Afrezza Pulmonary Safety Studies

[harryx1]

Below is a compilation of quotes, studies and articles that go back to 2005 that can help you make your decision on the safety of Afrezza.

Original thread credit: mnkd.proboards.com/thread/327/question-re-lung-toxicity#ixzz3UP9XSzMT

"It seems to me that the concern about lung cancer should have ended by now since there is no factual basis for such concern. Even for Exubera, there was no conclusion as to causality or acceleration and AFRESA is so very, very different. In relation with AFRESA, it is certainly less risky than for some other chronically entailed drugs and even less so than breathing in a large city. An advisory committee has dismissed any risk of lung cancer from AFRESA. While we are seriously concerned about this risk, all of the data gives us confidence that any concern about lung cancer with AFRESA is without foundation and is bogus. Nevertheless, we must address some perceptions that have been created."

-Alfred Mann

--------------------------------------------

MannKind has also undertaken a more comprehensive examination of the toxicology profile of Technosphere(R) Insulin than has been reported for any other inhaled insulin. Last year, MannKind completed a two-year carcinogenicity study in rats in which Technosphere(R) Insulin, and large doses of Technosphere(R) particles alone, were well tolerated after daily inhalations for 104 consecutive weeks. There were no indications in these studies that either Technosphere(R) Insulin or Technosphere(R) particles alone had any carcinogenic potential or caused any cellular proliferation in the lungs. MannKind also recently completed a six-month carcinogenicity study in transgenic mice, finding no macroscopic indications of carcinogenicity in animals given daily subcutaneous injections of Technosphere(R) Insulin or Technosphere(R) particles for 26 consecutive weeks. In addition, MannKind plans to submit data from over 100 preclinical studies supporting the safety of our product, the vast majority of which have already been completed.


LONG-TERM PULMONARY SAFETY ASSESSMENT OF AFREZZA™ IN RATS AND DOGS.
www.toxicology.org/AI/Pub/Tox/2011Tox.pdf (Page 179)
S. Greene1, K. Nikula2, J. Reynolds3, D. Poulin4, K. McInally5, D. Townson1
and P. Richardson1. 1MannKind Corp, Valencia, CA, 2Seventh Wave Laboratories,
Chesterfield, MO, 3J.A. Reynolds & Associates, Madison, CT, 4Charles River
Laboratories, Montreal, QC, Canada and 5ITR Laboratories, Montreal, QC, Canada.

The inhalable insulin Afrezza™ was evaluated in nonclinical safety studies as a
New Molecular Entity (NME) for diabetes treatment. Chronic inhalation and carcinogenicity
studies were conducted in Sprague Dawley rats and a chronic inhalation
study was conducted in Beagle dogs. Daily doses of either the novel excipient
Technosphere® (fumaryl diketopiperazine) particles or various doses of Afrezza™
(insulin adsorbed to Technosphere particles) were administered by the nose-only
(rats) or oronasal (dogs) routes. Tissues were evaluated by histopathology and respiratory
cell proliferation was assessed by immunostaining of proliferating cell nuclear
antigen (PCNA). There were no test article-related changes in the laryngopharynx,
larynx, trachea, bronchi or lung of rats. Test article and Technsophere
particle findings in the nasal cavity of rats were limited to the presence of
eosinophilic globules in the olfactory and respiratory epithelium that were considered
nonspecific responses to chronic, high level administration of particulate materials.
After 39-wks in dogs, there was a low incidence of minimal to mild alveolar
and/or bronchial interstitial neutrophil infiltrate in the lungs at the high Afrezza™
dose. This cellular infiltrate regressed completely during the 8-wk recovery period.
Based on evaluation of H&E stained tissues, there was no evidence of amyloid deposition
in any portion of the respiratory tract in either species. Inhalation of
Afrezza™ up to 104 wks in rats and 39-wks in dogs did not increase PCNA labeling
in alveoli, large bronchiolar or terminal bronchiolar tissues. Based on no test article-related
adverse findings in the lungs or increases in cell proliferation in rats or
dogs, the no adverse effect level was established in both species as the highest studied
doses. Chronic inhalation of Afrezza™ was well tolerated and supports the safe
use of this NME in humans over extended periods.

