorbed via lung inhalation. As far as insurance coverage, it would run into the same problem as afrezza in that the trials would need to show superiority, otherwise Amgen's financial muscle would keep it on the lower tiers. You are correct about sub-q, I was mistaken about IM... the mental picture of the auto-injector had a much longer needle than reality. I was unaware that mab's could not be loaded onto TS. That kind of sucks for future potential. Are you sure that it wasn't aerosol, because I know that is true. Aimovig isn't even well covered right now because it is so expensive. But the manufacturer doesn't care- they give prescription cards out for an entire year's worth of free medication knowing that insurance will eventually catch up once they see how much money it saves them in yearly ED visits. So they're giving people the free nose candy to get them addicted so that if their insurance decides to deny coverage, they'll hear hell from potentially millions of customers. It will not take much convincing once the data proves how valuable these preventative medications are. Unlike with Afrezza, the cost savings is immediately realized by insurance companies as migraines happen monthly vs ailments caused by decades of poor glucose control. I would contend superiority isn't even necessary right now as there is no true dominant player. This is an emerging and evolving field currently and all it would take is something to set one apart from the other. This is assuming of course that one does not prove to be vastly superior eventually. If given the option of injecting vs inhaling, there is a psychological barrier that many have to injecting. Once they get over it, it's not a big deal, but if a doctor gives them the option of inhaling or injecting and the results are even similar or mildly inferior, I'd be surprised if the inhaled version doesn't win out. This is all a moot point, of course, if MNKD can't figure out a way to load CGRPs onto TS. It would be the responsibility of the partner to do the marketing, coverage, and trials, too. This class is on its way and is going to be huge in the not too distant future. Hopefully MNKD can secure their slice of the pie. edit: Sorry for the detour from the OP. Didn't mean to steer this so far off topic. |
|
paul
Researcher
Posts: 134
|
Post by paul on Aug 31, 2019 23:41:24 GMT -5
Aimovig's insert says it is administered subcutaneously once a month. I don't see that inhalation would offer much advantage. Also, it's a monoclonal antibody and best I can tell from google those are not well absorbed via lung inhalation. As far as insurance coverage, it would run into the same problem as afrezza in that the trials would need to show superiority, otherwise Amgen's financial muscle would keep it on the lower tiers. You are correct about sub-q, I was mistaken about IM... the mental picture of the auto-injector had a much longer needle than reality. I was unaware that mab's could not be loaded onto TS. That kind of sucks for future potential. Are you sure that it wasn't aerosol, because I know that is true. Aimovig isn't even well covered right now because it is so expensive. But the manufacturer doesn't care- they give prescription cards out for an entire year's worth of free medication knowing that insurance will eventually catch up once they see how much money it saves them in yearly ED visits. So they're giving people the free nose candy to get them addicted so that if their insurance decides to deny coverage, they'll hear hell from potentially millions of customers. It will not take much convincing once the data proves how valuable these preventative medications are. Unlike with Afrezza, the cost savings is immediately realized by insurance companies as migraines happen monthly vs ailments caused by decades of poor glucose control. I would contend superiority isn't even necessary right now as there is no true dominant player. This is an emerging and evolving field currently and all it would take is something to set one apart from the other. This is assuming of course that one does not prove to be vastly superior eventually. If given the option of injecting vs inhaling, there is a psychological barrier that many have to injecting. Once they get over it, it's not a big deal, but if a doctor gives them the option of inhaling or injecting and the results are even similar or mildly inferior, I'd be surprised if the inhaled version doesn't win out. This is all a moot point, of course, if MNKD can't figure out a way to load CGRPs onto TS. It would be the responsibility of the partner to do the marketing, coverage, and trials, too. This class is on its way and is going to be huge in the not too distant future. Hopefully MNKD can secure their slice of the pie. edit: Sorry for the detour from the OP. Didn't mean to steer this so far off topic. I see no reason why mabs can't be engulfed by technosphere, but that doesn't do any good if the mabs can't cross the epithelial lining of the lung once they are delivered. Proof of superiority is necessary since for a non-inferior product, Amgen can negotiate deals with the insurers and PBMs sweeter than anything a small competitor has to offer. |
|
|
|
Post by prcgorman2 on Sept 12, 2019 19:42:32 GMT -5
Sub-q anything is going to have trouble competing with inhaled and in the bloodstream nearly instantly. I don’t get the feeling that Mannkind put CGRP on the pipeline with an emphasis because they thought they couldn’t do it or that it wouldn’t work or that there wouldn’t be any partners.
