Proud of be an AL Maniac and why MannKind is a great buy longterm

Let me start with a little disclaimer as always: I am not an adviser, a guy with a crystal ball and I do not advise anyone to buy or sell based upon my analysis of the company.
My only intention is to write a complete analysis because i am tired of the BS articles written and posted on Motely fool and Seeking Alpha that persuade retail to sell or buy on misinformation for their personal profit. I have traded in and out of MNKD several times based upon catalysts and technical analysis.
I currently have no position in MNKD but may open a position in the next 48 hours. The main reason I have written this article is to provide a valid analysis of MNKD as the latest debauchery on Seeking Alpha by author Derek Lowe is an insult to sentient beings everywhere. http://seekingalpha.com/article/1638982-mannkinds-latest-data
This is a very long article and i have outlined it into certain parts, if you are familiar with Mannkind's history, skip over it, if you are familiar with pathophysiology of diabetes, skip it, etc. etc.


According to the CDC :
"The estimated economic cost of diabetes in 2007 was $174 billion. Of this amount, $116 billion was due to direct medical costs and $58 billion due to indirect costs such as lost workdays, restricted activity, and disability due to diabetes. People with diagnosed diabetes incur average expenditures of $11,744 per year, of which $6,649 is attributed to diabetes. People with diagnosed diabetes, on average, have medical expenditures that are approximately 2.3 times higher than what expenditures would be in the absence of diabetes. Approximately $1 of $5 health care dollars in the United States is spent caring for someone with diagnosed diabetes, while approximately $1 of $10 health care dollars is attributed to diabetes."

With a current market cap of 2.29 billion, what do you think the potential of this company is?


Intro to MNKD
MannKind corporation is the brain child of CEO Alfred Mann. It is a biopharmaceutical company focused on the discovery, development and commercialization of therapeutic products for patients with diseases such as diabetes. MNKD lead product that recently finished phase III clinical trials is called AFREZZA. AFREZZA is a truly unique ultra rapid-acting mealtime insulin therapy used via inhalation. In the clinical trials Afrezza was used as treatment for both Type 1 and Type 2 diabetes to control hyperglycemia. Afrezza is an inhalation powder pre-metered into single use cartridges and the light and convenient dreamboat inhaler.The inhaler is easy to use, small, requires only one inhalation per cartridge and needs no cleaning because it is replaced after 15 days of use.

Example A: Awesome convenient Afrezza with the dreamboat inhaler

Example B: Exhubera, sir I'm going to need you to stop hitting your bong

Here is a description of AFREZZA  from its companies website http://www.mannkindcorp.com/about-us-overview.htm
 AFREZZA has a time-action profile unlike other insulin products. In the clinical trials to date, AFREZZA inhalation powder is rapidly absorbed into the bloodstream following inhalation, reaching peak levels within 12-14 minutes. Due to this unique and novel approach, AFREZZA produces a profile of insulin levels in the bloodstream that closely mimic the secretion of insulin seen in healthy individuals immediately following the beginning of a meal.
This is the third time that the company takes a run at the FDA to get approval for AFREZZA. 

According to the Centers of Disease Control and Prevention, in the year 2011 there were approximately 25.8 million patients in the United States who have been diagnosed with diabetes and the CDC expects that approx 1 in 3 people will have diabetes by the year 2050. The most obvious reason for the drastic rise in diabetes in the US is Type II diabetes being brought on by a sedentary life style and obesity. The International Diabetes Federation has estimated that approximately 366 million people have diabetes today and approximately 552 million people will have diabetes by the year 2030.

Technosphere of the future
Imagine being a patient that needs to take a shot of insulin before eating your food at a nice restaurant or for that matter, any restaurant. I can't tell you how many times i have had patients that were hypoglycemic (glucose less than 80 g/dl) at restaurants because it took too long to get their food or to even get a table. Most of these patients felt very embarrassed because upon EMS arrival they are unconscious, may have had a hypoglycemic seizure or worse could have been acting very bizarre due to the low glucose levels.

I tend to sit and talk to my patients and on multiple occasions i was informed that they took their insulin shot at home and didn't want to do it in public due to the stigmata associated with needles. Some of these folks had the cops called on them when they were giving themselves insulin shots in the bathroom. It seems people can't tell the difference between someone with a medical problem giving themselves shots in the abdomen vs a heroin addict giving himself a shot in a vein.

