Nephrotoxicity During Drug Development

A new review of this subject entitled Detection and Management of Nephrotoxicity during Drug Development has been recently published in Expert Opinion on Drug Safety. The article has been available ahead of print on-line since May 22, 2012.  The authors are members of Renal Safety Expert Group at Roche pharmaceutical company and have many years of combined experience in nephrology, drug development and drug safety.  Previous reviews of the subject have focused on acute kidney injury (AKI) and do not distinguish between different causes of AKI such as ischemia, sepsis or nephrotoxins.  The article by Loghman-Adham et al. is is one of the first articles that specifically addresses drug-induced nephrotoxicity (DIN) and provides practical guidance for risk mitigation and early detection of DIN during all phases of drug development. The application of biomarkers of nephrotxicity is discussed and there are a number of useful tables and figures that provide practical information on how to diagnose and manage DIN.  For complete disclosure, I am one of the authors of this paper.  Below is a link to the journal and the abstract of the article.

http://informahealthcare.com/doi/abs/10.1517/14740338.2012.691964

Reviewed  by Mahmoud Loghman-Adham, MD

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ALTITUTE trial of aliskiren on top of ACE or ARB discontinued on DSMB recommendation

Dec 20, 2011 Shelley Wood from heartwire
Basel, Switzerland – An increase in adverse events and no apparent benefits among patients randomized to aliskiren (Rasilez/Tekturna, Novartis) in the ALTITUDE trial has prompted the data safety and monitoring board (DSMB) for the study to recommend its termination, the sponsor announced today [Novartis press release here].

ALTITUDE was studying aliskiren on top of ACE-inhibitor or angiotensin-receptor-blocker (ARB) therapy in patients with type 2 diabetes and renal impairment compared with a placebo add-on.

In making its recommendation, the DSMB noted that the active-treatment group experienced an increased incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension over 18 to 24 months of follow-up. The committee concluded that patients were unlikely to benefit from aliskiren on top of standard antihypertensive therapy.

“Novartis is in ongoing discussions with health authorities worldwide about the implications of the findings from ALTITUDE for patients,” a press release reads. “As a precautionary measure, Novartis will cease promotion of Rasilez/Tekturna-based products for use in combination with an ACE inhibitor or ARB.”

The company is also checking in with the DSMBs of other clinical studies studying aliskiren alone or in combination.

ALTITUDE investigators are being told to remove aliskiren from their patients’ treatment regimen and review their current blood-pressure medications; patients in ALTITUDE are advised to contact their doctors.

Earlier this year, positive results of the ACCELERATE trial looking at aliskiren in combination with a calcium-channel blocker were published in the Lancet. Last year the FDA approved both a dual- and triple- combination drug including aliskiren, but neither drug included an ACE inhibitor or ARB.

Original source: Heartwire

Novartis Press Release: ALTITUDE press release

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The FNIH Biomarkers Consortium Launches Project to Improve Diagnosis of Kidney Injury

Bethesda, MD (November 1, 2011) – The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium announced today the launch of a two-year clinical study aiming to advance the acceptance of new biomarkers designed to detect drug-induced kidney injury in clinical trials. The study is being conducted in collaboration with the Predictive Safety Testing Consortium (PSTC), a public-private partnership founded by the Arizona-based non-profit Critical Path Institute (C-Path).

The potential toxic effect of some medications on the kidney – or drug-induced nephrotoxicity -can be a serious problem for drug developers. The current standard biomarkers used to detect acute kidney injury are not sensitive enough and can produce false positive results; sometimes forcing researchers to abandon otherwise promising drug candidates. The FNIH Biomarkers Consortium Kidney Safety project is designed to test new biomarkers that are more sensitive, and will establish better criteria for when kidney safety concerns should halt further testing of a drug in humans.

“Patient safety is and must be our primary concern as we develop potential new medicines,” explained Gary Herman, M.D., Vice President, Early Stage Development at Merck Research Laboratories. “The FNIH Biomarker Consortium Kidney Safety project is critical to help identify biomarkers that improve the process of developing effective medicines that are safe to test and use with patients.”

