ADA Scientific Session - Safety of Afrezza in Pediatric Patients

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The ADA is currently holding their annual scientific sessions. I came across some sessions on Afrezza that I thought were interesting.

I think that if Mannkind can show that Afrezza is safe for children, many more people would be willing to use it. So I’m particularly interested in the final results of that study. They presented some results at the scientific sessions. I’m pasting the full abstracts of the 3 presentations related to Afrezza below. The A1c improvement for Type 2 patients is pretty incredible.

Safety and Pharmacokinetics of Technosphere Insulin in Pediatric Patients

Author Block: MARSHALL L. GRANT, JOHN A. KRUEGER, MARK FINEMAN, GAURAV SHARMA, FRANK POMPILIO, DAVID M . KENDALL , Westlake Village , CA , San Diego , CA
Technosphere Insulin (TI) is an ultra-rapid, short-acting inhaled insulin that provides glycemic control in patients with diabetes. This ongoing, 2-part, open-label, interventional study aims to assess the efficacy and safety of TI in children aged 4 to 17 years with type 1 diabetes mellitus (T1DM) who are on a stable regimen of basal-bolus insulin therapy. Part 1 is a single-arm study that includes evaluation of insulin pharmacokinetics (PK) after a single prandial dose of TI (4, 8, or 12 units), followed by a 4-week titration period. Approximately 46 patients will be enrolled across 3 age cohorts: cohort 1 (13-17 years), cohort 2 (8-12 years), and cohort 3 (4-7 years). As of August 16, 2018, 15 patients had enrolled in cohort 1, 14 had received at least 1 dose, and 8 completed the titration period. Overall, 50% of the safety population (n=14) was female, mean duration of T1DM was 6.2 years, mean age was 15 years, and mean body mass index was 22.4 kg/m2. Initial PK results from cohort 1 demonstrated insulin metabolism similar to that in adult patients receiving TI. Insulin concentrations rapidly increased in the first 30 minutes after TI treatment and returned to baseline by 120 minutes for the 4-, 8-, and 12-unit doses. Mean postprandial glucose levels decreased within 1-hour postdose for the 8- and 12-unit dose groups. Seven patients developed treatment-related cough of mild (6 events) or moderate (1 event) severity. Seven patients experienced a total of 41 hypoglycemic events, but no patient required the assistance of another person to administer corrective carbohydrates. No clinically relevant declines in pulmonary function were reported. Two patients discontinued the study due to adverse events (cough, diabetic ketoacidosis). These data will help determine the appropriate age range for inclusion and recommended dosing for part 2, which will be a 1-year efficacy and safety study.

Technosphere Insulin Provides Better Early Postprandial Glucose Control than Subcutaneous Rapid-Acting Analog

Author Block: MARSHALL L. GRANT, FRANK POMPILIO, GAURAV SHARMA, JOHN A. KRUEGER, DAVID M . KENDALL , NADIA ZAVERI, Westlake Village , CA
In a recent study (STAT, NCT03143816), patients with type 1 diabetes mellitus (T1DM) treated with Technosphere Insulin (TI) demonstrated better early postprandial glucose (PPG) control than those on subcutaneous (SC) insulin aspart. The average daily dose of TI in patients who took TI as directed in the protocol was twice that of aspart (40.5 vs. 20.6 units). Despite the higher dose, the TI group experienced less time in hypoglycemia than the aspart group. These results prompted a retrospective analysis of mixed-meal tolerance tests (MMTTs) conducted in T1DM to further evaluate the 2:1 dosing ratio.
In study MKC-TI-009 (NCT00308308), patients with T1DM underwent 1 to 3 MMTTs. A total of 1326 PPG profiles were evaluable: 674 MMTTs from 261 patients on SC aspart and 652 MMTTs from 264 patients on TI. On average, the area under the PPG excursion curve (PPGE AUC) decreased with increasing dose, and the mean (SE) ratio of the aspart slope to the TI slope was 2.1 (0.3), consistent with the results of STAT. This was confirmed when doses of TI 8, 16, and 24 units were compared with mean (SE) aspart doses of 4 (1), 8 (1), and 12 (1) units, respectively (Figure).
The PPGE curves confirm the earlier onset and shorter duration of TI, while the tendency to drop below baseline in the late postprandial period reflects the longer duration of action of SC aspart. The timing of hypoglycemia (levels 1 and 2) follows the pattern of PPGEs.

Disclosures: M.L.Grant: Employee; Self; MannKind Corporation, Stock/Shareholder; Self; MannKind Corporation. F.Pompilio: Employee; Self; MannKind Corporation, Stock/Shareholder; Self; Amgen Inc., MannKind Corporation. G.Sharma: Employee; Self; MannKind Corporation. J.A.Krueger: Employee; Self; Eli Lilly and Company, MannKind Corporation, Stock/Shareholder; Self; Eli Lilly and Company. D.M.Kendall: Employee; Self; MannKind Corporation, Employee; Spouse/Partner; Amgen Inc., Stock/Shareholder; Self; MannKind Corporation. N.Zaveri: Employee; Self; MannKind Corporation, Stock/Shareholder; Self; Becton, Dickinson and Company.

