alexa Orally-Administered Chemokine Receptor CCR2 Antagonist CCX140-B in Type 2 Diabetes: A Pilot Double-Blind, Randomized Clinical Trial | Open Access Journals
ISSN: 2155-6156
Journal of Diabetes & Metabolism
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Orally-Administered Chemokine Receptor CCR2 Antagonist CCX140-B in Type 2 Diabetes: A Pilot Double-Blind, Randomized Clinical Trial

Markolf Hanefeld1, Ernest Schell2, Ioanna Gouni-Berthold3, Martin Melichar4, Ivana Vesela5, Dan Johnson6, Shichang Miao6, Tim J Sullivan6, Juan C Jaen6, Thomas J Schall6, Pirow Bekker6* and The CCX140-B Diabetes Study Group7

1Center for Clinical Studies in Endocrinology and Metabolic Disorders, Dresden, Germany

2Luedwigstr, Nuremberg, Germany

3Center of Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany

4Internal Medicine Outpatient Clinic, Pardubice, Czech Republic

5Internal Medicine and Diabetes Outpatient Clinic, Unicov, Czech Republic

6ChemoCentryx Inc, Mountain View, CA, USA

7See Appendix for complete list of study investigators

*Corresponding Author:
Pirow Bekker
ChemoCentryx Inc, 850 Maude Avenue
Mountain View, CA 94043, USA
Tel: 650-210-2924
Fax: 650-210-2910
E-mail: [email protected]

Received date: October 03, 2012; Accepted date: October 27, 2012; Published date: November 02, 2012

Citation: Hanefeld M, Schell E, Gouni-Berthold I, Melichar M, Vesela I, et al. (2012) Orally-Administered Chemokine Receptor CCR2 Antagonist CCX140-B in Type 2 Diabetes: A Pilot Double-Blind, Randomized Clinical Trial. J Diabetes Metab 3:225. doi:10.4172/2155-6156.1000225

Copyright: © 2012 Hanefeld M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



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Abstract

Study background: Inflammatory macrophages expressing the C-C chemokine receptor 2 (CCR2) accumulate in adipose tissue and contribute to insulin resistance. CCX140-B is an orally-administered antagonist of CCR2 expressed on monocytes and macrophages and blocks infiltration of these cells into adipose tissue. A pilot Phase 2 clinical trial was conducted in patients with type 2 diabetes with the primary objective to evaluate the safety and tolerability of CCX140-B. Key secondary objectives included assessment of glycemic parameters, fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c).

Methods: This is a randomized, double-blind, clinical trial of CCX140-B in 159 subjects with type 2 diabetes on stable metformin for at least 8 weeks prior to study entry. HbA1c was 6.5 to 10% and FPG 135 to 270 mg/dL at study entry. Randomized subjects received double-blind placebo (N=32), 5 mg CCX140-B (N=63), 10 mg CCX140-B (N=32), or pioglitazone 30 mg (N=32) once daily orally for 4 weeks, with a 4-week follow-up period.

Results: CCX140-B was well tolerated. No serious adverse events occurred with CCX140-B. FPG showed a CCX140-B dose-dependent decrease, with 10 mg CCX140-B showing a similar decrease to pioglitazone (leastsquares mean change at week 4 of -16.1 vs. -21.4 mg/dL, respectively). HbA1c least-squares mean changes from baseline to week 4 for the placebo, 5 mg CCX140-B, 10 mg CCX140-B, and pioglitazone groups were -0.09%, -0.09%, -0.23% (p=0.045 vs. placebo), and -0.13% (NS vs. placebo), respectively. No detrimental changes were seen in plasma monocyte chemoattractant protein-1 or blood monocyte counts with CCX140-B.

Conclusion: CCX140-B, an orally administered, specific CCR2 antagonist was found to be well tolerated and safe in this Phase 2 clinical trial and showed evidence of a beneficial effect on glycemic parameters. If confirmed, CCX140-B might be beneficial in treatment of patients with type 2 diabetes. (Clinical Trial Registry: clinicaltrials.gov identifier NCT01028963).

Keywords

Chemokine Receptor 2 (CCR2); CCR2 antagonist; MCP- 1; Chemokine; Chemokine receptor; Type 2 diabetes

Abbreviations

AE: Adverse Event; AUC: Area Under the Curve; CCL2: Chemokine Ligand 2; CCR2: C-C Chemokine Receptor 2; DMC: Data Monitoring Committee; FPG: Fasting Plasma Glucose; HbA1c: Hemoglobin A1c; HDL: High density lipoprotein; HOMA-IR: Homeostasis Mechanism of Insulin Resistance; hsCRP: High Sensitivity C-Reactive Protein; LDL: Low Density Lipoprotein; MCP-1: Monocyte Chemoattractant Protein-1; NEFA: Non-Esterified Fatty Acid; OGTT: Oral Glucose Tolerance Test; SAE: Serious Adverse Event; TC: Total Cholesterol

Introduction

Monocyte chemoattractant protein-1 (MCP-1) also named chemokine ligand 2 (CCL2), a potent chemoattractant for the C-C chemokine receptor 2 (CCR2)-expressing monocytes and macrophages [1,2], has been implicated in the pathogenesis of insulin resistance [3,4]. MCP-1, released by adipocytes, attracts CCR2-expressing monocytes into the adipose tissue where they differentiate into macrophages, leading to low-grade inflammation that contributes to insulin resistance [4].

