(insulin human [rDNA origin]) Inhalation Powder - Exubera Inhalation Powder
Status: marketing halted in Oct. 2007
Organizations involved:
Pfizer, Inc. – Manuf.: R&D; Tech.; World mark.
Bespak plc – Manuf. other
Nektar Therapeutics, Inc. – Manuf. other; R&D; Tech.
The Tech Group –Manuf. other
West Pharmaceutical Services – Parent
Consort Medical plc – Manuf. other
Bespak plc – Former
Novo Nordisk A/S – Patent dispute
Sanofi Aventis S.A. – Former
Aventis S.A. – Former
Cross ref.: See the Insulin Products entry.
Description: Exubera Inhalation Powder (Exubera) is an inhalable dry powder rapid-acting formulation of recombinant insulin expressed by transformed Escherichia coli (E. coli) bacteria stabilized in ~1 micron sized “glass-stabilized” particles using mannitol as an inert glass-forming matrix. These solid particles formed by fast drying have no internal order, and are in an amorphous glassy state. The insulin is essentially the same as in other non-modified insulin products (e.g., molecular weight of 5.808 kDa. Each dry inhalable particle of Exubera contains about three million insulin molecules. This inhaled insulin is designed to be used in place of short-acting insulin injections before meals in patients with both type 1 and type 2 diabetes. Unlike the rather large size of the Exubera inhaler, the inhaler used with Afrezza is small and hand-held.
Exubera is packaged as a white to off-white powder in unit dose blister packs each containing either a 1 mg or 3 mg dose of insulin in a homogeneous powder formulation containing sodium citrate (dihydrate), mannitol, glycine, and sodium hydroxide. The blisters are dispensed on perforated cards of six unit dose blisters (polyvinyl chloride/aluminum). The two strengths are differentiated by color printed and tactile marks that can be differentiated by touch. The 1 mg blisters and respective perforated cards are printed with green ink and the cards are marked with one raised bar. The 3 mg blisters and respective perforated cards are printed with blue ink and the cards are marked with three raised bars. Five blister cards are packaged in a clear plastic (PET) thermoformed tray. Each PET tray also contains a desiccant and is covered with a clear plastic (PET) lid. The tray of five blister cards (30 unit dose blisters) is sealed in a foil laminate pouch with a desiccant. The inhaler consists of the inhaler base, a chamber, and an Exubera Release Unit. A replacement chamber is available separately. Exubera Release Units are individually packaged in a sealed thermoformed tray, and are available as part of a Patient Pack, the Exubera CareKit, and as separate replacements. When not in-use (unopened), Exubera is stored at room temperature, 25ºC (77ºF), with excursions permitted to 15-30ºC (59-86ºF).
After an Exubera blister is inserted into the inhaler, the patient pumps the handle of the inhaler and then presses a button, causing the blister to be pierced. The insulin inhalation powder is then dispersed into the chamber, allowing the patient to inhale the aerosolized powder. Insertion into the inhaler generates a burst of air containing the powder, which the patient passively inhales slowly and deeply. The Exubera inhaler weighs four ounces and, when closed, is about the size of an eyeglass case.
Under standardized in vitro test conditions, Exubera delivers a specific emitted dose of insulin from the mouthpiece of the inhaler. A fraction of the total particle mass is emitted as fine particles capable of reaching the deep lung. Up to 45% of the 1 mg blister contents, and up to 25% of the 3 mg blister contents, may be retained in the blister. The 1 mg dose blister packs contain 1.7 mg for delivery of a nominal dose of 1 mg, an emitted dose of 0.53 mg, and fine particle dose of 0.4 mg. The 3 mg dose blister packs contain 5.1 mg for delivery of a nominal dose of 3 mg, an emitted dose of 2.03 mg, and fine particle dose of 1.0 mg. The actual amount of insulin delivered to the lung will depend on individual patient factors, such as inspiratory flow profile. In vitro, emitted aerosol metrics are unaffected at flow rates above 10 L/min.
Exubera is the first protein therapeutic delivered via the lungs, and the first truly novel insulin delivery option introduced since the discovery of insulin in the 1920s.
The Exubera inhaler is basically a canister with a triggering mechanism. To engage the device, patients pull a small handle on the bottom, with a plastic cone sliding on top of the triggering device. A blister pack containing the dry-powder insulin is inserted into the triggering device, and the trigger mechanism pulled back to pump-prime the device. A button is pressed that releases the insulin into the plastic cone, on top of which is a small mouthpiece, which patients use to take a slow, deep breath for five seconds. Because patients require different amounts of insulin, this process may need to be repeated more than once each time diabetics take their insulin. Pfizer recommends that patients clean the plastic cone and the base once a week. The unit that releases the drug should be replaced every two weeks, and the whole device should be replaced annually. Patients will likely need to purchase a case for the device, since many have remarked that it is not “pocket friendly.”
