- Email: [email protected]
The effect of exenatide re-exposure on safety and efficacy
Peptides 30 (2009) 1771–1774
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
Brief communication
The effect of exenatide re-exposure on safety and efficacy Peter Faludi a, Robert Brodows b, Jude Burger b, Tibor Ivanyi c, Daniel K. Braun b,* a
Uzsoki Hospital, Uzsoki utca 29-41, Budapest 1145, Hungary Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA c Eli Lilly and Company, Budapest, Hungary b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 May 2009 Received in revised form 22 June 2009 Accepted 23 June 2009 Available online 1 July 2009
Exenatide, a synthetic peptide originally isolated from salivary secretions of Heloderma suspectum, like other subcutaneously injected peptides, can cause antibody formation. Despite that antibody formation has been observed in some patients, results from previous clinical trials have not shown safety and efficacy concerns in exenatide-naı¨ve patients. The objective of this multicenter, open-label study was to investigate the response of anti-exenatide antibody formation and the incidence of immune-related and hypersensitivity reactions after exenatide re-exposure. Fifty-eight patients (57% male; 59 10 years; weight 85 19 kg; HbA1c 8.1 0.9%; duration of diabetes 10 5 years) were enrolled. At study initiation, 98.3% of patients were taking 1 or more antidiabetes drugs, including oral medication and various types of insulin. Treatment-emergent adverse events (TEAEs) at any time during the study were observed in 40 and 47% of patients with positive and negative treatment-emergent antibodies, respectively. Immune-related AEs were observed in 6 patients (4 were antibody positive). These AEs had not been reported in their previous exposure to exenatide. Re-exposure to exenatide did not result in increased hypersensitivity reactions. Overall, 72% of patients had a baseline to endpoint reduction in HbA1c (range 0.1 to 2.8%), and 87% of antibody negative versus 62% of antibody positive patients had an HbA1c endpoint reduction. The study design and the patients’ baseline characteristics, including diabetes treatment at study initiation, are confounding factors limiting clinical conclusions on exenatide’s glycemic effect in this patient population. The study results indicate that anti-exenatide antibody formation did not increase the incidence of TEAEs in patients re-exposed to exenatide. ß 2009 Elsevier Inc. All rights reserved.
1. Introduction Exenatide is a glucagon-like peptide 1 (GLP-1) receptor agonist that was approved in 2005 in the United States as adjuvant therapy for the treatment of type 2 diabetes. Exendin-4 (exenatide) was originally isolated from the salivary secretions of Heloderma suspectum (Gila monster) [6]. Consistent with the potentially immunogenic properties of protein therapeutics, their administration is often associated with antibody formation, such as the observed antibody formation resulting from insulin administration [5,9,10]. Results from previous exenatide clinical trials have shown that 41–49% of patients developed anti-exenatide antibodies, which were of titers of 125 [3,4,8,12]. In these trials, the presence of anti-exenatide antibodies was not predictive of exenatide’s glycemic effects in individual patients [10]. In most patients who developed anti-exenatide antibodies, the antibody titers decreased over time [1]. The effect of antibody formation on the safety and
* Corresponding author. Tel.: +1 317 277 6530; fax: +1 317 433 1021. E-mail address: [email protected] (D.K. Braun). 0196-9781/$ – see front matter ß 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2009.06.026
efficacy of exenatide following a period of treatment interruption has not been studied. It is important to determine whether reexposure to exenatide leads to excessive anti-exenatide antibody formation and whether as a result, hypersensitivity reactions are observed. The objective of this study was to evaluate whether reexposure to exenatide and any subsequent antibody formation resulted in safety issues, particularly immune-related and hypersensitivity reactions in patients who had stopped taking exenatide for at least 2 months. 2. Materials and methods In this Phase 3b, open-label, single-arm, multicenter, 24-week study, patients were eligible for study inclusion if they had been treated with exenatide in a past clinical trial (referred to in this manuscript as parent studies) [2,7,12]. Study participants were eligible for inclusion if they had a glycosylated hemoglobin (HbA1c) value 10.5% and had not been exposed to exenatide for at least 2 months prior to enrollment in this trial. Patients who were on fixed-dose combinations of sulfonylurea (SU) and metformin were switched to comparable doses of the individual drug
