Saturday, March 27, 2010

Afrezza and HbA1C - Part 2

(if some pics appear small, please click to enlarge them)

This is the part 2. Part 1 can be accessed in this link.

This part explores how the future will be like for insulin dependent type 2 if they are exposed to Afrezza. I believe the effect of Afrezza on Type 2 will be more dramatic compared to Type 1. In Type1, the damage is already done to the pancreas as the beta cells secrete little or no insulin. There is no "halt the progression of diabetes effect" for Type1 as compared to Type 2.

In case of Type 2, Afrezza can take the load off the Pancreas during post-meal, reduce postprandial glucose excursion dramatically, reduce gluconeogenesis (shut off the hepatic secretion of glucose), reduce oxidative stress on pancreas, and there by halt the progression of diabetes.

Both Fasting plasma glucose (FPG) and PostPrandial Blood glucose (PPG) influence HbA1C. The contribution of FPG and PPG varies depending on the A1C level. The relationship is given in this diagram.




It is clear from the diagram that at lower A1C's PPG plays a major role. Various studies have suggested that PPG is an independent risk factor for cardiovascular disease. Because impaired glucose tolerance (2-hour values of 140–199 mg/dl) and impaired fasting glucose (FBG of 100–125 mg/dl) are associated with macrovascular disease, whereas micovascular disease appears to be more related to the FPG of > 126 mg/dl,9 it is suggested that a lower glycemic threshold may exist for macrovascular disease.

Indeed, increasing evidence suggests that postprandial glucose excursions, more so than
fasting glycemia, contributes to HbA1c levels in the lower range (Diabetes Care
2003;26:881-5) and to the development of macrovascular complications via endothelial
damage (Arch. Intern. Med. 2004; 164:2090-5).

In the current treatment paradigm for Type 2, insulin comes in the end and it comes in the form of basal insulin. The basal is very poor in targeting PPG. Short acting (rapid acting analogues, NPH etc) is seldom added as this results in too many injections and the risk of Hypos also goes up. Now one can build a strong case of using inhaled insulin to handle PPG and there by better controlling A1C.

From Swedxa
There are two studies in the pipeline that you could call "superiority studies" for diabetes treatment – Study 117 and Study 142. Study 117 pits Afrezza and Lantus against Humalog/Lispro and Lantus in 230+ Type 1 diabetics. It started in May 08 and we will see results sometime this year, in time for commercialization. Study 142 will demonstrate that superior control, and even normal A1Cs, can be more readily achieved with Afrezza and a physiologically stable basal insulin.

Here is the exciting part. These tests show how Al is changing the rules of diabetes treatment. The current favored treatment measures the AVERAGE amount of glucose in the blood over time. The glucose swings that cause damage are not factored in aHbA1c reading. A healthy person has a fasting blood glucose level of 70-100 mg/dL. A diabetic may have huge swings because the pancreas does not make enough or any insulin, while they input insulin spikes occasionally to offset food intake. Those swings cause damage to the organs that threaten and shorten health and life. Since low blood glucose (hypoglycemia) is more damaging, doctors manage diabetes to keep a higher base blood glucose level with basal insulin, accepting long term damage to avoid hypos. MNKD is showing the diabetic world that it is possible to manage blood glucose at the same level a normally healthy body does. Huge change.

At the JP Morgan Healthcare Conference, Al Mann said, “You need to be below 140 at peak to avoid long term damage. Problem is, as long as you are operating that high you cannot safely bring fasting blood glucose levels to a normal level under 100. You can only do that with Afresa. Afresa is the only drug that will get you to normal levels. We want to get everyone to a normal A1c, and that will only be possible with a good basal insulin. We are doing two studies. Study 117 is in progress - taking patients on Lantus basal and comparing Afresa versus Humalog while attempting to keep blood glucose under 120. We wanted to keep blood glucose even closer to normal (100) but docs were scared of hypos even though all patients will be on continuous glucose monitors for safety. Study 117 will show superiority of Afresa in A1c or hypos, and probably both. Because we are limited by current basal insulins, we are doing Study 142. We hope to have a better basal in a few years. Until then we want to show what Afresa can do without the basal insulin."

These tests are likely to be very effective in moving the treatment of diabetes and the players in the space.


So it will be a paradigm shift for docs if Afrezza replaces basal or is used in conjunction with Basal for type 2. Mannkind certainly has its task cut out.