Nomenclature: Insulin, rDNA, inhaled/Pfizer [BIO]; Exubera [TR]; (insulin human [rDNA origin]) Inhalation Powder [FDA]; insulin, recombinant powder for inhalation [SY]
Biological.: Here the term “glass” refers to an amorphous solid state of matter, in this case primarily composed of mannitol, not the silicon dioxide (quartz)-based glass used in windows and other items. A glass is essential a liquid that has lost its ability to flow, i.e., it is a liquid with a very high viscosity (ranging from 1010 to 104 pascal-seconds). A glass is a metastable amorphous system in which the molecules have vibrational motion and reduced rotational motion, but have very slow (almost immeasurable) translational motion when compared to the liquid state. As a metastable system, it is stable for long periods of time when stored well below the glass transition temperature (similar to melting point).
To stabilize proteins after lyophilization (freeze-drying), excipients may be added to form an amorphous glass with the protein. By supercooling a solution comprising a protein and excipients, freezing, involving crystal formation, is bypassed and the solution forms a syrup, then a viscoelastic rubber, and finally a hard glassy substance. The result is an amorphous solid, in which the glassy excipient material, e.g. mannitol, is in an amorphous glassy form and encases the protein, preventing its unfolding and slowing any molecular interactions or crossreactivity to a point of essential nonexistence, due to greatly reduced mobility of the protein and other molecules within the glassy composition. This process has been postulated to occur either via mechanical immobilization of the protein by the amorphous glass or via hydrogen bonding to polar and charged groups on the protein, i.e., via water replacement, preventing drying-induced denaturation and inhibiting further degradation. As long as the glassy solid is stored at a temperature below its glass transition temperature and the residual moisture and, in some cases, oxygen remaining in the dried product is relatively low, the labile encased protein can remain relatively stable.
Many molecules are absorbed through the deep lung into the bloodstream naturally with high drug absorption and without the need for enhancers used by other non-invasive routes. This high bioavailability makes the lung a natural target for peptides, proteins and small molecules that would benefit from pulmonary delivery. The lungs take inhaled breaths of air and distribute them deep into the tissue to a very large surface, known as the alveolar epithelium, which is ~100 square meters in adults (about the size of a singles tennis court). This very large surface has approximately a 0.5 billion tiny air sacs, alveoli, that are enveloped by an equally large capillary network. The delivery of inhaled air to the alveoli is facilitated by a tree-like structure, the airways, which, starting with the single trachea, branch more than 22 times before reaching the grape-like clusters of tiny alveoli. Large molecule drugs, such as peptides and proteins, do not easily pass through the airway surface, because it is lined with a thick, ciliated mucus-covered cell layer making it difficult to permeate. The alveoli, on the other hand, have a thin single cellular layer enabling absorption into the bloodstream.
More drug can be contained in powders than in liquid forms. In contrast to aqueous aerosols, where only one to two percent of the aerosol particle is drug (the rest is water), powder aerosol particles can contain up to 50% to 95% of pure drug. This means that therapeutic doses of many protein and small molecule therapeutics can be delivered as a powder aerosol in one to three puffs. Powder aerosols can carry approximately five times more therapeutic agent in a single breath than metered dose inhaler (MDI) systems and many more times than liquid or nebulizer systems. A powder system for therapeutics requiring higher doses could decrease dosing time as compared with nebulizers. Compared to asthma drugs commonly delivered by inhalation, insulin has a much narrower therapeutic range and needs to get into the systemic blood circulation through the alveoli in deep in the lung.
Pulmonary delivery offers advantages to patients compared to injection and other routes of administration. Inhalation is noninvasive, involves fewer systemic side effects, uptake of drug is rapid, and the patient’s symptoms are rapidly treated. Inhalation drug delivery is particularly attractive for treatment of diseases where patients require frequent injections, such as diabetes.
Nektar’s dry powder formulation glass stabilization technology is used in the drying process to stabilize Exubera. In the liquid state, the mobility of individual molecules such as peptides and proteins is extremely high. When water is removed during drying, proteins and stabilizers undergo an immobilization process. Molecular mobility remains high and chemical stability low if too much water is left in the initial amorphous powder. With removal of a critical amount of water, molecular gridlock occurs, producing greatly increased chemical stability. In this state, previously mobile molecules slow down drastically. If too much water is removed, the molecule could become inactive. The goal is to stabilize materials in a thermodynamically unstable amorphous state.