|
|
paul
Researcher
Posts: 134
|
Post by paul on Sept 12, 2019 22:01:03 GMT -5
Sub-q anything is going to have trouble competing with inhaled and in the bloodstream nearly instantly. I don’t get the feeling that Mannkind put CGRP on the pipeline with an emphasis because they thought they couldn’t do it or that it wouldn’t work or that there wouldn’t be any partners. Where did you see that CGRP has been put in the pipeline? It doesn't show up on the Mannkind website. And is instantly really necessary for a drug that's designed to prevent migraines and is only given once a month or once a quarter? |
|
|
|
Post by peppy on Sept 12, 2019 22:29:47 GMT -5
Sub-q anything is going to have trouble competing with inhaled and in the bloodstream nearly instantly. I don’t get the feeling that Mannkind put CGRP on the pipeline with an emphasis because they thought they couldn’t do it or that it wouldn’t work or that there wouldn’t be any partners. Where did you see that CGRP has been put in the pipeline? It doesn't show up on the Mannkind website. And is instantly really necessary for a drug that's designed to prevent migraines and is only given once a month or once a quarter? Paul, try and keep up. Amgen makes Aimovig. Hey people the CGRP are, monoclonal antibodies. stevil really, this is what it takes to constrict blood vessels? www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aimovig/aimovig_pi_hcp_english.ashx2.1 Recommended Dosing The recommended dosage of AIMOVIG is 70 mg injected subcutaneously once monthly. Some patients may benefit from a dosage of 140 mg injected subcutaneously once monthly. 11 DESCRIPTION Erenumab-aooe is a human immunoglobulin G2 (IgG2) monoclonal antibody that has high affinity binding to the calcitonin gene-related peptide receptor. Erenumab-aooe is produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells. It is composed of 2 heavy chains, each containing 456 amino acids, and 2 light chains of the lambda subclass, each containing 216 amino acids, with an approximate molecular weight of 150 kDa. AIMOVIG (erenumab-aooe) injection is supplied as a sterile, preservative-free, clear to opalescent, colorless to light yellow solution for subcutaneous administration. Each 1 mL 70 mg single-dose prefilled autoinjector and 70 mg single-dose prefilled glass syringe contains 70 mg erenumab-aooe, acetate (1.5 mg), polysorbate 80 (0.10 mg), and sucrose (73 mg). Each 1 mL 140 mg single-dose prefilled autoinjector and 140 mg single-dose prefilled glass syringe contains 140 mg erenumab-aooe, acetate (2.0 mg), polysorbate 80 (0.10 mg), and sucrose (65 mg). Enclosed within the autoinjector is a single-dose, prefilled glass syringe. The solution of AIMOVIG has a pH of 5.2. 12.1 Mechanism of Action Erenumab-aooe is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function. |
|
|
|
Post by prcgorman2 on Sept 13, 2019 14:19:02 GMT -5
Sub-q anything is going to have trouble competing with inhaled and in the bloodstream nearly instantly. I don’t get the feeling that Mannkind put CGRP on the pipeline with an emphasis because they thought they couldn’t do it or that it wouldn’t work or that there wouldn’t be any partners. Where did you see that CGRP has been put in the pipeline? It doesn't show up on the Mannkind website. And is instantly really necessary for a drug that's designed to prevent migraines and is only given once a month or once a quarter? On the Wainwright thread there is a quote of MC talking about pipeline development and migraine pain relief. I went back and found it, but it says Sumatriptan, not CGRP. Reading at nih.gov on the topic of triptans and CGRPs it looks like they are not the same thing and is my mistake for confusing the two. And someone (might have been you) pointed out that not a lot of research on CGRP as compared to triptans so probably a good choice by Mannkind to focus on that. Easier to find a partner who can expect love (or less hate) from FDA. |
|
|
|
Post by mango on Sept 13, 2019 16:19:40 GMT -5
