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Focus On: Exubera An Orally inhaled insulin


Abstract

Long-term glycemic control substantially reduces the risk of diabetes mellitus-related complications. Insulin is a mainstay in therapy in type 1 and later-stage type 2 diabetes mellitus. Although insulin is effective in controlling blood glucose and hemoglobin A1c concentrations, the need for subcutaneous injection can be a burden for patients, which can impact compliance. Exubera (Nektar Therapeutics/Pfizer/Sanofi-Aventis) is an inhaled insulin that has demonstrated results similar to conventional short-acting insulin products while also increasing overall patient satisfaction. If approved, Exubera would be the first non-injectable insulin available in the United States. The product is administered as a dry powder fast-acting form of insulin via oral inhalation. FDA's Endocrinologic and Metabolic Drugs Advisory Committee recommended Exubera for approval in early September 2005. Exubera may offer an excellent alternative for patients suffering from diabetes who for health, personal, or societal reasons have difficulty administering subcutaneous insulin. (Formulary. 2005;40:429–436.)

Diabetes mellitus (DM) affects an estimated 194 million adults worldwide, including more than 18 million Americans.1,2 Type 1 DM accounts for only 5% to 10% of DM cases, while type 2 DM comprises the rest. Individuals with type 1 DM are more likely diagnosed as children, adolescents, or young adults, while people with type 2 diabetes usually develop the disease in adulthood.3 Type 1 DM is characterized by a failure of the pancreatic islet cells to produce insulin and requires exogenous insulin administration. Type 2 DM is characterized by inadequate insulin secretion or production superimposed on peripheral insulin resistance. There are many pharmacologic agents for glucose control in type 2 DM, but eventually daily insulin injections will be needed as well. Proper glucose control (as determined by hemoglobin A1c [HbA1c] values) can prevent diabetic ketoacidosis in type 1 DM and both microvascular and macrovascular complications in type 1 and 2 DM.

Subcutaneous (SC) insulin is effective for controlling blood glucose, but patients and physicians hesitate initiating insulin therapy for several reasons. Limitations include: concern that injections are painful and difficult to administer; multiple daily injections are inconvenient and are generally required to achieve effective glycemic control; and the perception that initiating insulin treatment signifies a dramatic worsening of the disease.4 Furthermore, these limitations could be possible reasons why patients often have poorly controlled HbA1c levels when on conventional insulin regimens.

Alternative insulin delivery methods ranging from transdermal patches to oral dosage forms are currently under investigation. The lungs are an excellent site for systemic delivery of proteins and peptides because they offer a larger area for systemic absorption compared with other routes of drug delivery.5 The pulmonary delivery of insulin eliminates many of the difficulties and concerns of conventional SC insulin. Inhaled insulin could potentially improve overall patient satisfaction and reduce the amount of insulin administered per day for many patients with diabetes as well as improve long-term outcomes.

Exubera (Nektar Therapeutics/ Pfizer/Sanofi-Aventis) is an inhaled insulin that has demonstrated results similar to conventional short-acting insulin products while also increasing overall patient satisfaction. If approved, Exubera would be the first non-injectable insulin available in the United States. The pro-duct is administered as a dry powder fast-acting form of insulin via oral inhalation. On September 8, 2005, FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 7 to 2 in favor of approving Exubera for the treatment of type 1 and 2 DM. This article will review the chemistry, pharmacology, pharmacokinetics, clinical trials, adverse events, patient satisfaction, and formulary considerations of Exubera.

CHEMISTRY/PHARMACOLOGY

The pulmonary alveoli have a surface area ranging from 75 to 100 m2 , allowing for effective absorption of molecules less than 30,000 Daltons in size. Insulin can be readily absorbed via this route given its molecular size of only 6,000 Daltons.6 However, in order to deliver these insulin molecules into the alveolar sac, they need to be delivered via a particle. Optimal particle size for settlement in the alveoli is 1.5 to 2.5 μm.

