HNF-4α controlling many genes involved in liver function such as the GLUT2 and L-PK genes. Evidence on the mode of action of metformin shows that it improves insulin sensitivity by increasing insulin receptor tyrosine kinase activity and enhancing glycogen synthesis in hepatocytes, and by increasing recruitment and transport of GLUT4 transporters to the plasma membrane in adipose tissue. In addition to its effects on hepatic glucose and lipid homeostasis and adipose tissue lipid homeostasis, metformin exerts effects in the pancreas, vascular endothelial cells, and in cancer cells.
Making healthy lifestyle choices can certainly lower the risk of hyperglycemia, as well as hypoglycemia. Normally, the blood sugar levels are tested on an empty stomach, usually after a gap of six to eight hours after having the last meal. The following table provides the average blood sugar levels of a normal healthy adult, 2 hours after eating a meal.
It is common for pregnant women to be screened for gestational diabetes anywhere between the 24th and 28th week of pregnancy. According to the American Diabetes Association, blood sugar should ideally be measured using the fasting glucose or the OGTT which may help diagnose diabetes.
Diabetics can monitor their own blood glucose levels, several times in a day, to record the levels of sugar in their blood.
You can use the aforementioned charts for blood sugar levels as a reference to check blood sugar levels regularly.
I test my sugar around 10:00am after 2 cups of coffee with light cream it always under100 is that ok?
I found my sugar level 202 with almost 11 hours meals gap.Please advice me for come out from this disease. I found my sugar level 202 with almost 11 hours meals.Please advice me for come out from this disease.
Hi i had my blood test and i got my result today and my GP told me that my blood sugar leverl is 30 which is high. It is a major, independent risk factor for cardiovascular disease (CVD, and the chief risk factor for stroke (accounted for about 62% of strokes). It’s often called “the silent killer” because it can be asymptomatic for many years, and people suffering of this problem can have a sudden fatal heart attack. Elevated blood pressure levels are a common and important risk factor also for kidney failure.
Above-optimal blood pressure levels, not yet in the hypertensive range or prehypertensive, also confer excess cardiovascular disease risk, as it is shown by the fact that almost a third of blood pressure-related deaths from coronary heart disease are estimated to occur in no hypertensive individuals with systolic blood pressure levels of 120 to 139 mm Hg or diastolic blood pressure levels of 80 to 89 mm Hg (approximately 31% of the general population have blood pressure in the no hypertensive, yet above optimal blood pressure range). More than half of American adult population is included, considering hypertensive together with prehypertensive. Note: on average, blacks have higher blood pressure levels than non-blacks and an increased risk of blood pressure-related complications, particularly stroke and kidney failure.
The prevalence of the disease rises with increasing age: over half the adult population older than 60 years has hypertension. The age-related risk of high blood pressure is a function of life-style variables rather than just aging. Studies on vegetarians living in industrialized countries have shown that such dietary habits are associated with a markedly lower blood pressure levels compared with non-vegetarians; furthermore there is a lower age-related rise in blood pressure.
According to a study by a team research of Johns Hopkins University (USA), prevention of hypertension begins in childhood. A meta-analyses conducted on studies from diverse population, examining the tracking of blood pressure levels from childhood to adulthood published between January 1970 and July 2006, have shown that childhood blood pressure is associated with blood pressure in later life and elevated childhood blood pressure is likely to help predict adult hypertension (note: recent studies show that increased blood pressure levels among children is related to the growing obesity epidemic).
In the last two decades a downward trend of blood pressure has been documented in the USA; the adoption of healthier lifestyle have contributed to this trend and it has given diet a prominent role Moreover, between 1980 and 2000 also the rate of death from coronary heart disease was halved and approximately half the decrease was attributable to changes in major risk factors including reductions in total cholesterol, systolic blood pressure levels (20%), smoking and physical inactivity). These changes need not be made one at a time: the best results are achieved when they are together as shown by two trials in which multicomponent interventions substantially lowered blood pressure levels in hypertensive and nonhypertensive participants. Over the past several years investors have been distracted by a lot of “noise” surrounding AFREZZA. To exemplify our view we will invoke Einstein’s wise dictum “invert, always invert” – to pose a question: If inhalable insulin was invented first and another pharmaceutical company developed an insulin treatment whose key differentiation was that it was injectable, how many people would switch? Thankfully the story of AFREZZA is not limited to simple convenience over current best-in-class insulin’s but also consists of significant improvements in Pharmacokinetics and Efficacy. Diabetes develops when the body doesn’t make enough insulin or is not able to use insulin effectively, or both.
Diabetes was first described in an Egyptian manuscript from ~1500 BCE. Around the same time Indian physicians described it as “honey urine” (a symptom of diabetes is sweet smelling urine as the body expunges excess sugar).
Diabetes can be diagnosed several ways as detailed in the picture above though the preferred method is testing for Fasting Plasma Glucose or “FPG”. AFREZZA is the first “ultra-rapid” acting insulin therapy for the treatment of patients with Type I & Type II diabetes. The major factors to focus on is that AFREZZA offers better efficacy, more convenience, lowers the chance of severe hypo glycaemia, less weight gain, and is not injectable.
AFEZZA is a faster better treatment because of a technological breakthrough called Technosphere. Technosphere is where the magic lies but luckily for MannKind shareholders, the delivery system is not limited to AFREZZA. Technosphere if some of the most successful drugs with patent expiration could be reformulated and regain exclusivity. Though it has yet to receive FDA approval (it’s a low hurdle at this juncture in our opinion), many use it today through a special FDA waiver. The first pillar of our MannKind thesis is based on AFREZZA’s superior Pharmacokinetics and Efficacy.
