CRT research update

 

Buy rating on stock with target price of $12.00

NDA Filing Has Been Deemed Complete by FDA; PDUFA Date is December 29TH
Uncertainty Reduced; We Continue to Anticipate Approval of AFFREZZA™

Regulatory Pathway Clear. MannKind has received notice that the FDA has accepted its supplemental filing for
approval of AFFREZA™ with the FDA setting a six-month PDUFA date of December 29, 2010, quelling the speculation that the FDA would require a formal resubmission of the NDA and set a 10-month review of that filing.

Near-term Upside Expected. We believe the 3.75% Senior Convertible Notes and Common Shares are poised for near term gains, recovering much of the securities’ lost ground which occurred after the FDA delayed action on the January 16th PDUFA date (converts then trading at 82% of par; shares then trading at $11.12). Yesterday’s closing prices were 58% of par and $6.21. MNKD later received a Complete Response Letter on March 12, 2010 which required additional information regarding MNKD’s most advanced inhaler and the “utility” of AFREZZA™. MNKD submitted clinical data, apparently on June 29th, from a recently completed TYPE 1 efficacy study, updated its pooled safety data and submitted comparability data regarding the next-generation inhaler system. The FDA has deemed the supplemental data to be sufficient for a complete filing, leading to today’s announcement.

Financial Resources in Place to Fund into 2011. The unsecured Founder Loan is sufficient, in our view, to fund
operating needs for at least a year, eliminating the near-term need for a dilutive capital raise. MNKD had utilized approximately $205 million as of the end of Q1 2010 under its $350 million unsecured line of credit provided by its Founder and Chairman, Al Mann (who also owns approximately 40% of the Company’s Common Stock). We believe the remaining availability under this line of credit plus the cash on hand at March 31, 2010 million) is sufficient to fund MNKD’s needs through the approval date. We estimated quarterly cash needs without partnering to approximate $40-to-$50 million per quarter during 2010.

AFREZZA™ remains unpartnered. We believe that the Company continues to be in discussions with prospective partners. We believe AFREZZA™ is partner-able and should be partnered worldwide.
We continue to anticipate approval of AFREZZA™ for the treatment of TYPE 1 and TYPE 2 diabetes by year end with a launch by the end of Q1 2011. We continue to believe MannKind’s AFREZZA™ will be approved by the FDA – and enter the market as the best inhaled insulin amongst a sea of previous competitor disappointments. While we acknowledge the Street’s anxieties and scrutiny of AFREZZA™, we continue to believe that the level of dta provided in the Company’s NDA is impressive – and speak to AFREZZA™’s efficacy and safety (with data from more than five years of study). We focus investors back to our previous research notes in which we hypothesize that AFREZZA™ may ultimately prove to be even ‘better’ than available short-acting injectable insulin products.

At the end of the day, we again focus on the data, not the hype – as will the FDA.

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The research projects Afrezza sales for Type 2 increasing from $15 million by end of 2011 to 1.113 Billion by end of 2016. For type 1, it is from 5 to 397 million for the same time period.

The report further states

We set a six-month price target of $12 today. This is based on a 4.0 times multiple of five year forward worldwide sales, discounted back over 5.5 years at 25%. We assume that the Founder’s Loan is fully drawn at $350 million. Our model assumes 118 million diluted shares (post option conversion) to be outstanding in six months. We believe that a multiple of sales is an appropriate valuation methodology. Assigning a four times multiple is relatively conservative, in our view, as we believe that sales will continue to ramp in outer years, and the product could be outright sale-able to large pharma at multiples in excess of four times. Clearly, there remains some risk to FDA approval. With a 25% discount rate, we believe we’ve appropriately discounted for both approval risk and launch risk. We continue to believe that MNKD should partner AFREZZA™ having never launched (within this corporate structure) a new drug, yet recognizing the business acumen of founder, Al Mann.