The clinical studies will be conducted at four major U.S. medical research centers: the University of Southern California, the University of Minnesota, the Brigham and Women’s Hospital/Dana Farber Cancer Institute and the MD Anderson Cancer Center. Blood and urine samples will be collected from patients undergoing treatment with two different drugs known to cause injuries to the kidney tubule; cisplatin, a common type of chemotherapy drug taken by patients with head and neck cancer, and aminoglycosides, a common type of antibiotic drug taken by patients with cystic fibrosis.

The project will enable the continued development of potentially valuable compounds across a number of therapeutic areas, such as cancer, cystic fibrosis and diabetes. The data generated from this project is aimed to advance regulatory acceptance of new biomarkers appropriate for monitoring kidney safety in the clinic. Importantly, this data will improve clinical diagnoses of drug induced kidney injury during drug development and patient therapy.

“We need better ways of predicting potential kidney injury from new therapies early on in the development process,” said Janet Woodcock, M.D., Director of the Center for Drug Evaluation Research at the U.S. Food and Drug Administration. “The Biomarkers Consortium project represents a powerful collaborative approach to qualifying the biomarkers needed to accomplish this.”

The studies, managed by the FNIH Biomarkers Consortium, will build significantly on previous work to qualify kidney safety markers for use in animal studies conducted by the PSTC. The PSTC and C-Path are also providing healthy volunteer data, database, and biorepository services to support the Biomarkers Consortium effort. The project, led by Frank Sistare, PhD, of Merck Research Laboratories, will also include participation of a diverse group of experts from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH), the Food and Drug Administration (FDA), several pharmaceutical companies, and academic organizations. Participating and funding organizations include Amgen, AstraZeneca, C-Path, Eli Lilly & Company, Johnson & Johnson, Merck Research Laboratories, and Pfizer.

For more information about this project, please visit www.biomarkersconsortium.org or www.fnih.org

About the Foundation for the NIH

Established by the United States Congress to support the mission of the NIH-improving health through scientific discovery in the search for cures-the Foundation for the NIH is a leader in identifying and addressing complex scientific and health issues. The Foundation is a non-profit, 501(c)(3) charitable organization that raises private-sector funds for a broad portfolio of unique programs that complement and enhance NIH priorities and activities. For additional information about the Foundation for the NIH, please visit www.fnih.org

About the Biomarkers Consortium

The Biomarkers Consortium is a public-private biomedical research partnership managed by the Foundation for the National Institutes of Health (FNIH) that endeavors to develop, validate, and/or qualify biological markers (biomarkers) to speed the development of medicines and therapies for detection, prevention, diagnosis and treatment of disease and improve patient care. For additional information about the Biomarkers Consortium, please visit www.biomarkersconsortium.org

Reported on November 9, 2011 by eteichert @ Fierecebiotech.com
Source URL: http://www.fiercebiotech.com/press-releases/fnih-biomarkers-consortium-launches-project-improve-diagnosis-kidney-injury-0

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STAT3 as a possible new drug target for polycystic kidney disease

