DEVELOPING THERAPIES FOR C3G: REPORT OF THE KIDNEY HEALTH INITIATIVE C3G TRIAL ENDPOINTS WORK GROUP.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3G, a rare glomerular disease. The Kidney Health Initiative (KHI) convened a panel of experts in C3G to: (1) assess the data supporting the use of the prespecified trial endpoints as measures of clinical benefit; and (2) opine on efficacy findings they would consider compelling as treatment(s) for C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work group reviewed the available evidence and uncertainties for the association between the three prespecified endpoints -- (1) proteinuria; (2) estimated glomerular filtration rate (eGFR); and (3) histopathology -- and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed endpoints they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, the evidence, and uncertainties, supporting the endpoints. Given the limitations of the available data, the workgroup was unable to define a minimum threshold for change in any of the endpoints that might be considered clinically meaningful. The workgroup concluded that a favorable treatment effect on all three endpoints would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three endpoints if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the endpoints in the aforementioned trials.

Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients.

Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.

End Point Considerations for Clinical Trials in Enteric Hyperoxaluria.

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration-approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include ( 1 ) an irreversible loss of kidney function as a surrogate for progression to kidney failure, ( 2 ) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, ( 3 ) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and ( 4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.

Overcoming Barriers to Drug Development in Children with CKD.

Like all sick children, children with CKD need access to safe and effective medicines that have been formulated and examined specifically for them. Despite legislation in the United States and the European Union that either mandates or incentivizes programs for children, conducting trials to advance the treatment of children continues to prove to be a challenge for drug developers. This is also the case for drug development in children with CKD, where trials face challenges in recruitment and completion and where there remains a substantial time lag between initial approval of a medicinal product for use in adults and completion of studies that result in the addition of pediatric-specific labeling for the same indication. The Kidney Health Initiative commissioned a workgroup of diverse stakeholders ( https://khi.asn-online.org/projects/project.aspx?ID=61 ), including participants from the Food and Drug Administration and the European Medicines Agency, to think carefully through the challenges in drug development for children with CKD and how to overcome them. This article provides an overview of the regulatory frameworks in the United States and the European Union that govern pediatric drug development, the current landscape of drug development and approval for children with CKD, the challenges in conduct and execution of these drug trials, and the progress that has been made to facilitate drug development for children with CKD.

Clinical Trial Considerations in Developing Treatments for Early Stages of Common, Chronic Kidney Diseases: A Scientific Workshop Cosponsored by the National Kidney Foundation and the US Food and Drug Administration.

In the past decade, advances in the validation of surrogate end points for chronic kidney disease (CKD) progression have heightened interest in evaluating therapies in early CKD. In December 2020, the National Kidney Foundation sponsored a scientific workshop in collaboration with the US Food and Drug Administration (FDA) to explore patient, provider, and payor perceptions of the value of treating early CKD. The workshop reviewed challenges for trials in early CKD, including trial designs, identification of high-risk populations, and cost-benefit and safety considerations. Over 90 people representing a range of stakeholders including experts in clinical trials, nephrology, cardiology and endocrinology, patient advocacy organizations, patients, payors, health economists, regulators and policy makers attended a virtual meeting. There was consensus among the attendees that there is value to preventing the development and treating the progression of early CKD in people who are at high risk for progression, and that surrogate end points should be used to establish efficacy. Attendees also concluded that cost analyses should be holistic and include aspects beyond direct savings for treatment of kidney failure; and that safety data should be collected outside/beyond the duration of a clinical trial. Successful drug development and implementation of effective therapies will require collaboration across sponsors, patients, patient advocacy organizations, medical community, regulators, and payors.

Treating Early-Stage CKD With New Medication Therapies: Results of a CKD Patient Survey Informing the 2020 NKF-FDA Scientific Workshop on Clinical Trial Considerations for Developing Treatments for Early Stages of Common, Chronic Kidney Diseases.