Mice deficient for CCR2 have reduced macrophage numbers in adipose tissue and display significantly improved metabolic parameters relative to wild-type counterparts [5]. Also, blocking CCR2 with the CCR2 antagonist propargermanium reduces adipose tissue macrophage infiltration, insulin resistance, and glycemia in diet-induced obese C57Bl6 [6], and the CCR2 antagonist RS504393 improves insulin resistance, lipid metabolism, and nephropathy in db/db mice [7]. These preclinical findings provided the basis for testing a CCR2 antagonist in patients with type 2 diabetes.

CCX140-B is an orally-administered, specific CCR2 antagonist. This pilot Phase 2 clinical trial was conducted with the primary objective to evaluate the safety and tolerability of CCX140-B given once daily for 28 days in subjects with type 2 diabetes. Secondary objectives included the evaluation of the anti-glycemic effect of CCX140-B and the pharmacokinetic profile of CCX140-B in these subjects.

Methods

This was a randomized, double-blind, placebo- and activecontrolled parallel group clinical trial conducted at 32 study centers in Australia, Czech Republic, Germany, Hungary, and New Zealand from January 2010 to November 2010. The target enrollment was 140 subjects. Responsible ethics committees at all study centers provided approval of the trial before subject enrollment and the trial was conducted according to the principles of the Declaration of Helsinki as revised in 2000. After obtaining written informed consent, a total of 159 subjects with type 2 diabetes were recruited and randomly assigned, in a 1:2:1:1 ratio, to receive placebo, 5 mg CCX140-B, 10 mg CCX140-B, or 30 mg pioglitazone once daily in 28 days, and then followed for a 28- day washout period without receiving study medication. The treatment duration was limited to 28 days, because, at the time of study launch, only 28-day toxicology data were available for CCX140-B to support dosing in humans. Therefore, only 4-week treatment was allowed by ethics committees and regulatory authorities. An independent Data Monitoring Committee (DMC) reviewed unblinded safety data twice over the course of the trial. No interim analysis for efficacy was performed. The study population included male and post-menopausal or surgically sterile female subjects, aged 18 to 70 years, inclusive, with type 2 diabetes. Subjects had a body mass index of at least 25 kg/m2 but less than 45 kg/m2, HbA1c of 6.5 to 10.0%, inclusive, fasting plasma glucose (FPG) of 135 to 270 mg/dL, inclusive, and were on a stable dose of metformin for at least 8 weeks prior to randomization (no minimum or maximum dose specified). All subjects were on background metformin treatment, because it was considered inappropriate to include subjects who were not on any anti-diabetic treatment in this first proof-of-concept clinical trial. Subjects on lipid-lowering agents were on a stable dose for at least 4 weeks prior to randomization, because one of the study objectives was to evaluate the potential effect of CCX140-B on plasma lipids, and changes in doses of lipid-lowering drugs prior to the dosing period could potentially be confounding.

CCX140-B (the sodium salt of CCX140) was given as hard gelatin capsules containing 2.5 mg CCX140 each. Matching placebo capsules were given to protect the study blind. The subjects in the placebo group received four placebo capsules daily, the 5 mg group received two 2.5 mg CCX140-B and two placebo capsules daily, and the 10 mg group received four 2.5 mg CCX140-B capsules daily. The active comparator group took one pioglitazone hydrochloride 30 mg tablet from commercial supply once daily in an open-label manner.

The primary objective was safety assessment based on adverse event incidence. Other safety assessments included physical examination abnormalities, vital signs changes, and clinical laboratory parameter changes (including chemistry, hematology, and urinalysis). Secondary efficacy parameters included change in FPG concentration and HbA1c. Other measurements included oral glucose tolerance test (OGTT) with insulin, homeostasis assessment of insulin resistance (HOMAIR), fasting plasma insulin, fasting plasma fructosamine, serum total adiponectin, plasma MCP-1, serum high sensitivity C-reactive protein (hsCRP), serum lipids including total cholesterol (TC), high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol, triglycerides (TGs), and non-esterified fatty acids (NEFAs). The pre-specified primary time point of interest was day 29 (end of treatment). Plasma concentrations of CCX140 were measured in samples taken at all post-baseline study visits (Days 8, 15, 22, 29, 36, 43, and 57).

With the planned sample size of 56 and 28 subjects for the 5 mg and 10 mg CCX140-B groups, respectively, a difference of approximately 14 and 17 mg/dL in fasting glucose between each of the active groups, respectively, and placebo could be detected with statistical power of at least 80%, assuming a type I error=0.025 and S.D. of change from baseline=20 mg/dL, to allow for comparison of each of the two CCX140-B groups and placebo. It was estimated that approximately 10% of subjects would not complete the study through day 29.