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components at treatment initiation. Patients who used basal insulin were asked to maintain their established insulin dose for the duration of the study, whereas patients who used rapid acting insulin or an insulin mixture were asked to decrease their established insulin dose by 25% at study initiation. SU and insulin dose were reduced in response to hypoglycemic events. Exenatide was administered twice daily by subcutaneous injection within 60 min of the morning and evening meals. Patients received 5 mg twice daily for the first 4 weeks of treatment and 10 mg for the remaining 20 weeks of treatment. A common clinical protocol study was approved for each site by an Institutional Review Board in accordance with the principles described in the Declaration of Helsinki, as revised in 2000 [11]. All patients participating in the study provided written informed consent prior to enrollment. The primary endpoint of the study was to assess the antibody response to exenatide re-exposure as measured by anti-exenatide antibodies and incidence of pre-defined treatment-emergent allergy and hypersensitivity reactions. The antibody status of post-dose subject samples was determined by a validated screening assay relative to the pre-dose control samples. Positive samples were then titrated, and antibody titers were reported at 1:5 dilutions starting at a titer level of 1:25, then 125, 625, etc. The criterion for negative antibody status at baseline was defined as a titer level of <25. Treatment-emergent antibody formation was defined as positive (TE ab+) if the patient experienced a change in antibody titer levels from baseline, and negative (ab ) if there was no change in antibody titers. Treatment-emergent ab status at different study time points were reported because antibody status could change for individual patients throughout the trial. For example, a patient who was ab at trial initiation may have become ab+ during the trial, and then could have returned to baseline levels by the end of the trial (ab classification at endpoint). A secondary endpoint was to examine the effect of antiexenatide antibody formation on clinical efficacy, specifically, changes in HbA1c. A minimum of 50 patients were planned for inclusion and power calculations were not considered for this study. Descriptive statistics were used to represent the data for the primary and secondary endpoints. Analyses were performed on intent to treat (ITT) patients who had evaluable post-baseline anti-exenatide antibody titers. 3. Results Baseline characteristics of patients were: 57% male, age 59 10 years, body weight 85 19 kg, HbA1c 8.1 0.9%, duration of diabetes 10 5 years, and 78% Caucasian/22% East Asian. The duration of days that patients had been off exenatide treatment since completion of the parent trials ranged from 240 to 1074 days. At study initiation, 98.3% of patients were taking 1 or more antidiabetes drugs, including oral medication and insulin. At study initiation, patients were treated with biguanides (65.5%), SU (58.6%), thiazolidinediones (10.3%), alpha-glucosidase inhibitors (3.4%), or a combination of oral antidiabetes agents (12.1%). The percentage of patients treated with insulins and insulin analogs was 36.2%. Of the 58 patients who enrolled in the study (ITT population), 55 patients completed the study, 2 patients discontinued due to subject decision, and 1 due to sudden death (not related to exenatide treatment). The patient who died did not have a postbaseline antibody measure and was not included in the endpoint analyses. At baseline, 50 (86%) patients were ab and 8 (14%) were ab+ (titers 125, n = 8; titers 625, n = 0). The number of patients who had ab and ab+ status at any time during the study were 15 (26%) and 42 (74%); titers 125, n = 25; titers 625, n = 17, respectively. At endpoint, 23 (40%) patients were ab and 34 (60%)
Fig. 1. Number of patients with antibody titers of <25, 125, and 625 in the parent and the current trials at baseline and endpoint are shown above. The number of patients with maximum titer values is also shown for the parent and current trials. Four percent of patients in the parent trials had anti-exenatide antibody titers 125 at baseline, suggesting that these patients were false-positive for anti-exenatide antibodies.