Rationale & Objective: With a growing number of medications and therapies available to treat chronic kidney disease (CKD), risk-versus-benefit discussions are increasingly critical. Balancing risks and benefits requires assessing patients' understanding of these, as well as incorporating patient preferences and tolerance for side effects into shared decision making. Study Design: A 26-question online survey was sent to people in the National Kidney Foundation patient email list and posted on associated social media pages to assess the respondents' willingness and comfort with taking preventative medications during earlier-stage CKD to inform a December 2020 scientific workshop co-sponsored by the National Kidney Foundation and the US Food and Drug Administration on clinical trial considerations in developing treatments for individuals with early stages of CKD. Setting & Population: Online survey of CKD patients, including broad demographic data and responses to risk-benefit scenarios, with surveys emailed to 20,249 people not identified as currently receiving kidney replacement therapy. Analytical Approach: Survey results are presented as descriptive data. Results: Of 1,029 respondents, 45 self-identified as at risk for CKD, 566 had CKD, 267 had received kidney transplants, 51 were receiving dialysis, and 100 replied other or did not answer. Respondents reported being willing to assume some risk with the goal of preventing the progression of CKD, with a greater willingness to assume risk and treatment burdens the closer they came to late-stage disease. Clinician recommendations regarding kidney therapies and clinician willingness to work with patients to address any side effects were important in respondents' willingness to initiate and persevere with a new medication. Limitations: Approximately 10% response rate with limited data on respondents. Conclusions: Risk-versus-benefit discussions appear key to patients and their care partners making well-informed decisions about taking a new medication that may or may not help the progression of their kidney disease. Future tools and strategies are needed to facilitate informed discussions of treatment in early-stage kidney disease.

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective.

On 16 December 2020, FDA approved Benlysta® (belimumab) for both the intravenous (IV) and subcutaneous (SC) administration routes for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy. This approval represents the first FDA approved treatment of patients with active LN.The approved IV dosing regimen (10 mg/kg dose Q2W for three doses, then 10 mg/kg Q4W thereafter) was based on a randomized double-blind placebo controlled clinical trial in adult patients with LN. For the approval of the SC dosing regimen (400 mg dose QW for four doses, then 200 mg QW thereafter), efficacy was supported solely by pharmacokinetics (PK) modeling and simulation which estimated a matched steady state average concentration and higher trough concentrations for the SC administration route, for bridging to the efficacy of IV belimumab in adults with LN. The safety and immunogenicity profile of the SC administration route has been assessed in the SLE studies.In a population PK analysis, higher proteinuria was associated with greater belimumab clearance and lower belimumab exposure. In an exposure response analysis, the efficacy of belimumab as evaluated by renal response was mainly driven by patients with lower proteinuria at baseline regardless of other baseline characteristics (e.g. baseline renal function, renal biopsy classification), induction therapies, or belimumab exposure levels (within 10 mg/kg dosing regimen), etc. However, post hoc analyses showed that belimumab had activity in LN patients with higher proteinuria at baseline. There is no adequate information to suggest that a higher dose would provide additional benefit for patients with lower exposure (e.g. higher proteinuria).

Value of Data Sharing to Advance Drug Development: A Regulatory Perspective.

New tools are needed to evaluate and predict the efficacy and safety of medical products. However, the development of such tools requires collaboration and effective data sharing. In this issue of Therapeutic Innovation & Regulatory Science, scientists from the Critical Path Institute (C-Path) discuss their experiences using patient-level data to facilitate innovation in drug development. We share our perspective on the issues discussed in the C-Path paper and offer suggestions on future efforts.

Evaluating Patients With Impaired Renal Function During Drug Development: Highlights From the 2019 US FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching.

Challenges of Cardio-Kidney Composite Outcomes in Large-Scale Clinical Trials.

Patients with chronic cardiovascular or metabolic diseases, including diabetes, hypertension, obesity, and heart failure, often have comorbid kidney disease. Long-term outcomes are worse in the setting of both cardiac and kidney disease compared with either disease in isolation. In addition, the clinical presentations of certain acute cardiovascular events (such as heart failure) and worsening kidney function overlap and may be challenging to distinguish. Recently, certain novel treatments have demonstrated beneficial effects on both cardiac and kidney outcomes. Sodium-glucose cotransporter-2 inhibitors have exhibited concordant risk reduction and clinically important benefits in chronic kidney disease with and without diabetes, diabetes and established cardiovascular disease or multiple atherosclerotic vascular disease risk factors, and heart failure with reduced ejection fraction with and without diabetes. Primary trial results have revealed that sacubitril-valsartan therapy improves cardiovascular outcomes in patients with chronic heart failure with reduced ejection fraction and post hoc analyses suggest favorable kidney effects. A concordant pattern of kidney benefit with sacubitril-valsartan has also been observed in chronic heart failure with preserved ejection fraction. Given the complex interplay between cardiac and kidney disease and the possibility that treatments may show concordant cardio-kidney benefits, there has been recent interest in formally acknowledging, defining, and using composite cardio-kidney outcomes in future cardiovascular trials. This review describes potential challenges in use of such outcomes that should be considered and addressed before their incorporation into such trials.