Resubmission, Production & Partnership

 

These are exciting times for Mannkind and its shareholders. With dreamboat bio-equivalency and resubmission done successfully, Mannkind’s management can focus on partnership & preparation for commercialization. They seem to be doing it in full swing. In the past they were a bit carried away by the enthusiasm. Now they seem to be very tight lipped. There was no news till a day or two back on the FDA submission. It caught many by surprise.

Partnership:

This partnership dance has been going on for a long time. The Pfizer cancer scare and pull out of competitors muddied the waters. Now things are getting clearer. Now is the time. Al Mann sure realizes that he can’t wait any longer. A partnership before year end will give them sufficient time to prepare for commercial launch. It’ll also avoid dilution at the current price.

More trials   

   Now is the time to play offense. The following trials should help them claim superiority.

   Study 163 in pump patients

    The pumps deliver a continuous basal insulin and this is another of Al Mann’s invention. A pump user can achieve a better fasting plasma glucose. The use of pump still doesn’t provide control of postprandial glucose excursions. This is where Afrezza comes in. Al Mann has stated in this article that the benefits of Afrezza doesn't manifest well in patients having above normal fpg. Now in this trial, with patients having better fpg, the use of Afrezza will result in better PPG (ie less excursions) and better A1C compared to the pump user taking RAA (like Humalog). This trial should show case the superiority of Afrezza.

This trial is more like the experiment that involved observing the moon’s eclipse to   prove that the Einstein’s theory of relativity is correct. 

 

 

   Studies 161 with Lantus background for Type 1 and 162 for Type2.

     The details are lacking, The clinicaltrials.gov and Mannkind website are not showing these studies.

Production capacity  (from Griffin report)

Mannkind expects to receive the first commercial-capacity production line in early August. That should give the Company sufficient time to have the line validated by the FDA for a commercial launch in early 2011. The equipment, which will have the capacity to produce 400 insulin cartridges per minute, will be installed in the Company’s Danbury, Connecticut plant. That facility has sufficient space to produce 2 billion cartridges per year, or enough Afrezza for about 1 million diabetic patients. Expanding the plant’s capacity will be achieved with another 400 cartridge-per-minute line, followed by production lines capable of turning out 600 cartridges per minute. We believe the facility will be used to supply the domestic market primarily and that Mannkind will ship its specially formulated insulin in bulk to contract manufacturers in other markets for filling and finishing. Indeed, discussions have already begun with such companies in six countries for local production. This strategy makes sense, since it would minimize Mannkind’s capital requirements and the cost of shipping Afrezza overseas.

Closing remarks

 

Now, I feel like Forrest Gump in Shrimp boat waiting for the big haul. I’ve bought my  boat, got my captain, put in my prayers and all I need is some shrimp. Shrimp is the fruit of the sea....You can barbecue it, boil it, broil it, bake it, sauté it....There's shrimp kabobs, shrimp creole, shrimp gumbo, pan fried, deep fried, stir fried, pineapple shrimp, lemon shrimp, coconut shrimp, pepper shrimp, shrimp soup, shrimp stew, shrimp salad, shrimp and potatoes, shrimp burger and a shrimp sandwich.

Comments from Griffin, Rodman&Renshaw – July 20th 2010

 

Rodman comments

“A rare, on time/earlier-than-expected, surprise: CRL response sent, accepted by FDA, new PDUFA set “. Market Outperform; Target Price: $18.00

MNKD submits CRL response on time (actually just a bit earlier than the “sometime in July” guidance), surprising even its supporters, FDA accepts the resubmission, and sets December 29th PDUFA: MannKind issued a press release this morning announcing that 1) it has submitted its response to the FDA’s Complete Response letter, and that the agency 2) has accepted the company’s resubmission, 3) has classified MannKind’s response as a class 2 resubmission, and 4) has set a new PDUFA date of December 29th, 2010.