Eligible subjects were stratified based on MCP-1 polymorphism status (base pair: -2518, G vs. non-G) as well as gender. Subjects were then randomized in a 1:2:1:1 ratio to one of four treatment groups: placebo, CCX140-B 5 mg, CCX140-B 10 mg, or pioglitazone 30 mg once daily. Therefore, twice as many subjects were randomized to the CCX140-B 5 mg group compared to the other treatment groups, because this dose was considered to potentially be the minimally effective dose, based on preclinical results available at the time the trial was designed. The CCX140-B doses of 5 mg and 10 mg were chosen based on data from a diet-induced obese mouse model of diabetes, where blockade of CCR2 resulted in an anti-glycemic effect at plasma concentrations corresponding to anticipated plasma levels-adjusted for relative potency of CCX140-B across species-with 5 or 10mg CCX140-B in humans. The pioglitazone dose of 30 mg was chosen because, according to the label, it was considered the appropriate starting dose to treat patients with type 2 diabetes. Stratification and randomization were performed centrally via an interactive voice/web response system. A blocked randomization schedule was generated pre-study by a biostatistician who was otherwise not involved in the study. To conceal the allocation sequence, placebo and CCX140-B capsules and bottles were identical in appearance and subjects received two bottles of study medication on day 1 and day 15, and were asked to take 2 capsules from each bottle every morning, after an overnight fast of at least 10 hours.

The placebo-controlled part of the study was double-blind. Blinding of the study was achieved by identical study medication bottle and capsule appearance, limited access to the randomization code, and blinding of efficacy data that would potentially have been unblinding, such as FPG results, unless required for safety monitoring.

No inferential statistical analysis was planned or performed on safety data because of the exploratory nature and relatively small size of the trial. The main efficacy hypothesis was that at least one dose of CCX140-B would result in a statistically significant reduction in FPG compared to placebo at Study day 29. This hypothesis was tested using linear contrasts of an analysis of covariance model with treatment group as a factor and baseline FPG as a covariate. All statistical testing was 2-sided, and Dennett’s adjustment was used to control the type I error rate at α=0.05. The primary efficacy analysis was performed in the Intent-to-Treat population. If the model was determined not to be appropriate due to non-normality of residuals, the Wilcoxon Rank Sum test was to be used to compare the CCX140-B dose groups to the placebo group.

The OGTT was conducted on day 1 (prior to the first dose) and day 29 as follows: After an overnight fast of at least 10 hours, an oral dose of 75 g of glucose in 1 cup (240 mL) of water was given in the morning and was consumed within 5 minutes. Blood samples for plasma glucose and insulin measurements were taken at time 0 (just before the glucose was taken), and at 30, 60, 90, 120, and 180 minutes after the glucose dose. Areas under the curve (AUCs) were calculated for each subject’s glucose and insulin profiles following the oral dose of glucose before treatment (Study day 1) and after treatment (Study day 29). The changes in AUC across treatment groups were compared. The rest of the efficacy variables were analyzed in a similar manner as FPG, i.e., based on change from baseline, except for serum lipids for which percentage change from baseline was analyzed.

Results

A flow diagram of screened and randomized subjects is shown in Figure 1. Most subjects (152 (96%)) completed the study. Three subjects were excluded from the intent-to-treat population, one each in the placebo and 10 mg CCX140-B groups, because their medications were accidentally switched for the first 2 weeks of the trial, while a third subject, in the pioglitazone group, was excluded because the subject did not receive any study medication.

diabetes-metabolism-subject-disposition

Figure 1: Subject disposition. A total of 293 subjects were assessed for eligibility for the clinical trial. Of these, 134 (46%) were excluded, mostly due to fasting plasma glucose or HbA1c not being high enough. Of the 159 subjects who were eligible, 32, 63, 32, and 32 subjects were randomized into the placebo, 5mg, 10mg CCX140-B, and 30mg pioglitazone groups, respectively. Three subjects were excluded from the intent-to-treat population because of study medication being switched accidentally (1 each in the placebo and 10mg groups) and one subject who withdrew consent before receiving any study medication (pioglitazone group). There were 7 early withdrawals from the study, 3 in the 5mg CCX140-B group, and 2 each in the 10mg CCX140-B and pioglitazone groups. The two adverse events leading to withdrawal were one event of dyspepsia in the 5mg CCX140-B group and one event of gouty arthritis in the 10mg CCX140-B group.

Eligible subjects were recruited from January 2010 until September 2010.

Baseline demographics and characteristics are presented in Table 1. The treatment groups were comparable with respect to demographic and baseline characteristics, except that the placebo group had a higher mean baseline FPG (182.9 mg/dL) compared to the other treatment groups (166.0 mg/dL in the CCX140-B 5 mg group, 163.1 mg/dL in the CCX140-B 10 mg group, and 169.8 mg/dL in the pioglitazone group). Due to the inclusion criterion regarding BMI, the majority of subjects were obese with an average BMI of 32.1 (± 4.4) kg/m2.

