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Mannkind’s lead product Technosphere inhaled insulin (TI) may suffer a similar fate as Pfizer’s Exubera as physicians say the long-term effects of insulin on the lungs could lead to structural abnormalities. The major concern is the long-term effects of intra-alveolar deposition of insulin within the lungs, physicians said.
Pfizer discontinued its inhalable insulin device Exubera, earlier in October, citing lackluster sales since its launch in 2006. The write-off cost Pfizer USD 2.8bn in 3Q07.
Many Exubera critics said it was the size of Pfizer’s device that lead to Exubera’s demise, but physicians said the main cause of failure was the potential danger surrounding the long-term effect of insulin in the lungs, as it is a growth protein and is known to have growth-promoting properties through its effects on IGF receptor.
Dr Zachary Bloomgarden, clinical professor in the division of endocrinology, department of medicine at the Mount Sinai School of Medicine, explained that insulin has multiple effects on tissue, and when lung tissue is exposed to markedly higher levels of insulin, it is possible for a variety of abnormalities to occur. “This has been documented in animal models, such as abnormalities of the alveolus,” he added.
Insulin is a growth promoting protein, and overgrowth of tissue in the respiratory tracts can lead to narrowing. This will lead to higher resistance to the passage of air in the respiratory tract. “There’s a huge study of evidence in animal models that there is impaired gas exchange,” added Bloomgarden.
Companies need to inform the public whether a decrease in pulmonary diffusing capacity occurs more frequently in patients receiving inhaled insulin, and if those effects are reversible, he said.
Dr Joel Zonszein, director of the clinical diabetes center at Montefiore Medical Center concurred saying that the long term effects of insulin in the lungs may lead to lung cancer. However, there is no long-term study data. “Pfizer had good safety data but we do not know the long-term effects and many physicians I have spoken with have that concern. The FDA had also similar concerns,” said Zonszein.
The FDA would not provide comment on this matter.
Alfred Mann, CEO and Founder of MannKind Corp told this news service, “Frankly, [the FDA] approved Exubera which did not meet several FDA standards. We have so far met all, so why should TI not be approved? What is yet to be established are any claims of superiority in our label.”
The insulin floating around the alveoli may have potential damaging effects, as “large doses of insulin will bind to IGF receptors that are carcinogenic,” added Zonszein.
Dr Gerald Bernstein, director of the diabetes management program at the Gerald J. Friedman Diabetes Institute at Beth Israel Hospital added that Mannkind’s product would likely fail in the same fashion as Exubera – as “the lung is meant for gases, not for proteins.”
There is also increasing data showing that a number of inhaled insulin devices indicate reduced lung capacity flow, said Bloomgarden. He added data has shown that the mean diffusing capacity for carbon monoxide has decreased along with the flow rate. This may make inhalation insulin unsuitable for patients with obstructive lung diseases.
Regarding physician comments on the lower bioavailability of inhaled insulin, Mann said TI is almost four times greater than the bioavailability of Exubera or Eli Lilly’s AIR inhaled insulin system. Half the TI is lost in the back of the throat (47% gets to alveoli), he said. “We have seen no accumulation in the lungs,” he added. However, he did not provide comment on TI against other non-inhalable diabetes drugs on the market.
The company has also conducted extensive studies of the effect of TI on lung tissue and has seen no effect whatsoever, as the residence of TI in the lungs is very brief, Mann emphasized.
Still, it is known that inhaled insulin has lower bioavailability, so higher doses are required, physicians argued. Zonszein explained that as the absorption rate is much lower, larger doses of insulin are required, which may make it more costly. ”This may make it less cost-effective than injected insulin. Insulin nowadays is inexpensive but inhaled insulin is expensive due to its low absorption rate,” he said.
Mannkind is currently undertaking several post-pivotal studies to show how TI improves overall safety and efficacy. “Our two-year safety trial has nine months to run, but many patients have been on TI for over four years,” added Mann. With Exubera, there was a small non-progressive impact on lung function that occurred in 3-4 weeks with no further effect thereafter, with a restoration a couple of months after cessation, he said.
“The effect was apparently from inflammation or accumulation of powder in the lungs, and not due to tissue damage, though the specific cause has not been concluded,” said Mann. TI does not exist on lung surfaces as a powder, and on contact with the moist alveolar surfaces at a pH of around 7.4, it instantly liquefies, the CEO noted.
Mannkind has conducted four studies of up to six months with careful evaluation of pulmonary function, and in every one of those studies no pulmonary effect was observed, he said.
Physicians are still skeptical. A major disadvantage with inhalable insulin is the potential requirement for pulmonary function tests. ”If you need to do actual lung diffusion capacity tests, you have to send patients to well-equipped pulmonary facilities, which can’t be done at physician offices. That’s a big burden,” said Bloomgarden.
Dr Sonal Singh, assistant professor of internal medicine at Wake Forest University School of Medicine agreed that apart from the lack of adequate human studies and the lack of long-term safety data, a practical concern is the complexity of administration of all inhaled insulin devices, and if it is going to be short acting then the challenge of administering several times a day may be a hurdle.
Bloomgarden, who voiced concerns about the safety of the drug, said the FDA could have saved Pfizer a lot of money by not letting Exubera out to the market. “Some people haven’t learned the lessons that Pfizer gave them,” added Zonszein.
Mannkind has a current market cap of USD 928m.
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