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This week, we are taking a break from our Clinical Text presentations, to bring you this exclusive interview with Al Mann, the legendary founder of Mannkind Corp, and the person primarily responsible for backing the development of the inhaled insulin product, Afrezza, soon to be on the market.

Steve Freed: Let’s start off by talking about how it all began. I know you’ve been involved in the diabetes arena for a number of years. Please tell us how you got involved, why you got involved, and why this product.

Al Mann: It can be a long story. I was a young physicist doing some work in electro-optical and semiconductor physics. In 1956, the US Army came to me seeking help in my area of expertise for an anti-tank missile guidance system, but my boss wouldn’t let me undertake that work. I therefore advised the Army team as to how I would address their problem. Their prior vendor on the project said they couldn’t do what I proposed, so the Army actually set me up in business. That first of my companies, Spectrolab, was very successful and it evolved into where the most significant of our products became solar electric systems to provide the electrical power for almost all the free world spacecraft. During my tenure at Spectrolab we actually powered about one hundred and fifty spacecraft….

One of our customers was the Applied Physics Laboratory, a government R&D organization operated by Johns Hopkins. In the late 1960’s, Hopkins was seeking to use the technology and methodology of APL to improve medical products. In 1969, they persuaded me to try to develop a cardiac pacemaker which would last more than the eighteen to twenty-one months typical life at that time. My father had died of a cardiac event, so I agreed to try. We developed a pacemaker with a target to last five years. I am proud to say that I learned our second patient who was implanted in July 1973 was still alive and using the very same pacemaker in 2011 after thirty-seven years. Creating medical products was very exciting for me. Thus, after all the military and aerospace government projects in which I had been involved, the success with a pacemaker motivated me to change my career and focus on medicine. I founded Pacesetter Systems to commercialize the cardiac pacemaker, and that is now the second largest pacemaker company and the primary business of St. Jude Medical. Trying to diversify that business in 1979 we created a list of fourteen different products that might be developed using our technology. From that list I decided to pursue development of an implantable insulin pump and soon afterwards we added external pumps. Pacesetter was sold in 1985 and the acquirer did not want to pursue pharmaceutical activity. The diabetes pump business was therefore spun-off into the founding of MiniMed which pioneered insulin pumps, continuous glucose sensors and even an artificial pancreas. That work proved to be very valuable and interesting.

While such technology provided the best clinical results in diabetes, I learned that the pharmacokinetics of the prandial insulin products delivered by the pumps were certainly not physiologic. The long persistence of existing insulins causes much of the hypoglycemia in diabetes therapy. I realized that the problem was that those insulins are formulated into six molecule hexamers to stabilize them, and that to utilize the insulin the body takes time to break down the hexamer into monomers. I became very interested in trying to find a way to improve the kinetics of prandial insulins.

We had been exploring ways to stabilize other large molecule drugs for pump delivery and discovered a viable technology that could greatly improve stabilization. I wondered if that technology could stabilize insulin monomers, so I directed creation of such a formulation that turned out to be very successful. When I saw the pharmacokinetics, I said, “My God, that will revolutionize diabetes!” That was before I later realized the magnitude of the challenges bringing a drug product to market, to develop what is now called Afrezza. MannKind has invested about 1.8 billion dollars, of which about 975 million dollars came from me personally. Although that development and regulatory process proved to be a huge challenge, Afrezza is now FDA-approved and we are excited to bring it to market. To be able to service a larger segment of the global diabetes community we have recently entered into a partnership with Sanofi to commercialize Afrezza. Sanofi is an enormous organization which serves diabetes patients throughout most of the world — far more than MannKind could ever have done on our own.

SF: So you made this an inhaled insulin. Had you ever thought of abandoning that effort?

