Thursday, December 31, 2009

MannKind's CFO Pfeffer Upbeat on Afresa's Future: NOV 2009

MannKind's CFO Pfeffer Upbeat on Afresa's Future
By David Phillips Nov 10, 2009
MannKind Corp.‘s announcement last month that no partnership deal was in the offing for its inhaled-insulin product Afresa this year has lead to widespread talk that this novel, investigational prandial drug therapy for diabetes care was dead-on-arrival. In a conference call with me on Wednesday, chief financial officer Matt Pfeffer vocally dispelled that notion and stressed that although uncertainty regarding Afresa’s approval had made it difficult to secure a partnership deal pre-FDA review, the company remained optimistic on Afresa’s commercial viability.
MannKind is seeking FDA approval of Afresa for the treatment of adults with type 1 or type 2-diabetes. Afresa is a drug-device combination product, consisting an ultra, rapid-acting insulin [an inhalation powder formulation] pre-metered into single unit dose cartridges and an inhaler.
BNET: Matt, could you provide color on any recent discussions held with the FDA — and what is the status of Afresa’s assigned Prescription Drug User Fee Act (PDUFA) date of January 16, 2010?
Matt Pfeffer: The FDA review seems to be proceeding routinely, and we haven’t seen anything to give us concern that there might be a delay. We are cautiously optimistic that they [FDA] will meet or beat the PDUFA date, but of course there is no guarantee.
BNET: Given the known health events associated with use of Pfizer’s [discontinued] inhaled-insulin product Exubera, such as higher risk of hypoglycemia and lung cancer in former smokers, there is recurring talk that Afresa is unlikely to get FDA approval without first being reviewed by the Endocrine and Metabolic Advisory Committee. Care to comment?
MP: We are not currently on the docket to appear before an FDA advisory committee scheduled to meet on December 15 — and there is not currently another advisory meeting scheduled before our PDUFA date. Therefore, we do not anticipate a special Afresa advisory panel will need to be convened. But this is not unusual, as most products are [approved] without an advisory panel.
BNET: Afresa is a powder formulation that is inhaled into the lungs. These days, labeling guidelines are usually not enough to ensure that healthcare providers are properly monitoring benefit-risk scale to patients: can you provide an update an lung function safety issues and is a post-marketing Risk Evaluation and Mitigation Strategy (REMS) request by the FDA to be expected with Afresa approval?
MP: It would be very unusual for a REMS program not to be required, so we are expecting one and, in fact, have proposed one to the FDA. We do not expect this to be a major burden, as these days this can usually be accomplished electronically. We look forward to working with the FDA to assure the safety of patients.
BNET: Matt, my understanding is that a REMS protocol is usually finalized prior to the last meet with the FDA. Does this mean that MannKind already is aware of the details of the surveillance endpoints the FDA is looking for — if so, could you elaborate?
MP: This is usually done just prior to approval, so it would be premature to comment with details prior to then.
BNET: Some confusion exists as to the length of time patients were prospectively followed while on Afresa therapy. In my opinion, this likely has to do with folks mixing up data points from different studies. Could you specifically address lung function safety concerns with long-term usage of Afresa?
MP: Our largest study was for two years, so we have thousands of patients with 2-year safety data and many beyond that, up to 4-5 years.
BNET: Could you paint in more detailed strokes the efficacy-safety profile of patients followed for at least four years?
MP: More than two hundred adult patients with type-2 diabetes who had completed past, randomized, phase 2 trials continued open-label therapy with Afresa as their exclusive insulin — with the predefined study endpoints being changes in lung function and glycemic control. And, over four years, changes in lung functions were small and mean A1C levels remained steady [slight decline at end of year-four].
BNET: What about the cough I keep hearing about with Afresa-treated patients?
MP: Many of the patients did develop a mild cough, though it usually resolved on its own within a few days — and less than three percent [in latest trial data presented] had to discontinue therapy because of it [cough].
BNET: Assuming a thumbs-up from the FDA come January, when would you expect to launch Afresa?
MP: Although we still are guiding to an early 2010 approval of Afresa, I caution that FDA approval of the drug does not mean we can go to market the next day or week: product labeling, marketing materials, other regulatory processes could add more than six months or more to launch.
BNET: Is it premature to talk about the next-generation device, called “DreamBoat,” and is it possible that this inhaler device could be launched simultaneously with the approval of Afresa?
MP: If I may correct you — Dreamboat is the designated internal name of the project. This smaller inhaler is intended to improve upon the current Afresa “MedTone Inhaler” in terms of size/convenience and [importantly] would be less costly and more reliable.
BNET: Could you elaborate?
MP: Less costly both in the actual cost of the inhaler (it is smaller and has many fewer parts) and in the cost of the ingredients used in the product — in that it would require about a third less units of insulin to get the same plasma concentration currently required of each dose with MedTone. This is primarily because the new device does a better job of delivering the drug to the deep lung where it has effect, rather than wasting the powder by leaving it in the cartridge or getting it stuck in the [patient's] throat.
BNET: What’s the anticipated launch date for the next-generation device? Also, would an amended NDA [with Afresa] be necessary?
MP: We are hopeful that one bioequivalence study will be enough to satisfy the FDA, as the requirements are fairly standardized and straightforward. We expect we could file a supplemental NDA — assuming no new delays with Afresa — in January. That said, we are still awaiting necessary feedback on our proposed study design.
BNET: To clarify — does MannKind plan to launch with the Afresa MedTone device — then switch patients over to Dreamboat — or whatever you end up calling Afresa’s successor?
MP: Our strong preference — and intention — is to wait and launch with the new “Dreamboat” inhaler. If things go as we hope, this will not cause any appreciable delay, and we believe that the advantages to the new inhaler are sufficient to justify this.
BNET: With the advent of injectable pens and smaller needle gauge sizes, some health care administrators would say that it is not such a big impediment anymore [compliance] for diabetics to inject insulin. As such, where does Afresa, or its successor device, stand with managed care — relative to say injectable insulins — especially when so many so many cheap versions of insulin (short & long-acting) are readable available for type I diabetics and generic sulfonylureas and metformin are around as first-line agents for type II diabetics?
MP: Unlike previously inhaled insulins, our product does not require a significant price premium over existing rapid acting analogs. This will be important in making sure it is reimbursable. Plus, when you add in our safety and other advantages, we think we have a compelling case to make to reimbursement agencies. In fact, we have met with quite a large number of them in preliminary discussions and walked away confident that we would start out in tier-3, with a move into tier 2 [most likely] pretty quickly for most payers.
BNET: Rumor has it that MannKind has resumed talks with Big Pharma. Would any deal include distribution terms for both Afresa and its successor inhaler? In addition, would MannKind be receptive to any overtures of a buyout from a deeper-pocketed company — say an Eli Lilly or Pfizer — looking to expand its own diabetes franchise?
MP: I cannot comment on specific deal discussions, but it is safe to assume that any such deal would include the new inhaler. And while I cannot identify particular parties we have spoken to, the vast majority have been global pharma companies.
MannKind’s detractors argue that even if Afresa wins FDA approval, incessant doubts with Pfizer’s inhaled-insulin Exubera is proof-positive that chronic administration of insulin through the lungs will limit the drug’s prospects. However, as rebutted by Matt Pfeffer in my interview, the PDUFA is progressing according to plan, with no indication from the FDA of any extraordinary issues about its efficacy and safety. In my opinion, the debate on Afresa’s commercial success would likely be resolved, too, upon the announcement of a definitive partnership deal [given the likely marketing reach of its partner].