I totally disagree. The CGRP antagonists are very new and lack robust safety data, especially long-term safety data. There also has not been any carcinogenesis and mutagenesis studies conducted with Aimovig. I'll assume the same is true for the others like it. It would be extremely high risk for MannKind to go this route. There simply has not been enough research and studies done with these etc... I don't see them taking this route this early on, and while there is more questions and unknowns that still remains with this new class. By the way, constipation is a common side effect, as well as pain from the injection. Cramps and muscle spasms was also experienced in participants during trials. Every novel drug that comes to market runs the risk of serious adverse effects. That's a given. However, doctors look at the whole picture when deciding whether to prescribe or not. How serious are the adverse reactions vs the benefits of therapy. You are correct about constipation. I forgot about that because, if memory serves, it was very insignificant- something like low single digits vs placebo. Doctors will consider it for people with GI illnesses like gastroparesis or other diseases and opioid dependence, but for the other millions of people, they won't bat an eyelash at constipation (or cramps and muscle spasms- btw, these will disappear if it is inhaled). There are calcitonin receptors in the GI system that cause the constipation, so this would likely remain even if inhaled. I'm not sure I'd take my patient seriously about their migraines if they told me they didn't want to prevent a migraine due to constipation. You're comparing what you know about Afrezza with other drugs. That is not how perception of other drugs work. Sure, there will be slow adopters with all things new, but this is different than Afrezza because there have already been multiple thousands of people on CGRPs without any serious events, and there hasn't been another drug in its class that already has red flags. You might see slow adoption with GP's, but if you're a neurologist, there is added pressure to make your patient's better. It is not unethical to reach for the biggest gun in your arsenal if it has proven to be safe over many patient years. There is a very large therapeutic index and it does not interact with other drugs. There are many other prophylactic regimens, but outside of botox, GPs generally know how to prescribe them. By the time referrals go to a neurologist, they have tried and failed all of those other medications and are seeking relief from their conditions. For many migraine sufferers, the risk is well worth it. Their quality of life is greatly diminished because their headaches are completely debilitating. Not sure why you insinuated that I was comparing Aimovig to Afrezza. Here’s some information to help you better understand. • Lawrence Robbins, a renowned neurologist and expert in the field, does not seem to align with you on the safety aspects. This is a write up by him from earlier this year in Practical Pain Management and he raises a number of long-term safety concerns. www.practicalpainmanagement.com/pain/headache/stake-possible-long-term-side-effects-cgrp-antagonists• The Institute for Safe Medication Practices published an article this August on safety data of four new drugs from Q4, 2018 and Q1, 2019. AIMOVIG, AJOVY, and EMGALITY were among 3 of them. Here’s a snippet of what was discovered Postmarket adverse event data. Our primary analysis focused on erenumab-aooe, which was the first to gain FDA approval, has the largest patient population, and generated the most adverse drug event reports. The most striking feature of the erenumab-aooe adverse event data was the sheer number of case reports for the 12 months ending in Quarter 1, 2019: 10,508 case reports, including 1,458 with a serious outcome.
Erenumab-aooe ranked first in the number of reports for the 33 new drugs approved in 2018 and accounted for more than twice as many cases as the other 32 new drugs combined. The large number of reports might be explained, in part, by a successful product launch and high number of outpatient prescriptions.
We identified a clear signal for constipation (n=1,169), which ranged from cases managed with laxatives to those requiring hospitalization and/or treatment discontinuation. This adverse effect was seen in clinical trials but at a very low rate (1% at the 70 mg dose). Participants in the trials may not have been asked about constipation, and higher incidences up to 20% have been documented when patients have been queried about this adverse effect. There was also a signal for alopecia (n=376; 64 classified as serious), even though this was seen in only 2 patients during clinical trials. Again, patients may not have been asked about this during trials, leading to underestimation of its effect.
We also identified a possible signal for cardiac arrhythmia (n=225), including palpitations, increased heart rate, and loss of consciousness. The risk of cardiovascular adverse effects was a concern during FDA-approval evaluations, but in pre-approval clinical studies, the agency did not identify a risk warranting a warning.