--------------------------------------------

"We also did high-definition CT scans on the 600 patients in our study. That’s the best you can do with people. We saw no change in their lungs, and some of them have been using the product for up to 5 years now."
-Al Mann
www.healthline.com/diabetesmine/the-truth-about-afresa-inhalable-insulin-a-chat-with-al-mann#3

---------------------------------------------

Mannkind has stated categorically that they have not found any more lung cancer in Technosphere Insulin-using patients than that in the general population. In their May 5th conference call, Mannkind said that up till then they have had 4,849 patients in 25 completed and 7 ongoing trials, 2,684 which used Technosphere Insulin and 2,165 which were controls. In patient-years, they have so far had 2,182 patient-years using Technosphere Insulin and 1,708 patient-years using controls. In all that, they have found 1 case of lung cancer, plus 1 case of lung involvement in metastatic colorectal cancer. A metastatic cancer is one in which the tumor has spread from its primary site in the body to another site. This patient was found to have colorectal cancer which then spread to the lung, and clearly does not reflect at all on the lung cancer risk with Technosphere Insulin. One case (who was a former smoker, by the way) out of 2,182 patient-years comes out to a cancer rate of .046%, lower than that normally found in the general population.


Pulmonary function over 2 years in diabetic patients treated with prandial inhaled Technosphere Insulin or usual antidiabetes treatment: a randomized trial
www.readcube.com/articles/10.1111%2Fj.1463-1326.2011.01500.x?r3_referer=wol&tracking_action=preview_click&show_checkout=1&purchase_referrer=onlinelibrary.wiley.com&purchase_site_license=LICENSE_DENIED_NO_CUSTOMER
Aims: Development of inhaled insulin has increased the need to understand its pulmonary safety. This study evaluated pulmonary function changes in diabetes patients receiving inhaled Technosphere Insulin (TI) or usual antidiabetes treatment (usual care).
Methods: This randomized, open-label study was conducted at 220 sites (25 July 2005 to 29 August 2008). Pulmonary function tests [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and lung diffusion capacity for carbon monoxide (DLCO)]were prospectively followed over 2 years in patients with type 1 or type 2 diabetes receiving TI (n = 730) or usual care (n = 824), along with a cohort without diabetes not receiving any special therapy (n = 145).
Results: Baseline demographics and pulmonary function were similar between diabetes treatment groups. Lung function declined frombaseline in all groups. TI was non-inferior to usual care for mean change in FEV1from baseline to month 24 [mean (s.e.m.) 0.037 (0.0119) l;95% CI 0.014 to 0.060] using mixed-model repeated-measure with a pre-speci?ed non-inferiority margin of 50 ml/year. After a greater initialdecline at month 3 with TI, rate of change (slope) in FEV1, FVC and DLCO(months 3–24) was not statistically different between treatment groups. TI was well tolerated; no serious safety concerns emerged. The most common respiratory event associated with TI was mild, transient cough, occurring within minutes of inhalation.
Conclusions: Observed changes in lung function with TI were small, occurred early after therapy initiation, remained non-progressive over 2 years and were unlikely to be clinically meaningful.
Keywords: diabetes, inhaled insulin, pulmonary function, Technosphere Insulin, usual antidiabetes treatment
Date submitted 30 June 2011; date of first decision 2 August 2011; date of final acceptance 20 September 2011



Safety of Technosphere Insulin as an Ultra-Rapid-Acting Prandial Insulin
www.ncbi.nlm.nih.gov/pmc/articles/PMC3440146/
The safety of TI has been studied extensively, both preclinically and in a clinical program involving more than 5600 subjects. The most common treatment-emergent adverse events were hypoglycemia, cough, and upper respiratory tract infection.17 Cough occurred in approxi-mately 32% of patients administering TI but tended to be mild and transient, occurring within minutes of inhalation.17 Furthermore, cough diminished over time and rarely led to study discontinuation.

A pooled analysis of cardiovascular events from nine clinical studies comprising 4467 patients who administered TI or usual diabetes care showed that the incidence of cardiovascular or cerebrovascular events was similar between the TI and usual diabetes care groups (relative risk, 1.01; 95% CI, 0.84 to 1.20).23

Lung function was examined in a 2-year prospective, multicenter, randomized, open-label study in patients with type 1 or type 2 diabetes administering TI (n = 730) or usual diabetes care (n = 824) and a cohort without diabetes who did not receive any specific therapy (n = 145).24 Lung function declined from baseline in all treatment groups, in line with normal age-related changes and as seen in diabetes in general. Compared with usual diabetes care, TI showed a small reduction in forced expiratory volume in 1 s (FEV1) from baseline to month 24 (-0.037 ± 0.0119 liter; 95% CI, 0.014 to 0.060). After a greater initial decline by month 3 with TI, the rate of change (slope) in FEV1, forced vital capacity, and diffusing capacity of the lung for carbon monoxide over months 3 to 24 was not statistically different between treatment groups. This observed treatment group difference was small, occurred early after therapy initiation, did not progress over 2 years, and resolved after discontinuation of therapy.

