Renal community needs to promote clinical research in nephrology

Issue: January 2020

ByFranklin Maddux, MD

ByKurt Mussina, MBA

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At least 20% of people between the ages of 65 and 74 years, and half of those older than 75 years, have chronic kidney disease.¹ Yet, development pipelines for the 10 largest pharmaceutical companies contain fewer than 30 active nephrology clinical investigations compared with more than 1,300 in oncology.² In contrast with the vast number of research protocols, cancer patients are encouraged to consider inclusion in clinical studies. That is not a standard opportunity for people with kidney disease despite their eagerness to participate.³

Why is this? How can the industry be encouraged to think differently to advance renal research for the betterment of public health?

Always a poor cousin

Since 1945, trials for renal indications have lagged behind other organ system categories. As clinical trial activity has increased, the gap between investigation of renal disease and other disease entities — notably, oncology and infectious disease — has widened (see Figure 1).^4,5

Source: Fresenius Medical Care

Not only is kidney disease often excluded from the focus of studies from pharmaceutical companies, but patients with kidney disease are often excluded from other studies. For example, a systematic review of randomized trials for cardiovascular disease (CVD) interventions between 2006 and 2013 revealed that of 371 trials, 57% (212) excluded patients with kidney disease.⁶ Renal disease affects so many physiological systems that researchers are reluctant to include these patients for fear of adverse effects. Yet, exclusion of this population seems imprudent. Kidney disease is common in people with CVD, and they could benefit from tested interventions.⁷

Human and financial costs

The number of people likely to be diagnosed with cancer in the United States is smaller than the number likely to be diagnosed with kidney disease. The NIH projects that by 2020, there will be 18.1 million cancer survivors with a projected annual cost of care of $157 billion (in 2010 dollars).⁸ While these numbers are staggering, the cost of kidney disease is also high, with more people affected by kidney disease than cancer. The CDC estimates the prevalence of CKD in the general adult population to be 15% (37 million).⁹ The 2018 U.S. Renal Data System (USRDS) Annual Report estimated the total Medicare spending on both patients with CKD and ESRD is in excess of $114 billion.¹⁰ It is difficult to estimate the cost of CKD and ESRD in combination with concomitant diseases that typically complicate renal care.

A person can lose 90% of kidney function before experiencing symptoms, making kidney disease a hidden public health crisis.¹¹ “There are many missed opportunities for [CKD’s] potential early detection and subsequent treatment implementation,” Rajiv Saran, MD, professor of internal medicine at the University of Michigan and director of the USRDS coordinating center, said. “For example, the relatively low testing rates for urine protein even among those with diabetes or hypertension — both well-known risk factors for kidney disease — remains a concern.”¹²

The idea that this disease has been overlooked for so long is astounding.

Engagement

In 2018, 15 new oncology treatments were introduced and the number of drugs in late-stage development expanded by 19%, up 63% since 2013.¹³ As of the second quarter of 2019, there is one nephrology study for every 39 cancer studies in the pipeline.¹⁴ This difference is disproportional to the prevalence of these diseases in the population.

Many factors affect research and development investment decisions, such as potential commercial value, competition, therapy novelty, likelihood of approval, development cost and time, and public perception. The public demand for effective oncological treatments has driven the development of precision and immune-oncology therapies, offering hope to millions. However, nephrology is a completely different landscape. There is little public demand and urgency to create novel kidney-related therapies because many patients will expire due to associated comorbid conditions, such as CVD, before they even know they have kidney issues.

Discrepancy in funding

In 2018, with a budget of $39 billion, the NIH provided 10-times more funding for cancer than for kidney disease ($6.34 billion vs. $598 million), while Alzheimer’s disease research received $1.91 billion.¹⁵ The American Society of Nephrology Research Advocacy Committee estimates that the NIH spent more than $500 annually per cancer patient but only $30 per patient with CKD.¹⁶ Indeed, Kaiser’s annual “Hot 100” indications list — a gauge of global research and development investment in pharma showed that in 2018, kidney transplant was listed at number 70, while epidermolysis bullosa, a genetic skin disorder with an incidence of one in every 50,000 live births, was number 41.¹⁷

Industry press has framed the $25 million KidneyX initiative — a partnership between the HHS and the ASN — as nephrology’s answer to the Cancer Moonshot program; however, funding for the Cancer Moonshot is $1.8 billion. That is 72 times the funding of KidneyX.¹⁸

It is difficult to determine to what extent research generates sales through improved or novel offerings, or how pharmaceutical sales increase interest in research, but in 2017, the global CKD drug market was estimated at $2.7 billion.¹⁹ In contrast, the global oncology drug market was valued at $97.4 billion.²⁰

Source: Chatzimanouil MKT, et al. J Am Soc Nephrol.2019;3:doi:10.168VASN.2018050515.

Even with reasonable funding, investigator and patient barriers to successful renal research remain. Kidney failure patients’ low glomerular filtration rate may alter the safety profile of certain drugs and devices.21 Multiple comorbidities also make trials in renal patients risky and confound results.