In order to prepare “glass-stabilized” particles, a solution containing the active molecule, usually a protein or a peptide, e.g., insulin, and stabilizers, usually a sugar-like compound, e.g., mannitol, is dried rapidly to form a solid particles with little residual water. The solid particles formed upon fast drying have no internal order, and are referred to as being in an amorphous glassy state. This state can be described as a liquid with the viscosity of a solid and contains randomly distributed molecules as in the liquid state, rather than in the highly ordered packing associated with the crystalline state. Analogous to the melting point in a crystalline solid, the glassy phase is characterized by a glass transition, which marks the loss of a solid-like viscosity upon heating. Nektar’s proprietary formulation process assures that the glass transition is well above any environmental temperatures that may occur during processing and normal patient use. An important feature of the glass transition is its dependence on water content. Water has the ability to decrease the glass transition temperature of an organic glassy material. The Exubera formulation and/or packaging are carefully designed to withstand relative humidity excursions that can occur over the shelf life of the product.
The dry powder technology developed by Nektar provides formulations that are room-temperature stable, deliver a high payload per inhalation, and resist microbial growth. Nektar scientists use screening techniques, based on material properties, to predict the long-term stability of amorphous glassy formulations. Nektar has modified standard powder processing equipment and developed custom techniques to enable it to produce fine dry insulin and other powders consistently with particle diameters of between 1-5 microns without drug degradation or significant loss of expensive bulk drug. Nektar achieves long-term stability partially by using individual blister packaging to provide a strong moisture barrier. Unit-dose packaging also enables precise dosing. The resulting powder aerosols are highly soluble in water and quickly dissolve in the fluid layer on the surface of the deep lung before passing through the thin single cellular layer of the alveoli.
Exubera delivers insulin by oral inhalation. The insulin is absorbed as quickly as subcutaneously administered rapid-acting insulin analogs and more quickly than subcutaneously administered regular human insulin in healthy subjects and in patients with type 1 or type 2 diabetes. In clinical studies in patients with type 1 and type 2 diabetes, after inhalation of Exubera, serum insulin reached peak concentration more quickly than after subcutaneous injection of regular human insulin, 49 minutes (range 30-90 minutes) compared to 105 minutes (range 60-240 minutes), respectively.
Companies.: Nektar Therapeutics, Inc. (originally Shearwater Corp., then Inhale Therapeutic Systems, Inc.) developed inhaled insulin through Phase I clinical trials and partnered with Pfizer Inc. in 1995, with Pfizer receiving exclusive worldwide rights. Pfizer subsequently partnered with Hoechst AG. later Aventis S.A, now Sanofi Aventis. Pfizer and Sanofi Aventis were to co-develop, co-promote, and co-Manufacture inhaled insulin, but later bought out Aventis’ interest.
Pfizer manufactured insulin for Exubera at Frankfurt, Germany, and a newer facility in Terre Haute, IN. [Note, upon Pfizer halting marketing (see below), it was reported that Hoeschst/Sanofi Aventis manufactured the insulin at its facilities in Frankfurt]. The Tech Group (Scottsdale, AZ), a subsidiary of Services, based in Arizona, and Bespak (U.K.) are the two contract manufacturers of the Exubera inhaler device. Nektar Therapeutics, Inc. manufactures the formulated insulin powders. Final assembly and filling is performed by Pfizer at its facilities in Indiana. The Tech Group. West Pharmaceutical Services, provided final packaging services, with Consort Medical plc (U.K.; formerly Bespak plc) providing comparable services for the European market.
In Jan. 2006, Pfizer acquired all rights to Exubera held by Sanofi Aventis for ~$1.3 billion, with this including Sanofi Aventis’ share in an insulin manufacturing facility in Frankfurt, Germany.
Nektar Therapeutics, Inc. receives royalty and manufacturing revenue, reported to be roughly 15% of worldwide Exubera sales. Nektar has stated its royalties from inhaled particle technology licensing is in the range of10%-20%. In Oct. 2004, Pfizer Inc. filed suit in New York state seeking a declaratory judgment that Sanofi’s acquisition of Aventis implemented a change of control provision in the companies’ collaboration agreement. Aventis (now Sanofi Aventis) asserted that the provision had not been triggered. Under their agreement, a change in control would give Pfizer the right to either sell its interest in the partnership to Aventis or buy out Aventis’ interest at fair-market value (to be determined by investment banks). The Jan. 2006 acquisition by Pfizer of Sanofi Aventis’ interest in Exubera ended this litigation.
Pfizer reports, “Exubera is the result of one of the most rigorous and innovative diabetes development programs ever and Pfizer’s investment now stands at more than $1 billion. Pfizer invested in two state-of-the art manufacturing facilities – the world’s largest insulin plant in Frankfurt, Germany, and a high-tech facility in Terre Haute, Indiana, U.S. – well ahead of regulatory actions, so that the product can reach patients as quickly as possible.”