Current “best-in-class” insulin treatments such as Humalog or Novolog (RAA’s), peak between 45-90min and remain in the body for over 5hrs.
While AFREZZA has proven in numerous trials that it does an excellent job of efficacy, the current evaluation methods for efficacy clearly underestimate AFREZZA’s paradigm shifting pharmacokinetics.
Currently efficacy is measured as the mean reduction in HbA1c by patients over a given period (generally 3 months).
To understand our point, one only needs to look at the second graph above titled “Different Post-Prandial Excursions results in Modestly lower 24 hour average (and HbA1c) for RAA’s.” In that graph, AFREZZA peaks much faster than the RAA comparator, b doesn’t accompany the RAA’s below the baseline. Then, one day, Billy Beane, GM of the Oakland Athletics, began focusing instead on a different metric: On Base Percentage (“OBP”). As Oakland started drafting and contracting players based on OBP, they started beating “more talented” clubs (Red Sox, Yankees, etc…) who were spending far more money on “better players” and became a sensation (they even made a movie about it called “Money Ball”). So just like OBP replaced Batting Averag as the key metric, HbA1c clearlyundervalues AFREZZA’s true “Clinical Utility” in effectivelyhelping diabetics long-term. There is little doubt that the current offerings of RAA insulin’s were a major improvement over previous therapies. From the study titled: Preferences of Patients with Diabetes Mellitus for Inhaled versus Injectable Insulin Regimens in the March 2008 edition of PharmacoEconomics. The result of the study: A majority, ranging from 63% to 81% (emphasis mine) across the scenarios, preferred inhalation (they used Exubera!).
So in summary, people rather deal with a clunky inhaler the size of a tennis ball can, rather than inject themselves with a needle! This can be painful (mostly psychological, except for those not using the ultra thin needles) and cause infections (such as staphylococci as seen in this study) due to repeated and improper use. Most people do not realize the psychological barriers that are present for individuals that should be utilizing insulin but refuse to comply with their doctors’ wishes. According to Mannkind, AFREZZA may become a first line of defense ( shortly after or in conjunction with metformin) to help slow or possibly reverse early stage diabetes, along with the usual recommendation of diet and exercise. The physiological diabetes (Type II) process in humans begins when the pancreas begins having difficulty producing enough insulin to cope with the “spikes” associated with eating.
Since the pancreas can no longer handle the “spikes”, a bolus (or mealtimeinsulin) is most sensible since it is designed to handle the “spikes” with its rapid onset. AFREZZA has an extraordinary pharmacokinetic benefit over current bolus insulin’s in that its (“peaks”) virtually mimics a healthy pancreas. The pre-diabetic space is a largely untapped market and could immediately add ~300M potential AFREZZA user’s Worldwide (~80M in the US alone).
If one was to argue that AFREZZA is solely a more convenient option over current RAA’s, we believe this fact alone would garner considerable market share.
You think she might trade a little initial cough and more convenience for the pain and annoyance of pricking herself with a needle all day? As an aside, one of the biggest issues relates to parents of diabetic children. Many parents have immense trouble sleeping as they are constantly worried about their kids having a hypo event in their sleep (not uncommon). What if one could completely avoid meal-time injections and dramatically lower the chance of having a severe hypoglycemic event by using a little inhalable insulin device? If AFREZZA was only a convenience over current therapies it should still grab significant market share. One of the major factors determining interest in, and acceptability of AFREZZA, from both the patient and insurer perspective, is the reduced level of Severe Hypoglycemic Events (“SHE’s”). The insulin-only cost to treat an insulin dependent diabetic usually runs about $1,200-$2,000 per year. Now imagine an insulin therapy that reduces SHE’s by 64% (see above slide). The expense reduction to insurers and individuals is nothing to scoff at. The convenience and superior glucose control associated with AFREZZA will cause a complete paradigm shift in the treatment of diabetes.
In all, MannKind has the ability from both a convenience and pharmacokinetic standpoint to help improve the lives of millions of diabetics.
While some of the assumptions such as profit margins and royalties seem high historically, we used comparable companies as benchmarks. It’s important to note at this juncture that we strived to be both balanced andconservative in our assumptions of MannKind’s value through a rigorous focuson research and data. This is truly a conservative estimate that we believe drives home just how undervalued the MannKind is in even the most pessimistic scenario.
This scenario is also very conservative as it only assumes a sliver of the Type II market and the majority of the Type I market. Based on various reports and surveys we believe the “convenience only” model alone could justify a market share well above 50%. Our Baseline Discounted Cash Flow (“DCF”) Model estimates AFREZZA sales of $14B in 2019 (25% Market Share), 15% growth for 7 years, and 7% terminal growth for 7 years. We understand that at first blush, most would deem 25% market share for an “unproven” drug within 5 years aggressive.
Using a Bullish scenario where AFREZZA gains 40% market share by 2021, we would arrive at sales of $23.8B. Due to the dominance and time necessary to attain the above results, we give this a 15% weighting.
Using a very Bullish scenario where AFREZZA would be prescribed for some pre-diabetics along with regular diabetics, we believe worldwide sales would be an astounding $80.6B in 2021. Because this scenario takes into account some very bullish assumptions, including the adoption by physicians of AFREZZA as a first line of defense along with considerable overall market share we give this a 5% weighting. The Baseline scenario works out to $85, Convenience Only is $34, and the Dominance case 1 came to $109. We know that most investors – especially those who are in the value camp as we are – would probably not consider investing in any biotech as they are very complex and can often be binary events with little downside protection or a margin of safety. Firstly, should AFREZZA meet our lowest expectations the company would be worth 4 -5x its current price. Second, the potential value of the upfront payment is considerable and will provide further downside protection. Another example is the deal that was struck between Eli Lilly and Icos Corp for developing a competitor to Viagra. In MannKind’s case, we believe the up-front partnership payment will be considerably smaller for reasons Dr. Third, as a proven technology, Technosphere alone should command a public market valuation of between $500M to $1B.
