Authors:
Jonathan Barratt, PhD, FRCP. The Mayer Professor of Renal Medicine, University of Leicester
Claudio Hegenberger, MD. Vice President, Scientific and Medical Affairs, Emerald Clinical
For decades, rare glomerular diseases sat at the margins of drug development. Despite devastating lifelong consequences for young patients, conditions such as IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and C3 glomerulopathy (C3G) were widely viewed as scientifically complex, operationally risky, and commercially uncertain. Clinical trials were slow, endpoints were misaligned with disease biology, and sponsors struggled to demonstrate value to regulators and payers.
That era is ending with the advent of the “glomerular revolution.”
Leading nephrology experts describe it as a new period defined by regulatory innovation, therapeutic momentum, and unprecedented global trial activity. For sponsors, this moment represents both opportunity and urgency. Agile organizations that rethink how renal trials are designed, executed, and supported in the coming decade will be able to deliver new innovations to patients that seemed previously inaccessible.
From Therapeutic Desert to Accelerating Pipeline
The transformation in glomerular disease development has been rapid and structural. Only five years ago, placebocontrolled trials with long timelines and hard outcomes (doubling of serum creatinine, ESKD, or death) were the only accepted pathway. That approach was never realistic for slowly progressive, heterogeneous, rare diseases.
Regulatory agencies, most notably the US FDA, worked collaboratively with academia, patient groups, and industry to redefine what constitutes meaningful clinical benefit. Surrogate endpoints such as proteinuria reduction and eGFR slope are now accepted for accelerated approvals. The impact has been catalytic.
As a result, we have since seen:
- Multiple first-in-class approvals in IgAN and C3G
- The first FDA approved therapy in FSGS, following regulatory alignment on endpoints
- A robust mid and late stage pipeline targeting complement, endothelin, B cell biology, and mucosal immunity
Fortunately for patients, what was once deemed a high risk niche has become one of the most dynamic areas in nephrology R&D.
Biological Heterogeneity Demands Better Trial Strategy
While progress is undeniable, sponsors must recognize a critical reality: glomerular diseases are not monolithic. Identical diagnoses can mask profoundly different biological drivers, immune signatures, and response patterns. Trial readouts consistently show heterogeneous responses, simply because biology is variable.
The next generation of rare glomerular disease development will shift away from broad, diagnosis based inclusion criteria toward deliberate endotyping and biomarker driven strategies that reflect the underlying biological heterogeneity of these conditions. However, this evolution requires trials to be designed from the outset with embedded biorepositories, enabling systematic collection of blood, urine, and kidney tissue to support mechanistic insight and responder identification.
Increasingly, repeat kidney biopsy studies and single cell transcriptomic approaches are becoming essential tools, allowing sponsors to directly assess target engagement, pathway modulation, and tissue level effects rather than relying solely on downstream clinical surrogates. Sponsors that continue to rely on “onesizefitsall” trial designs risk either underestimating assets that may be highly effective in defined patient subsets or overexposing programs to biological variability that could have been anticipated and mitigated through more precise, biology informed trial design.
The Rapid Evolution of Trials
Another inflection point is already emerging: how to run trials in a post approval world. In IgAN, for example, approved therapies now exist. This fundamentally changes ethical considerations, control arms, background therapy expectations, and patient willingness to enroll.
Regulators are increasingly asking sponsors and investigators to reimagine clinical trial design in response to a rapidly evolving treatment landscape. This includes moving beyond traditional placebo controlled models toward addon and combination trial designs, adopting adaptive designs with shorter and more flexible comparative windows, and integrating real world evidence alongside long term extension strategies to better capture durability of effect. For sponsors, this shift means that trial design is no longer purely a scientific consideration. It has, in fact, become a strategic decision with significant regulatory, operational, and timeline implications if not approached thoughtfully and proactively.
The glomerular revolution has also proven something else: the nephrology community will deliver when trials are designed correctly. Recruitment that once took years is now measured in months, driven by global site networks, motivated investigators, and patients who actively seek trial participation.
However, execution remains complex. These are rare diseases and have to contend with additional factors: sites may be geographically dispersed, pediatric extensions are increasingly expected, and endpoint collection requires exceptional rigor and consistency. This is where many promising programs will succeed or stall.
What Sponsors Should Do Next
As momentum accelerates, sponsors have an opportunity to move with greater purpose and clarity than in the past. Here are 5 actions that sponsors should take now:
- Invest early in renal specific trial design expertise Endpoints, background therapy, biopsy strategy, and patient selection in glomerular disease are highly specialized. Generalist approaches increase risk.
- Plan for heterogeneity, not averages Build biomarker and endotype strategy into Phase 2 rather than waiting until Phase 3.
- Design trials for an evolving standard of care Post approval landscapes demand flexible, regulator aligned trial models.
- Anticipate pediatric and life course development early Regulators and investigators are ready. Delaying pediatric strategy can slow programs by years.
- Choose a CRO partner with deep renal expertise Sponsors should work with a CRO that understands nephrology biology, investigator networks, regulatory expectations, and operational realities. The CRO should be able to actively help guide trial design, site strategy, and execution in this increasingly sophisticated therapeutic area.
The glomerular revolution is not a future promise. It is already happening now. Sponsors that align scientific ambition with the right expertise and partnerships will not only reach approval faster, but will help redefine what is possible for patients who, until recently, had none.
To learn more about the glomerular revolution, please watch this webinar with Drs. Hegenberger and Barratt.