Tuesday, December 29, 2009

Fate of Mankind

Article link

"From the beginning, when I saw the kinetics of Afresa and Technosphere insulin [TI], it was clear to me that this was a unique product that would revolutionize diabetes care," says Mann.

The Fate of Mannkind


Pharmaceutical Executive

Let's get one thing straight right up front: We're not talking about inhaled insulin. Sure, it comes out of an inhaler; yes, you breathe it in; and of course it's absorbed deep in the lungs. But please don't use those two unfortunate words. Inhaled insulin was a misguided idea—an attempt to replace needles and injections with something ostensibly more convenient. When Pfizer actually put that product on the market (the ill-fated Exubera in its giant bong of an inhaler), patients and doctors ignored it in droves. After that, Lilly and Novo Nordisk, big players in diabetes care, promptly folded their fast-acting inhaled insulin programs as well. No better than injected insulin, not all that convenient, and potentially dangerous. That was inhaled insulin.

Of course, if you could develop an insulin that worked better than injectable and was just as safe—and it just happened to be delivered by inhalation—that would be a completely different story. Wouldn't it? Patients and doctors would say, "That's different from Exubera." And they'd turn this drug—let's call it Afresa—into a blockbuster.

At least, that's what Al Mann is betting. And a hell of a bet it is. Mann, the legendary 82-year-old serial entrepreneur behind Afresa (also known as Technosphere insulin (TI)) has sunk $919 million of his own money into the project, and has signed a commitment to lend MannKind Corporation, his latest entrepreneurial venture, an additional $350 million to see Afresa through to market. MannKind filed Afresa's new drug application with FDA in mid-March, and though Mann and company are confident, the drug still has to clear some daunting hurdles. Will FDA approve another inhaled insulin in this safety-obsessed political climate, especially after the Exubera disaster? Will the agency weigh Afresa's label down with warnings that have less to do with MannKind's drug and more to do with Pfizer's? Will MannKind be able to find a partner that can set aside memories of the most dismal pharmaceutical launch in recent memory? And will physicians, payers, and patients see past the inhaler and recognize Afresa as an important step forward in diabetes control?

The stakes are high. Indeed, you could say they're nothing less than the survival of MannKind.

The Mann From MannKind

Alfred Mann is Hollywood's idea of a scientist—the tinkerer who invents gadgets for fun and turns them into a billion-dollar fortune, all the while thinking nothing of it. With products like solar panels, hearing aids, and pacemakers to his name, Mann has turned himself into an indispensable cog in the machine of American healthcare.

The saga starts in 1956, when the Portland, OR, native—UCLA physics degree in hand—founded his first company, Spectrolab, to produce solar panels for spacecraft. Mann liked what he'd created, and over the years launched numerous other companies built around his inventions, including Heliotek (semiconductors and solar cells), Pacesetter Systems (cardiac pacemakers), and Advanced Bionics (neuroprosthetics). In the process, he became a very rich—in 2008, Forbes estimated his net worth at $1.8 billion, ranking him number 262 on its list of the richest Americans.

Mann also became a force in philanthropy; he first turned to diabetes in 1979, developing an implantable insulin pump. MiniMed (now part of Medtronic), the company he formed around the pump, went on to concentrate in diabetes and microinfusion drug delivery. It was so successful that Mann started exploring other pathways in diabetes care.