In Oct. 2008, with neglibible sales and mounting reports of adverse effects, Pfizer withdrew Exubera from the market (halted marketing). Pfizer took a loss of $2.8 billion against its 3rd quarter earnings. This included a write off $454 million in fixed assets and $661 million in inventory. Other major exit costs likely included expenses and commitments made to Hoechst/Sanofi Aventis to fund a new insulin manufacturing facility in Frankfurt; and Pfizer had also probably had to write off its Indiana facility as a loss.
In April 2008 (after reports from ongoing trials, among reports many concerning adverse lung events, that new cases of lung cancer in former smokers were observed in Exubera patients as compared to the control group), Nektar Therapeutics ceased all activities related to Erbitux (i.e., abandoned finding a new marketing partner after losing Pfizer).
FDA class: Drug NDA
Approvals: Date = 20060127; original NDA, no. 021868
Date = 20080409; BLA supplement; Indications: = product insert/labeling modified to include: "In clinical trials of Exubera, there have been 6 newly diagnosed cases of primary lung malignancies among Exubera-treated patients, and 1 newly diagnosed case among comparator treated patients. There has also been 1 post-marketing report of a primary lung malignancy in an Exubera-treated patient. In controlled clinical trials of Exubera, the incidence of new primary lung cancer per 100 patient-years of study drug exposure was 0.13 (5 cases over 3900 patient-years) for Exubera-treated patients and 0.02 (1 case over 4100 patient-years) for comparator-treated patients. There were too few cases to determine whether the emergence of these events is related to Exubera. All patients who were diagnosed with lung cancer had a prior history of cigarette smoking."
Date = 20080928; NDA supplements; Indications: = unspecified (upon approval) labeling changes
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling; upon approval]:
Exubera is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. Exubera has an onset of action similar to rapid-acting insulin analogs and has a duration of glucose-lowering activity comparable to subcutaneously administered regular human insulin. In patients with type 1 diabetes, Exubera should be used in regimens that include a longer-acting insulin. In patients with type 2 diabetes, Exubera can be used as monotherapy or in combination with oral agents or longer-acting insulins.
Status: The NDA was submitted on Dec. 27, 2004 and accepted for filing on March 2, 2005 for treatment of adult patients with type 1 and type 2 diabetes. In Sept. 2005, the Endocrinologic and Metabolic Drugs Advisory Committee, FDA, voted 7-2 to recommend approval of Exubera for the treatment of adults with type 1 and type 2 diabetes. In late Oct. 2005, FDA informed Pfizer and Sanofi Aventis that it was delaying for another three months the original six months targeted decision date to review additional chemistry data submitted by the companies. Approval was granted to Pfizer on Jan. 27, 2006 (approval time = ~10.8 months).
Although approved in Jan. 2006, U.S. launch by Pfizer was delayed to September due to manufacturing problems.
A MAA for European Union (EU) approval for the same indications: was filed in Feb. 2004. EU approval was granted on Jan. 26, 2006, a day before receiving FDA approval. Analysts had reported that EU approval was less certain or could be delayed, relative to the U.S. application. The EU application contained one-year safety data, while the U.S. filing had more comprehensive two-year safety data.
FDA is presumed to have intensely scrutinized the NDA, because Exubera is a drug that millions of patients will receive for years and it has a novel delivery method.
Pfizer has committed to carrying out long-term post-marketing studies of Exubera’s safety.
Exubera began its European launch in Germany in May 2006. At the time in Europe, Exubera was also approved in Ireland, and the U.K.
In early April 2008, Pfizer and Nektar reported noting an increased number of lung cancer cases among patients taking the therapy during clinical trials; and a Dear Doctor letter was sent to all U.S. physicians. See the approvals section for the related language inserted into the product insert.
Tech. transfer: By now, basic recombinant and other technology for the manufacture of insulin is well known and in the public domain. See the Insulin Products entry.
Nektar, originally Shearwater Polymers, developed and has licensed to Pfizer several technologies to solve the problems of systemic inhalation delivery of insulin. As discussed in the Biological section, the company’s technologies convert insulin into optimally sized sugar-based glass particles (1-3 microns) that can be delivered efficiently to the deep lung for rapid drug absorption into the bloodstream. Glass stabilization of the particles maintains powders stability at room temperature and eliminates the need for refrigeration, while enabling rapid dissolution of the particles in the presence of lung fluids. A special powder-filling technique handles micron-size cohesive powders and measure individual drug doses into small blister packs. A portable, easy-to-use inhaler delivers reproducible and flow-rate independent drug doses efficiently into the lungs.
