Wednesday, June 30, 2010

June 30 – 2010 Highlights from Rodman & Renshaw report

 Certain sections were already given in Barron’s blog. Rodman & Renshaw reiterate their $18 buy rating.

Highlights from the report (emphasis are mine)
-------------------------
How did Afrezza do at ADA? We provide an analysis of the data from the most relevant Afrezza studies presented at ADA 2010 in our report, but in summary, we view the T2D data presented at ADA 2010 as clearly positive, and helping bolster the core of our thesis that “1) Afrezza is just as good as injectable insulins at lowering HbA1C, 2) it works faster, 3) mimics the body’s endogenous insulin response, and comes with 4)
lower hypoglycemia, and with 5) less weight gain”. Furthermore, we view the ADA 2010data as consistent with the existing dataset on Afrezza’s overall safety and efficacy, and with our long-standing thesis that Afrezza is a safe and effective alternative to sc insulins that will eventually be approved by the FDA and get to the market. There is absolutely zero change to our thesis, and we continue to be bullish on Afrezza and
MNKD and expect that the FDA will surprise many investors and approve Afrezza.

Our Market Outperform rating and $18 12-month price target on MNKD is based on our view that MannKind’s lead product, Afrezza, will be approved by the FDA and launched in the US in 2011 and will become the first successful inhaled insulin in the market. We believe that Afrezza is a far superior product to Exubera, the closest and unfortunate comparable for Afrezza, since it 1) closely mimics the rapid phase of natural insulin secretion, 2) is a much more convenient product to Exubera, and 3) has proven to have a much cleaner safety profile, with no signal
of lung function damage, or lung cancer (which we incidentally believe was incorrectly attributed to Exubera use).

We like Afrezza’s chances for approval and point to the fact that remaining Exubera patients we allowed to transition to Afrezza, a decision we do not believe would have been made, should the FDA have significant doubts about Afrezza’s safety profile.

Our bet is that this will be a very good year for MannKind. We expect that the next 12 months will bring unprecedented success to MannKind, with a number of important events that we believe will end up going MannKind’s way and will lead to significant price appreciation in MNKD shares. The most impactful events in the next 12 months will be 1) FDA approval in 2011, followed by 2) the signing of a worldwide partnership with a large pharma company, and 3) the US launch of Afrezza in 2011. In addition, in the next 12 months, we expect data from the Phase IIIb trials that will provide additional answers towards Afrezza’s safety profile.

Pharma partnership to provide significant boost to the stock. Contrary to significant investor doubt, we believe that MannKind will be successful in its efforts to secure a worldwide partner for Afrezza and that the announcement of this partnership will be a significant to MNKD shares because 1) it will serve to de-risk the company and its lead product in the eyes of investors, 2) will provide capital infusion through upfront and downstream milestones and royalties, 3) will provide MannKind with a knowledgeable partner that will help drive the marketing and commercialization effort, and 4) will signal the return of big pharma to the inhaled insulin space.
Afrezza is NOT Exubera. We believe that there are more differences among the two products than differences.

Exubera was an unsuccessful drug for multiple reasons, including 1) relative inconvenience for a convenience drug, 2) a lack of compelling clinical data to drive sales, 3) evidence it diminished lung function, and 4) a speculated link to lung cancer. We believe the last two issues continue to weigh even in the minds of those investors who appreciate Afrezza’s advantages. We believe a careful reading of the scientific data suggests that no pulmonary
insulin has shown a lung cancer signal, with observed rates of lung cancer not significantly different from the general population of diabetic ex-smokers. In addition, given the time it takes for lung cancer to develop and become detectable (on average 20 years) we consider it implausible that a pulmonary insulin could cause a cancer that would have been detected this quickly.

In summary: We believe that MannKind’s current valuation significantly under represents the value of both Afrezza and the Technosphere technology. True stock appreciation will likely await both positive FDA action and a partnership announcement as the Exubera lung issues probably still weigh heavily on the minds of many investors.

We continue to believe the FDA has already tipped its hand on this issue by allowing Exubera patients to be switched to Afrezza irrespective of smoking history. In our view, the FDA has seen a great deal of data for pulmonary insulins, from many companies, that are likely to point to the Exubera lung effects as drug-specific and we expect the Afrezza data and eventual approval to further validate the Technosphere delivery technology and stimulate MannKind’s development of a profile of Technosphere-delivered proteins, such as GLP-1 and its
oncology efforts.

Briefing.com MNKD alert

Mannkind: ADA data still point to a better, faster insulin;we continue to expect Afrezza in the market in 2011 - Rodman & Renshaw (6.71)               
                                                                             
Rodman & Renshaw views the T2D data presented at ADA 2010 as clearly positive,
and helping bolster the core of its thesis that "
 1) Afrezza is just as good as injectable insulins at lowering HbA1C,
 2) it works faster,
 3) mimics the body's endogenous insulin response, and comes with
 4) lower hypoglycemia, and with
 5) less weight gain". Furthermore, firm views the ADA 2010 data as consistent with the existing dataset on Afrezza's overall safety and efficacy, and with its long-standing thesis that Afrezza is a safe and effective       
alternative to sc insulins that will eventually be approved by the FDA and get to the mkt.        