Two cases of cancer involving the lung have been reported during clinical trials, both in ex-smokers. The incidence does not exceed what would be expected in a similar, nontreated population.25 A 2-year carcinogenicity study in rats26 and a 6-month study in transgenic mice (data on file, MannKind Corporation) did not indicate a carcinogenic potential.

---------------------------------------------

Technosphere® Insulin: Defining the Role of Technosphere Particles at the Cellular Level
www.ncbi.nlm.nih.gov/pmc/articles/PMC2769873/pdf/dst-03-0545.pdf


---------------------------------------------

Insulin Lung Deposition and Clearance Following Technosphere® Insulin Inhalation Powder Administration
link.springer.com/article/10.1007/s11095-011-0443-4
Purpose
To determine distribution and deposition of Technosphere® Insulin (TI) inhalation powder and the rate of clearance of fumaryl diketopiperazine (FDKP; major component of Technosphere particles) and insulin from the lungs.
Methods
Deposition and distribution of 99mpertechnetate adsorbed onto TI immediately after administration using the MedTone® inhaler was quantified by gamma-scintigraphy. Clearance from the lungs was studied in a second experiment by serial bronchoalveolar lavage (BAL) after administration of TI inhalation powder and assay of the recovered fluid for FDKP and insulin.
Results
Following inhalation, ~60% of radioactivity (adsorbed on TI) emitted from the inhaler was delivered to the lungs; the remainder of the emitted dose was swallowed. Clearance from the lung epithelial lining fluid (ELF) of FDKP and insulin have a half-life of ~1 hour.
Conclusion
TI inhalation powder administered via the MedTone inhaler was uniformly distributed throughout the lungs; ~40% of the initial cartridge load reached the lungs. Insulin and FDKP are quickly cleared from the lungs, mainly by absorption into the systemic circulation. The terminal clearance half-life from the lung ELF, estimated from sequential BAL fluid measurements for both components, was ~1 hour. Since there is an overnight washout period, the potential for accumulation on chronic administration is minimal.

---------------------------------------------

INNOVATION IN DRUG DELIVERY BY INHALATION
www.mannkindcorp.com/Collateral/Documents/English-US/Innovation%20In%20Drug%20Delivery%20by%20Inhalation.pdf

---------------------------------------------

TECHNOSPHERE® TECHNOLOGY: A PLATFORM FOR INHALED PROTEIN THERAPEUTICS
www.scribd.com/doc/31037239/Ti-Pulmonary

---------------------------------------------

davetud from tudiabetes.org
www.tudiabetes.org/forum/topics/wary-of-interested-in-using-afrezza-you-should-read-this
Like many, I was concerned about just what exactly was happening in my lungs when Afrezza is put into it. I'm especially attuned to this question having followed some injectible "ultrafast" insulins being developed, and the biochemical techniques used to speed absorption.

[mnholdem]

NOTE TO READERS: Some of these quote use the spelling Afresa, which was the official name several years ago that has since been changed to Afrezza. The information regarding deposition in the lungs is still relevant, though.

Thanks, harryx1, for compiling these links. I know davetud (who's link is among yours listed) may be interested in some of these links on articles/research related to lung issues.

[Chris-C]

Regarding pulmonary safety surrounding inhaled insulin or other medicine:

The FUDsters know that they can exploit three factors by using this as a scare tactic:
1. The unfounded rumor out there that Exubera failed because of safety issues. Patently not true.
2. The known correlation between smoking and lung cancer. (Never mind the huge difference between smoke particles and technosphere particles).
3. The fact that in science no finding can EVER be considered iron-clad no matter how many studies or how robust the findings because it's impossible to rule out chance occurrences and have 100% certainty on any study. Some people scoff at studies with p=<.001 and stronger probability findings, meaning that there is less than a one in one thousand chance that the finding has chance error. Ironically, those people routinely touch benches with wet paint signs and blithely accept that the universe has an infinite number of stars. Go figure.

No sense trying to convince them of anything —it's wasted energy. So they'll use this excuse (miniscule probability of carcinogenic consequences (which applies to countless substances people use everyday)to beat up on Afrezza, yet happily jump in their cars and drive our crazy roadways without anxiety (even when texting) despite the huge and documented risk that this entails.

Logic is clearly not the coin of the realm.

Chris C

[suebeeee1]

They used PUPPIES to test?

[mnholdem]

Yep. They should have used kittens, don't you think?

[liane]

Mar 18, 2015 7:26:31 GMT -5 mnholdem said:

Yep. They should have used kittens, don't you think?

Careful there!

[frumenti]

What a guy!!! What would we do without Harry? Probably not very well. Thanks for your outstanding rebuttal!! congratulations on destroying that stupid claim on lost lung capacity. Be careful crossing streets. Don't sit with your back to the door.

