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Next-generation calcineurin inhibitors in development for the prevention of organ rejection

Authors Gheith O , Al-Otaibi T, Mansour H

Received 16 October 2013

Accepted for publication 12 December 2013

Published 25 March 2014 Volume 2014:6 Pages 23—30

DOI https://doi.org/10.2147/TRRM.S35875

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3



Osama Gheith, Torki Al-Otaibi, Hany Mansour

Department of Nephrology, Hamed Al-Essa Organ Transplant Center, Ibn Sina Hospital, Shuwaikh, Kuwait

Abstract: Calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression after renal transplantation despite their adverse effects. Some CNIs have well known negative impacts on the cardiovascular system, including hypertension, hyperlipidemia, new onset diabetes after transplantation (NODAT), neurotoxicity, hypertrichosis, and nephrotoxicity. Many clinical trials dealing with CNI avoidance or elimination were associated with higher risk of rejection of the transplanted organ. New generation CNIs are concerned with modifying CNI molecules so that they become more potent and are suitable for patients with suboptimal adherence with less adverse effects. In this review, we address these issues.

Keywords: calcineurin inhibitors, organ transplant, rejection

Introduction

Calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression after renal transplantation despite their adverse effects, which have a negative impact on the cardiovascular system. These side effects include hypertension, hyperlipidemia, new onset diabetes after transplantation (NODAT), neurotoxicity, hypertrichosis and nephrotoxicity. However, many clinical trials dealing with CNI avoidance or elimination are associated with higher risk of rejection of the transplanted organ.13

On the other hand, three different studies compared belatacept and cyclosporine (CsA) and all confirmed significantly better renal function among patients who received belatacept.46 Moreover, extended criteria donor (ECD) kidney transplant recipients who were treated with belatacept-based immunosuppression regimens achieved similar patient/graft survival, better renal function, and exhibited improvement in the cardiovascular/metabolic risk profile versus CsA-treated patients; however, there was an increased incidence of post-transplant lymphoproliferative disorder (PTLD). These differential findings might be explained by the use of CsA as the control group. Furthermore, head-to head studies have recognized better renal graft function in the tacrolimus (TAC) group compared to the CsA-based group. In the ELITE-Symphony study, the authors verified a significant advantage of TAC over CsA in estimated glomerular filtration rate (eGFR) preservation up to 3 years after transplantation.7

Compared to mycophenolate mofetil (MMF)/CNI treatment, a 2-year regimen of MMF and sirolimus (SRL) resulted in similar measures of renal function but with fewer deaths and a trend of less biopsy proven acute rejection (BPAR) and graft loss.8 Flechner9 reported that at 1–2 years of their study, the GFR was superior for the SRL group, with a loss of tolerability for about 20%. Moreover, Shamseddin and Gupta,10 in a letter to the editor, questioned the sparing effect of SRL in the Spare-the-Nephron trial.11

CsA is cyclic, non-ribosomal peptide of fungal origin containing eleven amino acids including a single D-amino acid. It is used as an immunosuppressive agent for the prevention of solid-organ transplant rejection12 and in the treatment of autoimmune disorders, such as psoriasis.13

The main action of CsA is to inhibit the activity of T-cells and their immune response. It exerts this immunosuppressive effect through a cascade of actions when it combines with cyclophilin A forming a complex. Once this complex is formed, it will bind to and suppress intracelluler phosphatase CN, which is followed by inhibition of activation of transcriptional activator 1 nuclear factor (by dephosphorylation) inside active T-cells and its subsequent translocation to the nucleus. Finally, the production of many cellular products, such as cytokines and lymphokines, will be blocked and the immune reaction is suppressed.14 Moreover, CNI can inhibit fibroblast proliferation and the release of other vascular growth factors related to endothelial growth.1517

However, the chronic use of CsA is restricted due to its side effects, most notably nephrotoxicity.18,19 In an attempt to reduce such side effects, a modified CsA formulation has been generated with better bioavailability; nevertheless, it has more or less similar side effects. In a meta-analysis by Shah et al,20 which considered all published trials, they concluded that CsA (modified) is favored over CsA because of a lower rejection incidence and a trend towards less adverse events. However, when they limited their analysis to only randomized prospective trials (especially blinded studies) they found that CsA (modified) was associated with more adverse events. On the other hand, when analyzing open-labeled studies alone, they found that CsA was associated with more adverse events. Therefore, careful individual consideration must be given when choosing the best possible CsA formulation.