Exubera is a dry powder that contains recombinant human insulin, mannitol, glycine, and sodium citrate.7,8 Dry powders are stable formulations at room temperature; they deliver a high dose-per-puff compared with liquid formulations and resist microbial growth during storage.9 The average Exubera particle size is between 1 to 5 μm. Exubera particles are transported across the cell membranes of the alveolar epithelium by being encapsulated in alveolar vesicles. These vesicles are transported from the alveolar capillary endothelium and released into the alveolar capillary bloodstream for absorption. Only 6% to 10% of the inhaled insulin is actually absorbed into systemic circulation from the respiratory mucosa.8

PHARMACOKINETICS


Table1 Pharmacokinetics of Exubera and comparator conventional insulins
The pharmacokinetics of Exubera are summarized in Table 1.10 Rave et al10 evaluated the onset of action for Exubera in healthy nonsmoking males. Exubera was compared with 2 SC-injected insulins, injected insulin lispro (ILP), and regular human insulin (RHI). The onset of action of Exubera (defined as time to half-maximal effect) was much more rapid than lispro and regular insulin (P<.001 [INH vs RHI]; P<.05 [INH vs ILP], respectively). However, time to maximal metabolic action with Exubera was similar to regular human insulin and slower than lispro insulin (P<.01 [INH vs RHI]; NS [INH vs ILP], respectively).10 In another trial conducted by Heise et al,11 inhaled insulin was compared with SC regular insulin and SC lispro insulin in 18 healthy nonsmoking men. Inhaled insulin had a faster onset of action compared with the subcutaneous insulins (P=.0011 [INH vs RHI]; P=.0704 [INH vs ILP], respectively).11

The duration of action of Exubera is approximately 6 hours.8 The aforementioned study by Rave et al determined that the duration of action with Exubera was longer than the lispro insulin (P<.01) but comparable to the regular insulin.10


Table2 Clinical trials of Exubera in type 1 diabetes
The pharmacokinetics of Exubera in 20 elderly obese subjects was also determined. Patients received 2 inhalations of Exubera and 2 SC injections of regular insulin in this randomized crossover trial. At doses producing comparable systemic exposure over 6 hours, Exubera exhibited faster absorption than SC insulin.12

CLINICAL TRIALS


Table3 Clinical trials of Exubera in type 2 diabetes
The clinical trials of Exubera in type 1 and type 2 DM are summarized in Tables 2 and 3, respectively. Phase 2 Exubera trials have demonstrated efficacy in both type 1 and type 2 DM. Skyler et al13 conducted a 12-week, open-label, randomized, and proof-of-concept trial in 72 patients with type 1 diabetes. Patients in the treatment group received pre-prandial inhaled insulin plus a bedtime SC ultralente insulin injection. Patients in the control group received their usual regimen of 2 to 3 injections per day. Changes in HbA1c levels and fasting and postprandial glucose concentrations were comparable between the 2 groups.13

In another study, Quattrin et al14 conducted an open-label, 6-month, multicenter, randomized, parallel group, comparative trial. The study compared the safety and efficacy of pre-meal inhalation plus a single bedtime injection of long-acting SC insulin versus conventional SC insulin therapy in patients with type 1 diabetes. Patients had similar results in reduction of target HbA1c in both groups after 24 weeks. In addition, there was a greater reduction in fasting glucose and in 2-hour post-pre-prandial glucose after 24 weeks in the inhaled group.14

Cefalu et al15 conducted a randomized, open-label trial evaluating the efficacy and safety of Exubera over a 4-week baseline lead-in phase and a 12-week treatment phase in patients with type 2 diabetes. Twenty-six patients were to receive their usual 2 to 3 insulin regimens along with weight management education, home glucose monitoring, pulmonary function testing, and meal studies. After the end of the lead-in phase, patients received inhaled insulin before each meal plus a bedtime injection of ultralente insulin for the duration of the study period. Inhaled insulin improved HbA1c levels compared to baseline (0.71%0.72%).15

In another phase 2 trial, Weiss et al conducted a randomized, open-label, multicenter, parallel group study that included a 4-week run-in phase and a 12-week treatment phase in type 2 DM patients who were poorly controlled on oral agents only. After the lead-in period, patients were randomized to receive additional inhaled insulin or continue on their usual regimen. Patients who received inhaled insulin demonstrated significant improvements in HbA1c levels compared with the control group (P<.001).4

In a phase 3 trial, Hollander et al16 conducted an open-label, parallel-group, comparative study over a 6-month randomized treatment phase. Patients received either premeal inhaled insulin plus a bedtime dose of ultralente or at least 2 daily injections of SC insulin (mixed regular/NPH [neutral protamine Hagedorn]). Mean HbA1c levels were similar between the 2 groups, but more patients achieved HbA1c levels <7% in the inhaled group.16