Limited activity in kidney research has impacted the evidence base for CKD treatment, resulting in the lack of useful surrogate end points for progression from early stage CKD hindered trials. Several costly phase 3 trials recently failed to achieve improved outcomes, further curtailing industry interest.²² At present, there are relatively few therapies in development for the treatment of CKD, and the global CKD drug market consists mainly of calcium channel blockers and ACE inhibitors — therapies that have hardly changed in the past 30 years; however, the sodium-glucose transport protein 2 inhibitors have begun to show promise and the active early stage research for more drug targets seems to be growing.²³

New interest in kidney research

A 2018 joint National Kidney Foundation, FDA and European Medicines Agency massive data meta-analysis has begun to yield basic insight — for instance, the value of albuminuria for tracking early CKD disease progression.²⁴ Current genetic techniques should uncover more sensitive biomarkers to help identify and follow patients with early onset CKD.²⁵

Despite inadequate funding and scarce high-quality randomized trials, important clinical research studies do exist. For example, small-molecule drugs for the treatment of anemia in patients with CKD have been developed. A glucuretic proximal tubule transport inhibitor is also in trials to evaluate its effect on renal outcomes and cardiovascular mortality in patients with CKD.²⁶

The renal research and patient communities are resolved to change; however, only 22% of patients heard about clinical trial opportunities from their nephrologist, their most trusted source of information. This statistic is in stark contrast to patients with melanoma (45%) and lung cancer (58%) whose oncologists frequently shared information about clinical trial opportunities. As patients and investigators are the bedrock of successful clinical trials, changing this pattern is key.²⁷

Within the nephrology and renal care ecosystem, building awareness of the potential economic and clinical benefits of trial participation should help recruit high-performing investigative sites. Clinically, study patients may be able to receive treatments otherwise unavailable, plus they can have the satisfaction of giving back, an important consideration for many renal patients.²⁸ As patients are seen by both clinical and research teams, they benefit psychologically and medically from the increased level of care. Although not confirmed in renal trials, study patients in other disease areas have shown increased engagement and better adherence with improved clinical outcomes.^29,30

Despite the benefits, physicians often avoid adding the complexity of clinical research to their patient practices. Today, however, the industry is motivated to relieve the research burden to increase physician participation. Outsourcing services can be engaged to essentially manage administrative research tasks. Principal investigators can enjoy the benefits of participating in clinical studies, yet still have time to care for patients.

Conclusion

While kidney research faces challenges, the renal research community must mobilize to overcome them. Enlisting the help of front-line nephrologists and easing barriers for participation in clinical trials are important steps in making kidney research more attractive for prospective investigators.

Pointing to frenzied and redundant investments in oncological research and biotech, Jay Bradner, Novartis research and developement president, questioned in a 2018 Forbes interview: “Can we as a society be over-invested in working to cure cancer?”³¹ Maybe investors should be asking the same question. It is time we all take a closer look at kidney research — an almost uncharted area with vast, hidden potential.

• For more information:
• Kurt Mussina, MBA, is senior vice president of Fresenius Medical Care and president of Frenova Renal Research.
• Franklin Maddux, MD, FACP, is global chief medical officer and member of the management board for Fresenius Medical Care AG & Co. KGaA.

Disclosures: Mussina and Maddux report they are employed by Fresenius Medical Care.

• References:
• 1. United States Renal Data System. 2018 Annual Data Report. CKD in the general population. www.usrds.org/2018/view/v1_01.aspx.
• 2. BioPharm Insights. Top ten therapeutic classes by estimated 2017 global pharmaceutical sales. www.biopharmainsights.com. Accessed Nov. 5, 2018.
• 3. SCORR Marketing & Antidote Technologies. Research report: The patient perspective on clinical trials. www.scorrmarketing.com/resources/the-patient-perspective-on-clinical-trials/.
• 4. Breyer MD, et al. Semin in Nephrol. 2016;doi:10.1016/j.semnephrol.2016.08.001.
• 5. Chatzimanouil MKT, et al. Jrnl Am Soc Nephrology. 2019;doi:10.1681/ASN.2018050515.
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• 8. National Cancer Institute. Cancer prevalence and cost of care projections. https://costprojections.cancer.gov. Accessed May 22, 2019.
• 9. CDC. Chronic Kidney Disease in the United States, 2019. www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html. Accessed May 22, 2019.
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• 17. National Organization for Rare Disorders. Rare disease database. https://rarediseases.org/rare-diseases/epidermolysis-bullosa. Accessed May 22, 2019.
• 18. DelBene, Bucshon applaud inclusion of $10 million for KidneyX funding and innovation. https://delbene.house.gov/news/documentsingle.aspx?DocumentID=2446. Accessed June 3, 2019.
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• 21. Decker E, et al. Advances in Chronic Kidney Disease. 2014;doi:10.1053/j.ackd.2014.02.012.
• 22. Breyer MD, et al. Semin in Nephrol 2016;doi:10.1016/j.semnephrol.2016.08.001.
• 23. Mendu MM, et al. American Journal of Public Health. 2016;doi:10.2105/AJPH.2015.303009.
• 24. National Kidney Foundation. First reports from ambitious workshop. www.kidney.org/news/first-reports-ambitious-kidney-disease-clinical-trial-endpoints-workshop-to-be-published-lancet. Accessed May 22, 2019.
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• 28. Ibid.
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