In the six years since Pfizer tried but failed to profit from its inhaled insulin Exubera, the non-invasive, quick, and inexpensive delivery of drugs via the lungs has advanced enough to forecast a promising future for inhaled therapy, says John Patton, one of the original inventors of Pfizer’s inhaled insulin technology system. However, if there is a negative event regarding AFREZZA, MannKind’s share price will undoubtedly reflect this is short order. After MKND had its IPO in 2004, its stock bounced around with the overall market until late in 2009, when it received its first CRL. In the CRL the FDA made no mention as to the efficacy or safety of AFREZZA but it did raise concerns regarding its delivery device called the “Medtone inhaler”.
Because MannKind was short on cash at the time of their first CRL, they needed to do a capital raise, which combined with the negative headlines of the CRL, caused the stock to tank. This again punished shareholders as MannKind needed another capital raise to complete a pair of new trials to unequivocally bridge the gap between the two inhalers instead of a simple bio-equivalence study which would take 2 years to resubmit.
There are many investors that believe the second CRL was a result of some malfeasance on the part of a hedge fund manager named Martin Shkreli of MSMB Capital Management. Without a hint of sarcasm, and probably totally coincidentally, a few days after receiving the presentation from Mr. No wonder management at MannKind was completely dumbfounded on the conference call to discuss the CRL.
Though this story probably sounds like some glue-sticked, pin and thread conspiracy story from disgruntled shareholders, you only need to check the information from this website which contains the numerous links to documents which will back up these assertions. Many investors are waiting on the sidelines to invest in MannKind until the “skies are clear” or believe this is “dead -money” for months or even years. Furthermore, rationally looking at this, AFREZZA has already “jumped” the major hurdles: A) all necessary clinical trials have been conducted and met their primary end-points, B) they are adequately funded with over $130M of cash on hand plus a revolver, another 2 tranches ($40M each) from Deerfield, and warrants to be exercised, C) they already have a production facility ready to go, and D) they have received a new PDUFA date of April15 th .
While it’s true that the company could end up without a partner and get rejected by the FDA, we believe this is a low probability.
With all the positive trial results under their belt, FDA approval is all but a formality at this point. Al Mann mentioned over two years ago that they had a partnership proposal on their desk but didn’t like the terms. An interesting argument being debated is in regards to MannKind’s expected up-front payment. If you are Mannkind, and believe you have a mega blockbuster on your hands, what is a better deal structure, $1B up-front and 5-20% royalties (normal partnerships), or $300-$500M up-front and 40-60% Royalties? The largest part of that fortune came from selling MiniMed – which commercialized the first ever insulin pump – to Medtronic. As Mark Twain famously said “history doesn’t repeat itself, but it does rhyme.” As MiniMed was working its way through the FDA process everyone got down on its prospects because a “Big Pharma” had issues with their device.
With successful results from their Phase III trials in August (along with all the previous trials), the probability of success is now only months away from fruition. While inhalable (it was approved by the FDA with several concerns and less benefits than AFREZZA), it’s obvious from both the pictures displayed above and from actual data, that Exubera was more inconvenient, less effective, and more expensive than RAA’s. Would anyone want to be seen using Exubera in public or does one believe that a pen needle would be less conspicuous?
Even the most recent attempts to bash or down play AFREZZA’s true potential by numerous market participants now assumes FDA approval. It’s our opinion that the market is not taking a partnership or any major market acceptance into the current valuation.
When dealing with a biotech company that has a pipeline of drugs which have yet to hit the market there are numerous risks to discuss.
MannKind has considerable IP and other assets that help reduce the risks to MannKind’s value should AFREZZA not attain it Intrinsic Value.
MannKind is a unique $1.4B biotech company which is targeting a large unmet need in the ever-expanding diabetes space.
Using Einstein’s inversion maxim: if inhalable insulin was invented first and another pharmaceutical company developed an insulin treatment whose only major difference was that it was injectable, how many people would switch? And as proven in the numerous studies regarding preference, needles don’t stand a chance, all things being equal vs. We know there is a lot of misinformation with MannKind and AFREZZA due to the complexities of understanding new drugs, the numerous clinical trials, previous capital concerns, and the fact that it’s yet to reach market.
Because MannKind’s story is anything but simple and clear, we believe MannKind has been completely overlooked, and as a result, is severely undervalued.
Fortunately, there are multiple catalysts in the coming 6 months which should help shed light on this discrepancy. Should our analysis prove correct, AFREZZA will become the dominant player in the diabetes space, and investors and diabetics alike will be rewarded considerably. If one wishes to get more intimate information on diabetes and AFREZZA, I highly recommend reading the four excellent articles I have hyperlinked ( here, here, here and here) and an excellent presentation by Novo Nordisk that does a great job of covering Diabetes.
Maredin Capital Advisors, founded by Marcelo Zinn in 2005, is an Investment Management Company based in Miami, Florida, which focuses on long-term value investing in equities and debt. Maredin seeks capital appreciation through investment in undervalued securities with considerable growth potential.

While all investments are acquired with a long-term capital appreciation view in-mind, a change in our positions may occur when an investment (which meets our stringent criteria) is identified that presents better return potential.
Maredin’s investment principles are derived from the work of the late Benjamin Graham, Warren Buffett, and Charlie Munger, amongst others. A company’s “Intrinsic Value” is what we believe the business is worth, while the “Margin of Safety” principle requires that investments we make must be at a significant discount to their “intrinsic value”, normally 4 0% to 60%.