Monday, June 28, 2010

Mannkind’s naysayers speak out after ADA – Hapoalim & Oppenheimer

As they say, keep your friends close and enemies closer. It is always better to hear what your opponents have to offer.
Hapoalim reiterates $1 sell rating and calls “ADA Uneventful; It’s All up to the FDA”.
Hapoalim note: (note, all is not bad, they are grudgingly accepting Afrezza now)
MannKind presented final results from the pivotal 030 trial, with Afrezza and usual care showing similar A1c lowering after two years in type 2 diabetics. We continue to have concerns whether small changes in A1c are sufficient for Afrezza approval, continue to expect a drawn out FDA approval process (10 month PDUFA review is possible) and do not expect a partnership without an approved label. We reiterate our Sell rating and $1.00 Price Target.
a) 2-Year 030 Data – MannKind presented 2-year data for the 030 study that compared adding prandial Afrezza to usual diabetes care (UC), to UC without Afrezza. At 2 years, there was comparable reduction in A1c (0.70% [Afrezza], 0.59% [UC], p=0.30). While Afrezza was slightly numerically better at lowering HbA1c, we note that a 0.11% difference in A1c is hardly impressive. In our view, this minimal difference in A1c is part of the “clinical utility” issue with Afrezza. While the risk profiles of existing diabetes drugs are largely known, many of the potential issues with Afrezza are largely unknown (long-term pulmonary function and cancer risk). Because of these unknowns, we have concerns whether a 0.1% difference versus UC is sufficient for Afrezza approval. Additionally, we do not know if these trial results are based only on completers or on all patients that entered the trial (LOCF), which could alter the results.
b) Dream Boat Looks Good but Could Delay Approval: Dream Boat in the FDA filing could cause the second review of the Afrezza application to be a 10-month, as opposed to a six-month, review.
c) Valuation – Our price target of $1.00 for MannKind shares is based on a sum-of-the-parts model (factoring in our peak sales estimate of products, pipeline value, and shareholders’ equity).
d) AFREZZA VS USUAL ANTIHYPERGLYCEMIC REGIMEN
MannKind presented 2-year data for the 030 study that compared adding prandial Afrezza to usual diabetes care (UC), to UC without Afrezza. Patients in the trial had type 2 diabetes with inadequate glycemic control (A1c>6.6%, ≤12.0%). Subjects either incorporated Afrezza into their usual antihyperglycemic regimen (n=656), or continued their usual antihyperglycemic regimen, which could include insulin, oral hypoglycemics, and/or diet and exercise (UC group; n=678) over 2 years. Mean baseline characteristics were similar between groups. At 2 years, there was comparable reduction in A1c (0.70% [Afrezza], 0.59% [UC], p=0.30). While Afrezza was slightly numerically better at lowering HbA1c, we note that a 0.11% difference in A1c is hardly impressive. In our view, this minimal difference in A1c is part of the “clinical utility” issue with Afrezza. While the risk profiles of existing diabetes drugs is largely known, many of the potential issues with Afrezza are largely unknown (long-term pulmonary function and cancer risk). Because of these unknowns, we still have concerns whether a 0.1% difference versus UC is sufficient for Afrezza approval. Additionally, we do not know if these trial results are based only on completers or on all patients that entered the trial (LOCF), which could also alter the results.
e) AFREZZA DOES SHOW FEWER HYPOGLYCEMIC EPISODES
f) DREAMBOAT SHOWS IMPROVED PARTICLE DISTRIBUTION
g) ADVERSE EVENTS FOR AFREZZA VERSUS COMPARATORS
image
Hapoalim cites a dozen reasons as to why Afrezza is a failure, they are seen to be believed. The reasons go from legitimate (dream boat delay, funding story) to patently absurd (Exubera failed, again failure of exubera, FDA has no incentive to approve Afrezza, No panel is negative, A1C is more important to glucose excursion, Afrezza has to be big) and are not worth mentioning here.
This time, Hapoalim has not only thrown the kitchen sink, but the whole house.
Let the Market and FDA decide Mannkind’s fate
Oppenheimer:
a) Final Type 2 Data Highlight Safety Risk, Control Arm in TI-117 Likely Invalid
On 6/24, MNKD announced data from study MKC-TI-102 was published in the 6/26 version of The Lancet journal. Importantly,


(1) we believe adverse events including upper respiratory tract infections and cough will be problematic for AFREZZA.

(2) The fact that AFREZZA demonstrated poorer HbA1c reduction relative to control in this study, is also concerning to us.

(3) Based on our review of a meta-analysis, we believe the control arm in study TI-117 (which we believe MNKD will use in AFREZZA resubmission) showed an abnormally low reduction in HbA1c and may render the study invalid.

(4) We believe a cash raise from MNKD may be imminent and continue to expect an FDA rejection of AFREZZA by YE10.

Thursday, June 24, 2010

WebMD article on inhaled insulin - June 24-2010

The news about  Mannkind's inhaled insulin is spreading far and wide.
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Title:"Inhaled Insulin May Help Treat Diabetes" Link is here

By Katrina Woznicki
 
WebMD Health News
Reviewed by Laura J. Martin, MD

June 24, 2010 -- Inhaled insulin proved to be as effective at lowering blood sugar levels as standard insulin injection treatment, and with minimal side effects, among patients with uncontrolled type 2 diabetes, according to a new study.

Reporting in this week's American Diabetes Association meeting and in The Lancet, researchers compared two approaches to managing type 2 diabetes among patients ages 18 to 80 from 10 different countries. The patients were nonsmokers and had poor control of blood sugar despite insulin therapy.

A total of 211 patients received inhaled insulin plus insulin glargine, a long-lasting form of insulin taken by injection, before bedtime to help manage blood sugar. They were compared with a comparison group of 237 patients who did not use the inhaler, but received insulin injections instead.

One year after treatment, the researchers found that:
  • Blood sugar levels were similar in the two groups; 22% of patients in the inhaled insulin/insulin glargine group reached a goal A1c level of 7% or less while 27% of those solely on insulin injections reached the goal.  
  • Patients using the inhaler gained less weight -- a major concern among diabetes patients.  The inhaler group gained only an average of about 2 pounds, whereas the control group gained an average of about 5.5 pounds.
  • Patients using the inhaler had fewer episodes of hypoglycemia -- a sudden drop in blood sugar -- than those in the comparison group, occurring in 31% of patients on inhaled insulin/insulin glargine group vs. 49% of those in the insulin injection group.
  • Patients using the inhaler reported more side effects with coughing and upper respiratory infections. Most of the coughing occurred within the first 10 minutes of inhalation and primarily during the first week of treatment and declined as treatment continued.
  • Prior use of metformin, an oral drug commonly taken to manage blood sugar, did not affect results among the two groups of patients.
"Our findings show that inhaled insulin plus insulin glargine, alone or in combination with an oral antidiabetes drug such as metformin, is an effective alternative to conventional insulin therapy (biaspart insulin) in uncontrolled type 2 diabetes," study researcher Julio Rosenstock, MD, and colleagues write. "Inhaled insulin ... could provide improved blood sugar control with lower weight gain and rates of hypoglycaemia in many individuals with type 2 diabetes."

Search for New Ways to Manage Diabetes

This research was funded by MannKind Corp., a California-based biopharmaceutical company that manufactures Technosphere, the inhaler device used to deliver the insulin in this study.  MannKind is using Technosphere to administer an inhaled insulin drug called Afreszza, which has not yet been approved by the FDA.
There is a great deal of interest among drug companies and patients in finding new ways to better manage diabetes. According to the American Diabetes Association, nearly 8% of the U.S. population has either type 1 or type 2 diabetes. There are 1.6 million new cases of diabetes diagnosed in people aged 20 and older every year.

In an accompanying editorial, British researchers Clifford J. Bailey, MD, from Aston University and Birmingham Children's Hospital, and Anthony H. Barnett, MD, from the Heart of England NHS Foundation Trust and the University of Birmingham, suggest that more research is needed to flesh out any possible safety issues with using inhaled insulin, particularly concerns over how inhaled insulin affects the alveoli -- tiny air sacs in the lungs.

They conclude: "The opportunity for convenient inhaled bolus insulin, to facilitate complex insulin delivery regimens, will be welcomed by some patients. For now, we say: proceed with caution."
Inhaled insulin was recently introduced to the U.S. market when Exubera, manufactured by the New York-based pharmaceutical corporation Pfizer, was approved by the FDA in 2006. However, Pfizer discontinued Exubera the following year due to poor sales.

Bank of America/Merrill upgrade – part 2

 

The BofA/ML’s reinstating with a buy ($8 target, not $18 as widely reported) reminds me of Theodore Roosevelt’s saying “Keep your eyes on the stars, but remember to keep your feet on the ground”. The report is so conservative that they have anchored their feet on the ground. But conservatism is good & it adds to the margin of safety. The report does offer a peek at the stars. Lets review the report in some detail.

1) Penetration rate: The report only talks about Afrezza occupying a niche in the market for prandial insulin. The 20% royalty revenue is decent, but the 2% penetration rate is uber-conservative. You can come up with a similar model given in the report. Once we know the sales and its growth, we can expect a wave of upgrades. This may potentially happen in 3rd and 4th quarters of 2011, assuming approval in early 2011.

image 

2) Valuation: One can understand assigning zero valuation to the oncology portfolio as it is in very early stages. The valuation completely ignores the TI as a platform. If Mannkind signs up a partner, the spotlight will be on the TI platform. This will unleash lot of interest in pulmonary delivery of drugs using technosphere particle. It will get easy for Mannkind to sign up a partner for GLP-1 and obesity drug. Here Mannkind has the potential to become Minimed on steroids. The good news is that the platform is not priced in.