I did some research and came across two documents.

One is from Pfizer's Exubera and other is from a UK study. Think of Afrezza as next generation Exubera. Comparing Afrezza to Exubera is like comparing a human to a chimpanzee.

The drawbacks of Exubera (lung issues, poorer PK/PD, increase in anti-bodies, dosage issues, device issues) are completely eliminated in Afrezza. If Exubera looks good, you can bet that Afrezza will be far superior.

Nevertheless, good research has been done by Pfizer to explore this option and I recommend the readers to read this doc that I've uploaded. I'll present a few pages here. BTW, my upload mannkind ppt seems to be quite popular.








Lets see what the UK study (Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes Rury R. Holman, Kerensa I. Thorne, Andrew J. Farmer, Melanie J. Davies, Joanne F. Keenan, Sanjoy Paul, Jonathan C. Levy, for the 4-T Study Group N Engl J Med 2007, 357: 1716-30) says.

Slide 5
Trial design:

Slide 5Three-arm trial in 708 patients with type 2 diabetes from 58 UK and Irish centres
Evaluating addition of three different analogue insulin regimens to dual oral antidiabetic therapy
Open-label randomisation to:
1) Twice a day biphasic insulin (NovoMix 30)
2) Three times a day prandial insulin (NovoRapid)
3) Once a day basal insulin (Levemir) before bed, with a morning injection added if necessary

Sample Size
700 patients required to detect a 0.4% difference in achieved HbA1c, allowing for 15% loss to follow up

Outcomes at One Year
Primary
To compare HbA1c levels achieved by the three regimens
Secondary outcomes include:
Proportion with HbA1c =6.5%
Proportion with unacceptable hyperglycemia i.e. HbA1c >10% or two successive values >8.5% at or after 24 weeks
Hypoglycaemia rates
Impact on body weight
Quality of Life (EQ-5D)
Eight-point self-measured capillary glucose profiles
Proportion requiring a morning basal insulin injection




Lets see the end-result. This is beautiful. We've to extrapolate this as RAA was novorapid. Afrezza has far better PK/PD compared to RAA. There was one major problem in Prandial case. The prandial cases showed a higher hypo events. Again if Afrezza is used, this issue will be completely eliminated. Who says you can't have your cake and eat it too?



Look at how the glucose levels are lower; again if Afrezza is used, the hypos will be far less or absent.


Now comes the final piece, and this calls for some major extrapolation.
a) The PPG for afrezza will be much better as hepatic glucose is shut off; AUC for Afrezza is the best
b) Afrezza showed drop in weight or is weight neutral compared with RAA
c) Afrezza showed better hypo events (less) compared with RAA




I can't wait to see this used for Type 2's once FDA approves it. It'll be great to come back to this page and see if my understanding was right.

Monday, March 22, 2010

Afrezza and HbA1C

Well, I never planned on writing this but after reading the Analyst LeCroy's comment in Barron article, I thought I should share this.

When I read the long term A1C data from the Mannkind's website, it was a bit confusing.
Mean HbA1c was 7.97% at baseline, 7.88% at month 3, 7.79% at month 6,
7.97% at month 12, 7.87% at month 18, 8.04% at month 24, 8.06% at month 30, 7.81% at month
36, 7.40% at month 42, and 6.45% at month 48.

I was trying to understand why there was such an inconsistency in the A1C results. The overall A1C dropped over a period of time (which is a good thing), but why was it not an orderly drop. I emailed to Anders Boss of Mannkind and he in turn sent that email to CFO, and Matt had this to say
"This e-mail was forwarded to me, as it is our policy that all investor inquiries go through our investor relations department, which unfortunately only consists of me at this point.

HbA1c is affected by many factors and will change over time. It is true that at the final measurement point of the study that it was numerically inferior to the control group, at other points it was numerically superior. But neither of these things are of great import, as the differences were not considered clinically significant as predefined with the FDA."

I also posted this question to the Mannkind's private yahoo board and SilentBobSilent was kind enough to give this great reply. This reply makes the best sense.

"A1c doesn't measure blood glucose. Rather it measures hemoglobin that absorb glucose over time. These proteins reside in our red blood cells which generally live for four months. So by measuring how many of these hemoglobin proteins absorbed glucose you get an approximation of the average blood glucose level over the previous 2 to 3 months.

So why doesn't Afrezza have a greater effect on average blood glucose?