Glass powder stabilization and powder delivery systems are described in U.S. patents assigned to Nektar including 6,685,967 and 6,737,045, "Methods and compositions for pulmonary delivery of insulin," expiring March 7, 2014; 6,589,560 (and related 6,309,671 and 6,258,341), “Stable glassy state powder formulations,” expiring Apr 14, 2015; 6,630,169, “Particulate delivery systems and methods of use,” expiring Mar 31, 2019; 6,638,495, “Stabilized preparation for use in metered dose inhalers,” expiring Jun 29, 2018; 6,655,379, “Aerosolized active agent delivery,” expiring March 11, 2019; and 6,797,258, “Compositions and methods for the pulmonary delivery of aerosolized macromolecules,” expiring Jul 8, 2012.
In August 2006, Novo Nordisk filed a patent infringement suit in U.S. District Court, including seeking an injunction against U.S. sales of Exubera. The suit included allegations that that Exubera infringes five Novo Nordisk’s inhaled insulin-related patents, and that sales of Exubera may cause “irreparable harm” for future sales of Novo Nordisk’s inhaled insulin, AERx (launch projected in 2010 or 2011). In Dec. 2006, a judge refused to grant an injunction, citing public health benefits of Exubera. In April 2007, Novo Nordisk reduced the scope of its patent challenge to two key patents. Novo Nordisk remains confident of its case, which will go to trial (eventually). [In related news, in Nov. 2006, Novo Nordisk reported it was challenging a U.S. patent office rejection of a patent application covering aspects fo AERx, with the patent office allegeding a lack of novelty for the inhaler. AERx is the only inhaled insulin device currently in clinical trials that uses a liquid formulation, requiring the insulin to be refrigerated. It is also quite large - about the size of a paperback book].
On Oct. 10, 2008, Novo Nodisk reported settling its patent dispute concerning Exubera. Terms were not disclosed (and between the product's low sales and it haing just been pulled from the market, any monetary settlement would have been negligible by the standards of the companies involved).
Trials: The safety and efficacy of Exubera have been studied in approximately 2,500 adult patients with type 1 and type 2 diabetes. Exubera reached peak insulin concentration more quickly than regular insulin administered by an injection. Peak insulin levels were achieved at 49 minutes (range 30-90 minutes) with Exubera compared to 105 minutes (range 60-240 minutes) with regular insulin. Phase III clinical trials indicated that Exubera is a viable treatment option for both Type 1 or Type 2 diabetes. Patients preferred using Exubera, and have reported significant improvements in overall treatment satisfaction. Type 1 diabetes patients taking Exubera have indicated that reducing the number of injections through inhalation delivery greatly increased their acceptance of intensive insulin therapy without compromising blood sugar control.
Exubera has been studied in more than 2,500 patients, some for over seven years. Based on expectations for widespread use, Pfizer and Aventis announced in Oct. 2002 that larger, more controlled studies focusing on lung function would be completed prior to filing for approvals. Exubera was successfully (re)tested in Phase III trials after an initial long-term Phase III study failed, because statistical analyses could not rule out an effect on lung function.
Exubera trials involved evaluations of pulmonary safety, because the insulin is absorbed by the lungs rather than under the skin. Studies have shown that some patients experience a small decline in lung function. But overall, FDA has characterized the changes in lung function as “very small” and generally no more than 10% as measured with various tests.
The bioavailability of Exubera in only about 10%, i.e., only about 10% of the dose administered ever reaches the bloodstream (with 90% of the insulin wasted). In contrast, injected insulin has 60–90% bioavailability. Inhalation administration provides consistent dosing, often better (more consistent) than by injection, particularly in obese patients. Efficacy of inhaled insulin is comparable or identical to that of injected insulin. Recombinant insulin is now a relatively inexpensive commodity, so wastage is not a major concern. The major concern affecting the the approvals and adoption of Exubera is the long-term safety of its inhalation and use.
Results from a two-year safety study to assess potential damage to patients’ lungs from long-term use were reported in Dec. 2004, including new pulmonary function data. After 24 weeks of treatment, there were no major differences in pulmonary function (FEV1) between patients on Exubera and injected insulin. However, patients taking Exubera with an oral glycemic control agent had a slight decrease in lung function after six months. After two years of treatment, Exubera patients had a mean HbAlC level of 7.7, compared to the mean HbAlC of 8.1 for patients on oral agents. Results indicated Exubera may be as efficacious as injected insulin and superior to oral agents in lowering blood glucose in patients with diabetes; and that Exubera has a unique effect on both fasting plasma (blood glucose measurement before breakfast) and two-hour postprandial glucose levels (blood glucose measurement taken after meals) vs. conventional treatment.
A large number of clinical trial participants reported experiencing cough when taking Exubera, but the severity of the coughing problems was generally mild. Most coughing problems amounted to patients having to clear their throat after using inhaling Exubera Inhaler. There also appears to be a large learning curve for those using Exubera. Clinical studies showed a wide variation of dosing among new users, a problem that was largely attributed to patients’ unfamiliarity with the inhaler.