[compound26]

There were some great discussions on the safety of Afrezza in this update given by DRs. PETTUS, BODE & McGILL (ENDO 2017 Townhall - Updates on Inhaled Insulin, Reaching for the Stars in Post Prandial Glucose Control).  

goo.gl/EJCUXW

Dr. Jeremy Pettus: Question: So next one is - Are Lung Function Tests required - Full FPTs or just FEV 1.


Reply Dr. Janet McGill: Just FEV1


Reply Dr. Bruce Bode: So in the development phase, they did full function initially, and realized, the FDA realized this, the Pulmonologist consultants said, you don't need to do this, just an FEV1, and that is very quick. Obviously, Primary Care Doctors do it, obviously Pulmonologists have them all the time. But Endocrinologists don't have them, they think it's a very big thing. It's so easy, it's a very inexpensive kit. You can buy hand held ones that are very inexpensive / disposable. But why do you want something disposable when you can buy something for $1000 and you can use it on hundreds and hundreds of patients. You get reimbursed, but its not much, it's $30, I don't know, it's about $30 or $40, but you will have it it payed for almost immediately. So we do about these. It only takes our staff 3 minutes. What's the length of doing that. Typing in the name and the date of birth and their weight. They do it 3 times and get the average.


Question: Safety of Inhaled Insulin (AFREZZA)

Reply: Dr. Bruce Bode: One thing, I think, is the safety. Most ENDOs won't prescribe because of the safety. I have been around enough of these lung biologists and experts, because I've been involved with them for the last 10 years. They'll convince you "it's perfectly safe". And the other thing, this drop of 40 mililiters, it's like me sitting here and I go back like this, I drop 40 mililiters of my FEV1 by just lying down. That's less that one per cent, one and a half per cent of your FEV1 overall. Lung Function: That's the safety. But that's hard for people to get over. And then the big thing is: People are, especially Type 1s, that are stuck on their 4 and 8 units; "I use the half unit here, the 2.5 units there. Tell them, it's in and out so quickly, it's gone so quickly. The hypoglycemia is related to, from Hour 2 to Hour 5. People going low before lunch all the time, people going low in the afternoon, people going low early in the bedtime and they are eating, they are going low at bedtime ad they eat a bunch of food. They are high and they are taken insulin, and they are over-correcting and they go low. This (AFREZZA) is in and out so quickly.

Initially on the market back in the 1920s, nobody would have ever taken a SubQ Insulin for meals, never! But unfortunately, everybody is used to SubQ Insulin, and that's all they know. They have this precise carb in ratio on their pumps. And in our Hybrid Closed Loop development, the group out of Santa Barbara, did a trial using inhaled insulin (AFREZZA) versus rapid acting insulin Lispro in the Artificial Pancreas Project. In the inhaled insulin, totally flattened out the meal rise and it did not have any reactive hypoglycemia.

Question: Give the latest post marketing data on lung cancer:

Dr. Bode, Reply: "As far as I know, there's no reported (cases). The ones' who had lung cancer, there were a total of four, 2 during and 2 afterwards. These people - 2 of them had long standing history of smoking. One person only used it (AFREZZA) a very short time, less than a few weeks. So you know, obviously, so many people think this rate of lung cancer of these 4 cases is so unexpected. They also showed that when they looked at the Chest xRay, 2 out of the 4 had changes on their xRay that was misdiagnosed unfortunately. So there's no way that inhaled insulin can cause cancer within. You know, 10 weeks, 20 weeks, and this thing (AFREZZA) doesn't hang out in the lungs. There's no activity in the lungs. So it just either gets absorbed. If your's silly, bring it back up and cough it out when you swallow".

[otherottawaguy]

As I recall what the study doesn't mention is that the incidence of cancer within the test group is actual 50% less than that of the general population. The FUDsters can spin up the negative correlations into a froth but the positives ... just ignored.

OOG

[lakers]

Other thing we're focused on is around the risk benefit or the safety profile of Afrezza. We are going to increase the awareness of lung function in cancer data or evidence that currently exists. There is a tremendous amount of missed information out there and these efforts will be directed to counteract that information.

Next let me talk a little bit about the long-term safety study. The protocol has been finalized and we're putting the operational components into place. As you may have been heard from me previously, we are aggressively managing the cost of this study while still driving to meet the FDA timelines. We are still on target to do so.

Dr Bode said "Most ENDOs won't prescribe because of the safety."

It's true from my meetings with PCPs and Endos. It's #1 impediment. When we can debunk that myth scientifically and officially, the floodgates will open wide.