MannKind And Afrezza's NDA Evaluation: What Is The Real Justification For The Advisory Committee?

| About: MannKind Corporation (MNKD)


“Diabetes Mellitus” the disease - it's very complicated. Some implications of the disease on body systems and hence, treatment-related risks.

Negative patient realities associated with daily subcutaneous injection of insulin, which impact patient compliance and hence, justify the need for a better diabetes management option.

Challenges associated with inhalable drug administration, including Afrezza (dry powder) insulin, which could impact NDA decision and patient compliance.

The role and rationale for an “Advisory Committee (AD-COM)” in the NDA process.

I am a Pharmacologist/Toxicologist and a longstanding diabetic since 1993, taking multiple subcutaneous injections of insulin daily for over a decade. I have an interest in any significant improvements in the options to manage my diabetes. As a pharmacologist, I have invested myself in understanding both the technical cellular biology mechanisms and systems impacts of this complex disease, in an attempt to better manage my diabetes. As well I needed to better understand the "Risk:Reward" profile of this new treatment option from an investor perspective, since I decided to buy MannKind (NASDAQ:MNKD) shares in early 2013 and have added more since then.

As I began to understand the combined pharmacological and investment considerations and how they related to each other, I thought other retail investors like myself might benefit from my insights to help them better understand their investment risks. In this article, I will attempt to summarize some of the "real" pharmacological and diabetes disease and treatment facts that can impact our individual and collective investment risks.

I have been following MannKind and its Afrezza for some time, and taken and held a long position since early 2013. Like most MannKind investors, I have been anxious about the outcome of the upcoming FDA-NDA evaluation process. Why? I am an informed diabetic, ready and willing to embrace the new treatment resource of "inhalable insulin." As well, the uncertainty of the FDA decision and its impact on my limited retirement/investment resources causes concern for us all.

There has been much discussion and many articles expressing diverging opinions about the rationale and implications of the FDA requiring the "Advisory Committee (AD-COM)" as part of their evaluation of the Afrezza program. I have been following Seeking Alpha articles with interest and found many very helpful, while others were clearly attempts to sow disinformation. Uncertainty is the enemy of "risk management," as I am sure those authors are well aware. I have decided to jump into the discussion with this, my first article. So I ask you to bear with me as I learn how to navigate in this forum.

I have come to the view that many people who have been writing about the ADCOM and other Afrezza related issues may not have the insight I have as both a diabetic and a toxicologist. With that in mind, I have reviewed relevant scientific literature and rely on that, as well as my over 40 years of experience dealing with drugs and how they interact with the body and each other, and my personal diabetes experience to support my views expressed below.

My short message is that after my review, I believe there is an evidence based support for the potential of inhalable measured doses of dry power insulin (Afrezza) via the delivery technology of the "Dreamboat" inhaler to be a significant improvement over current subcutaneous injections of insulin in the management of this complex and challenging disease. My goal is to share and present information and insights that will eliminate some of the uncertainty in those investors without scientific or diabetic experience: I offer:

1. Some of my insights about the nature of the disease, how it disrupts many body systems and some implications of these disruptions, as justification to find better options for diabetics.

2. Description of real experiences in attempting to manage diabetes with multiple daily subcutaneous injections of insulin. I will describe some of the very real negative outcomes and associated risk factors, which contribute to fear, non-compliance and poor efficacy from such use.

3. Explain some established toxicological concepts and information relating to administering drugs/insulin via the lungs, which will hopefully bring some clarity to the uncertainty surrounding the Afrezza evaluation challenges of the FDA NDA.

4. An objective review of some of the important positive and negative considerations relating to MannKind's Afrezza system of inhaling "dry powder" particles (Technosphere Insulin) compared to the existing subcutaneous injection options currently in use.