3) RAA: It took the medical community years to warm up to the concept of RAA. Now RHI is passé and RAA is du jour. The medical community is well primed to accept RAA and it’ll be a easy sell to have them shift to Afrezza. You can really see that the stock performance of Novo Nordisk has mirrored the growth of RAA usage.image 

4) Survey: BofA/ML did a survey of 100 physicans (50 endos, 50 PCP). The survey shows 10-15% of patients do not take insulin for fear of needles and for the 1/3rd that get RAA, the docs will transition 40% to Afrezza. This shows that Afrezza will expand the market for rapid acting insulin. The 40% is huge given Exubera’s demise and Afrezza’s lack of long term safety data. I believe the physicians in the survey may not have seen the superiority of Afrezza. It won’t take long for the other 60% to join the band wagon.

5) Study 117: In the intent-to-treat (ITT) population, Afrezza lowered HbA1C from baseline by -0.10% as compared to -0.03% in the Humalog group. The mean difference of -0.07% between the two groups had an upper CI that was below the non-inferiority margin of 0.4% (95% CI of -0.31, to 0.17). Similar results were also observed in the ITT with last observation carried forward population, or LOCF (-0.04%; 95% CI of -0.25 to 0.18). A significantly higher percentage of Afrezza patients (9.6%) reached an HbA1c goal of <6.5% vs the Humalog group (3.5%, p = 0.0277).

A picture is worth a thousand words.

image

image 

6) Study 119: This trial enrolled 6 type 2 diabetes patients ≥18 and ≤70 years old with type 2
diabetes for ≥12 months. Patients had ≤4 visits to optimize their Afrezza doses to achieve a 1-hour PPG <150mg/dL without hypoglycemia for breakfast and lunch. Patients then underwent a meal challenge for four consecutive weeks with varied carbohydrate (CHO) meal contents (50%, 100%, and 200% of calculated CHOs
and no meal). Results showed that post prandial glucose levels for Afrezza treated patients remained within 35 mg/dL of the fasting blood glucose level, regardless of meal size.

Conclusion: The BofA/ML presents a very conservative outlook of Mannkind’s prospects. Even if you don't agree with their estimates, you will not find fault with their reasoning and analysis. Maybe the folks in Hapoalim & Oppenheimer can learn a thing or two from this report.

Wednesday, June 23, 2010

Bank of America/Merrill upgrade - part 1

Low expectations priced in; reinstating with a Buy

Reinstating coverage with Buy and $8 price objective MNKD is a biotechnology company mainly focused on developing inhaled insulin therapy. The stock is down 45% post the receipt of FDA’s Complete Response
letter (CRL) in March for the company’s new drug application for Afrezza, its rapid-acting inhaled insulin product. In our view, recently completed studies, bioequivalence analyses, facility inspections, lack of safety signals, lack of weight gain and significant clinical benefits should adequately address issues in the CRL
and position the product for approval in 2011. Our $8 PO is based on a DCF analysis of projected revenue for Afrezza. Our downside scenario (another 2 year delay) corresponds to a $3/share value, but we view our $12/share upside scenario (2011 approval with global partner) as more probable.


Our survey suggests a meaningful niche for Afrezza Our survey of 100 physicians indicated that Afrezza could achieve a peak penetration of 15% of the diabetic population. These estimates were larger than
we expected, given the respondents’ concern about the lack of long term safety data and the poor experience with Pfizer’s Exubera, the first inhaled insulin to be approved by the FDA. We are more cautious in our valuation analysis, assuming a 2% peak penetration rate. We assume a 20% sales royalty rate for Afrezza,
which is relatively high but justified by MannKind’s fully inspected scalable manufacturing facility and low cost position in human insulin.

We are reinstating coverage of MannKind with a Buy rating and DCF-derived price objective of $8, which is driven entirely by its Technosphere insulin (Afrezza) product for treatment of type 1 and type 2 diabetes. We assume a 2011 launch with a 90% probability of success based on our review of the FDA issues
raised in the March 2010 Complete Response letter and MannKind’s supplemental analyses from recent months.

We have assumed a peak penetration rate of 2% for Afrezza, which could prove low, based on much higher estimates from our survey of physicians. However, we are more cautious due to expected concerns about long-term safety issues and the previous failure of Pfizer’s inhaled insulin product Exubera could lead to a
slow adoption rate. We assume a 20% sales royalty rate for Afrezza, which is relatively high, but MannKind has a fully inspected commercial manufacturing facility and a low cost insulin supply

MannKind has two oncology drugs in clinical development, both with phase 1 results, which we have conservatively not included in our valuation analysis.

Our downside scenario (another 2 year delay and lower peak penetration) corresponds to a $3/share value, but we view our $12/share upside scenario (2011 approval with global partner) as more probable. See Table 3 at the back of the report for details of the DCF analysis.

Upside to our price objective could come from the announcement of a marketing agreement with a global biopharmaceutical company with experience in marketing diabetes products, and/or an earlier than expected approval from the FDA. Downside risks include an FDA delay or rejection of Afrezza’s NDA, need for additional financing, failure to secure a commercialization partner and a slower than expected launch of Afrezza.

Thursday, June 17, 2010

Beyond Hemoglobin A1c; Dr. Hirsch article in JAMA

For a long time, the medical community was putting patient's one hand in hot water and one in cold water and was measuring the average temperature of water. Every one was happy when the average looked good. No one paid attention to the scalding on one side and frost bites on the other. Now the times are changing. Al Mann had repeatedly said that we need to control PPG to prevent long term macrovascular complications. 

Now read this article and it will make a lot of sense that A1C is just one data point and adequate attention should be paid to glycemic variability. Note that Afrezza controls glycemic variability better than any other product out there.


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<< I copied this from the link http://www.natap.org/2010/HIV/060810_01.htm without permission >>

Beyond Hemoglobin A1c-Need for Additional Markers of Risk for Diabetic Microvascular Complications - commentary
 
Irl B. Hirsch, MD; Michael Brownlee, MD
 
JAMA. June 8 2010;303(22):2291-2292.
 
In 1993, The Diabetes Control and Complications Trial1 demonstrated that intensive therapy lowered time-averaged blood glucose values (measured as hemoglobin A1C [HbA1C]) and significantly reduced development of microvascular complications in type 1 diabetes. For example, intensive therapy reduced the risk of sustained retinopathy progression by 73% compared with standard treatment. Such significant reductions led to the recommendation by professional societies that for microvascular disease prevention, the HbA1C goal for nonpregnant adults should be less than 7% or even less than 6.5% of total hemoglobin.
 
However, few physicians recognized that only 6.6% of the variation in risk of retinopathy for the entire study cohort was explained by the difference in the treatment groups, although it was widely appreciated that nearly all of this treatment group effect was explained by differences in the mean level of HbA1C over time.2 The trial results also considered the instantaneous risk of retinopathy (ie, whether a patient would develop retinopathy at a particular point in time during the study) rather than eventual risk of retinopathy (whether a patient would develop retinopathy over his or her entire life). However, this latter outcome is not feasible to study because it would require lifetime follow-up of patients.
 
