Afrezza vs lispro

[Deleted]

matt "Similarly, with respect to describing Afrezza as "ultra rapid" I don't know that anybody has shown that the rate of absorption is clinically relevant because the onset of activity is the same as lispro."

Read more: mnkd.proboards.com/user/2019/recent#ixzz4qxc0MiY1

matt do you believe your statement is correct?

[Deleted]

For an explanation of the difference between pharmacokinetics and pharmacodynamics please refer to the thread

mnkd.proboards.com/thread/6969/pharmacodynamics

[peppy]

Cmax and AUC were dose proportional for TI but slightly sublinear for
Lispro; saturable GIRmax was obtained over the dose range for both
insulins. Onset of activity for TI occurred ca. 25-35 minutes earlier than for
Lispro. TI duration of action is about 2 hours shorter than an equivalent
dose of Lispro. Dose-response was almost linear up to 48U TI and 30 U Lispro.

www.mannkindcorp.com/Collateral/Documents/English-US/Baughman%20poster%20100-LB%20FINAL%20X2.pdf

Cmax and AUC for Afrezza and Lispro were approximately doseproportional
over the dose range studied
• Each 4 unit Afrezza cartridge provides approximately the same
insulin exposure as 3.1 U Lispro

Doctor: Why do you want afrezza?

Patient: I don't want to die.

"Afrezza, Demand Life."

[Deleted]

Initial onset between Afrezza and lispro is about the same, but to say there is no difference is false. The area under the curves in the pharmacodynamics graphs are vastly different. Afrezza's area is much less than lispro's, hence the reason for the smaller likelihood of hypoglycemia with Afrezza.

[matt]

Aug 27, 2017 13:03:20 GMT -5 @kastanes said:

Initial onset between Afrezza and lispro is about the same, but to say there is no difference is false. The area under the curves in the pharmacodynamics graphs are vastly different. Afrezza's area is much less than lispro's, hence the reason for the smaller likelihood of hypoglycemia with Afrezza.

You will have to convince FDA that the difference in clinically relevant.  The current label reads as follows:

                    Absorption: The pharmacokinetic profiles for orally inhaled AFREZZA 8 units relative to

                    subcutaneously administered insulin lispro 8 units from a study in 12 patients with type 1

                    diabetes are shown in Figure 3(B). The maximum serum insulin concentration was reached

                    by 12-15 minutes after inhalation of AFREZZA 8 units and serum insulin concentrations

                    declined to baseline by approximately 180 minutes. However, the faster absorption of

                    insulin from Afrezza [see Figure 3(B)] did not result in a faster onset of activity compared to

                    insulin lispro [see Figure 3(A)].

The reason you take a drug is to experience a beneficial pharmacologic effect, and the onset of that activity is not faster compared with lispro.  I never said that Cmax did not peak earlier, it clearly does, but that does not make it a rapid acting insulin.  It makes Afrezza a rapidly absorbed insulin.  The company is trying to get the label changed to make the claim of ultra-fast acting, and that is not same thing as ultra-fast absorption. 

That is the hurdle they will have to jump over to get the FDA to change the label, and that takes data.  However, I believe the other hurdle that will come along for any drug company asking for a label that says ultra-fast acting rather than rapid acting is to show that the difference is meaningful, which the FDA looks at as being clinically relevant.  Making the case of exactly how many minutes before onset of activity is needed for a rapid label versus ultra fast label is new territory for FDA, which is why it will be difficult to get that on the label. 

[mnholdem]

Certainly that is what the current label says about onset of action. So what? The newest study data submitted with the sNDA presents new conclusions:

• Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro.
  
• TI duration of action is about 2 hours shorter than an equivalent dose of Lispro.
  
• Dose-response was almost linear up to 48U TI and 30 U Lispro.
  
  

Based on what the new data reveals, the FDA would be justified in creating the new class of insulin. Novo Nordisk is also pushing for the new "ultra rapid-acting" class for its RAA Fiasp, whose onset of activity is only 12-15 minutes faster than its other RAA - much slower than Afrezza. Also, it's likely that recent medical publications touting the significance of triggering the first phase insulin response (i.e. signaling the liver to shut off production of glycogen) that a healthy pancreas releases is not a coincidence, IMO.