Our take on the news: Even though acceptance of a resubmission means very little (actually nothing) in terms of an application’s chances of being approved, we see today’s news as an incremental positive for MNKD in that it disarms yet another prevalent bear theory: given that the company was able to submit its response to the FDA in a matter of 2-3 weeks after meeting with the agency (meeting with the FDA was announced June 10th and the December 29th, 2010 PDUFA roughly points to a June 29th, 2010 resubmission date), the bear theory that the agency may have requested new, longer trials seems to lose even more ground. In addition (and granted that this may be little consolation to long-term MNKD followers that have been dealing with a number of significant timeline delays, especially in the past 2 years), it is good to see the company meet and actually deliver earlier than expected for a change on a guided timeline. Recall that the CRL was received on March 15th, and so we view that having the company’s response back to the FDA in three and a half months was an efficient turnaround.

Absolutely no change to our long-term thesis: We continue to expect that Afrezza will be approved, partnered and in the market. With the FDA back and forth now done (at least for this round), the next most significant milestone is the agency’s decision on the resubmission by the end of the year. In addition, we expect that the company will re-engage in partnership discussions and we continue to believe that it will be successful in finding a partner for Afrezza, especially with the re-submission process completed without the requirement for additional trials. We are not sure whether a partnership will be consummated by PDUFA, or whether partners may want to wait for approval, but we view the importance of the timing of a partnership as secondary; we believe that the most important questions for investors are whether Afrezza gets approved or not, and whether it gets partnered or not….and we remain bullish on the outcome of both.

We reiterate our Market Outperform rating and 12-month PT of $18/share on MNKD. We reiterate our thesis that A) Afrezza should NOT be bundled together with Exubera et al. as just another inhalable insulin, but that it is a “better” insulin, that just happens to be delivered via inhalation, B) we believe that Afrezza will be approved by the FDA and will get to the market, C) the company will be able to secure a worldwide partnership for Afrezza, and that D) it is a product that in the long-run, has the potential to become a multi-billion dollar product. We reach our 12-month PT of $18 by using a 30x P/E multiple of our fully diluted 2013 EPS (the company’s second year of profitability) and discounting back using a 25% discount rate.

Griffin

Griffin has a very detailed report, i’ll prepare one later. here is the brief

• FDA accepts amended NDA for Afrezza™ and sets PDUFA date of December 29th.
• Securing a global marketing partner is now a high priority.
• Receipt of the first commercial production line is expected in early August.
• Clinical trials are planned to support the marketing program.
• We reiterate our BUY recommendation and our target price of $26 per share.

PDUFA Date announced; Leerink comments

 

Today Mannkind has announced that FDA has accepted the response to CRL. The resubmission will be Class 2 and the new PDUFA date is set to Dec 29th of 2010. Now nothing should stop Mannkind from signing a partner. I hope to expect a partner in the next 1-2 months.

Meanwhile Leerink is coming a full circle with its latest report.

The snap shot of the report is as given here.

Bottom Line: We met with MNKD management today to discuss the current outlook for Afrezza. Progress is being made on the regulatory front for Afrezza and we expect a resubmission of the NDA will occur in 2H10. Overall, we believe that Afrezza is an approvable drug in the long term but visibility on timing of approval and the ability to find a partner to successfully commercialize the drug is poor.        

• Refiling Should Occur Soon: MNKD expects minutes from its FDA meeting on 6/9/10 imminently and should be in a position to file shortly thereafter with the incremental 117 study data that might help address lingering FDA questions.

• Dreamboat Device to Be Part of Amended NDA: The company intends to file an amended NDA which will include the second generation inhalation device ("Dreamboat"). This strategy will allow the company to save some time because it will not have to wait six months for a sNDA approval of the Dreamboat device.

• Additional Trials for Marketing Purposes Expected: MNKD intends to start two trials in Type 1 diabetics (Study 161 with Lantus background, Study 163 in pump patients) and another study in Type 2 diabetics (Study 162 versus Lantus) to help position the drug in the marketplace. The new trials will utilize the Dreamboat device which will bolster the available bioequivalence data between the first generation Medtone device and the Dreamboat device. It is unclear to us whether the Pulmonary Division will require these additional safety data for the Dreamboat device; such a requirement would further delay approval.

