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The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial
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Antifibrotic activity of dual CCR5/CCR2 antagonist cenicriviroc in a mouse model of renal fibrosis.....http://www.natap.org/2014/IAC/IAC_106.htm
"In conclusion, 5 mg CCX140-B once a day lowers albuminuria in patients with type 2 diabetes and proteinuria, on top of standard of care, and without any marked side-effects. These results suggest that CCX140-B is a promising candidate for further clinical development to reduce the unmet need for treatments for diabetic renal disease.
Repeated measures analysis showed a significant least squares mean change from baseline in albuminuria for CCX140-B 5 mg (figure 2): -18% (95% CI -26% to -8%; p=0⋅0004) compared with placebo -2% (95% CI -11% to 9%; p=0⋅72) during 52 weeks; the difference between 5 mg CCX140-B and placebo was -16% (one-sided 95% upper confidence limit -5%; p=0⋅01). The 10 mg dose showed a -11% (95% CI -20% to -1%; p=0⋅02) least squares mean change from baseline during 52 weeks; -10% (upper 95% confidence limit 2%) compared with placebo (p=0⋅08). Figure 2 also shows the albuminuria changes in time. Geometric mean UACR of 363 mg/g (95% CI 287–460) at baseline in the 5 mg group was reduced to 276 mg/g (199–383) (-24% change; p=0⋅0007) after 12 weeks of treatment, and remained stable, ending at 296 mg/g (217–404) (-20% change; p=0⋅03) at 52 weeks. The 10 mg dose of CCX140-B showed a similar profile of response in the first 12 weeks, -20% (95% CI -32 to -7) reduction compared with baseline (p=0⋅005), but the effect dissipated during the subsequent weeks. For patients receiving placebo, baseline UACR showed no significant change over time. 4 weeks after drug discontinuation, geometric mean UACR remained at similar levels as the in-trial results for all groups (figure 2).
CCX140-B improves proteinuria and glycaemia in mice13 and our study points to similar effects in human beings......The exact mechanism of the renoprotective effect of CCR2 inhibition is unknown. Several possibilities have been discussed11, 13, 15, 16 including blocking renal macrophage infiltration, inflammation, oxidative stress, improving podocyte number and function, and interaction with the RAS. Our trial was designed to inform the design and study population for a potential phase 3 trial. It was not designed to explore the mechanism by which CCX140-B lowers albuminuria, and thus does not further detail the mechanism of CCR2 inhibition in renal protection.
What are the chances that 5 mg CCX140-B will be renoprotective and delay hard renal endpoints? We noted that changes in eGFR were not markedly different between the placebo group and the 5 mg CCX140-B after 1 year. However, a difference was not expected in view of the the fact that the study was not statistically powered for this endpoint. Moreover previous hard outcome trials have shown renal protection in end stage renal disease endpoints without marked changes in eGFR slopes during 1 year.18 The finding that CCX140-B lowered albuminuria by 16% compared with placebo, on top of standard of care, could be an indicator of potential renal protection. Findings of a recent meta-analysis showed that all interventions that lower albuminuria by more than 15% in the first months of treatment are associated with an improvement in hard renal outcomes compared with standard of care.19 Whether this will hold true for CCX140-B, which has a novel mechanism of action compared with existing treatments, is unknown. The current profile of CCX140-B does not show any emerging side-effects such as hyperkalaemia or cardiovascular events that could offset its beneficial renoprotective properties."
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Summary
Background
Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care, including ACE inhibitors or ARBs.
Methods
In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2 diabetes aged 18–75 years with proteinuria (first morning void urinary albumin to creatinine ratio [UACR] 100–3000 mg/g), estimated glomerular filtration rate of 25 mL/min per 1⋅73 m2 or higher, and taking stable antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratified based on baseline UACR and renal function (estimated glomerular filtration rate), and then randomly assigned (1:1:1) via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol amendment. The primary efficacy measure was change from baseline in UACR during 52 weeks in the modified intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. According to a prespecified analysis plan, we analysed the primary endpoint with one-sided statistical testing with calculation of upper 95% confidence limits of the differences between active and control. This trial is registered with ClinicalTrials.gov, number NCT01447147.