In another phase 3 trial, DeFronzo et al17 investigated whether inhaled insulin can achieve target glycemic control in patients failing on diet and exercise alone. In this open-label, parallel-group, multicenter study, patients with type 2 diabetes were randomized to a 12-week treatment of either Exubera before meals or rosiglitazone along with a diet and exercise plan. A higher proportion of patients in the inhaled insulin group reached the study goal of HbA1c levels <8% compared with the rosiglitazone group (P=.0003).17

ADVERSE EVENTS

In studies, Exubera was generally well tolerated and the most common adverse events were hypoglycemia, cough, and bitter taste. While hypoglycemia was reported, the risk is lower than with SC insulin therapy.14,16 Quattrin and colleagues demonstrated that patients receiving a regimen including premeal inhaled insulin plus bedtime ultralente exhibited a lower risk for developing hypoglycemia than those receiving a regimen including 2 to 3 injections of regular plus NPH insulin (8.6 vs 9.0 events/subject month, respectively; risk ratio 0.96; 95% CI, 0.93–0.99). This occurred even though doses of short-acting insulin (21.00 vs 21.28 units) and long-acting insulin (35.37 vs 34.48 units) were similar between groups.14 In another trial, patients with type 2 diabetes receiving premeal inhaled insulin plus a bedtime dose of ultralente demonstrated a lower risk of developing hypoglycemia compared with patients receiving at least 2 daily injections of subcutaneous insulin (1.4 vs 1.6 events/subject month, respectively; risk ratio 0.89; 95% CI, 0.82–0.97).16

Overall, cough was more frequent in the Exubera-treated group compared with the conventional group. Quattrin et al14 reported a greater incidence of cough with Exubera than the injectable insulin, but the incidence and prevalence decreased as the study progressed. The cough experienced was of mild-to-moderate severity. Additionally, subjects that experienced cough did not exhibit any symptoms of respiratory distress at rest or during exercise.14 DeFronzo et al17 demonstrated similar findings with cough. Exubera-treated patients had a greater frequency of cough compared with patients treated with rosiglitazone, but there was also a decreased incidence with Exubera over the study period.17

Exubera was associated with greater antibody response than SC insulins, but this was not correlated with any adverse clinical consequences.6 Fineberg et al evaluated antibody response to inhaled insulin from phase 2/3 trials, as well as a phase 3 extension study that lasted 24 months. Data from 1,597 patients with type 1 and 2 DM were pooled into 3 groups based on insulin treatment status at baseline: patients with type 1 DM, patients with type 2 DM using insulin, and patients with type 2 DM not using insulin. From the phase 2/3 trials, there was a higher amount of insulin antibody-binding activity seen in patients receiving inhaled insulin vs SC insulin. Furthermore, greater antibody responses were seen in patients with type 1 DM, and the lowest responses were observed in patients with type 2 DM not using insulin. Fineberg et al also evaluated antibody-binding to pulmonary function, hypersensitivity reactions, and hypoglycemic events and found no significant correlation.6


Table4 Baseline and 24-week pulmonary function test
Since Exubera is administered via the pulmonary system, the impact on pulmonary physiology and structure is an important consideration. Clinical studies have not demonstrated an increased cellular proliferation in patients receiving Exubera, but these studies are no longer than 4 years in duration.18 Limited short-term data demonstrate no significant changes in lung function. In the aforementioned study by Quattrin et al, pulmonary function testing at 12 and 24 weeks did not show any significant between-group differences for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and diffusing capacity for carbon monoxide (DLco) (see Table 4).14 In two 12-week open-label studies extended to 1 year, Rosenstock et al19 determined the mean changes in PFTs were small and similar between the 2 groups.

PATIENT SATISFACTION


Table5 Evaluations of patient satisfaction with Exubera
Patient satisfaction studies are summarized in Table 5. Cappelleri et al20 evaluated satisfaction in a 12-week, open-label, parallel-group, controlled trial in which patients completed a Patient Satisfaction and Insulin Therapy Questionnaire. Patients were randomized to receive either a SC insulin regimen or an inhaled insulin regimen. Even though both treatment groups had a HbA1c reduction of 0.7% (–0.7% 0.7%), overall patient satisfaction was substantially greater with the inhaled insulin regimen compared with the SC insulin regimen (P<.05).20

In an open-label, multinational, comparative study conducted by Testa et al,21 quality of life and satisfaction were evaluated in patients with type 2 DM uncontrolled on sulfonylurea monotherapy. Patients poorly controlled on sulfonylurea therapy were randomized to receive either adjunctive premeal inhaled insulin or metformin for 24 weeks. Results demonstrated a significantly better effect on HbA1c for patients in the inhaled insulin group compared with the metformin group (P=.025). When patients were stratified into high HbA1c, the increase in overall improvement satisfaction was 42% greater for the inhaled insulin-treated patients compared with the metformin-treated patients (P=.02).21

