|
|
Post by agedhippie on Aug 20, 2019 10:08:03 GMT -5
The problem is that word presumed. This circles back to your original point about needing trials to prove and not presume. Even TIR itself is not on rock solid ground. There are trials and surveys going on into that now. There is a presumption that TIR leads to better results, but it's not yet proven. Happily Mannkind will not be the ones bearing the cost on that one, and Lilly and Novo both have an interest in getting that data. So the ADA added TIR recommendations to their SOC based upon presumptions? I'm not doubting what you said though it just seems odd to me as I was under the impression that they base the SOC on large clinical studies? As it stands today TIR is about minimizing hypos while achieve an OK HbA1c. With the range chosen, 180 - 70, each 10% TIR equates to roughly 1.0 in HbA1c with 70% TIR being an A1c of 7.0. What still needs to be proven is that TIR reduces complications independently from the effect you get from managing HbA1c and that will take data. The issue is that whereas it's possible to go back and mine treatment and outcome data generally TIR is new enough for that historical data set to not yet exist so it has to be developed and that takes time. |
|
|
|
Post by agedhippie on Aug 20, 2019 10:21:26 GMT -5
Aged - how many trials do we need to show that BG over 140 for 2+hours causes vascular degeneration? How many trials do we need to show nothing can bring post meal BG's down as fast as afrezza? Stop the post meal 140+ spike, get it back to a fasting under 140 and do you think you will see improved cardiovascular health? Talk about Jardiance and Victoza. I will say afrezza will win that trail hands down and with out the thyroid cancer. Degeneration needs to be quantified. Is the degeneration so low that it's going to take a couple of hundred years before there is a significant impact, or is it a matter of weeks? What is the impact of being at 180 vs. 140? What is the impact of being at 250? How important is deviation vs. level? Taking your question. "Stop the post meal 140+ spike, get it back to a fasting under 140 and do you think you will see improved cardiovascular health?" The key is to quantify the results; what is the percentage improvement, how much is the change, does any effect tail off over time, what is the cost per patient for any effect? Before the medical world goes over to 140 they need the data to prove that it makes a measurable and worthwhile difference, is cost effective, and will have reasonable compliance. Without that nothing changes. |
|
|
|
Post by agedhippie on Aug 20, 2019 11:07:54 GMT -5
When the FDA approved Afrezza, in addition to requiring lung safety tests using FEV equipment to avoid prescribing to folks with chronic lung disease, they also required a long-term safety study (or studies). I think it may be shown on the Mannkind slides from 2Q. I could be wrong but I recall that the FDA waived the study about 12-18 months ago. They deferred the trial, they did not waive it. The FDA are looking for a 5-year trial with 8,000-10,000 patients with Type 2 diabetes combined with "The patient population should be enriched with respect to lung cancer risk (i.e., predicted incidence of no less than 200/100,000 patient-year)". I suspect that there are not currently that number of people with Type 2 on Afrezza given the insurance position and that is probably why the FDA is letting Mannkind defer this - if the risk group is tiny and the probability is small it's unlikely you could ever attribute any incidence of cancer to a particular cause (barring heavy smokers). When that Type 2 group gets larger expect to see this trial kick off. |
|
|
|
Post by boca1girl on Aug 20, 2019 18:43:19 GMT -5
When the FDA approved Afrezza, in addition to requiring lung safety tests using FEV equipment to avoid prescribing to folks with chronic lung disease, they also required a long-term safety study (or studies). I think it may be shown on the Mannkind slides from 2Q. I could be wrong but I recall that the FDA waived the study about 12-18 months ago. I asked MC at the ASM in May if the lung safety study is still required and he said yes and it will begin “shortly”. Has it begun, I don’t know but the requirement has not gone away. |
|
|
|
Post by sayhey24 on Aug 20, 2019 20:23:21 GMT -5