As part of its FDA approval, Pfizer agreed to conduct a post-marketing surveillance study (Study 1069) in 5,000 patients and to complete two ongoing studies in diabetic patients with asthma or chronic obstructive pulmonary disease (COPD). Study 1069 is expected to start in 2006, and will look for significant declines in lung function over time. The ongoing asthma study (Study1028) is expected to end in 2008 and the COPD study (Study 1030) is expected to end in 2011. Pfizer also will study the number of smokers and those with a history of smoking taking Exubera to see if the label’s warning against use by these patients is effective.
In July 2006, interim data from a 5-year open-label Phase III trial in 582 patients with Type I diabetes showed that both Exubera and subcutaneous insulin provided similar improvement in HbA1c levels. Differences in changes from baseline in forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusing capacity (DLco) between patients given Exubera and those given subcutaneous insulin were small, occurred early, and did not progress for up to 2 years. Overall, patients receiving Exubera had 4 hypoglycemia events/subject-month vs. 3.8 in those receiving subcutaneous insulin. Also, in July 2006, interim data were reported from a 5-year open-label Phase III trial in 635 patients with Type II diabetes. Both Exubera and subcutaneous insulin had similar improvements in HbA1c levels from baseline after 2 years of treatment. Differences in changes from baseline in FEV1 and DLco between patients given Exubera and those given subcutaneous insulin were small, occurred early, and remained stable with no progression for 2 years. Overall, patients receiving Exubera had 0.8 hypoglycemia events/subject-month vs. 1 event/subject-month in those receiving subcutaneous insulin. Exubera led to less weight gain vs. subcutaneous insulin (1.7 vs. 3 kg).
Medical: Exubera is administered within 10 minutes before the start of a meal. A 1 mg unit dose blister gives about the same dose as an injection of 3 IU of fast-acting subcutaneous insulin, and a 3 mg unit dose blister about the same as 8 IU of fast-acting subcutaneous insulin. Thus, Exubera is not suitable when small (less than 3 IU) adjustments of insulin are necessary (e.g., in patients with low body weight). Overall, based on studies in type 1 and type 2 diabetes, Exubera can be expected to provide blood glucose control similar to that given by fast-acting subcutaneous human insulin.
Nearly 21 million Americans have diabetes, with about 95% having type 2 diabetes. All people with type 1 diabetes and a large and growing percentage of those with type 2 require treatment with insulin. In type 1 diabetes, inhaled insulin may be added to longer acting insulins as a replacement for short-acting insulin taken with meals. In type 2 diabetes, inhaled insulin may be used alone, along with oral (non-insulin) pills that control blood sugar, or with longer acting insulins. Most patients still have to use a long-acting injectable insulin for background coverage, but Exubera can dramatically cut the number of injections they need to control their blood sugar each day.
Labelling for the Exubera notes that a small decrease in lung function can occur during Exubera treatment, although this change occurs within the first months of treatment and should not worsen as treatment is continued. Also, patients should also not take Exubera, if they have poorly controlled or unstable lung disease, or if they smoke or have stopped smoking less than six months prior to starting treatment.
Market: Exubera was reported to cost $4.50/day in the U.S. and $3.00/day in Europe. This compares to about $2-$3 average daily cost of mealtime injected insulin for type 1 diabetics, assuming patients are taking three to four injections daily. Pfizer reported that most patients take Exubera before each meal, or at least three times a day.
With nearly 21 million Americans having diabetes, with about 95% having type 2 diabetes, Exubera has considerable market potential, depending largely on perceptions of its safety, efficacy, cost-benefits and convenience. Early adopters of Exubera were expected to include type 2 diabetes patients in the U.S. who are failing oral agents and should already be on insulin, but are not because of needle-aversion. This is just a subset of the, perhaps, 10% of three million type 2 patients failing oral agents. Inhaled insulin could provide a more convenient and less painful method of insulin administration, particularly for the 9.5 million diabetes patients in the U.S. who take mealtime insulin.
However, even before it hit the market, there was considerable uncertainty about market potential. Many questioned whether Exubera (and other inhaled insulins) will be perceived as better or not than the current standard-of-care (injected insulins and oral antiglycemic drugs). Physicians have not hurried to switch patients from injectables to inhalables, and may not do so, until they have many more years of safety data for Exubera.
The 2007 Average Wholesale Price (AWP) of the Exubera Chamber inhalation device was $18.00, with a Direct Price (discount price) of $15.00; Exubera Combination Pack 12, 180s, $134.40; Exubera Combination Pack 14, 270s, $168.00, with a Direct Price of $140.00; and Exubera Release Unit inhalation device, $6.00, with a Direct Price of $5.00 (Red Book, 2007).