Because it only does what it should be doing: quickly lowering post prandial glucose levels and quickly disappearing from the blood. This short action does not affect the average greatly. That should really be done by the basal insulin, or the pancreas in case of early to medium type2 diabetes.

So why does RAA affect A1c so much? Because it works so poorly. First, it does NOT lower the post prandial peak since it gets in the blood too slowly, and then it stays in the blood for hours and hours, lowering the blood glucose often to dangerous levels. Unfortunately this lowers the A1c reasonably well so superficially it seems effective, but instead it is very dangerous because of
the high post prandial glucose peak, because of the hypo danger afterward, and because doctors want to manage their patients at a high A1c because of the hypo fear.

One advantage of Afrezza is that it has much lower hypo risk, so you can manage your patients at a much lower A1c if the doctor chooses to do so (that will require some time). A lot less hypo risk is important too. Convenience, weight neutral, etc... those are minor benefits.

But the main advantage is the elimination of the post prandial glucose peak. That peak is really the cause of most diabetes complications. It has been shown that it is preferrable to have a high but stable A1C over a low A1c that has high post prandial peaks.

There is not a single RAA in the world that can eliminate those peaks.

Only Afrezza can."

I also emailed the trial participant of Afrezza and asked him how his experience was.
------------------------------------------------------------
I was in the Technoshpere 2-year trial, but I am now on a pump. I am also Type 1 so I am totally dependent on delivered insulin. Primarily the TI insulin is a different method to deliver the insulin comparing it to either a syringe or a pump. I think the TI also had advantages in that it started working very quickly and it did not last as long as the fast-acting injected
insulin such as Humalog. This resulted in less extreme spikes in blood sugar levels after a meal and also a low incidence of low blood sugars.

To get to your question initially my A1c started at 6.8 and after about 3 months it was 7.2. However, this rise in A1c was entirely due to a problem getting my Basal insulin doses (injected Lantus) figured out. At 6 months my A1c went down to 6.3 after I got my Basals correct.. At the end of the trial my last A1c was 5.9. I think that the reduction of A1c levels is much more related to the motivation an individual has to achieve control of their diabetes than any
particular medication including the Technosphere Insulin. That being said I also think that the characteristics of the action of the TI can give a valuable tool to help develop this control.

I haven't kept track of the current status of TI. I have heard of Afresa, which I believe is the same medication. I would like to see it approved for sale, but I am not aware of this at this point in time.
------------------------------------------------------------


After much analysis, my thought is
IN the short term (1-2 years), the patients taking Afrezza have better glycemic control during prandial but do not have the high insulin levels (unlike patients with RAA) during fasting times. So there's a temporary reduction in A1C for RAA patients.
As time goes on, the patients in RAA are having more stressful pancreas compared to Afrezza as Afrezza is better in taking load off the Pancreas during meal time. In longer run, the patients with RAA must show more degradation of Pancreas, so type 2's will slowly become type 1's. SO I'm guessing, type 2 patients with afrezza should continue to remain Type 2 for decades

For patients using Afrezza in longer run, the pancreas is able to better function and handle the basal loads compared to RAA. And this results in reduction of A1C.

So Afrezza is really there when the body needs it and gets out of the system when body doesnt need it. So this has an indirect effect on A1C.

Sunday, March 21, 2010

FDA's CRL and the possible next steps

On Mar-15th Mannkind got a complete response letter (CRL) regarding Afrezza. Mannkind hasn't published the letter, but the press release gives us enough information to draw some conclusions.

Let us explore what this means for Mannkind. First of all, FDA is doing away with Approvable or Not approvable letters with Complete response letter. As per the FDA's regulation, this is what is contained in a CRL. The two pdf files in the above link has detailed descriptions of the CRL.

Complete Response Letter
• States that FDA will not approve NDA or ANDA in its present form.
• Describes all specific deficiencies that FDA has identified in the application
(except when the agency determines that data submitted
are inadequate to support approval and issues a complete response
letter without first conducting required inspection and/or reviewing labeling).
Deficiencies could be minor (e.g., requiring labeling
changes) or major (e.g., requiring additional clinical trials).
• Reflects complete review of data in NDA or ANDA and any amendments
FDA has reviewed.
• When possible, recommends actions applicant might take to place
application in condition for approval.

