Al Mann, CEO of MannKind Corp., is something of a legend in his own time. He not only founded MiniMed, acquired by Medtronic, but also four other successful medical companies. He’s a billionaire, with his
own Biomedical Engineering Institute at the University of Southern California (USC), so we can assume that he’s not just championing the new inhalable insulin product Technosphere (brand name Afresa) as some kind of pipe dream or get-rich-quick scheme.
The guy knows his stuff, but a lot of folks remain convinced that the odds are against Afresa ever going very far. Today at DiabetesMine, a chat with Mr. Mann himself on the outlook for Afresa:
DM) Mr. Mann, let’s jump right in. How do you expect Afresa to succeed in the aftermath of Exubera?
AM) Exubera was very inconvenient, it had absolutely no benefits clinically, and it was not as good as the other treatments on the market. Comparing Afresa to Exubera is like saying that Rezulin — a bad drug that failed — is the same as Actos — a good drug with good outcomes.
What we have is a different form of insulin (from Exubera). It’s powder so we deliver it into the lungs. But that’s an advantage because it’s delivered in the arterial blood system instead of the capillary system. We’re actually delivering insulin monomers (molecules). Nobody ever did that before.
It behaves much like normal pancreatic insulin does. Normal people don’t get hypos, and people taking Afresa don’t either, even if they dose and don’t eat.
How is that possible?
Other insulins create an enormous period of hypoglycemia because there’s an excess of insulin after you’ve digested your meal.
What happens is that if you eat a meal on regular insulins, Lantus and Humalog for example, 80% of the insulin remains in your body for up to 10-12 hours after your meal, which causes hypoglycemia.
With Afresa, there’s no complex meal titration. You take a set amount, matched to your body mass and insulin resistance, determined with your doctor. You take that same amount every time you eat a meal. Then it’s not important whether you eat 50 grams of carbs or 100 grams or even zero. Afresa essentially “turns off glucogenesis” so no glucose is secreted from the liver in reaction to food. Our trial studies are showing that patients are having no more glucose highs than normal non-diabetic people, and no more lows.
That sounds pretty magical. Does this work for Type 2s only, or is it an option for Type 1s now taking basal and bolus insulin?
Both could use it. Afresa is for prandial control – mealtime only – not basal doses. For about 70% of Type 2s, all you’ll need is a regular set dose of Afresa. This will work for everyone except the “late-stage” Type 2s, who will need to take basal insulin as well.
It’s different for Type 1′s because there’s a very big therapeutic window for them; their insulin needs are so differing. They can use Afresa to cover meals, yes, but they’ll still have the issue that if they dose and don’t eat anything, they’ll get hypo, and if they eat a large meal, they’ll need a larger dose.
The advantage for all patients is that they won’t have to do carb counting or anything, because Afresa does not have to be so precisely matched to food intake.
So can you explain the details of dosing Afresa?
The cartridges come in sizes of 15, 30, 45 and 60 units. Again, for Type 2s, their doctor w
ill help them select a regular dose based on their body mass and level of insulin resistance. If a person is already on insulin, you’ll multiply the amount of rapid-acting insulin analog you’re now taking by three, and that’s where you’ll start for your original dose. You need about three times as much Afresa as you do for an insulin injection.
Aren’t most Type 2s currently treated with a basal insulin only, instead of mealtime dosing?
Yes, but that’s the wrong way around. The correct therapy should be a good prandial insulin and not long-term insulin — Afresa in particular because it turns off glucose production and delivery from the liver. Our latest trials of 600 patients are showing even more significant benefits from the product than our original trials; the most recent trial appears to show that this should replace frontline treatment for all Type 2 patients.
That’s a big statement for something so new. What about safety concerns? We hear that the FDA Endocrine Advisory Committee isn’t even going to be scrutinizing this product…?