were ab+ (titers 125, n = 31; titers 625, n = 3). In the parent trials, 31 patients were TE ab+ at endpoint and 27 of these patients were also ab+ at endpoint in this re-treatment study. Out of the 26 patients who were ab at endpoint in the parent trials, 19 were also ab in the re-treatment study. The number of patients with antibody titers in the parent and the current trials at baseline and endpoint are shown in Fig. 1. Similar percentages of patients in the TE ab+ and ab groups (40% [17/42] vs. 47% [7/15], respectively) experienced at least 1 treatment-emergent adverse event (TEAE) at any time during the study. The incidence of TEAEs is summarized by ab status in Table 1. Of those patients with TE ab+ status, TEAEs were observed at any time during the study in 44% (11/25) of patients with antibody titers of 125 compared with 35% (6/17) of patients with antibody titers of 625. Four patients reported 5 TEAEs which were possibly related (as assessed by the investigator) to exenatide; eye allergy (n = 1), injection site pruritus (n = 1), injection site rash (n = 1), diarrhea (n = 1) and vomiting (n = 1). Six patients reported at least 1 potentially immune-related TEAE. Arthralgia (n = 1) and spinal osteoarthritis (n = 1) were observed in 2 ab patients. Four ab+ patients reported either injection site pruritus (n = 2), injection site rash (n = 1) and rash (n = 1), and 1 of the patients with injection site pruritus also reported the event of eye allergy. None of the patients with potentially immune-related TEAEs in the re-treatment study reported immune-related TEAEs in the parent study. Two serious adverse events (SAEs) were reported during this study, one sudden death (unattended, unknown origin) which occurred prior to establishing postbaseline antibody status. One patient with TE ab+ status experienced a malignant hepatic neoplasm. Both SAEs were determined by the investigator to not be related to exenatide. Overall, 72% of patients had a baseline to endpoint reduction in HbA1c (range 0.1 to 2.8%), and 87% of ab versus 62% of ab+ patients had an HbA1c reduction at endpoint. The mean changes in HbA1c from baseline to endpoint were 0.9 0.8% (mean SD) for ab status at endpoint (n = 23) and 0.2 0.9 for patients with ab+ status at endpoint (n = 34). At endpoint, mean HbA1c changes of 0.3 0.8% and +0.7 1.7% were observed in the 125 (n = 31) and 625 (n = 3) antibody subgroups, respectively. The changes from
P. Faludi et al. / Peptides 30 (2009) 1771–1774 Table 1 Treatment-emergent adverse events by antibody status. Treatment-emergent antibody status (ITT patients = 58)a
Patients with 1 TEAE Nasopharyngitis Influenza Injection site pruritus Toothache Viral infection Diarrhea Cough Eye allergy Headache Hepatic neoplasm malignant Injection site rash Lower respiratory tract infection Non-cardiac chest pain Pharyngolaryngeal pain Rash Respiratory tract infection Respiratory tract infection viral Rotator cuff repair Sinusitis Upper respiratory tract infection Arthralgia
Negative (n = 15), n (%)
Positive (n = 42), n (%)
7 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1
17 (40.5) 2 (4.8) 2 (4.8) 2 (4.8) 2 (4.8) 2 (4.8) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 0 (0)
(46.7) (6.7) (0) (0) (0) (0) (6.7) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (6.7)
The data presented show TEAEs at any time during the study organized by antibody status. a One patient did not have a post-baseline antibody measure and was not included in the table.