In 1997, he was presented with an inhaled insulin product created by a small company called Pharmaceutical Discovery. His MiniMed colleagues thought it could be a breakthrough; Mann wasn't so sure. But Pfizer was experimenting with a puffed product of its own, and Pfizer wasn't stupid. Or so he thought.

What really changed Mann's mind, was a glucose clamp study MiniMed conducted to test the new drug's pharmacokinetics. The conditions were far from perfect—researchers delivered the drug via two-dollar drugstore inhalers—but the results were astonishing. At mealtimes, the body of a normal patient delivers a jolt of insulin to the bloodstream, with the level peaking in about 12 to 14 minutes. A diabetic taking prandial (mealtime) insulin gets a peak in about an hour, regardless of whether the drug is delivered by injection or inhalation. But the drug MiniMed was examining peaked in 12 to 14 minutes, just like the body's own insulin boost. And the bioavailability of the new drug was four times greater than that of the other emerging inhaled insulin products.

"From the beginning, when I saw the kinetics of Afresa and Technosphere insulin [TI], it was clear to me that this was a unique product that would revolutionize diabetes care," says Mann. He bought Pharmaceutical Discovery, folded it in with a couple of his other companies, and MannKind was born.


Technosphere Technology

There are two secrets to why Afresa behaves the way it does. The first is the insulin's delivery platform—the Technosphere particle. Described as "tiny sponges" by MannKind Chief Scientific Officer Peter Richardson, Technosphere particles are formed of multiple small crystals of fumaryl diketopiperazine (FDKP), which under certain conditions become just the right size for inhalation (approximately three to five microns in diameter). FDKP also has another property that makes it very useful for pulmonary drug delivery: Put it in an acid solution, and particles spontaneously assemble. Put the particles in a base environment—such as the human lung, with a pH of 7.3 or 7.4—and they dissolve. The particles have multiple surfaces; in photos, some Technosphere particles look a bit like a rose in bloom, flaring out in dozens of "petals." Powdered human recombinant insulin adheres to the particle's surfaces electrostatically, which means that the particle and drug do not interact chemically. Deep in the lung, the Technosphere dissolves and the insulin is absorbed in the bloodstream with remarkable speed.

"Under the right conditions, FDKP forms a complex crystalline lattice which then forms the particles," says Richardson. "Someone thought: 'What happens if we put drugs or peptides on them?' They found that peptides do tremendously well in adhering to them. And because they're pH-sensitive, you have an opportunity for a direct delivery."

At this point, secret number two kicks in. Conventional insulin tends to form hexamers—structures consisting of six monomers—the basic unit of insulin. Hexameric insulin cannot bind to insulin receptors, and has to be broken down before it's usable. Some insulin analogs, such as Lilly's Humalog and Novo Nordisk's Novolog, are modified to prevent the formation of hexamers. This makes them faster acting than traditional insulins, but because they are administered subcutaneously, they still take between 30 and 60 minutes to peak.

The manufacturing process for Afresa results in monomeric insulin. Pulmonary delivery and instant availability makes Afresa faster than conventional fast-acting insulins. And that turns out to have many advantages for patients. In clinical trials, Afresa provides superior postprandial glycemic control, as well as improved fasting glucose control. It can easily be synchronized to meals, cutting chances of hypoglycemia and—very desirably—reducing the risk of weight gain.

"A surprise upside of this product was its effect on weight," says Richardson. "In Phase II, we began to see a difference in the weight profile of patients on conventional insulin versus TI. Patients either stayed weight-neutral or lost weight on TI. They didn't get as much hypoglycemia and didn't have to snack between meals. That's a major potential benefit."

In total, MannKind has conducted 44 clinical trials of Afresa on thousands of patients over 10 years. In Phase III, MannKind rolled out a 3,000-patient series of trials. The first was a one-year study in 550 Type I patients, comparing TI against injectable therapies and rapid-acting analogs given at mealtime. The second examined 700 Type II patients—those who are not necessarily insulin-dependent, but use insulin to control their diabetes—and compared TI results to those of common, fixed-mixture, short- and long-acting insulin analog therapies. The series wrapped up with a two-year study that analyzed pulmonary function in 2,500 patients with both types of diabetes. The successful trials and supporting product data led to Afresa's March 16 NDA submission for the control of hyperglycemia in adults with Type I or II diabetes mellitus.

Kinetics notwithstanding, it won't be easy to promote an inhaled insulin in the post-Exubera era. The drug's remarkable failure tainted the category and left physicians, patients, and analysts skeptical about the approach, especially where it pertains to safety.

"Obviously, a way to take insulin that doesn't involve injections appeals to a lot of patients," says Dr. Boyd Metzger, professor of Metabolism and Nutrition in the Division of Endocrinology, Metabolism & Molecular Medicine at Northwestern University's Feinberg School of Medicine. "But any time a new product is not filling a unique kind of therapy, it's best to be cautious. Not everything potentially good or negative about the product is discovered during the clinical trials."

But the hurdle can be cleared by getting a Big Pharma partner to help penetrate the global market. MannKind could handle a sales campaign targeting only specialists, says COO Hakan Edstrom, but 90 to 95 percent of diabetes patients are treated by primary care physicians, and MannKind has neither the resources nor the skill set to cover them all.

"There is a heavy educational component to introducing this product to the market," says Edstrom. "We want to find a company that has done this successfully in the past."

Moreover, the biotech's pipeline is thin. It has a few cancer products in early-stage development, and Mann believes that the Technosphere platform will show value in enabling pulmonary delivery of a variety of drugs. But with no products currently on the market, a partner with deep pockets isn't just preferable for MannKind, it's necessary.