Effective Treatment of T2D Patients Uncontrolled on Multiple Diabetes Medications by Adding Afrezza Mealtime Ultra-Rapid Insulin

Author Block: PHILIP LEVIN , LEE A. BROMBERGER, SIMON R. BRUCE, Baltimore , MD , San Diego , CA
Fourteen T2D subjects in a real-world practice setting, uncontrolled on oral/injectable combo therapy (mean A1C 9%), received inhaled human insulin (INH-Afrezza), added to current therapy and titrated weekly for up to 12 weeks. A1C and 2-week continuous glucose monitoring (CGMS) profiles (Libre Pro) were collected at baseline and after 3 months.
All subjects started INH 4 units (u) prior to each meal and titrated rapidly to 12 u/meal over 9 days. Thereafter, INH was adjusted for each meal once weekly, based on PPG at 2-2.5 hours measured on days 1 and 2 of each week, as follows: Add 4 u if PPG > 160 mg/dl, no change if PPG 90-160 mg/dl and decrease by 4 u if PPG < 90 mg/dl. More than 1/2 of subjects were taking basal insulin.
Addition of the only available inhaled ultra-rapid rapid mealtime insulin (Afrezza) lowered glucose safely in patients with T2D inadequately controlled on oral and/or injectable therapy. Initiation and titration, following a simple algorithm, resulted in significant A1c reduction (-1.6%, p<.0001), a decrease in mean daily glucose (~50 mg/dl), and a 76% increase in time-in-range on CGMS, with no significant increase in hypoglycemia (Time<70 mg/dL). No severe hypoglycemia occurred. Final mealtime Afrezza doses achieved were 18, 16 and 20 u at breakfast, lunch, dinner respectively.

Disclosures: P.Levin: Research Support; Self; MannKind Corporation, Novartis AG, Novo Nordisk Inc., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Sanofi. L.A.Bromberger: None. S.R.Bruce: Consultant; Self; Dance Biopharm Holdings Inc., MannKind Corporation, Oramed Pharmaceuticals.

There were many presentations that looked incredibly interesting. You can look at the full calendar by clicking on the “Online Planner” link on the page below.
https://professional.diabetes.org/scientific-sessions

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This comment is going to get me in trouble with two groups rather than just one, but they also approved the 670G for children… and I personally think… I think you guys know what I personally think.

I don’t know what my point is. Maybe just that, very unfortunately, having something approved for children doesn’t always guarantee its safety?

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Well, sure. Any of the drugs we take every single day have risks.

Is there anything that actually would convince you that Afrezza is safe to take?

If there isn’t, then I guess you don’t really need to think about Afrezza. You can just keep doing what works for you and let others do what works for them.

Taking insulin intravenously at home hasn’t been approved by the FDA at all, but that’s something you’re comfortable with doing. I wouldn’t be comfortable doing that. I suppose we each have our comfort levels.

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An interesting lineup of papers. The first two are a bit suspect in that the authors either work for the company or have significant conflicts. But the 3rd paper is interesting, especially the simplified algorithm for Type 2’s that are unable or unwilling to go all the way to carb counting. We are awaiting the safety study for minors since our physician is unlikely to prescribe Affrezza without that study being completed. Even then , I suspect it will be an uphill battle.

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Maybe I misunderstood the first study. I thought it was the results of the first phase of the safety study. Is it a separate study altogether?

I’ll look up the safety trial when I get home.

The second one isn’t particularly interesting IMO either. Seems like they showed the action profile of Afrezza plenty in prior studies.

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Yes, it was probably done so the authors could go to the conference.

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Sure.

There is, and in that it’s my self-management, I do plan to continue thinking about, and questioning, all forms of insulin available. I’m not sure what in my comment made you think you had the right to take that from me.

I was doing that. The reason I read your thread is because I am very interested in everything that’s available. Being interested doesn’t mean I will ever try it, and questioning it doesn’t mean I won’t. I was in here in this thread doing what I thought we did here at FUD— participating in a discussion.

Agreed.

It is, and, yes, we all have our different comfort levels. I would never encourage you to try it. I would never discourage you from expressing concern over it. You’re right that I am comfortable in how I’m handling my own disease at this time, and I am very careful, as always, in how I communicate that to others. If someone came to my thread voicing concern, I would do my best, speaking from my own experience, to explain how I address such concerns or why I don’t feel I need to. It’s absolutely wonderful that we have a place for this kind of discussion. This kind of discussion surrounding Afrezza was why I asked my doctor for a sample in the first place.

It wasn’t a personal attack, @Katers87.

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You first post may not have been, but there were elements of your most recent post that most certainly were.

There was a serious amount of defensiveness in that post.

What exactly were you intending to communicate to me here?

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It was not my intention to limit you. I’m sorry if that’s how it came across.