Findings
The study ran from Dec 7, 2011 (first patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the modified intention-to-treat population. UACR changes from baseline during 52 weeks were -2% for placebo (95% CI -11% to 9%), -18% for 5 mg CCX140-B (-26% to -8%), and -11% for 10 mg CCX140-B (-20% to -1%). We recorded a -16% difference between 5 mg CCX140-B and placebo (one-sided upper 95% confidence limit -5%; p=0⋅01) and a -10% difference between 10 mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0⋅08). Adverse events occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study.
Interpretation
Our data suggest that CCR2 inhibition with CCX140-B has renoprotective effects on top of current standard of care in patients with type 2 diabetes and nephropathy.
Introduction
Patients with type 2 diabetes and proteinuria have a high renal and cardiovascular morbidity and mortality. Treatment of diabetic nephropathy, including with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), has been effective in reducing cardiovascular and renal risk. These renal and cardiovascular protective properties of renin-angiotensin-system (RAS) inhibitors have, besides blood pressure lowering, been partly attributed to their albuminuria lowering effect.1, 2, 3, 4, 5 Despite the success of RAS inhibitors, residual renal and cardiovascular risk is very high6 and seems to be related to the residual high albuminuria in these patients.1Increasing the blockade of the RAS with ACE inhibitors, ARBs, or renin-inhibition combinations has not been successful in further reducing renal or cardiovascular risk in this patient population.7, 8
Novel treatment options that target other pathways involved in the pathophysiology of diabetic nephropathy are needed. Monocyte chemoattractant protein-1 (MCP-1), also called C-C chemokine ligand 2 (CCL2), one of the ligands for C-C chemokine receptor type 2 (CCR2), has been implicated, not only in insulin resistance,9, 10 but also in progressive renal injury and has been suggested to be a potential marker of renal disease.11 MCP-1 promotes monocyte and macrophage migration and activation.12CCX140-B is a small-molecule CCR2 antagonist that inhibits CCR2 and blocks MCP-1-dependent monocyte activation and chemotaxis. Data from preclinical studies suggested that oral CCX140-B improved glycaemia and albuminuria in a mouse model of diabetes.13 Our aim in this study was to test the efficacy and safety of two doses of CCX140-B on albuminuria in patients with type 2 diabetes and proteinuria.
Research in context
Evidence before this study
We searched PubMed on May 4, 2015, and again on July 24, 2015, with the following search terms: "CCR2" AND "clinical trial", "CCR2" AND "diabetes", and "CCR2" AND "diabetic nephropathy". This did not reveal any previous clinical trials with any CCR2 drug in diabetic nephropathy. Before this clinical trial, no other studies had been published for drugs targeting the chemokine receptor CCR2 in patients with diabetic nephropathy. One phase 2 study has been published with CCX140-B in patients with type 2 diabetes. Patients in that study did not have renal disease.
Added value of this study
To the best of our knowledge, the results from our trial provide the first evidence that CCR2 inhibition lowers albuminuria in patients with type 2 diabetes on standard-of-care treatment, with no major side-effects. These effects are achieved through interference with a novel pathway compared with existing treatments.
Implications of all the available evidence
Albuminuria lowering is surrogate evidence for renal protection. The results of this trial showing that CCX140-B lowers albuminuria should be translated into hard evidence in follow-up studies that test whether CCX140-B also limits progression to end-stage renal disease. If this is the case, CCX140-B might have the potential to alter and attenuate the relentless decline of renal function in patients with type 2 diabetes and proteinuria and thereby the need for expensive renal replacement treatment.