baseline to endpoint in HbA1c of the 3 patients with titer levels 625 at endpoint were +0.4%, +2.5%, and 0.9%. In this group, the antibody titers of the patients with the largest increase and greatest reduction in HbA1c increased to 3125 on weeks 4, 8, and 12 but decreased to 625 at endpoint. 4. Discussion In this study, anti-exenatide antibody formation did not increase the incidence of TEAEs in patients re-exposed to exenatide. In previous exenatide clinical trials [3,4,8,12], patients naı¨ve to exenatide were monitored for anti-exenatide antibody formation. In previous exenatide clinical trials, anti-exenatide antibody formation was not predictive of glycemic effects of exenatide in individual patients [10]. Moreover, in these trials, most patients who developed anti-exenatide antibodies had decreased antibody titers over time [1]. Similar findings with respect to safety were found in the parent and current trials. However, due to the study design limitations, a clear relationship between TEAEs and anti-exenatide antibody status is difficult to determine because of the overall imbalance between the numbers of ab+ and ab patients. It is of interest to note that in this trial ab+ status was not associated with increased TEAEs and did not strongly support an immune-related etiology. In fact, patients with higher titers had a lower incidence of TEAEs and there were very few immune-related AEs observed overall. The results from the current trial did not show an increased risk of clinically serious hypersensitivity reactions in patients reexposed to exenatide. None of the patients with potentially immune-related TEAEs in the re-treatment study reported immune-related TEAEs in the parent study. Although there were some skin-related events that were potentially immune-related, the overall incidence of skin-related events was low. In general, patients who were TE ab+ at endpoint in the parent trials (exenatide naı¨ve) were likely to remain ab+ at endpoint in this study (re-exposure to exenatide). Similarly, patients who were ab
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at endpoint in the parent trials were likely to remain ab at endpoint following exenatide re-treatment. In this trial, greater HbA1c reductions were observed in ab patients compared to ab+ patients. However, the study design limitations (overall sample size and disparity between subgroups) and the dissimilar diabetes treatment at study initiation do not allow for conclusions to be drawn on the HbA1c findings. The changes in HbA1c from baseline to endpoint were disparate for the 3 patients with endpoint titers 625. HbA1c increased in 2 out of these 3 patients by 0.4% and 2.5%, and decreased in the third patient by 0.9%. The antibody titers of the patients with the largest changes in HbA1c increased equally during the study but decreased at endpoint. Thus, the presence of higher antibody titers was not predictive of the magnitude of exenatide’s glycemic effect in individual patients, because despite having similar changes in antibody titers, these 2 patients had opposite changes in HbA1c. Moreover, previous exenatide clinical trials have shown that antiexenatide antibody formation was not predictive of exenatide’s glycemic effects [10]. 5. Conclusion This is the first study that explored the safety of exenatide reexposure in patients who had discontinued exenatide treatment. Given the known immune responses to treatment with other therapeutic peptides [9,5], it was important to determine whether exenatide re-exposure could result in treatment-emergent reactions. Although the study was not powered to show statistical significance, the results of this study did not indicate that there was an increased risk of clinically serious hypersensitivity reactions in patients re-exposed to exenatide. The results from this study do not indicate an increased risk of clinically important adverse events with exenatide re-exposure. Acknowledgments The study was funded by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company. PF has received honoraria from Eli Lilly and Company for conducting clinical trials. RB is former employee of Eli Lilly and Company. JB and TI are employees and stockholders of Eli Lilly and Company. The authors would like to thank Ken F. Mace for providing his expert opinion in writing this manuscript, and Keyla Brooks, Justin Northrup and Maria C. Jimenez for their technical support in preparing this manuscript. The authors also wish to thank the clinical site investigators: Anthony Roberts, Australia; Thomas Elliott, Canada; Irene Hramiak, Canada; Stuart Ross, Canada; Mihaly Dudas, Hungary; Peter Faludi, Hungary; Tamas Oroszlan, Hungary; Renato Lauro, Italy; Geremia Bolli, Italy; Antonio Pontiroli, Italy; Bong-Soo Cha, Korea; Moon-Kyu Lee, Korea; Hak-Chul Jang, Korea; and Kun Ho Yoon, Korea for their valuable expertise and contribution in conducting the study. References [1] BYETTA1 (exenatide) injection, Prescribing information. http://www.byetta. com, 2009. [2] Barnett AH, Burger J, Johns D, Brodows R, Kendall DM, Roberts A, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther 2007;29:2333–48. [3] Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylureatreated patients with type 2 diabetes. Diabetes Care 2004;27:2628–35. [4] DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28: 1092–100. [5] Di MU, Arduini P, Tiberti C, Lombardi G, Pietravalle P, Andreani D. Immunogenicity of biosynthetic human insulin. Humoral immune response in diabetic
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patients beginning insulin treatment and in patients previously treated with other insulins. Diabetes Res Clin Pract 1986;2:317–24. [6] Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402–5. [7] Gao Y, Yoon KH, Chuang LM, Mohan V, Ning G, Shah S, et al. Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea. Diabetes Res Clin Pract 2009;83:69–76. [8] Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients
[9]
[10] [11] [12]
with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083–91. Marcos C, Cuesta J, Cuevas M, Balsa J, Fraj J, Alvarez-Cuesta E. Specific IgE antibody response to human insulin in diabetic subjects. Allergol Immunopathol (Madr) 1993;21:141–4. Schnabel CA, Fineberg SE, Kim DD. Immunogenicity of xenopeptide hormone therapies. Peptides 2006;27:1902–10. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2000;284:3043–5. Zinman B, Hoogwerf BJ, Duran GS, Milton DR, Giaconia JM, Kim DD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2007;146:477–85.