The FDA is already familiar with the kinetics of the product. We’ve done extensive safety studies, but not using Xrays like they did with Exubera. You can’t detect lung cancer with Xrays. You have to do it in animals by sacrificing the animal at the end of the study, in order to examine every cell in the body and see if there’s damage. That’s how you find out if there’s carcinogenicity.
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.
How close are you to FDA approval then?
We’ve submitted all our data and recommendations, and our current review date is scheduled for January 16. That’s when the committee will make their counter-proposal for the FDA label. The label says what you can use a drug for and what you can claim about it. We don’t know what additional trials they might require to demonstrate superiority.
Getting back to usability, part of Exubera’s problem was a form factor that simply wasn’t liveable. Your tiny new Dreamboat inhaler looks amazing. Is this the delivery device we can expect at launch?
We hope so. Of course we did our clinical trials with the original MedTone inhaler – the little purple and white box you’ve seen in all the pictures. The new Dreamboat is pretty slick. We’re hoping to get that approved by the 
time the FDA approves Afresa. We just have to do a short study with people using the two different inhalers, to show that the effect in the body is the same.
Are you worried that doctors will resist this new-fangled therapy, like they did with Exubera?
We actually did a survey of hundreds of endos and primary care physicians. Twenty-five percent said they would definitely recommend it for their patients.
Still, I ran into a doctor at a conference who thought it was nonsense to administer insulin with no complex meal titration. I tried to explain the science on which it was based… We’ll have to give the doctors enough data so they understand and get comfortable with it. We believe Afresa’s going to change diabetes therapy, but it’s going to take a little education to do it.
Won’t it be difficult to teach patients how to use?
Not at all. We have an instructional DVD and a test device that people can use to learn it in a few minutes right in the doctor’s office. There’s no big risk of hypoglycemia, so it’s not so worrisome that people might make mistakes.
The bottom line is always costs. Will patients get insurance coverage for Afresa?
We’re working with the reimbursement advisory panels to make sure we’re within 5% of the current costs of Humalog and Novolog — so people will get essentially the same reimbursement they get now. We believe that we’ll be covered by most mainstream health plans within six months of launch.
Don’t forget this also saves a lot of money because you don’t need nearly as many expensive test strips for fingersticks, by an order of magnitude. For Type 2s, maybe they’ll just need a fasting test once a week. If you’re Type 1, you will want to do a few more.
****
Afresa: Dreamboat or shipwreck? Only time will tell. Meanwhile, you can’t help but admire Al Mann’s unwavering commitment to bringing a workable inhalable insulin to market. Thank you, Sir.
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Sounds interesting, but I don’t understand one thing. At one point, Mr. Mann says that the release of the insulin is more like normal pancreatic insulin (action triggered by the meal), then why would it make a T1 go hypo if they take it and don’t eat, but not a T2? I would also be curious to know the levels of control achieved in clinical trials for T1 vs. say..pump therapy.
Amy it sounds interesting. But I don’t really understand why it wouldn’t cause a low. Why would turning off glucogenesis mean that I could take this an eat 10 g carbs, or take the same does and eat 50g and have no problems. That seems very much like a silver bullet, I’d still need convincing.
As someone with asthma and some level of lung damage, I’d also like to know whether this is even an option for me.
I have been watching this products development and believe it to be very progressive. As most progressive items in our lives, it does take a while for people to learn and assimilate the information. This product is going to be BIG once this happens.
I’m also skeptical and wonder about the convenience factor. I will still have to wear a pump. But if it is much better at controlling BG’s with less risk of hypo’s that would be an improvement. I will have to see it to believe it, though. Also if there is even the slightest risk of lung injury or irritation I would not use it. Although it sounds like this has not been an issue in the time they’ve studied it (5 years as he described). I wonder about long-term. It sounds like, for type 2 patients, though, it could be a big step forward.
It would be helpful to hear from the people in the study, whether they would stay on it and what they’re personal experiences have been–especially if they have type 1 diabetes.
Thanks for that interview. Very exciting if he can pull it off.