When Exubera was pulled in 2007, MannKind suspended partnership talks. But this year they're back at the negotiating table, and prospects are promising. "Considering the size of the market opportunity and the thorough data package, we assume that Afresa will attract a major pharmaceutical partner in 2009, despite the controversy that still swirls around inhaled insulin," says Cory Kasimov, a biotech analyst with JPMorgan.

The unknown variable is the product label. "If information about no pulmonary side effects, less hypoglycemia, and significantly less weight gain is on the label, then the sales force would have a lot more ammunition," says Karen Andersen, a senior biotech analyst at Morningstar. Even if MannKind does find a partner, Andersen says, it won't necessarily solve the company's financial woes. "I don't see them getting much of a payment up front from a partner," she says.

But partnership doesn't mean that MannKind is just going to hand over Afresa and sit on the sidelines. Edstrom says MannKind plans to assemble its own sales force for the North American specialty market. "We want to stay in close contact with users because we feel that part of our success has been working with key opinion leaders," says Edstrom. "The timing of a launch of a MannKind sales force depends on the structure of the deal we get, and the market."

Although the company has already invested $200 million in a manufacturing facility (in Danbury, CT) big enough to support at least 200,000 and eventually 2 million patients, MannKind wants to guarantee long term supply at a reasonable price. So on March 9, the biotech struck a $33 million deal to purchase a Pfizer insulin facility at Industriepark Hoechst, Frankfurt am Main, Germany—a factory that until recently was dedicated to producing Exubera. With the acquisition, MannKind obtained "an immediate supply of insulin and the ability to supply our insulin needs for the future, which brings Afresa one step closer to commercial readiness," says Mann.

The Cancer Question

To MannKind, Afresa's key selling point is its clinical superiority. But some analysts aren't sure that will be enough. "I don't think claiming it's clinically more effective will have a positive impact on initial sales," says Grant Zeng, a biotech analyst at Zacks Investment Research. "When Pfizer began to market Exubera, they also said it was a very good product, and it turned out to be a flop."

Patients will need convincing, too, especially after a 2008 report potentially linking Exubera to lung cancer. According to Andrew Mandell, executive director of the Defeat Diabetes Foundation (who also goes by the pseudonym Mr. Diabetes), any company will have to do a lot to prove the efficacy of a new inhaled insulin product. "You can't fool around with insulin," he says. "If it isn't done right, the wrong is absolutely deadly."

But according to Richardson, Afresa's clinical trials have produced no evidence that the drug is carcinogenic. "Our data have shown one case of reported lung cancer, and that was in a smoker of 40 years," he says. MannKind took sequential, high-resolution CT scans of 600 patients and found no changes in lung function in TI patients. "We'll be looking for any signals in a postmarketing situation, but at present, there's no data supporting any concerns about Afresa and lung cancer specifically," says Richardson.

The key to Afresa's success lies in MannKind's ability to distinguish its product from Exubera—and that's not going to be easy. Physicians, patients, and Wall Street are still skeptical, and the small biotech is, well, small. But that hasn't disheartened Mann.

"People looked at TI as just another form of inhaled insulin, but that's not really what it is. We say to people, 'Yes, it's insulin, and yes, it's inhaled. But what's unique about it is its well-synchronized kinetics.' It eliminates almost all of the problems of prandial insulin therapy, or at least substantially reduces them."

MannKind has a product that could change diabetes therapy. But first, it has to persuade FDA, at least one potential partner, a whole lot of doctors, and even more patients that it isn't what it looks like. Sometimes changing perceptions is even harder than curing diseases. If Al Mann can pull this one off, the great inventor and entrepreneur can take credit for his most difficult achievement of all.



Seeking alpha MNKD Transcripts

Seeking alpha MNKD Transcripts

*** Must read/see interviews ****

Von Liebig Forum: Alfred Mann

Confessions Of A Serial Entrepreneur

Interview by Davidovit (2009)

CNBC Giant leap for mankind Jun 09

Al Mann's white house speech on technology transfer

Mannkind ppt presentation

Mannkind: Overlooked Biotech With Excellent Prospects
: by Ahithophel Weissberger:

BOSPENC's 4 Part series

Inhaled insulin comparable to insulin aspart for T2DM.

Inpharma Weekly; 9/23/2006, Issue 1556, p6-6, 1/3p
The article provides information on the results of a study that claims that inhaled insulin of Technosphere Insulin System has similar efficacy and tolerability to injected insulin aspart in patients with type 2 diabetes mellitus that was presented at the Annual Meeting of the European Association for the Study of Diabetes. A mean weight loss of 0.76 kilogram is achieved by patients in the inhaled insulin group.
Inhaled insulin [Technosphere Insulin System]* has
similar efficacy and tolerability to injected insulin aspart
in patients with type 2 diabetes mellitus (T2DM),
according to results from a study presented at the
Annual Meeting of the European Association for the
Study of Diabetes.
308 patients with T2DM were randomised to receive
either inhaled insulin (n = 150) or injected insulin
aspart, at mealtimes for 24 weeks. All participants also
received insulin glargine as basal insulin. Participants
were then followed up for an additional 24 weeks.
After the 24-week treatment period, patients in both
the inhaled insulin and insulin aspart groups showed
significant improvements from baseline in haemoglobin
Ale levels (improvements of 1.05% and 1.30%,
respectively). There were no significant between-group
differences in pulmonary function both after the
treatment period and after the follow-up period. A
significantly lower proportion of inhaled insulin
recipients experienced hypoglycaemia, compared with
insulin aspart-treated patients.
After the 24-week treatment period, patients in the
inhaled insulin group had a mean weight loss of 0.76kg,
whereas patients in the insulin aspart group had a mean
weight gain of 0.23kg (p = 0.0007). A minority of
patients in the inhaled insulin group experienced mild
cough during the study.