The Mannkind's PR specifically states

The Complete Response letter related to the AFREZZA application requested several items, including information and currently available clinical data that support the clinical utility of AFREZZA and information about the comparability of the commercial version of the MedTone inhaler to the earlier version of this device that was used in pivotal clinical trials. The letter cited no safety concerns, but requested updated safety data related to AFREZZA. The letter also requested changes to the proposed labeling of the cartridges, foil pouches and cartons.

The letter did not require any additional pre-marketing clinical studies in order for the FDA to complete its review of the NDA. As recommended by the FDA, MannKind will request an End-of-Review meeting with the agency to discuss its approach for resolving the remaining issues.

What are the next steps?

We can go for Class I resubmission, Class 2 resubmission and Supplemental filing. Mannkind's original plan was to file for supplemental NDA for dreamboat after the approval of original NDA.
A class 1 resubmission of an NDA starts a new 2-month review cycle. The class 2 starts a new 6 month cycle.

Can Afrezza use the class I submission? I certainly think so.

This is what FDA says
Proposed § 314.3(b) would have defined ‘‘Class 1 resubmission’’ as the resubmission of an application, following receipt of a complete response letter, that contains final printed labeling, draft labeling, certain safety updates, stability updates to support provisional or final dating periods, commitments to perform Phase 4 studies (including proposals for such studies), assay validation data, final release testing on the last lots used to support approval, minor reanalyses of previously submitted data, and other comparatively minor information.

Class 2 resubmission means the
resubmission of an application or efficacy supplement, following receipt of a complete response letter, that includes any item not specified in the definition of ‘‘Class 1 resubmission,’’ including any item that would require presentation to an advisory committee.

One can make a stronger case for Afrezza's Class I resubmission compared to Class 2.

Here is my case. (click on the diagram to enlarge it)


Class 2 also calls for new trials. The Mannkind management also stated in their CRL meeting that FDA is not planning on sending Afrezza to advisory committee. FDA hasn't asked for new trials either.

The amendment also looks like a valid option as Mannkind is not planning on selling Medtone Inhaler version. The dreamboat is cheaper to make and has better bio-availability. Here Mannkind will submit all their Dreamboat bio-equivalency data (the data will be ready by Q2-'10) and potentially get the approval within 6 months. This adds some uncertainty to the partnerships though. At the moment either option doesn't seem to derail the Mannkind's timetable of selling Afrezza starting Q1 of 2011.

The fda/shorts conspiracy theories not withstanding, the CRL may prove to be a minor bump in the long road of giving Diabetics a much needed alternative to injections (prandial insulin)

Sunday, March 7, 2010

Killing two birds with one Inhaler

First bird: mimic the endogenous secretion of insulin

I read a couple of articles that highlight the fact that first-phase insulin secretion is very important and the absence of this leads to the progression of diabetes.

The following three articles talk about the importance of first-phase insulin secretion. Afrezza mimics the endogenous secretion of insulin. This is the first bird we kill.





From Link:
A reduced early insulin response to glucose ingestion is quite a common defect in type 2 diabetes, and this abnormality can be a contributing factor in the development and progression of the disease. In fact, in patients with impaired glucose tolerance or in the early stages of type 2 diabetes, the impairment of the early insulin response contributes to postprandial hyperglycemia. This maintains the beta-cell under a condition of prolonged stimulation, which eventually leads to late-phase hyperinsulinemia. Chronic postprandial hyperglycemia and hyperinsulinemia have detrimental effects on the glucose-insulin system. Chronic hyperglycemia is capable, through the mechanism of glucotoxicity (99), of further worsening beta-cell secretion. Chronic hyperinsulinemia may lead to beta-cell exhaustion, may cause downregulation of the insulin receptor thus increasing insulin resistance (32), and may produce the well-known negative consequences on the vascular endothelium (106, 111). This vicious cycle plays a significant role in the pathogenesis and evolution of type 2 diabetes [as thoroughly examined in some recent surveys (34, 59, 97)]. Thus interventions to restore the early insulin surge should contribute to improving glucose tolerance in type 2 diabetic patients. In a study by Bruce et al. (16), type 2 diabetic patients received an identical dose of insulin in three different regimens at mealtime: insulin administered intravenously over 30 min at the beginning of a meal in such a way as to mimic a normal early insulin response, with the same profile but delayed by 30 min, and as a constant infusion over 60 min. The best result in terms of postprandial glucose tolerance was obtained with the early administration of insulin, in keeping with the proposed direct effect of the early insulin response on hepatic glucose production. The beneficial effect of a short intravenous insulin infusion mimicking the early insulin response in type 2 diabetic patients has been subsequently confirmed by Luzio et al. (69).

