Possible Ways to Improve Postprandial Glucose Control in T1D

[mango]

This paper briefly mentions the STAT study (published online June 1) and Satish K. Garg, MD is also an author. He was the investigator that initiated and led the STAT study and is on the MannKind Scientific Advisory Board. This paper also confirms the STAT study was a multicenter trial, and not single-site, as some on here have claimed.


Possible Ways to Improve Postprandial Glucose Control in Type 1 Diabetes


Inhaled insulin has been studied in several forms in an effort to utilize an alternate delivery method (pulmonary absorption) to alter PK/PD of mealtime insulin, while the earlier attempts at pulmonary insulin were generally unsuccessful due to low bioavailability (Exubera®) and limited improvement in time action profile, technology using fumaryl diketopiperazine (the excipient representing an essential part of Technosphere insulin [TI]) for pulmonary delivery of insulin (TI, Afrezza®; Mannkind, Westlake Village, CA). TI had demonstrated even more rapid onset of action compared to the RAIA insulin lispro.79 TI appears in the blood in <1 min, thought to be due, in great part, to the extent of pulmonary alveolar space available for insulin absorption and due to the rapid dissolution of the insulin delivery particles.80 TI also results in more rapid and higher peak action.81 In addition, a study of subjects with T2D has shown more rapid suppression of endogenous glucose production with TI at doses of 24 and 16 U compared to lispro 10 U.82

Recently, data were provided to the U.S. FDA that resulted in changes in labeling language for TI that support the observation of the first measurable insulin effect that occurs in ∼12 min, and peak effect is noted ∼35–45 min after dosing with a return to baseline insulin effect levels after ∼1.5–3 h.83 Based on the PD, in these studies, the dose of TI required to achieve a similar glucose effect based on glucose infusion rate has been modified to at least 1.5 times the usual dose of subcutaneously injected RAIA. Whether this is the result of formulation properties, pulmonary delivery, or other changes in insulin action or clearance is not known. However, dosing (as an example) for a patient currently utilizing 8 U of RAIA may require 12 U of TI as an initial dose to achieve the similar glucose-lowering effect.84 This dosing recommendation is further supported by analysis of the doses of TI ultimately utilized to achieve similar glucose control in the randomized clinical trials comparing TI to RAIAs where equivalent dose ratios approximating 1.5–2 times dose of TI to RAIA were reported after 12 or more weeks of titration.85–87

TI was shown (by design) to achieve a noninferior reduction in HbA1c when compared to RAIA in registration trials in those with T1D. This noninferiority was achieved with significantly less reported hypoglycemia and lesser weight gain compared to the use of RAIA.85 Additional studies confirmed reduced hypoglycemia—an outcome that is, in part, attributed to its rapid “on and off” insulin action with TI.85,88–90 The PD profile reported confers a faster onset and shorter duration of action that may permit more rapid postprandial insulin action that coincides with the rates of glucose absorption after meals.80 A simulation study using modeled data from TI clinical trials suggested that higher doses of TI premeal or split dosing premeal and postmeal of TI may provide improved PPG profile with lesser fluctuations in postmeal glucose than conventional treatment with subcutaneously administered rapid-acting insulin products, and would be likely to do so without increasing the risk of hypoglycemia.91

In current clinical use, there are higher rates of reported “underdosing” of TI as documented by lesser clinical effect when 1:1 mealtime insulin dose conversion is used. However, with additional clinical experience, patients and healthcare providers have been advised to consider the higher dose conversion when switching between RAIA and TI, and appropriate titration may allow for more aggressive and higher dosing of TI when clinically indicated.84 TI has a significantly shorter duration of action and different time action profile compared to RAIAs, and for many individuals may require a modified approach to both initiation and titration as well as supplemental dosing 1–3 h postmeal (by inhalation) to achieve the optimal clinical effect. Similarly, with shorter mealtime insulin action following TI inhalation, individual patients may also need to alter (generally increase) their basal insulin dose.

A small number of individual reports have identified those who have used TI for PPG control with the hybrid closed-loop (HCL) pump therapy. Given the short duration of action of inhaled TI with meals, and the flexibility of basal adjustments with HCL, some individuals report clinical improvement, although this is not currently an indicated use of TI. However, using TI with HCL system will not account for the total daily insulin dose and thus many patients may experience higher fasting glucose values, and usually not recommended.