My goal in this review is to improve the clarity about real risks and real benefits of both the status quo and the new opportunity represented by MannKind's Afrezza program and to help readers understand the very appropriate justification for the Advisory Committee. Here goes:

1. Diabetes Mellitus, the disease - it's very complicated… some implications of the disease on body systems:

Diabetes is described as a disease of failure of the body's ability to produce insulin (Type 1) and or a loss of sensitivity of the body to the effects of insulin produced (Type 2). The factors contributing to either cause are beyond the scope of this article. I will instead focus on the end result of this situation.

Every cell of the body requires an ongoing supply of energy to fuel its operations. Therefore, a continuous and or stored supply of "fuel" is needed by every cell to keep the cellular energy flowing, otherwise cellular operations decline and the cells may die. Every organ has its own energy production facility or "fuel cell" operating within a protected sub component of each cell, called the "mitochondria." Without a constant source of fuel, these energy production units cannot create the portable energy molecules needed by every operation of every cell, leading to cell dysfunction and death. There is emerging science indicating that many modern "chronic degenerative diseases" may be a result of such shutdown of the energy supply and management of cells and hence organ systems.

Insulin is generally discussed in the context of its role to regulate carbohydrate (sugar/glucose) in the body. Insulin works like a "key" for specialized "lock" mechanisms located on the outer surface of every cell. The insulin is the primary key that can open the lock to the doors to every cell of the body, to allow glucose/sugar to enter the cells as needed. This glucose/sugar is the fuel used by these cellular engines. When no insulin is available or the cells' receptors no longer respond to available insulin, the fuel needed by the cells cannot enter, leading to reduced functionality or death of the respective cells.

However, the role insulin plays in the body is much greater than many people understand. In addition to glucose, insulin regulates/controls the entry (and hence the use) of other critical fuels and nutrients, such as fatty acids, amino acids (the building blocks of protein), minerals and vitamins, etc. The brain runs almost entirely on glucose (and needs a continuous uninterrupted supply), while the heart runs mostly on fatty acids. These two systems experience dramatic disruption when sugars, fatty acids and other vital nutrients are not available.

When the insulin system is not working, all the cells and organ systems of the body essentially become starved. These cells detect this adverse environment and are designed to send out distress messengers within and outside the cells into the blood. These distress messengers circulate throughout the body, activating any number of complex metabolic processes designed to increase the production of more glucose, fatty acids, amino acids and cofactors, etc., which are delivered throughout the body to meet the starving cells' needs. However, without insulin and the effect of insulin, these fuels and raw materials circulate in a futile manner, unable to enter the cells to alleviate the internal stresses. Ironically, the cells are starving while all around them there is excess glucose and nutrients.

This situation is relived hourly and daily by diabetics, especially those who are poorly controlled. Clearly, with chronic stresses such as these, the cells and organ systems succumb to dysfunction and ultimately manifest as complications that become diagnosable signs and symptoms of the progression of the disease.

The big picture here is that without insulin, virtually every cell and hence every organ in the body is at risk of disruption and death as a result of insufficient or inconsistent supply of needed fuels and nutrients. Uncontrolled diabetes can thus contribute to many complications and loss of function of body systems. The list of acute and chronic "complications" is long and growing. Uncontrolled diabetes reduces functionality and productivity, quality of life, while contributing "secondary diseases" in the kidney, cardiovascular system, obesity, arthritis, mental health, etc., all of which impose massive costs to every society where it occurs.

A new and very significant discovery relating insulin and the survival of cancer cells is emerging. It appears that newly formed cancer cells have figured out how to overtake the internal controls of the production and allocation of insulin receptors on that cell. Apparently cancer cells have been discovered to posses many more insulin receptors (the "lock" part of the "lock and key" analogy I used above). These additional insulin receptors will be able to respond to available insulin, by opening the doors to the cell and allowing larger amounts of glucose and nutrients into the cancerous cell. This information helps me to understand how cancer cells can grow so much faster than normal healthy cells. This manipulation of the cell biology is an adaptation, which allows the cancer cells to thrive and survive the body's efforts to control them. Clearly, this new insight suddenly places a new priority on the need to understanding consequences of not effectively managing diabetes. Diabetes is now clearly a cancer risk factor. It further justifies why aggressive management of diabetes is necessary and any new and effective treatment option should receive high priority in development by Biotech/Pharmaceutical companies and approval by regulatory agencies.