Because intravenous infusions aimed at achieving an early and adequate supply of insulin are clearly impractical, simpler alternatives, applicable to everyday life, have been devised to correct a defective early insulin response in diabetic patients whose disease is inadequately controlled by diet and exercise. One is the subcutaneous administration of fast-acting insulin analogs; another is the use of pharmacological agents (such as repaglinide, nateglinide, and similar compounds) that exert a preferential stimulation of the early insulin secretion in those patients still having a residual -cell function. Such therapeutic approaches have been shown to be effective in reducing postprandial glucose and insulin excursions in type 2 diabetic patients, as illustrated in recent review papers by Del Prato and colleagues (34, 36).


The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus
Stefano Del Prato 1 *, Antonio Tiengo 2


Abstract

Type 2 diabetes is a heterogeneous disorder characterized by defects in insulin secretion and action. Insulin resistance is a key feature of type 2 diabetes. However, insulin resistance alone does not appear to be sufficient to cause diabetes. Longitudinal studies have shown that the development of overt hyperglycemia is associated with a decline in -cell secretion. In patients with impaired glucose tolerance or in the early stages of type 2 diabetes, first-phase insulin release is almost invariably lost despite the enhancement of second-phase secretion. Both animal and human studies support the critical physiologic role of the first-phase of insulin secretion in the maintenance of postmeal glucose homeostasis. This effect is primarily mediated at the level of the liver, allowing prompt inhibition of endogenous glucose production (EGP) and thereby restraining the mealtime rise in plasma glucose. In type 2 diabetes, the loss of the early surge of insulin release is a precocious and quite common defect that plays a pathogenic role in postmeal hyperglycemia and one that may require specific therapeutic intervention. This becomes even more apparent if the negative impact of prandial glucose spikes is taken into consideration. Epidemiological evidence exists to indicate that 2-h postload plasma glucose levels are strongly associated with all-cause and cardiovascular mortality relative risk. Indeed the acute elevation of plasma glucose concentration triggers an array of tissue responses that may contribute to the development of diabetic complications. Considering that type 2 diabetes begins with meal-related hyperglycemia in many patients, it becomes apparent that normalization of postmeal plasma glucose levels should be the target for rational therapy and the goal in the early stages of the disease. If a primary goal of diabetes therapy is control of postmeal glucose excursion, then the regulation of glucose absorption from the gut and entry into the circulation is an important mechanism to consider. The restoration of the rapid increase in plasma insulin concentration may be quite an efficient therapeutic approach. Copyright © 2001 John Wiley & Sons, Ltd.


Significance of an Abnormal First-Phase Insulin Response

It is well recognized that diminished first-phase insulin secretion is an early marker of beta-cell dysfunction, appearing long before significant changes in absolute glucose concentrations are apparent. Studies of human subjects with impaired glucose tolerance (IGT) demonstrate multiple abnormalities in both qualitative and quantitative measures of insulin secretion. Among them, first-phase insulin secretion is already markedly reduced.[1] Prandial insulin release after an oral glucose load or mixed meal is delayed as well, permitting the elevated postprandial glucose concentrations that are characteristic of these individuals, despite relatively normal fasting glucose levels.[2]

Further evidence that abnormal first-phase insulin secretion is an early event in the deterioration of beta-cell function is seen in women with a history of gestational diabetes but with normal postpregnancy glucose tolerance. These women, who are at very high risk for the future development of diabetes, exhibit a diminished first-phase insulin response to both oral and intravenous glucose, while other markers of beta-cell function appear normal.[3] Subjects with completely normal glucose tolerance who are relatives of type 2 diabetic patients are also found to have lower early-phase beta-cell responses to oral glucose.

First-phase insulin responses have been examined in individuals across a broad range of glucose tolerance and are shown to correlate inversely with glucose tolerance status. Often expressed in relationship to the insulin sensitivity measured in each individual, this normalized measure of insulin secretion has been utilized in multiple populations as the principal predictor of future development of type 2 diabetes.[6,7] Early insulin secretion quantified during oral glucose tolerance testing has also been shown to inversely correlate with the 2-hour glucose excursion.[8] During the second hour of an oral glucose tolerance test, glucose and insulin are highly correlated, suggesting that the failure of early insulin secretion to suppress the glycemic excursion begets late postprandial hyperinsulinemia, the augmented second phase of insulin secretion typical of type 2 diabetes.