A small (n = 15) pilot feasibility single-arm study using TI showed a decrease in HbA1c in 6 weeks.92 An investigator-led collaborative open-label, multicenter randomized pilot study (Study Comparing Prandial Insulin Aspart vs. Technosphere Insulin in Patients with Type 1 Diabetes on MDI- or STAT Study) compared TI with insulin aspart effects on PPG control and postprandial time in range (TIR) for 0–4 h postmeal using CGM data. The STAT study showed that PPG was significantly lower at 1 and 2 h postprandial with TI compared to insulin aspart.89,90 In the per-protocol analysis (with additional postprandial TI dose), mean glucose values and postprandial TIR significantly improved compared to insulin aspart.89,90 Details of the STAT study results will be presented at the 2018 ADA and EASD annual meetings in Orlando, FL, and Berlin, Germany, respectively89,90 (data on file with BDC).

Effective PPG control still requires multiple daily efforts that include, but are not limited to the following: proper and accurate assessment of carbohydrate intake (DAFNE trial), food composition, insulin dose adjustments based on physical activity, current glucose level (as measured by SMBG), or real-time CGM.30 CGM data allow patients and healthcare providers real-time feedback to control PPG more effectively.117–119 Patients using insulin pumps may bolus with different options (standard, square wave, modified combination, and dual wave) to improve PPG control, especially in patients with gastroparesis.120–122 Development of ultra-RAIA and proper use of very rapid-acting pulmonary insulin such as TI can assist a number of patients in their effort to improve PPG. Until another very rapid-acting prandial insulin is available, appropriate use of currently available insulins (aspart, lispro, glulisine, FIasp, and Technosphere Insulin) along with glucose monitoring (SMBG/CGM) should be considered the standard of care to mitigate/reduce PPG elevations and excursions.


www.liebertpub.com/doi/abs/10.1089/dia.2018.0114?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

[mannmade]

I have a very good friend who is a leading diabetes doc in his area and he says Satish is a global Rock Star in diabetes and was a big coup for the SAB.

[mnholdem]

More publications are coming, IMO. Awareness will grow among endocrinologists, primary care physicians and other diabetes healthcare professionals.

[compound26]

Jul 25, 2018 10:11:03 GMT -5 mannmade said:

I have a very good friend who is a leading diabetes doc in his area and he says Satish is a global Rock Star in diabetes and was a big coup for the SAB.

What is SAB?

[mannmade]

Strategic Advisory Board that Dr. K announced he assembled from leading KOL’s in diabetes

[harryx1]

www.mannkindcorp.com/about-us/scientific-advisory-board/

[agedhippie]

Jul 25, 2018 9:23:03 GMT -5 mango said:

...
Effective PPG control still requires multiple daily efforts that include, but are not limited to the following: proper and accurate assessment of carbohydrate intake (DAFNE trial), food composition, insulin dose adjustments based on physical activity, current glucose level (as measured by SMBG), or real-time CGM.30 CGM data allow patients and healthcare providers real-time feedback to control PPG more effectively.117–119 Patients using insulin pumps may bolus with different options (standard, square wave, modified combination, and dual wave) to improve PPG control, especially in patients with gastroparesis.120–122 Development of ultra-RAIA and proper use of very rapid-acting pulmonary insulin such as TI can assist a number of patients in their effort to improve PPG. Until another very rapid-acting prandial insulin is available, appropriate use of currently available insulins (aspart, lispro, glulisine, FIasp, and Technosphere Insulin) along with glucose monitoring (SMBG/CGM) should be considered the standard of care to mitigate/reduce PPG elevations and excursions.

The section in bold is also the final sentence of the paper's conclusion. It is what I have been saying - Afrezza will be added to the RAA insulins for prandial insulin in the standard of care rather than replacing them.