  Placebo (N=32) 5mg CCX140-B (N=63) 10mg CCX140-B (N=32) 30mgPioglitazone (N=32) All (N=159)
Mean ± SD age—yr 58.5 ± 8.02 58.8 ± 6.36 57.5 ± 5.51 60.0 ± 6.36 58.7 ± 6.56
Male—no. (%) 20 (62.5) 40 (63.5) 21 (65.6) 20 (62.5) 101 (63.5)
Race—no. (%)
Caucasian
Asian
Black/African
Other

32 (100.0)
0
0
0

62 (98.4)
1 (1.6)
0
0

30 (93.8)
1 (3.1)
0
1 (3.1)

31 (96.9)
0
1 (3.1)
0

155 (97.5)
2 (1.3)
1 (0.6)
1 (0.6)
Mean ± SD body mass index—kg/m2) 32.4 ± 4.04 32.3 ± 4.58 32.1 ± 4.30 31.3 ± 4.68 32.1 ± 4.42
Mean ± SD waist circumference—cm 107.8 ± 11.56 107.7 ± 12.59 106.7 ± 13.21 105.3 ± 10.83 107.1 ± 12.12
Mean ± SD diabetes duration—months 81.0 ± 60.41 83.7 ± 66.43 75.3 ± 57.91 89.4 ± 52.62 82.6 ± 60.58
MCP-1 base pair at -2518 position = GG or AG—no. (%) 14 (43.8%) 30 (47.6%) 15 (46.9%) 15 (46.9%) 74 (46.5%)
Mean ± SD FPG—mg/dL 182.9 ± 52.95 166.0 ± 34.23 163.1 ± 37.08 169.8 ± 40.40 169.6 ± 40.61
Mean ± SD fasting insulin—mIU/L 18.0 ± 11.86 16.6 ± 16.18 17.9 ± 17.48 13.5 ± 8.27 16.5 ± 14.38
Mean ± SD total adiponectin—mg/mL 6.4 ± 3.67 6.2 ± 3.34 6.4 ± 2.73 6.2 ± 3.58 6.2 ± 3.32
Mean ± SD HOMA-IR 8.5 ± 6.62 7.2 ± 8.64 7.3 ± 7.00 5.7 ± 3.49 7.2 ± 7.14
Mean ± SD HbA1c— % 7.6 ± 1.00 7.4 ± 0.74 7.3 ± 0.81 7.6 ± 0.86 7.5 ± 0.83
Mean ± SD fructosamine— μmol/L 291.6 ± 51.60 285.3 ± 36.48 286.3 ± 43.47 289.6 ± 36.05 287.6 ± 40.87
Mean ± SD plasma MCP-1—pg/mL 444.9 ± 129.72 432.0 ± 138.35 383.8 ± 78.19 420.7 ± 81.13 423.0 ± 117.87
Mean ± SD C-reactive protein— mg/L 4.3 ± 6.00 6.3 ± 11.63 3.2 ± 2.91 6.9 ± 9.58 5.4 ± 9.11

Table 1: Demographics and baseline characteristics of the study population.

Regarding the primary study objective, evaluation of the safety and tolerability of CCX140-B in subjects with type 2 diabetes, no serious adverse events (SAEs) were observed in subjects receiving CCX140-B. One subject, in the placebo group, experienced an SAE of syncope of unknown origin for which the subject was hospitalized. Two subjects withdrew from the study due to a treatment-emergent adverse event (AE). One subject, in the CCX140-B 5 mg group, experienced an AE of dyspepsia, which led to discontinuation of study medication. Another subject, in the CCX140-B 10 mg group, experienced an AE of gouty arthritis, which led to discontinuation of study medication. This subject had a medical history of gout. In Table 2, AEs reported by at least 3% of subjects in any treatment group during the 28-day treatment period are shown. Changes in safety laboratory parameters, vital signs, and ECGs were not clinically meaningful (data not shown). After review of safety data at two time points during the study, the DMC recommended on both occasions to continue the study unchanged.