• U.S. Launch Expected in Mid-2011: MNKD noted that it wants to have sufficient manufacturing capacity to support a launch. The company currently has a machine which can generate 400 cartridges/minute for the Dreamboat device but would prefer to have two or three machines set up by the time of launch.

• How Much Profit Can Potential Partner Expect? MNKD estimates that 2.5x the insulin is required to achieve the same insulin AUC as injected insulin, although presented data compare 60-90IU Afrezza versus 10IU s.c. insulin. This estimate, a royalty owed to MNKD and the need to support a primary care salesforce suggest profitability of Afrezza to a commercial partner may be somewhat challenging.

Reviewing the Nice UK’s Exubera recommendation – part 1

 

I came across this NICE (National Institute for Health & clinical excellence) analysis of Exubera. NICE is an independent organization responsible for providing national guidance on promoting good health and preventing and treating ill health. UK has a socialized medical system. If NICE says no, the UK government will not pay for the medical costs. Their analysis has been very detailed and the main link is here. This is a treasure trove of information and I recommend serious Mannkind shareholders to take a look at this. The reason why this is important is, the yardstick used for measuring Exubera will be used for Mannkind as well. NICE UK came to the similar conclusion as their German counterpart.

I seriously think that the Exubera’s failure will pave the way for Mannkind Afrezza’s success. Historically speaking, this is like the tragedy of Apollo 1 that paved the way for the success of other Apollo launches. Any keen reader of history can notice this pattern repeated again and again.

There are thousands of pages of information and I’ll try to synthesize come up with a few articles. In a nut shell, Stephanie Amiels (posted under Expert comment) best summarizes it

1. Inhaled insulin is no better than currently available injectable short acting insulins and lacks the fast run off of the fast acting analogues, so the only advantage is the avoidance of injections. It does not replace basal insulin requirements.

2. Refusal to take insulin is usually more complex than just fear of needles per se, although there are undoubtedly many people who would prefer to avoid them if possible

3. Diagnosing that poor glycaemic control is due to insulin avoidance simply because of fear of needles is not easily done in routine diabetes clinic visits.

4. As always with a new drug, there are no long term safety data (in particular with regard to lung) and the drug is much more expensive than the currently available equally effective option.

5. Pre-prandial insulin dosing requires pre-prandial home blood glucose monitoring, for safety and to achieve rapid dose titration to establish optimal control

6. In Type 1 patients, the inflexibility of dose of the present version of inhaled (Exubera) and the potential for a large antibody response makes the insulin unattractive from a purely biomedical perspective

7. In the Type 2 patients, our current recommendation when first starting insulin therapy is adding bedtime NPH insulin (or one of the peakless analogues if there are problems with NPH) to oral agents – one injection a day, minimal risk of hypoglycaemia and minimal weight gain compared to other regimens, with comparable benefits in control. Intensifying insulin therapy may then require pre-prandial dosing.

8. If the patient is refusing insulin because of fear of injections, giving insulin without injection should produce a very major improvement in control.

9. We have, as far as I am aware, no data showing either that inhaled is more patient acceptable than bedtime only insulin in Type 2 or that it results in more patients with Type 2 starting insulin and achieving tight control earlier and more effectively when there are no other confounders. We don’t even have a comparison of patient acceptability between inhaled and pen injections!

The following section is a must read for those who say patients do not care about injections.

    From “Table of Comments from the web site on the second ACD”