The point i am trying to make here is that when you see someone with asthma or COPD use their inhaler, no one thinks twice about it but someone pulls out a needle and the general public assumes the worst.

Afrezza uses the technosphere formulation, basically meaning it is used via an inhaler and is directly absorbed into the blood stream through pulmonary circulation. How convenient would that be for one of the 25.8 million diabetics in the US?

The technosphere technology is not limited to insulin delivery. It is a versatile drug delivery platform that may allow pulmonary administration of certain drugs that require administration by injection and multiple other types of medication such as viagra. The advantage here is that drugs can be absorbed very rapidly into the arterial circulation, essentially mimicking intra-arterial administration. A faster acting viagra and your date just thinks she made you nervous and you needed to use the inhaler.

Patents providing protection for the dreamboat inhaler and cartridges have terms extending into 2023 and 2030, and the company has certain treatment claims that have terms extending into 2026 and 2029.

Prior Failures
According to the company yearly report: In March 2009, MNKD submitted a new drug application, or NDA, for Afrezza to the FDA, which the company sought approval of the product with the MedTone inhaler. In March 2010, the company received a Complete Response letter from the FDA that requested additional information about the clinical utility of Afrezza and about the commercial version of the MedTone inhaler. After meeting with the FDA in June 2010, the company decided to submit information regarding the bioequivalence of the MedTone inhaler and the dreamboat inhaler. In June 2010, the company submitted a thorough data for both devices along with additional evidence of efficacy of Afrezza in response to 2010 CRL by the FDA.


In January 2011, MNKD received a second Complete Response letter in which the FDA requested two clinical studies with the Dreamboat inhaler (one in patients with Type 1 diabetes and one in patients with type 2 diabetes), with at least one trial including a treatment group using the MedTone inhaler in order to obtain a head-to-head comparison of the pulmonary safety data for the two devices. 

Needless to say the stock price suffered, investors took heavy loses and the company was forced to do multiple stock offerings diluting share holders value to raise funds to continue the clinical trials.

DIABETES-PATHOPHYSILOGY
 The term diabetes refers to a metabolic disorder in which the ability of the pancreas to metabolize (break down) simple carbohydrates, such as glucose, becomes impaired because of the lack of insulin or inadequate production of insulin.
The pancreas is the primary blood glucose regulator. Digestive enzyme production and insulin and glucagon production takes place in the islets of Langerhans (sounds magical doesn't it). The beta cells in the islets of Langerhans produce insulin and amylin, the alpha cells release glucagon. Insulin and glucagon are the hormones responsible for keeping the blood glucose levels within normal ranges of 80-120 mg/dL.
In patients with diabetes there is a passage of large quantities of urine containing glucose, this can cause significant thirst and deterioration of body function. Insulin also helps with the re uptake of potassium back into the cells. Patients with diabetes who have progressed into renal failure and are on dialysis can have cardiac episodes due to the hyperkalemia they suffer from on a regular basis. Cardiac events vary from a few Premature ventricular contractions (PVC's), lethal arrhythmia's such as V-tach/V-fib or Myocardial Infarction. Suffice to say, insulin is a very important hormone.

• Type 1 Diabetes 
•  generally has been referred to as Children's diabetes or juvenile diabetes, although now patients are developing type 1 diabetes in adulthood as well. Type 1 diabetes can be caused hereditary predisposition, environmental factors such as an infection that can cause an autoimmune disorder in which the body forms antibodies and destroys the insulin producing islets of Langerhans. 
• Most of these patients do not produce insulin and require daily injections of supplementary, synthetic insulin throughout their lives to control their blood glucose levels. This disease requires constant regulation of blood glucose levels and patients are not always complaint as is the case with most young children, athletes, alcoholics and patients with multiple medical problems.