Aged - how many trials do we need to show that BG over 140 for 2+hours causes vascular degeneration? How many trials do we need to show nothing can bring post meal BG's down as fast as afrezza? Stop the post meal 140+ spike, get it back to a fasting under 140 and do you think you will see improved cardiovascular health? Talk about Jardiance and Victoza. I will say afrezza will win that trail hands down and with out the thyroid cancer. Degeneration needs to be quantified. Is the degeneration so low that it's going to take a couple of hundred years before there is a significant impact, or is it a matter of weeks? What is the impact of being at 180 vs. 140? What is the impact of being at 250? How important is deviation vs. level? Taking your question. "Stop the post meal 140+ spike, get it back to a fasting under 140 and do you think you will see improved cardiovascular health?" The key is to quantify the results; what is the percentage improvement, how much is the change, does any effect tail off over time, what is the cost per patient for any effect? Before the medical world goes over to 140 they need the data to prove that it makes a measurable and worthwhile difference, is cost effective, and will have reasonable compliance. Without that nothing changes. Aged - I am not sure how bad things would be after a "couple of hundred years" but the Honolulu study was 12 years and followed over 8000 participants and showed the incidence of coronary artery disease was twice as high in patients with postprandial glucose levels between 157 and 189 mg/dl compared to those with levels under 144 mg/dl. www.ncbi.nlm.nih.gov/pubmed/3569669There are a ton more studies which pretty much all say the same thing. The list is long. When you keep studying the same thing over and over and keep getting the same result, saying we still need just one more study sounds like insanity to me when we finally have a real solution to address the problem. We know the cost per patient is $5 per day thanks to insulinsavings.com to reduce the risk of a heart attack by 50%. Is that cost effective? I would say yes but maybe some would rather risk it and have the heart attack. As far as compliance, a little puff or two with each meal seems pretty doable. |
|
|
|
Post by prcgorman2 on Aug 20, 2019 20:55:21 GMT -5
seyhey24 - I'm confident you're right about cardiac and blood system comorbidity being proven, but doesn't there need to be a sizable body of data that shows Afrezza not only increases TIR, but also reduces comorbidity? I see the correlation you're drawing and know you must be right, but will the FDA, especially, permit a claim of superiority of Afrezza over RAA based on TIR study only, but no concomitant study of comorbidity with improved TIR?
|
|
|
|
Post by ktim on Aug 20, 2019 21:20:04 GMT -5
seyhey24 - I'm confident you're right about cardiac and blood system comorbidity being proven, but doesn't there need to be a sizable body of data that shows Afrezza not only increases TIR, but also reduces comorbidity? I see the correlation you're drawing and know you must be right, but will the FDA, especially, permit a claim of superiority of Afrezza over RAA based on TIR study only, but no concomitant study of comorbidity with improved TIR? This is probably getting into gray areas where it would be dependent on FDA judgement. Hard to predict what they will do for all circumstances when each disease state and what is known about it differs. I doubt MNKD could make specific claims about comorbidity using logical inference, however being able to claim better TIR in adverts could still carry weight if it is generally accepted that better TIR leads to cardiovascular benefits. Currently RAAs aren't advertised as reducing cardiovascular events, but they are advertised as lowering A1c and almost everyone acknowledges link between out of control A1c and cardiovascular disease. Anti-glycemic oral agents were perhaps assumed to have cardio benefit until it turned out they don't necessarily, and now have to prove it. For it to benefit Afrezza significantly, the improvement in TIR vs other prandials would need to seem significant relative to the info currently known about TIR and comorbidity... and that would be in the eyes of the many medical beholders rather than being directly spelled out as "Afrezza reduces cardiovascular risk." What is required for MNKD to use TIR in consumer marketing? It might have been FDA was waiting for evidence that TIR is meaningful, but with ADA now adopting guidelines it seems it would meet that threshold. Was MNKDs study simply not large enough? or perhaps they are already working with FDA to be allowed to talk about TIR? I think regardless, the state of the profession shifting from A1c focus to TIR will be a slow evolution, so I wouldn't expect a seismic shift in MNKDs fortunes even if they can start talking about TIR. Much cheaper CGMs so that majority of insurance covers for T2, or the holy grail of a non-invasive meter, would help to speed that up I would think... but neither of those things seems imminent. |
|
|
|
Post by letitride on Aug 21, 2019 1:19:14 GMT -5
The truth about superiority may be in A!C alone. Can T1 users of afrezza achieve lower A1C than users of any other treatment regimen?