Methods
Study design and participants
We did this randomised, double-blind, placebo-controlled trial at 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. The initial study included a 12-week treatment period because toxicology results were not available at the time to support longer term dosing. After long-term toxicology had been successfully completed, we amended the protocol to extend dosing from 12 weeks to 52 weeks with a 4-week follow-up visit after stopping treatment. This protocol amendment specified that for patients already enrolled, only those who completed the initial 12-week study visit within the previous 16 weeks were eligible for continuation to 52 weeks. Therefore, 95 of 332 patients were not eligible to continue to 52 weeks because they had been off study treatment for more than 16 weeks at the time the protocol amendment was approved.
Eligible patients were aged 18–75 years inclusive and had type 2 diabetes with proteinuria (first morning urine albumin to creatinine ratio [UACR] 100–3000 mg/g), a glomerular filtration rate based on the modification of diet in renal disease equation (estimated glomerular filtration rate [eGFR]) of greater than or equal to 25 mL/min per 1⋅73 m2, a baseline HbA1c between 6–10% (4⋅2–8⋅6 mmol/mol), and a fasting plasma glucose of less than 270 mg/dL (15 mmol/L). Patients were on stable diabetes treatment and ACE inhibitors or ARBs at a recommended therapeutic dose for at least 8 weeks.
Patients were excluded if they had type 1 diabetes or known non-diabetic renal disease; a BMI higher than 45⋅4 kg/m2; cardiac failure (class III or IV), history of unstable angina, symptomatic coronary artery disease, myocardial infarction or stroke within 12 weeks before screening; haemoglobin less than 10 g/dL (6⋅18 mmol/L); or evidence of hepatic disease (aspartate aminotransferase, alanine transaminase, or bilirubin >two times the upper limit of normal). Patients were also excluded if they had poorly controlled blood pressure (systolic blood pressure >155 mm Hg or diastolic blood pressure >95 mm Hg). Additional exclusion criteria were use of bardoxolone, atrasentan, or other endothelin antagonist within 8 weeks before screening; chronic (>7 days continuously) non-steroidal anti-inflammatory drug treatment within 2 weeks before screening, or any infection requiring antibiotic treatment within 4 weeks before screening. The appendix contains the full list of inclusion and exclusion criteria.
The trial was done in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees and institutional review boards approved the research protocol. All patients gave written informed consent before starting the trial.
Randomisation and masking
After the lead-in period, patients were stratified based on baseline UACR (100–300 mg/g, 301–800 mg/g, and 801–3000 mg/g) and baseline eGFR (25–59 mL/min per 1⋅73 m2 and ≥60 mL/min per 1⋅73 m2), and then randomly assigned (1:1:1) to receive oral placebo, CCX140-B 5 mg, or CCX140-B 10 mg once a day for 52 weeks according to a non-centre-specific randomisation scheme. Stratification and randomisation was undertaken centrally via an interactive web response system. The system used a minimisation algorithm14 to maintain balance among the three treatment groups with respect to the three baseline UACR ranges, the two baseline eGFR ranges, and study centre. Patients and all study personnel (except the safety monitoring committee) were masked to treatment allocation. CCX140-B is the sodium salt of CCX140. All study drugs were in identical capsules, and supplied in identical bottles labelled appropriately so as to maintain the allocation masking.
Procedures
Patients who were randomised collected first morning void urine on 3 separate days at baseline and week 52, and single measurements at weeks 2, 4, 8, 12, 16, 20, 28, 36, 44, and 56 for assessment of UACR. Urine albumin was measured by a nephelometric assay and creatinine was measured by a kinetic colorimetric assay in a central laboratory (Medpace Reference Laboratory, Leuven, Belgium). Serum creatinine, phosphorus, blood urea nitrogen, and urinary MCP-1 to creatinine ratio were measured at baseline and 2, 4, 8, 12, 16, 20, 28, 36, 44, 52, and 56 weeks. Serum creatinine was used to calculate eGFR with the modification of diet in renal disease equation:
eGFR=175 x (serum creatinine, mg/dL)-1⋅154 x (age, years)
-0⋅203 x (0⋅742 if female) x (1⋅212 if black).