Abstracts 1

Inhaled insulin improved glycemic control :
Diabetes Care. 2008;31:2177-2182.
Patients with type 2 diabetes randomly assigned to Technosphere inhaled insulin for 12 weeks experienced greater improvements in HbA1c and postprandial glucose concentrations than with Technosphere powder.

Researchers at various U.S. institutions, including Dallas Diabetes and Endocrine Center and the University of Texas Health Science Center, studied the efficacy, safety and tolerability of Technosphere inhaled insulin (MannKind Corporation) compared with Technosphere powder placebo. The researchers recruited 126 insulin-na├»ve patients with suboptimally controlled type 2 diabetes for participation in the double blind, placebo-controlled, multicenter, parallel group study. Inhaled insulin or powder was added to the patients’ oral antidiabetes regimen.

After 12 weeks of treatment, patients assigned to inhaled insulin experienced greater reductions in HbA1c from baseline compared with patients assigned to powder (–0.72 vs. –0.30; P=.003). Inhaled insulin users also experienced a 56% reduction in postprandial glucose excursions compared with a 43% reduction with powder.

“The significant HbA1c reductions with Technosphere insulin were clinically meaningful, especially considering the mildly elevated HbA1c at baseline (inhaled insulin, 8%; powder, 7.8%),” the researchers wrote.

Incidences of adverse events, such as cough, were low in both groups. No significant differences in hypoglycemia (P=.321) and hyperglycemia (P=.871) were reported with either formulation. Body weight remained unchanged in both groups.

“This first proof-of-concept trial demonstrated that Technosphere insulin is well-tolerated and substantially reduced HbA1c levels and meal-related glucose excursions in type 2 diabetic patients. Technosphere insulin may become an important treatment option in type 2 diabetes. Larger, long-term clinical trials are in progress to further evaluate the efficacy and safety of Technosphere insulin reported in this study,” the researchers wrote. – by Katie Kalvaitis

Technosphere inhaled insulin is effective, useful and patient-friendly. On the other hand, will it be valuable? Time will tell. Technosphere is the third in a row of inhaled insulins. Exubera (Pfizer) was taken off the market in 2007 for lack of interest and Eli Lilly also had an inhaled insulin but investigation was stopped. All of the inhaled insulins look very effective, and would be very useful for patients who fear the needle. Adverse events are a concern, namely fibrosis, reduced pulmonary function and potential risk for cancer; I think, probably, the side effects are overrated. There is still a lot of interest in inhaled delivery of drugs and a need for more investigation remains.

– Derek LeRoith, MD, PhD

Endocrine Today Editorial Board member


Pharmacokinetics and linear exposure of AFRESA™ compared with the subcutaneous injection of regular human insulin.

Diabetes, Obesity & Metabolism; Jul2009, Vol. 11 Issue 7, p715-720, 6p
Aim: AFRESA™ [Technosphere® Insulin (TI); MannKind Corporation, Valencia, CA], a dry powder preparation of regular human insulin (RHI), utilizes a novel and versatile drug carrier platform that enables pulmonary administration of medications typically administered by injection. The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of three different inhaled doses of TI with those of subcutaneous (s.c.) RHI. Methods: This randomized, open-label, four-way crossover study of 11 healthy, non-smoking volunteers evaluated PK and PD profiles following single inhalations of 25, 50 or 100 U TI and 10 IU RHI administered subcutaneously using a euglycaemic clamp technique. Results: Following inhalation of TI, peak insulin concentrations ( Cmax) were achieved approximately 2 h earlier than with RHI (12–17 min for TI vs. 134 min for RHI). Area under the insulin concentration–time curve (AUC) and insulin Cmax values increased with increasing TI dose. Insulin exposure, as measured by AUC, was found to be linear over the dose range studied. Compared with s.c. RHI, TI at doses of 25, 50 and 100 U showed a relative bioavailability of 25, 23 and 21%, respectively. The maximum bioeffect, as measured by the glucose infusion rate, occurred approximately 2 h earlier for all three TI doses (42, 50 and 58 min, respectively) than for s.c. RHI (171 min). No treatment-related adverse events were reported with TI. Conclusion: TI is an inhaled insulin with a more rapid absorption and a more rapid elimination than subcutaneously administered RHI, resulting in a quick onset and short duration of action. Insulin exposure following TI administration was found to be linear over the dose range of 25–100 U. [ABSTRACT FROM AUTHOR]