The postprandial hyperglycemia that results from impaired first-phase insulin secretion is not accounted for solely by an insufficient insulin concentration, however. Both animal and human studies suggest that intact early insulin secretion is critical to restraining hepatic gluconeogenesis and that the increased postprandial endogenous glucose production characteristic of the diabetic state contributes significantly to the glycemic excursion.[8-10]

Finally, experimental manipulation of the timing of insulin delivery lends further support to the importance of intact first-phase insulin secretion in maintaining normal glucose tolerance. When type 2 diabetic subjects were administered identical amounts of insulin at mealtime within 30 minutes of the meal to mimic first-phase insulin secretion, or during the second 30 minutes after the meal, or as a constant infusion, only the insulin delivery that mimicked first-phase insulin secretion resulted in improved glucose tolerance and reduced subsequent endogenous insulin secretion. The postprandial elevations in glucagon and free fatty acids characteristic of type 2 diabetes were also significantly reduced.[11] Similar results are seen when lispro insulin is substituted for regular insulin. Mimicking early insulin release with lispro also more promptly suppressed endogenous glucose production.[12]



The second bird: Early intervention.

The value of early intervention is also discussed here. Afrezza reduces the barriers to insulin without the negative effects (hypos, injections etc)

The importance of initiating insulin earlier is explained in this Pfizer powerpoint given to FDA

Some of the barriers to Insulin Use are
Patient resistance: compliance issues, fears of scarring, difficulties in administration, pain, etc
Physician resistance: lack of resources, time to plan/follow intensive regimen
Perceived and real adverse effects: Weight gain, hypoglycemia
Optimal glycemic control requires multiple daily injections
Injected Insulin still only viable route of administration

The diabetes train crash in slow motion:

What is happening in today's world? The patient tries the Oral anti diabetic therapies (metformin, glyburide, actos, Januvia), and as Diabetes progresses, they become Insulin dependent Type 2. The vicious cycle explained above already sets in. Diabetics are given Basal insulin and no attention is paid on the first insulin response. As time goes by, the beta cell function deteriorates. Slowly but surely Type 2 becomes Type 1.







By using Afrezza earlier, the diabetics get insulin early thereby avoiding injections and hypos. No wonder, Al Mann made a bold assertion that Afrezza can stop the progression of diabetes.


Tuesday, March 2, 2010

BOSPENC's 4 part

PART 1

MannKind to Present at the 28th Annual J.P. Morgan Healthcare Conference This event is the premier conference of its kind, bringing together established industry leaders, emerging fast-growth companies, innovative technology creators and globally minded Service providers. This year they expect more than 300 companies, both public and private, to deliver presentations to more than 3,500 investors. The format is 30 minute presentations followed by 30 minute Q&A sessions in a separate room.
Jan 5, 2010 http://www.news.mannkindcorp.com/phoenix...

Alfred E. Mann - A Mann of His Word
2009 http://davidovit.com/articles/Al-Mann-Ar...

Rodman & Renshaw Maintains Positive Stance On MannKind's (MNKD) Afresa
Jan 6, 2010 - http://www.streetinsider.com/Analyst+Com...

MannKind Expects U.S. FDA to Approve Inhaled Insulin
Jan 6, 2010 http://www.bloomberg.com/apps/news?pid=2...

MannKind prepares for FDA ruling on insulin device
Jan 5, 2010 http://www.reuters.com/article/idCNN0511...

The Truth about Afresa Inhalable Insulin: A Chat with Al Mann
Nov 17, 2009 http://www.diabetesmine.com/2009/11/the-...

MannKind's CFO Pfeffer Upbeat on Afresa's Future: NOV 2009
Dec 31, 2009 http://afresa.blogspot.com/2009/12/mannkinds-cfo-pfeffer-upbeat-on-afresas.html



Top Picks for 2010: MannKind (MNKD)
Jan 5, 2010 http://www.bloggingstocks.com/2010/01/05...

MannKind Seeks To Ease Concerns About Afresa Approval
http://online.wsj.com/article/BT-CO-2009...

MannKind Corporation Q3 2009 Earnings Call Transcript
Nov 20, 2009 http://seekingalpha.com/article/170681-m...