International consensus definitions of clinical trial outcomes for kidney failure: 2020.

Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.

Comparative Effectiveness and Safety of Oral Anticoagulants Across Kidney Function in Patients With Atrial Fibrillation.

BACKGROUND: Patients with atrial fibrillation and severely decreased kidney function were excluded from the pivotal non-vitamin K antagonist oral anticoagulants (NOAC) trials, thereby raising questions about comparative safety and effectiveness in patients with reduced kidney function. The study aimed to compare oral anticoagulants across the range of kidney function in patients with atrial fibrillation. METHODS AND RESULTS: Using a US administrative claims database with linked laboratory data, 34 569 new users of oral anticoagulants with atrial fibrillation and estimated glomerular filtration rate ≥15 mL/(min·1.73 m2) were identified between October 1, 2010 to November 29, 2017. The proportion of patients using NOACs declined with decreasing kidney function-73.5%, 69.6%, 65.4%, 59.5%, and 45.0% of the patients were prescribed a NOAC in estimated glomerular filtration rate ≥90, 60 to 90, 45 to 60, 30 to 45, 15 to 30 mL/min per 1.73 m2 groups, respectively. Stabilized inverse probability of treatment weighting was used to balance 4 treatment groups (apixaban, dabigatran, rivaroxaban, and warfarin) on 66 baseline characteristics. In comparison to warfarin, apixaban was associated with a lower risk of stroke (hazard ratio [HR], 0.57 [0.43-0.75]; P<0.001), major bleeding (HR, 0.51 [0.44-0.61]; P<0.001), and mortality (HR, 0.68 [0.56-0.83]; P<0.001); dabigatran was associated with a similar risk of stroke but a lower risk of major bleeding (HR, 0.57 [0.43-0.75]; P<0.001) and mortality (HR, 0.68 [0.48-0.98]; P=0.04); rivaroxaban was associated with a lower risk of stroke (HR, 0.69 [0.51-0.94]; P=0.02), major bleeding (HR, 0.84 [0.72-0.99]; P=0.04), and mortality (HR, 0.73 [0.58-0.91]; P=0.006). There was no significant interaction between treatment and estimated glomerular filtration rate categories for any outcome. When comparing one NOAC to another NOAC, there was no significant difference in mortality, but some differences existed for stroke or major bleeding. No relationship between treatments and falsification end points was found, suggesting no evidence for substantial residual confounding. CONCLUSIONS: Relative to warfarin, NOACs are used less frequently as kidney function declines. However, NOACs appears to have similar or better comparative effectiveness and safety across the range of kidney function.

End Points for Clinical Trials in Primary Hyperoxaluria.

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy.

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.

Addressing the Need for Clinical Trial End Points in Autosomal Dominant Polycystic Kidney Disease: A Report From the Polycystic Kidney Disease Outcomes Consortium (PKDOC).

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Expansion of multiple cysts throughout both kidneys is thought to lead to progressive loss of kidney function and kidney failure in some patients. In recent years, much has been learned about the pathophysiology of ADPKD. However, to date, only one therapy has been approved in the United States and in other regions for the treatment of ADPKD. Feasible end points and a clear regulatory pathway may stimulate further development in this area and ultimately lead to more treatments for ADPKD successfully reaching the market. In July 2016, the PKD Outcomes Consortium under the auspices of the Critical Path Institute and the PKD Foundation convened a PKD Summit to facilitate a discussion among patients, regulators, pharmaceutical sponsors, and academic clinical trialists regarding trial end points and the regulatory path to approval of new drugs for ADPKD. Following the summit, participants continued the dialogue using regularly scheduled teleconferences. This article addresses key considerations related to the design of clinical trials in ADPKD based on these discussions.

Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.

African Americans, Kidney Disease, and Drug Development: A Regulatory Perspective.

Given the burden of kidney disease in African Americans, the discovery of safe and effective medical products to slow the progression of kidney disease and reduce the risk for kidney failure would have a tremendous impact on this population. Differences in response to treatment have been observed in African Americans, highlighting the importance of studying medical products in African Americans. Although historically the African American community has not been well represented in clinical trials, efforts are underway to address this issue. Recent advances in understanding the genetic contributions to disease progression in African Americans, including the discovery of risk variants in the apolipoprotein L1 gene (APOL1), raise the possibility of using genetic information to better tailor treatments for African Americans. One could envision developing therapies that target these variants or possibly using them to help enrich trial populations with patients more likely to experience disease progression.