Efficacy and Safety of Technosphere Inhaled Insulin Compared With Technosphere Powder Placebo in Insulin-Naive Type 2 Diabetes Suboptimally Controlled With Oral Agents.
Diabetes Care; Nov2008, Vol. 31 Issue 11, p2177-2182, 6p, 2 charts, 2 graphs
OBJECTIVE -- This double-blind, placebo-controlled, randomized, multicenter, parallel-group study compared the efficacy, safety, and tolerability of Technosphere insulin with Technosphere powder as placebo in insulin-naive type 2 diabetic patients whose diabetes was suboptimally controlled with oral antidiabetic agents. RESEARCH DESIGN AND METHODS -- Patients (n = 126) were randomly assigned to 12 weeks of therapy with Technosphere insulin or Technosphere powder after lifestyle education on nutrition, exercise, and instructions on inhaler use. The primary efficacy outcome was change in A1C from baseline to study end, and the secondary efficacy outcome was area under the curve for postprandial glucose levels during a meal test at treatment weeks 4, 8, and 12. RESULTS -- A1C reduction from a mean baseline of 7.9% was greater with Technosphere insulin than with Technosphere powder (-0.72 vs. -0.30%; P = 0.003). Postprandial glucose excursions were reduced by 56% with Technosphere insulin compared with baseline, and maximal postprandial glucose levels were reduced by 43% compared with Technosphere powder. Incidences of hypoglycemia, hyperglycemia, cough, and other adverse events were low in both groups. Body weight was unchanged in both groups. CONCLUSIONS -- Technosphere insulin was well tolerated and demonstrated significant improvement in glycemic control with clinically meaningful reductions in A1C levels and postprandial glucose concentrations after 12 weeks of treatment.

Inhaled Technosphere®/Insulin Improves Glycemic Control Without Weight Gain
Diabetes; Jun2007 Supplement 1, Vol. 56, pA125-A125, 1/4p
Improved glycemic control with insulin treatment is generally associated with weight gain. Two open-label randomized trials were conducted to compare the effect of inhaled Technosphere®/Insulin (T/I) with that of subcutaneous insulin aspart (Asp) on glycemic control and weight. Diabetic patients receiving glargine as basal insulin were randomized to receive T/I or Asp, with glargine as basal insulin in two separate trials; a 12-week study of 110 patients with type 1 DM and a 24-week study with a 22-week follow-up period of 309 patients with type 2 DM. Type 1 diabetic patients receiving T/I experienced a mean weight loss of 0.45 kg over 12 weeks, versus a mean gain of 0.80 kg in the Asp group (P=-.0017). In the 24-week treatment period, type 2 diabetic patients receiving T/I experienced a weight loss of 0.78 kg (P=-.0016) compared with a mean gain of 0.23 kg in the Asp group. When type 1 and type 2 patients were combined for analysis, the T/I patients experienced a mean loss of 0.69 kg (P=.0001) at Week 12. Type 2 diabetic patients who participated in the 22-week follow-resumed conventional therapy. Patients initially randomized to receive Asp had a mean weight gain of 0.81 kg during follow-up. Patients originally in the T/I group similarly gained a mean 0.74 kg following resumption of conventional therapy (P=.8125). In addition to treatment, baseline BMI, categorized into three groups (<27,>29) was found to be a significant factor in weight change at 24 weeks (weight gain, no weight gain) based on multivariate logistics regression model for subjects with type 2 diabetes. Subjects with BMI 27-29 are 3.09 (95% CI: 1.285-7.420) times more likely to have weight loss or no weight gain than those with BMI<27. T/I and Asp produced similar improvement in glycemic control as prandial insulin together with a basal insulin. There was a weight increase in the group receiving Asp, while there was no increase in weight during T/I treatment; when returning to conventional therapy, these patients gained weight. We conclude that in contrast to Asp, T/I offers the advantage of similar glycemic control without associated weight gain.

Glycaemic control: only a breath away with Technosphere insulin
Inpharma Weekly; 11/25/2006, Issue 1565, p7-8, 2p
The article focuses on two studies which compared the efficacy and tolerability of Technosphere insulin and insulin aspart in patients with types 1 and 2 diabetes. The effects of Technospehe insulin and insulin aspart are evaluated. The link between Technosphere insulin and post-prandial excursions is discussed. The tolerability of both drugs is also described.

Friday, December 25, 2009

ADA 2009: New Inhaled Insulin Has Rapid Onset of Action With No Adverse Effect on Lung Function

June 8, 2009 (New Orleans, Louisiana) — A new formulation of inhaled insulin called technosphere insulin (Afresa, Mannkind Corp) is safe and effective, with an onset of action similar to endogenous insulin. It has an extremely low incidence of hypoglycemia and is associated with some weight loss in patients with type 2 diabetes.

Importantly, the new formulation appears to have little adverse effect on pulmonary function, unlike its former competitor Exubera (Pfizer, taken off the market in October 2007).

Inhaled technosphere insulin is the subject of a large number of presentations here at the American Diabetes Association 69th Scientific Sessions.

Elizabeth Potocka, MD, clinical researcher at Mannkind Corporation in Valencia, California, and colleagues conducted a comparison of 45 U of inhaled technosphere insulin, 12 IU of subcutaneous lispro insulin (Humalog, Eli Lilly), and 4 mg of inhaled Exubera insulin with a meal challenge in 18 insulin-treated patients with type 2 diabetes and normal pulmonary function.

Swift Mechanism of Action

Technosphere insulin had an onset of action that was evident within 10 minutes of administration, compared with 30 to 40 minutes with both lispro and inhaled Exubera, Dr. Potocka told meeting attendees.

Peak trough in blood glucose was approximately 1.0 mmol/kg per minute with technosphere insulin at 40 minutes, compared with just over 2.0 mmol/kg per minute at approximately 70 minutes with lispro and 2.0 mmol/kg per minute at 2 hours with Exubera.

"Significant differences between lispro and Exubera were observed for up to 40 minutes, compared with technosphere insulin (P < .002), and up to 2 hours for the Exubera–technosphere insulin comparison (P < .05)," Dr. Potocka and colleagues write in their abstract.