As a result of the continuous search for immunosuppressive agents with better efficacy and safety profiles, CsA derivative ISA247 (voclosporin; VCS) was successfully created. This was possible by studying the molecular structure of the CsA-CN complex and modifying the molecule to make it fit better against the hydrophobic CN surface, a property that increases its binding affinity with lower dosages and lower adverse effects.21

VCS

Mechanism of action

VCS is a novel CNI intended for the prevention of organ graft rejection and treatment of lupus nephritis.22 It has a strong immunosuppressant effect by reversible inhibition of T-lymphocyte proliferation and release of cytokines through blocking the cytoplasmic calcium dependent phosphatase.15 Inside lymphocytes, voclosporin binds to immunophilins forming complexes that inhibit CN.23,24 This scenario prevents translocation of the nuclear factor of active T-cells, followed by impairment of the transcription of genes encoding interleukin (IL)-2 and some other cellular products, especially lymphokines.16,23,24

Creation of VCS was carried out by changing the functional group on the amino acid residue at position one of the molecule,25 with more favorable pharmacokinetic properties compared to CsA26,27 and increased its immunosuppressive effects by nearly 4-fold.28

Moreover, such a change in the molecule enhances the binding of the VCS-cyclophilin complex to CN receptors with faster elimination of its metabolites. Thus, increasing its potency and lowering the drug dose and its metabolites led to optimized kinetic and dynamic properties in addition to enhanced CN inhibition compared to the original component.25,29,30

Results of Phase I, II, and II clinical trials confirmed optimization of the pharmacokinetic/pharmacodynamic (PK/PD) properties of VCS.26,27 In continuation of such research work, initial systemic use of VCS in rats has been reported to be successful for the prevention and treatment of experimental autoimmune uveoretinitis.31

Clinical trials with VCS

In experimental animals (Table 1), Stalder et al32 found that VCS was more potent than CsA in suppressing T-cell function in monkeys. During initial studies, VCS has been evaluated among healthy volunteers. In single-dose studies, the dose ranged between 0.25 to 4.5 mg/kg, while in multi-doses studies, the dosage ranged between 0.25 to 1.5 mg/kg twice daily (bid). The drug showed good bioavailability, rapid absorption, and linear increases in the area under the curve (AUC) and maximum concentration (Cmax) with multiphasic elimination along 24 hours. In another study using multi-doses of VCS ranging between 0.25 to 0.5 mg/kg bid for a longer time period (10 days), the half-life (T1/2) ranged between 6.9 to 7.8 hours and 30.1 to 33.2 hours on the first and thirteenth days, respectively. The authors confirmed potency of this new agent: nearly 4-fold compared to the original molecule (CsA) with accumulation up to the thirteenth day. Moreover, they found that VCS can inhibit CN in dose-proportional manner up to 1 mg/kg bid up to the tenth day after which inhibition plateaus.33 The use of such new agents for organ transplantation or autoimmune disorders as psoriasis has been reported to be successful, suggesting a possible role for it in the treatment of other autoimmune disorders.

Table 1 Summarizing most voclosporin clinical trials
Abbreviation: bid, twice daily.

Cytochrome P450 (CYP450) 3A4/5 acts as the primary enzyme involved in the initial phase of VCS metabolism. With extensive first-pass hepatic metabolism the drug will be hydroxylated and demethylated into active metabolites.33,34 VCS can inhibit the activity of CYP450 3A4, but not CYP2D6 or CYP2C9. VCS should be taken without food for better absorption to ensure adequate drug concentration. Moreover, animal studies showed that the primary route of excretion is through the gut.33

For further assessment of this new drug, a randomized, multicenter, open-label study Phase IIA study for 12-weeks involving 132 stable renal transplant recipients who were switched from CsA (modified) to VCS was undertaken. Acute rejection was considered as primary endpoint of the study.25,26 VCS generated an immunosuppressive effect that was comparable to CsA (modified) at 33% of the blood drug level. In addition, they found strong correlations between the concentration of drug in plasma after 12 hours and immediately before the morning dose (C0) and both AUC and level of CN inhibition by VCS; a correlation that was lacking with CsA (modified).

Similarly, in another conversion study concerning stable renal transplant patients, VCS drug efficacy and tolerability were confirmed.25 Moreover, in Phase II/III studies using VCS among patients with other autoimmune disorders – namely plaque psoriasis – the authors confirmed its efficacy with minimal nephrotoxicity.3436

To compare the efficacy and safety of VCS versus TAC among de novo renal transplant recipients, Gaston et al37 completed a randomized, open-label, Phase IIB trial. They started VCS in doses of 0.4, 0.6, and 0.8 mg/kg bid and TAC in a dose of 0.05 mg/kg bid, and optimized the doses according to target trough concentrations. Among the first 116 patients who completed up to 4 months of therapy (range, 3.7±2.2 to 4.5±2.2 months), Busque et al38 found that the two agents have similar efficacy, as measured by the number of biopsy-proven acute rejection episodes. Moreover, renal graft function was good in all patients who were managed by VCS regardless the dosage used.38