[peppy]

Jul 25, 2018 17:58:11 GMT -5 agedhippie said:

Jul 25, 2018 9:23:03 GMT -5 mango said:

...
Effective PPG control still requires multiple daily efforts that include, but are not limited to the following: proper and accurate assessment of carbohydrate intake (DAFNE trial), food composition, insulin dose adjustments based on physical activity, current glucose level (as measured by SMBG), or real-time CGM.30 CGM data allow patients and healthcare providers real-time feedback to control PPG more effectively.117–119 Patients using insulin pumps may bolus with different options (standard, square wave, modified combination, and dual wave) to improve PPG control, especially in patients with gastroparesis.120–122 Development of ultra-RAIA and proper use of very rapid-acting pulmonary insulin such as TI can assist a number of patients in their effort to improve PPG. Until another very rapid-acting prandial insulin is available, appropriate use of currently available insulins (aspart, lispro, glulisine, FIasp, and Technosphere Insulin) along with glucose monitoring (SMBG/CGM) should be considered the standard of care to mitigate/reduce PPG elevations and excursions.

The section in bold is also the final sentence of the paper's conclusion. It is what I have been saying - Afrezza will be added to the RAA insulins for prandial insulin in the standard of care rather than replacing them.

that should have been done already.

[sayhey24]

It seems Dr. Kendall is starting to gain some traction in his efforts of getting afrezza properly recognized in the T1 standard of care. This is the first publication I can remember seeing afrezza recommended as part of the standard. While not yet recommended to be used as step 1 in prandial care prior to RAA use IMO, as Joe Biden would say, this is a Big F'ing deal.

"Until another very rapid-acting prandial insulin is available,appropriate use of currently available insulins (aspart, lispro,glulisine, FIasp, and Technosphere Insulin) along with glucose monitoring (SMBG/CGM) should be considered the standard of care to mitigate/reduce PPG elevations and excursions."

[agedhippie]

Jul 25, 2018 18:20:36 GMT -5 sayhey24 said:

It seems Dr. Kendall is starting to gain some traction in his efforts of getting afrezza properly recognized in the T1 standard of care. This is the first publication I can remember seeing afrezza recommended as part of the standard. While not yet recommended to be used as step 1 in prandial care prior to RAA use IMO, as Joe Biden would say, this is a Big F'ing deal.

"Until another very rapid-acting prandial insulin is available,appropriate use of currently available insulins (aspart, lispro,glulisine, FIasp, and Technosphere Insulin) along with glucose monitoring (SMBG/CGM) should be considered the standard of care to mitigate/reduce PPG elevations and excursions."

I really don't know why it wasn't done immediately after the approval of Afrezza on the basis of the 171 non-inferiority finding. That finding made Afrezza equivalent to RAA and hard to argue that it should not be added on those grounds. I am curious as to what (if anything) was previously done to achieve that.

[sayhey24]

Aged - you ask a great question. Add in the reduced hypo's and Dr. Kendall was calling it a superior insulin a few weeks ago at the Investor presentation.

I think the short answer is Al had never developed or sold a pharmaceutical before and he did not have the experience and he did not have a CMO with the experience of Dr. Kendall. He also never anticipated selling it on his own. His model was always to sign a sales and marketing partner and they would bring the expertise MNKD lacked.

That raises the question why was that not the first thing on SNY's agenda? How did they ever expect to sell an inhaled insulin which was in the shadows of Exubera and not in the standard? You would think SNY should have known step 1 was getting it in the standard and until it was, it was not getting prescribed on a large scale. Did SNY ever want to sell afrezza? It doesn't look that way.

Then again what was Pfizer doing? They pulled Exubera due to poor sales but they were not in the standard either. I have been told when they saw afrezza approval on their heels they did everything they could to poison the well.

I have been asking for years the question you raised. At the 2015 shareholders meeting the entire SNY show was FEV1 was the huge sales issue and that was the problem. They had Al so convinced he was carrying around a an FEV1 tester. I had a long discussion with him that I did not believe the FEV1 was really the issue. Metformin's success is solely driven by it being Step 1 in the standard even when Ralph DeFronzo now calls it the biggest waste in T2 treatment. Clearly metformin sales are not being generated by all the Metformin TV commercials.

The good news is Dr. Kendall at the Investor presentation in not so many words raised the same issue. He noted how few papers have been presented and how few presentations have been given over the years. He turned to Steve Edelman and asked how could this be.