Two discoveries at UC Santa Barbara point to potential new drug therapies for patients with kidney disease. The findings are published in this week’s issue of the Proceedings of the National Academy of Sciences.
Over 600,000 people in the U.S., and 12 million worldwide, are affected by the inherited kidney disease known as autosomal dominant polycystic kidney disease, or ADPKD. The disease is characterized by the proliferation of cysts that eventually debilitate the kidneys, causing kidney failure in half of all patients by the time they reach age 50.
Currently, no treatment exists to prevent or slow cyst formation, and most ADPKD patients require kidney transplants or lifelong dialysis for survival, explained Thomas Weimbs, director of the laboratory where the discoveries were made. Weimbs is an associate professor in the Department of Molecular, Cellular and Developmental Biology and the Neuroscience Research Institute at UCSB.
First, Weimbs and his research team discovered a molecular mechanism that sheds light on the disease. The mechanism concerns polycystin-1, a protein that is mutated in ADPKD patients. The team discovered how this protein regulates a well-known transcription factor called STAT3. Transcription factors transcribe information from DNA to RNA, from specific genes. Second, the team discovered that STAT3 is strongly, and aberrantly, activated in polycystic kidneys.
“The clinical significance of these discoveries lies in the fact that STAT3 is also known to be aberrantly activated in many forms of cancer and is considered an important drug target for cancer therapy,” said Weimbs. “Numerous STAT3 inhibitors are currently being developed and tested, and several experimental drugs are already available. Our results suggest that STAT3 activation is a driving force for the cyst growth that leads to polycystic kidneys in ADPKD. Therefore, STAT3 may be a highly promising drug target for the treatment of ADPKD.”
Weimbs explained further that STAT3 is a signaling molecule that is activated in response to many different growth factors binding to specific receptors on the surface of kidney cells. In response to these growth factors hitting the cell, STAT3 is activated. That causes STAT3 to turn on the expression of certain genes. This activity causes the cells to proliferate, as they do in cancer.
“In polycystic kidney disease, we have strong proliferation, but it is similar to having benign tumors — where the tumor stays in place,” said Weimbs. “The cysts keep growing, but they do not metastasize or invade other tissues as do cancerous tumors. Polycystic kidneys are full of small, benign tumors or cysts. This is still very destructive, because eventually the disease will destroy the kidney.” The research team is currently testing STAT3 as a drug target in mice with ADPKD.
The National Institutes of Health funded the research.

Source: ScienceDaily (Apr. 26, 2011)
http://www.sciencedaily.com/releases/2011/04/110426131817.htm
The original article can be found at PNAS: http://www.pnas.org/content/108/19/798

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Affymax’s peginesatide one step closer to FDA approval

The US Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) voted 15 to one, with one abstention, that peginesatide (formerly known as Hematide), demonstrated a favorable benefit/risk profile for use in the treatment of dialysis patients with anemia due to chronic kidney disease (CKD). The drug’s sponsor is US drugmaker Affymax (Nasdaq: AFFY) which has as its partner Takeda Pharmaceutical (TSE:4502), Japan’s largest pharma firm. The news pushed Affymax shares 30.5% higher to $7.65.
Given that the drug gets final FDA approval, peginesatide would compete with blockbusters such as Amgen’s Epogen (epoetin alfa), which generated $2.5 billion in revenue last year, and Johnson & Johnson’s Procrit (epoetin alfa), with 2010 sales of $1.9 billion.
“We’re encouraged by the panel’s positive view of the benefit/risk profile of peginesatide in the dialysis setting,” said John Orwin, president and chief executive of Affymax, noting that “anemia affects many patients in the dialysis setting, and we look forward to working with the FDA as they complete their evaluation of peginesatide. As a once-monthly treatment, peginesatide, if approved, has the potential to be an important option in the management of anemia in patients living with this condition.”
While the FDA is not bound by the recommendations of its advisory committees, their guidance will be considered by the FDA in its review of the New Drug Application (NDA) that was submitted for peginesatide in May 2011. The scheduled Prescription Drug User Fee Act (PDUFA) date for peginesatide is March 27, 2012.
“Today’s ODAC vote represents an important step in the peginesatide New Drug Application review process,” said Azmi Nabulsi, president, Takeda Global Research & Development Center, Inc. “As we heard from the discussion today, limited therapeutic options are available for the treatment of anemia in dialysis patients with chronic kidney disease. Affymax and Takeda will continue efforts to make this alternative available to dialysis patients and the providers who treat them,” he added.
Source: The Pharma Letter
http://www.thepharmaletter.com/file/109484/fda-committee-backs-affymax-ckd-drug.html

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The NIH Conference: Impact of Chronic Kidney Disease, opportunities for randomized clinical trials

On July 19 and 20, I attended a conference and workshop organized by the NIH, entitled “Reducing the Impact of Chronic Kidney Disease, opportunities for randomized clinical trials”. It was attended by over 150 people representing academic nephrologists, NIH, FDA, as well as a dozen pharmaceutical companies (Abbott, Amgen, Ardelyx, Celgene, Concert, CoreMedix, Eli Lilly, Genzyme, Kureha, Mitsubishi-Tanabe, Otsuka, Pfizer, Questcor, Reata, Sanofi-Aventis…).