The bottom line message derived from a large body of scientific literature and based on many large scale longitudinal studies is absolutely clear. An aggressive approach to managing blood glucose levels is the only way (at present) to slow the progression of the disease and minimize the many progressive, debilitation complications associated with diabetes. That means, how one keeps their blood sugar in as close to the normal range as possible, is less important than achieving that endpoint.

I make these points in the context of helping investors and diabetics understand the potential demand/market for any new treatment, which can substantially improve treatment outcomes and reduce mortality. I view this Afrezza delivery system as having potential to make a real difference for diabetics worldwide.

2. Negative patient realities associated with multiple daily subcutaneous injections of the variety of insulins currently in use that impact patient experience and hence, compliance.

How does all the above relate to MannKind and Afrezza? There are many limitations associated with the subcutaneous injection of insulin products currently in use, which I believe will motivate diabetics and their physicians to adopt this new treatment option. Here are some of them:

There is typically a lag period between when insulin is injected and when peak concentrations are achieved and hence glucose lowering effects. If the diabetic does not coordinate the timing and dose of the appropriate insulin injection with food intake, there is often a disconnect between the time the insulin is reaching its peak concentration and the time when the food is mostly digested (when the rate of glucose entering the blood is slowing). This leads to an initial spike in blood glucose following the meal, followed by an exaggerated drop in blood glucose (hypoglycemic crash) several hours after the meal. In response to the low blood sugar crash, the patient often responds with gorging on high glycaemic foods to bring their blood sugar up.

However, what commonly happens is the ingestion of too much high glycaemic foods (high sugar), causing another spike in hyperglycemia. These large roller-coaster like fluctuations cause disruptions in every cell of the body on a cyclical basis throughout the day, week, month and chronically for years. The diabetic experiences a wide range of symptoms secondary to stressful intra-cellular and subsequent physiological disruptions associated with such fluctuations. These experiences are typically negative in nature and lead the diabetic to become discouraged, lose hope and eventually poor blood glucose control. (I am speaking from experience here.) Diabetic complications develop and grow over time in such situations. My thinking is that Afrezza's rapid uptake from the lungs will more naturally parallel the insulin release and response to requirements of the body and eliminate many of these fluctuations and secondary consequences.

There are many insulin "injection site" problems seldom discussed. I will list and explain some of the more common and problematic ones:

a) Insulin preparations contain one or more "preservative" chemicals to prevent bacterial contamination or survival. Every time insulin is injected, a small amount of these preservatives are injected along with it. Since these preservatives are toxic enough to kill bacteria, one could deduce that they might well be toxic to the cells and tissues in the injection site area. You would be correct. However, the concentrations are very low to minimize the nature and extent of damage or reaction from a given injection. However, some people may be sensitive to them initially, damage may occur without us knowing, while others may develop a sensitivity to them over time. The body's immune system can develop antibodies to them, which can contribute to ongoing irritation and inflammatory responses in the injection sites.

b) These same chemicals also are capable of killing some of the cells in the injection site area. Over time, the tissue in the injection site can develop scar tissue in response to this damage. This scar tissue contributes to poor distribution of the insulin in the site over time, which leads to reduced uptake of the insulin and hence reduced efficacy. This is more likely when the same injection site is used excessively over time. People are creatures of habit and tend to use the same general area for injections.

c) The micro environment of the injection site is subject to frequent subcutaneous lacerations caused by the unintentional, random movement of the laser sharpened tip of the injection needle. The slightest movement of the insulin cartridge/syringe held by the diabetic while the injection is in progress can cause an erratic sweeping movement of the needle tip under the skin, cutting small blood vessels, connective tissue, nerves and other tissues. This is especially likely to occur when attempting to inject insulin while moving in a vehicle or other similar situation. Again, over time these damages result in the production of more scar tissue and loss of function in the area, which again contributes to reduced uptake of insulin.