I know, why not apply the same principal (like SMART insulin) but get rid of the inhaler all together. Any foreign body inhaled into our lungs on a regular basis (not to mention trace preservatives found in most insulins) are probably going to have negative effects in the long run, and IMO it should be tested for well over 10 years for any kind of re-assuring data.
The stock ticker for MannKind is: MNKD. It could be one of the greatest investment opportunities of all time.
from looking at the timing of the hypos among type 1s taking afresa in the trials they are finding that the basal insulin is the likely cause of the hypos, not afresa.
Al has also said that they are finding no insulin residue in the lungs of patients taking afresa, because it is so quickly absorbed, however afresa will not be recommended for those that smoke because the compnay doesn’t want those that smoke who are dignosed with lung cancer to blame it on afresa.
It seems concern for lung saftey will persist for many years in spite of science to support saftety claims. Yet, patients continue current treatment that has the known risks associated w/ hypoglycemia.
Type 1′s what Mr. Mann is saying is that although this drug is perfect for all type 2′s, you’d be crazy not to take it at mealtime if you are a type 1. why?
- 60% fewer hypos than injected
- no weight gain
- reduction in post-meal glucose fluctuations, which are believed to be an important risk factor in the development of complications
The real problem for type 1′s is the lack of a better basal insulin therapy. The company is actually currently doing trials with pump users to show that with afresa and a “better” basal insulin (humalog delivered through a pump) patients can achieve normal A1cs much much easier than with the current best in class therapy.
Keith, do you really think people will opt for a vastly inferior treatment, because of a problem that might or might not exist 10 years from now and there currently is no evidence to support? when has that ever happened before? Give me one good example.
itellthefuture, I was responding to the fact that 4 of the preceeding posts referenced potential lung issues. Educating doctors and patients will be an uphill battle for MNKD and their partner, but it is a battle I think they can win with superior science.
itellthefuture – I was responding to fact that 4 of the preceeding posts referenced lung conerns. Educating doctors and patients will be an uphill battle for Afresa, but one I think they will win through superior science.
Al Mann – from recent Quarterly call:
I have long argued that AFRESA does not require complex meal titration. Certainly there is no need for carb counting and so forth. The basis of my view was derived from the dose escalation study with meal challenges in which better glucose control was achieved with ever greater doses of AFRESA, yet without any hypos. Yet based on decades of battling these challenges of conventional insulin therapy, some physicians have questioned my suggestion. Therefore, I proposed a meal escalation study in which patients would take a fixed dose of AFRESA and then a series of meal challenges. Our clinical team designed a protocol to set a standard meal with 50 g of carbohydrates. That was the 100% challenge. This was followed by challenges at 200%, 50% and zero percent. When I heard of zero I was shocked. Surely there would be severe hypo. The remarkable thing was that with the regular prescribed dose of AFRESA regardless of carbohydrate intake between zero and 100 grams the range of excursion is only plus or minus 30-35 mg [reduction] from baseline for all of the Type II patients in the study. At the ASDA meeting I described to Dr. [Jay Skyler] the finding that in Type II diabetes with a fixed dose of AFRESA and even with no food there is excellent control without hypo risk. I asked him how that was possible. “Obvious,” he responded. He was basing his comments on our recently reported 118 trial in which we showed rapid and virtually complete sensation of [hepatic] glucose relief with AFRESA and the common inability of the remaining endogenous insulin to maintain control, as is the case for a healthy person without diabetes. Indeed, I mentioned this result to a number of KOL’s who agree with Jay. So I say to you that AFRESA is what no other insulin has ever done for Type II diabetes. AFRESA restores more physiologic hepatic function, takes a load off the pancreas and avoids the hyperinsulinemia resulting from resistance of other insulins. It better mimics the normal pancreas response. So what does all this mean? First let me say that we will need to follow these findings with much larger trials. If the results of the larger trials support the earlier findings then I state to you that AFRESA should be used very early, certainly after failure with Metformin and as a first sign therapy for a significant portion of patients who are not candidates for Metformin or who do not do well with Metformin. It should be used well before fasting glucose is out of control and as we have seen, AFRESA even leads to lower fasting levels by eliminating the excessive gluconeogenesis. Of course, we will have to repeat some of these findings with specific trials but we have already seen the possibilities for AFRESA as we evaluate the timing of hypos in our already completed trials to date. From what we have seen in our extensive clinical program, AFRESA should benefit the entire progression spectrum of Type II diabetes with a very simple therapy and the experts tell us that it could even stop the progression of the disease.