There were presentations on investigator-initiated pilot studies of anti-oxidants, bicarbonate, mineralocorticoid receptor blockers, pentoxifylline, and vitamin D in the prevention or slowing of progression of CKD. There were several workshops with the goal of identifying and designing studies to prevent progression. The investigator-initiated studies were in general of small scale and the drugs used are currently approved for other indications or are generic unpatented drugs such as bicarbonate. However, they provide information on interesting targets for improvements on the existing drugs or the development of new molecular entities. The use of aldosterone receptor blockers on top of ACEI and ARBs is associated with a relatively high incidence of hyperkalemia, and this could be much higher in patients with stage 4 CKD. So their widespread use is unlikely. Pentoxifylline has beneficial effects but high doses (1800 to 2400 mg) are needed, leading to poor GI tolerance. Studies of vitamin D supplements are becoming more complicated since 25-OH-D levels in the general population is increasing as more people are taking large doses of vitamin D supplements.

The session on industry-sponsored studies included reports of the BEACON trial (patients with diabetic nephropathy with stage 3 CKD) by Reata, which is co-developing Bardoxolone with Abbott. The results of this phase 2, dose finding and efficacy trial were published last month in the NEJM (see link to press release by Reata and to the article). The safety remains an issue with 60% of patients at higher doses having muscle spasms and 14-23% having hyperkalemia. These were significantly higher than for the placebo group. The drug also has hemodynamic effects, rising GFR rapidly within the first 4-8 weeks, which then remains unchanged for 52 weeks. The presenter said that there is not an effect on the Cr measurements. Only eGFR was measured, but in preclinical studies they used inulin clearance which showed similar findings. The higher GFR seems to last for 4 weeks after stopping the drug, which suggest that there may be real improvements. Clearly they need to tease out the hemodynamic versus structural changes. Perhaps renal biopsy may be needed.

Concert pharmaceuticals use a proprietary method to replace H+ atoms on existing drugs with deuterium (D), which results in improvements in their pharmacodynamics properties. They have deuterated versions of pentoxifylline called CTP-499. More information on their website.

The presentation by Celgene was on AC-011, which is an activin receptor fusion protein. It is being co-developed with Aceleron and Celgene to improve bone metabolism and increase bone density. Although it did have effects on bone, patients suffered from thrombotic related side effects and hypertension, which were related to a rapid rise in hemoglobin. They are now focusing on the use of this drug for the treatment of chemotherapy-induced anemia. The mechanism of action is not well understood. It does result in a dose-dependent increase in Hb, up to a mean of 3.6 g/dL at the highest dose of 10 mg/kg. It is given once every 28 days. See the publications and a recent poster presentation on this drug on Aceleron website. Considering the restriction on the use of ESAs in CIA, the commercial success of this drug in this indication may not be certain, but it has revealed a new mechanism of anemia correction, which could lead to new drugs for anemia of CKD.

Abbott presented the results of their phase 2 dose ranging study on atrasentan, an endothelin-1a receptor antagonist in patients with diabetic nephropathy and overt proteinuria. The results have been published in JASN. Briefly, there was a marked reduction in urinary albumin excretion which was dose dependent. The major side effect was edema, which occurred in 18% of those on the 0.75 mg dose (optimum dose to take forward). A summary is also available at Abbott website.

Mitsubishi-Tanabe showed data on AST-120, a resin that binds uremic toxins. It has been marketed in Japan for over 10 years and has a good safety record, as it is not absorbed systemically. They are conducting a phase 3 global outcomes trial on 4000 patients in the US and Europe with the aim of obtaining approval. They also have a similar resin to be used as phosphate binder, which is also in phase phase 3 (see company website). I think that MP-146 is the same drug.

Questcor Pharmaceuticals presented data on Acthar, which is their porcine ACTH. The drug has been marketed for many years but new information has emerged on its action on melanocortin receptors and on oxidative stress, which opens the possibility of using it to alter progression of renal disease and other diseases. They are using it in diabetic nephropathy. Proteinuria was significantly reduced and serum Cr did not increased in treated patients, but it did in controls. Some preliminary data were also presented at last year’s ASN meeting (see press release). This is a very interesting concept and may lead the path to the development of NMEs affecting the melanocortin receptors in a more selective fashion. See also a recent paper in JASN.