#	Comment	Response from NICE-UK
1	I am a 48 year old type 2 diabetic my daughter is 11 and a type1 diabetic, I was diagnosed when she was born and she was diagnosed 2 years ago we are both injecting 4 times per day. My stomach and bottom are covered in bruises and my bottom also, I am quite thin. My daughter will only inject in her bottom, having originally only allowed us to inject in her thin thighs. Her bottom is a mass of bruises and often painful. She is a bright well mannered young girl and will shortly be going to senior school, she is traumatised by the fact that her best friend who helps her with prick tests and injections is going to a different school and she will not be with her to support. How much easier it would be if she could inhale, sadly we are both mentally stable-what nonsense. Neither myself or my daughter became diabetic as a result of obesity; a tag I fear is too often associated with our disease. To restrict the freedom to enjoy life to the full for a young girl is not fair, inhaling insulin will give her so much more freedom and a lot less pain, discomfort and embarrassment. If the people making this decision had seen their daughter wince and scream on a regular basis then they might think differently. I make sure my daughter does not see my stomach as I am trying to convince her to take her rapid insulin in her stomach as it is more effective-but I can’t let her see my bruises.	The guidance states that people with severe and persistent problems with injection sites (for example, as a consequence of lipohypertrophy) despite educational support and injection site rotation will be eligible to receive inhaled insulin.
2	Regarding 2.7, please consider people who have been enduring injecting regimes for almost forty years. Not only it is painful; it restricts lifestyle (eg, travelling and the humiliation of the airport search and explaining the purpose of syringes); and the humiliation of injecting in public places.	Although individual choice is important for the NHS and its users, they should not have the consequence of promoting the use of interventions that are not clinically and/or cost effective”
3	My argument is that long-suffering diabetics should be given the opportunity to use inhaled insulin. The Committee is concerned about longterm safety; however people who have endured injections for almost forty years did not know the long-term safety of their injections when first diagnosed. It is these people who should be offered the opportunity of a respite from the daily pricking regime. Diabetics were paying for needles when drug addicts were given free needles, until the inequality was addressed. It would seem that yet again economic factors are outweighing human compassion and quality of life.	The Committee does not consider the affordability of new technologies, (cost to the PCTs0 but rather their cost effectiveness in terms of how its advice may enable the more efficient use of available healthcare resources
4	This appraisal clearly ignores the discomfort - often pain - together with the embarrassment of injecting, for example, on an aircraft (Difficult anyway!) or other public place - indeed, even in meetings at work. Injections often go less than satisfactorily; e.g.: the insulin may not disperse quickly enough at the chosen site, resulting in a painful lump until it disperses; one may inject through a nerve or blood vessel. In the latter case, the bleeding after withdrawal of the needle often causes insulin to be expelled with the blood, so the dose is inaccurate. I inject twice per day. However, I am likely to need to inject more than this before long, probably 4 times per day. Some people need to inject 6 times per day. Surely the benefit of not having to inject so often, and using an inhaler instead, would be worthwhile? I am trying hard to avoid going onto more frequent injections, so my HbA1c figure is too high, and inevitably I will suffer problems later on - and those problems will cost me quality of life, and the NHS a lot more money. Also, I will probably die sooner; but I guess that would be welcome to the NHS in terms of reduced cost.	The Committee discussed the evidence on quality of life with injected and inhaled insulin in detail.
5	I recently read your recommendations that in order for patients with diabetes to receive inhaled insulin they must be paranoid about needles. I could not believe what I read. I have a daughter that has been type 1 diabetic for nine years. She has probably taken around 10,000 shots and pricked her finger as many times. As a parent I would be willing to get a second job in order to buy inhaled insulin. You are NOT NICR! In fact, I would laugh if it weren’t so scary that people like you who have not dealt with diabetes on a daily basis can throw out recommendations like this one. The next time you tell a diabetic child that they must see a shrink in order to get inhaled insulin, I would like for you to vision a pile of 10,000 needles and 10,000 lancets. The next time you go to the doctor and get a shot in vision those 10,000 needles. The next time you get your finger pricked for a minor test at the doctor’s office in vsion my daughter’s 10,000 lancets. Diabetes has almost put me in the poor house but I would sell my house tomorrow if I thought I could take away 2/3 of the shots my daughter must have. I am so aggravated. If only someone in power had a child with diabetes!	The Committee considered evidence from patient groups and took this into account when making its recommendations. Patient experts were present at the Committee meeting
6	I can not believe this. Do you know what it’s like to have gotten over 10,000 shots? The next time you suggest to a type 1 diabetic that they must see a shrink in order to get inhaled insulin, please picture a child getting over 10,000 shots in nine years and pricking her finger as many times! And she is 15! Imagine how many shots she will have had my the time she is 50! I want to scream!!!!!!!!!!!!!!!!!!!!!!!! Diabetes is a relentless disease. I have spent countless sleepless nights. Even with insurance I spend thousands every year. But I would sell every thing I own tomorrow in order to lessen the pain she must got through EACH day. The next time you get a shot, imagine 10,000 shots. And the next time you get your finger pricked for a routing blood test, imagine 10,000 pricks. Maybe then you will stop and think what a diabetic child has to go through each day!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!	It needs to be noted that inhaled insulin has a marketing authorisation only for adults with diabetes.