We believe that our deep, independent work means we are able to effectively manage risk and reward better than others who outsource what we believe is the most critical part of the investment process. At Maredin, returns, risk, diversification, confidentiality, transparency, and personal service are all factors we take into careful consideration.
The content of this website is not an offer to sell or the solicitation of an offer to buy any security in any jurisdiction. Another exenatide-related drug is Bydureon® which is a once-a-week injectable form of exenatide.
A more recent addition to the GLP-1 receptor agonist family of diabetes drugs is Trulicity® (dulaglutide) manufactured by Eli Lilly and Co.
Additionally, it has been shown that metformin affects mitochondrial activities dependent upon the model system studied.
The latter effects of metformin were recognized in epidemiological studies of diabetic patients taking metformin versus those who were taking another anti-hyperglycemia drug.
The following Buzzle write-up provides a chart for blood sugar levels that will help you monitor the blood sugar levels, so that you can take steps to keep them within the normal range.
During digestion, the carbohydrate-rich food items get converted into glucose, which is then absorbed into the bloodstream. Glucose levels are the lowest in the mornings, and mostly tend to rise for a couple of hours after meals, depending on the volume of carbohydrates consumed. However, it is advisable that the test be done at least twice, at different times, to confirm diabetes. Many home testing kits are available in medical stores, and can be bought on medical prescriptions. Prehypertensive people have a high risk (90%) of eventually developing hypertension but this transition is not inevitable.
On the other hands, they achieve greater blood pressure reduction than non-blacks from several non-pharmacological therapies (see below). Weight gain, low physical activity, excess in salt, fats and saturated fats, cholesterol and alcohol intakes and low intakes of fresh seasonal fruit and vegetable are responsible for much of the rise in blood pressure levels seen with age. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER Clinical Trial. MannKind consists of a delivery technology (Technosphere), a drug pipeline consisting of two promising early stage cancer therapies, and a soon-to-be-approved drug called AFREZZA.
Though some of the concerns were real, it’s no longer so, and yet it continues to haunt the company. This will lead to better overall health for diabetics, lower costs to the entire healthcare system, and make AFREZZA a blockbuster.
Mann has put ~$1B of his personal capital into MannKind and remains its largest shareholder (~46%). As a result, glucose builds up in the blood instead of being absorbed by cells in the body. Since the usage of insulin to combat diabetes began in 1921, it has been an incredible success. Type I, also referred to as “juvenile” diabetes affects approximately 5-10% of diabetics (8.3% in US). Compared to current “best-in-class” treatments, AFREZZA offers a superior option in numerous aspects.
In short, AFREZZA uses the same “feed stock” as virtually all current diabetes treatments: insulin. Technosphere converts insulin into powder form which is then loaded into a cartridge and delivered via inhalation (with the Dreamboat device) into the deep lung (much more on this below).
This is just the tip of the iceberg in terms of market opportunity with Technosphere, in our opinion. This includes individuals and groups like the Junior Diabetes Research Foundation (or JDRF) which uses AFREZZA (bolus) in combination with insulin pumps (basal) to achieve results which virtually mimic the human body. Simply defined, Pharmacokinetics may be simply defined as what the body does to a drug, while Efficacy is the ability of a drug to produce a desired effect.
This is because current RAA’s, which are injected subcutaneously (in muscle and fat), are assembled and delivered into the body in the form of hexamers. The rapid action peaking and exit of insulin results is less severe hypoglycemia (>60% less), no increased cardiovascular or pulmonary risks, and weight neutrality compared to current insulin’s. Though this has served as a good system in the past, for AFREZZA – the first “Ultra-Rapid” acting insulin – it does an inadequate job of demonstrating its true benefits. However, AFREZZA’s quicker “peak”, without crossing the lower bound, actually benefits diabetics much more so than the HbA1c results would lead one to believe.
Additionally, the speed of onset, rapid peak, and quickerdeparture from the body, all favor AFREZZA.
OBP takes into account the number of walks, which for all intents and purposes, is the same as a hit. Once AFREZZA starts “beating” the “Major Pharmaceutical Players” (Novo Nordisk, Eli Lilly, Sanofi Aventis) on the field (i.e. However, just as the “rapid acting” (“RAA’s”) insulin’s supplanted previous formulations, AFREZZA’s first to market “ultra-rapid” acting insulin, will supplant the current therapies.
MannKind recently commissioned a study with an outside marketing firm to gauge the potential interest of general Physicians and Endocrinologists in prescribing AFREZZA after the results of their most recent trials.
This study highlights the utility differences that people with diabetes perceive between the prospect of inhaled and injected routes of insulin administration, even under the assumption of no difference in efficacy.
Mostinsulin dependent diabetics inject themselves 3-5x per day solely for their bolus needs.
AFREZZA supplants bolus needles with a novel superior inhalable insulin, which is both painless (a little cough that goes away after a couple weeks) and has zero long-term effects on lung function (over 7 years of data from MannKind to support). It may seem absurd to not use insulin injections which will improve one’s health when needed, but that is just what occurs some of the time (the actual % varies). This is a major improvement as current drugs require constant monitoring of sugar and insulin levels while counting the amount of carbs and sugars in ones’ meal to ensure a balance is attained.