|
|
|
|
Post by ktim on Aug 21, 2019 2:20:28 GMT -5
The truth about superiority may be in A!C alone. Can T1 users of afrezza achieve lower A1C than users of any other treatment regimen? There are some on Afrezza that have higher A1c than some others on RAAs (particularly AP pump users I think). To be meaningful one has to look at statistics. STAT had a statistically meaningful reduction for those that were compliant with dosing protocol, though many in medical profession discount results like that somewhat if it appears the protocol tends to lead to non-compliance. |
|
|
|
Post by sayhey24 on Aug 21, 2019 5:23:42 GMT -5
seyhey24 - I'm confident you're right about cardiac and blood system comorbidity being proven, but doesn't there need to be a sizable body of data that shows Afrezza not only increases TIR, but also reduces comorbidity? I see the correlation you're drawing and know you must be right, but will the FDA, especially, permit a claim of superiority of Afrezza over RAA based on TIR study only, but no concomitant study of comorbidity with improved TIR? Dr. Kendall needs to mimic what was done for Victoza. There is lots of grant money and lots of Universities looking to grab it. I would think with CGMs there will be a zillion TIR studies. With afrezza we are talking beyond TIR. Most TIR is considered 70 -180. As you can see once you go over 140 things go bad fast. Staying at 175 is significantly different than 135. Dr. Kendall seems to have turned into Casper the Ghost. I hope when he said this was the easiest job he ever had it was not because he planned on just taking a long nap. |
|
|
|
Post by letitride on Aug 21, 2019 6:24:53 GMT -5
The truth about superiority may be in A!C alone. Can T1 users of afrezza achieve lower A1C than users of any other treatment regimen? There are some on Afrezza that have higher A1c than some others on RAAs (particularly AP pump users I think). To be meaningful one has to look at statistics. STAT had a statistically meaningful reduction for those that were compliant with dosing protocol, though many in medical profession discount results like that somewhat if it appears the protocol tends to lead to non-compliance. The question remains which one can achieve the lowest A1C ? Not can Afrezza users go higher? |
|
|
|
Post by ktim on Aug 21, 2019 7:38:01 GMT -5
There are some on Afrezza that have higher A1c than some others on RAAs (particularly AP pump users I think). To be meaningful one has to look at statistics. STAT had a statistically meaningful reduction for those that were compliant with dosing protocol, though many in medical profession discount results like that somewhat if it appears the protocol tends to lead to non-compliance. The question remains which one can achieve the lowest A1C ? Not can Afrezza users go higher? I don't think medical professionals would necessarily agree that is terribly relevant question. There is some level of A1c below which it would be considered that there isn't any clinical advantage. And mostly they are concerned about what is achievable by the majority of users, not just the statistical outliers of each arm. But I do realize many here view things differently than most medical professionals... hence not understanding why sales are what they are. Sounds like MNKD is grinding away at producing the necessary statistical data so that the types of questions asked by doctors can be convincingly addressed. |
|
|
|
Post by letitride on Aug 21, 2019 18:52:22 GMT -5
If the latitude of the outliers for Afrezza are 5s and the outliers of the others are 6s then I would say you have statistical evidence of superiority. These anomaly only provide further proof of safety where others would fail. The STAT study may have well lit the fire for TIR.
|
|
|
|
Post by agedhippie on Aug 21, 2019 21:58:45 GMT -5
If the latitude of the outliers for Afrezza are 5s and the outliers of the others are 6s then I would say you have statistical evidence of superiority. These anomaly only provide further proof of safety where others would fail. The STAT study may have well lit the fire for TIR. The problem for the A1c argument is that Afrezza was rated the same in the only Type 1 large scale trial. This may be due to dosing, conversions, timings, etc. but that's the score on the board and anything else will be seen as outliers. STAT requires repeating at scale before it gets any attention as it was only a pilot (their description). Ultimately STAT-2 may be more valuable for showing an A1c reduction than TIR as A1c is better understood generally. |
|
|
|
Post by ktim on Aug 26, 2019 19:25:10 GMT -5
If the latitude of the outliers for Afrezza are 5s and the outliers of the others are 6s then I would say you have statistical evidence of superiority. These anomaly only provide further proof of safety where others would fail. The STAT study may have well lit the fire for TIR. You seem to be using outlier in a different meaning than what I was. I was referring to the best A1c achieved in one arm vs another... i.e. the good outliers. So in this case having outliers further from average (best achieved individual A1c for Afrezza vs control) would increase the standard deviation despite being the positive you are rightly citing it as. I was simply pointing out that medical professionals tend to look at what occurs in the middle of the distribution not the best achieved outliers. Some people achieve damn good A1c on RAAs... but it's likely being very strict about diet and exercise beyond what most people are willing to tolerate (or using a closed loop pump). The people that achieve the best results on Afrezza have a different aspect of adherence and mindfulness... i.e. need for monitoring and follow up doses. Most people aren't going to achieve the best possible results with any insulin. And actually, no, a lower standard deviation is not always better. If some treatment were to result in everyone tightly grouped around 8.5% A1c, that's not at all a good outcome despite having low standard deviation. |
|
