Inhalable insulin
Encyclopedia
Inhalable insulin was available from September 2006 to October 2007 in the United States as a new method of delivering insulin
, a drug used in the treatment of diabetes
, to the body. After the withdrawal of the only inhalable formulation, all currently available insulin formulations are administered by subcutaneous or intravenous injection
.
The first such product to be marketed was Exubera, a powdered form of recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed. Insulin has also been known to help patients with breast cancer, namely women.
Once it has been absorbed, it begins working within the body over the next few hours. Type 1
diabetics still need to take a longer acting basal insulin by injection.
A systematic review
concluded that inhaled insulin "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective."
In October 2007, Pfizer
announced that it would be discontinuing the production and sale of Exubera due to poor sales.
Several other companies are developing inhaled forms of the drug to reduce the need for daily injections among diabetics.
in 1921 as an injectable agent. German researchers first introduced the idea of inhalable insulin in 1924.
Years of failure followed until scientists realized they might be able to use new technologies to turn insulin into a concentrated powder with particles sized for inhalation.
This technology was developed so that the inhaled insulin can effectively reach the lung capillaries where it is absorbed.
Nektar Therapeutics of San Carlos, California developed this technology that paved the way for pharmaceutical companies to begin testing and formulating inhalable insulin.
Once concrete methods were developed, human tests began in the late 1990s.
In January 2006, the U.S. Food and Drug Administration (FDA) approved the use of Exubera which is a form of inhalable insulin developed by Pfizer
.
It is manufactured by Pfizer
in collaboration with Nektar Therapeutics and is licensed for use by both type 1 and type 2 diabetics. However in the UK
its use in under the National Health Service
"should not be recommended because it could not be proven to be more clinically or cost effective than existing treatments",
except under special circumstances.
In April 2006, the UK's National Institute for Health and Clinical Excellence
issued a preliminary statement advising against the use of inhalable insulin on the grounds that the benefits of avoiding injections did not justify the higher cost of the new product. At that time, NICE recommended use of the new drug only in clinical trials.
Concerns have been expressed by the Institute for Safe Medication Practices about a serious risk of dosing errors when prescribing Exubera.
Insulin is traditionally prescribed in international units, but Exubera is prescribed in milligrams. 1 mg of Exubera is equivalent to 3 units of insulin, however, the increment is not linear: 3 mg of Exubera is equivalent to 8 units of insulin and not 9 units as might be expected, and the prescriber is strongly advised to refer to the manufacturer's conversion table before prescribing. Furthermore, because of retention of blister contents, three consecutive doses of 1mg blisters of Exubera results in a higher dose of insulin than a single 3mg blister of Exubera, further complicating prescribing calculations.
Exubera is considered a short or rapid acting insulin. In clinical studies, Exubera reached peak concentration levels faster than some insulins administered by injection.
Thus, this form of insulin would begin working within the body faster than those forms of injected insulin. Type 1 and 2 diabetics will still need an injection of longer acting insulin to maintain a basal level for a 24 hour period.
As of October 18, 2007, Pfizer has announced that it will no longer manufacture or market Exubera. According to Chairman and CEO Jeffrey Kindler this is because Exubera "failed to gain acceptance among patients and physicians."
At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including Alkermes working with Eli Lilly and Company
,
MannKind Corporation
,,
and Aradigm working with Novo Nordisk
. However, by March 2008, all of these products had been discontinued except for MannKind’s Afrezza product. As of March 2010 Afrezza was still under FDA review.
In a letter 18 June 2008, Pfizer informed UK doctors of the above mentioned six cases, noting that they all had a prior history of cigarette smoking and that they were planning to investigate further the "observed imbalance in diagnosed lung cases" with an international observational trial. Pfizer's letter also stated that Nektar had stopped searching for a new marketing partner and therefore Pfizer would withdraw its Marketing Authorisation around September 2008.
, a Danish diabetes pharmaceutical company, filed suit against Pfizer on August 1, 2006, claiming patent infringement.
The lawsuit seeks both compensatory damages and injunctive relief. Novo sought a preliminary injunction preventing the release of Pfizer's planned September 2006 launch of the diabetes drug. A federal judge, however, delayed any decision on Novo Nordisk's request for injunctive relief until at least December 4, 2006 when a court hearing is scheduled in the case.
Pfizer's answer contends that Novo wants to deny diabetics access to Exubera, the only FDA approved inhaled insulin, and interfere with the company's pharmaceutical business.
On December 14, 2006 a federal judge denied Novo Nordisk's request for a preliminary injunction
to halt sales of Pfizer's inhaled insulin.
The patent lawsuit, however, has not been dismissed, and Pfizer's legal defenses are preserved. The pharmaceutical companies are still litigating in court over their respective inhaled insulin patent
claims, a process that could take some time to resolve.