AM: Afrezza is a powder with a particle size ideally suited for pulmonary delivery. The stability is compromised when it is dissolved. Moreover, in those days people were excited about Exubera from Pfizer, and both Lilly and Novo were also developing inhaled products. When I saw the kinetics and dynamics of our insulin powder compared to the poor characteristics of Exubera I reasoned that Pfizer’s marketing power might make it a success, but within a year after launch of Afrezza we ought to capture most of that business. Frankly it seemed clear that Exubera would not be a viable product; the size of the inhalation device was outrageous; it was difficult to use and it was also difficult to maintain. Importantly the kinetics of Exubera and of those other inhaled insulins in development were not even as effective as the kinetics of the injected rapid acting analog insulins. All that led me to be confident that Afrezza would likely be the only true success of all those inhaled insulins and the need for better insulins is so great that I could not imagine abandoning the effort.

SF: So, with the problems that Pfizer had, how do you feel? Well maybe it’s not your issue anymore, but maybe it is Sanofi’s issue to overcome the Exubera fiasco. It just never took off. People had negative issues about it, especially the endocrinologists. How do you feel it is best to handle that issue?

AM: As I said, Exubera was very difficult to deliver, very inconvenient, it was quite expensive and its clinical effects were not adequate. Exubera and the other inhaled products in development were not even clinically as good as injected insulin. I’m not surprised that endocrinologists were not enthusiastic about Exubera; also we expected it to fail. We used to joke about it. Yet people do remember the Exubera fiasco, may not understand why it failed and some would likely relate Afrezza to Exubera. We will have to overcome that reference so it is important that we make sure endocrinologists do understand that Exubera’s failure was not because it was inhaled but due to its clinical deficiencies and expensive pricing. They must be made to realize that Afrezza is very convenient and that it has kinetics which truly mimic natural pancreatic insulin. It has none of the long persistence leading to the hyperinsulinemia which causes so much of the hypoglycemia in current insulin therapy. Afrezza is so very different from all those early efforts to create an inhaled insulin. We just have to educate people to understand how valuable and important are the kinetics of Afrezza and not just that it is delivered by inhalation. Of course, patients really do appreciate that you don’t have to inject it and they enjoy the simplicity and convenience of Afrezza. Patients will surely create substantial demand for Afrezza, but in my view it is the significant clinical value of Afrezza resulting from its kinetics that will assure its success.

SF: Before we get into some of those questions, now that you have a partnership with Sanofi, the biggest question would be, when might it be available in the pharmacies?

AM: The plan is to launch Afrezza in the first quarter of 2015. We will spend the next few months preparing for that launch. Sanofi had already done a great deal of work preparing for the launch — they started even before we had signed the agreement. They have set up an extensive team for the commercialization and that team is hard at work in planning the launch.

SF: I know it’s expensive to bring a product to market, especially a product like insulin, because it can have devastating effects. What was the total cost from day one to get this thing through and passed?

AM: MannKind spent about 1.8 billion dollars.

SF: Do you think that is what it takes for any new drug for diabetes to get through?

AM: I’m not sure that it would cost that much for any drug in diabetes but an insulin costs a great deal. Perhaps it shouldn’t have cost as much or taken as long. Maybe it could have been done for a billion dollars, but the major cause that led to the higher cost for us was the unexpected Complete Response Letter from the FDA three and a half years ago. The resultant delay ended up costing us another half billion dollars.

SF: Right. What would the total number of patients involved in all the studies be?

AM: About six thousand five hundred.

SF: Do you recall how many may have dropped out?

AM: I don’t know the number but not many dropped out of the Afrezza cohorts. There was some loss of patients in the comparator groups using other therapies because they really didn’t see any benefits.

SF: Do you recall what was the best drop of A1c?

AM: I don’t know the largest drop, but many Afrezza patients achieved HbA1cs under 7% and quite a large number even under 6.5%. Frankly part of the problem in the trials was that from experience with other insulins the fasting glucose was generally not lowered as it should have been; had that been done the A1c results would have been much better.

SF: Was that when you changed to the new device?

AM: No, I think that a problem during the trials was that some patients took their dose of Afrezza even before starting to eat. The trial protocols called for Afrezza to be dosed “at the beginning of the meal,” but sometimes it was taken even before. We need to do additional trials to gain more experience with optimized dosing times. Actual ingestion of food in most meals in the United States except in restaurants takes only about 30 minutes, so I believe that the first Afrezza dose really ought to be taken ten or fifteen minutes after starting to eat. For a longer meal, which is not very common, a second dose might be taken fifty or sixty minutes after starting to eat. For a long feast that lasts for an hour and a half or more, I suggest a third dose be taken at maybe one and a half hours after start. Interestingly I believe the size of all those doses should probably be the same for most patients. Unfortunately the trial protocols called for dosing at the beginning of the meal so we will need to do more trials to be able to gain FDA label approval of optimized dosing.