System Organ Class Preferred Term Placebo (N=32) 5mg CCX140-B (N=63) 10mg CCX140-B (N=32) 30mgPioglitazone (N=32)
Subjects reporting any adverse events—no. (%) 6 (19.4) 19 (30.2) 6 (19.4) 7 (22.6)
Subjects with adverse events by system organ class with an incidence of ≥ 3% in any treatment group—no. (%)
Gastrointestinal disorders 2 (6.5) 10 (15.9) 1 (3.2) 2 (6.5)
Nausea 0 (0.0) 1 (1.6) 1 (3.2) 0 (0.0)
Constipation 0 (0.0) 2 (3.2) 0 (0.0) 0 (0.0)
Diarrhea 1 (3.2) 2 (3.2) 0 (0.0) 2 (6.5)
Dry mouth 1 (3.2) 1 (1.6) 0 (0.0) 0 (0.0)
Dyspepsia 0 (0.0) 2 (3.2) 0 (0.0) 0 (0.0)
Flatulence 0 (0.0) 2 (3.2) 0 (0.0) 0 (0.0)
Infections 3 (9.7) 3 (4.8) 1 (3.2) 1 (3.2)
Nasopharyngitis 2 (6.5) 1 (1.6) 1 (3.2) 0 (0.0)
Influenza 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.2)
Urinary tract infection 1 (3.2) 1 (1.6) 0 (0.0) 0 (0.0)
Nervous system disorders 2 (6.5) 2 (3.2) 1 (3.2) 2 (6.5)
Headache 1 (3.2) 0 (0.0) 1 (3.2) 1 (3.2)
Dizziness 1 (3.2) 2 (3.2) 0 (0.0) 1 (3.2)
Syncope 1 (3.2) 0 (0.0) 0 (0.0) 0 (0.0)
General disorders and administration site conditions 1 (3.2) 2 (3.2) 1 (3.2) 1 (3.2)
Fatigue 1 (3.2) 1 (1.6) 1 (3.2) 0 (0.0)
Edema peripheral 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.2)
Investigations 2 (6.5) 2 (3.2) 0 (0.0) 0 (0.0)
Liver palpable subcostal 1 (3.2) 0 (0.0) 0 (0.0) 0 (0.0)
Occult blood positive 1 (3.2) 0 (0.0) 0 (0.0) 0 (0.0)
Musculoskeletal and connective tissue disorders 0 (0.0) 1 (1.6) 1 (3.2) 2 (6.5)
Gouty arthritis 0 (0.0) 0 (0.0) 1 (3.2) 0 (0.0)
Back pain 0 (0.0) 0 (0.0) 0 (0.0) 2 (6.5)
Vascular disorders 0 (0.0) 4 (6.3) 0 (0.0) 0 (0.0)
Hypertension 0 (0.0) 3 (4.8) 0 (0.0) 0 (0.0)
Metabolism and nutrition disorders 0 (0.0) 2 (3.2) 0 (0.0) 1 (3.2)
Hypoglycemia 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.2)
Skin and subcutaneous tissue disorders 1 (3.2) 1 (1.6) 1 (3.2) 0 (0.0)
Pruritus 0 (0.0) 0 (0.0) 1 (3.2) 0 (0.0)
Rash papular 1 (3.2) 0 (0.0) 0 (0.0) 0 (0.0)

Table 2: Summary of treatment-emergent adverse events during the treatment period .

Regarding the efficacy endpoints, the fasting plasma glucose levels over the course of the study are shown in Figure 2A. The FPG profiles indicate a CCX140-B dose-dependent decrease from baseline through day 29, with larger decreases observed during the 4-week treatment period with 10 mg than with 5 mg CCX140-B once daily. The leastsquares mean change from baseline to day 29 (with the last observation carried forward) for FPG was -10.7, -4.3, -16.1 and -21.4 mg/dL in the placebo, CCX140-B 5 mg, CCX140-B 10 mg groups, and pioglitazone groups, respectively (Table 3). The 10 mg CCX140-B and pioglitazone group least-squares mean decreases in FPG were comparable (-16.1 and -21.4 mg/dL, respectively; Table 3).

    Placebo (N=31) 5 mg CCX140-B (N=63) 10 mg CCX140-B (N=31) 30 mg Pioglitazone (N=31)
FPG (mg/dL) Baseline 183.9 (9.61) 166.0 (4.38) 163.3 (6.77) 169.8 (7.26)
  Change to Day 29a -10.7 (4.55) -4.3 (3.18) -16.1 (4.51) -21.4 (4.49)
  Difference from Placebob   6.4 (-6.7, 19.6) -5.3 (-20.5, 9.9) -10.7 (-25.8, 4.4)
HbA1c (%) Baseline 7.58 (0.180) 7.38 (0.095) 7.33 (0.157) 7.54 (0.153)
  Change to Day 29 -0.09 (0.050) -0.09 (0.035) -0.23 (0.052) -0.13 (0.051)
  Difference from Placebo   0.00 (-0.14, 0.15) -0.14 (-0.31, 0.03)c -0.04 (-0.21, 0.12)
Fructosamine (mmol/L) Baseline 291.5 (9.27) 284.1 (4.58) 286.2 (8.73) 289.4 (6.69)
  Change to Day 29 0.7 (4.12) -3.8 (2.94) -3.6 (4.41) -10.6 (4.19)
  Difference from Placebo   -4.6 (-16.5, 7.4) -4.3 (-18.6, 10.0) -11.4 (-25.3, 2.5)
OGTT Glucose AUC (mg/dL•hr) Baseline 840 (33.5) 801 (22.7) 771 (28.5) 809 (32.9)
  Change to Day 29 -35 (16.8) -18 (12.2) -29 (18.4) -115 (17.0)
  Difference from Placebo   17 (-32, 66) 6 (-53, 65) -80 (-136, -22)d
OGTT Insulin AUC (mIU/mL•hr) Baseline 142 (31.2) 126 (12.2) 130 (16.4) 135 (36.4)
  Change to Day 29 -8.4 (10.4) -8.4 (7.3) 9.7 (11.2) -33.5 (10.2)
  Difference from Placebo   0 (-30, 30) 18 (-18, 54) -25 (-59, 10)
Fasting Plasma Insulin (mIU/mL) Baseline 18.0 (2.17) 15.3 (1.64) 17.9 (3.19) 13.3 (1.54)
  Change to Day 29 -1.8 (1.23) -0.7 (0.87) -2.5 (1.23) -3.1 (1.25)
  Difference from Placebo   1.1 (-2.5, 4.7) -0.7 (-4.8, 3.4) -1.3 (-5.4, 2.9)
HOMA-IR Baseline 8.5 (1.21) 6.6 (0.98) 7.2 (1.28) 5.6 (0.65)
  Change to Day 29 -1.4 (0.65) -0.5 (0.46) -1.9 (0.65) -1.9 (0.66)
  Difference from Placebo   0.9 (-1.0, 2.8) -0.4 (-2.6, 1.7) -0.4 (-2.6, 1.8)