Similarly, HbA1C and duration of diabetes (glycemic exposure) explained only about 11% of the variation in retinopathy risk for the entire study population, suggesting that the remaining 89% of the variation in risk is presumably explained by other factors independent of HbA1C.2 Given the magnitude of the effect of unmeasured elements in the Diabetes Control and Complications Trial, identification of these elements is critically important for designing more effective therapy for type 1 diabetes.
 
What factors not captured by HbA1C measurements might explain the remaining 89% of microvascular complications risk? Possible factors unrelated to blood glucose levels include genetics, environmental toxins, and metabolic consequences of abnormal insulinization such as increased free fatty acid levels. Possible factors related to blood glucose levels most likely reflect the fact that since HbA1c represents the time-averaged mean level of glycemia, it provides no information about how closely the fluctuations of blood glucose levels around that mean mimic the normal narrow range of blood glucose excursion. In addition, patients with identical HbA1C values differ significantly in amplitude and duration of glycemic spikes.3
 
Thus, a potential determinant of microvascular complications not captured by HbA1C could be greater magnitude and frequency of glycemic excursions.4 This hypothesis is provisionally supported by experimental evidence that prior episodes of transient hyperglycemia trigger persistent increases in proinflammatory gene expression during subsequent periods of normal glycemia by inducing stable epigenetic changes in the promoter of NF-{kappa}B p65, which increase p65 expression. This in turn causes persistent increased expression of the proinflammatory proteins monocyte chemotactic protein-1, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interleukin-6, and inducible nitric oxide synthase.5-7 These persistent changes in gene expression are induced by spikes of hyperglycemia that have durations considered too short (6-16 hours followed by 6 days of normal glycemia) to influence HbA1C values.5
 
During the course of the Diabetes Control and Complications Trial,1 blood glucose was measured 1 day every 3 months at 7 time points throughout that day. However, calculation of within-day standard deviation and standard deviation of mean blood glucose values between these quarterly assessments revealed that neither of these measures of glucose variability was associated with increased risk of microvascular complications.8 This result is not surprising because recent continuous subcutaneous glucose monitoring data from patients with type 1 diabetes (288 data points/24 hours) show enormous variability within a single day and between days.9 Furthermore, many of the formulas previously used to estimate glycemic variability (such as mean amplitude of glycemic excursion) only yield data about relative variability, whereas the absolute magnitude of glycemic spikes may be more relevant to the induction of long-lasting changes in gene expression.5
 
Realizing that the aspects of glycemia that explain the approximately 89% of microvascular complications are unknown, 2 practical questions arise: (1) how should hyperglycemia be treated in patients with diabetes; and (2) how can the critical aspects of hyperglycemia not captured by HbA1C be identified so that more effective therapies can be designed?
 
Given the lack of studies specifically aimed at reducing glycemic variability to determine the effect of such reductions on clinical end points, new treatment guidelines targeting glycemic variability per se cannot be justified. Since HbA1C, the first long-term marker of glycemic control, did predict the vascular complications of type 1 diabetes,1 despite its low overall contribution to the progression of diabetic retinopathy, it remains the only confirmed predictor. The wider use of clinical monitoring tools such as continuous glucose monitoring and laboratory markers such as 1,5-anhydroglucitol, which indicates the extent to which postprandial hyperglycemia has occurred over the past 2 to 3 weeks,4 will allow a more definitive examination of the effects of glycemic variability on clinical end points. Newer therapeutic tools such as more rapidly acting prandial insulins (now in development), pramlintide, and incretins could allow further reductions in glycemic spikes than traditionally available drugs allow. It is also possible that factors independent of glycemia explain a substantial fraction of the risk.
 
Recent evidence suggests a role for both blood pressure and lipids in the pathogenesis of diabetic microvascular complications.10 Thus, it seems prudent to integrate earlier use of medications and other approaches to control blood pressure and lipid levels, as well as to include frequent follow-up assessments of retina and renal status into an overall treatment strategy. "Glucometrics" (the complete descriptive analysis of all aspects of glycemia) for assessing variability with continuous glucose monitoring and home blood glucose monitoring are rapidly evolving, along with software programs that can download and analyze these data. Advances in understanding the molecular basis for the variation in diabetes complication risk not explained by HbA1C, combined with development of new tools for measuring glycemic variability now allow prospective studies designed to determine the relationship between glycemic variability and clinical end points.
 
Increasing understanding about the mechanisms underlying glycemic variability and its potential deleterious consequences and determining how better to reduce the magnitude and frequency of glycemic spikes should become near-term priorities for translational and clinical type 1 diabetes research. Equally important near-term priorities are determining the contribution of abnormalities in metabolism that are independent of glycemia, as well as of genetic differences in individual responses to the metabolic consequences of abnormal insulin action. Physicians will have to realize that much remains to be done in identifying important factors contributing to microvascular complications risk, which are not captured by the HbA1c. The future identification of these factors will have important implications both for devising additional markers for monitoring glycemic control and for designing better treatment methods for achieving it.
 
AUTHOR INFORMATION
 
Corresponding Author: Irl B. Hirsch, MD, University of Washington Medical Center-Roosevelt, 4225 Roosevelt Way NE, Ste 101, Seattle, WA 98105 (ihirsch@uw.edu).
 
Financial Disclosures: Dr Hirsch reports being a consultant for Johnson & Johnson, Roche, and Abbott and receiving grant support from Novo Nordisk and Mannkind Corp. Dr Brownlee reports no disclosures.
 
Additional Contributions: We thank Ted Gooley, PhD, Fred Hutchinson Cancer Research Center and Department of Biostatistics, University of Washington, Seattle, for his assistance in biostatistical consultation. Dr Gooley received no compensation in association with his contribution to this article.
 
Author Affiliations: Division of Metabolism, Endocrinology, and Nutrition, School of Medicine, and Diabetes Care Center, University of Washington, Seattle (Dr Hirsch); and Diabetes Research Center and Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York (Dr Brownlee).
 

Wednesday, June 16, 2010

Reviewing the safety profile of Biodel’s Viaject

      Viaject® is a Biodel’s ultra rapid acting insulin & is a proprietary form of regular human insulin. Viaject has a better pharmacokinetic profile than the existing Rapid acting analogs. Biodel has submitted a New Drug Application to the FDA for approval to market VIAject® as a treatment for Type 1 and Type 2 diabetes. The PDUFA date for Viaject is 10/30/10. Biodel has taken an unconventional route 505(b)(2) regulatory pathway to get FDA approval. This approach cuts the total time to market from 10+ years to 4 years.

     Viaject’s Insulin reaches half of max concentration at ~ 16-18 minutes. Insulin is an hexamer in the natural form. If hexameric insulin is injected as a prandial insulin (meal-time), it takes the body quite some time to break it into a monomer. The body can only use monomeric insulin. You need the prandial insulin to be in monomeric form so that it can be used quickly by the body to absorb meal glucose. The Biodel’s Viaject is a monomeric insulin. Biodel took the regular human insulin (which has zinc molecule surrounded by 6 insulin molecules), and added a chelating agent (EDTA) to chelate zinc out the hexamer. So the insulin is no longer clustered together, and are therefore in its active monomer form immediately when injected. Viaject insulin also uses citric acid to bind to specific areas on the insulin to prevent re-clustering.