The list goes on and on (for both pros and cons). What is revealing is, if Brits who are diabetic are clamoring for Exubera, the chorus is going to get louder for Afrezza. More to follow.

Exubera Rapid report by IQWIG

 

IQWiG (Institute for Quality and Efficiency in Health Care) says its website “IQWiG is an independent scientific institute that investigates the benefits and harms of medical interventions  for patients. We regularly provide information about the potential advantages and disadvantages of different diagnostic and therapeutic interventions.”

IQWiG analyzed “Exubera” (Pfizer’s failed inhaled insulin product) in detail and issued a rapid report. I think this report played an influential role in contributing to Exubera’s demise in Germany. The full report can be accessed through this link.

This report is available for free and I’ve pasted the discussion part. When you read it, you should start thinking what is different in Afrezza. Afrezza will be subjected to a similar review by IQWIG.

The report basically concludes that Exubera can only be used in situations where the patients are extremely needle phobic.

  From the report: (any emphasis are mine)

This systematic evaluation of the relevant studies performed with Exubera® demonstrates that the available data, taken together, are inadequate.

There is not a single study on type 2 diabetes in which Exubera® was compared with subcutaneous insulin, with identical therapeutic regimes. Only a single study compared Exubera® with subcutaneous insulin at all and even in this case the treatment regimes were different (intensified vs. conventional insulin therapy). Nevertheless, more serious episodes of hypoglycaemia were recorded under Exubera® than under subcutaneous insulin, even though the reductions in blood sugar were comparable. It cannot be inferred from this study that Exubera® is an equivalent and - importantly – safe alternative to subcutaneous insulin for patients with type 2 diabetes, if identical therapy regimes are used. On the one hand, the increase in weight over 24 weeks was less with Exubera®, with a mean value of 1.3 kg. On the other hand, cough and formation of insulin antibodies were frequent adverse events with Exubera®. Moreover, the published data do not demonstrate the long-term pulmonary safety of Exubera®. In contrast, the published results of instrumental measurements are somewhat inconsistent and indicate that there may be a potential pulmonary risk. This is also reflected in the Summary of Product Characteristics provided by the EMEA and the requirements for training programmes discussed above [13].

There were only two studies on patients with type 1 diabetes mellitus in which Exubera® was compared with subcutaneous insulin, using intensified insulin therapy. The larger of these included almost 40% children and adolescents - for whom Exubera® has not been approved - without the results for adults being separately reported. It remains unclear whether the Exubera® results from this study for adults would be more or less favorable. Currently published studies show that severe hypoglycaemia occurs statistically significantly more often with Exubera® than with subcutaneous insulin, using intensified insulin therapy and with comparable reductions in blood sugar. On the basis of currently published studies on the treatment of type 1 diabetes mellitus using intensified insulin therapy, there is no evidence that Exubera® provides any additional benefit in comparison with subcutaneous human insulin - although there is evidence for more potential damage. Moreover, the above comments on the questionable long-term pulmonary safety apply to type 1 diabetes too [13]. The approval text for type 1 diabetes particularly emphasizes the importance of carefully considering benefits and risks [13]. Bearing this in mind, the published data do not permit the identification of any group of type 1 diabetes patients for whom this consideration would yield a favourable result. In this context, the only plausible reason for treatment with Exubera® would be if the patient totally rejects subcutaneous injections, thus putting his life at risk.