• Type 2 diabetes
• the most common form of diabetes in the US and the world
• referred to as adult-onset diabetes
• Approximately 90% of all diabetics in the United States have type 2 diabetes and the onset of the disease is becoming prominent in younger years due to the alarming rate of increasing obesity in our country.
• In many patients with type 2, the pancreas actually produces insulin but the body cannot effectively use it or is not making enough insulin to meet the metabolic needs of the body, leading to episodes of hyperglycemia (glucose levels being high)

• Hypoglycemia
• often the result of having taken too much medication, not eating enough food, or physical exertion.
•  The central nervous system including the brain depend entirely on glucose as their main source of energy, unlike other tissue which can metabolize fat or protein in addition to glucose. If the blood glucose levels drop drastically, the brain is essentially starved and if the hypoglycemia persists, cerebral dysfunction progresses very quickly to permanent brain damage.
• Signs/Symptoms of hypoglycemia include Altered Mental Status, slurred speech, stroke-like symptoms, seizures, diaphoresis (sweating profusely), Anxiety, hostility, and of course hunger.
• patients who are on oral hypoglycemic agents occasionally suffer from hypoglycemia and the cause is sometimes more sinister than taking too much medication. The oral hypoglycemic agents are metabolized in the body and then excreted by the kidneys; however, if the kidneys have become damaged, the patient is unable to rid themselves of the drug, so it continues to work beyond its half life. The drug recirculates, more insuling produced and in the middle of the night the spouse notices that the patient is diaphoretic and wont wake up. 
• Renal insufficiency and failure is common in patients with uncontrolled diabetes because the damage the molecules cause to virtually all organs and tissue in the absence of insulin. 

• Hyperglycemia and Diabetic ketoacidosis
• Hyperglycemia is clinically defined as a blood glucose level greater than 120 mg/dL, however clinically patients are encouraged to keep their glucose levels below 160 mg/dL and above 80 mg/dL. 
• Hyperglycemia can be caused by excessive food intake, insufficient insulin dosages, infection, illness, injury, stress, surgery and even emotional trauma. Onset can take hours or days. 
• If left untreated, hyperglycemia will progress to diabetic ketoacidosis (DKA), which is a life threatening condition that occurs when acids begin to accumulate in the body because insulin is not available to metabolize glucose.
• Most patients in DKA that i have come across are young patients who are non compliant with insulin, patients who are homeless (lacking a place to properly store insulin), alcoholics or patients suffering from some sort of infection.
• In DKA, the cells are unable to utilize glucose due to the insulin deficiency. Since the body cannot use glucose, it turns instead to other sources of energy, such as fat. The metabolism of fat generates acids and ketones as waste products. Because glucose must be excreted in the urine, the body loses excessive amounts of water and essential electrolytes due to the patients constant urination. This cause a shift in water balance and leads to an acid-base imbalance.
• The body continues to find a balance while glucose levels accumulate in the blood stream. The patient undergoes massive osmotic diuresis (polyuria). This diuresis, together with vomiting and the rapid, deep respirations (Kussmaul respirations) will cause progressive dehydration and acidosis, ultimately leading to shock, coma and death. 
• The process of DKA progresses slowly, during a period of 12-48 hours, with the patient's level of consciousness deteriorating gradually. 
• Signs/Symptoms include Fruity smelling breath, polyuria (frequent urination), polydipsia (excessive thirst), polyphagia (excessive hunger or increased appetite), Deep/rapid respirations, dehydration, hypotension (low blood pressure), tachycardia (fast heart rate), warm/dry skin and mucous membranes, and confusion.

The problem with Diabetes drugs
According to the National Institute of health NIH Anti-diabetic drugs have been linked to pancreatic cancer. Pancreatic cancer is the 4th leading cause of death in the United States.
According to the results of the study done, link above,  Diabetes was associated with a 2.37-fold increased risk for pancreatic cancer [95% confidence interval]. The safest drug was listed as metformin.

According to another NIH article NIH 2:
 "The side effect profile of thiazolidinediones includes fluid retention, heart failure; and an increased risk of fracture. A recent controversial meta-analysis suggested that rosiglitazone increases the risk of myocardial infarction, which is possibly related to thiazolidinedione-induced lipid changes, weight gain, congestive heart failure, and anemia. Metformin is restricted to patients with normal renal function because of concerns that metformin may cause lactic acidosis."