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
Brief communication
The effect of exenatide re-exposure on safety and efficacy Peter Faludi a, Robert Brodows b, Jude Burger b, Tibor Ivanyi c, Daniel K. Braun b,* a
Uzsoki Hospital, Uzsoki utca 29-41, Budapest 1145, Hungary Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA c Eli Lilly and Company, Budapest, Hungary b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 May 2009 Received in revised form 22 June 2009 Accepted 23 June 2009 Available online 1 July 2009
Exenatide, a synthetic peptide originally isolated from salivary secretions of Heloderma suspectum, like other subcutaneously injected peptides, can cause antibody formation. Despite that antibody formation has been observed in some patients, results from previous clinical trials have not shown safety and efficacy concerns in exenatide-naı¨ve patients. The objective of this multicenter, open-label study was to investigate the response of anti-exenatide antibody formation and the incidence of immune-related and hypersensitivity reactions after exenatide re-exposure. Fifty-eight patients (57% male; 59 10 years; weight 85 19 kg; HbA1c 8.1 0.9%; duration of diabetes 10 5 years) were enrolled. At study initiation, 98.3% of patients were taking 1 or more antidiabetes drugs, including oral medication and various types of insulin. Treatment-emergent adverse events (TEAEs) at any time during the study were observed in 40 and 47% of patients with positive and negative treatment-emergent antibodies, respectively. Immune-related AEs were observed in 6 patients (4 were antibody positive). These AEs had not been reported in their previous exposure to exenatide. Re-exposure to exenatide did not result in increased hypersensitivity reactions. Overall, 72% of patients had a baseline to endpoint reduction in HbA1c (range 0.1 to 2.8%), and 87% of antibody negative versus 62% of antibody positive patients had an HbA1c endpoint reduction. The study design and the patients’ baseline characteristics, including diabetes treatment at study initiation, are confounding factors limiting clinical conclusions on exenatide’s glycemic effect in this patient population. The study results indicate that anti-exenatide antibody formation did not increase the incidence of TEAEs in patients re-exposed to exenatide. ß 2009 Elsevier Inc. All rights reserved.
1. Introduction Exenatide is a glucagon-like peptide 1 (GLP-1) receptor agonist that was approved in 2005 in the United States as adjuvant therapy for the treatment of type 2 diabetes. Exendin-4 (exenatide) was originally isolated from the salivary secretions of Heloderma suspectum (Gila monster) [6]. Consistent with the potentially immunogenic properties of protein therapeutics, their administration is often associated with antibody formation, such as the observed antibody formation resulting from insulin administration [5,9,10]. Results from previous exenatide clinical trials have shown that 41–49% of patients developed anti-exenatide antibodies, which were of titers of 125 [3,4,8,12]. In these trials, the presence of anti-exenatide antibodies was not predictive of exenatide’s glycemic effects in individual patients [10]. In most patients who developed anti-exenatide antibodies, the antibody titers decreased over time [1]. The effect of antibody formation on the safety and
* Corresponding author. Tel.: +1 317 277 6530; fax: +1 317 433 1021. E-mail address: [email protected] (D.K. Braun). 0196-9781/$ – see front matter ß 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2009.06.026
efficacy of exenatide following a period of treatment interruption has not been studied. It is important to determine whether reexposure to exenatide leads to excessive anti-exenatide antibody formation and whether as a result, hypersensitivity reactions are observed. The objective of this study was to evaluate whether reexposure to exenatide and any subsequent antibody formation resulted in safety issues, particularly immune-related and hypersensitivity reactions in patients who had stopped taking exenatide for at least 2 months. 2. Materials and methods In this Phase 3b, open-label, single-arm, multicenter, 24-week study, patients were eligible for study inclusion if they had been treated with exenatide in a past clinical trial (referred to in this manuscript as parent studies) [2,7,12]. Study participants were eligible for inclusion if they had a glycosylated hemoglobin (HbA1c) value 10.5% and had not been exposed to exenatide for at least 2 months prior to enrollment in this trial. Patients who were on fixed-dose combinations of sulfonylurea (SU) and metformin were switched to comparable doses of the individual drug