The science will prevail. 

[golfeveryday]

Aug 27, 2017 17:32:45 GMT -5 mnholdem said:

Certainly that is what the current label says about onset of action. So what? The newest study data submitted with the sNDA presents new conclusions:

• Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro.
  
• TI duration of action is about 2 hours shorter than an equivalent dose of Lispro.
  
• Dose-response was almost linear up to 48U TI and 30 U Lispro.
  
  

Based on what the new data reveals, the FDA would be justified in creating the new class of insulin. Novo Nordisk is also pushing for the new "ultra rapid-acting" class for its RAA Fiasp, whose onset of activity is only 12-15 minutes faster than its other RAA - much slower than Afrezza. Also, it's likely that recent medical publications touting the significance of triggering the first phase insulin response (i.e. signaling the liver to shut off production of glycogen) that a healthy pancreas releases is not a coincidence, IMO.

The science will prevail. 

In my opinion the FDA almost has to create a new class for Afrezza and I suppose Fiasp. Not doing that is borderline dangerous in my opinion from a patient perspective. Putting Novolog in the same class as something that is SO much faster suggests to patients, and docs, that it is the same. It's clearly not.

[mnholdem]

Perhaps. But on the other hand, MannKind would benefit by whatever studies are conducted by Novo which validate the benefits of a faster onset. Novo may not see MannKind as a major threat compare to Eli-Lilly and Sanofi, but MannKind's marketing department would benefit by hitch-hiking the data Novo provides to show why faster insulin is better for patients AND the can lay hold to the claim that Afrezza is faster than Fiasp. The FDA granting an "ultra" class to both Afrezza and Fiasp could very well be a Win-Win for cash-strapped MannKind.

[compound26]

Aug 27, 2017 18:01:47 GMT -5 golfeveryday said:

Aug 27, 2017 17:32:45 GMT -5 mnholdem said:

Certainly that is what the current label says about onset of action. So what? The newest study data submitted with the sNDA presents new conclusions:

• Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro.
  
• TI duration of action is about 2 hours shorter than an equivalent dose of Lispro.
  
• Dose-response was almost linear up to 48U TI and 30 U Lispro.
  
  

Based on what the new data reveals, the FDA would be justified in creating the new class of insulin. Novo Nordisk is also pushing for the new "ultra rapid-acting" class for its RAA Fiasp, whose onset of activity is only 12-15 minutes faster than its other RAA - much slower than Afrezza. Also, it's likely that recent medical publications touting the significance of triggering the first phase insulin response (i.e. signaling the liver to shut off production of glycogen) that a healthy pancreas releases is not a coincidence, IMO.

The science will prevail. 

In my opinion the FDA almost has to create a new class for Afrezza and I suppose Fiasp. Not doing that is borderline dangerous in my opinion from a patient perspective. Putting Novolog in the same class as something that is SO much faster suggests to patients, and docs, that it is the same. It's clearly not.

Totally agree.   If FDA declines to give Afrezza a separate category, then FDA will be slapping its own face if it turns around gives Fiasp a separate category.  And we can assume that Novo Nordisk will try its best to convince FDA that Fiasp warrants a separate category.

[thall]

Aug 27, 2017 17:32:45 GMT -5 mnholdem said:

Certainly that is what the current label says about onset of action. So what? The newest study data submitted with the sNDA presents new conclusions:

• Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro.
  
• TI duration of action is about 2 hours shorter than an equivalent dose of Lispro.
  
• Dose-response was almost linear up to 48U TI and 30 U Lispro.
  
  

Based on what the new data reveals, the FDA would be justified in creating the new class of insulin. Novo Nordisk is also pushing for the new "ultra rapid-acting" class for its RAA Fiasp, whose onset of activity is only 12-15 minutes faster than its other RAA - much slower than Afrezza. Also, it's likely that recent medical publications touting the significance of triggering the first phase insulin response (i.e. signaling the liver to shut off production of glycogen) that a healthy pancreas releases is not a coincidence, IMO.