Viaject technology
biodel_viaject

The current trials done so far have shown less hypos, less weight gain, better PPG control and less HbA1c compared to the gold standard RAA.

This approach is ingenious but raises several safety issues. Let us explore them.
1) The EDTA (ethylenediaminetetraacetic acid) that is used as a chelating agent (chelate – a greek word that means to claw) is used to claw out the zinc molecule. FDA considers this as GRAS (“generally regarded as safe.”). However, its primary medical use is for emergency treatment of lead, mercury and other heavy metal poisoning. The effect of EDTA in multiple daily injections over a lifetime could be worrisome.

2) Some physicians who were involved in the trials say that Viaject is so acidic that it burns when injected and that the results are not much different from Humalog and Novolog.

3) It has been documented that EDTA damages tissue. Take a look at the image below where EDTA Disrupts Tight Junctions.

viaject_edta_junction_disruption

Biodel has a market capitalization of $100 million. The company should consider itself lucky if FDA approves Viaject without raising safety issues (that will call for a more elaborate trials). It is interesting to note that Biodel is yet to find a partner for Viaject.

The diabetes epidemic is so huge that there is room for many products. If approved Viaject might be appealing to some diabetics.

Disclaimer: The author is neither short nor long Biodel shares.

Tuesday, June 15, 2010

A physician’s perspective – June 15, 2010

One of the questions that we Mannkind shareholders constantly try to answer is, “How will Afrezza be embraced by the medical community?”

Here is one response from a renowned endocrinologist (whose name has been withheld to protect his privacy). I want to thank my friend for sharing this with me. 

 

The world of diabetes is an ever changing one with some old constants remaining.

The A1c target discussed is the goal of the studies to demonstrate a reduction in A1c (usually required to be greater than 0.5 to be able to declare an intervention as superior).

The actual goal should be non-inferiority with A1c but improved post prandial control with lessened hypoglycemia. Based on the type 2 data that has come from ACCORD ( a study that I was involved in attempting to assist with a design for increased glucose monitoring capability) the avoidance of hypoglycemia assumes increased importance as a prevention of cardiac death. Jeff Flier MD (Currently Dean of Harvard Medical School but a High School Classmate of mine at Bronx H.S. of Science graduating in 1967) and his lab at Harvard showed conclusively that hypoglycemia in type 2 diabetes causes autonomic nerve dysfunction which prevents hyper-perfusion of the coronary arteries and ischemic death of the myocardium following hypo-perfusion from spasm.

Ultimately the drug Afrezza will be approved as an adjuvant to existing treatments for diabetes (mostly GLP-1 or basal insulin) to control glucose and prevent A1c deterioration and minimize hypoglycemia. This very much sounds like the marathon that Amylin went through with Symlin except that Afrezza actually works while we searched for 16 years for a reason to use and get approval for Symlin.

The humalog studies and basal studies that are part of the current dossier are using an approach to show superiority in A1c and using fasting glucose as targets. The A1c is linked to fasting and post prandial dinner more than to any other point measurements and it is not surprising to see no difference in endpoint achievement.

I think that Afrezza has a huge market potential if one looks forward to recognition that post prandial near normalization  is a powerful endpoint  and that prevention of hypoglycemia and maintenance of A1c is a non inferiority outcome that is also superior in treatment.

Diabetes Mellitus Type 1 and Type 2 is a disease state that is based upon individual choices for the patient and not on treating to the mean. In the world of increasing BMI and increasing insulin resistance and increasing insulin requirements for treatment inhaled Afrezza will rule (certain populations such as Middle eastern and Indian and African American ethnicities have more severe insulin resistance and higher cardiovascular disease as well).

Sunday, June 13, 2010

A look at FDA guidelines for Afrezza’s approval

Please read my earlier article regarding the complete response letter that Mannkind received for Afrezza’s NDA submission. (FDA’s CRL and next possible steps)
This post will cover the FDA’s guidelines for Diabetes drugs and will also look at how well Mannkind has prepared for this.

The new FDA guidelines (click on link to open the pdf file), “Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention” was issued in March 2008 and “Diabetes Mellitus: Evaluating Cardiovascular Risks in New Antidiabetic Therapies to Treat Type 2 Diabetes” was issued in December 2008. The new guidelines are tougher and are one of the reasons as to why the competitors folded their plans for inhaled insulin at a significant cost. (Eli Lilly/Alkermes – Air insulin, Novo Nordisk/Aradigm – AERx). The Pfizer/Nektar’s Exubera was pulled after the FDA approval for a host of other reasons. The new guidelines also address inhaled insulins.

Developing a anti-Diabetes drug is an expensive affair and the new FDA guidelines have set the bar higher. Depending on the therapeutic class and type of diabetic patient, it has been estimated that the cost for a single patient in a diabetes trial can range from $15,000 to $30,000 and the new guidelines will increase it by 30-50% (source Quintiles). If you don't include the opportunity cost, Mannkind has spent around 1.5 billion since inception. Even after FDA approval, there’ll be a host of post approval trials/studies. The “Exubera Advisory Committee Briefing document” lists the studies that Pfizer planned to do or was doing already after approval.
  1. Long-term PFT Studies (5-year Extensions of Studies 1022/1029).
  2. Asthma (Study 1028).
  3. COPD (Study 1030).
  4. Large Simple Trial (Study 1069: Real World Study).
  5. Epidemiologic Study of Lung Cancer.
  6. Pediatric Studies.
  7. PFT Mechanism – Clinical Studies
You can expect something similar for Mannkind too.
Mannkind also held extensive talks with FDA when the newer guidelines were published to make sure that they are adhering to get the approval. It has been reported that 4 FDA divisions (probably endocrinology, cardiology, pulmonology and devices) will be present in the face to face meeting that will be held in June 2010. (As I typed this, it was reported that Mannkind met with FDA and will resubmit by July).
FDA’s guidelines are not some ironclad rules, they are suggestions and recommendations. I think FDA looks into the overall risks/benefit equation for a given submission and approves it for a given use (label). The FDA has an unenviable job of refereeing the eternal tug of war between society’s demand for safer drugs and pharma’s need for quick profits. Given the overall increase in longevity for last 100 years, one can conclude that they have done a decent job. Of course, there is always room for improvement. 

I’m not planning on covering the trial design. The focus will be on end-points. The fact is, Mannkind has repeatedly said that FDA is not asking for any new trials for approving the drug (except for performing some Phase 4 studies).

FDA guideline (verbatim) Afrezza Trial/Study outcome
HbA1c is considered a well-validated surrogate for the short-term clinical consequences of hyperglycemia and long-term microvascular complications of diabetes mellitus.

For purposes of drug approval and labeling, final demonstration of efficacy should be based on reduction in HbA1c (i.e., HbA1c is the primary endpoint of choice, albeit a surrogate), which will support an indication of glycemic control.

Of note, all drugs currently approved for the treatment of diabetes are indicated to improve glycemic control. The FDA currently bases approval of these drugs and biologics on HbA1c.
Mannkind was able to show non-inferiority when compared with RAA. The differences in HBA1c were statistically insignificant.

The only controversial aspect was the study 009 (Afrezza Vs Lispro) which showed that the A1C difference was in border line (data spread, the upper 95% Ancova confidence level was .401%). Al Mann has given his thoughts in this article.