The breakout sessions were on: pediatric studies of progression, trials with bicarbonate, trials with pentoxifylline, trials with mineralocorticoid receptor blockers, and trials with phosphate control and vitamin D. I participated at the pediatric session. The aim was for the teams to identify areas where clinical trials are needed to settle unanswered questions such as to confirm the results of observational studies. The teams were also charged to recommend high level study designs/protocols for such studies. The studies will be multi-center studies of approximately 5-years in duration and most likely funded through NIH via specific RFAs issued based on these recommendations.

Copyright © Mahmoud Loghman-Adham, MD

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Use of Biomarkers in Renal Diseases

1. BACKGROUND AND INTRODUCTION

Traditional risk factors for CV disease (CVD) derived from the Framingham Heart Study do not predict all deaths due to cardiovascular events or stroke [Stenvinkel P 2006]. Biomarkers can supplement the information provided by traditional risk factors and help identify patients at risk of CV disease and death. A biomarker can be defined as ‘a biochemical feature or facet that can be used to measure the progress of disease or the effects of treatment’ [MedicineNet.com, Ref 2].
The inclusion of biomarkers should be considered beginning in phase II and throughout phase III development program for any new drug. They include either biomarkers that allow selection of sub-populations likely to respond to the study drug (e.g. genotyping) or those that identify early changes associated with serious adverse events or death in the study population (risk stratification biomarkers). A separate informed consent is required for the use of biomarkers.
Due to a high prevalence of cardiovascular disease in the CKD population, the inclusion of biomarkers that can predict CVD and mortality has been proposed in randomized clinical trials in this patient population. The following biomarkers have been relatively well characterized: homocysteine, high–sensitivity C-reactive protein, cardiac troponin I (cTnI) and troponin T (cTnT), B-type natriuretic peptide (BNP), NT-proBNP, asymmetric dimethyl arginine (ADMA), and cystatin C. Additional biomarkers, particularly those related to genetic polymorphisms are being discovered at a rapid pace. This article describes the currently proposed biomarkers that may be included in studies of patients with CKD and anemia.

2. HIGH SENSITIVITY C-REACTIVE PROTEIN
C-reactive protein (CRP) is an acute phase reactant which is elevated during infections and inflammation. CKD patients, especially those receiving dialysis treatments have a microinflammatory state [Kaysen 2001]. High levels of CRP have been associated with increased mortality from cardiovascular complications in the general population. Compared to individuals without CKD, baseline CRP levels are much higher in CKD patients both in those not yet on dialysis and in those receiving dialysis. Increased CRP levels have been shown to be a reliable marker of morbidity and mortality in CKD Patients.

3. B-TYPE NATRIURETIC PEPTIDE (BNP) AND N-TERMINAL PRO-BNP
BNP is a peptide released from ventricles in response to wall tension. Its levels are increased in patients with congestive heart failure and in acute coronary syndromes such as unstable angina [Jenberg 2002]. Increased levels of both tests correlate with increased risk of death from cardiovascular complications in patients with chronic kidney disease [Austin 2006]. Measurement of NT pro-BNP is a useful tool for risk stratification in patients with a variety of conditions including those with chronic kidney disease [Costello-Boerrigter 2005].

4. CARDIAC TROPONIN T (CTNT)
Troponin T is a cardiospecific, highly sensitive marker of myocardial damage [Ohman1996]. Myocardial cell injury leading to elevated serum cTnT concentrations can occur not only after myocardial infarction but also in congestive heart failure, cardiomyopathy, acute coronary syndromes and heart contusion [Ohman 1996]. Cardiac troponin T may also be used as a biomarker for the assessment of mortality in ESRD patients. Elevated cTnT levels can identify ESRD patients who have poor survival and are at a high risk of cardiac death [Khan 2005].

The use of a multi-biomarker panel including hsCRP, NT pro-BNP, and cTnT or cTnI has been shown to increase the ability to predict the relative risk for all cause mortality in ESRD patients, compared to the risk prediction when each biomarkers is used separately [Apple FS, 2004].