Your prior posts on this topic have overall left me with the impression that you found Afrezza to be unsafe. I admit to being frustrated with reading posts of this kind over and over again on different forums. The FDA has approved Afrezza for adults, and certainly, approving Afrezza for children doesn’t mean that it couldn’t have some unknown side effect 20 years from now. But yes, I found it very frustrating that the knee-jerk response to an FDA approval for children was that it would mean essentially nothing to someone (I recognize this as my impression only) who doubts Afrezza’s safety.

I do have an interest in the success of Afrezza because it has benefited me significantly. I hope the company’s position will improve over time so that I can continue to use it.

I don’t care whether you use Afrezza or not. You’re welcome to criticize or applaud it however you wish. I am also entitled to respond to your posts with my viewpoint. I do not think it is out of line to point out the differences in our comfort levels with different treatment methods.

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Yes, it looks like this was the first phase of the clinical trial assessing safety for children. I would have thought that there would need to be a longer time frame in the safety assessment though. 6-8 weeks doesn’t seem like long enough.

https://clinicaltrials.gov/ct2/show/NCT02527265

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My first post absolutely wasn’t, and my second one…

was in response to that.

Exactly what I said. I’m not sure what you think I was intending. I’m saying that I am very careful in how I talk about IV… and really in how I talk about everything I do for my diabetes.

It did come across that way, but I gladly will accept that it was miscommunication.

Not that I have found it to be unsafe. I’ve never used it, researched it, or performed any studies on it. I can’t have found it to be unsafe. As a thinking diabetic though with a good, (knock on wood) healthy set of lungs, I have also questioned long term effects.

As far as knee jerk, you said

And I responded to that thought.

Absolutely.

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I feel like that was just a bunch of my own quotations thrown at me as if that explains your response to any of them.

You don’t need to respond to me or explain anything though. I do not think my post was worthy of a personal attack.

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Sounds good. :+1:

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I have thought about and thought about replying in this post and feel I want to. First off I am nobody, just struggling 20+ year t1d, my memory is going to hell so I don’t always express my intentions as I would like.
So let me say i AM NOT attacking anyone or any thing said. I just want to say IMHO this site is amazing, I love all the info I gain, all the discussions happening and being able to hear all the differing view points. And I feel that’s how it should be.
That being said @Katers87 I enjoyed the articles you posted and went and read more. Very interesting. I could NOT begin to tell you how many studies, papers, company statements I read in a day. To me they are all part of the pitcure, as are dissenting and differing view points.
Alot of us (diabetics in general) have very negative viewpoints on varing products and that also is important, if to me more so because we live it.
I in no way thought @Nickyghaleb’s initial responce was in any way disparaging to you or your post, just a negative responce to product (quite tempered for her I may add) and that also is important.
Your responce, I was sorry to read, it was personal. We can not all agree on any matters (except t1d sucks, mabey others) and all options should be welcomed. I agree we can get frustrated by hearing differing viewpoints, but this should be completely acceptable on this forum.
@Katers87 and @Nickyghaleb I truly enjoy reading both your posts, as with many others your vast knowledge and skills at communicating are impressive to me, love reading them and truly hope they continue.
I don’t think we have to many advocates here either for or against products on this site, many personal options and view points, but would we want it any diffrent? As we know all PWD are diffrent and IMHO this difference keeps us strong and informed.
I really hope I didn’t or don’t rub anyone the wrong way but it gets to me when people’s view point is ummm attacked?

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As I’ve been saying…

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Well, that’s certainly not true. You’ve been a part of this forum for awhile now! I’m glad that you’ve enjoyed reading the posts here as much as I have.

I appreciate your post. I apologized to Nicky for the comment regarding limiting her input to the discussion. In prior posts, I explained my reaction and why I reacted the way I did.

I welcome future discussion on Afrezza that is open-minded and preferably occurs with a little bit of research along with any negative or positive comments.

I’m not really interested in continuing this discussion further. I’m not offended by your comment, but the altercation with Nicky is not something I want to rehash.

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@T1john, I appreciate you reaching out and trying to make this place better by playing peacemaker! @Michel does this often and it is part of what makes this place able to sustain dialogue when so many others break down into attacks. Thanks!

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I mean, the concerns my endo cited (such as long-term lung damage and a risk of future lung cancer) will definitely not be alleviated by a short-term study showing adequate blood glucose control and an acceptable short-term side effect profile. My guess is they’ll want to see data on adults for 10, 15, 20 years out before they can feel comfortable about that…

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The unfortunate part of that, is that by the time that data exists the product likely won’t be on the market anymore. But I have known conservative docs, and nothing short of the study you mentioned with long term safety data would be enough to convince. The good news is that great results can be achieved without it, but it would be really nice for dealing with frequent highs that need to be landed. My excitement for Affrezza was lessened a bit when Basal IQ worked well for us in landing highs without carbs. Without Basal IQ our carb ingestion was getting to be a problem.

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@Chris, I mean I agree, it’s quite a conservative stance and I’m not sure it’s necessarily warranted – I just know the particular concerns they voiced, the timescale at which that increased risk would be detected – it’s loooong.