The David Kendall Effect

[Deleted]

Think we got some people's attention. Up .04 cents in premarket on some light to medium trading(for $MNKD). A precursor of things to come?

[pantaloons]

Jun 24, 2018 15:44:55 GMT -5 pantaloons said:

Jun 24, 2018 15:14:37 GMT -5 gareaudan said:

yeah well the statistically significant p number is arbitrary determine so even if it is globally accepted, it is questionnable. For such a small n, p=0.1022 is not bad. But you are right, technicaly, it is not statisticaly significant and we should Wait. That said, im not a statisticien but im pretty sure it is not equally probable to increase the hypo. The p value only Says the your first hypothesis is valid or not. Not the possibilities of anything.

I'd have to agree with gareaudan 's response regarding p values. That is, in clinical research, p-values equal to or less than 0.05 are (arbitrarily) considered "statistically significant". To clarify, it simply means that there is a 5% chance or less that the difference in means is due to random chance. By that vain, strictly speaking, it is not correct to state that there are equal (i.e., a 50-50 chance) probability that either Afrezza and insulin Aspart would demonstrate greater TIR in one than the other. For a p-value of 0.1022, there is approximately a 10% chance that this finding is due to random error. For every 10 times this experiment is performed, 9 of those times, Afrezza would show greater TIR, and 1 of those times, insulin Aspart would show greater TIR.

As can be inferred from the very definition of p-values, there is a degree of arbitrariness and therefore, it is prudent to also consider the various contexts in which these numbers are presented. Randomized clinical trials are considered the highest standard of clinical data (aside from meta analyses and in contrast to case studies/series, which are the least rigorous), but it is also important to note that this is but a single (yet insightful) trial with a modest sample size.

With that said, the results are promising, but this is just the beginning and what will be important in the coming months will be the interpretation of this data by endocrinologists (and health insurance payers), as they will ultimately be prescribing and funding these treatments.

A compelling shift in the standard of care will likely require clinical trials on the order of hundreds if not thousands, depending on the power of the study and how well measurable the effect of the novel treatment is. Nonetheless, it is noteworthy that this initial study has shown promise and surely will be the nidus for many subsequent, impactful studies spearheaded by a world-class expert (Kendall).

I will add one more caveat regarding p-values. In the case above, where p = 0.1022, i.e., is not statistically significant, there are two possibilities. First, there may indeed not be any effect of the treatment on TIR when compared to controls (insulin Aspart). Second, the sample size of the treatment and control groups were too small. The latter case would be known as a "type II" error, i.e., there was no significant effect demonstrated when in reality there should be (in contrast, a type I error would occur when analysis demonstrates a statistically significant difference when there should not be.) This can be addressed by increasing the sample size in a subsequent study. In the design of any clinical trial, a power analysis is performed in order to estimate the minimum sample sizes required to measure a difference in outcomes between treatment vs. control groups. This is highly dependent on the expected magnitude of the effect of the novel treatment of interest. Therefore, initial studies are prone to both type I and II errors. In general, if the effect of treatment is very dramatic, smaller sample sizes are required to demonstrate statistical significance, and vice versa.

In the case of insulin treatments for diabetes, many important primary outcomes (such as BG levels, TIR, HbA1c) can be assessed relatively quickly (on the order of weeks to months). In contrast, other outcomes, such as cardio-/peripheral vascular, renal and neuropathic disease will take years to decades. In other words, there are short-term and long-term outcomes. Ultimately, in this case, the long-term outcomes are of more clinical, societal, and economic consequence. It will be crucial to demonstrate that indeed certain short-term outcomes translate to statistically significant long-term outcomes. Two treatments might have different short-term outcomes, but their long-term outcomes can still be identical. In the case of insulin treatment for diabetes, it is well-established that HbA1c is associated with diabetes-related morbidity and mortality. Compared to HbA1c, the association between TIR and morbidity/mortality is not as well studied yet appears to be gaining traction as a prognostic tool. Moving forward, it will be important to demonstrate that Afrezza is effective in managing both HbA1c and TIR.

[compound26]

Jun 24, 2018 18:01:58 GMT -5 mannmade said:

My "take"on the stat study has been determined in part on the actual results, which by and large seem actually pretty good, but also on what I consider to be the promise of what it has shown us and for which Dr. K is integral in the storytelling and explanation both because he "sees" it and because he has the gravitas to tell it/sell it to other experts in diabetes.

When the stat study first came out I was expecting more positive comments from people. I am not a true science person so I was a bit confused at what I thought was the underwhelming response to the study, espcially given a few people on this board whom I respect for their science background that did not see the merits as very positive..