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P. Faludi et al. / Peptides 30 (2009) 1771–1774
components at treatment initiation. Patients who used basal insulin were asked to maintain their established insulin dose for the duration of the study, whereas patients who used rapid acting insulin or an insulin mixture were asked to decrease their established insulin dose by 25% at study initiation. SU and insulin dose were reduced in response to hypoglycemic events. Exenatide was administered twice daily by subcutaneous injection within 60 min of the morning and evening meals. Patients received 5 mg twice daily for the first 4 weeks of treatment and 10 mg for the remaining 20 weeks of treatment. A common clinical protocol study was approved for each site by an Institutional Review Board in accordance with the principles described in the Declaration of Helsinki, as revised in 2000 [11]. All patients participating in the study provided written informed consent prior to enrollment. The primary endpoint of the study was to assess the antibody response to exenatide re-exposure as measured by anti-exenatide antibodies and incidence of pre-defined treatment-emergent allergy and hypersensitivity reactions. The antibody status of post-dose subject samples was determined by a validated screening assay relative to the pre-dose control samples. Positive samples were then titrated, and antibody titers were reported at 1:5 dilutions starting at a titer level of 1:25, then 125, 625, etc. The criterion for negative antibody status at baseline was defined as a titer level of <25. Treatment-emergent antibody formation was defined as positive (TE ab+) if the patient experienced a change in antibody titer levels from baseline, and negative (ab ) if there was no change in antibody titers. Treatment-emergent ab status at different study time points were reported because antibody status could change for individual patients throughout the trial. For example, a patient who was ab at trial initiation may have become ab+ during the trial, and then could have returned to baseline levels by the end of the trial (ab classification at endpoint). A secondary endpoint was to examine the effect of antiexenatide antibody formation on clinical efficacy, specifically, changes in HbA1c. A minimum of 50 patients were planned for inclusion and power calculations were not considered for this study. Descriptive statistics were used to represent the data for the primary and secondary endpoints. Analyses were performed on intent to treat (ITT) patients who had evaluable post-baseline anti-exenatide antibody titers. 3. Results Baseline characteristics of patients were: 57% male, age 59 10 years, body weight 85 19 kg, HbA1c 8.1 0.9%, duration of diabetes 10 5 years, and 78% Caucasian/22% East Asian. The duration of days that patients had been off exenatide treatment since completion of the parent trials ranged from 240 to 1074 days. At study initiation, 98.3% of patients were taking 1 or more antidiabetes drugs, including oral medication and insulin. At study initiation, patients were treated with biguanides (65.5%), SU (58.6%), thiazolidinediones (10.3%), alpha-glucosidase inhibitors (3.4%), or a combination of oral antidiabetes agents (12.1%). The percentage of patients treated with insulins and insulin analogs was 36.2%. Of the 58 patients who enrolled in the study (ITT population), 55 patients completed the study, 2 patients discontinued due to subject decision, and 1 due to sudden death (not related to exenatide treatment). The patient who died did not have a postbaseline antibody measure and was not included in the endpoint analyses. At baseline, 50 (86%) patients were ab and 8 (14%) were ab+ (titers 125, n = 8; titers 625, n = 0). The number of patients who had ab and ab+ status at any time during the study were 15 (26%) and 42 (74%); titers 125, n = 25; titers 625, n = 17, respectively. At endpoint, 23 (40%) patients were ab and 34 (60%)
Fig. 1. Number of patients with antibody titers of <25, 125, and 625 in the parent and the current trials at baseline and endpoint are shown above. The number of patients with maximum titer values is also shown for the parent and current trials. Four percent of patients in the parent trials had anti-exenatide antibody titers 125 at baseline, suggesting that these patients were false-positive for anti-exenatide antibodies.