In the PROMISE study, Busque et al39 compared the results of VCS versus TAC in renal transplant recipients after 6 months of transplantation. They found that it has the ability to prevent acute rejection more or less equally to TAC, with fewer incidences of NODAT. They added that cases that were exposed to low and medium doses of VCS showed similar renal function with a clear PK/PD relationship.39 Moreover, they found no significant difference between eGFR among these two groups and the TAC control group (68 mL/minute versus 69 mL/minute, P<0.05). Such data suggest a potential upper limit of exposure associated with renal function. In addition, in the same study, the authors found that VCS demonstrated an excellent correlation between trough level of the drug and its area under the curve (r2=0.97) and found no difference in mycophenolic acid (MPA) exposure compared to TAC. Similarly, both Busque et al4 and Vincenti et al40 reported a clear relationship between VCS exposure, degree of CN inhibition, and risk of acute rejection. They added that acute rejection rates were equivalent to recent studies utilizing new immunosuppressant drug with tremendous renal function in all treatment groups with eGFR around 70 mL/minute.

CsA is recognized to be less diabetogenic than TAC;40 however, both agents interfere with the CN nuclear factor of the active T-cell signaling pathway, which is needed for insulin secretion and islet physiology.41

Øzbay et al42 used retrospective Kaplan–Meier estimates of biopsy proven acute rejection and post-transplant diabetes according to the 2003 American Diabetes Association (ADA) guidelines among 28 VCS treated patients. These patients were exposed to trough levels within the range planned for future assessment (35 to less than 60 ng/mL), and they compared data with the TAC treated group; they found no significant difference between the two groups (P>0.05). They added that the two drugs might be different, but TAC reduces insulin secretion earlier than CsA. They found that the incidence of NODAT increased with higher exposure to VCS – as seen in the high-dose group – with a similar incidence as the TAC group. However, the number of VCS-treated patients with NODAT required less anti-diabetic treatment than the TAC-treated patients. Therefore, they concluded that VCS may be similar to CsA with respect to its diabetogenicity. However, the high level of VCS exposure associated with higher incidence of NODAT similar to TAC may not be needed for adequate rejection prophylaxis.

Vincenti et al5 and Busque et al4 had reported that adverse effects were generally similar between VCS and TAC treatment groups. However, they observed more diarrhea among TAC treated patients with continuation of neurological symptoms – especially tremors – beyond the third month after transplantation. Regarding common CsA adverse effects, such as hypertension, hyperlipidemia, and gingival hyperplasia, they found no significant difference between TAC and VCS; however, they reported mild and infrequent hypertrichosis among VCS cases. The authors added that in spite of the fact that their studies were relatively short-term in nature, VCS was not associated with an increased incidence of infections or post-transplant lymphoma as seen with studies concerning other new immunosuppressives.

The PK and PD evaluation performed in PROMISE indicates that VCS trough level monitoring can be a tremendous marker of drug exposure and CN inhibition. It does not reduce MPA exposure (simulating TAC, in contrary to CsA) when combined with MMF.43 Post hoc analyses of VCS trough exposure were performed to evaluate clinical outcomes in all patients on VCS therapy to determine the optimal exposure that minimizes both rejection and NODAT in such cases. It was observed that NODAT incidence of more than 8% would be seen with higher VCS levels than 60 ng/mL, while BPAR would be associated with a significantly lower (<35 ng/mL) exposure. Moreover, BPAR was seen in the low and mid-dose groups after the third month of mandatory exposure reduction that was associated with trough levels <30 ng/mL. On the other hand, the high dose group remained free of rejection with an exposure more than 31 ng/mL. They concluded that a VCS target range between 35 to <60 ng/mL may result in comparable rejection rates and nearly 50% the rate of NODAT seen in TAC group. However, the limitations of this study include the enrollment of patients at relatively low risk for rejection and no delayed graft function, and therefore the results observed may not be applicable to all renal transplant recipients. Moreover, the TAC levels were higher than in the ELITE-Symphony study and protocol biopsies were not performed to assess the impact of different VCS exposures on the development of interstitial fibrosis and tubular atrophy.5

Gupta et al44 studied the PK and PD of VCS in a Phase III, randomized, placebo-controlled, multicenter, double-blind study and they concluded that its concentration was highly correlated with CN inhibition (r=0.79), and the percentage of that inhibition was highly correlated with mean percent reduction in the efficacy endpoint (r=0.86). Based on these data, Bissonnette et al35 concluded that VCS appears safe and effective for treating moderate to severe psoriasis.