We measured HbA1c, fasting plasma glucose, and homoeostatic model assessment of insulin resistance (HOMA-IR) at baseline and 4, 8, 12, 20, 28, 36, 44, 52, and 56 weeks. HOMA-IR was calculated with the following equation: fasting plasma glucose (mg/dL) x fasting insulin (μU/mL)/405. Plasma MCP-1 concentrations were measured at baseline and weeks 12, 28, 52, and 56. CCX140 plasma concentrations were measured at each study visit using high-performance liquid chromatography with tandem mass spectrometric detection (lower limit of detection 1 ng/mL).
Safety was monitored at baseline and 2, 4, 8, 12, 20, 28, 36, 44, 52, and 56 weeks by assessing adverse events and laboratory data. Reported adverse events were recorded during the trial and analysed with a standard coding dictionary (MedDRA, version 12.0) to classify adverse event terms. Serious adverse events were defined as any adverse event that resulted in death, was immediately life threatening, required hospital admission, resulted in persistent or substantial disability or incapacity, was a birth defect, or was an important event that might heavily jeopardise the patient or might have required intervention to prevent any of the above.
We assessed patient compliance with taking study drug based on returned capsule counts at each study visit as well as plasma CCX140 concentrations measured over the course of the trial.
Outcomes
The primary efficacy endpoint for the study was change from baseline in UACR at 52 weeks. Because the treatment period in the original protocol was 12 weeks, change from baseline in UACR over 12 weeks was also analysed. Secondary endpoints included change from baseline in eGFR and HbA1c at 52 weeks. Other endpoints included change from baseline in blood urea nitrogen, serum phosphorus, fasting plasma glucose, fasting plasma insulin, HOMA-IR, urinary MCP-1 to creatinine ratio and plasma MCP-1 at week 52, and the plasma concentration of CCX140 over the course of the study.
Statistical analysis
The planned sample size was at least 135 patients, 45 in each group. However, the protocol made provision for an enrolment target of 270 patients, 90 in each group, with the anticipation that the trial dosing period might be extended with potential loss of patients while the protocol amendment was processed. Assuming a standard deviation of 0⋅85, a sample size of 45 per group was estimated to provide 80% power to detect a mean between-group difference in UACR change of 0⋅51, corresponding to a 40% between-group difference. A sample size of 90 per group was estimated to provide 80% power to detect a mean between-group difference in UACR change of 0⋅36, corresponding to a 30% between-group difference.
We did efficacy analyses on the modified intention-to-treat population, which consisted of all patients with uninterrupted dosing between the 12 week and 16 week study visits. We excluded from the modified intention-to-treat population patients who stopped dosing at week 12, either permanently, under the original protocol, or temporarily, due to delay in protocol amendment approval. The statistical analysis plan was revised during the study to reflect the dosing period extension and change in primary endpoint (from week 12 to week 52). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. Analyses were based on comparisons between placebo and CCX140-B groups as assigned by randomisation, irrespective of whether patients followed through the protocol or were fully compliant with the protocol procedures.
The primary analysis was a mixed effects model, repeated measures (MMRM) analysis of change from baseline to each post-baseline measurement of log UACR using SAS (version 9.1). The model included treatment, visit, and treatment-by-visit interaction as factors, and baseline log UACR, eGFR, HbA1c, and mean arterial pressure as covariates. UACR was log-transformed before entering the data in the MMRM analysis to alleviate the skewness of the data.
Visits were included as repeated measure units from the same patients. To allow generality for the covariance structure for the repeated measures, the variance-covariance matrix was assumed to be unstructured—ie, purely data dependent. In this MMRM model, all patients and all datapoints were included. No patients were excluded because of missing data and no imputation was done for missing data. We estimated the treatment group difference at week 52 with the simple contrast and the overall between-group difference over the course of the study with the main effects (contrast) with the missing at random assumption. We compared the contrast between each drug dose group and the placebo group at week 52 with a prespecified one-sided significance level of 0⋅05; treatment differences at other timepoints were also analysed.