In mid-2007, sales had not reached expectations and were a major disappointment for Pfizer, with only about 3-4,000 patients receiving Exubera. One source reported 2006 sales of only $7.8 million. Despite six months or more of marketing to physicians, Exubera was receiving only about one of every 500 prescriptions for insulin written in the U.S. Originally expected to be launched in the U.S. in July or August 2006, this was delayed several times. A new diabetes pill, Januvia, from Merck was approved after Exubera, and was already being prescribed about 40,000 times/week in the U.S., about 25 times as often as Exubera. Also, in the last two years, two other new diabetes therapeutics entered the market, Byetta and Symlin, as well as Levemir, a longer-acting version of injectable insulin (see related entry), so patients and physicians had greater choice.
In April 2007, Pfizer relaunched Exubera in the U.S. (its last chance to gain significant market share). Exubera was transferred from Pfizer’s pain management to its cardiovascular (CV) sales force, which began detailing doctors regarding the importance of earlier initiation of insulin and use in patients with needle phobia. Pfizer also began a direct-to-consumer (DTC) advertising campaign to help stimulate demand. However, perceptions that Exubera is simply inconvenient and difficult to use were a major factor hindering sales, e.g., the device is considered large and unweildly, requiring repeated pumping, and dosing conversions (from units to milligrams) vs. conventional injections are difficult to perform. Costs, reimbursement and persistent concerns about safety were other major factors restricting uptake and sales. Patients must take a lung-function test before beginning Exubera, something that discouraged doctors from prescribing it and increased exposure to liability issues. Newer, smaller needles have reduced the pain and discomfort from insulin self-injections. Many patients (and physicians) simply did not perceive Exubera as providing significant benefits over injected insulin, leaving the market for Exubera to those with needle phobia. Surveys showed that nearly 90% of physicians were already familiar with Exubera, indicating that Pfizer will have difficulties in changing their views of the product.
Friedman Billings and Ramsey (FBR) analysts originally expected >100,000 patients in the U.S. to be on Exubera by year-end 2006, with total U.S. 2006 sales of $166 million, but corrected this (March 2007) to just $7.8 million, mostly in the fourth quarter. FBR projected (March 2007) $295.6 million in worldwide sales in 2007 (down from original estimate of $943 million), $613.3 million in 2008 (originally, $1.6 billion), $843.2 million in 2009 (originally $1.8 billion), $1.020 (achieving blockbuster status) in 2010 (originally $2.1 billion), $1.213 billion in 2011, and $1.417 billion in 2011.
FBR in late 2006 projected U.S. sales to be $5.1 million in 2006, $120.3 million in 2007, $498 million in 2008, $642.8 million in 2009, $874.2 million in 2010, and $976.8 million in 2011, In June 2007, BioMedTracker revised its estimates for peak annual sales of Exubera from a prior $2.5 billion to $410 million/year. Datamonitor now forecasts Exubera sales to stabilize at $207 million by 2015. Merrell Lynch analysts have recently projected worldwide sales of $310 million in 2012 (down from $630 million). Other analysts now project sales in this range. Sales on these levels (few $100 million) would interpreted as a major failure for Pfizer and Exubera.
In summer 2007, second quarter sales were reported for Exubera - only ~$4 million (equivalent to ~$16 million/year). This showed that the relaunch of the product earlier in the year had been ineffective (a disaster by industry standards) and that Exubera would likely remain a product ignored and/or avoided by physicians and diabetics. Many began to point to Exubera as a prime example of a product failure, with a major disconnect between marketing-driven expectations (hype) and the real world, where consumer preferences, perceptions of safety, inability to show cost-benefit or other advantages, and lack of acceptance by insurers can doom a product to failure. However, the concept of inhaled insulin remains attractive, and some point to the example of insulin pumps, first launched in the early 1980s with low sales, but with improvements (new products) now have a very large market.
Some analysts were skeptical/critical that Exubera would ever capture significant market share. At about four-times the price of conventional injected insulin, with comparable efficacy, and with its major attraction being convenience, the product may not offer an attractive cost-benefit ratio. Some pointed to the marketing failure of FluMist (nasal spray influenza vaccine; see related entries) and disappointing sales of Amevive from Biogen Idec as examples of products not delivering on a cost-benefit basis. And, Pfizer had not yet demonstrated that the switch from injected to inhaled insulin results in improved compliance, or that its use results in fewer or less severe adverse effects. Many endocrinologists were slow to prescribe Exubera, and following their lead, many primary care physicians were not prescribing Exubera.