VCS safety

In view of VCS tolerability and safety in all initial trials in doses up to 4.5 mg/kg, evolution of trials had been progressed to Phase II and III trials among renal transplant recipients and patients with psoriasis.21,25,28,35,44,45 In such trials, some side effects, such as headache, diarrhea, and hypertension were reported.26,35,44 Such adverse effects appear to be dose-dependent. To date, most studies do not show any significant changes in lipid profiles represented by serum levels of cholesterol, triglycerides, other biochemical parameters, NODAT, or infectious complications.

Regarding renal function, most patients enrolled in all studies had stable renal graft function, which was assessed by creatinine clearance. Moreover, in a Phase III study in psoriasis patients, the highest mean change in serum creatinine in any dosing group (0.2, 0.3, or 0.4 mg/kg bid) at week 12 was 5.6% above baseline, which was considered to be within normal physiological variation.46

In a small study including 100 patients, the drug was withdrawn due to a clinically significant decrease in kidney function (4% in the high VCS dose and 1% in the mid-dose group). However, at 24 weeks there were no clinically significant changes in mean serum creatinine or GFR, but five patients withdrew due to a 30% reduction in GFR.47 After 60 weeks of follow up, mean renal function represented by serum creatinine remained stable. Nevertheless, significant changes in renal function developed in 4% of patients.

VCS therapeutic monitoring

The data derived from safety studies suggested a broader therapeutic window of VCS in contrary to other CNIs, such as CsA and TAC, which required drug monitoring to correlate the parent substance and its metabolites with other clinical parameters.48,49 Within the therapeutic range of inhibition of CN (40% to 70%), VCS showed no significant changes in mean creatinine clearance, mean arterial blood pressure, or serum magnesium levels. Deleterious effects of VCS on creatinine clearance has only been observed when CN inhibition is more than 70%.50 Similarly, other data indicate that 40% CN inhibition is achieved with VCS at an AUC of 226 ng × hour/mL, but with a 15% rise in serum creatinine occurs only at a VCS AUC of 3448 ng × hour/mL.22,50

Ling et al22 concluded that mild to moderate hepatic impairment resulted in a 1.5- to 2-fold increase in VCS exposure. VCS can be administered safely to patients with mild to moderate renal impairment without dose modification. Appropriate safety monitoring with concentration-based adjustments in transplantation are recommended for patients with severe renal impairment and for patients with hepatic impairment.

New trends in other CNIs

Advagraf® (Astellas Pharma US, Inc, Way Northbrook, IL, USA) is a new slow release form of TAC with a once-daily formulation, which has the potential advantage of better adherence and a safer profile by avoiding toxic peak concentrations. Yatscoff et al51 found a significant decrease in TAC exposure after switching to Advagraf. Therefore, they recommend that switching from TAC to Advagraf should be performed under close medical supervision. Moreover, Carcas-SansuÁn et al showed that Advagraf bioequivalence cannot be ensured in pediatric populations and they found significant changes in TAC levels and dose on long-term follow-up.52 Tanaka et al53 and Carcas Sunsuan et al54 reported that conversion from TAC to Advagraf in live donor liver transplants can be performed safely and effectively without affecting liver, renal, and immune functions. Wu et al55 concluded that the policy of converting to Advagraf with the purpose of improving medical adherence should be individualized in routine clinical practice. Moreover, among patients who represented the European kidney transplant population – the OSAKA trial – they found that TAC once per day (QD)-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day TAC twice per day.56

Although Carcas-SansuÁn et al57 reported that conversion from TAC to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline, a 1-year follow-up showed a transient reduction in TAC levels that requires closer monitoring of drug levels post-conversion. To overcome this problem, Ma et al58 found that conversion from TAC to Advagraf in renal allograft recipients with or without diltiazem co-treatment required an increase in the daily dose by nearly 30% to maintain the target blood trough level. Similarly, Ghodsizad et al59suggested that Advagraf is a safe alternative to Prograf® (Astellas Pharma US, Inc.) for patients who have undergone heart transplantation; trough levels were comparable after an adjustment period and there were no differences between the two groups with respect to their 1-year mortality rates. Furthermore, Kuypers et al60 reported that TAC once daily is significantly superior to the bid regimen that overcomes the residual prevalence of suboptimal adherence that will have to be countered by means other than reformulation and regimen simplification.

Conclusion

Much effort is being expended to create a newer generation of CNIs for the prevention of organ rejection and to avoid adverse effects. Volcosporin is a more potent promising immunosuppressive agent with fewer side effects than CsA while Advagraf is comparable to TAC especially in patients with suboptimal adherence; however, Advagraf requires close monitoring of levels until it reaches therapeutic significance.

Disclosure

The authors report no conflicts of interest in this paper.


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