The between-group geometric mean change (%) was derived by 100*(exp [least squares mean change]–1), and the same transformation was applied to the 95% confidence limits to obtain an approximate upper 95% confidence limit for the geometric mean change (%). The rationale for one-sided testing for UACR was that in this phase 2 clinical trial, the main goal was to test whether CCX140-B treatment can reduce albuminuria. This was not a pivotal clinical trial, in which a two-sided test would be more appropriate. We used similar statistical models to assess treatment group differences in other efficacy and safety variables, such as eGFR, HbA1c, and urinary MCP-1 to creatinine ratio. We calculated two-sided 95% confidence intervals for eGFR.
A sensitivity analysis of change from baseline in log UACR was done by an ANCOVA model with treatment as a factor and baseline eGFR, HbA1c, and mean arterial pressure as covariates, and last observation carried forward imputation for missing data. Concomitant drugs including RAS inhibitors, diuretics, β blockers, calcium channel blockers, glucose-lowering drugs, and lipid-modifying drugs were summarised by treatment group.
The study was registered with ClinicalTrials.gov, number NCT01447147.
Role of the funding source
The study was overseen by an advisory committee, including members from the funder. The advisory committee oversaw the design of the study, the conduct of the trial, and the management and analysis of all data. The funder was involved in the design of the study, in the collection and analysis of the data, and in writing the report. All authors had access to study results, and the lead author takes responsibility for the accuracy and completeness of the data reported. The lead author and the advisory committee had the final decision to submit the publication.
Results
The study ran from Dec 7, 2011 (first patient enrolled) until Aug 4, 2014. We screened 883 patients of whom we enrolled 332. 111 patients were assigned to placebo, 110 to CCX140-B 5 mg, and 111 to CCX140-B 10 mg. 209 patients continued after the 12-week period of whom 192 had uninterrupted treatment after week 12 (modified intention-to-treat population). 182 of the 192 patients completed 56 weeks (figure 1).
Baseline demographics, clinical and biochemical characteristics, and concomitant drugs were similar between the three groups (table 1 and appendix). Apparent slight baseline imbalances in average baseline plasma MCP-1 concentrations are explained by one outlier value each in the 5 mg and 10 mg CCX140-B group.
Repeated measures analysis showed a significant least squares mean change from baseline in albuminuria for CCX140-B 5 mg (figure 2): -18% (95% CI -26% to -8%; p=0⋅0004) compared with placebo -2% (95% CI -11% to 9%; p=0⋅72) during 52 weeks; the difference between 5 mg CCX140-B and placebo was -16% (one-sided 95% upper confidence limit -5%; p=0⋅01). The 10 mg dose showed a -11% (95% CI -20% to -1%; p=0⋅02) least squares mean change from baseline during 52 weeks; -10% (upper 95% confidence limit 2%) compared with placebo (p=0⋅08). Figure 2 also shows the albuminuria changes in time. Geometric mean UACR of 363 mg/g (95% CI 287–460) at baseline in the 5 mg group was reduced to 276 mg/g (199–383) (-24% change; p=0⋅0007) after 12 weeks of treatment, and remained stable, ending at 296 mg/g (217–404) (-20% change; p=0⋅03) at 52 weeks. The 10 mg dose of CCX140-B showed a similar profile of response in the first 12 weeks, -20% (95% CI -32 to -7) reduction compared with baseline (p=0⋅005), but the effect dissipated during the subsequent weeks. For patients receiving placebo, baseline UACR showed no significant change over time. 4 weeks after drug discontinuation, geometric mean UACR remained at similar levels as the in-trial results for all groups (figure 2). Results from a sensitivity analysis using an ANCOVA model were consistent with the MMRM analysis (appendix). The UACR response to CCX140-B showed no interactions with the different baseline parameters except for HbA1c, although the latter with no consistent pattern (appendix). Because many patients who completed the original 12-week protocol were ineligible to participate in the 52-week protocol, we assessed the results for all randomly assigned patients to assess whether the results were consistent. The albuminuria change at week 12 was -18% (upper 95% confidence limit -7%; p=0⋅006) for the 5 mg CCX140-B and -4% (upper 95% confidence limit 9%; p=0⋅29) for the 10 mg group compared with placebo. The baseline characteristics of all randomly assigned patients versus the 52-week population showed no meaningful differences (appendix), suggesting that the 52-week population was representative of the randomised population.