SF: What is the time to peak and what is the duration?

AM: Afrezza rises to a peak in about twelve to fifteen minutes and is almost gone in about two and half to three hours. Afrezza reduces average glucose levels to near physiologic levels during the prandial period and does not have any of the postprandial persistence. In the trials the fasting levels for the Afrezza patients was to be reduced to under 120 mg/dl or until there was a hypoglycemic incident, but out of habit that reduction of fasting glucose was generally not properly done. There is hardly any difference in the kinetics of Afrezza from that for the sum of published curves for the phase 1 and phase 2 spikes of normal pancreatic insulin. With Afrezza there is none of the excessive postprandial persistence of current prandial insulins which is a major cause of hypoglycemia and weight gain.

SF: You are going to be coming out with two dosage cartridges, do you need more?

AM: We didn’t want to risk another delay in FDA approval so we didn’t add any additional cartridges in the regulatory filing. We are already planning supplemental submissions to the FDA for cartridges with two larger doses that would be equivalent to 12 and 16 iu of injected insulin. The submission for the 12 iu cartridge will be filed momentarily and should be approved at about the time of launch; the supplemental application for the 16 iu cartridge will be somewhat later. Some patients will require even higher doses and those people will likely need two cartridges for some meals, but that is easy. In our trials we have seen almost no patient resistance to two or even three cartridge inhalations. We do have plans for still larger size doses later.

SF: What will be the initial dose cartridges, to begin with?

AM: The labeling says they are equivalent to 4 and 8 units of injected rapid acting analog. The new cartridges will be equivalent to 12 and 16 units.

SF: So, you will have four doses?

AM: We will have four doses in the near term and those will serve most patients with one though for some people two cartridges would be needed for a meal. We have developed another process that enables us to go to extremely high doses. We’ve already demonstrated the equivalent of 36 units with that process. However cartridges with that powder will likely not be available for some time.

SF: One of the issues with Exubera was when a person has chest congestion, flus, colds, asthma, COPD issues.

AM: We have not seen any difficulty with colds or flus but the label for Afrezza contraindicates for people with asthma or COPD.

SF: Can the use of other inhaled medications lessen or increase the effect of Afrezza? Are there any warnings that you can’t use it with other inhaled medications, or osteoporosis medications?

AM: We have seen no problems. After all, we are only supplying the very same insulin as from the pancreas. Afrezza just fills in for any deficiencies in the amount of physiologic insulin.

SF: How accurate is it? So, if I know that one unit of Humalog or Novolog lowers my blood sugars 30 mg/dl, can I expect a 4 unit cartridge will lower my blood glucose 120 mg/dl?

AM: The FDA has concluded that a cartridge containing 10 iu of insulin is equivalent to a dose of 4 iu of injected RAA insulin. A cartridge containing 20 iu of insulin is labeled as equivalent to 8 units of injected RAAs, and so forth. The lowering of blood glucose should be comparable to what occurs with the “equivalent” dose of an injected RAA insulin, though the actual prandial effect is greater and the effect would probably be more consistent.

SF: How will the product be priced compared to injected insulin? Will it be similar to Humalog?

AM: I cannot offer a precise answer because we have just executed our partnership agreements with Sanofi, and Sanofi is responsible for establishing the pricing. Our intention has been to sell it at very close to the same price as the equivalent dose of pen delivered rapid acting analogs, and we believe Sanofi is in agreement.

SF: If someone gets a hypoglycemic reaction, is it predictable? Do we get a predictable response when glucagon is required compared to injected insulin?