5. HEPCIDIN AND PRO-HEPCIDIN
This test allows the determination of the influence of inflammation and cytokines in resistance to erythropoietic stimulating agents. Hepcidin is an iron-regulatory peptide that is increased during inflammation [Deicher 2004]. It can block intestinal absorption of iron and the release of iron from macrophages. High hepcidin levels are expected in ESRD patients and may be correlated with resistance to iron and to ESA therapy.

6. ASYMMETRIC DIMETHYLARGININE (ADMA)
ADMA is an endogenous inhibitor of nitric oxide (NO) synthase. High levels of ADMA can result in endothelial dysfunction and atherosclerosis. ADMA levels are markedly increased in patients with CKD [Zoccali 2006], suggesting that it may play a role in atherosclerotic complications in these patients. ADMA levels correlate with left ventricular mass and with intima-media thickness of the carotid artery [Zoccali et al. 2006]. Therefore, studies are needed to explore its usefulness as a biomarker of CVD progression in CKD patients.

7. CYSTATIN C
Serum Cystatin C measurements have been advocated as a more accurate measure of kidney function. Recent studies in an elderly population with no evidence of CKD showed that elevated cystatin C ((≥ 1.0 mg/L) can be used as a biomarker to predict the risk of death, heart failure, stroke and myocardial infarction [Shlipak MG, 2006]. In contrast, serum creatinine or GFR, calculated by the MDRD formula, could not predict death and only showed a weak correlation with CV death. Subjects with elevated cystatin C had a 4-fold increased risk of progression of CKD.

8. REFERENCES
1. Stenvinkel P. Inflammation in end-stage renal disease: the hidden enemy. Nephrology (Carlton). 2006;11(1):36-41.
2. http://www.medterms.com/script/main/art.asp?articlekey=6685
3. Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation. 2006;113(19):2335-2362
4. Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem. 2001;47(3):403-411.
5. Kaysen GA. The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol. 2001;12(7):1549-1557
6. Apple FS, Murakami MM, Pearce LA, Herzog CA. Multi-biomarker risk stratification of N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and cardiac troponin T and I in end-stage renal disease for all-cause death. Clin Chem. 2004;50:2279-2285.
7. Deicher R, Hörl WH. Hepcidin: a molecular link between inflammation and anaemia. Nephrol Dial Transplant 2004;19:521-524.
8. Jenberg T, Stridsberg M, Venge P, Lindahl B. N-Terminal Pro brain natriuretic peptide on admission for early risk stratification with chest pain and no ST-segment elevation. J Am Coll Cardiol 2002;40:437-45.
9. Austin WJ, Bhalla V, Hernandez-Arce I, Isakson SR, Beede J, Clopton P, Maisel AS, Fitzgerald RL. Correlation and prognostic utility of B-type natriuretic Peptide and its amino-terminal fragment in patients with chronic kidney disease. Am J Clin Pathol. 2006 Oct;126(4):1-7.
10. Costello-Boerrigter LC, Burnett JC Jr. The prognostic value of N-terminal proB-type natriuretic peptide. Nat Clin Pract Cardiovasc Med. 2005;2(4):194-201.
11. E. Magnus Ohman et al. Cardiac Troponin T Levels for Risk Stratification in Acute Myocardial Ischemia. 1996; 335:1333-1342.
12. Khan NA, Hemmelgarn BR, Tonelli M, Thompson CR, Levin A. Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease: a meta-analysis. Circulation. 2005;112(20):3088-3096.
13. Zoccali C, Mallamaci F, Tripepi G. Asymmetric dimethylarginine (ADMA) as a cardiovascular risk factor in end-stage renal disease (ESRD). Eur J Clin Pharmacol. 2006; 62 Suppl 13:131-5.
14. Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, Seliger SL, Kestenbaum B, Psaty B, Tracy RP, Siscovick DS. Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern Med. 2006;145:237-246

Copyright © M. Loghman-Adham 2011

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New Drugs for Kidney Disease

Welcome to Kidney Disease Drug Development Website.  This site is dedicated to the presentation and discussion of articles and news releases related to the general topic of drug development with emphasis on drugs for kidney diseases.

The views expressed are those of the authors and do not represent endorsement by authors’ employers or sponsors.

 

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