Table 3: Summary of Glycemic Parameter Outcomes.

The FPG decrease from baseline to day 29 in the two MCP-1 strata in the 10 mg CCX140-B group was similar, 16 mg/dL in the non-G polymorphism stratum and 17 mg/dL in the G stratum. CRP level changes in the 10 mg CCX140-B group over the 4-week treatment period were also similar in the two polymorphism strata: mean CRP changed from 2.9 to 3.2 mg/L (median from 2.0 to 1.6 mg/L) in the non-G stratum; mean CRP changed from 3.5 to 3.0 mg/L (median from 2.2 to 1.8 mg/L) in the G stratum.

The least-squares mean change from baseline in HbA1c was -0.09%, -0.09%, -0.23%, and -0.13% in the placebo, CCX140-B 5 mg, CCX140-B 10 mg, and pioglitazone group, respectively (Figure 2B; Table 3). The 10 mg CCX140-B group decrease was significantly different compared to the placebo group; p=0.045, Wilcoxon Rank Sum test. The fructosamine levels trended to be lower in the active dose groups compared to placebo (Table 3). Treatment with CCX140-B for 28 days in this study was not associated with significant changes from baseline to study day 29 in fasting plasma insulin, fasting HOMA-IR, glucose or insulin OGTT AUC, serum adiponectin, or hsCRP (Tables 3 and 4). The pioglitazone group showed the anticipated decrease in glucose OGTT AUC and hsCRP, an increase in serum adiponectin (Tables 3 and 4). CCX140-B treatment did not negatively affect the serum lipid profiles (TC, HDL and LDL cholesterol, TG, or NEFAs) over the 4-week treatment period. Pioglitazone treatment increased HDL cholesterol, as anticipated (Table 4).

    Placebo (N=31) 5 mg CCX140-B (N=63) 10 mg CCX140-B (N=31) 30 mg Pioglitazone (N=31)
Total adiponectin (mg/mL) Baseline 6.4 (0.66) 6.1 (0.43) 6.3 (0.49) 6.1 (0.65)
  Change to Day 29 -0.5 (0.54) 0.1 (0.38) 0.2 (0.54) 6.3 (0.55)
  Difference from Placebo   0.6 (-0.9, 2.2) 0.8 (-1.0, 2.6) 6.9 (5.1, 8.7)c
Plasma MCP-1 (pg/mL) Baseline 445 (23.3) 431 (17.7) 384 (14.3) 421 (14.8)
  Change to Day 29 11 (12.2) 21 (8.6) 26 (12.5) -27 (12.4)
  Difference from Placebo   9 (-26, 44) 14 (-27, 56) -39 (-80, 3)
CRP (mg/L) Baseline 4.3 (1.08) 6.3 (1.49) 3.2 (0.53) 7.1 (1.76)
  Change to Day 29 -1.2 (0.98) -1.2 (0.69) -1.5 (1.00) -1.2 (1.00)
  Difference from Placebo   0.0 (-2.9, 2.8) -0.3 (-3.6, 3.0) 0.0 (-3.3, 3.3)d
Total Cholesterol (mg/dL) Baseline 180.4 (6.91) 180.4 (4.86) 184.2 (5.53) 182.3 (6.55)
  % Change to Day 29 0.7% (2.64) 0.1% (1.87) -1.9% (2.64) 0.3% (2.64)
  % Difference from Placebo   -0.6% (-8.3, 7.0) -2.6% (-11.4, 6.3) -0.4% (-9.2, 8.4)
HDL cholesterol (mg/dL) Baseline 44.7 (2.35) 45.6 (1.60) 43.8 (2.15) 44.1 (1.68)
  % Change to Day 29 5.2% (2.33) 0.1% (1.65) 3.2% (2.46) 13.1% (2.33)
  % Difference from Placebo   -5.1% (-11.9, 1.6) -1.9% (-9.9, 6.1) 7.9% (0.1, 15.7)e
LDL cholesterol (mg/dL) Baseline 99.7 (5.96) 101.9 (5.06) 98.0 (5.38) 107.4 (5.86)
  % Change to Day 29 2.1% (3.49) -0.4% (2.51) 1.1% (3.77) -0.4% (3.50)
  % Difference from Placebo   -2.5% (-12.7, 7.7) -1.0% (-13.2, 11.1) -2.5% (-14.2, 9.2)
Triglycerides (mg/dL) Baseline 194.9 (16.35) 185.4 (14.48) 205.5 (15.66) 157.6 (14.64)
  % Change to Day 29 -0.2% (6.61) 10.6% (4.67) -0.8% (6.86) -9.3% (6.66)
  % Difference from Placebo   10.8% (-8.3, 29.9) -0.6% (-23.1, 21.9) -9.1% (-31.4, 13.1)
NEFAs (mmol/L) Baseline 0.67 (0.044) 0.67 (0.034) 0.64 (0.048) 0.58 (0.040)
  % Change to Day 29 -1.7% (5.81) 1.4% (4.14) 9.0% (6.11) -17.5% (6.04)
  % Difference from Placebo   3.1% (-13.8, 20.0) 10.7% (-9.3, 30.7) -15.9% (-35.8, 4.1)
Monocyte count (x103/mL) Baseline 0.45 (0.146) 0.46 (0.172) 0.49 (0.167) 0.46 (0.164)
  Day 29 0.42 (0.171) 0.45 (0.155) 0.47 (0.183) 0.44 (0.143)
Hematocrit (%) Baseline 42.5 (3.58) 42.5 (3.37) 42.3 (3.00) 42.0 (3.26)
  Day 29 42.5 (3.51) 41.9 (2.89) 42.1 (2.73) 41.2 (2.58)
Body Weight (kg) Baseline 93.3 (15.6) 94.1 (17.0) 95.1 (19.7) 91.8 (15.9)
  Day 29 93.2 (15.6) 93.7 (17.3) 94.8 (20.0) 91.6 (16.0)