There have been concerns among physicians for years that using Type II diabetic drugs can lead to some patients forming insulin resistance and there have been discussions with FDA about the use of insulin early on in Type 2 diabetes. In march of this year, the FDA issued a statement that it was looking into diabetes drugs such as Januvia, Byetta and other diabetes drugs being linked to Pancreatic cancer and pancreatitis.   Here is the link to adverse events AE

With the clinical trials recently concluded and having met their primary endpoint, this seems to a very lucrative form of the disease that most retail investors seem to have forgotten.


AFREZZA STUDY DESIGN
The study in patients with type 1 diabetes, known as study 171, was an open label study in which all patients are first optimized on their basal insulin regimen before randomized to one of the three arms: a control arm, in which patients utilized an injected insulin at mealtimes; or one of the two Afrezza arms, one for the MedTone inhaler and one for the Dreamboat inhaler. After the mealtime insulin was titrated to effect, there was a 12-week observation period on relatively stable doses of the mealtime insulin to assess A1c levels. The primary endpoint of the study is to show non-inferiority of the change in A1c levels in the Dreamboat group compared to the injected insulin analog group.

The other study that was requested by the FDA is known as study 175, a placebo-controlled study in patients with Type 2 diabetes who are inadequately controlled on metformin with or without a second or third oral medication. Patients were assigned to treatment with Afrezza or placebo powder in a randomized fashion. There was a titration period that allowed the dosages to be adjusted followed by a 12-week observation period to assess A1c levels. The primary objective of this study was to show superiority of the Afrezza group over the placebo group in lowering A1c levels.

The clinical studies were conducted in the US, Eastern Europe and South America. Recruitment for the trials concluded in October 2012 and the company expected completion of the studies in second quarter of 2013.


POSITIVE RESULTS from Study 175
Aug 14, 2013 MNKD announced positive preliminary results from study 175, see above.
Afrezza combined with oral therapy showed:

• superior reductions in A1C levels
• significantly more patients reached A1C target levels
• reduced postprandial glucose excursions  (PPG refers to plasma glucose concentration after eating)
• no significant difference in the incidence of severe hypoglycemia
• No Afrezza patient discontinued because of hypoglycemic adverse events
• over the 24 week treatment period A1C levels decreased by 0.82% compared to a decrease of 0.42% in the comparator oral-therapy group. This was a statistically significant p value of less than 0.0001, thereby establishing the superiority of Afrezza over the other treatment.
• 37.7% of patients in the Afrezza group achieved an A1c levels below 7.0%
• 15.9% of the patients in afrezza group achieved A1c levels below 6.5%
• by week 24 mean glucose did not exceed 170.2 mg/dL
• serious adverse effects were lower in the Afrezza group (2.8%) compared to the oral therapy group (5.1%)
• Adverse events resulting in discontinuation Afrezza 4.0% and oral therapy 5.1%
• Patients in Afrezza group gained an average of 0.49 kg over the treatment period (24 weeks) compared to an average loss of 1.13 kg by patients in the comparator group.

• So the super analysts of the world who tell you to sell when the price is low and then tell you to buy when the price is high have shaken the confidence of many retail investors due to the following clinical findings:

• the incidence of mild to moderate hypoglycemia was higher, 67.2% of the patients in the Afrezza group compared to the comparator oral-therapy group, 30.01% of patients, representing a p value of less than 0.0001. However, there was not a significant difference in the incidence of severe hypoglycemia, which was reported in nine, 5.51% afrezza patients compared to three, 1.7%, oral-therapy patients; representing a p value of 0.0943

• most common adverse effect was a cough, occurring in Afrezza patients 23.7% and oral therapy 19.9% (who were also taking a placebo powder). Cough was predominately dry, intermittent, and usually occurred within 10 minutes of inhalation. The incidence of cough in both treatment groups was highest during the first week of the treatment period and diminished thereafter without causing pulmonary compromise.

So lets break this down, Insulin can cause episodes of hypoglycemia and patients are aware of that side effect. Hypoglycemia is easily treatable in this patient population as they have not taken massive amounts of insulin and the effects of Afrezza and short lived. If patients blood glucose started dropping after dinner and simple and hopefully healthier dessert would do the trick.

It is far more beneficial to a patients health to have a decreased A1C level and a rare episode of hypoglycemia rather than a chronically high A1c, causing damage to multiple organ leading to renal failure, neuropathy, blindness, etc.