were ab+ (titers 125, n = 31; titers 625, n = 3). In the parent trials, 31 patients were TE ab+ at endpoint and 27 of these patients were also ab+ at endpoint in this re-treatment study. Out of the 26 patients who were ab at endpoint in the parent trials, 19 were also ab in the re-treatment study. The number of patients with antibody titers in the parent and the current trials at baseline and endpoint are shown in Fig. 1. Similar percentages of patients in the TE ab+ and ab groups (40% [17/42] vs. 47% [7/15], respectively) experienced at least 1 treatment-emergent adverse event (TEAE) at any time during the study. The incidence of TEAEs is summarized by ab status in Table 1. Of those patients with TE ab+ status, TEAEs were observed at any time during the study in 44% (11/25) of patients with antibody titers of 125 compared with 35% (6/17) of patients with antibody titers of 625. Four patients reported 5 TEAEs which were possibly related (as assessed by the investigator) to exenatide; eye allergy (n = 1), injection site pruritus (n = 1), injection site rash (n = 1), diarrhea (n = 1) and vomiting (n = 1). Six patients reported at least 1 potentially immune-related TEAE. Arthralgia (n = 1) and spinal osteoarthritis (n = 1) were observed in 2 ab patients. Four ab+ patients reported either injection site pruritus (n = 2), injection site rash (n = 1) and rash (n = 1), and 1 of the patients with injection site pruritus also reported the event of eye allergy. None of the patients with potentially immune-related TEAEs in the re-treatment study reported immune-related TEAEs in the parent study. Two serious adverse events (SAEs) were reported during this study, one sudden death (unattended, unknown origin) which occurred prior to establishing postbaseline antibody status. One patient with TE ab+ status experienced a malignant hepatic neoplasm. Both SAEs were determined by the investigator to not be related to exenatide. Overall, 72% of patients had a baseline to endpoint reduction in HbA1c (range 0.1 to 2.8%), and 87% of ab versus 62% of ab+ patients had an HbA1c reduction at endpoint. The mean changes in HbA1c from baseline to endpoint were 0.9 0.8% (mean SD) for ab status at endpoint (n = 23) and 0.2 0.9 for patients with ab+ status at endpoint (n = 34). At endpoint, mean HbA1c changes of 0.3 0.8% and +0.7 1.7% were observed in the 125 (n = 31) and 625 (n = 3) antibody subgroups, respectively. The changes from
P. Faludi et al. / Peptides 30 (2009) 1771–1774 Table 1 Treatment-emergent adverse events by antibody status. Treatment-emergent antibody status (ITT patients = 58)a
Patients with 1 TEAE Nasopharyngitis Influenza Injection site pruritus Toothache Viral infection Diarrhea Cough Eye allergy Headache Hepatic neoplasm malignant Injection site rash Lower respiratory tract infection Non-cardiac chest pain Pharyngolaryngeal pain Rash Respiratory tract infection Respiratory tract infection viral Rotator cuff repair Sinusitis Upper respiratory tract infection Arthralgia
Negative (n = 15), n (%)
Positive (n = 42), n (%)
7 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1
17 (40.5) 2 (4.8) 2 (4.8) 2 (4.8) 2 (4.8) 2 (4.8) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 1 (2.4) 0 (0)
(46.7) (6.7) (0) (0) (0) (0) (6.7) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (6.7)
The data presented show TEAEs at any time during the study organized by antibody status. a One patient did not have a post-baseline antibody measure and was not included in the table.