Table 4: Summary of Other Clinical Trial Measurements.

diabetes-metabolism-glycemic-parameters

Figure 2: Glycemic parameters. (A) Fasting plasma glucose (mean, SEM) in the 4 study groups over the course of the 4-week treatment period and the 4-week follow-up period; yellow = placebo (N=31), orange = 5 mg CCX140-B (N=63), maroon = 10 mg CCX140-B (N=31), and green = pioglitazone 30 mg (N=31); (B) Least-squares mean (SEM) change from baseline to Day 29 (Week 4) in HbA1c in the 4 study groups. The least-squares mean change from baseline in HbA1c was -0.09%, -0.09%, -0.23%, and -0.13% in the placebo, CCX140-B 5mg, CCX140-B 10mg groups, and pioglitazone group, respectively. The 10mg CCX140-B group decrease was statistically significantly different compared to the placebo group; p=0.045, Wilcoxon Rank Sum test. The changes in the CCX140-B 5mg and pioglitazone groups were not statistically different compared to placebo.

CCX140-B treatment did not affect plasma MCP-1 levels. Circulating monocyte counts were not changed by CCX140-B treatment (Table 4). There was no significant effect of CCX140-B treatment on body weight, and no evidence of hemodilution (based on hematocrit data) with CCX140-B treatment over the course of the clinical trial (Table 4).

The mean (± SD) day 22 trough plasma concentration of CCX140 was 1370 ± 548 ng/mL for the 5 mg CCX140-B dose group and 2450 ± 1050 ng/mL for the 10 mg dose group, indicating that plasma exposure was dose-proportional. The mean apparent half-life was 74.2 ± 13.3 hours for the 5 mg dose group and 76.4 ± 12.4 hours for the 10 mg dose group.

Discussion

This randomized, double-blind, placebo- and active-controlled, pilot Phase 2 clinical trial in 159 subjects with type 2 diabetes on a stable dose of metformin met its primary objective by demonstrating the safety and tolerability of CCX140-B over 28 days of dosing in these subjects. Pioglitazone was selected as an active comparator because at the time of study launch it was considered an effective and safe treatment for patients with type 2 diabetes with a reproducible effect on glycemic parameters [8,9]. The subject study completion rate was 96%, supporting the good tolerability profile. No serious adverse events (SAEs) occurred in subjects receiving CCX140-B and only 2 subjects receiving CCX140-B discontinued early from the trial due to adverse events. Review of the adverse event profile in subjects receiving CCX140-B indicated no safety concerns. Review of serum chemistry, hematology, and urinalysis parameters indicated no safety concerns regarding hepatic, renal, metabolic, hematologic or immunologic systems. Of particular note, there was no evidence of a detrimental effect of CCX140-B on circulating monocyte counts. A CCR2 antibody tested previously in a rheumatoid arthritis trial showed a 39% decrease in monocyte counts [10], indicating that not all CCR2 antagonists behave similarly in this regard. The reason for this difference is unclear but may be related to a direct depleting effect of the CCR2 antibody on circulating monocytes or blockade of monocyte precursor release from bone marrow into the blood stream by the CCR2 antibody but not by the small molecule CCX140-B. There was no evidence of hemodilution with CCX140-B treatment based on hematocrit changes, or peripheral leg edema over the course of the trial. Electrocardiogram data and vital signs measurements over the course of the trial did not indicate any cardiovascular safety concerns with CCX140-B.