In another trial, Gerber et al22 conducted a 12-week, randomized, open-label, multicenter, parallel study in type 1 DM patients. Patients were placed on either an inhaled insulin regimen or SC insulin regimen. Patients were asked to complete patient satisfaction questionnaires at baseline and Week 12. Overall improvements in patient satisfaction were higher in the inhaled insulin group compared with the conventional insulin group (P<.01). In addition, patients on the inhaled insulin regimen reported a greater improvement in convenience and ease of use (P<.01).22

Rosenstock et al19 evaluated patient preference and satisfaction in a 1-year study. Patients who successively completed the 12-week parent studies evaluating efficacy and tolerability were given the choice to participate in an open-label therapy extension in which they were allowed to choose between inhaled insulin or SC insulin. Overall, inhaled insulin was preferred over SC insulin, which also increased patient satisfaction over 1 year in both type 1 and type 2 DM patients.19

DRUG INTERACTIONS

Cigarette smoking enhances total systemic exposure of Exubera. In a trial of nondiabetic active smokers without pulmonary disease, the absorption rate of inhaled insulin was 50% higher than in the normal population (AUC 63.2 milliunits/L/h versus 40.0 milliunits/L/h). In addition, the time to reach peak concentration was reduced by about 40% (31.5 min versus 53.9 min).23 In another study, the effects of smoking cessation and subsequent resumption on absorption of orally inhaled insulin were evaluated. When smoking cessation occurred, there was up to a 50% reduction in the AUC within 1 week. Smoking resumption completely reversed the effects of smoking cessation on the AUC.24 Structural lung damage secondary to smoking may also impact Exubera pharmacokinetics, but this has not been evaluated. Based on these observations and theoretical considerations, SC insulin may be a better option for smokers until more work is done in this area.

Absorption of orally inhaled insulin has not been studied in patients with common lung diseases.8 Patients diagnosed with asthma, chronic bronchitis, emphysema, and cystic fibrosis could show significant changes in alveolar deposition of inhaled insulin. There are no published data on the use of this product in patients with ventilation perfusion mismatch, congestive heart failure, primary pulmonary hypertension, pulmonary embolism, pneumonia, or other pulmonary structural disorders; these patients also should avoid Exubera therapy until more data are available.

DOSING AND ADMINISTRATION

Exubera is packaged in individual dose-packs that include either 1 or 3 mg of recombinant insulin in a powder form, with each milligram equivalent to 2 to 3 units of SC insulin.13,15

An individual blister pack is placed into the Nektar Pulmonary Inhaler. The individual blister is placed into a slot on the device and is dispersed by the inhaler into an aerosol cloud that is captured in a holding chamber for delivery. The patient inhales the aerosol at the beginning of a slow, deep breath in which air is drawn into the chamber, releasing the aerosol into the pulmonary system.7 FDA-approved dosing and administration directions for Exubera are not yet available. It is currently unclear whether multiple doses can be dispersed into the holding chamber or whether individual blister packs must be inhaled separately; hence, patients requiring insulin doses greater than 9 units per dose may need multiple inhalations.8


Formulary Considerations
Additionally, the FDA briefing document for Exubera states that three 1-mg blisters packs provide greater systemic insulin exposure than one 3-mg blister, and recommends that substitutions/interchanges not be made, complicating dosing further.25 Based on phase 2 and 3 Exubera trials,4,11,13–17 inhaled insulin should be administered within 10 minutes prior to meals.

Dr Patel is a pharmacoeconomics and outcomes fellow in the Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital, Hartford, Conn. Dr White is associate professor at the Drug Information Center, Hartford Hospital. He can be reached at
. Dr Coleman is assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, director of Drug Information Services at Hartford Hospital, and associate clinical professor, University of Connecticut School of Pharmacy, and by Dr Coleman.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

REFERENCES

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3. American Diabetes Association: Type 1 diabetes mellitus. Available at: http:// http://diabetes.org/type-1-diabetes.jsp. Accessed November 29, 2005.

4. Weiss SR, Cheng SL, Kourides IA, Gelfand RA, Landschulz WH; for the Inhaled Insulin Phase II Study Group. Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents. Arch Intern Med. 2003;163:2277–2282.