Until Mannkind can show conclusively that Afrezza is superior in reducing A1C in a larger trial, only the non-inferiority claim will stick. The recently published 117 which had poorly controlled Type 1 patients, Afrezza showed superiority (secondary end point) in A1C and PPG compared to Lispro. Study 117 had 65 in Afrezza arm with Type 1 patients.

In practice, I would expect the physicians to continue adjusting basal/bolus as long as patients don't get hypos. This iterative process will help demonstrate the superiority of Afrezza and better glycemic control.
Section c. New insulin analogues or insulin receptor binding agonists:

The risk of hypoglycemia under conditions of use ultimately recommended in labeling, relative to approved insulin products and regimens. In this regard, both test and control groups should achieve improved and similar glucose control as assessed by HbA1c.
This has been well documented in several studies and Afrezza is shown to be clearly superior to current gold standards.

One can attribute the pharmacokinetic profile for this behavior. (the rapid suppression of hepatic glucose and gentle slope after reaching peak insulin levels)
CV risk:
The FDA recognizes that diabetes mellitus is associated with an increased risk of macrovascular complications and that reducing long-term cardiovascular complications in patients with diabetes should be an important goal of disease management. However, a premarketing recommendation to demonstrate macrovascular risk reduction in the absence of a signal for an adverse cardiovascular effect may delay availability of many effective antidiabetic drugs for a progressive disease that often requires multiple drug therapy. A reasonable approach may be to conduct long-term cardiovascular studies post-approval in an established time frame. We recommend that the design of such trials be discussed with the FDA and perhaps with clinical trialists and experts in endocrinology and cardiology.


“Approvable drugs will have an upper bound of the two-sided 95% confidence interval for the estimated risk ratio of less than 1.8. If this result is in the 1.3-1.8 range and the risk-benefit analysis otherwise supports approval, a post-marketing trial will be necessary to demonstrate that the actual upper bound of the 95% confidence interval for the estimated risk ratio is less than 1.3.”


Therapies that have not demonstrated a deleterious effect on cardiovascular outcome during extensive premarketing evaluation may need further post-approval assessment for their effects on long-term macrovascular disease. If the premarketing application contains clinical data that show that the upper bound of the two-sided 95 percent confidence interval for the estimated increased risk (i.e., risk ratio) is less than 1.3 and the overall risk-benefit analysis supports approval, a postmarketing cardiovascular trial generally may not be necessary.
Diabetes itself increases the risk of Cardiovascular diseases. There is evidence that diabetes is associated with a 7-fold increase in risk for developing cardiovascular disease.

There is a direct correlation between CV risk and glycemic control. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, the original patients in the DCCT were followed for an average of 17 years. The patients in the intensive therapy group were no longer treated intensively, but they demonstrated a 42% reduction in risk of any cardiovascular event. The authors concluded that the initial 6.5 years of intensive treatment created a “metabolic memory” that provided some protection against CVD.



The good news is, Afrezza shows the CV risk ratio of 1.01. 









The good news is that Mannkind may not have to perform a postmarketing CV trial. 
Section c:
Pharmacokinetic variability should be evaluated, according to injection site, thickness of fat layer, and other parameters known to affect absorption, distribution, metabolism, and excretion characteristics. Additionally, pharmacodynamic characteristics should be carefully studied to direct dosing interval (for long-acting products) and timing of dosing relative to meals (for short-acting products). Assessment of insulin receptor binding (affinity and dissociation rates), receptor autophosphorylation, phosphorylation of signaling elements and promotion of mitogenesis may add important data to the characterization of new insulin analogues.
It is an accepted fact that the variability of Inhaled insulin is way less than s.c. injections due to the method of delivery.

Section c:
Immunogenicity

As a complex biological protein, insulin has the potential to be immunogenic. Adequate assays should be developed that measure antibodies to the test product before the submission of an application. Antibody titers, the timing of their detection and disappearance (if applicable), and correlation with pharmacological effects should be ascertained. The potential for any of the antibodies to neutralize the effects of a new insulin should be assessed, particularly in the presence of high titers of antibodies, and in the presence of allergic reactions or suspicion of immune-complex deposition, or apparent loss of clinical effectiveness.
Exubera showed a 30 fold increase in antibodies; this is more a phenomenon of Inhaled insulin I guess.

The clinical significance of increased antibodies is unclear.

The immunogenicity of Afrezza has been well documented. The recent ADA abstract “0216-OR Insulin Antibodies Associated with Technosphere® Insulin” throws some light on this.

Type 2: Afrezza showed <3 fold increase, control arm 2 fold increase;

Type 1: Afrezza 8-fold vs 2-fold for sc insulins. 

d. Inhaled insulins

Investigations of insulin delivered by inhalation should include preclinical safety, pulmonary safety, pharmacokinetics, pharmacodynamics, dose proportionality, and hypoglycemic risk. The extent of preclinical studies needed depend, in part, on the novelty of the formulation (e.g., what excipients are used) for the inhaled route. Typically, the minimum preclinical program should be comprised of two 14-day inhalation studies focusing on the histopathology of the respiratory tract, followed by a 6-month bridging study in the most appropriate species. The pharmacokinetics (including bioavailability), pharmacodynamics, and hypoglycemic risk of inhaled insulin in humans should be compared to that of subcutaneously administered insulin. Intrasubject pharmacokinetic variability should be evaluated.
Afrezza does better than Exubera and is on par or better than RAA in these aspects.

My earlier article comparing Afrezza and Exubera covered these extensively.
contd..

We encourage sponsors of inhaled insulin products to enroll at least some patients with underlying pulmonary disease, such as chronic obstructive pulmonary disease and asthma, to assess not only effects of inhaled insulin on their pulmonary function, but also the effects of their disease on insulin kinetics. Cigarette smoking affects inhaled insulin bioavailability, and airway status may lead to alterations in drug delivery to the absorption site. Therefore, sponsors should investigate the potential effect of cigarette smoking and inhalational drugs for pulmonary disease on the efficacy and safety of the inhaled insulin product, including assessments of the effects on insulin pharmacokinetic and pharmacodynamic endpoints and the rates and timing of hypoglycemia.

The good news is, Afrezza was tested in patients with COPD. The patients may have to increase dosage but the PK profile is not altered. Link 

The variability in absorption is greater for patients with COPD, Asthma.  

It is counter-intuitive to see that smokers absorb inhaled insulin better due to the fact that smoking increases the permeability of the alveolar-capillary barrier. But acute smoking does have an impact.

If Afrezza is approved, the initial label may exclude patients who are smokers, having COPD or Asthma. 

The PK profile is virtually unchanged for patients who take TI along with Albuterol or Fluticasone. Link

The off label uses of TI for Asthma patients can not be ruled out.  
contd..

Sponsors developing inhaled insulin products should evaluate the pulmonary safety of these inhaled insulin products (including excipients). Safety assessments should include pulmonary function as measured by the full battery of pulmonary function tests, including spirometry, lung volumes, and diffusion capacity. Serial pulmonary function tests should be performed and the long-term effects of the inhaled insulin product on pulmonary function should be established. Additional safety assessments include high resolution computed tomography of the chest at baseline and on treatment. Because of the potential effects of diabetes mellitus on the pulmonary system, a comparator group is recommended for these safety assessments. In addition, assessment of anti-insulin antibody responses is essential in the overall safety assessment of the inhaled insulins, because the inhaled route may lead to a different propensity toward immune responses. Pre-use storage and in-use handling conditions during these studies should be designed to mimic actual use of the products. Accuracy of use and dosing should be assessed and documented.
Though pulmonary delivery of drugs were even reported in ancient Egypt, the modern world has taken an Ostrich stance with a comment like “Lungs are meant only for gases”. This area has been extensively researched. Mannkind has published several findings comparing FEV, FCV and DLco of Afrezza and comparator arms.