Rodman & Renshaw reiterates 12-month price target of $18
Oct 6, 2009 https://rodman.bluematrix.com/docs/pdf/R...

#277 Al Mann - Forbes Billionaire List
Pacesetter Systems (SOLD) - MiniMed(SOLD) - Advanced Bionics(SOLD) - Second Sight (Private) Quallion, LLC (Private)
Sep 30, 2009 http://www.forbes.com/lists/2009/54/rich...

An insulin inhaler that does away with needles
Oct 14, 2009 http://www.smartplanet.com/business/blog...

MannKind buys Pfizer’s insulin for $33M
Mar 9, 2009 http://uk.biz.yahoo.com/09032009/323/upd...

Afresa: A New Insulin (By the Way, It's Inhaled)
Oct 5, 2009 http://www.diabeteshealth.com/read/2009/...

Technosphere insulin offers a significant advance from previous delivery methods
Sep 2, 2009 http://www.liebertonline.com/doi/pdf/10....

FDA to consider small inhaler for diabetes patients – MedCity Morning Read, Oct. 12, 2009
Oct 12, 2009 http://www.medcitynews.com/index.php/200...

FDA Considers New Insulin Inhaler
Oct 12, 2009 http://abcnews.go.com/Health/Healthday/h...


Part 2

A New Way to Inhale, Not Inject, Insulin
http://www.nytimes.com/2009/10/11/busine...

Will FDA Approve MannKind's Insulin Inhaler?
Oct 9, 2009 http://industry.bnet.com/pharma/10004709...

The Scoop on MannKind's Afresa Partnership Delay
Oct 11, 2009 http://industry.bnet.com/pharma/10004734...

Al Mann/Mike Huckman - Giant Leap for Mannkind (ADA - New Orleans)
2009 http://www.bing.com/videos/watch/video/g...

MannKind Bulls, Bears Face off in Wake of Afresa Partner Delay
Oct 8, 2009
http://www.bioworld.com/servlet/com.accu...

Study Shows AFRESA® Provides Rapid Suppression of Endogenous Glucose Production in Diabetes Patients
Sep 30, 2009 http://www.medicalnewstoday.com/articles...

AFRESA® Phase 3 Data Show Sustained Glycemic Control, Normal Lung Function in Patients over Four Years of Treatment
Oct 2, 2009 http://www.drugs.com/clinical_trials/afr...

MannKind says no Afresa partnership in 2009
Oct 6, 2009 http://www.thestreet.com/story/10607817/...

BUYINS.NET Issues Short Sale Report On MannKind
Oct 8, 2009 http://finance.yahoo.com/news/BUYINSNET-...

Rumor that Merck is interested in $666 million (market cap) therapeutics MannKind
Oct 12, 2009 http://blogs.barrons.com/stockstowatchto...

MannKind Corporation F1Q09 Earnings Call Transcript
May 04, 2009 http://seekingalpha.com/article/135180-m...

Von Liebig Forum: Alfred Mann (Get inside Al’s Head)
http://www.youtube.com/watch?v=HML_bmwlH...

Mann's Inhaled Insulin Passes Big Test
Sep16, 2008 http://www.medgadget.com/archives/2008/0...

Part 1: Inhaled Insulin, the wave of the future
Jun 8, 2008 http://seekingalpha.com/article/80475-ma...

Part 2: Pfizer's cancer announcement and its irrelevance to Mannkind's future
Jun 11, 2008 http://seekingalpha.com/article/80843-ma...

Part 3: Pfizer fails with Exubera, Mannkind forges on with Technosphere Insulin; Why they're different
Jun 13, 2008 http://seekingalpha.com/article/81190-ma...

Part 4: Mannkind's partnership opportunities for Technosphere Insulin
Jun 17, 2009 http://seekingalpha.com/article/81604-ma...

Part 5: Mannkind's pipeline potential
Jun 19, 2008 http://seekingalpha.com/article/81899-ma...

Part 6: Conclusion - Summary, vaulation, and risks
Jun 22, 2008 http://seekingalpha.com/article/82180-ma...

Hapoalim Securities Continues To Expect No Approval for MannKind's (MNKD) Afresa
Jan 5, 2010 http://www.streetinsider.com/Analyst+Com...