The company received a CRL on January 19, 2011, denying approval of Afrezza as "questions remain that preclude approval in its current form." MannKind also reported the FDA requires 2 additional clinical trials on its next-generation inhaler compared to the MedTone Inhaler to assess "performance characteristics, usage, handling, shipment and storage," updated safety information related to AFREZZA, as well as proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap and cartons.
can undergo desiccation
, yet survive and revive after water absorption. A. Carl Leopold
, began studying this capability at the Boyce Thompson Institute for Plant Research
at Cornell University
in the mid 1980s. He found soybeans and corn to have a range of soluble carbohydrate
s protecting the seed's cell viability. Patents were awarded to him in the early 1990s on techniques for protecting "biological membranes" and proteins in the dry state. Using the knowledge gleaned from studying the preservation of proteins in dry soybeans, Carl developed a method to preserve peptide hormones like insulin in the glassy state so that they can be pulverized into a powder and inhaled by diabetics as an alternative to self-injection
What Leopold, who has died, could not have foreseen is that his research on soybeans would lead to techniques that allowed insulin to be dried and later processed into an inhalable insulin
, named Exubera by Pfizer..
And now: On 9/13/2011 it was announced that a form of inhalable insulin, aerosolized insulin, applied deep into the nostrils may delay the onset of Alzheimer
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, a drug used in the treatment of diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, to the body. After the withdrawal of the only inhalable formulation, all currently available insulin formulations are administered by subcutaneous or intravenous injection
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
.
The first such product to be marketed was Exubera, a powdered form of recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed. Insulin has also been known to help patients with breast cancer, namely women.
Once it has been absorbed, it begins working within the body over the next few hours. Type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
diabetics still need to take a longer acting basal insulin by injection.
A systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
concluded that inhaled insulin "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective."
In October 2007, Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
announced that it would be discontinuing the production and sale of Exubera due to poor sales.
Several other companies are developing inhaled forms of the drug to reduce the need for daily injections among diabetics.
History
Insulin was introduced by Banting and Best from the University of TorontoUniversity of Toronto
The University of Toronto is a public research university in Toronto, Ontario, Canada, situated on the grounds that surround Queen's Park. It was founded by royal charter in 1827 as King's College, the first institution of higher learning in Upper Canada...
in 1921 as an injectable agent. German researchers first introduced the idea of inhalable insulin in 1924.
Years of failure followed until scientists realized they might be able to use new technologies to turn insulin into a concentrated powder with particles sized for inhalation.
This technology was developed so that the inhaled insulin can effectively reach the lung capillaries where it is absorbed.
Nektar Therapeutics of San Carlos, California developed this technology that paved the way for pharmaceutical companies to begin testing and formulating inhalable insulin.
Once concrete methods were developed, human tests began in the late 1990s.
In January 2006, the U.S. Food and Drug Administration (FDA) approved the use of Exubera which is a form of inhalable insulin developed by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
.
Approval and competing drug development
Exubera is the brand name of first formulation of inhalable insulin to receive the US FDA approval.It is manufactured by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in collaboration with Nektar Therapeutics and is licensed for use by both type 1 and type 2 diabetics. However in the UK
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
its use in under the National Health Service
National Health Service
The National Health Service is the shared name of three of the four publicly funded healthcare systems in the United Kingdom. They provide a comprehensive range of health services, the vast majority of which are free at the point of use to residents of the United Kingdom...
"should not be recommended because it could not be proven to be more clinically or cost effective than existing treatments",
except under special circumstances.
In April 2006, the UK's National Institute for Health and Clinical Excellence
National Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
issued a preliminary statement advising against the use of inhalable insulin on the grounds that the benefits of avoiding injections did not justify the higher cost of the new product. At that time, NICE recommended use of the new drug only in clinical trials.
Concerns have been expressed by the Institute for Safe Medication Practices about a serious risk of dosing errors when prescribing Exubera.
Insulin is traditionally prescribed in international units, but Exubera is prescribed in milligrams. 1 mg of Exubera is equivalent to 3 units of insulin, however, the increment is not linear: 3 mg of Exubera is equivalent to 8 units of insulin and not 9 units as might be expected, and the prescriber is strongly advised to refer to the manufacturer's conversion table before prescribing. Furthermore, because of retention of blister contents, three consecutive doses of 1mg blisters of Exubera results in a higher dose of insulin than a single 3mg blister of Exubera, further complicating prescribing calculations.
Exubera is considered a short or rapid acting insulin. In clinical studies, Exubera reached peak concentration levels faster than some insulins administered by injection.
Thus, this form of insulin would begin working within the body faster than those forms of injected insulin. Type 1 and 2 diabetics will still need an injection of longer acting insulin to maintain a basal level for a 24 hour period.
As of October 18, 2007, Pfizer has announced that it will no longer manufacture or market Exubera. According to Chairman and CEO Jeffrey Kindler this is because Exubera "failed to gain acceptance among patients and physicians."
At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including Alkermes working with Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
,
MannKind Corporation
MannKind Corporation
MannKind Corporation , based in Valencia, California, is a biopharmaceutical company focusing on the discovery, development, and commercialization of therapeutic products for diseases such as diabetes and cancer. The company, while technically founded in February 1991, took its present form in 2003...
,,
and Aradigm working with Novo Nordisk
Novo Nordisk
Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
. However, by March 2008, all of these products had been discontinued except for MannKind’s Afrezza product. As of March 2010 Afrezza was still under FDA review.