The bottom line is, Mannkind reports that the changes (decrease) are non-progressive, reversible and statistically insignificant. In some cases, Afrezza arm shows superiority.

The changes are little bit worse for Type 1 compared with Type 2. This makes sense as poorer glycemic control in turn impacts lung function.  

There is one sticking point that detractors are happy to point out (John Newman – Oppenheimer & co).

The point is the DLco for study 009 (Type 1 patients, total of 293 patients received Technosphere Insulin, and 272 patients received insulin aspart) lower bound of 95% confidence interval doesn’t cross zero. See the image in link uploaded earlier in my blog.

The PR says
Over the entire 52-week treatment period, Technosphere Insulin was generally well tolerated. No pulmonary neoplasms were reported. Consistent with the results from earlier studies of a shorter duration, after 52 weeks of treatment, there were no between-group differences in pulmonary function measures, including FEV1 (forced expiratory volume in one second), FVC (forced vital capacity), DLCO (carbon monoxide diffusing capacity) and TLC (total lung capacity). All safety data will be further analyzed along with data from the recently completed two-year pulmonary safety study.


Is this a statistical anomaly? I’ll let you decide.

You can surely expect a label from FDA that asks for an initial FEV/(possibly PFT) test to get the baseline lung function data and a periodic test (once a year) to monitor the lung function.

One can also make an argument that to the extent Afrezza improves (the fpg & ppg and hence) A1C/glycemic control, the lung function tests may show better results in Afrezza patients. We need lung function results for study 117 to make this conclusion.

Conclusion:

Since FDA approved Exubera, I can not imagine them declining Afrezza. Even if FDA approves with some restrictive label for Type 1 compared to Type 2, Afrezza will be a resounding success.

Friday, June 11, 2010

Rodman & Wachovia comments - June-11-2010 :

Michael Tong, CFA, PhD, Senior Analyst
MannKind Corporation (MNKD-NASDAQ)--Outperform (1) / V

Price as of 6/10/2010: $5.62
FY 10 EPS: $0.00
FY 11 EPS: $-1.01
Shares Out.: 113.0 MM
Market Cap.: $635.06 MM

Sector Rating: Specialty Drugs, Market Weight

MNKD: Positive Comments from Management Following Meeting with FDA

***MNKD management suggested that it can submit its response to FDA's complete response letter on Afrezza in July 2010.

***Mgmt is optimistic that data for Dreamboat will be included in its response, but cannot predict if the response will trigger a 2-month, 6-month, or 10-month review cycle.  Given additional data will be part of the response, a 2-month review cycle is unlikely, in our view.

***In addition, the company announced a 16-week trial comparing Afrezza plus basal insulin against lispro plus basal insulin demonstrated that Afrezza was non-inferior to lispro.

***Furthermore, subjects in the Afrezza arm had significantly lower rates of hypoglycemia, post-prandial glucose level, and fasting glucose levels.

***These data continue to support the approvability of Afrezza, in our opinion.


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Rodman & Renshaw comments on Afrezza data ($6.86 +$0.61)
In a pre-open note, Rodman reiterated its thesis that Afrezza is a better inhalable insulin product than Exubera, that it will be approved by the FDA, and that it will get to the market. Firm also believes the company will secure a partnership for the drug following FDA approval. Rating is market outperform with a target of $18


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Thursday, June 10, 2010

Highlights from Jefferies 2010 Global Life Sciences Conference

Who Presented: Alfred Mann, CEO (change from schedule)
 
What’s New: MNKD expects to meet with the FDA “shortly” to discuss complete response letter for Afrezza, with potential for a late July resubmission and January 2011 PDUFA through a Class 2 FDA response. The company believes it currently has cash for operations through 1Q 2011, but cautions that it may have to extend the cash runway through financing depending on the outcome of partnership discussions and FDA decision on Afrezza, an inhaled rapidly acting insulin. In the clinical profile, the company highlighted that Afrezza differentiates itself with its ultra rapid onset of action, which they believe is most similar to the way that insulin works naturally in the body. The company disclosed that 117 study data, showing noninferiority to humalog and which has been released as topline data, will be a major part of the company’s resubmission of Afrezza to the FDA. This is alongside data supporting use of the new DREAMBOAT inhaler device, which the company previously disclosed it would include in the Afrezza resubmission to the FDA.
 
What Investors Asked About:
1)    Further color on the FDA’s timing of responses? has a meeting been set?
2)    What were the main issues FDA disclosed in the complete response letter?
3)    Potential pricing.
4)    If you have to do FEV (forced expiratory volume) pulmonary testing, how frequent would that be?
5)    Will you do a deal before the end of the FDA review?
6)    Could you get an (earlier) class 1 FDA response?
7)    Where are you on answering the FDA’s question on “clinical utility”?
8)    Have you designed the next study with Afrezza? How large might that trial be?
9)    How many patients will you have treated in total across all trials?
10) Backup strategies for addressing 1Q2011 runway if the FDA decision and partnership for Afrezza are delayed?

Friday, June 4, 2010

Interview with Alfred Mann, CEO of Mannkind corp.


I have had the honor and privilege to interview Alfred E. Mann, CEO of Mannkind corp. I want to thank him for taking time from his busy schedule. This is an original interview and has not been posted anywhere else. I received his written answers on June 3rd 2010.

This June is a crucial month for Mannkind. The company is meeting with the FDA to address the issues raised in the complete response letter and the submission of additional data, that includes the bio-equivalency data for dreamboat inhaler. 


1) Critics of inhaled insulin say, even with Afrezza, people with Diabetes still have to take injections. Is Mannkind planning to come up with basal inhaled insulin using the Technosphere particle in near future?

Mr. Mann: AFREZZATM addresses prandial (mealtime) glucose. But glucose is supplied by the liver between meals so in type 1 and late stage type 2 a person also needs a basal insulin. Basal insulin today requires one or two injections daily. However, for the 70% of type 2 diabetics who have not progressed to basal/bolus therapy. AFREZZA alone without basal injections has provided excellent control in a recent trial.

MannKind has been exploring various technologies to provide better basal insulins. We cannot yet speak about these.

2) Is there sufficient data to get approval in Europe, Japan and other countries for Afrezza?

Mr. Mann: We have extensive data that is adequate for approval in most countries However, the European Union requires a separate ultrasound study for cardiovascular risk. That measurement is being done in one of our current studies but the data won't be available until next year. In the AFREZZA trials the CV risk for the US FDA was only 1.01 --- showing essentially no risk and far below the Agency's acceptable level of 1.30.

3) What is the time line for launch of Afrezza outside US?

Mr. Mann: We are planning to file for the EU next year. Many countries quickly follow US FDA approval and several of these are already in discussions with us. There are a few such regions in which partnerships could likely be finalized outside of a “global” partnership.

4) Has Mannkind found licensing opportunities for the Technosphere platform?

Mr. Mann: We are in discussions for several opportunities to deliver drugs with the Technosphere platform.