PART 3

Afresa could be the most valuable medical product of all time. -Alfred Mann

Lung cancer: 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

Advisory panel: I don’t understand the basis for some of the people having a negative interpretation regarding the FDA’s decision not to call an advisory panel for AFRESA. Some time ago we were told in a telephone conversation with the agency that the FDA did not believe there was any question about AFRESA that would justify an advisory panel. Because the agency could later decide on a meeting we didn’t share that comment. However, now that it is official we can say that the FDA is not calling the panel meeting for AFRESA and that is certainly not a negative thing. That should be interpreted as a very positive factor. We continue to have interaction directly with the agency on various subjects regarding AFRESA. So far there have been no difficult questions and we are pleased with the depth of the FDA’s review and evaluation. While we were sort of looking forward to and preparing for the advisory panel, we are sort of relieved we don’t have to do it. -Alfred Mann

FDA approval: Some analysts have questioned whether the FDA would approve, when the FDA would approve AFRESA or even asked if they would approve it. The agency is data driven and they understand diabetes and glucose control. It seems to me that the enormous body of the data in the NDA presents a very convincing argument for approval of AFRESA. I cannot imagine on what bases there would be any doubt about approval. After all, it is regular human insulin and its kinetics mimic normal prandial physiology and part better than any other glucose lowering effect, our [Inaudible 24.34] and even the FDA noted that and we have seen no safety signals. The present med is primary pivotal starting the study target of non-inferiority to rapid analogs, today's goal standard and had showed superiority in many key areas. So, what would be the basis for not approving AFRESA? Indeed, I am personally confident of approval. -Alfred Mann

PDUFA date: We are certainly very pleased with our progress and are looking forward to the PDUFA date and we have no reason to believe that the FDA will not meet that date. They are certainly working diligently towards that goal. The more we see of AFRESA the happier we are and the more convinced we are that it will be a very significant product. -Alfred Mann

We have enough cash in the bank to last us until well into the first quarter of 2011, so there is no panic. -Alfred Mann

"I expect to make ten to one hundred times return on my investment in startup companies." - Alfred Mann

“Afresa could be the most valuable medical product of all time." - Alfred Mann

"We have enough cash in the bank to last us until well into the first quarter of 2011, so there is no panic," - Alfred Mann

"We want to get the right deal done at the right price." - Alfred Mann

The more we learn about AFRESA the more we see that this is not just a cranial insulin, but rather a diabetes drug therapy for all phases and all types of diabetes.
- Alfred Mann


PART 4

AFRESA - HIGHLIGHTS AND SAFETY
* First-in-class: ultra acting insulin for diabetes treatment
* Closely mimics the normal pattern of post-meal insulin secretion in healthy individuals
* Addresses significant market opportunity
* Demonstrated safety and efficacy
* Pivotal Phase 3 studies met endpoints
* NDA filed and accepted; January 16, 2010 PDUFA
* Strong financial position – funded into 2011
* Safety of AFRESA has been extensively studied
* AFRESA is well tolerated
* Most common adverse events were cough and hypoglycemia
* NO-clinically significant changes in pulmonary function
* No increased cardiovascular rick
* No increased cancer rick observed
* Significant reduction in the risk of mild, moderate and severe hypoglycemia compared with sc insulin’s

AFRESA’s unique pharmacokinetic profile results is:
* Consistent improvement in HbA1c reductions, as good as best current insulin therapies
* No adverse effects on pulmonary function
* Marked benefits for patients:
- Hypoglycemia
- Fasting blood glucose control
- Weight loss
- Postprandial glycemic control

Rationale for Pulmonary Route

From
Inhaled Insulin: Promises and Concerns
Jean-Louis Sélam, M.D

The pulmonary route is the only route that can absorb
enough insulin with the best bioavailability without
promoters. Table 1 gives an overview of alternative routes
that avoid injections with the percentage of bioavailability,
which is the major obstacle. Promoters make membranes
more permeable, although they are always toxic and, like
other surfactants, are tolerated very poorly. Because of
its huge surface, which is almost the surface of a tennis
court, the pulmonary route is thus the only route that
does not need a surfactant or promoter to be effective
enough. However, the real problem is getting the insulin
particles down to the alveoli. Usually with most of the
inhaler devices, insulin particles stop, either in the mouth
or in the bronchial system. To get down to the deep lung,
it is necessary to have a special, very precise diameter of
each particle, which is why it was so difficult to design a
good device for an inhaler.