Practically all relevant questions on essential aspects of the implementation in normal daily health care are still open. Thus it is unclear how intensively the patients in the studies were trained, either in general aspects of insulin treatment, or in specific aspects of using the inhalation device. Questions about this were not properly answered by Pfizer. The handbooks provided cannot fully correspond to the materials used in the studies, as these also employed oral instruction and audiovisual material. Moreover, they do not fully cover the training content suggested by the EMEA. It is unclear whether the present version of the handbook would be used after the introduction of Exubera®. It is also unclear that, at the time of market launch, there will be a training and treatment programme, evaluated to guarantee adequate handling of the device, including insulin dosage etc., so that safe use in the target population can be assumed. If this is not the case, this can be regarded as an additional and essential uncertainty for the safe use of Exubera®.

There has been no conclusive answer to the question as to whether or to what extent syringes for self-filling or pen systems were used in the studies. There are however several indications that pen systems were used relatively rarely, at least in the studies performed in North America. The transferability of the results of these studies thus appears to be generally questionable. In this context, Pfizer’s statement that “It was not possible in these studies to distinguish between patient preference (PRO) for inhaled insulin on the one hand and insulin administered by pen or syringe on the other. This was not an objective either,” appears to be relevant. With this, Pfizer contradicts the views of many specialists on Exubera® as expressed in reviews (see too Appendix A.3). However, this statement appears plausible, as judged by the general design of the studies - with their emphasis on efficacy parameters, lack of blinding, high frequency of self-measurement of blood sugar in the subcutaneous insulin patients (often without therapeutic justification), etc.

Before Exubera® is widely prescribed in Germany, it must be demanded that an adequate randomised intervention study should be performed, which should address the open questions on the implementation in normal daily health care. This could be guaranteed by a “simple real world RCT” with random allocation to two treatment groups (Exubera® vs. subcutaneous insulin therapy), under the conditions in Germany, including the performance of evaluated training programmes, the usual type of administration of subcutaneous insulin, etc.. A randomised “real world” study - primarily designed to answer health economic questions - is now being planned and can in principle serve as an example [40].

It should finally be mentioned that the present Rapid Report is exclusively based on published information on Exubera®. Study reports of studies which have not yet been completely published were not requested from Pfizer and this was indeed not planned during writing. The documents provided to the public by the American registration agency (FDA) [15,16,41] raise many relevant questions about Exubera® and these can only be answered, if at all, by extensive study reports on the studies with Exubera® which have not yet been published. These include questions about pulmonary safety (e.g. results from study 1027), the clinical relevance of the formation of insulin antibodies, differences in the safety and efficacy between adults and children or adolescents etc.. Essential aspects of the evaluation of the relevant studies might also change if the study reports are assessed. Thus, it is pointed out in the document “Initial clinical review for inclusion in advisory committee briefing” [15] that the number of drop-outs because of adverse events under Exubera® is presumably greater than published, as the author states that there were many misclassifications, particularly in favour of Exubera®. On the other hand, the “preliminary model” of the FDA questions the statistical significance of the severe hypoglycaemia in study 107. It is also pointed out in this document that the severe episodes of hypoglycaemia observed in these studies occurred most frequently in the early morning hours and that the blood sugar values were often clearly below the given target range. These data indicate that the risk of nocturnal hypoglycaemia may be raised under Exubera®, although they do not permit any firm conclusions. Finally, it is evident from the documents that, aside from the published per-protocol analyses, intention-to-treat analyses were planned and performed. It is currently unclear to what extent this additional and as yet unpublished information would modify the evaluation of the study results.

It summary, it is recommended that in the short-term additional evaluation of Exubera® should be performed on the basis of unpublished data, in so far as Pfizer provides this information.