5) If Mannkind signs a partnership for Afrezza, will it include only the TI (Technosphere insulin) or both TI & the platform?

Mr. Mann: Our partnership talks on AFREZZA at this time are only for TI and not on the platform. We are in several separate discussions for use of Technosphere with other molecules.

6) You have seen the potential of Technosphere particle a decade back, given all the results of trials done so far, what aspect of TI surprised you the most?

Mr. Mann: I have long recognized that there is no need for complex titration of AFREZZA for different meal sizes. What has surprised me most is that in Study 119 it seems that in type 2 --- at least before end stage --- a person can take a dose of AFREZZA and will not have a hypo even if nothing is eaten.

7) Over the years, do you think FDA significantly tightened the regulatory processes and stacked the odds against start up biotech companies?

Mr. Mann: The FDA has certainly tightened the regulatory process, in my view beyond what is necessary. The absolute aversion to risk in the US is likely to choke off innovation.

8) Critics say, even if FDA approves the drug, the sales of inhaled insulin won't be great. Are you still confident that Afrezza will see billion+ dollar sales?

Mr. Mann: We have had multiple market surveys performed with physicians that all refute the assertions from the naysaying analysts. In a survey performed last year with 613 physicians, about half in the US and half about equally divided in the five major European markets, there were almost uniform projections that about 25% or more of their patients would be appropriate for AFREZZA, and that they expected to adopt AFREZZA for most such patients within one year (over 90% of the estimates at one year).

9) Given the costs of running a public company, the hostile reception of Wall Street & others, if you have to do it all over again, would you have kept Mannkind private until FDA approval?

Mr. Mann: Being a public company certainly has its disadvantages, yet a benefit is that so many people are now aware of AFREZZA and this may expedite early use. Perhaps we would have been better off keeping the company private, but we cannot turn back the clock.

10) Do you think Mannkind’s oncology drug has better potential than Dendreon’s ProvengeTM?

Mr. Mann: As to our oncology program, our vaccines certainly have many potential advantages over ProvengeTM. Our vaccines are "off the shelf' and far less costly. Our early clinical trials are very promising and appear to be more effective, at least for certain cancers. On the other hand we are at least three years away from approval.

Tuesday, June 1, 2010

Prandial insulin’s effect on HbA1c – Alfred Mann’s thoughts

I want to thank Alfred E. Mann, Chairman and CEO of Mannkind Corporation for sharing his thoughts on prandial insulin’s effect on HbA1c. Certain references to names have been removed. None of Mr. Mann’s original wording has been modified. Here it goes.

In 1992 the results of the NIH sponsored DCCT study correlated HbA1c to three major long-term complications of diabetes, and since then the goal in therapy has been to reduce HbA1c to as close as possible to normal levels (~5.7%). Because of the difficulties of achieving that goal the usual targets are 7.0% for the ADA and 6.5% for most other expert societies.

The long-term complications of diabetes can be devastating, but short-term hypoglycemia is also serious and can result in coma and even death. It is estimated that about 8% of Type 1 diabetics die of hypoglycemic incidents. The challenge in diabetes therapy is to balance long term safety issues with short-term safety issues.

With today's prandial products, insulin persists and is present in the body long after the meal is already digested. This excessive insulin persistence without counter-balancing glucose leads to a late postprandial drop far below baseline (i.e. below the level before the meal/injection). To reduce this short-term safety risk of hypoglycemia patients are managed at high fasting glucose levels. The basal insulin dose is lowered in practice to increase the fasting glucose. These high fasting levels increase HbA1c and also mask the advantages of a superior prandial (mealtime) insulin. That is why trials with AFREZZATM do not usually result in a better HbA1c. Let me explain:

HbA1c is essentially an approximate measure of a person's average glucose levels over about three months. The correlation of HbA1 c to estimated average glucose (eAG) is as follows:

HbA1c (%)
eAG (mg/dl)
5
97
6
126
7
154
8
183
9
212
10
240
11
269

To see the effect of this let us look at a recent study in which the cohort using insulin Lispro (HumalogTM) had an almost unchanged HbA1c over the life of the study, with an average 7.62% at the start and 7.61% at the end. These HbA1c’s would translate into an estimated average glucose level of 171.8 mg/dl. Yet the fasting glucose level was 178mg/dl so the average glucose level over those few months was actually lower than baseline. How is that possible?

The explanation is simple. If the late postprandial reduction in glucose is larger than the prandial increase for the meal, the average glucose can actually be below baseline. An ultra-fast acting Insulin that does not have that persistent hyperinsulinemia would not have the late postprandial plunge and would thus have a higher average glucose and of course a higher HbA1c.

Indeed, if there were an absolutely perfect prandial insulin that has zero excursions- no highs and no lows --- no matter what a person eats, in the trial cited above the HbA1c would have been higher because the eAG would have been 178, not 172 mg/dl.

That is what I tried to convey in my presentation at the Merrill Lynch Conference. The fasting glucose level in study 009 in type 1 diabetes was 188 mg/dl and the HbA1c improvement was less than for the insulin Lispro arm and, because of the data spread, the upper 95% Ancova confidence level was .38% or .401% depending on the statistical methodology. The FDA limit for non-inferiority, i.e equivalency, is .400%. In its Complete Response Letter (CRL) the FDA specifically indicated it was not asking for new trials but invited us to present further analysis of existing data and new data to support the non-inferiority of AFREZZA compared to insulin Lispro.

We have in fact responded to the Agency with both additional analysis of our earlier data and new data in type 1, especially from Study 117, in which HbA1c for AFREZZA was a tiny bit better than for insulin lispro.

Since in Study 009 the HbA1c for AFREZZA was not better than for insulin lispro and since HbA1c is today’s measure of efficacy, why should anyone use AFREZZA? First, I am convinced that AFREZZA is certainly a better prandial insulin that more closely matches typical meal digestion. Only with such insulin that does not exhibit late postprandial hyperinsulinemia can fasting glucose levels be reduced enough to enable people to safely reach a normal HbA1c. Secondly, AFREZZA is clearly better in all the other important secondary measures. It has less risk in hypoglycemia (even though this is also partially masked by the insulin glargine (LantusTM) basal dosing) and also there is less weight gain --- usually weight loss. For AFREZZA to reach better HbA1c’s compared to current injectable insulin, physicians must recognize that AFREZZA itself does not cause the hyperinsulinemia so that they will be more comfortable in reducing fasting levels safely to near normal.

I believe that even in type 1 diabetes AFREZZA will become recognized as the superior prandial insulin that does not itself lead to hyperglycemia, lowers postprandial highs, is weight neutral, does not need complex meal titration, does not require multiple daily finger sticks, and is more convenient and discreet in prandial therapy. Certainly we cannot make such claims based on the registration trials to date. Interestingly, about 15 years ago, based on the registration trials, the FDA saw no benefits of insulin Lispro compared to regular insulin other than convenience in not having to take the injection 45-60 minutes before the meal. Today no one rationally questions that RAAs are superior in SC injections. It will require physicians and patients to become more comfortable with the better safety profile of AFREZZA in real world therapy before they will lower fasting levels that will support a claim of superiority in HbA1c for AFREZZA. I expect that will follow soon after several planned studies are published which I am certain from the science will establish the advantages of AFREZZA.

------------------------ End of Mr. Mann's comment ---------------------------------------------