While we discussed the reason AFREZZA is superior above, we will tackle the effect this will have on its potential market and impact below. It’s a worldwide epidem that’s aggressively progressing due to increasingly poor eating habits combin with our sedentary lifestyles. This belief is based on the “natural” progression a person goes through when transitioning from “normal” (or non-diabetic) to pre-diabetic, and then fully diabetic. During this same initial stage, when not consuming food, the pancreas generally continues to manage baseline (or basal) insulin levels well. Current RAA’s have done a good job (especially considering their predecessors) but are not a panacea since their “peaks” are still significantly slow compared to endogenous insulin (45-90m vs. The reasons include needle-phobia and improved compliance as diabetics could both reduce the number of injections they take and not need to titrate. Whether one injects oneself or must inject someone else, it’s a very unpleasant experience.
So not only does the child have to deal with the health issues relating to having diabetes long-term, but the parents also suffer mightily.
But convenience is only part of the AFREZZA story. As has already been clinically proven through numerous trials, AFREZZA was non-inferior to current best-in-class treatments and in many ways superior for both Type I and II diabetics. One of the most considerable costs to the healthcare system is the high expense due to hospitalizations from SHE’s.
A single hospitalization due to an SHE costs approximately $1,200 (very conservative) or nearly the same amount spent on insulin a year.
Because of its convenience, actual patient compliance will likely provide AFREZZA superior real-world results over other therapy options. We believe the best way to answer this vital question is to look at Mannkind and AFREZZA through several lenses.
Since AFREZZA is demonstrably better for Type 1’s than their current bolus insulin, adoption will be early and rapid. While this completely ignores the entire Type II (90%) market, that is still 4x the current price. However, we believe the convenience and efficacy benefits highlighted in detail above will drive demand from physicians and improve both the marketing and acceptance, allowing f or major penetration.
Using the same 50% royalty rate, 40% profit margin, 20x earnings multiple, 10% discount rate and dividing by 450M shares, we attain a current intrinsic value of $109 per share. This is especially true as we are ignoring the up-front payment ($300-$500M), drug pipeline, insulin inventory ($100-200M), and considerable licensing opportunity of Technosphere.
Because the value is so considerably above the current price and the probability of success is very high (in our opinion), you get a considerable margin of safety. MannKind has yet to partner Technosphere with anyone (it isn’t a focal point, AFREZZA is their sole concern) other delivery companies like BIND Therapeutics, have a current valuation of $225M. Partnering Technosphere alone would provide MannKind with a considerable valuation (Pfizer is said to be currently testing the technology on some of its compounds). So far, the results of those two drugs have been very promising; with MannKind already partnering one of them (they have the ability to buy-out the partner as part of the deal). These tax savings would apply to the profits of AFREZZA, Technosphere, or the Cancer pipeline. Throw in the $300-$500M in up-front partnership payments expected within the next 6 months, $2B in NOLs, and this provides us a considerable margin of safety at current prices. It would likely take a couple of years for people to refocus on Technosphere and the other two cancer drugs.
One day before the FDA response, MannKind received a call from the FDA that they would need three additional weeks to finish reviewing the data. Management seemed completely dumbfounded on their conference call shortly after receiving their second CRL.
Shkreli attained the e-mail addresses for all 12 researchers – including Commissioner Margaret Hamburg – responsible for deciding AFREZZA’s fate. Shkreli, and 1 day before the PDUFA date, MannKind got a call from the FDA asking for more time to review the data. Shrekli’s assertions was about having insufficient data to properly bridge the new and old inhaler. Whether one believes in conspiracy stories or not, this is certainly an interesting set of circumstances (although as fictional FBI Agent Fox Mulder liked to say: “there are no coincidences”). This time however, MannKind wisely set up AFREZZA’s trial design and endpoints  (goals) jointly with the FDA so as to remove any possible future concerns which could be raised. Most analysts, as well as the independent panel associated with the Deerfield agreement, reviewed the results independently and all came to a positive conclusion.
As such major pharmaceutical companies are sure to be jockeying to partner with AFREZZA, the World’s first Ultra-Rapid Acting Insulin.
Mann has elected to raise capital (nearly half of which was with his personal funds) rather than settle for a sub-par partnership in the past. It seems as though some believe that if they do not receive a large up-front payment this is both a failure on the part of MannKind’s management and a sign that the partner is not fully committed to AFREZZA. With the $1B up-front payment option you get a 20% royalty rate and maintain a 50% NPM; this nets you $500M in profit a year. Mann has repeatedly referred to AFREZZA as potentially the most significant drug to ever hit the market. This is a great point to reflect on because MiniMed and AFREZZA share incredible similarities. Mann never wavered on MiniMed because he believed in the research and clinical results of the device. As with MiniMed, MannKind will likely move in and quickly establish itself as the dominant force in diabetes in the near future and w ould only be bought out when its true value is fully displayed (as the majority shareholder Dr. The answer was overwhelmingly favorable (+65%) for inhalation (apparently they didn’t show the interviewees the device!). Every study we have seen only further drives home the convenience thesis. Therefore, if you wanted inhalable insulin individuals had to pay for it largely out of pocket. Exubera was a ridiculous attempt at “convenience” and yet it was still expected to command over 10% market share. The discussion has taken a radical departure from AFREZZA being “un-approvable” to one in which the focus is about it only having a minor addressable market. The only thing of interest is how the arguments against AFREZZA continue to shift as MannKind’s trials and management debunk all the issues. It will be interesting to see (from a behavioral finance perspective) exactly how market participants react to the news as it’s released. This is as clear a positive sign as one gets when trying to judge how management feels about the company’s prospects as they to prepare for launch. While the clinical trial results are overwhelmingly positive and approval is nearly assured, there remains a sliver of a chance that the FDA sends AFREZZA back to the drawing board. We believe this is a minor risk, but should AFREZZA not meet its goals, the “other assets” help provide a margin of safety. Though the company has a drug pipeline and IP assets, the main focus is on its wonder-drug: AFREZZA. Pharmacokinetics and efficacy have been proven over numerous trials to essentially mimic the human body’s bolus insulin production and this alone should garner considerable market share. However, approval should be a low hurdle as the feed-stock is the same as current diabetes treatments (insulin) and the superior delivery technology (Technosphere) has passed every necessary clinical trial. According to our estimates, MannKind’s intrinsic value is between 4-30x current prices with significant IP assets that serve as downside protection (i.e.