d) In the area where the insulin is injected, the concentration of insulin is very high for a period of time based on the type of insulin used and how long it takes to be diluted and absorbed from the injection site. It sometimes takes hours for the insulin to dissipate or be removed from the site of injection. During this delay period, the higher concentration of insulin causes the cells around it to take up greater amounts of fuels and nutrients (glucose, fatty acids, amino acids, vitamins, etc.), thereby over feeding those cells frequently with every injection until the insulin is taken away by the blood supply. Most diabetics tend to inject themselves in the "abdominal fat pad" most of the time, trying to vary the injection site within that area. The consequence of that overfeeding of the cells in the abdominal and lateral fat area is to cause further accumulation of fat, which creates a number of other problems, not to mention appearance concerns and further variability in insulin uptake after injections, leading to more variation in blood sugar levels.

e) Some of the insulin preparations in use today are modifications of the original human insulin. They are either complexed/joined with another molecule to alter uptake or duration of effect, the amino acid combination may be slightly modified, additives may be present, etc. The body's immune system can detect some of these differences from human insulin and can develop antibodies, which may compromise their efficacy over time (this may occur with any route of administration).

f) The withdrawing of the injection needles often is followed by blood leakage from the needle hole. The blood originates from the sub surface lacerations mentioned above. This blood leakage is frequent. In my own experience, I would say it is at least 20% of all injections, even with my best efforts. The exposed blood at an entry point in broken skin is an opportunity point for bacterial contamination, especially in the presence of poor hygiene and non-sterile practices. A typical insulin dependent diabetic requires 2-4 injections per day over 365 days, which equals 730-1460 injections yearly. With a 20% occurrence of blood leakage, that represents 146-292 opportunities for infection per year. You can do the rest of the math. Given that diabetes is likely to be a lifelong partner to diabetics, this is a significant ongoing risk factor.

g) Taking insulin by injection typically requires some personal privacy. Often diabetics will delay taking their injection due to the circumstances of the activity or absence of privacy at the time it should be taken. Sometimes, it is then forgotten as we become engaged in other activities. This is relatively common for busy, on the go diabetics and further contributes to ineffective management of blood sugar levels and related disruptions and complications over time. Afrezza would be much less problematic and enhance timely dosing.

h) Diabetics who inject insulin and who are using medications (such as Warfarin®, Aspirin®), which thin the blood or prevent blood clotting, are at risk of another problem. Any person whose blood clotting mechanisms are either intentionally altered to delay clotting under medical supervision, or inadvertently experience the same outcome as a result of other factors, are at risk of frequent blood leakage at injection sites (again due to the internal lacerations from the needle). More blood would escape than in those with normal clotting. This leaked blood accumulates in the injection site area and becomes a "bruise," visible to the diabetic and others. Again (using the numbers in item "f" above), the frequency would be even higher in diabetics with compromised clotting times. As it takes some time for bruises to go through their biological healing cycle, it is not uncommon to have multiple bruises simultaneously present and visible. This, of course, is another negative factor that can contribute to tenderness, scarring, infection or embarrassment, all of which can lead to poor compliance.

These are some common realities experienced by most insulin injecting diabetics. The occurrence and severity will vary by person and their circumstances. The prospect of being able to take insulin by oral inhalation directly into the deep lungs would significantly reduce most of these consequences of injection and improve glycaemic control, leading to delay of diabetes progression, reduction of complications and better quality of life.