But upon further study and hearing more comments it is now my personal beleif that the stat study results are quite positive and lay the groundwork for the new mannkind and the new conversation about Afrezza that goes with it. That conversation imho is as follows:

1. Stat study showed how Afrezza can accomplish exactly, if not better control, as what an RAA can accomplish in less time with less hypos. To me, this in and of itself is good news. You can debate whether or not the numbers are statiscally relevant. Does it make Afrezza superior? I beleive it does.

2. Now the promise... what the study did not do is show how Afrezza can work to keep better control and TIR at significanntly lower levels of fasting BG which would require in many cases higher does of basal insulin and/or adjusments to prandial dosing. But as we know from the many anecdotal posters on social media, they are getting non diabetic numbers in the 5's and even more of them in the low to mid 6's for Hba1c's using Afrezza by targeting lower fasting BG at anywhere from 120 to 140.

So why didn't the stat study show this as a goal? because imho it could not as a first of its kind study with a comparison to RAA's as its basis, since doing so would require dosing that most docs will not do with traditional RAA insulins as it would drive pwd into more severe hypos. (The stat study targeted 160 for fasting BG.)  A separate study targeting lower BG will likely have to be done under more direct management if a comparison is done or with Afrezza only.

THIS is the NEW story that could not be told now without the stat study... Remember that the ADA recently raised the acceptable Hba1c level to 8 from 7 or so because it has been too hard to get pwd to the lower levels without hypos and compliance is difficult with all that it entails for a T1. Afrezza changes all of this. Just think if you can now get pwd to a range of 5.5 to 6.5 with the same or less hypos... You don't think this would have to be the new SOC?

And this is what Dr. likely meant when stating that Afrezza should be the SOC.

Now again I do not have diabetes and I am not a science person so someone with a better understanding may be able to correct me if I have mispoken and hope they will but what imho I beleive is the true value of the stat study is the conversation Dr. K and the reps can now have with other docs that they had no basis for prior to the stat study...

After listening to Dr Kendall's presentation to the investors yesterday, I now can clearly see that the STAT trial results are very significant. For anyone interested, please listen to the presentation, especially starting from about 1 hour into the presentation where Dr. Kendall discussed the details about the STAT trial. Here is the link to the replay of the presentation. lifesci.rampard.com/20180627/index.jsp#

Based on Dr. Kendall’s presentation, here are my thoughts:

1.    For the dosing compliant group, if you look at the charts included in the slides shown during presentation, the BG level of Afrezza group vs the RAA group at 1 hour after meal is roughly 145 vs 185.

You can draw your own conclusion whether that is significant or not or whether Afrezza is superior on that front.

2.    The above obviously superior result is achieved while the Afrezza arm of patients are clearly under-dosing themselves.

Dr. Kendall explained that, for the trail purpose, the dosing is set to be 1 to 1, i.e., if a patient used to take 1 unit of RAA, he is taking 1 unit of Afrezza for the trial. Jeremy H. Pettus, MD has commented that, “based on clinical experience, 4 units of Afrezza is roughly equivalent to 2.5 units of SC insulin. [see slide 77 of this Medscape Education presentation]. That observation is line with many Afrezza users’ experience who shared their experience on social media.

Based on the above, if properly dosed, I am pretty certain the BG level of Afrezza group vs the RAA group at 1 hour after meal will be even more impressive than 145 vs 185 as achieved by the STAT trial. 125 vs 185 will certainly be an attainable target here as there is little hypo concern with Afrezza when taken at a relatively high BG level.

3.    The 12% improvement in range in time is also very significant improvement. To bring that data point into context, Dr. Kendall noted that the 12% improvement in range in time with Afrezza is basically the same improvement that CGMs achieved when CGMs first got FDA approval. And Dr. Edelman is stating CMGs is now standard of care.

4.    And in my personal opinion there are many other reasons why the STAT results could be even better if better trial protocols are used. You can read Sam’s article on this particular subject: How come Afrezza is WAY better now than on the Trials?

5.    Dr. Kendall further noted that over the entire history of insulin development, no new insulin actually has clearly out-performed competition within same class. Afrezza is the only exception based on the STAT trial data.

[sportsrancho]

If you own stock listen to the webcast. You will then be assured where this is going!
16 people called me yesterday and asked me what I thought of the call because they didn’t listen to it. Do your own gosh darn homework! Don’t ask somebody else to. You have to hear it or see it with your own ears:-) They got this!