Lung cancer concerns
On April 9, 2008, Pfizer announced in its "Dear Doctor" letter that Exubera may have been associated with lung cancer: of the 4,740 patients who used Exubera in clinical trials, six have developed lung cancer as of April 2008, compared to only one of the 4,292 patients in the placebo group. The association was not statistically significant, and Pfizer maintained in its letter that "Exubera remains a safe and effective medication."In a letter 18 June 2008, Pfizer informed UK doctors of the above mentioned six cases, noting that they all had a prior history of cigarette smoking and that they were planning to investigate further the "observed imbalance in diagnosed lung cases" with an international observational trial. Pfizer's letter also stated that Nektar had stopped searching for a new marketing partner and therefore Pfizer would withdraw its Marketing Authorisation around September 2008.
Pfizer patent infringement lawsuit
Novo NordiskNovo Nordisk
Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
, a Danish diabetes pharmaceutical company, filed suit against Pfizer on August 1, 2006, claiming patent infringement.
The lawsuit seeks both compensatory damages and injunctive relief. Novo sought a preliminary injunction preventing the release of Pfizer's planned September 2006 launch of the diabetes drug. A federal judge, however, delayed any decision on Novo Nordisk's request for injunctive relief until at least December 4, 2006 when a court hearing is scheduled in the case.
Pfizer's answer contends that Novo wants to deny diabetics access to Exubera, the only FDA approved inhaled insulin, and interfere with the company's pharmaceutical business.
On December 14, 2006 a federal judge denied Novo Nordisk's request for a preliminary injunction
Preliminary injunction
A preliminary injunction, in equity, is an injunction entered by a court prior to a final determination of the merits of a legal case, in order to restrain a party from going forward with a course of conduct or compelling a party to continue with a course of conduct until the case has been decided...
to halt sales of Pfizer's inhaled insulin.
The patent lawsuit, however, has not been dismissed, and Pfizer's legal defenses are preserved. The pharmaceutical companies are still litigating in court over their respective inhaled insulin patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
claims, a process that could take some time to resolve.
MannKind's AFREZZA
On March 16, 2009 MannKind submitted an NDA for their inhalable insulin product, AFREZZA. The drug is an ultra rapid acting form of inhalable insulin with peak plasma concentrations that mimic physiologic mealtime response at 12-14 minutes. The drug has performed well in clinical trials and was originally scheduled for FDA approval on December 29, 2010. However, in December the FDA announced it needed an additional 4 weeks to complete its review.The company received a CRL on January 19, 2011, denying approval of Afrezza as "questions remain that preclude approval in its current form." MannKind also reported the FDA requires 2 additional clinical trials on its next-generation inhaler compared to the MedTone Inhaler to assess "performance characteristics, usage, handling, shipment and storage," updated safety information related to AFREZZA, as well as proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap and cartons.
Aerogen and Dance Pharmaceuticals
January 2011: Aerogen in Galway, Ireland and Dance Pharmaceuticals in San Francisco, California have announced a drug-delivery partnership for the production of inhaled insulin.Inhalable insulin may delay onset of Alzheimer
Remarkably, seeds such as soybeans containing very high levels of proteinSoy protein
Soy protein is a protein that is isolated from soybean. It is made from dehulled, defatted soybean meal. Dehulled and defatted soybeans are processed into three kinds of high protein commercial products : soy flour, concentrates, and isolates. Soy protein isolate has been used since 1959 in foods ...
can undergo desiccation
Desiccation
Desiccation is the state of extreme dryness, or the process of extreme drying. A desiccant is a hygroscopic substance that induces or sustains such a state in its local vicinity in a moderately sealed container.-Science:...
, yet survive and revive after water absorption. A. Carl Leopold
A. Carl Leopold
Aldo Carl Leopold was an American academic and plant physiologist. His father was Aldo Leopold, renowned ecologist and employee of the United States Forest Service, and his mother was Estella Leopold....
, began studying this capability at the Boyce Thompson Institute for Plant Research
Boyce Thompson Institute for Plant Research
The Boyce Thompson Institute for Plant Research is a research and education organization devoted to plant science currently located on the campus of Cornell University in Ithaca, New York...
at Cornell University
Cornell University
Cornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions...
in the mid 1980s. He found soybeans and corn to have a range of soluble carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s protecting the seed's cell viability. Patents were awarded to him in the early 1990s on techniques for protecting "biological membranes" and proteins in the dry state. Using the knowledge gleaned from studying the preservation of proteins in dry soybeans, Carl developed a method to preserve peptide hormones like insulin in the glassy state so that they can be pulverized into a powder and inhaled by diabetics as an alternative to self-injection
What Leopold, who has died, could not have foreseen is that his research on soybeans would lead to techniques that allowed insulin to be dried and later processed into an inhalable insulin
Inhalable insulin
Inhalable insulin was available from September 2006 to October 2007 in the United States as a new method of delivering insulin, a drug used in the treatment of diabetes, to the body...
, named Exubera by Pfizer..
And now: On 9/13/2011 it was announced that a form of inhalable insulin, aerosolized insulin, applied deep into the nostrils may delay the onset of Alzheimer