Most patients can sense when their sugar is dropping and if they are not being stubborn or trying to impress a date, will eat a piece of candy or another type of fast acting sugar to mitigate the hypoglycemia.  Patients with hyperglycemia don't know their sugar is high until they present with serious side effects. I actually had a patient who lost 30 pounds in a month and had no idea why, he was a diabetic who was non compliant on checking his glucose levels but he was complaint with his medication. His glucose levels were in the excess of 900 and there is no way to tell how long it had been that high, at least a month? 


 POSITIVE Results from Study 171
Afrezza-gen2 compared to insulin showed:

• Non-inferior decrease in A1C levels (primary endpoint)
• significantly less hypoglycemia was observed in the Afrezza-Gen 2 group (9.80 events per subject-month) compared to the insulin aspart group (13.97% events per subject-month); representing a p value of less than 0.0001
• the event of severe hypoglycemia was also lower in Afrezza group (8.05 per subject-month) compared to 14.45 events per subject-month is insulin aspart group.
• significant weight advantage, patients in Afrezza group lost an average of 0.39kg over the treatment period compared to an average gain of 0.93 kg in the insulin aspart group (p=0.0102)
• changes in pulmonary function observed with the dreamboat inhaler were no different than those observed in an Afrezza treatment group that utilized the MedTone inhaler. 
• Mean Fasting blood glucose levels DECREASED by 25.3 mg/dL by the end of the treatment period whereas the insulin aspart group experienced and an INCREASE of 10.2 mg/dL (p=0.0027)

Conclusion
I am bullish on MNKD. Al Mann has personally financed this company and owns majority shares. There are plenty of biotech companies out there but none with as much potential and promise as MNKD. I have been a fan of Al Mann for a long time and considering his history and understanding the potential of not only Afrezza but the technosphere technology, MNKD is a sure bet in my book.


MNKD has a market cap of 2.29 billion, shares outstanding at 290.88 million, public float 153.3 million with a short percentage of 30.73%, approx 47.16 million shares sold short as of 07/31/2013.
With the profits of companies like MERK and Pfizer dropping significantly over the next year this stock has a lot of room to run. With the incidence of Pancreatitis and pancreatic cancer, metformin and Afrezza may become life long friends. The true potential of the diabetes market is in type 2 and the clinical results have exceeded my expectations.

Imagine what the parent of a child has to go through to get their child to take insulin shots multiple times a day. How amazing would it be to be a kid at school that doesn't have to go to the nurses office everyday before lunch, instead allowed to be a normal child and go to the cafeteria with friends and use a convenient inhaler.


Last thing i would like to add is that any comparison to Exubera, etc shows intellectual inferiority or perhaps a lack of due diligence.

Afrezza is a blockbuster drug and I am a proud Al Maniac. Good Luck to all longs and as always, please correct me if i missed something, I am always open to learning from others. Thank you.

AFREZZA utilizes our proprietary Technosphere^® formulation technology, which is based on a class of organic molecules that are designed to self-assemble into small particles onto which drug molecules can be loaded. We believe Technosphere represents a versatile drug delivery platform that may allow pulmonary administration of certain drugs that currently require administration by injection, such as GLP-1. Beyond convenience, we believe the key advantage of drugs inhaled as Technosphere formulations is that they have been shown to be absorbed very rapidly into the arterial circulation, essentially mimicking intra-arterial administration. MannKind is also developing other inhalation technologies, including an innovative line of patient-focused, breath-activated, dry powder inhalers and inhalation profiling to characterize patient inhalation. - See more at: http://www.mannkindcorp.com/about-us-overview.htm#sthash.w4aLK11N.dpuf

