Certainly lots of Biotech companies fit that description as well. Fortunately Mannkind is not one of them given the current set of facts (you are entitled to your opinions but not to your facts). The landscape of Biotech-ville is littered with corpses of dead companies that were long on promise and short on (efficacious) products. The allure of bio-tech companies is simple. The promise of untold riches. I call this the low "P/D" syndrome. The D is for dreams, you just keep dreaming big about payoffs and any price (P) is justified & worth paying. Just like airline industry, the biotech industry as a whole has failed to deliver any returns. Though the biotech shareholders as a whole have suffered, the products that successful biotech companies brought have benefited patients and the general society enormously.
For every Amgen that succeeds, there are a thousand companies that took a one way ticket to oblivion. It pays to be vigilant. The motto should be Trust but verify. As I am long Mannkind, I follow "Bruce Berkowitz" (founder of Fairholme capital management) principle. Berkowitz principle is, you try to kill your idea. I wake up every day trying to punch hole in my theory. So far I've not yet found one. If you have one, please email me or post a comment.
Mannkind certainly makes some bold claims regarding Afrezza.Let's take a critical look.
Mannkind claims Afrezza (a.k.a. Technosphere Insulin, TI, Afresa) can
- Reduce postprandial glucose excursions to normal levels
- Virtually avoid causing hypoglycemia
- Require no complex meal titration
- Reduce the need for mealtime glucose measurements – likely just to infrequent fasting glucose measurements
- Cause no weight gain
- Eliminate prandial injections
I've three sources of information. One is from Mannkind's PR, next is the journal articles written by researchers (some of them are affiliated to Mannkind) and last is the Afrezza trial participants. I've had email conversations with one such participant named Pat. His feedback has been real useful to confirm the validity of several Mannkind's claims. He has written extensively about Afrezza in some diabetes forums. I've compiled the postings in this link. The participant is just another data point.
Claim 1: Reduce postprandial glucose excursions to normal levels
Validity: A good prandial insulin should be there when the body needs it and be out of the system when its no longer required. Lets explore how Afrezza stacks up.
a) A rapid suppression of endogenous glucose production can contribute to reduced PPG levels, and hence better control of PPG (indirectly).b) On a head to head comparison with aspart, the PPG control was better in Afrezza
c) There has been numerous journal articles written on PPG excursions. Given the PK/PD profile, it is easy to conclude that this claim has merit.
Another measure of PPG is the AUCglucose (area under the curve). This result is from a phase 2 trial comparing Afrezza (TI -technosphere insulin) and Novolog. The table below is from Mannkind's PR.
Claim 2: Virtually avoid causing hypoglycemia
Validity: Insulin and hypos go like peas and carrots. Hypos have been identified as one of the barriers of initiating insulin therapy.
a) From Mannkind's side, the best article on this is a poster titled "Reduced Incidence and Frequency of Hypoglycemia in an Integrated Analysis of Pooled Data from Clinical Trials of Subjects with Type 1 Diabetes Using Prandial Inhaled Technosphere® Insulin".
The pooled analysis shows a reduction in both mild to severe hypos compared to the RAA.
b) The best validation comes from Pat (the afrezza trial participant).
"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 one can conclude that though hypos are not eliminated, the frequency and severity of hypos are way less compared to the RAA.
Claim 3 & 4: No complex titration, infrequent fpg measurement.
If you talk to any diabetic, they will consider this as the most dubious of all claims. This is based on countless feedback from insulin users. If this is even partly true, then it'll be the greatest of all selling points. This claim challenges the conventional wisdom of internists, endocrinologists & patients. Even if this claim is true, it is going to take Mannkind considerable effort to change the mind-set.
Mannkind has put in lot of effort to back this claim. Let us see what Al Mann has to say on this in one of the 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. "
This is what Pat had to say regarding the carb counting. The emphasis are mine. (Pat Godin | November 18th, 2009 at 2:56 pm)
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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.
----------------------------------------------------------------------- end of Pat's commentI have also analyzed this issue a little bit. Why is carb-counting needed now? The simple reason is, in current treatment paradigm, you get hammered if you take a lot of insulin (resulting in hypos) and again if you do not take enough (hyperglycemia, higher A1C etc). The other reason is, if you know you made a mistake first, the correction becomes even more complicated. Any correction dose you take will get stacked on the existing dose (that is still in the body). The RAA's have a tail and you need to figure out accurately the correction dosage. (for folks who know math, think of superimposing one sinusoid curve with another and where the starting points are the same, it is a complex task.) Talk about adding insult to injury. In some ways, the current prandial insulin is unforgiving if correct dosage is not computed. So one has to count the carb, measure their fpg, use the sliding scale to compute the prandial insulin dose and then take the injection.
So what is the deal with Afrezza?
a) The Tmax of peak insulin is 12-14 minutes, so any corrective dosage acts real quick
b) The bolus doesn't crash (look at the PK profile of both TI and RAA, RAA comes down very fast), it is a gentle glide down
c) The tail of Afrezza is much shorter than RAA. Like a duracell battery ad, RAA goes on and on and on even when it is not needed.
d) To the extent Afrezza shuts off hepatic glucose, the body can use it later when it really needs it (reduce hypos etc)
It appears that Afrezza is much more forgiving to the dosage miscalculations.
Let us see what "Pat" says in a different post
"A limitation for some especially insulin sensitive individuals may be the dosing for the TI insulin. Basically there are two doses to work with in various combinations. For me I found them quite easy to figure out and work with in most meal situations. I found if I overestimated the dose and my blood sugar dropped too low the fall of blood sugar in the second hour after bolusing was very gentle and never "crashed" like I became accustomed to with injected Humalog. Therefore no bad hypos."
Claim 5: Causes no weight gain
Validity: A lot of evidence has been shown by Mannkind to validate this. Some studies have shown a weight loss and some have shown weight neutral.
Intuitively it is easy to understand. Due to the hypos or fear of hypos, the patients resort to frequent snacking. This snacking causes weight gain.
And last but not least, the claim 6 "Eliminate prandial injections" needs no validation.
Validity: A lot of evidence has been shown by Mannkind to validate this. Some studies have shown a weight loss and some have shown weight neutral.
Intuitively it is easy to understand. Due to the hypos or fear of hypos, the patients resort to frequent snacking. This snacking causes weight gain.
And last but not least, the claim 6 "Eliminate prandial injections" needs no validation.
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