Reimbursement remained a major problem for Exubera. Many insurers were limiting Exubera’s availability to patients, imposing high co-payments, or rejecting its coverage outright, and patients had to pay for it themselves. Even health plans with a rigorous prior authorization system (i.e. physicians must receive prior approval from the insurance company prior to being reimbursed) and managed care plans were denying payment. With a monthly cost of at least $150, Exubera costs roughly twice as much or more than conventional insulin. Managed care and the government showed that they are not going to pay for a therapeutic perceived as not having a real efficacy benefit and only a convenience advantage to injectable insulin.
The U.K. National Institute of Health and Clinical Excellance, which provides recommendations based on cost-benefit assessments for the U.K. National Heath Service (NHS) and the Scottish Medicines Consortium, decided not to support Exubera, i.e., that Exubera should only be used in patients with seriously uncontrolled blood glucose (haemoglobin A1c level of more than 9%) and either “a proven injection phobia diagnosed by a psychiatrist or psychologist, or severe persistent problems with injection sites [infections].” NICE originally ruled in April 2006 that Exubera should not be used at all, since no data showed it would increase treatment compliance among diabetics and/or reduce the overall cost of managing the disease. This was tempered to the current policy in June 2006. NICE estimated that the average annual cost of Exubera would be around £1,102 per patient, almost twice the cost of injectable-only insulin therapy. Around 800,000 diabetics in the U.K. use insulin injections.
Germany’s Institute for Quality and Efficiency in Health Care (IQWIG), which looks at the clinical role of new therapeutics, but does not make judgements on cost-effectiveness, concluded that there is no evidence of any advantages with Exubera over short-acting human insulin or insulin analogues administered subcutaneously.
In Oct. 2008, Pfizer withdrew from marketing Exubera. On Oct. 17, 20008, The Wall Street Journal characterized the failure of Exubera as "one of the drug industry's costliest failures ever. The only potential winner (or those who did not lose big-tme) from Exubera was Sanofi-Aventis, which received $1.3 billion from Pfizer for purchase of the product; and possibly, Nektar, which manufactured the formulation and receives a reported 15% royalty on sales.
Competition: Exubera had a significant lead over its closest competitors (insulins with novel delivery methods), including Eli Lilly/Alkermes and Novo Nordisk/Aradigm, with these companies’ inhaled insulin products still in late-stage clinical testing or abandoned. See also the R&D section of the Insulin Products entry for further discussion of inhalable and other novel insulin delivery methods and products advancing in development.
Exubera’s nearest competition (inhaled insulin in development) is AEsRx insulin Diabetes Management System (AERx iDMS) involving liquid droplets of insulin (NN1998) with an electromechanical inhaler from Aradigm and Novo Nordisk Pharmaceuticals. This device pushes out a fine spray of tiny droplets only when a patient is inhaling at the correct airflow rate. This entered Phase III trials in late 2002 using AERx from Aradigm for mealtime delivery of insulin. In May 2004, results were reported from the Phase III trial, including attaining the primary safety and efficacy endpoints. In Sept. 2004, Novo Nordisk acquired Aradigm’s technology and manufacturing equipment and facilities for $55 million. Aradigm will receive royalties on sales. In July 2006, Novo Nordisk paid Aradigm $12 million to assume ownership of its inhaled insulin patents. Novo Nordisk and Aradigm began their collaboration in 1998.
The AIR System (involving dry powder with a passive inhaler) from Alkermes and Eli Lilly & Co. is in Phase III trials. This uses a dry powder with larger, porous particles that disperse when inhaled passively. Inhaled insulin using the Technosphere delivery system form Mannkind is also in Phase III trials. Other inhaled insulin products are in earlier phases of clinical testing.
Companies involvement:
Full monograph
194 Insulin, rDNA, inhaled/Pfizer
Nomenclature:
Insulin, rDNA, inhaled/Pfizer [BIO]
Exubera [TR]
(insulin human [rDNA origin]) Inhalation Powder [FDA]
9004-10-8 [CAS RN]
insulin, recombinant powder for inhalation [SY]
molecular weight (kDa) = 5.8
FDA Class: Drug NDA
Year of approval (FDA) = 2006
Date of 1st FDA approval = 20060127
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2019, based on multiple delivery system patents; not approved, no biosimilars or generic drug versions possible |
U.S. Patent Expiration Year: | N.A. |
U.S. Biosimilars Data Exclusivity Expiration: | |
U.S. Biosimilars Orphan Exclusivity Expiration: | |
U.S. Biosimilars Launchability Year: | N.A. |
U.S. Biobetters Launchability Year: | 2019 |
Biosimilars/biobetters-related EU Patents: | not approved, no biosimilars possible; 2019 arbitrarily used as expiration date |
EU Patent Expiration Year: | 2019 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: | 2019 |
Index Terms:
biopharmaceutical products
hormones
insulin, recombinant human
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
GL- 3
glycine
lyophilized (freeze-dried)
mannitol
sodium citrate
sodium hydroxide
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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