It is important to note that with the current treatment options available, the use of the Afrezza system does not eliminate the need for subcutaneous injections of insulin. Rather, it permits reduction of the number of injections daily (and their related adverse effects as noted above), from 4 or 5 down to one of long acting "Basal" insulin, which works quietly in the background between meals, over 24 hours. Again, using the numbers in paragraph "f" above, the diabetic could reduce the number of insulin injections and related adverse effects by approximately 730-1825 (the actual number depends on their existing treatment program). This combination will reduce health risks and improve quality of life, while bringing greater control over this complex disease for diabetes.

These points are made in the context of helping investors understand what are real "motivating" factors, which will influence patients and physicians to migrate to and accept this new treatment choice. This consideration positively influences the market potential of MannKind's Afrezza insulin delivery system.

3. Established toxicological concepts and information relating to administering drugs/insulin via the lungs, which will hopefully bring some clarity to the uncertainty surrounding the Afrezza evaluation challenges of the FDA NDA.

Background: I will provide a brief overview of lung structure, design and function and how they are implicated in the challenges to administer drugs/insulin into the body for therapeutic purposes via the lungs. The following points are intended to help the MannKind investor to understand the real challenges to (and benefits of) the Afrezza dry powder Technosphere Insulin Dreamboat inhalation system. Knowing these very real challenges, I hope will help investors to not be so concerned about the FDA's requirement of the Advisory Committee in this upcoming NDA process. Instead of being a negative factor, I believe you will appreciate that the presence and role of the AD-COM will be seen more as a positive, prudent measure on behalf of the FDA, which will ensure appropriate risk assessment and risk mitigation are performed, leading to the long-term success of Afrezza.

To put this issue in context, our legal system requires us to think of an accused person in our society as "innocent until proven guilty." However, from a toxicological perspective, we are trained to think of drugs and chemicals as "guilty until proven innocent." There are many examples in history where drugs and chemicals were licensed without adequate knowledge of the harm they can cause. There is substantial work to get to that point, and in my opinion, the AD-COM is a necessary and prudent part of that process, which protects the users first and then the investors. A short-sighted party may rush the process, to the detriment of all stakeholders.

All systems of our bodies are designed to be able to communicate with each other. The Respiratory system is no exception. The respiratory system contains miles of airways, 3-500 million efficient alveoli in clusters capable of gas exchange and drug uptake, with a total surface area of approximately 70-100 square meters (roughly half a tennis court) and over 600 miles of small blood vessels supporting its functions (from Wikipedia). It is these features that make the lung an efficient means to administer drugs to the body. Clearly, the large surface area of the deep lung tissue offers a massive entry port for drugs to be taken up into the body. The uptake potential for inhalable insulin is massive, compared to an insulin injection in a small localized subcutaneous area of +/- one square inch, with low uptake of the insulin due to being surrounded by fat and relatively poor blood supply to enhance insulin absorption.

This system is the major gateway to the interior of the body and agents able to reach the deep lung can have profound effects on all the interior systems. Most toxins enter the body via inhalation and migrate to either the lungs or the intestinal tract to be absorbed into the body. The respiratory system is essentially divided into two major structural components based on function. The upper portion, from the mouth to the tubular branches well into the chest, primarily conducts air flow with no gas exchange. From there, the lower portion proceeds into the deepest lung area where small bronchial tubes branch into millions of (grape like) clusters of thin (Alveolar) sacks of (Alveolar) cells filled with blood vessels. This is where gas exchange occurs and chemical agents enter the body. This deep lung area is where the inhalable drugs/insulin needs to reach in order to enter the systemic circulation to be distributed throughout the body to be effective. However, there are many barriers and challenges to the drugs/insulin on this journey.

The Respiratory system has two major functions to meet the body's needs. (There are other functions, but for this article they are not relevant.) First, is to move air in and out of the lungs for the purpose of exchanging important gases, oxygen and carbon dioxide. The second is to function as an early warning and defense system to protect the body from foreign and toxic substances that might threaten the function and survival of the body. That is, it is closely integrated with our immune system. A variety of immune system components are distributed all along the respiratory system, from the mouth to the deep lung. They are able to detect and clear unwanted agents in the upper portion and detect and destroy those able to reach deeper into the lungs. In both areas, the immune system can produce protective antibodies to these agents, which may reduce the efficacy of any drugs taken by this route.

