Investigational drugs for the treatment of kidney transplant rejection

ABSTRACT

Introduction

Kidney transplant rejection remains an important clinical problem despite the development of effective immunosuppressive therapy. Two major types of rejection are recognized, T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), which have a different pathophysiology and are treated differently. Unfortunately, long-term outcomes of both TCMR and ABMR remain unsatisfactory despite current therapy. Hence, alternative therapeutic drugs are urgently needed.

Areas covered

This review covers novel and investigational drugs for the pharmacological treatment of kidney transplant rejection. Potential therapeutic strategies and future directions are discussed.

Expert opinion

The development of alternative pharmacologic treatment of rejection has focused mostly on ABMR, since this is the leading cause of kidney allograft loss and currently lacks an effective, evidence-based therapy. At present, there is insufficient high-quality evidence for any of the covered investigational drugs to support their use in ABMR. However, with the emergence of targeted therapies, the potential arises for individualized treatment strategies. In order to generate more high-quality evidence for such strategies and overcome the obstacles of classic randomized controlled trials, we advocate the implementation of adaptive trial designs and surrogate clinical endpoints. We believe such adaptive trial designs could help to understand the risks and benefits of promising drugs such as tocilizumab, clazakizumab, belimumab, and imlifidase.

KEYWORDS:

• Adaptive trial design
• Antibody-mediated rejection
• Immunosuppressive drugs
• Kidney transplantation
• Rejection
• Surrogate clinical endpoints
• T-cell-mediated rejection

Article highlights

• IL-6 plays a critical role in the pathophysiology of chronic ABMR and IL-6 directed therapy (tocilizumab and clazakizumab) holds potential for the treatment of chronic ABMR.

• Belimumab holds potential as B lymphocyte-targeted therapy, as it blocks the binding of BLyS to the B cell receptor, thereby preventing the survival of B lymphocytes and their differentiation into plasma cells, without causing general lymphocyte depletion.

• Cleavage of IgG-molecules and antigen-bound IgG by imlifidase could potentially replace plasma exchange in the treatment of ABMR.

• Complement inhibition is a potential, effector-mechanism targeted therapy for subtypes of ABMR characterized by high levels of complement activation.

• Implementation of adaptive trial designs and the use of surrogate clinical endpoints should be stimulated in kidney transplantation in order to facilitate more efficient data collection to enable rapid evaluation of new therapies of interest, and to develop individualized treatment strategies.

Declaration of interest

AE de Weerd has received consultation fees from HANSA for the Expert Workshop about imlifidase. The fees have been transferred to the kidney transplantation fund of Erasmus MC.

D.A. Hesselink has received lecture fees and consulting fees from Astellas Pharma, Chiesi Pharma, Medincell, Novartis Pharma, Sangamo Therapeutics, and Vifor Pharma. He has received grant support from Astellas Pharma, Bristol-Myers Squibb, and Chiesi Pharma.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.