SCICONX Journal of Nephrology

Emerging Innovative Drug Development Strategies for Kidney Diseases and Beyond

Author(s) info »

Abstract

Reaching end-stage kidney failure (ESKD) confers a higher 5-year mortality (~50%) than any malignancy, except for lung (~80%) and pancreatic (~90%) cancers [1]. Yet the nephrology f ield had the lowest productivity in new drug approvals, largely due to the decades-long standing regulatory standards of demonstrating benefit in reaching doubling of serum creatinine, ESKD, or death (referred to as TRAD going forward), which are clinical endpoints requiring several years and large numbers of study participants to achieve statistical significance between active vs. comparator (usually placebo) arms. Conducting trials in rare kidney diseases, typically defined as a prevalence <200,000 or <50 in 100,000, has the additional challenge of small numbers of eligible patients.

Master protocols, synthetic control arms, virtual twins, in silico trials

INTRODUCTION

Reaching end-stage kidney failure (ESKD) confers a higher 5-year mortality (~50%) than any malignancy, except for lung (~80%) and pancreatic (~90%) cancers [1]. Yet the nephrology f ield had the lowest productivity in new drug approvals, largely due to the decades-long standing regulatory standards of demonstrating benefit in reaching doubling of serum creatinine, ESKD, or death (referred to as TRAD going forward), which are clinical endpoints requiring several years and large numbers of study participants to achieve statistical significance between active vs. comparator (usually placebo) arms. Conducting trials in rare kidney diseases, typically defined as a prevalence <200,000 or <50 in 100,000, has the additional challenge of small numbers of eligible patients.

Nephrology is experiencing a renaissance where the biopharmaceutical industry has moved into this space with energy and intent in recent years. A major tipping point was the 2016 workshop by Kidney Health Initiative (KHI), a joint effort between American Society of Nephrology and FDA, which led to the establishment of surrogate endpoints in place of TRAD ones: Namely, statistically significant slowing of eGFR slope decline over two years for full approval and the “surrogate of a surrogate” measure of ≥ 30% proteinuria reduction at 9 months for accelerated approval in IgA nephropathy [2]. As a consequence, beginning in late 2021, multiple new therapies have been approved and marketed to treat IgAN with many more in development with diverse mechanisms of action.

NEWER CLINICAL STUDY APPROACHES

How can we further capitalize on this momentum? Master protocols represent an innovative and promising option, which was successfully pioneered in oncology drug development. Briefly, in contrast to the traditional clinical trial design where study participants are randomized to a single candidate drug vs. standard of care/placebo, master protocols include multiple diseases and/or experimental therapies within the same trial. For further reading on master protocols in kidney diseases, see recently published manuscripts in by this author [3,4].

Incorporation of Real World Evidence (RWE) signifies another promising area for progress. A well-executed randomized, double-blinded clinical trial is the susperior experiment designed to minimize probability of false positive results, because of 1 standardization of timing and execution of laboratory as well as clinical assessments; and 2 more importantly, because it should control for measured and unmeasured confounders, sources of potential bias. Regulators have typically and appropriately rejected the utilization of external comparator arms from historical cohort’s natural history studies for registrational/ pivotal trials with very rare exceptions, due to important confounders such as change in standard of care over time or the certainty of presence of unmeasured confounders especially in rare disease trials with small sample sizes.

Evolving RWE thinking includes parsing through advantages and disadvantages of very large data sets with limited details and/or laboratory results vs. smaller data sets with deep clinical and laboratory data to serve as potential appropriate comparators for new trials. Sources of RWE include claims, electronic health records (e.g. UK RaDaR), retrospective and prospective cohorts (whether through a patient registry like Alport Syndrome Foundation or an observational cohort such as NEPTUNE), and placebo arms of sponsored clinical trials. Notably for rare kidney and other rare diseases, individual patient-level longitudinal data with many years of follow up, high quality, reliable data assessments (especially for primary or key secondary endpoints), and the ability to create a matched comparator arm for the experimental arm should have a higher probability of regulatory acceptance. As with master protocols, oncology has been a leader with 17% of cancer drugs approved by EMA between 2017-2021 employing external controls [5]. Further evolution of external comparators includes hybrid control arms where the comparison group is a blend of concurrent randomized controls within the trial plus fully external controls whereby statistical power can be achieved through augmentation of comparators with external controls. The resulting increased proportion of study participants randomized to the new active drug vs. placebo (e.g. 3:1) translates into increased enthusiasm to join a study from the patients and their families as well as from study investigators.