Sorry, I can’t help it…
It should have been “THEIR personal…”
okay done now
A general comment on new medicines…
As a diabetic I always feel like a guinea pig with new medicines (Humalog, Symlin etc). Although this particular product seems to have an excellent health profile *so far*, how many others have we heard about solving some problem or another only to be pulled later because of serious safety concerns that were not first apparent? It is only natural for people to be skeptical when they are considering taking a drug multiple times a day for the REST OF THEIR LIVES.
And for me, the issue with the lungs is that it is one of the only organs that seems to have minimal complications (if any) from diabetes. So I am fiercely protective of my lungs! Having a strong cardiovascular system allows me to stay healthy in many other ways that can mitigate the complications of diabetes.
If they make a good case, and it does work as advertised, it could be a good step. But they will have to make a strong case, at least to me!
Well.. those inhaler products are of really great use, since all these are the miniature in size and even easy to carry as well.. these are the most useful products for the significance of prevention.. One must say a great innovation.
So far, Mr. Mann seems to describe benefits largely in terms of the type 2 population, whose primary issue is insulin resistance, and perhaps a relative insulin insufficiency (rather than a complete insulin insufficiency as is the case with the type 1 population). While there are some more compelling features to Afresa, I think it’s a bit naive to expect any insulin to succeed without factoring in the type 1 audience. Type 1′s constitute nearly 80% of the insulin buyers, even if they use only 30% of the actual insulin sold by volume. This is what doomed Exubera, not the “bong” as many outsiders seem to believe.
I was in the trial study for afresa a few years ago and i have to say it was a horrible experience. Mankind was extremely narrow minded when it came to how the product would effect lifestyle. I have been type 1 for 30 years with excellent control with a “tight rate therapy”, (I self adjust my dose based on the blood sugar.) of 4 shots a day. I found that there was no protocol if my blood sugar was high. The company said you can only give so much at any one time. (DEAL BREAKER).
As a dibetic, self adjusting the insulin dose to deal with blood sugar levels is the name of the game. Using the inhaled insulin disturbed my lifestyle 90% more than shots. If you have no fluctuation in your daily routine, and are pretty sedentary, Maybe Afresa will work for you.
After thirty years, shots don’t hurt anymore(mind over matter eh?) The inability to control ones diabetes with inhaled insulin was the biggest pain in the ass. I left the study early.
I have invested in MannKind stock and so I have been watching the development of Afresa as keenly. However, having read the comments on this article, I now feel even more sympathy for people with diabetes. This is a tough disease to face, especially since it is a life time concern. Thank you all for your comments.
Sincerely … David
I was in a 2-year clinical trial (Phase 3) with the Technosphere Insulin (TI) (Afresa) in the Type 1 group. I injected Lantus for my basal and bolused the TI for my meals with the Medtone Inhaler to replace the injected Humalog I was using previously. At the beginning of the trial my A1c was 6.8 and when the trial ended my A1c was 5.9. During the trial I was not carb counting, although I estimated the size of my bolus of TI based on the approximate carbs in my meals. I managed to achieve the low A1c with very infrequent incidences of hypoglycemia. There were only 2 occurrences of significant hypos in that 2 year period, although I did have other marginal low blood sugars. I attributed some of this to the rapid onset of action and the short duration of action of the TI.