[ilovekauai]

Indeed Sports, we got this. Sit back and enjoy the slow ride to a successful conclusion with MNKD and Afrezza!

[centralcoastinvestor]

Jun 28, 2018 10:34:27 GMT -5 compound26 said:

Jun 24, 2018 18:01:58 GMT -5 mannmade said:

My "take"on the stat study has been determined in part on the actual results, which by and large seem actually pretty good, but also on what I consider to be the promise of what it has shown us and for which Dr. K is integral in the storytelling and explanation both because he "sees" it and because he has the gravitas to tell it/sell it to other experts in diabetes.

When the stat study first came out I was expecting more positive comments from people. I am not a true science person so I was a bit confused at what I thought was the underwhelming response to the study, espcially given a few people on this board whom I respect for their science background that did not see the merits as very positive..

But upon further study and hearing more comments it is now my personal beleif that the stat study results are quite positive and lay the groundwork for the new mannkind and the new conversation about Afrezza that goes with it. That conversation imho is as follows:

1. Stat study showed how Afrezza can accomplish exactly, if not better control, as what an RAA can accomplish in less time with less hypos. To me, this in and of itself is good news. You can debate whether or not the numbers are statiscally relevant. Does it make Afrezza superior? I beleive it does.

2. Now the promise... what the study did not do is show how Afrezza can work to keep better control and TIR at significanntly lower levels of fasting BG which would require in many cases higher does of basal insulin and/or adjusments to prandial dosing. But as we know from the many anecdotal posters on social media, they are getting non diabetic numbers in the 5's and even more of them in the low to mid 6's for Hba1c's using Afrezza by targeting lower fasting BG at anywhere from 120 to 140.

So why didn't the stat study show this as a goal? because imho it could not as a first of its kind study with a comparison to RAA's as its basis, since doing so would require dosing that most docs will not do with traditional RAA insulins as it would drive pwd into more severe hypos. (The stat study targeted 160 for fasting BG.)  A separate study targeting lower BG will likely have to be done under more direct management if a comparison is done or with Afrezza only.

THIS is the NEW story that could not be told now without the stat study... Remember that the ADA recently raised the acceptable Hba1c level to 8 from 7 or so because it has been too hard to get pwd to the lower levels without hypos and compliance is difficult with all that it entails for a T1. Afrezza changes all of this. Just think if you can now get pwd to a range of 5.5 to 6.5 with the same or less hypos... You don't think this would have to be the new SOC?

And this is what Dr. likely meant when stating that Afrezza should be the SOC.

Now again I do not have diabetes and I am not a science person so someone with a better understanding may be able to correct me if I have mispoken and hope they will but what imho I beleive is the true value of the stat study is the conversation Dr. K and the reps can now have with other docs that they had no basis for prior to the stat study...

After listening to Dr Kendall's presentation to the investors yesterday, I now can clearly see that the STAT trial results are very significant. For anyone interested, please listen to the presentation, especially starting from about 1 hour into the presentation where Dr. Kendall discussed the details about the STAT trial. Here is the link to the replay of the presentation. lifesci.rampard.com/20180627/index.jsp#

Based on Dr. Kendall’s presentation, here are my thoughts:

1.    For the dosing compliant group, if you look at the charts included in the slides shown during presentation, the BG level of Afrezza group vs the RAA group at 1 hour after meal is roughly 145 vs 185.

You can draw your own conclusion whether that is significant or not or whether Afrezza is superior on that front.

2.    The above obviously superior result is achieved while the Afrezza arm of patients are clearly under-dosing themselves.

Dr. Kendall explained that, for the trail purpose, the dosing is set to be 1 to 1, i.e., if a patient used to take 1 unit of RAA, he is taking 1 unit of Afrezza for the trial. Jeremy H. Pettus, MD has commented that, “based on clinical experience, 4 units of Afrezza is roughly equivalent to 2.5 units of SC insulin. [see slide 77 of this Medscape Education presentation]. That observation is line with many Afrezza users’ experience who shared their experience on social media.

Based on the above, if properly dosed, I am pretty certain the BG level of Afrezza group vs the RAA group at 1 hour after meal will be even more impressive than 145 vs 185 as achieved by the STAT trial. 125 vs 185 will certainly be an attainable target here as there is little hypo concern with Afrezza when taken at a relatively high BG level.

3.    The 12% improvement in range in time is also very significant improvement. To bring that data point into context, Dr. Kendall noted that the 12% improvement in range in time with Afrezza is basically the same improvement that CGMs achieved when CGMs first got FDA approval. And Dr. Edelman is stating CMGs is now standard of care.