Muscle and joint pain, and hypersensitivity were seen both in clinical trials and early adverse drug event data. Large numbers of complaints about the drug not being effective (n=2,086) were also observed, which is expected given studies that showed limited or no benefit in 15% of patients and only modest reductions in headaches in many others.www.ismp.org/resources/quarterwatchtm-includes-new-data-quarter-4-2018-and-quarter-1-2019-focus-four-new-drugs• Aimovig is produced in Chinese hamster ovary cells using recombinant DNA technology, and is a very new drug with very little safety data, very little non-clinical study data, very limited human study data, and no long-term safety data—in conjunction with its significant number of adverse events reports in just a mere 12 months, common sense tells me much remains to be seen with these and several red flags have been raised in since their approvals. |
|
paul
Researcher
Posts: 134
|
Post by paul on Sept 26, 2019 17:47:21 GMT -5
Spencer Osborne has written about Arena Pharmaceuticals: seekingalpha.com/article/4293615-recent-dip-presents-buying-opportunity-arena-pharmaceuticalsHe brings up Mannkind and adcirca: "As it turns out, MannKind has done the necessary studies on an inhaled version related to the $10-million dollar option. The results have been available for over a month, but indications would seem to be that United is not going any further with the inhaled version of Adcirca at this time. Had United moved forward, MannKind would have been eligible for $30 million more in milestones." However, I can't find the adcirca results he mentions. Can anyone direct me to them? |
|
|
|
Post by mnkdfann on Sept 26, 2019 18:32:37 GMT -5
Spencer Osborne has written about Arena Pharmaceuticals: seekingalpha.com/article/4293615-recent-dip-presents-buying-opportunity-arena-pharmaceuticalsHe brings up Mannkind and adcirca: "As it turns out, MannKind has done the necessary studies on an inhaled version related to the $10-million dollar option. The results have been available for over a month, but indications would seem to be that United is not going any further with the inhaled version of Adcirca at this time. Had United moved forward, MannKind would have been eligible for $30 million more in milestones." However, I can't find the adcirca results he mentions. Can anyone direct me to them? I may be confused, but is this maybe it? No publicly available results, just an informal announcement as below: In the last earnings call (August 7), Castagna said: "United Therapeutics is going very nicely ... We anticipate achieving our second milestone with $12.5 million in the second half of 2019. The research agreement for the undisclosed PH compound is substantially complete. We expected decision with United Therapeutics in Q3." I believe Spencer is assuming the secret compound is Adcirca (aka Tadalafil). I'm not sure / do not recall whether that has been officially confirmed. The transcript is available on SA if you are a paying member, otherwise you can search google for a cached copy. But IIRC it doesn't say anything more on the subject than what I quoted above. |
|
|
|
Post by brentie on Sept 26, 2019 19:44:52 GMT -5
Spencer Osborne has written about Arena Pharmaceuticals: seekingalpha.com/article/4293615-recent-dip-presents-buying-opportunity-arena-pharmaceuticalsHe brings up Mannkind and adcirca: "As it turns out, MannKind has done the necessary studies on an inhaled version related to the $10-million dollar option. The results have been available for over a month, but indications would seem to be that United is not going any further with the inhaled version of Adcirca at this time. Had United moved forward, MannKind would have been eligible for $30 million more in milestones." However, I can't find the adcirca results he mentions. Can anyone direct me to them? I may be confused, but is this maybe it? No publicly available results, just an informal announcement as below: In the last earnings call (August 7), Castagna said: "United Therapeutics is going very nicely ... We anticipate achieving our second milestone with $12.5 million in the second half of 2019. The research agreement for the undisclosed PH compound is substantially complete. We expected decision with United Therapeutics in Q3." I believe Spencer is assuming the secret compound is Adcirca (aka Tadalafil). I'm not sure / do not recall whether that has been officially confirmed. The transcript is available on SA if you are a paying member, otherwise you can search google for a cached copy. But IIRC it doesn't say anything more on the subject than what I quoted above. I'm not a member but I can get it. Try this... seekingalpha.com/article/4283046-mannkind-corporation-mnkd-ceo-michael-castagna-q2-2019-results-earnings-call-transcript?part=single |
|