The answer is pretty simple - MNKD management lacked the experience and never had a CMO who knew what needed to be done. Now they do. Usually, the complex is simple when you have someone who knows what they are doing.

[morgieporgie]

Jul 26, 2018 19:23:20 GMT -5 sayhey24 said:

Aged - you ask a great question. Add in the reduced hypo's and Dr. Kendall was calling it a superior insulin a few weeks ago at the Investor presentation.

I think the short answer is Al had never developed or sold a pharmaceutical before and he did not have the experience and he did not have a CMO with the experience of Dr. Kendall. He also never anticipated selling it on his own. His model was always to sign a sales and marketing partner and they would bring the expertise MNKD lacked.

That raises the question why was that not the first thing on SNY's agenda? How did they ever expect to sell an inhaled insulin which was in the shadows of Exubera and not in the standard? You would think SNY should have known step 1 was getting it in the standard and until it was, it was not getting prescribed on a large scale. Did SNY ever want to sell afrezza? It doesn't look that way.

Then again what was Pfizer doing? They pulled Exubera due to poor sales but they were not in the standard either. I have been told when they saw afrezza approval on their heels they did everything they could to poison the well.

I have been asking for years the question you raised. At the 2015 shareholders meeting the entire SNY show was FEV1 was the huge sales issue and that was the problem. They had Al so convinced he was carrying around a an FEV1 tester. I had a long discussion with him that I did not believe the FEV1 was really the issue. Metformin's success is solely driven by it being Step 1 in the standard even when Ralph DeFronzo now calls it the biggest waste in T2 treatment. Clearly metformin sales are not being generated by all the Metformin TV commercials.

The good news is Dr. Kendall at the Investor presentation in not so many words raised the same issue. He noted how few papers have been presented and how few presentations have been given over the years. He turned to Steve Edelman and asked how could this be.

The answer is pretty simple - MNKD management lacked the experience and never had a CMO who knew what needed to be done. Now they do. Usually, the complex is simple when you have someone who knows what they are doing.

They pulled Exubera even though they had about 19,000 people who loved it. I believe Mike C said they had that many in an interview I saw once. You would think these people would love Afrezza, if they could just find out about it!

[agedhippie]

Jul 26, 2018 19:23:20 GMT -5 sayhey24 said:

That raises the question why was that not the first thing on SNY's agenda? How did they ever expect to sell an inhaled insulin which was in the shadows of Exubera and not in the standard? You would think SNY should have known step 1 was getting it in the standard and until it was, it was not getting prescribed on a large scale. Did SNY ever want to sell afrezza? It doesn't look that way.

....

The good news is Dr. Kendall at the Investor presentation in not so many words raised the same issue. He noted how few papers have been presented and how few presentations have been given over the years. He turned to Steve Edelman and asked how could this be.

The answer is pretty simple - MNKD management lacked the experience and never had a CMO who knew what needed to be done. Now they do. Usually, the complex is simple when you have someone who knows what they are doing.

That raises three questions.

Why did SNY not get Afrezza into the standard of care? I suspect the answer is more complex in that case. There was the idea needles where a huge issue for diabetics, and while once that may have been the case by the time of Exubera, never mind Afrezza, that issue was stone dead (this seems to be something non-insulin users have immense difficulty with). That left Exubera with the problem of the bong and Dreamboat eliminated that obstacle. By the time it became clear that diabetics didn't see the lack of needles as a reason to change SNY were already looking to offload it so why waste political capital with the ADA on a drug you were about to dump.

Dr Kendall is no genius, he has just had the benefit of those years at Lilly seeing how a real pharma gets it's drugs to market at a strategic level. All he is doing now is what should have been done years ago - create an environment where every time you hear Afrezza it isn't joined at the hip to the word crisis. He is simply putting in place the world that doctors expect to see.

I think the problem was that the Mannkind management are inexperienced in their roles (these were not the roles they were hired for) that they did not realize there was a gap. If you see a gap that big you fill it either with a hire, or with a consultant. Instead you got a string of tactical moves like Reversed, Dame Dash (I have no idea why anyone thought either of those was a good idea), and the ever changing sales force.