The science will prevail. 

Some questions.  First, the graphs in the insert came from the data collected in MKC-TI-177: clinicaltrials.gov/ct2/show/NCT01544881. Why is the new data be different from the old and what argument will MNKD offer to use the new data to supplant the old?

[mnholdem]

Simply read the first three publications on the corporate website and you'll have your answer.

www.mannkindcorp.com/research-development/publications/

Although it doesn't get mentioned often, there is also a publication where a meta-analysis was conducted which indicates that conclusions of three studies by the FDA - upon which the FDA based the current label - were incorrect in the conclusion that Afrezza's onset of action was similar to insulin lispro. A correct analysis would have revealed that Afrezza is much faster. This is an excerpt of that study, which was presented as a poster at the 2016 ADA:

Inhaled Technosphere ® Insulin (TI) Afrezza® is characterized by fast absorption and short half-life. It was previously reported that TI insulin has similar onset of action as subcutaneous (SC) Insulin Lispro despite its faster absorption, based on 12 patients from study MKC-TI-177. We aim to verify whether pharmacokinetic (PK) properties of TI translate into a faster onset of action compared to SC regimens. Data from 3 euglycemic clamp studies were analyzed using WinNonlin Phoenix® software. 1) MKC-TI-176 in 32 healthy volunteers at TI doses of 10, 30, 60, and 80 U versus SC RHI at 15 U; 2) MKC- TI-177 in 12 type1 diabetics at TI 20 U versus SC insulin Lispro at 8 U; 3) MKC-TI-116 in 25 type1 diabetics at TI 30 U versus SC insulin Lispro at 10 U. Area under glucose infusion rate (GIR) from time 0 till 240 min (GIRAUC0-240) and time (T) to reach partial areas (10 and 50% GIRAUC0-240) were estimated using the linear trapezoidal rule. GIR profiles were fitted to first order input and first order output mathematical models to estimate time to maximum GIR (T-GIRmax) and time to 20 and 50% GIRmax. PK parameters of insulin were determined using non-compartmental methods. The conclusion on onset of action of TI insulin from data of MKC-TI-177 study seems to be inconsistent with results of the pooled analysis using larger sample sizes. This pooled analysis demonstrated faster onset of action for TI than SC insulins based on all GIRmax and GIRAUC0-240 parameters. Time to 20% GIRmax ranged from 2.5 to 18 min for TI and from 13 to 34 min for SC insulin. Time to 10% GIRAUC0-240 ranged from 25 to 34 min for TI and from 53 to 60 min for SC insulin. The faster onset of action of TI compared to SC insulin can be relevant for optimal dosing of TI with respect to meals.

Source: www.mannkindcorp.com/assets/Hijazi-2016-TI-has-a-more-rapid-onset-of-action-than-sc-insulins-ADA-931-P.pdf

[thall]

Aug 27, 2017 20:09:00 GMT -5 mnholdem said:

Simply read the first three publications on the corporate website and you'll have your answer.

www.mannkindcorp.com/research-development/publications/

Although it doesn't get mentioned often, there is also a publication where a meta-analysis was conducted which indicates that conclusions of three studies by the FDA - upon which the FDA based the current label - were incorrect in the conclusion that Afrezza's onset of action was similar to insulin lispro. A correct analysis would have revealed that Afrezza is much faster. This is an excerpt of that study, which was presented as a poster at the 2016 ADA:

Inhaled Technosphere ® Insulin (TI) Afrezza® is characterized by fast absorption and short half-life. It was previously reported that TI insulin has similar onset of action as subcutaneous (SC) Insulin Lispro despite its faster absorption, based on 12 patients from study MKC-TI-177. We aim to verify whether pharmacokinetic (PK) properties of TI translate into a faster onset of action compared to SC regimens. Data from 3 euglycemic clamp studies were analyzed using WinNonlin Phoenix® software. 1) MKC-TI-176 in 32 healthy volunteers at TI doses of 10, 30, 60, and 80 U versus SC RHI at 15 U; 2) MKC- TI-177 in 12 type1 diabetics at TI 20 U versus SC insulin Lispro at 8 U; 3) MKC-TI-116 in 25 type1 diabetics at TI 30 U versus SC insulin Lispro at 10 U. Area under glucose infusion rate (GIR) from time 0 till 240 min (GIRAUC0-240) and time (T) to reach partial areas (10 and 50% GIRAUC0-240) were estimated using the linear trapezoidal rule. GIR profiles were fitted to first order input and first order output mathematical models to estimate time to maximum GIR (T-GIRmax) and time to 20 and 50% GIRmax. PK parameters of insulin were determined using non-compartmental methods. The conclusion on onset of action of TI insulin from data of MKC-TI-177 study seems to be inconsistent with results of the pooled analysis using larger sample sizes. This pooled analysis demonstrated faster onset of action for TI than SC insulins based on all GIRmax and GIRAUC0-240 parameters. Time to 20% GIRmax ranged from 2.5 to 18 min for TI and from 13 to 34 min for SC insulin. Time to 10% GIRAUC0-240 ranged from 25 to 34 min for TI and from 53 to 60 min for SC insulin. The faster onset of action of TI compared to SC insulin can be relevant for optimal dosing of TI with respect to meals.

Source: www.mannkindcorp.com/assets/Hijazi-2016-TI-has-a-more-rapid-onset-of-action-than-sc-insulins-ADA-931-P.pdf

That actually caused more questions. The first paper on that page references "Pharmacodynamics of TI: mean baseline-corrected glucose infusion rate of TI versus RAA in type 1 diabetes (Study 116)." Best I can tell that study was done 7-8 years ago. Trial 177 was done only 3-4 years ago. Then again the data from the more recent poster seems to duplicate the older study. How do they explain the differences? I would think that a glucose clamp should be pretty easy to replicate. So what argument will be presented to convince the FDA that the 177 glucose clamp data is less accurate than the more recent?

Unfortunately, that paper refers to the 177 study but doesn't mention the PD data, doesn't show the graph of that data and doesn't offer any explanation as to why the results differed from 116.

[mnholdem]

It sounds like you haven't fully read the publication which chronologically presents the various trials with both Medtone and Gen2 inhalers, which concludes with:

Discussion

TI has a more rapid absorption and clearance profile compared with subcutaneously injected RAAs. As a consequence of this, TI has a faster onset of action and a shorter duration of action, partly due to a more rapid effect on the liver, resulting in a more rapid EGP suppression and coverage of prandial insulin needs (Table 1).24,27-29,37,38 These effects are independent of inhaler used for delivery or subject population. Though TI is labeled as rapid-acting insulin, its unique PK/PD profile supports previous characterization as an URAI [Ultra Rapid Acting Insulin].

Source: www.ncbi.nlm.nih.gov/pmc/articles/PMC5375067/

[thall]

Aug 27, 2017 21:10:12 GMT -5 mnholdem said:

It sounds like you haven't fully read the publication which chronologically presents the various trials with both Medtone and Gen2 inhalers, which concludes with:

Discussion

TI has a more rapid absorption and clearance profile compared with subcutaneously injected RAAs. As a consequence of this, TI has a faster onset of action and a shorter duration of action, partly due to a more rapid effect on the liver, resulting in a more rapid EGP suppression and coverage of prandial insulin needs (Table 1).24,27-29,37,38 These effects are independent of inhaler used for delivery or subject population. Though TI is labeled as rapid-acting insulin, its unique PK/PD profile supports previous characterization as an URAI [Ultra Rapid Acting Insulin].

Source: www.ncbi.nlm.nih.gov/pmc/articles/PMC5375067/

What I'm trying to figure out is why did trial 177 with the gen2 inhaler produce the graph shown on the insert which is quite a bit different than the 116 trial graph, while the latest abstract replicated the data from the 116 trial which used the medtone. How will MNKD explain the difference between what trial 177 produced and what the latest abstract produced?

Also, I was a little disappointed when I read that latest abstract again. It says they used 29 males and 1 female; 29 were white and 1 was black. That's not a very representative population sample.

[mnholdem]

Are you serious? Do you really think that gender and/or race affects how the pancreas functions or how the body responds to TI?