AM: Any hypoglycemic incident in a patient using Afrezza would be treated in the same way as he/she would be treated today with any other exogenous insulins. We cannot make any claims about hypoglycemic risk since the label does not enable us to, but the kinetics of Afrezza were included in the package insert and those should suggest that unless the dose is taken on an empty stomach Afrezza should not cause a real hypoglycemic risk. During the prandial period it would be difficult to deliver enough Afrezza to cause a hypoglycemic incident and Afrezza is virtually gone before the digestion is completed. There should be almost no risk of a post prandial hypoglycemic event.

SF: But you have to be concerned about hypoglycemia if you take an inhaled dose, and for some reason your meal is delayed, there is still the chance of hypoglycemia, isn’t there?

AM: What I am saying is that a dose of Afrezza should really not be taken until after some food has already been ingested, so there should not be such a problem. However, the FDA only permits us in the label to say the dose should be taken “at the beginning of the meal.”

SF: Is that instruction not on the label to take it after you start eating?

AM: The label says the dose should be taken “at the beginning of the meal.” We are planning new trials to provide more data to validate what should be more optimal dosing protocols for most patients.

SF: What does it say on the label? Take it before eating?

AM: Take it “at the beginning of the meal.”

SF: For someone who is on a low carbohydrate diet, do they have to be more concerned with the dosing?

AM: We haven’t seen any such problem.

SF: Do you have any plans to do a similar basal insulin?

AM: MannKind is not developing a basal insulin but improvements are also needed in basal insulins. Sanofi has submitted its NDA for Jouveo to the FDA for review. Toujeo is said to be an improvement over Lantus. I have not seen the data so I cannot make a definitive judgment as to likelihood of FDA approval or patient adoption. Hopefully that new basal insulin will be approved and will work better with Afrezza even than does Lantus.

SF: Where is this going to be placed on the ADA schedule, as first treatment, second treatment, etc., for type 2s? Right now the number one drug is to be metformin. Will this be in the second or third choice?

AM: I can’t really answer that; placement for its recommended placement is really up to the ADA. However an insulin that causes no or little hypoglycemia should have application early in type 2. For the MKC 175 trial the FDA suggested evaluation of Afrezza as a second therapy after metformin. We did have a few hypoglycemia events in our 175 trial, but 43% of those were in one patient who was also using a sulfonylurea, and we don’t have data on the other few incidents so we cannot say what caused those hypos — other antiglycemics or pre-meal dosing with Afrezza or whatever else. We believe that insulin in the form of Afrezza which closely mimics pancreatic insulin would be a very good first or second therapy in type 2. On the other hand, you have to take a dose of Afrezza with every meal and, even though Afrezza is so easy to take, many patients would probably rather just take one pill a day or one injection a week, so at this early time I can’t suggest where I believe the ADA should recommend Afrezza on its list.

SF: On the label, Afrezza is approved for type 2. What about type 1s?

AM: Afrezza was approved by the FDA as an effective and safe prandial insulin for adults with type 1.

SF: People with type 2 are usually started out on a basal insulin.

AM: Well, that is medically incorrect. Starting a type 2 on basal insulin is done today because current prandial insulin products are not physically sound so they are delayed about as long as they can be. Lantus has been so successful as the first insulin used in type 2 because of the problems with current prandial products.

SF: Some studies or most of the studies have shown that type 2 diabetes starts as a post prandial disease. Would it make more sense to start a type 2 on a post prandial insulin or on a prandial insulin, rather than even a basal insulin?

AM: The first loss in type 2 is really the early phase 1 pancreatic spike and that is then followed by loss of the phase 2 prandial insulin. Almost all postprandial issues are from use of current prandial insulins. What is needed first in type 2 should be a very fast acting prandial insulin, not a basal insulin. Afrezza provides insulin kinetics close to the kinetics of pancreatic insulin in response to a glucose spike. Afrezza should be the first insulin employed and that should actually be prescribed in early type 2.

SF: Do you plan on any more studies, or are you required to do any more studies?

AM: We are required to do more trials, and we plan to do other studies to validate more optimal dose timing and to better demonstrate the effectiveness of Afrezza.

SF: Is Afrezza more forgiving because there is less hypoglycemia, so if it’s taken in 4 or 8 unit equivalent increments is the formula more forgiving than injected insulin? For example, if you need 10 units, would you take 8 or 12 equivalent units of Afrezza?