Fully synthetic control arms are AI-generated and have been derived from existing patient datasets (including placebo arms of clinical trials) to include clinical characteristics, treatment, outcomes, and biomarkers. Another type of simulated patient data are virtual twins, where a multi-dimensional digital version of a patient, organ system, or biological system is generated from real life and updated with new data; when virtual twins are incorporated into external control arms, they may additionally provide prognostic covariates for more accurate treatment effect estimates. Finally, in silico trials are simulated treatment intervention experiments comprised entirely of virtual treated and placebo patients with some published analyses reported to mimic results of real-world clinical trials; they should be considered as complementary and not a replacement for actual clinical trials data, however. For further details on these approaches and their potential application in pediatric drug development, please refer to the review by M. Pammi et al [6].

Moreover, urgency in quickly advancing approved drugs for pediatric populations have led to other applications of Modeling and Extrapolation. PDUFA VI (2018-2022) launched and then PDUFA VII (FY 2017-2023) formalized FDA’s Model-Informed Drug Development (MIDD) program, which the agency uses for pediatric PK/PD modeling and related extrapolation discussions via a paired-meeting pathway. An ex-US example of label expansion in the EU SmPC to include adolescents as young as 12 years based entirely on modeling is caplacizumab for immune TTP, an ultrarare disease with an estimated prevalence of 3 to 11 per million [7]. The Connect 4 Children Chronic Kidney Disease Meeting held on April 28-29, 2025 in Heidelberg, Germany as well as the Kidney Health Initiative Pre-Meeting Workshop on Advancing Pediatric Kidney Clinical Trials Through Data Extrapolation held on May 21, 2025 in Washington, DC, USA should be considered harbingers of growing attention to this area.

CONCLUSION

In conclusion, moving away from nephrology TRAD endpoints has opened the door for broader and more diverse investigations. This commentary summarizes recent promising approaches in the conduct of clinical trials to more quickly expand the palette of safe and effective treatments available to kidney patients, a sizeable global community who continue to have a very high unmet need. This author’s hope is that readers will be motivated to further explore and apply as well as ultimately develop new, innovative methodologies. Importantly, meaningful advances in accelerating approvals for new drugs to slow perhaps even halt progression of kidney disease requires the continued commitment and full engagement of all stakeholders (academic scientists, investigators, healthcare providers, industry researchers, patient advocacy groups, professional societies, regulators, and payers) to bring increasing creativity and dialogue to current and future collaborations. Consider this another voice in the call for progress.

REFRENCES

1. Naylor KL, Kim SJ, McArthur E, Garg AX, McCallum MK, Knoll GA. Mortality in incident maintenance dialysis patients versus incident solid organ cancer patients: A population-based cohort. Am J Kidney Dis. 2019;73(6):765-776.

   [Google Scholar] [PubMed] [Crossref]

2. Thompson A, Carroll K, Inker LA, Floege J, Perkovic V, Boyer-Suavet S, et al. Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. Clin J Am Soc Nephrol. 2019;14(3):469-481.

   [Google Scholar] [PubMed] [Crossref]

3. Lin J, Radhakrishnan J. What are baskets, umbrellas, and platforms doing in nephrology clinical trials? J Am Soc Nephrol. 2024:10-681.

   [Google Scholar] [PubMed] [Crossref]

4. Lin J, Radhakrishnan J. Master protocols: A promising approach to accelerate drug development in rare kidney diseases. Ther Innov Regul Sci. 2025:1-3.

   [Google Scholar] [PubMed] [Crossref]

5. Wang X, Dormont F, Lorenzato C, Latouche A, Hernandez R, Rouzier R. Current perspectives for external control arms in oncology clinical trials: Analysis of EMA approvals 2016-2021. J Cancer Policy. 2023;35:100403.

   [Google Scholar] [PubMed] [Crossref]

6. Pammi M, Shah PS, Yang LK, Hagan J, Aghaeepour N, Neu J. Digital twins, synthetic patient data, and in-silico trials: Can they empower paediatric clinical trials? Lancet Digit Health. 2025;7(5).

   [Google Scholar] [PubMed] [Crossref]

7. Bergstrand M, Hansson E, Delaey B, Callewaert F, De Passos Sousa R, Sargentini-Maier ML. Caplacizumab model-based dosing recommendations in pediatric patients with acquired thrombotic thrombocytopenic purpura. J Clin Pharmacol. 2022;62(3):409-421.

   [Google Scholar] [PubMed] [Crossref]

Author(s) Info

Received date: 18-Sep-2025 Accepted date: 10-Oct-2025 Published date: 14-Oct-2025