5. Mandal T. Inhaled insulin for diabetes mellitus. Am J Health-Syst Pharm. 2005; 62:1359–1364.

6. Fineberg S, Kawabata T, Finco-Kent D, Liu C, Krasner A. Antibody response to inhaled insulin in patients with type 1 or type 2 diabetes. An analysis of initial phase II and III inhaled insulin (Exubera) trials and a two-year extension trial. Endocrinol Metab. 2005; 90:3287–3294.

7. Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med. 2003;20:886-898.

8. Odegard P, Capoccia K. Inhaled Insulin: Exubera. Ann Pharmacother. 2005;39:843–853.

9. Newhouse MT. Tennis anyone? The lungs as a new court for systemic therapy. CMAJ. 1999; 161:1287–1288.

10. Rave K, Bott S, Heinemann L, Sha S, Becker R, et al. Time-action profile of inhaled insulin lispro and regular human insulin. Diabetes Care. 2005;28:1077–1082.

11. Heise T, Bott S, Tusek C, et al. The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin. Diabetes Care. 2005;28:2161–2169.

12. Mudaliar S, Henry R, Fryburg D, et al. Within-subject variability of inhaled insulin (Exubera) versus subcutaneous regular insulin in elderly obese patients with type 2 diabetes mellitus (abstract 802). Diabetologia. 2003;52(suppl 2):A277.

13. Skyler J, Cefalu W, Kourides I, et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study. Lancet. 2001; 357:331–335.

14. Quattrin T, Belanger A, Bohannon N, Schwartz S. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes. Diabetes Care. 2004;27:2622–2627.

15. Cefalu WT, Skyler JS, Kourides IA, et al. Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann Intern Med. 2001;134: 203–207.

16. Hollander P, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes. Diabetes Care. 2004;27:2356–2362.

17. DeFronzo R, Bergenstal R, Cefalu W, et al. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise. Diabetes Care. 2005; 28:1922–1928.

18. Skyler J for the Exubera Phase II Study Group. Sustained long-term efficacy and safety of inhaled insulin during 4 years of continous therapy [poster]. Presented at the American Diabetes Association 64th Annual Sessions; June 5–8, 2004, Orlando, FL.

19. Rosenstock J, Cappelleri J, Bolinder B, Gerber R. Patient satisfaction and glycemic control after 1 year with inhaled insulin (Exubera) in patients with type 1 or type 2 diabetes. Diabetes Care. 2004;27:1318–1323.

20. Cappelleri J, Cefalu W, Rosenstock J, Kourides I, Gerber R. Treatment satisfaction in type 2 diabetes: A comparison between an inhaled insulin regimen and a subcutaneous insulin regimen. Clin Ther. 2002; 24:552–564.

21. Testa MA, Turner RR, Hayes JF, Scranton RE, Simonson, DC. Satisfaction and quality of life with sulfonylurea plus either metformin added after failure on metformin monotherapy: an international randomized phase 3 trial [abstract]. Diabetes. 2004;53:A115.

22. Gerber RA, Cappelleri JC, Kourides IA, Gelfand R. Treatment satisfaction with inhaled insulin in patients with type 1 diabetes: A randomized controlled trial. Diabetes Care. 2001;24:1556–1559.

23. Himmelmann A, Jendle J, Mellen A, et al. The impact of smoking on inhaled insulin. Diabetes Care. 2003;26:677-682.

24. Sha S, Becker RHA, Willavise SA, et al. The effect of smoking cessation on the absorption of inhaled insulin (Exubera) (abstract 538-P). Diabetes. 2002; 51(suppl 1): A133.

25. Advisory Committee Briefing Document: Exubera. Available at: http:// http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169_01_01-Pfizer-Exubera.pdf. Accessed November 30, 2005.

The labeling for darbepoetin alfa (Aranesp, Amgen) and epoetin alfa (Epogen, Amgen and Procrit, Ortho Biotech) was revised to include information on reports of pure red cell aplasia and severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin in patients treated with the agents. This has been reported predominantly in patients with chronic renal failure receiving these products by subcutaneous administration.

This dual-acting antidepressant is believed to exert its effect through the inhibition of neuronal serotonin and norepinephrine reuptake. Venlafaxine was approved on November 18, 2005, for the treatment of panic disorder, with or without agoraphobia, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).

Diabetic peripheral neuropathy, one of the most common late complications of diabetes, is associated with decreased quality of life and increased morbidity. The pathophysiology of diabetic neuropathy (DN) is multifactorial, contributing to ischemic and painful events and neuronal damage.

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