"Endogenous glucose production was suppressed earlier following [technosphere insulin] administration, compared with subcutaneous insulin lispro and inhaled Exubera, which suggests that treatment with [technosphere insulin] may result in a more physiologic endogenous glucose production suppression," they conclude.

Comparable Efficacy, Less Weight Gain

A separate comparison of inhaled technosphere insulin with a rapid-acting analog (lispro), both given in combination with a long-acting analog (glargine, Lantus, Sanofi-Aventis), showed that Afresa plus glargine resulted in "comparable A1c reductions, more favorable 1-hour postprandial glucose levels, significantly less weight gain, and significantly less risk of hypoglycemia," Richard M. Bergenstal, MD, executive director of the International Diabetes Center in Minneapolis, Minnesota, told Medscape Diabetes & Endocrinology.

In a 52-week study, patients with type 1 diabetes and hemoglobin A1c values of 7% or greater were randomized to inhaled insulin with meals plus glargine (293 patients) or to glargine plus lispro (272 patients).

A1c reductions were similar in both groups, with a drop of 0.17% (±1.09) with inhaled insulin plus glargine and a drop of 0.47% (± 0.91) with glargine plus lispro (P = 0.38).

Fasting plasma glucose levels were significantly lower with glargine plus insulin (–44.9 ± 04.7) than with glargine plus lispro (–23.4 ± 0.3; P = .0052).

One-hour postprandial glucose levels were 165.7 mg/dL (±8.2 mg/dL) with inhaled insulin plus glargine and 201.7 mg/dL (±82.3 mg/dL) with glargine plus lispro (P = .0022).

The inhaled insulin group lost weight (0.5 ± 0.1 kg), whereas the glargine plus lispro group gained weight (1.4 ± 3.9 kg), with a statistically significant difference (P < .0001).

Finally, the inhaled insulin plus glargine group had a statistically significant reduction in the incidence of mild-to-moderate hypoglycemia, compared with glargine plus lispro (odds ratio [OR], 0.474; confidence interval [CI], 0.0271 - 0.831; P = .0091), and total episodes of hypoglycemia (OR, 0.488; CI, 0.278 - 0.856; P = .0124).

No Adverse Effect on Pulmonary Function

Technosphere insulin appears to have no adverse effect on pulmonary function compared with Exubera, John Gerich, MD, professor of medicine at the University of Rochester School of Medicine in New York, told Medscape Diabetes & Endocrinology in an interview during the meeting.

Dr. Gerich was commenting on results presented by Nikhil Amin, MD, of Mannkind Corporation, who reported data on forced expiratory volume in 1 second (FEV1), forced vital capacity, total lung capacity, and carbon monoxide diffusion test over a 2-year period in 730 patients with type 1 or 2 diabetes on inhaled insulin, 824 patients on usual oral antidiabetic medications, and 145 healthy controls on no specific therapy.

Pulmonary function tests declined equally in all 3 groups over the 2-year period, including the nondiabetics, Dr. Amin told meeting attendees.

"There was no difference in mean change in FEV1 from baseline to 24 months between inhaled insulin and usual care," he said.

"This drug comes up clean in safety testing, which was a concern with Exubera," Dr. Gerich said. "In addition, it showed noninferiority with conventional diabetic therapy."

"The absence of hypoglycemia and the lack of weight gain were significant findings. There was even a suggestion of weight loss with [inhaled insulin]," Dr. Gerich added. "Afresa has a profile that is very similar to the body's own insulin production in response to meals. The kinetics are about the same as in people without insulin."

"Patients tend to prefer a once-a-day pill, in my experience. They don't want to have to take something every time they eat unless they have to," Dr. Gerich commented. "But this is easy to deliver, with a device that is the very similar to a regular inhaler, for coverage with meals for patients who need that."

These studies were supported by Mannkind Corporation. Dr. Gerich disclosed receiving some financial support from Mannkind Corporation, but he was not directly involved with these studies.

American Diabetes Association (ADA) 69th Scientific Sessions: Abstract 232-OR, presented June 6, 2009; abstract 479-P, presented June 8, 2009; and abstract 570-P, presented June 7, 2009.

Friday, December 18, 2009

The case for Mannkind

From capital side
-----------------
1) Backed by a billionaire who wants to protect shareholders
2) Fully funded till end of 2010 (without partnership)
3) Al Mann putting $ where his mouth is

From product side
-----------------
1) AFRESA's carrier (FDKP - fumaryl diketo piperazine) is inert, not metabolized, excreted completely
2) Monomeric insulin - nothing artificial (like analogues), human body is exposed to insulin for last 80+ years.
3) No hypos, no weight gain
4) No lung deposition, FCV/FEV tests show no clinically significant drops; High-Resolution Computerized Tomography of the Chest shows no impact
5) product is in and out so fast; mimicks endogenous insulin production; makes pancreas last longer,
6) Shuts off hepatic glucose production (gluconeogenesis)
7) Potential use in juvenile, gestational diabetics

From investment side
--------------------
1) 99% of upside is not priced in
2) Safety/efficacy has been proven with largest trials of modern times;
3) Al Mann to negotiate the terms of the deal
4) Economics is very interesting, we've a plant, we've insulin, we've dreamboat, all we need is marketing & approval. The price will be comparable to current treatment, COGS sooo low to make a decent profit.
5) Exploding population of diabetics; this is a Doctor's/Pharma's dream come true. the patients wont die, have to take the drug till they die, if they dont take it, they face severe repurcussions. there's no cure. (sounds similar to Gillette's razor blade.)
6) Once they are hooked on AFRESA, there's no turning back
7) Use of TI as platform for peptides/protein, GLP-1 not priced in
8) Cancer drugs are not priced in

Technical side
----------------
1) Big short positions, possible heavy covering
2) Possible upgrades by scores of sell side analysts
3) Way too much negativity that if product is successful, there'll be too many positive articles that'll float around

Thursday, December 17, 2009

Why is Afrezza better?

