- PARASOL working group confirms eGFR as an approved surrogate endpoint for FDA approval of treatments for focal segmental glomerulosclerosis
- The working group also determined that proteinuria alone may also be suitable for FDA full approval, providing potential benefit for Dimerix with a choice of either eGFR or proteinuria as the primary endpoint for its ACTION3 clinical trial
- Nephrologist and PARASOL co-chair Dr Laura Mariani appointed to Dimerix Medical Advisory Board
Special Report: Global medical collab PARASOL has broadened the potential surrogate endpoints for FDA approval of treatments for a rare kidney disease treatment, potentially boosting a Phase 3 trial by Dimerix.
Dimerix (ASX:DXB) also announced it had appointed Dr Laura Mariani – expert nephrologist and co-chair of Project PARASOL – to the ACTION3 Medical Advisory Body overseeing its Phase 3 trial of lead drug DMX-200 in patients with focal segmental glomerulosclerosis (FSGS).
FSGS is a rare kidney disease – see further below for more explanation.
PARASOL is a collaborative, academic, and regulator-led international effort with the goal to define quantitative relationships between biomarkers like proteinuria and eGFR and long-term outcomes for FSGS patients.
The organisation’s scientific workshop was held in Washington, D.C. earlier this month and its findings, published on October 25, further support the use of proteinuria-based endpoints to accelerate or traditionally approve treatments for FSGS kidney disease.
PARASOL findings back DXB trial endpoints
DXB’s Phase 3 trial titled Angiotensin II Type 1 Receptor (AT1R) & Chemokine Receptor 2 (CCR2) Targets for Inflammatory Nephrosis (ACTION3) is designed to capture sufficient evidence of proteinuria and kidney function (eGFR slope) for support of marketing approval.
The pivotal, multi-centre, randomised, double-blind, placebo-controlled study is assessing the efficacy and safety of DMX-200 in FSGS patients on a stable dose of an angiotensin II receptor blocker (ARB).
An interim analysis released in March found that DMX-200 outperformed the placebo in reducing proteinuria (efficacy).
A second blinded interim analysis is planned after the first 144 patients reach 35-week treatment, expected around mid-2025.
To date, 129 patients have been randomised/dosed in the ACTION3 Phase 3 clinical trial, with 16 patients in stabilisation, titration or screening ahead of potential randomisation
(subject to meeting inclusion/exclusion criteria).
Dimerix plans FDA meeting
DXB actively supports the working group and participated in workshops held in June and October 2024.
The October 2024 PARASOL Scientific Workshop, attended by clinicians, patients, key opinion leaders, statisticians, FDA representatives, and industry sponsors (companies), presented preliminary analysis of observational data from FSGS patients globally.
The dataset included a broad demographic range and was not limited to randomised trial data like the DXB ACTION3 Phase 3 clinical trial.
The preliminary analysis, shared at the American Society of Nephrology (ASN) meeting in San Diego on October 25 confirmed a strong correlation between the surrogate endpoint of eGFR improvement and reduced risk of end-stage kidney disease.
DXB said notably eGFR was the current primary endpoint for the ACTION3 trial.
The analysis also proposed that proteinuria may also be an appropriate primary endpoint for full FDA approval. The working group recognised that FSGS patients often retained residual kidney scarring, which may prevent some from reaching low proteinuria levels seen in other kidney diseases.
The PARASOL data showed that higher proteinuria thresholds, including 0.7 g/g, 1.0 g/g, and up to 1.5 g/g, were associated with a reduced risk of progression to renal failure, offering new potential FDA approval targets for FSGS drug candidates.
The FDA expressed general support for the PARASOL data’s correlation between proteinuria reduction and decreased kidney disease progression risk.
However, DXB said each industry sponsor would likely need to justify the chosen proteinuria threshold and demonstrate the biological mechanism of their candidate drug.
DXB said for its ACTION3 Phase 3 clinical trial, and subject to FDA approval, it was likely that the company may now have a range of proteinuria endpoints that could acceptable as primary endpoint for FDA approval.
As both eGFR and proteinuria data are collected over two years, no study changes were expected.
DXB said it planned to request a meeting with the FDA to confirm the proteinuria endpoints for DMX-200 in the ACTION3 trial.
Rare disease with limited treatment options
FSGS is rare disease that attacks the kidney’s filtering units, called the glomeruli, where blood is cleaned.
This results in irreversible scarring, leading to permanent kidney damage and eventually end-stage kidney failure, requiring dialysis or transplantation.
DXB said the prognosis for those diagnosed with FSGS was poor with the time from diagnosis to complete kidney failure only five years on average.
The disease affects both adults and children as young as two years old. For those fortunate enough to receive a kidney transplant, ~60% will experience a recurrence of FSGS in the transplanted kidney.
Currently, there are no drugs specifically approved for FSGS anywhere in the world, limiting treatment options and overall prognosis.
DXB said the FSGS market was significant, with more than 80,000 people in the US affected and around 220,000 worldwide.
‘Look forward to advancing DMX-200’
Co-chair of PARASOL and assistant Professor in Nephrology at the University of Michigan Dr Laura Mariani said she looked forward to joining DXB’s medical advisory board.
Mariani has expertise in observational studies for glomerular disease with her research focusing on developing statistical methods for defining and predicting kidney disease progression and linking clinical phenotype with novel biomarkers to target glomerular disease therapies.
“The PARASOL objective is to improve the understanding of proteinuria and eGFR-based endpoints, supporting accelerated and traditional approvals of FSGS treatments,” she said.
“FSGS remains a challenging disease with limited therapeutic options, and I look forward to advancing DMX-200 as a potential new treatment.”
This article was developed in collaboration with Dimerix, a Stockhead advertiser at the time of publishing.
This article does not constitute financial product advice. You should consider obtaining independent advice before making any financial decisions.
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