Starting insulin early

 

I read some interesting articles. It lends more credence to the hypothesis that bolus insulin should be started early. The pharmacokinetics of Afrezza makes it ideally suited here. The prevailing approach is two fold:

1) Beat pancreas to death slowly by not giving insulin after meal time (other words, start insulin therapy late, and fail to mimic endogenous first phase spike)
2) Squeeze the last drop of insulin from pancreas

Now, read these

a) The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Link

The article states this in conclusion

“individuals who later develop diabetes may manifest primary defects in insulin action and insulin secretion which predispose them to diabetes while they retain NGT. This longitudinal study makes it clear that, in addition to these primary defects, individuals who develop diabetes manifest progressive impairments in both insulin action and insulin secretion that directly contribute to worsening glucose tolerance. In addition, our results indicate that these progressive defects occur early during the development of diabetes — during the transition from NGT to IGT — and worsen as glucose tolerance further deteriorates toward diabetes. An increase in EGO is evident only during the transition from IGT to diabetes, and therefore represents a relatively late abnormality. The inability to compensate for either a defect in insulin action or a defect in insulin secretion distinguishes individuals who develop diabetes from those who are able to maintain NGT. These findings suggest that intervention to prevent diabetes in people who are at risk should begin at an early stage and should target both insulin resistance and insulin secretory dysfunction.”

b) The journal of family practice article titled “The role of insulin”. Link

The summary is

The ability of nonpharmacologic and oral pharmacologic therapies to maintain glycemic control in type 2 diabetes almost invariably dissipates. Insulin therapy, therefore, is eventually needed in the majority of patients with type 2 diabetes. While many options are available, the newer insulin analogs (insulin glargine, biphasic insulin aspart 70/30, and 75% insulin lispro protamine/25% insulin lispro), which more closely mimic the release and action of endogenous insulin in healthy persons, offer several advantages over conventional human insulins. Comprehensive care for the person with type 2 diabetes includes diabetes education, ongoing adjustments and changes to therapy, and self-management support guided by appropriate monitoring and screening for the complications of diabetes.

    One thing is really clear, Afrezza is not going to cure diabetes. The causes of Diabetes are still researched (amyloid deposition etc). There are thousands of research articles that point to the fact that starting insulin therapy early, slows down the progression of Diabetes.

Role of TI at cellular level

This article in Journal of Diabetes Science and Technology is a good read. The full text can be accessed here from NIH website. This is an old article (Volume 3, Issue 3, May 2009), but I came across this recently.

A few comments

a) I recently wrote an article regarding the Viaject's safety profile. Review how EDTA impairs permeability (used in Biodel's Viaject) in the NIH article.

b) FDA will take a hard look on the long term impact of using TI (Technosphere insulin) as a diabetic who is 25 years old and living till 75 will be taking around 50,000+ inhalations. The lung function of a healthy individual shows a gradual decline and is more for a diabetic. The last thing you need is TI worsening this condition. The safety of TI should be beyond doubt & reproach and this article provides good analysis.


c) The safety of Technosphere particle will validate its use as a platform for delivering other proteins and peptides. Mannkind is using it for GLP-1 and anti-obesity drugs that are in pre-clinical trials.


Abstract

Background:
Technosphere® Insulin (TI) is a novel inhalation powder for the treatment of diabetes mellitus. Technosphere Insulin delivers insulin with an ultra rapid pharmacokinetic profile that is distinctly different from all other insulin products but similar to natural insulin release. Such rapid absorption is often associated with penetration enhancers that disrupt cellular integrity.

Methods:
Technosphere Insulin was compared to a panel of known penetration enhancers in vitro using the Calu-3 lung cell line to investigate the effects of TI on insulin transport.

Results:
Measures of tight junction integrity such as transepithelial electrical resistance, Lucifer yellow permeability, and F-actin staining patterns were all unaffected by TI. Cell viability and plasma membrane integrity were also not affected by TI. In contrast, cells treated with comparable (or lower) concentrations of penetration enhancers showed elevated Lucifer yellow permeability, disruption of the F-actin network, reduced cell viability, and compromised plasma membranes.

Conclusions:
These results demonstrate that TI is not cytotoxic in an in vitro human lung cell model and does not function as a penetration enhancer. Furthermore, TI does not appear to affect the transport of insulin across cellular barriers.

J Diabetes Sci Technol 2009;3(3):545-554