4.    And in my personal opinion there are many other reasons why the STAT results could be even better if better trial protocols are used. You can read Sam’s article on this particular subject: How come Afrezza is WAY better now than on the Trials?

5.    Dr. Kendall further noted that over the entire history of insulin development, no new class of insulin actually has clearly out-performed the previous class. Afrezza is the only exception based on the STAT trial data.

Compound, great summary.  Dr. Kendall is the real deal.  One of the items that Dr. Kendall cleared up yesterday for me was the reason patients were non-compliant on Afrezza .  It turns out that the patients were so used to having insulin stacking from normal RAAs that they didn’t trust doing the follow up doses of Afrezza even though they were instructed to do so.  So it isn’t like the non compliance was do to difficulty in using Afrezza, it was due to hang ups about the current standard of care and the insulin stacking that occurs with current RAAs.  Imagine that.

[churchmouse]

I just wish we could restart our 20 year patent clock.  I would have to assume we only have about 12 years left on the FDKP particle.  But perhaps MNKD's other patents rewind our clock back to 15 years.  In any case, the clock is ticking.

[mytakeonit]

Jun 28, 2018 11:36:41 GMT -5 ilovekauai said:

Indeed Sports, we got this. Sit back and enjoy the slow ride to a successful conclusion with MNKD and Afrezza!

This reminds me of when we took our young daughter to Disneyland and could only ride "It's a small world" ... over and over and over ... I knew every doll by their first name when we left.

[prcgorman2]

Jun 28, 2018 12:25:14 GMT -5 centralcoastinvestor said:

Jun 28, 2018 10:34:27 GMT -5 compound26 said:

After listening to Dr Kendall's presentation to the investors yesterday, I now can clearly see that the STAT trial results are very significant. For anyone interested, please listen to the presentation, especially starting from about 1 hour into the presentation where Dr. Kendall discussed the details about the STAT trial. Here is the link to the replay of the presentation. lifesci.rampard.com/20180627/index.jsp#

Based on Dr. Kendall’s presentation, here are my thoughts:

1.    For the dosing compliant group, if you look at the charts included in the slides shown during presentation, the BG level of Afrezza group vs the RAA group at 1 hour after meal is roughly 145 vs 185.

You can draw your own conclusion whether that is significant or not or whether Afrezza is superior on that front.

2.    The above obviously superior result is achieved while the Afrezza arm of patients are clearly under-dosing themselves.

Dr. Kendall explained that, for the trail purpose, the dosing is set to be 1 to 1, i.e., if a patient used to take 1 unit of RAA, he is taking 1 unit of Afrezza for the trial. Jeremy H. Pettus, MD has commented that, “based on clinical experience, 4 units of Afrezza is roughly equivalent to 2.5 units of SC insulin. [see slide 77 of this Medscape Education presentation]. That observation is line with many Afrezza users’ experience who shared their experience on social media.

Based on the above, if properly dosed, I am pretty certain the BG level of Afrezza group vs the RAA group at 1 hour after meal will be even more impressive than 145 vs 185 as achieved by the STAT trial. 125 vs 185 will certainly be an attainable target here as there is little hypo concern with Afrezza when taken at a relatively high BG level.

3.    The 12% improvement in range in time is also very significant improvement. To bring that data point into context, Dr. Kendall noted that the 12% improvement in range in time with Afrezza is basically the same improvement that CGMs achieved when CGMs first got FDA approval. And Dr. Edelman is stating CMGs is now standard of care.

4.    And in my personal opinion there are many other reasons why the STAT results could be even better if better trial protocols are used. You can read Sam’s article on this particular subject: How come Afrezza is WAY better now than on the Trials?

5.    Dr. Kendall further noted that over the entire history of insulin development, no new class of insulin actually has clearly out-performed the previous class. Afrezza is the only exception based on the STAT trial data.

Compound, great summary.  Dr. Kendall is the real deal.  One of the items that Dr. Kendall cleared up yesterday for me was the reason patients were non-compliant on Afrezza .  It turns out that the patients were so used to having insulin stacking from normal RAAs that they didn’t trust doing the follow up doses of Afrezza even though they were instructed to do so.  So it isn’t like the non compliance was do to difficulty in using Afrezza, it was due to hang ups about the current standard of care and the insulin stacking that occurs with current RAAs.  Imagine that.