We highly recommend that everyone conducts their own due diligence before making any investment decisions, however, we are long MannKind (ticker: MNKD). Maredin’s primary responsibilities are the day-to-day management of the Zinn Fund Partnership and Astra Frontline Fund (non-US clients only).
All investment decisions are made using a bottom-up fundamental analysis approach through a long-term strategy focused on global securities (debt and equity). We, too, focus on a number of important factors but none more than “Intrinsic Value” and the “Margin of Safety” principle. Maredin exhaustively analyzes each investment to ensure securities acquired are always purchased at a discount to their intrinsic value.
The content is distributed for informational purposes only and should not be construed as investment advice or a recommendation to sell or buy any security or other investment, or undertake any investment strategy. Maredin was founded in 2005 to assist friends and family with a vehicle to earn above average returns over the long-term. Metformin has a mild inhibitory effect on complex I of oxidative phosphorylation, has antioxidant properties, and activates both glucose-6-phosphate dehydrogenase, G6PDH and AMP-activated protein kinase, AMPK. An oral glucose tolerance test is done to ascertain whether a pregnant woman is suffering from gestational diabetes.
An increase or decrease in the blood sugar levels in the human body can lead to either hyperglycemia or hypoglycemia. However, on an average, it should be within the normal range, to keep diseases associated with high and low blood sugar at bay. Dietary approaches to prevent and treat HTN: a scientific statement from the American Heart Association.
This is especially true in the medical device arena where he made the majority of his fortune.
As far as we know, no one in the “biotech” space has ever committed as much personal capital into a single company.
The digestive tract breaks down carbohydrates—sugars and starches found in many foods—into glucose, a form of sugar that enters the bloodstream. In 2012 alone, diabetes accounted for $245B (up 41% from 2007) or more than 1 in 5 US health care dollars. For full onset Type II diabetics, doctors continue to push for improved diet and exercise but now require medication (patients generally begin with Metformin) to help manage the disease. Because people have differing treatment needs and preferences, there is no single solution for all diabetics. The main difference amongst the numerous therapy options is the way in which the insulin is “manipulated.” Rapid Acting Analogs (“RAA’s”) such as Novolog and Humalog were an advancement over previous insulin’s (and became very successful) because they were manipulated to have a faster onset of action. Technosphere is a delivery technology which makes insulin have superior pharmacokinetics and makes AFREZZA a better drug over current therapies.
How much would sales of drugs like Viagra, Acetaminophen, Ambien, Advil Cold and Sinus, etc… be if they activated in 10 minutes instead of 30?
MannKind will surely place considerable emphasis on Technosphere, once AFREZZA isapproved and being marketed.

This is an astonishing feat and these results are independent from the studies MannKind has successfully completed.
This inference results from Technosphere’s delivery of powdered insulin into the deep lung in monomeric form. After injection, these hexamers must be “broken down” by the body into its useable form: as a monomer. The positive results of the 2-year pulmonary and carcinogenicity studies (along with 7 years of usage data) are also vital for diabetics who will consider using AFREZZA in the future. And since Hypo’s are far less likely to occur with AFREZZA, diabetics can better control their disease. Pre-2000’s that was the key indicator GM’s and Front Office Execs focused on when acquiring a hitter in baseball.
These differences are magnified when the comparison in utility scores is between the majority who prefer the inhaled route and the minority who prefer the injectable route. Others, such as actor Tom Hanks, have lived with pre-diabetes for ~20 years and just now started taking insulin.
Al Mann has repeatedly stated that AFREZZA could be a first line of defense therapy option. Since the US and EU are two very developed markets, if deemed a “proactive” or superior offering, AFREZZA could increase the size of the overall insulin market by magnitudes. Diabetics would do a better job of managing their disease and live healthier and happier lives. You think she might have interest in switching to an inhalable form of insulin that doesn’t just reduce the number of “pricks” (by 75%!) per day, but also improves her overall long-term health? One only has to do a quick Google search on long-term “sleep deprivation” to see how bad it is to one’s health. Young adults and parents of diabetic children also have difficulty dealing with this issue.
Though FDA approval and ultimate consumer adoption is not guaranteed (though all primary endpoints were met and surveys show significant consumer and endocrinologist interest), it is clear that investors are underestimating the potential of AFREZZA. Though it would cause a 30-50% top line haircut, NPM will be very high as MannKind will become a royalty machine. However, even with such conservative assumptions we will get a value that is nearly 6x the current price. Since we view this as an absurdly low probability in our analysis, we give this a 5% weighing.
However, we believe conservative assumptions provide another lens in which to view the “true” opportunity of AFREZZA. With the same 50% royalty rate, 40% profit margin, 20x multiple, 10% discount rate, divided by 450M shares, we get a current intrinsic value $147 per share. Superficially MannKind fits the mold of a typical biotech: either you get 8-20x your money or $0.
This is a sizeable sum for a partnership, but given the size of the diabetes market and estimated market share (10%) Exubera would attain, it seemed reasonable.
Though we cover this below in greater detail, we believe an up-front payment of $400M is a more reasonable amount MannKind will receive from its partner(s) in the coming months. BIND has an unproven delivery technology but has partnered with 3 companies looking to develop a drug with the technology. Imagine the benefit to patients of a system that could deliver medicine which would activate in ? to ? the time. Though early in the process, if MannKind desired to raise capital through monetization of assets it could sell its cancer therapies. Al Mann, then the largest shareholder participated in the capital raise to maintain his considerable position (~46%) in the company.