AM: Since the ultimate goal is low HbA1c and there would be no postprandial hyperinsulinemia the actual dose with Afrezza is not so critical as is practiced in current prandial insulin therapy. Much of the hypoglycemia seen in insulin therapy today occurs in the postprandial period due to the hyperinsulinemia caused by the excessive persistence of current prandial insulin products. Afrezza has none of that persistence and the label does include data comparing Afrezza and RAAs but the FDA did not authorize us to make a specific claim of less hypoglycemia.

SF: Are there any cognitive effects of Afrezza, if any?

AM: We haven’t seen anything. Again I say that Afrezza simply supplies prandial insulin deficiencies of the pancreas.

SF: Is there any neuro-protective, or neurotropic, or neuro-enhancing effects?

AM: I do not know of any and there should be no effects different from what is caused by insulin from a healthy pancreas.

SF: Does the effectiveness of it only apply to people with the metabolic defects of type 2 diabetes?

AM: I do not understand your question.

SF: Say you have a type 2 diabetic who is thin, which is kind of unique, maybe they call it type 3, would Afrezza be as effective, or would it be more effective for those people who are overweight and have metabolic syndrome?

AM: Afrezza provides the very same insulin that you would get from a healthy pancreas and it is delivered with timing more or less comparable with what would occur in a healthy person responding to a short food ingestion. Afrezza just makes up for any deficiency in pancreatic delivery. However more studies really have to be done to support any formal claims to be allowed by the FDA.

SF: Is Sanofi going to help support you with all these studies?

AM: Sanofi will actually do most of them.

SF: Do you plan to submit to the FDA for any other indications of Afrezza?

AM: Afrezza is simply a rather physiologic formulation of prandial insulin and is intended to be used to replace any pancreatic insulin deficiencies. We wouldn’t be seeking any other application for Afrezza other than to replace deficiencies of pancreatic insulin for meals.

SF: What I mean is, to be used with other, maybe, oral medications, like SGLT-2, DPP IV, etc.

AM: The delivery system using the Technosphere® technology has many applications, and we are already exploring a number of other uses. We can deliver many other drugs in the same way. A major benefit afforded by Technosphere delivery is that the molecule becomes effective very rapidly; it gets into the arterial blood very quickly. There would be many potential uses for that; for example, a pain drug becomes effective in only a few minutes. Also such delivery eliminates any adverse digestive effects of some drugs when delivered into the stomach or even into subcutaneous tissue. We have seen none of those problems with the Technosphere pulmonary delivery system.

SF: Will it have the same effect for people with gastroparesis?

AM: We have done no such studies so we can make no claims.

SF: I appreciate you taking this time. One of the most important things where Exubera probably failed is on the educational piece, educating physicians and patients. That’s going to be kind of an involved process, and I’m sure you’ll have information on your website, training, etc.?

AM: Actually education for use of Afrezza is not difficult. Exubera delivered its insulin with substantial difficulty and I am told it took about an hour just to train a patient to use the system. That much time would be difficult for most doctors or therapists. Afrezza delivery seems obvious and the most I have heard is for it to take for training is about two minutes. While diabetes therapy itself requires considerable education, the basic disease treatment is actually even quite a bit simpler with Afrezza because the meal dosage is not so critical.

SF: Will the cartridges be separate from the inhaler? I know they’ll come as one piece, originally, but with refills, how will that work?

AM: The plan is to deliver two inhalers with every month’s supply of cartridges.

SF: So they will be disposable after they are used?

AM: A device is to be used for about two weeks and then disposed.

SF: Is there anything else you’d like to share? What are the biggest impacts, the biggest plusses, and are there any negatives?

AM: Unfortunately, we can’t make claims that are not in the label, so we can’t make specific claims about hypoglycemia or weight gain. All we can say is that Afrezza peaks in 12-15 minutes, and is virtually gone in 2½to 3 hours and that is really about the same as for pancreatic physiologic insulin from a healthy person. We will be doing more trials to validate additional benefits.

SF: But didn’t you show that there is less hypoglycemia than regular prandial insulins?