To be able to carry out these functions, the respiratory system has evolved to be highly sensitive and selective as to which agents it will accept or reject and how it will respond to them. For example, we all know even a drop of water or piece of food entering our "wind pipe" can trigger a violent coughing spasm, which is very distressing. The lining of the air conducting upper part of the respiratory system is highly sensitive to many physical or chemical agents and air quality characteristics. Examples of agents that will adversely affect the respiratory system include, air borne particulate matter (e.g., dust and Afrezza dry power insulin); corrosive or toxic gases, heavy metals, liquids; extremes of temperature and humidity; concentrations of oxygen and carbon dioxide; changes in atmospheric pressure; organic agents such as pollen and other microbes and many other agents the respiratory system is designed to intercept, transport and destroy in its role to protect the body. The system's response to such agents can be acute and violent or gradual or chronic. Whenever violent responses occur they place great strain on the heart, up to and including cardiac arrest in some individuals with co-existing pulmonary or cardiovascular diseases.

The physical design of the system can be compared to that of a mature hardwood tree, looking at it turned upside down and without the roots. That is, it has a complex structure with a main trunk, a series of branching tubes that conduct the liquids and nutrients between the roots, leaves and fruit. The leaves are the primary production components, as are the deep lung alveolar sacks and cells in human lungs. This physical configuration of all the branching components means that any incoming air borne particles will collide with the moist side walls and branch points or forks, and much of the "drug/insulin" will be taken up by these tissues on the inside of the conducting tubes long before it gets to the deep lung areas. The actual disposition of an inhaled drug particle while en route to its destination is affected by many factors, including its size, shape, density, solubility, whether it has an electrical charge on it, velocity of air flow, how the lining of the contact surface of the lung reacts and many other considerations.

The tendency for drugs and particles to be trapped on their way to the deep lung contributes to a large portion of any drug dose administered by inhalation to never reach the deep alveolar region where it can be taken up into the blood. In other words, typically only a small fraction (as low as 10%) of the starting dose actually reaches the absorption area of the lungs. Particles can be trapped in the upper non-absorbing areas and may be exhaled or cleared as mucus or swallowed. The immune system may attack and destroy the drug before it can act. Some patients do use their inhalers incorrectly, which further reduces delivery efficiency. These factors create numerous practical challenges to determining what the administered dose should be in order for enough drug to be taken up and be pharmacologically effective.

Establishing with certainty these dosing parameters is still likely to be a challenge for MannKind and Afrezza until enough clinical experience is acquired following approval of the product. It will require years of real world experience with a large population of patients with a wide variety of personal characteristics and medical conditions to achieve the required clarity needed for effective and safe dosing of any inhaled drug. I expect the FDA will be advised by the AD-COM of this reality, and hence the need for ongoing clinical monitoring following an approval.

Individuals with existing pulmonary and other chronic disease that compromise lung function, cardiovascular, immune systems, etc., are at greater risk of a wide range of adverse responses and outcomes following the administration of ANY drug given via the lungs, some of which are noted above. Further, individuals taking many medications (known and unknown to their physicians) that may compromise or have adverse effects on the respiratory system, cardiovascular and immune systems are typically excluded from most clinical trials. For example, some cardiovascular drugs like Beta Blockers, blood pressure lowering, immune suppressants, pulmonary asthma and allergy drugs and many more could interact with the drugs given via the lungs. These patients may often be excluded from clinical trials.