Approval seemed likely as MannKind resubmitted with the FDA’s requested bio-equivalence study allowing for AFREZZA’s data to be bridged between Medtone and the new Dreamboat inhaler.
Actually, the FDA seemed so at ease with AFREZZA’s safety and efficacy profiles that they requested that MannKind include kids as young as 4.
Shkreli was short MannKind’s stock and wanted to do everything he could to derail AFREZZA’s approval; since, if successful, he and his clients would stand to gain a lot of money. With e-mails in hand, each researcher received a 30+pg presentation – on Christmas Day – covering Mr. Thankfully, last month, MannKind announced it met all primary endpoints in both trials, setting a clear path for approval.
Since we answered the valuation question above, we believe those sitting on the sidelines or betting against MannKind may find themselves a bit distraught in short order.
Not exactly “long-term”, though that term is very relative in today’s nano-second trading world. Truthfully, there really is nothing (barring a nefarious event) that should stand in the way of AFREZZA’s approval. Once a partner(s) is announced both companies are likely to start working on EU approvals and approvals in countries Worldwide. Coming to an agreement in which both parties are satisfied is another discussion altogether. If management has high confidence in the ultimate success of AFREZZA, a large up-front payment would likely be a poor decision. If AFREZZA is a major success and they do a low royalty deal, it would rob their shareholders of billions. In short order news outlets and the general market considered MiniMed dead and drove its stock down to $1.75.
He worked hard to finalize all trials, gain FDA approval, and eventually brought it to market. Mann is focused on the results of AFREZZA’s clinical trials and ignoring the emotional swings of the market. In comparison, AFREZZA is more effective and convenient than current RAA’s, will be priced similarly (thus killing any insurer concerns), and results in >60% reduction is severe hypoglycemic events. There is little standing in the way of MannKind’s success at this point but that will likely not prevent partially informed talking heads and “drive-by” writers from debating its merits ad nauseam.
There will be little middle ground in the short-term and any news will have a major impact on the stock.
The FDA has somewhat “moved the goal posts” previously and while we would like to believe that there’s nothing funny going on at the FDA, it cannot be completely ruled out. Biotech’s such as MannKind are generally valued at what the market perceives as its potenti al value which is then discounted. However, it’s important to remember that all the heavy lifting (with exception of a partnership) has all been accomplished. Both the Zinn Fund Partnership and Astra Frontline Fund cater to those who are interested in investing in global st ocks on a long-term value basis.
There are no warranties, expressed or implied, as to the accuracy, completeness, or results obtained from any information set forth on this website. The importance of AMPK in the actions of metformin stems from the role of AMPK in the regulation of both lipid and carbohydrate metabolism (see AMPK: Master Metabolic Regulator for more details).
Insulin, which is a hormone that is secreted by the pancreas, facilitates the absorption of glucose by the cells and tissues of the body. A drop of blood taken from the pricked finger is placed onto a glucose strip, which is then inserted into the glucose meter; a small machine that provides a digital record, as well as a readout of the blood glucose level.
In 2001 MannKind purchased the Technosphere technology from Solomon Steiner and went public in 2004 with a small $70M offering.
With the help of the hormone insulin, cells throughout the body absorb glucose and use it for energy. Diabetics spend on average $7,900 or 2.3x more than a non-diabetic on healthcare related expenses per year.
While insulin has greatly improved the lives of diabetics, their current form and delivery methods are not a panacea. The remainder shows up in other forms such as gestational (pregnancy can sometimes cause diabetes, though this tends to be temporary). As proven over numerous trials, it offers a unique clinical utility for diabetics from a convenience and efficacy stand-point. Likewise, AFREZZA is an advancement over current RAA’s for the same reason: it’s faster and thus superior. AFREZZA is really a story about a unique delivery technology (Technosphere), not radically new insulin. Imagine the royalties to MannKind for Technosphere if some of the most successful drugs with patent expiration could be reformulated and regain exclusivity.
Since it’s delivered in monomeric form, peak insulin levels are achieved within 12 to 14 minutes of administration with all insulin out of the system within 3hrs.
The human body’s physiological process of “breaking down” insulin is largely responsible for RAA’s 2-3x delay in peak activation versus AFREZZA. The difference is comparable to driving 30miles in a buggy or Ferrari. The size and positive reaction (over 300 physicians interviewed) to the trial results cannot be understated. Removing that barrier with a small inhaler wil l not only improve convenience, but also compliance, which will create a long -term positive feed-back loop for diabetics.
There is no guarantee that this will bear fruition, but as with most progressive diseases, attacking it early is usually the smartest and best option both short and long term. This in and of itself should fulfill the FDA’s criteria for where AFREZZA fits in the armamentarium of diabetes treatment. Parents must have an especially terrible time when their kids go to school and have to either self-administer, or have to have a school nurse administer the insulin.
Additionally, the reason MannKind will be able to command such a high royalty figure is due to the fact that MannKind already paid for all the clinical trials for AFREZZA.
With a 50% royalty rate, 40% Net Profit Margin and 20 earnings multiple, you get a $15B market capitalization.
Though Exubera was a total debacle, and a poor comparable in virtually every way, it does underscore the value a major pharmaceutical company ascribes to partnering with a potential blockbuster drug assumed to garner ~10% of the diabetes market. The big difference with this deal and that of Exubera’s is that the Eli Lilly deal was struck before the drug entered the final phase (III) of the clinical trial process.
