The Fate of Mannkind
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.
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.
Exuberant? Not So Much
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.
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