AM: Well, the package insert has data that shows less hypoglycemia, but the written word part of the label does not allow us to make that claim.

SF: So, when a representative goes into the doctor’s office, he’s going to say that the onset is more rapid?

AM: I can’t really answer that. The physician presentation will primarily be up to Sanofi.

SF: In final, I would like to congratulate you. I’ve been paying attention to Afrezza since the beginning and all the troubles you had to go through. I figured eventually you were just going to drop out of the process but you had so much invested into it, in time and energy. I think most people would have just dropped and said, just forget it!

AM: First of all, you have to understand that I am about 89 years old, so I’m not worried about supporting my family or myself for the rest of my life. My family has already been cared for financially. My personal commitment for decades has been in trying to solve unmet or poorly met medical needs, and not just in diabetes. I’ve fostered many developments that have made substantial differences in peoples’ lives though diabetes is the greatest medical problem faced today throughout the entire world, and the need is enormous. There are close to a billion people with either diabetes or pre-diabetes who should benefit from Afrezza. The problem we have earlier faced was completion of the US regulatory process but now Afrezza is approved. Most other countries outside of Europe actually rely to a large extent on the US or EU to foster local approval, so use in much of the world will soon become possible. The problem will be in creating greater manufacturing capacity.

SF: I know you’ve been involved with the artificial pancreas and there’s been a lot of new information coming out, some trials that have proven successful. Do you really think that there is going to be, some day, an artificial pancreas, a machine that will control someone’s life that could go wrong and actually kill someone, possibly? The FDA is probably going to require so many tests and studies to be done. Do you ever think it is a possibility that it could happen?

AM: I have to answer that in two ways. First of all, will an artificial pancreas be created that could effectively and safely control glucose levels in diabetes? I believe the answer to that question is “yes.” Do I think that it should be developed, and for the following reason I believe the answer to that question is “probably not.” After introduction of insulin pumps by MiniMed over thirty years ago, and soon afterward also glucose sensors, only 35% of people with type 1 diabetes in the United States are using insulin pumps, even fewer outside the United States, and hardly any type 2s globally. While insulin pumps do provide the best insulin therapy today, they don’t adequately address what I call my three Cs: cost, convenience and complexity. They are too expensive. They are too complicated. They are too inconvenient. I believe that a combination of Afrezza plus a reasonable basal insulin may not provide glucose control quite as good as by an artificial pancreas, the results would not be much poorer and would actually be good enough so that I don’t really see a real business opportunity for such a sophisticated and expensive system as the artificial pancreas. Surely there will likely be some type 1 patients that would use an artificial pancreas but the real need is for therapy that would be much more widely used.

SF: I want to thank you, again, for your time. I really congratulate you for what you’ve accomplished.

AM: I was only just leading the team in getting to this point. We have a great team at MannKind that should be credited for achieving the amazing results.

SF: No, but you pushed forward, and you didn’t give up. You could have pulled the plug at any time.

AM: When we got the CRL three and a half years ago I myself came up with another 350 million dollars to make sure that we were adequately funded.

SF: Most people would not have been able to do that, or thought that they were in a situation which was throwing good money after bad money, but you decided to do it.

AM: Well, that may have been so, but I’ve been fortunate in being quite successful with my many businesses, so coming up with additional money to fund such an important need really wasn’t so difficult for me. I just want to help solve the huge global diabetes pandemic. I had the money to spend, and anyway I’m giving most of what I have away to charity; 90% of my estate is already committed for philanthropy. Clearly the question was whether to spend it for general charity or to spend it trying to solve the diabetes pandemic. Deciding to fund Afrezza really didn’t make much difference for me personally but it should make an enormous difference to the world.

SF: Do you think this is a greater accomplishment than what you developed at MiniMed, because this can affect so many more people?

AM: In my view it will affect so many more people. If we can combine Afrezza with better basal insulins the combination will make an enormous difference that will certainly affect far more people than we could ever imagine. Indeed, some key opinion leaders are saying that Afrezza therapy in early stage type 2 diabetes should slow, probably stop and maybe even reverse type 2 diabetes. Today diabetes is the greatest need in medicine globally.

SF: Thank you, Mr. Mann.

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