When you compare, there is no comparison.

1) The time action profile is very different and explains the differentiated behavior


2) Afrezza shuts off hepatic secretion of glucose as it acts sooner. This eliminates the fasting blood sugar death spiral

(courtesy of http://www.phlaunt.com/diabetes/14046621.php)
When the beta-cells are no longer to keep fasting blood sugar normal, this is often a sign that the pancreas no longer has enough beta cell capacity to keep up even with the production of even low levels of insulin needed for basal insulin secretion. This usually signals that a critical amount of irreversible beta-cell death has occurred.

When this happens, blood sugar control can deteriorate very swiftly. This is because when the beta cells can no longer provide a steady basal insulin release, the liver interprets the very low fasting insulin level as a sign that it is time to raise blood sugar, Then, no matter what the actual concentration of sugar in your blood, the liver dumps a large dose of glucose into the bloodstream.

This effect explains why fasting blood sugar tends not to deteriorate slowly and steadily but often takes a sudden upward surge of 50 mg/dl (2.8 mmol/L) or more. That sudden surge is a sign that the insulin level has dropped so low that the liver has interpreted it as a sign of dangerously low blood sugar and has started to dump glucose.

1. Poor glucose control leads to high blood sugar
2. High blood sugar leads to glucose toxicity
3. Glucose toxicity leads to insulin resistance and dead beta cells
4. Insulin resistance and dead beta cells and lead to even poorer glucose control

Repeat 1 through 4 until you are insulin dependent.

Afrezza controls mealtime glucose levels and shuts down glucogenesis, therefore no vicious circle, no disease progression.


3) Afrezza controls post prandial glucose excursions better than any other method.


4) The barrier to the initiation of insulin is greatly reduced if Afrezza is used.
if insulin is given earlier, the progression of diabetes is greatly reduced. By the time patients are put in insulin (that body really needs), their condition has already worsened. It is no wonder Al Mann says, starting Afrezza earlier may stop the progression of Diabetes.

Refer this pfizer ppt


“The high median HbA1C that preceded the initiation of insulin in our population is particularly troubling and suggests that there are substantial barriers to its Initiation”

Cook et al: Glycemic Control continues to deteriorate after Sulfonylureas Are Added to Metformin Among Patients with Type 2 Diabetes. Diabetes Care 28: 995-1000, 2005

Effects of delaying insulin therapy are given in this link

5) Better glycemic control with Afrezza

Link

2.2.2. Importance of Glycemic Control in DM
Over the past several decades, it has become clear that chronic hyperglycemia is an important causative factor in the development of many diabetic complications. The Diabetes Control and Complications Trial (DCCT)12 and the Stockholm Diabetes Intervention Study13 showed that improvement of glycemic control by an intensive insulin treatment regimen using multiple daily insulin injections delayed the onset and slowed the progression of microvascular complications in individuals with type 1 DM. The DCCT further showed that the benefits of improved glycemic control occurred over the range of glycated hemoglobin (HbA1c) values suggesting that, at any HbA1c level, improvement is beneficial. 14 Similar benefits of tight control have been demonstrated in the type 2 population in the UK Prospective Diabetes

Study (UKPDS)15, which compared intensive insulin or sulfonylurea treatment to diet, and in the Kumamoto Study16, which evaluated intensive insulin treatment. Furthermore, the cost effectiveness of intensive treatment has been demonstrated in both type 1 and type 2 DM.17,18,19 A reduction in cardiovascular events along with improved glycemic control was also noted in the DCCT and UKPDS, but the results were not statistically significant. A subsequent epidemiological analysis of the UKPDS cohort showed a statistically significant effect of HbA1c lowering with an approximate 14% reduction in myocardial infarction for every 1% reduction in HbA1c.20 Some potential disadvantages of intensive treatment were also identified: increased weight gain and hypoglycemia.

6) Better HbA1C



7) Dosage is linear.



8) Comparison of Exubera and Afresa


Exubera

Afresa

Bulky device, difficult to use and clean

Dosage is hard to understand

Very discreet

Easy to understand dosages

Uses insulin in hexameric form

Uses monomers; mimics the profile of healthy pancreas

low bio availability

upto 25% bio availability

Dose units are not linear

Insulin exposure, as measured by AUC, was found to be linear over the dose range

Lung deposition, reduced FEV1

No deposition, afresa turns to liquid, no effect on FEV1

Costs: slightly higher

We still don’t know the costs, but Mannkind is making every effort to make it cheaper than Exubera: the new dreamboat uses 30% less insulin

The time-action profile of Exubera is not different than

that of rapid-acting insulin analogues when it comes

to the onset of action;

PK profile is quite different

From Health care payer point of view:

As per Al Mann

Exubera is just another expensive way to take insulin

Afresa offers better solution from weight loss, reduced hypos, suppress hepatic glucose production, reduction in HbA1c, etc

Mannkind is doing another study 117 where using Afresa to maintain normal fasting glucose levels