4. The objective review of some of the important positive and negative considerations relating to MannKind's Afrezza system of inhaling "dry powder" insulin particles (Technosphere Insulin), compared to the existing subcutaneous injection options currently in use, can help investors understand the rationale and role of the Advisory Committee in the NDA process

The science of administering drugs via the lungs is not as well understood compared to giving them subcutaneously or by other routes. However, the potential to greatly improve drug administration and hence their effects is huge. The uncertainty about how the lungs and body will respond to administering insulin by this route, (due to the relative absence of knowledge of this means of giving the drug), is a major area needing to be understood by the FDA and AD-COM relative to Afrezza. It appears to me that the evidence to support Afrezza inhaled insulin being an effective treatment for diabetes seems clear.

The immune detection and protection role of the respiratory system is massive and cannot be underestimated as a possible mediator to the presence of the dry powder insulin as an agent to trigger an inflammatory or auto-immune response. Questions relating to this aspect of the inhalation of insulin also need to be explored and monitored following any approval and be used to justify post approval clinical monitoring.

There are currently well established precedents for the administration of a variety of drugs via the lungs. For example, patients with allergies, asthma and other pulmonary dysfunction and diseases have been taking medications to help manage their diseases and symptoms for decades. Bronchodilators, steroids, inflammation "mediators," immune suppression agents and others under development have been used for decades, meaning many of the dosing and body responses to inhalation drug delivery are being better understood and managed. In that context, I believe we can take some measure of comfort that the "inhaled" insulin can benefit from the collective science of pulmonary drug delivery technology and ongoing experience. In addition, it is apparent MannKind has developed its own proprietary technology and system for formulation and delivery of their unique insulin preparation. I view their technology as a delivery system that will offer capability to deliver many other drugs as well.

The uncertainty lies in not knowing the impacts of this route of administration due to this being a novel approach to administer insulin. Therefore, I believe MannKind is unlikely to be able to provide all the needed answers to the FDA/AD-COM about the effects of its inhaled product on the respiratory and immune systems. Therein lays the need for oversight by competent advisors to the FDA and hence the need for and role of the Advisory Committee. Without such oversight and guidance, an approval without requirements to closely monitor and report on patients' responses to Afrezza inhalation would be poor risk assessment and poor risk management from a toxicological perspective.

As stated above, the prudent approach to evaluating a new drug (including its delivery system) is to consider it "guilty until proven innocent." The various points presented in this article support the rationale of the FDA to utilize the Advisory Committee as a resource in MannKind's Afrezza evaluation process. It provides both expertise and meets their due diligence needs when reviewing a novel drug and a novel delivery mechanism and novel route of entry into the body.

The problems associated with the current subcutaneous injection of a wide variety of insulin preparations may be the driver to find a better solution and motivate physicians and diabetics to adopt the Afrezza option if approved. On the other hand, there are real, but in my opinion as a pharmacologist/toxicologist, relatively manageable uncertainties and challenges associated with the Afrezza inhalation system.

I am not aware of the actual make-up of the Advisory Committee, but would hope there is expertise relating to respirology, toxicology, immunology, internal medicine, medical device, physical chemistry and other disciplines relevant to the issues needing to be addressed.

I believe the concerns raised recently about justification for an AD-COM and about the integrity and objectivity of the members of the Advisory Committee were adequately addressed by SA author Jeff Eiseman and others.

From my perspective as a diabetic looking for a better choice to manage my diabetes, and as a toxicologist familiar with the reality I face if I am not successful, I believe the delivery method challenges and patient acceptance issues are very manageable and worth the effort. I will be watching with great interest the proceedings and outcome of the FDA decision and any conditions placed upon any approval given.

The points and views made in this article are totally mine and reflect my perspective as a diabetic using insulin as my primary treatment measure and as a toxicologist. I apologize for the length of the article. The scientist and teacher in me needed to provide a foundation for the readers to understand my opinions and conclusions. It was my goal to bring some clarity to the perplexing question of "why" the Advisory Committee is necessary, while providing insights that may aid MannKind investors and diabetics in better understanding the risk assessment issues needing to be understood and addressed. I am long MannKind. Good luck to all. Any feedback on my points or views is welcome.

Disclosure: I am long MNKD. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.

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