baseline to endpoint in HbA1c of the 3 patients with titer levels 625 at endpoint were +0.4%, +2.5%, and 0.9%. In this group, the antibody titers of the patients with the largest increase and greatest reduction in HbA1c increased to 3125 on weeks 4, 8, and 12 but decreased to 625 at endpoint. 4. Discussion In this study, anti-exenatide antibody formation did not increase the incidence of TEAEs in patients re-exposed to exenatide. In previous exenatide clinical trials [3,4,8,12], patients naı¨ve to exenatide were monitored for anti-exenatide antibody formation. In previous exenatide clinical trials, anti-exenatide antibody formation was not predictive of glycemic effects of exenatide in individual patients [10]. Moreover, in these trials, most patients who developed anti-exenatide antibodies had decreased antibody titers over time [1]. Similar findings with respect to safety were found in the parent and current trials. However, due to the study design limitations, a clear relationship between TEAEs and anti-exenatide antibody status is difficult to determine because of the overall imbalance between the numbers of ab+ and ab patients. It is of interest to note that in this trial ab+ status was not associated with increased TEAEs and did not strongly support an immune-related etiology. In fact, patients with higher titers had a lower incidence of TEAEs and there were very few immune-related AEs observed overall. The results from the current trial did not show an increased risk of clinically serious hypersensitivity reactions in patients reexposed to exenatide. None of the patients with potentially immune-related TEAEs in the re-treatment study reported immune-related TEAEs in the parent study. Although there were some skin-related events that were potentially immune-related, the overall incidence of skin-related events was low. In general, patients who were TE ab+ at endpoint in the parent trials (exenatide naı¨ve) were likely to remain ab+ at endpoint in this study (re-exposure to exenatide). Similarly, patients who were ab
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at endpoint in the parent trials were likely to remain ab at endpoint following exenatide re-treatment. In this trial, greater HbA1c reductions were observed in ab patients compared to ab+ patients. However, the study design limitations (overall sample size and disparity between subgroups) and the dissimilar diabetes treatment at study initiation do not allow for conclusions to be drawn on the HbA1c findings. The changes in HbA1c from baseline to endpoint were disparate for the 3 patients with endpoint titers 625. HbA1c increased in 2 out of these 3 patients by 0.4% and 2.5%, and decreased in the third patient by 0.9%. The antibody titers of the patients with the largest changes in HbA1c increased equally during the study but decreased at endpoint. Thus, the presence of higher antibody titers was not predictive of the magnitude of exenatide’s glycemic effect in individual patients, because despite having similar changes in antibody titers, these 2 patients had opposite changes in HbA1c. Moreover, previous exenatide clinical trials have shown that antiexenatide antibody formation was not predictive of exenatide’s glycemic effects [10]. 5. Conclusion This is the first study that explored the safety of exenatide reexposure in patients who had discontinued exenatide treatment. Given the known immune responses to treatment with other therapeutic peptides [9,5], it was important to determine whether exenatide re-exposure could result in treatment-emergent reactions. Although the study was not powered to show statistical significance, the results of this study did not indicate that there was an increased risk of clinically serious hypersensitivity reactions in patients re-exposed to exenatide. The results from this study do not indicate an increased risk of clinically important adverse events with exenatide re-exposure. Acknowledgments The study was funded by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company. PF has received honoraria from Eli Lilly and Company for conducting clinical trials. RB is former employee of Eli Lilly and Company. JB and TI are employees and stockholders of Eli Lilly and Company. The authors would like to thank Ken F. Mace for providing his expert opinion in writing this manuscript, and Keyla Brooks, Justin Northrup and Maria C. Jimenez for their technical support in preparing this manuscript. The authors also wish to thank the clinical site investigators: Anthony Roberts, Australia; Thomas Elliott, Canada; Irene Hramiak, Canada; Stuart Ross, Canada; Mihaly Dudas, Hungary; Peter Faludi, Hungary; Tamas Oroszlan, Hungary; Renato Lauro, Italy; Geremia Bolli, Italy; Antonio Pontiroli, Italy; Bong-Soo Cha, Korea; Moon-Kyu Lee, Korea; Hak-Chul Jang, Korea; and Kun Ho Yoon, Korea for their valuable expertise and contribution in conducting the study. References [1] BYETTA1 (exenatide) injection, Prescribing information. http://www.byetta. com, 2009. [2] Barnett AH, Burger J, Johns D, Brodows R, Kendall DM, Roberts A, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther 2007;29:2333–48. [3] Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylureatreated patients with type 2 diabetes. Diabetes Care 2004;27:2628–35. [4] DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28: 1092–100. [5] Di MU, Arduini P, Tiberti C, Lombardi G, Pietravalle P, Andreani D. Immunogenicity of biosynthetic human insulin. Humoral immune response in diabetic
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patients beginning insulin treatment and in patients previously treated with other insulins. Diabetes Res Clin Pract 1986;2:317–24. [6] Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402–5. [7] Gao Y, Yoon KH, Chuang LM, Mohan V, Ning G, Shah S, et al. Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea. Diabetes Res Clin Pract 2009;83:69–76. [8] Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients
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