OMG.  Not willing to stack because of their experience with RAA.  That so completely resonates with posts from PWDs I've read on-line.  RAA for meals is a constant roller-coaster.  The time it takes to get RAA out of the system is so long that other metabolic processes associated with activity and digestion of meals with varying levels of complexity in the carbohydrates or the foods they're combined with just makes it a complete nightmare to guess with any degree of accuracy whether stacking will cause a low which requires snacking.  They'd rather endure a high than a low.  Given that hypoglycemia can kill you (DOES kill PWDs year in and year out), their reluctance to "experiment" with stacking Afrezza is completely understandable.  The best results I've read about consistently come from seasoned veteran (and activist) Afrezza users.  And by "activist", I mean ones that take their BG levels very seriously and check them frequently using CGM and tabs.  Hackneyed phrase or not, Afrezza really is a paradigm shift.

[Deleted]

Jun 28, 2018 12:57:04 GMT -5 churchmouse said:

I just wish we could restart our 20 year patent clock.  I would have to assume we only have about 12 years left on the FDKP particle.  But perhaps MNKD's other patents rewind our clock back to 15 years.  In any case, the clock is ticking.

I agree, yet for someone to replicate Afrezza. They nees both tool(inhaler) ans actual drug. Not replicated easily. And not cheaply for that matter.

[agedhippie]

Jun 28, 2018 10:34:27 GMT -5 compound26 said:

3.    The 12% improvement in range in time is also very significant improvement. To bring that data point into context, Dr. Kendall noted that the 12% improvement in range in time with Afrezza is basically the same improvement that CGMs achieved when CGMs first got FDA approval. And Dr. Edelman is stating CMGs is now standard of care.

I should just say here that there was a gap after FDA approval before insurers would cover CGMs. The first CGMs as we would recognize them were approved around 2005 (the Guardian RT CGM, and the Dexcom STS CGM System). It took another 4 years before an insurer would cover them, and took a major JDRF trial to force that. A CGM now gives around a 25% improvement.

[mannmade]

Jun 28, 2018 19:37:46 GMT -5 agedhippie said:

Jun 28, 2018 10:34:27 GMT -5 compound26 said:

3.    The 12% improvement in range in time is also very significant improvement. To bring that data point into context, Dr. Kendall noted that the 12% improvement in range in time with Afrezza is basically the same improvement that CGMs achieved when CGMs first got FDA approval. And Dr. Edelman is stating CMGs is now standard of care.

I should just say here that there was a gap after FDA approval before insurers would cover CGMs. The first CGMs as we would recognize them were approved around 2005 (the Guardian RT CGM, and the Dexcom STS CGM System). It took another 4 years before an insurer would cover them, and took a major JDRF trial to force that. A CGM now gives around a 25% improvement.

Guess mnkd is right on schedule...

[agedhippie]

Jun 28, 2018 20:06:42 GMT -5 mannmade said:

Jun 28, 2018 19:37:46 GMT -5 agedhippie said:

I should just say here that there was a gap after FDA approval before insurers would cover CGMs. The first CGMs as we would recognize them were approved around 2005 (the Guardian RT CGM, and the Dexcom STS CGM System). It took another 4 years before an insurer would cover them, and took a major JDRF trial to force that. A CGM now gives around a 25% improvement.

Guess mnkd is right on schedule...

All we need it the major JDRF trial...

More seriously that trial was key and without it I doubt they would be covering CGMs yet. The insurers really did not want to cover CGMs because they are expensive so they argued for them as adjunct therapy (the argument Medicare finally gave up last year after 11 years) and unproven since there had been no big trial. Even then they managed to get kids largely excluded.

[babaoriley]

Jun 28, 2018 11:29:50 GMT -5 sportsrancho said:

If you own stock listen to the webcast. You will then be assured where this is going!
16 people called me yesterday and asked me what I thought of the call because they didn’t listen to it. Do your own gosh darn homework! Don’t ask somebody else to. You have to hear it or see it with your own ears:-) They got this!

I assume none of those who called you noticed how bullish you've been over the years?     Sports, it's obvious they were calling just to talk to you.  I can't say I blame them...

[sayhey24]

Jun 29, 2018 8:10:04 GMT -5 agedhippie said:

Jun 28, 2018 20:06:42 GMT -5 mannmade said:

Guess mnkd is right on schedule...

All we need it the major JDRF trial...

More seriously that trial was key and without it I doubt they would be covering CGMs yet. The insurers really did not want to cover CGMs because they are expensive so they argued for them as adjunct therapy (the argument Medicare finally gave up last year after 11 years) and unproven since there had been no big trial. Even then they managed to get kids largely excluded.

Aged - any idea of the relationship/timeframe between CGM approval, when they got into the standard of care and insurance?