Changes in eGFR, HbA1c, fasting plasma insulin, HOMA-IR, serum phosphorus, blood urea nitrogen, blood pressure, and urinary MCP-1 in participants who received CCX140-B were not significant compared with those who received placebo (table 2 and appendix). There was a greater change in fasting plasma glucose in the 5 mg CCX140-B group compared with placebo (-1⋅12 mmol/L, upper 95% confidence limit -0⋅24; p=0⋅01). The average plasma concentration of CCX140 was roughly twice as high in the 10 mg CCX140-B group compared with the 5 mg CCX140-B group, and remained stable over the course of the study (appendix). The average plasma MCP-1 concentration rose significantly in the 10 mg CCX140-B group but not in the other two groups (table 2 and figure 3A). The UACR response (baseline to week 52) seemed to be attenuated in the presence of higher rise in plasma levels of MCP-1 upon treatment (figure 3B).
The study drug was generally well tolerated (table 3). Adverse events were consistent with the age and underlying medical conditions of the patient population. We noted that serious adverse events occurred in a similar proportion of participants in the placebo and 5 mg CCX140-B groups (13 [11⋅7%] in the placebo group and 13 [11⋅8%] in the 5 mg CCX140-B group). The 10 mg CCX140-B group had a higher incidence of serious adverse events: 25 (22⋅5%). Two serious adverse events in the placebo group, and one each in the 5 mg and 10 mg CCX140-B groups, were reported to possibly be related to the study drug: complete atrioventricular block and myocardial infarction; Staphylococcal bacteraemia after tooth extraction (5 mg CCX140-B) and subcutaneous abscess (10 mg CCX140-B). Two patients died during the course of the study, neither deemed drug related by the investigators (one due to stroke in the 5 mg CCX140-B group and one due to myocardial infarction in the 10 mg CCX140-B group). None of the patients had a renal event: no confirmed doubling of serum creatinine over the course of the study, none underwent dialysis, and none had an eGFR of less than 15 mL/min per 1⋅73 m2.
Patient compliance with taking study drug was high: 108 (97%) of 111 in the placebo group, 108 (98%) of 110 in the 5 mg CCX140-B group, and 108 (97%) of 111 patients in the 10 mg CCX140-B group took more than 90% of their prescribed study drug. Compliance was further substantiated by the plasma CCX140 concentration measurements over the course of the study. Six (3%) of 221 patients, three in each of the CCX140-B groups, had evidence of non-compliance based on plasma CCX140 concentrations.
Discussion
In patients with type 2 diabetes with proteinuria who were on a therapeutic dose of ACE inhibitor or ARB, a dose of 5 mg CCX140-B lowered albuminuria by 18% overall versus 2% with placebo during the course of the study without major side-effects. The magnitude of this effect is deemed clinically meaningful and could translate into further renal benefit with long-term treatment.
Recently the focus of renoprotective treatments has switched from targeting haemodynamic pathways to inflammatory pathways. Further inhibition of the RAS seems to cause increased side-effects that might counteract the beneficial effects of reducing classical risk factors like glucose, blood pressure, and albuminuria. Targeting other pathways might be a better option for enhanced renal protection in advanced type 2 diabetes. The chemokine receptor 2 pathway seems interesting in view of the fact that this pathway has been associated with progressive renal function loss,11 and that inhibition of CCR2 affords renal protection in experimental models of renal disease.13 This is the first study describing the effect of CCR2 inhibition on renal risk parameters such as albuminuria, in patients with type 2 diabetes and nephropathy.