The FPG profiles over the course of the trial indicated a CCX140-B dose-dependent decrease from baseline over 4 weeks, with the 10 mg CCX140-B dose showing larger decreases than the 5 mg CCX140-B group. The magnitude of the decrease from baseline in FPG was relatively similar in the CCX140-B 10 mg once daily group compared to the active drug pioglitazone (least-squares mean change from baseline to day 29 of -16.1 compared to -21.4 mg/dL, respectively). The decrease from baseline in FPG of 21.4 mg/dL with pioglitazone 30 mg was in line with the decrease of approximately 25 mg/dL over 4 weeks of treatment reported previously for this drug [8,9].

Results from the 4-week change from baseline in HbA1c are consistent with the glucose-lowering effect seen with the CCX140-B 10 mg group. Four weeks are obviously not long enough to fully elucidate the anti-glycemic effect of most drugs for diabetes treatment. Nevertheless, the least squares mean decrease in HbA1c of 0.23% over 4 weeks observed with 10 mg CCX140-B is consistent with the 0.2 to 0.4% decrease observed with other effective anti-diabetic treatments such as thiazolidinediones, glucagon-like peptide-1 analogs, incretin mimetics, dipeptidyl peptidase-4 inhibitors, and an IL-1 receptor antagonist [8,11-16]. Now that long-term toxicology data are available with CCX140-B, longer term clinical trials have been initiated to more fully elucidate the effect of CCX140-B on HbA1c.

Of note is that the results with CCX140-B were achieved as add-on treatment to metformin which is recommended in all guidelines as first line drug for type 2 diabetes. Furthermore, we selected patients with BMI>25kg/m2 resulting in an average BMI of 32 kg/m2, since inflamed adipose tissue is thought to be the major target organ of CCR2 receptor antagonists [3-5]. Thus, the significant effect of CCX140-B may be considered as proof of principle of the potential beneficial effects of add-on treatment with such a new class of drugs.

There were no detrimental effects of CCX140-B treatment on plasma MCP-1 levels. This is in contrast to what has been observed with other CCR2 antagonists tested in animals and humans [10,17-19]. It is unclear why these differences have been observed, but it may be due to relative specificity of the various compounds for CCR2, pharmacokinetic profile differences of the drugs, or the nature of the interaction between various antagonists and CCR2, for example with macro-molecules such as antibodies compared to small molecules such as CCX140-B.

Treatment with CCX140-B for 28 days in this study was not associated with significant changes from baseline in other glycemic parameters. This suggests that improving insulin sensitivity may not be the major driver of anti-glycemic effects of CCX140-B 10 mg in humans based on the FPG and HbA1c decreases observed over 4 weeks of treatment. Other possible modes of action include a decrease in hepatic gluconeogenesisand possible improvement in beta cell function through its anti-inflammatory effect, as has been observed with the anti-inflammatory drug IL-1 ra [16]. It is also possible that the 4-week treatment period was too short to fully evaluate the effect of CCX140-B treatment on measurements of insulin sensitivity.

CCX140-B treatment did not negatively affect the serum lipid profiles over the 4-week treatment period and there was no significant effect of CCX140-B treatment on body weight or hematocrit over the course of the trial.

It was of interest to assess whether a previously identified polymorphism in the MCP-1 promoter region (bp: -2518, G vs. non-G) would influence the glycemic or CRP changes in response to a CCR2 antagonist, since a previous report indicated that there might be a difference in these populations [20]. The FPG data in the two strata (G vs. non-G) did not provide evidence that the anti-glycemic effect of CCX140-B differs between the two strata. CRP changes in the two strata were also not different. However, it should be noted that the sample size in each stratum in our study was relatively small, and the CRP levels at baseline in our study were lower than the levels reported in the study from Gilbert et al. [20].

CCX140 in plasma showed a long terminal half-life based on plasma concentration measurements. The trough plasma concentrations were also consistent with the long plasma half-life of CCX140, which makes it suitable for low dose once daily dosing in humans.

Limitations of the clinical trial include the relatively small size and short duration of the study. Larger and longer term clinical trials are in progress.

This clinical trial met its primary objective by demonstrating that treatment with CCX140-B was safe and well tolerated. No safety issues were identified in this study. FPG and HbA1c results with CCX140-B treatment, although not definitive, are encouraging. If confirmed by further clinical trials, blocking CCR2 might provide a novel mechanism to treat diabetes and its complications. Longer-term clinical trials in patients with diabetic nephropathy are currently underway to further evaluate the safety and efficacy of CCX140-B in diabetes and diabetic nephropathy.

Acknowledgement

Results from this clinical trial were presented at the American Diabetes Association and European Association of the Study of Diabetes meetings in 2011.

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