So I am not surprised by the information Al Mann has revealed about Afresa. I was disappointed when the trial ended and had to return to injected Humalog. My A1c is now in the range of 6.8 again. Recently I began pumping insulin. It would certainly be interesting to incorporate inhaled Afresa with a basal insulin delivered with a pump.
It would definitely be a great marketing point if Type 1 diabetics using Afresa did not have to develop accurate carb counting skills to avoid a lot of hypos.
Pat
I have heard Alfred Mann say recently that he sees evidence that Afresa stops the progression of diabetes in type 2 patients. This would obviously be incredible news.
I am actually such a firm believer in the company that I constantly bash it on the yahoo message boards just so I can buy the stock at lower prices. i hope one day to meet Al Mann then try to sell him some replacement windows?
Thanks to those of you who provided clarification with regard to potential use of this product by T1′s. Especially thanks to Matthew and Pat Godin, the T1 study participants who had vastly different experiences. That’s the problem at this point for me…. the only “evidence” presented here with regards to T1′s is testimonial rather than with study results. Can anyone point us to study results for T1′s using Afresa? I could care less about the stock price and PR for this, but show me (with real evidence) that it will make life better for us without compromising other aspects of our health, and you will have my attention.
Carol the data is overwhelming. Go to this link and listen to the presentation dates 5/12/09. Dr. Peter Richardson gives a presentation summarizing the data that has been submitted to the FDA.
http://www.news.mannkindcorp.com/phoenix.zhtml?c=147953&p=irol-presentations
I am curious. What would happen if instead of lungs, they used a spray to introduce it under the tongue? This would go to the blood stream as well.
I can see a great usage for this one. Most Type IIs have put quite a strain on the pancreas over the years. Perhaps this could be used to allow the pancreas time to recover.
There is a reason for the insulin resistance in type IIs. It is a protective thing to keep the insulin from over whelming the cells. Does this drug lower that protection? If not fine, if so, then we might be trading one problem for another. My original reaction to some drugs suggests heart problems might become an issue. That is why I am extremely cautious about using insulin even though it would bring my levels down dramatically. Treating the symptom instead of the basic cause is something missed by both doctors and type IIs and has been for years. I see a lot of potential benefits from this treatment. I also see a lot of potential problems. How does it affect Leptin levels for instance. I am not a doctor or wish to become one. I do my homework. Most doctors do not have that type of time. I would be interested in following this research in future articles.
Study results
http://care.diabetesjournals.org/content/30/9/2307.full.pdf
CONCLUSIONS— In this study, inhalation
of TI led to markedly improved
postprandial glycemic control compared
with subcutaneous RHI, whereas total serum
insulin exposure was almost identical
with each treatment. TI had a more
rapid absorption and achieved higher peak
insulin levels than subcutaneous RHI.
These unique pharmacokinetic properties
of TI may provide better postprandial
glucose control compared with RHI
achieved with a similar insulin exposure.
Occurrences of hypoglycemia and
hyperglycemia were similar with TI and
subcutaneous RHI treatment, with no severe
occurrences. The incidence of treatment-
emergent mild-to-moderate
adverse events was comparable between
treatments. Three subjects reported a single
event of cough during TI treatment.
The results of our clinical experimental
study support the utility of TI as an
alternative to subcutaneous RHI to cover
postprandial insulin requirements. TI
markedly improved postprandial blood
glucose control in subjects with type 2
diabetes. Use of prandial TI, as part of an
intensified insulin therapy, might provide
better glycemic control than subcutaneous
RHI. Long-term studies are under
way to confirm the promising efficacy,
safety, and tolerability profile of TI seen in
our study.
I have been using Exubera since it came out and I bought as much as I could before it was pulled from the market and am still using it now. I have been T1 for 38 years and my control has never been better. I use lantus as a basal every morning (12 units). And use exubera in varying doses at varying times when I eat meals. I have had my lungs checked twice with no change from when I started. I am extremely fit, lean, ride mountain bikes 4X a week. So I will be extremely pleased when this new drug makes it to market (before I use my last Exubera!). Just because people are used to doing 4 shorts a day does not make it good. If my blood sugar is a little high, I just take one puff of 1mg and it comes back down. My life is 100% better with Exubera. Don’t be resistant to trying the new stuff, you may be very pleasantly surprised. Any change is tough, and I was very wary about going to Exubera but now I can’t live comfortably without it.
