Overcoming obstacles for successful clinical trials in kidney disease

Introduction

The incidence and prevalence of chronic kidney disease (CKD) has been increasing, led by diabetes (DM) and hypertension (HTN) that are consequences of poor lifestyle and dietary habits (see USRDS 2012). Although effective treatments are available for both DM and HTN, recent observations from two large observational studies, namely Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) have shown that HTN is poorly controlled in CKD patients with only 20-40% of patients meeting the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) criteria for BP control.  The same reports show that, in diabetic patients with CKD, renin-angiotensin system (RAS) blockade with the use of ACE inhibitors and ARBs is vastly under-utilized, with only about 40% of diabetic CKD patients receiving such treatments [Vassalotti et al.], despite evidence that it can slow progression.

Very few drugs have been developed specifically to treat kidney disease.  Below is a list of drugs approved between 2003 and 2013 for CKD or kidney-related diseases or conditions (Reference):

Procysbi (cysteamine bitartrate) for the management of nephropathic cystinosis

Omontys (peginesatide) for anemia in dialysis patients

Soliris (eculizumab) for atypical HUS

Afinitor (everalimus) for kidney transplant rejection

Mircera (methoxy polyethylene glycol epoetin beta) for anemia associated with CKD

Renvela (sevelamer carbonate) for hyperphosphatemia

Fosrenol (lanthanum carbonate) for hyperphosphatemia

Sensipar (cinacalcet) for secondary hyperparathyroidism

Fabrazyme for Fabry’s disease

Most of the approved drugs listed above are for supportive care of CKD patients or for rare orphan diseases involving the kidneys.  Treatments are mainly focused on comorbidities such as diabetes,  hypertension, anemia, hyperlipidemia and disorders of mineral metabolism.  Despite a significant increase in R&D budgets in the past dacade, no new pharmaceutical agent has been approved specifically for the treatment of the underlying causes of AKI or CKD or for different types of glomerulonephritis.  Dialysis and  transplantation, although lifesaving procedures, are not ideal treatments.  They are associated with significant costs and the need for multiple treatments, including immunosuppressive drugs for transplantation.

What are the major gaps that need to be filled?

The current unmet needs in nephrology include: (1) Prevention and treatment of acute kidney injury; (2) Prevention and treatment of renal fibrosis and vasculitis, (3) diabetic nephropathy; (4) Lupus nephritis; (5) IgA nephropathy; (6) Steroid-resistant nephrotic syndrome, particularly focal segmental glomerulosclerosis; (7) MPGN and other types of glomerulonephritis; (8) Chronic transplant nephropathy; (9) Polycystic kidney disease.  Some relevant publications can be found here and here.

Why have so few drugs been developed to specifically target renal diseases?

The are many reasons but the main ones are as follows: (1) Kidney diseases are heterogeneous, comprising genetic/hereditary, metabolic, infectious, immunological and inflammatory diseases; (2) Multiple mechanisms underlie kidney disease progression, so drugs acting on a single target may not be effective; (3) Successful results in animal models of AKI and CKD do not always translate into clinical successes; (4) FDA does not accept surrogate endpoints such as reduction in proteinuria for approval, but is evaluating options. Currently only hard outcomes are acceptable, which requires 2-4 year studies and large numbers of subjects; (5) Nephrologists traditionally have not been organized to conduct large scale clinical trials, but the situation is changing through formation of consortia.

What should be done to accelerate the development and approval of novel drugs for kidney diseases?

A few ideas are presented here but new and fresh ideas are sorely needed:  (1) Better education of academic nephrologists in drug discovery, clinical trials and regulatory issues; (2) Development of a one-year pharmaceutical and clinical trials fellowship track, with certification.  This could be combined with existing trainings in this area from other sub-specialties; (3) Development of courses and symposia organized  by ASN, ISN and NKF on renal drug discovery and clinical trials.  4) Identification of new targets and new pathways of kidney injury and progression; (5) Development and validation of diagnostic and prognostic biomarkers to identify injury early and to be used as surrogate markers for registration trials.  Some of these ideas are already being evaluated.  NIH, in conjunction with the FDA,  academic and pharmaceutical scientists, has organized workshops for evaluation of drug targets and endpoints in both CKD and AKI (see here and here and here).  Next year, there will be an ISN Nexus 2014 symposium entitled “Efficient drug discovery and clinical trials in kidney disease”.  ISN Nexus 2014. Finally, FDA, in collaboration with NIH, academia and pharmaceutical companies, has initiated the Critical Path initiative, tasked at identifying such biomarkers.  C-Path is also working on developing Patient- Reported Outcomes (PROs) measurement instruments for drug development in CKD (see PROs in CKD).  A review of C-Path initiatives and completed projects is available at the C-Path website and in a 2008 review by Drs Janet Woodcock and Raymond Woosley.

© Copyright: M. Loghman-Adham, MD

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