This is not an un usual valuation and there are plenty more examples as cancer has huge market potential and no cure is in sight. Upon approval, AFREZZA will be able to help millions of diabetics live better and improve the fortune of shareholders. The ultimate outcome will be interesting, but I believe both will agree before approval (April 15 th ). With the level of conviction Al Mann seems to possess in AFREZZA, he is likely bargaining hard for a smaller initial payment and high royalty fees.
Mann himself touched on in the MannKind Q4 2011 conference call: “Some of you may recall a somewhat parallel story regarding my experience in MiniMed, which had protocol which had pioneered in insulin pumps and continuous glucose sensors. The fact that AFREZZA is inhalable and diabetics won’t have to poke themselves is icing on the cake.
That is, until AFREZZA is finally approved and has achieved major success (even then they will probably find something to harp on to draw hits to their sites. Once the “74 day letter” and a partnership with a Major Pharma is announced this will greatly reduce our concerns.
MannKind is undoubtedly better off with Mann at the helm – so we wish him nothing but to remain in good health – but the wonder drug that is AFREZZA can and will survive long after Dr. Below are some additional interesting articles and websites for more information on diabetes, insulin and AFREZZA. In adipose tissue, metformin inhibits lipolysis while enhancing re-esterification of fatty acids. Glucose that is stored in the liver as glycogen, gets reabsorbed in the bloodstream, when the sugar levels drop. Mann has done this is due to his belief and understanding of AFREZZA’s disruptive technology and believes it will ultimately be the best selling drug in history and a major boon for suffering diabetics Worldwide. Diabetes was the leading cause of blindness, kidney failure, and non-traumatic lower-limb amputations in the United States in 2011.
As such, it will have a considerable place in Physician’s armamentarium for the battle against diabetes. We cover this is greater detail in the section below titled: Convenience = Better Compliance = Increased Insulin Sales + Healthier Lives. Though not the only reason (there are numerous economic and psychological issues), needles certainly serve as a great excuse to avoid insulin. Using needles is not an enjoyable experience for anyone.
MannKind will fall somewhere in-between these two deals as it has finalized all its trials successfully and has a market potential that’s more on par with Exubera.
After some negative publicity by the serious problem with another company’s pumps, the 3 major companies competing for that market all dropped out. This summary is meant in no way to limit or otherwise circumscribe the full scope and effect of the complete Terms of Use. The activation of AMPK by metformin is likely related to the inhibitory effects of the drug on complex I of oxidative phosphorylation. We will attempt to address the facts in this report and show why MannKind is so undervalued. He never worked less than 80hrs a week until well after his 80’ (he’s 87 now), graduated from High School at 15, and holds a BA and MS in Physics from UCLA. As the blood glucose level rises after a meal, the pancreas is triggered to release insulin. MannKind will surely place considerable emphasis on Technosphere, once AFREZZA is approved and being marketed.
Expectations are that there will be ~552M diabetics and another 470M pre-diabetics Worldwide by 2030.
Mann is a serial entrepreneur who built up a personal fortune of nearly $2B through the founding, development and marketing of over a dozen companies. Mann is putting both his vast expertise in diabetes and devices, along with over $1B (not a typo, he owns ~46% of the company) of his personal fortune (more than half his net worth) to ensure MannKind and AFREZZA will succeed. Much like what Charlie Munger and Warren Buffett have built, not much else a man could ask for in terms of a lasting legacy. This would lead to a reduction in ATP production and, therefore, an increase in the level of AMP and as a result activation of AMPK. These charts have proved to be very useful to doctors, while determining the need for oral medication or insulin.
Mann’s history and unparalleled insight in both the device and diabetes space, combined with stellar clinical trial results, we agree with his conviction in AFREZZA’s future. Within the pancreas, clusters of cells called islets contain beta cells, which make the insulin and release it into the blood. This is largely due to the long-term effects of volatile swings of glucose and insulin in diabetics’ circulatory systems. In fact, since the cells of the gut will see the highest doses of metformin they will experience the greatest level of inhibited complex I which may explain the gastrointestinal side effects (nausea, diarrhea, anorexia) of the drug that limit its utility in many patients. Mann founded and ran over a dozen successful companies, the vast majority of which he eventually sold off to large companies. I am not suggesting an ultimate future gain by a factor of over 100 for MannKind, but I do remain very optimistic about the value of AFREZZA as well as several other product opportunities at MannKind”.
However, I now have a secret weapon to conquer my fear of salad. I love red onions, and I love garlic. So the two together created a delicious flavor explosion in my mouth that I just have to share.. Determined to overcome my salad challenged attitude, I began looking at various recipes on the web for chopped salads, and using several as a guide (to which I added my own twist of course) I came up with this great tasting blend of fresh corn, black beans, olives, peppers and avocado. But rest assured that this delicious looking AND TASTING vegan hamburger recipe will have you happy and feeling great about your cruelty free choice. Instead, you can join the party with something just as tasty, happy in your stance of cruelty free food choices.
And though most vegan cheeses aren’t QUITE the same as cow or goat milk based cheeses, there are many commercial brands and some home made versions which definitely fill the void.
The sender was raving about the fabulousness of this mac and cheese, which I have to admit got my attention. The part I didn’t like was burning my oven for two hours to cook four patties of wheat meat. We were surprised that such a modestly priced mix passed our taste test for vegans and omnis with flying color and a five-star rating.

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  1. 08.12.2014 at 18:58:15

    Absorb blood glucose as it uses with hypoglycemia.

    Author: ElektrA_RaFo
  2. 08.12.2014 at 21:32:51

    Levels can cause fatigue, blurred vision have had diabetes for family doctors have.

    Author: INTELLiGENT_GiRL