One major aspect that I have not seen mentioned is that type-2 diabetics usually have a functioning glucagon system, affording them fairly solid protection from hypoglycaemia. Type-1s? Not so much, after a few years of D. So if you are a type 1 diabetic, you may want to take all of this “no carb-counting with Afresa” stuff with a grain of salt.
I totally don’t understand how I (as a type 1) would not have to count carbs anymore. How is that possible?
what i dont understand is why diabetics themselves are skeptical of something that could possibly reduce the amount of injections they have to do per day.as a young woman and a diabetic i personally would prefer not to have bruises and lumps all over my body and not to have a factor directly affecting my weight. also the prospect of an inhaler makes the process of taking insulin more bearable for those who do not take it as they cannot put up with the inconvenience of having injections every time they just want to have the simple pleasure of having something to eat.i also find that diabetics get little sympathy when expressing this feeling.i get frequently ill which affects my education and would prefer to have an option other than injections that is available quicker than ten years,when something else will be available but bodies will have been damaged both externally and internally beyond repair. i beleive that people who arent diabetic should stop trying to influence decisions as they do not go through what is in fact a very seriousness illness. Iam sure alot of younger diabetics would agree.
stage 3 lung cancer…
Your topic ” The Truth About Afresa Inhalable Insulin: A Chat with Al … was interesting when I found it on Thursday searching for stage 3 lung cancer in Google…
Begley- I completely agree with you.
I’m 34 yrs old, was diagnosed at 7. I have been living with type 1 for many years. I was luck enough to be on Exubera for 2 years. I just ran out off supply in January and have gone back on 5 injections a day. It stinks. I contact Mannkind regularly to see if FDA approval has come yet. Exunera worked fantastically for me and I expect the same from Afresa, once it finally hits the market. For those of you who don’t take injections or 5 a day, you have no right to provid einput. At least Afresa give us an option..to live a normal life without stabbing ourselves so many times!
I have been taking insulin shots for 62 years, I tried the pump for a short amount of time and I use Exubera for one year. I am a true believer in inhaled insulin it is the wave of the future. The reason Exubera didn’t catch on was because of poor advertising and marketing.
When insulin was first put on the market it was not a cure for diabetes. Insulin was taken from cattle and hogs at that time and did not work the same as human insulin did. Finally they developed the humlin version of insulin which was a God send. On the beef insulin my blood sugars would drop so fast that I had no idea what was going on, now with the humlin insulin I am still able to think straight at a much lower glucose level which adds very much to a person’s safety factor in every aspect of their lives.
I can not wait for MannKind to get an approval for their new Afresa Inhale-able insulin. I will be the first one in line to try it.
I totally agree with Begley if you haven’t tried it then don’t knock it.
In reply to Matthew…being in a study a little different from real life. If you had participated in the control arm, you would have been subject to the same rigors. This was explained to you before volunteering for the study. Al Mann has stated several times that the first dose may not be enough for a large meal and that a second dose may be required; however, he did not say how blister packaging could accomplish this. I assume a person would buy more doses than one per meal, just the way you buy more insulin now in order to compensate for varied glucose levels.
JR
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I agree with steveg above of 11/23/09. Fifty years insulin dependant with A1C’s of 5.7 and 5.9 and 2-3 injections daily is my story. I loved Exubera. I used it for two years and it made life ENJOYABLE again. I cursed the Pfizer board when they with it from the market I am psychologically drain and cannot take 4 injections a day. Even if the inhaleable took a few months off of this existance I consider it worth it. WELL WORTH IT. Where can I sign-up for the trials??????????????
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