The exact mechanism of the renoprotective effect of CCR2 inhibition is unknown. Several possibilities have been discussed11, 13, 15, 16 including blocking renal macrophage infiltration, inflammation, oxidative stress, improving podocyte number and function, and interaction with the RAS. Our trial was designed to inform the design and study population for a potential phase 3 trial. It was not designed to explore the mechanism by which CCX140-B lowers albuminuria, and thus does not further detail the mechanism of CCR2 inhibition in renal protection. We selected CCX140-B doses of 5 mg and 10 mg once a day because both result in plasma concentrations that block CCR2-mediated cell migration at about 90% or greater,13 and both doses were found to be safe and well tolerated in an earlier study in patients with type 2 diabetes.17
CCX140-B improves proteinuria and glycaemia in mice13 and our study points to similar effects in human beings. Could the effect on proteinuria and glycaemia be related? In mice, the effect on proteinuria was noted earlier after treatment onset, and at lower doses of the CCR2 inhibitor, than was the effect on glycaemia.13 The beneficial effect of CCR2 inhibition on glycaemic control is thought to be related to a reduction in the macrophage content in adipose tissue, leading to improved insulin sensitivity.9, 10 The effect on proteinuria is probably caused by other mechanisms, such as reduced inflammation or improved podocyte integrity.
An important finding was the apparent lack of a dose response in our study. The 10 mg dose seemed to have less albuminuria-lowering effect than 5 mg CCX140-B. The drug was adequately absorbed, as participants in the 10 mg CCX140-B group had twice the plasma drug levels as the 5 mg dose. However, we also noted that concentrations of an endogenous ligand for CCR2, MCP-1 (also known as CCL2) rose with increasing dose of the drug. Within each of the groups that received CCX140-B, we noted that higher MCP-1 levels were associated with less reduction in albuminuria, especially in the 10 mg group.
We hypothesise that the increased concentrations of MCP-1 compete with the drug. This is consistent with reaching the plateau of the dose response with 10 CCX140-B mg at 12 weeks and attenuation of the albuminuria-lowering effect after week 12 in the 10 mg CCX140-B group. Compliance as shown by the reported taking of study drug was high and similar across groups. Additionally, CCX140 plasma concentrations were consistent across all study visits. The dropout rate in the 5 mg and 10 mg CCX140-B groups was similar. Therefore, non-compliance with study drug or patient dropout were unlikely to explain the attenuation of the drug's effect after week 12 in the 10 mg group.
Our study design has limitations. In particular, the study was amended from a 12-week study to a 52-week study; not all patients enrolled in the 12-week study could continue into the 52-week study because at the crucial time of re-enrolment into the study extension, the long-term toxicology data were not yet available. This resulted in a loss of patients that had been exposed to drug or placebo without interruption between weeks 12 and 16. However, UACR results at week 12 for all randomly assigned patients were consistent with the results from patients with uninterrupted treatment after week 12, suggesting that we did not selectively lose patients.
What are the chances that 5 mg CCX140-B will be renoprotective and delay hard renal endpoints? We noted that changes in eGFR were not markedly different between the placebo group and the 5 mg CCX140-B after 1 year. However, a difference was not expected in view of the the fact that the study was not statistically powered for this endpoint. Moreover previous hard outcome trials have shown renal protection in end stage renal disease endpoints without marked changes in eGFR slopes during 1 year.18 The finding that CCX140-B lowered albuminuria by 16% compared with placebo, on top of standard of care, could be an indicator of potential renal protection. Findings of a recent meta-analysis showed that all interventions that lower albuminuria by more than 15% in the first months of treatment are associated with an improvement in hard renal outcomes compared with standard of care.19 Whether this will hold true for CCX140-B, which has a novel mechanism of action compared with existing treatments, is unknown. The current profile of CCX140-B does not show any emerging side-effects such as hyperkalaemia or cardiovascular events that could offset its beneficial renoprotective properties.
In conclusion, 5 mg CCX140-B once a day lowers albuminuria in patients with type 2 diabetes and proteinuria, on top of standard of care, and without any marked side-effects. These results suggest that CCX140-B is a promising candidate for further clinical development to reduce the unmet need for treatments for diabetic renal disease.
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