MannKind Corporation (Nasdaq: MNKD) is a biopharmaceutical company focused on the discovery, development and commercialization of therapeutic products for patients with diseases such as diabetes.
Our lead investigational product candidate, AFREZZA^® (pronounced uh-FREZZ-uh) is a novel, ultra rapid-acting mealtime insulin therapy. AFREZZA is in late stage clinical investigation for the treatment of adults with type 1 or type 2 diabetes for the control of hyperglycemia. It is a drug-device combination product, consisting of AFREZZA inhalation powder pre-metered into single use dose cartridges and the light, discreet and easy-to-use AFREZZA inhaler. Because of its unique pharmacokinetic profile, AFREZZA may be a promising new therapy for patients with Type 1 and Type 2 diabetes, as it controls post meal-time glucose levels with less weight gain and lower risk of hypoglycemia.
AFREZZA utilizes our proprietary Technosphere^® formulation technology, which is based on a class of organic molecules that are designed to self-assemble into small particles onto which drug molecules can be loaded. We believe Technosphere represents a versatile drug delivery platform that may allow pulmonary administration of certain drugs that currently require administration by injection, such as GLP-1. Beyond convenience, we believe the key advantage of drugs inhaled as Technosphere formulations is that they have been shown to be absorbed very rapidly into the arterial circulation, essentially mimicking intra-arterial administration. MannKind is also developing other inhalation technologies, including an innovative line of patient-focused, breath-activated, dry powder inhalers and inhalation profiling to characterize patient inhalation.
- See more at: http://www.mannkindcorp.com/about-us-overview.htm#sthash.w4aLK11N.deavor of Alfred Mann http://aemf.org"

MannKind Corporation (Nasdaq: MNKD) is a biopharmaceutical company focused on the discovery, development and commercialization of therapeutic products for patients with diseases such as diabetes.
Our lead investigational product candidate, AFREZZA^® (pronounced uh-FREZZ-uh) is a novel, ultra rapid-acting mealtime insulin therapy. AFREZZA is in late stage clinical investigation for the treatment of adults with type 1 or type 2 diabetes for the control of hyperglycemia. It is a drug-device combination product, consisting of AFREZZA inhalation powder pre-metered into single use dose cartridges and the light, discreet and easy-to-use AFREZZA inhaler. Because of its unique pharmacokinetic profile, AFREZZA may be a promising new therapy for patients with Type 1 and Type 2 diabetes, as it controls post meal-time glucose levels with less weight gain and lower risk of hypoglycemia.
AFREZZA utilizes our proprietary Technosphere^® formulation technology, which is based on a class of organic molecules that are designed to self-assemble into small particles onto which drug molecules can be loaded. We believe Technosphere represents a versatile drug delivery platform that may allow pulmonary administration of certain drugs that currently require administration by injection, such as GLP-1. Beyond convenience, we believe the key advantage of drugs inhaled as Technosphere formulations is that they have been shown to be absorbed very rapidly into the arterial circulation, essentially mimicking intra-arterial administration. MannKind is also developing other inhalation technologies, including an innovative line of patient-focused, breath-activated, dry powder inhalers and inhalation profiling to characterize patient inhalation.
- See more at: http://www.mannkindcorp.com/about-us-overview.htm#sthash.w4aLK11N.dpuf

MannKind Corporation (Nasdaq: MNKD) is a biopharmaceutical company focused on the discovery, development and commercialization of therapeutic products for patients with diseases such as diabetes.
Our lead investigational product candidate, AFREZZA^® (pronounced uh-FREZZ-uh) is a novel, ultra rapid-acting mealtime insulin therapy. AFREZZA is in late stage clinical investigation for the treatment of adults with type 1 or type 2 diabetes for the control of hyperglycemia. It is a drug-device combination product, consisting of AFREZZA inhalation powder pre-metered into single use dose cartridges and the light, discreet and easy-to-use AFREZZA inhaler. Because of its unique pharmacokinetic profile, AFREZZA may be a promising new therapy for patients with Type 1 and Type 2 diabetes, as it controls post meal-time glucose levels with less weight gain and lower risk of hypoglycemia.
AFREZZA utilizes our proprietary Technosphere^® formulation technology, which is based on a class of organic molecules that are designed to self-assemble into small particles onto which drug molecules can be loaded. We believe Technosphere represents a versatile drug delivery platform that may allow pulmonary administration of certain drugs that currently require administration by injection, such as GLP-1. Beyond convenience, we believe the key advantage of drugs inhaled as Technosphere formulations is that they have been shown to be absorbed very rapidly into the arterial circulation, essentially mimicking intra-arterial administration. MannKind is also developing other inhalation technologies, including an innovative line of patient-focused, breath-activated, dry powder inhalers and inhalation profiling to characterize patient inhalation.
- See more at: http://www.mannkindcorp.com/about-us-overview.htm#sthash.w4aLK11N.dpuf