What's the latest update on the ongoing clinical trials related to Primary hyperoxaluria?

Overview of Primary Hyperoxaluria

Definition and Types
Primary hyperoxaluria (PH) is a rare, autosomal recessive inborn error of glyoxylate metabolism that results in excessive endogenous oxalate production. There are mainly three well‐characterized forms:
• PH type 1 (PH1) is the most common and severe form, caused by mutations in the AGXT gene that encode the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT).
• PH type 2 (PH2) is due to mutations in the GRHPR gene, leading to a deficiency in glyoxylate reductase/hydroxypyruvate reductase.
• PH type 3 (PH3) is associated with mutations in the HOGA1 gene affecting the enzyme 4-hydroxy-2-oxoglutarate aldolase 1.

The clinical variability among these types is notable, with PH1 typically leading to early-onset nephrocalcinosis, recurrent kidney stone formation, and progression to end-stage renal disease (ESRD) if left untreated, whereas PH2 and PH3 may have a comparatively milder course in some instances.

Pathophysiology and Causes
The molecular defect in PH disrupts the detoxification of glyoxylate, which is normally converted into less harmful metabolites. In PH1, a deficiency of AGT causes glyoxylate to be shunted towards oxalate production via lactate dehydrogenase (LDH). The excessive oxalate then combines with calcium to form insoluble calcium oxalate crystals, leading to nephrocalcinosis, urolithiasis, and eventually systemic deposition known as oxalosis once the glomerular filtration rate declines. Genetic mutations play a central role in the etiology, and while many patients are diagnosed in infancy or childhood, delayed diagnoses in adult patients with recurrent kidney stones have also been reported.
Furthermore, clinical heterogeneity is compounded by phenotypic variability, as the same genotype may present with different severities, and environmental or epigenetic factors might modulate disease progression.

Current Treatment Options

Standard Treatments
The adopted treatment for PH traditionally revolves around supportive measures. These include:
• High fluid intake and dietary modifications, which are intended to dilute urinary oxalate concentrations and reduce the likelihood of stone formation.
• Crystallization inhibitors such as citrate formulations help prevent the nucleation and aggregation of calcium oxalate crystals by binding urinary calcium.
• Pyridoxine (vitamin B6) therapy is recommended in certain genotypes, particularly in responsive PH1 patients, where it has been shown to reduce urinary oxalate excretion by improving residual enzyme function.
• In advanced disease, renal replacement therapies – including intensive hemodialysis or peritoneal dialysis – are utilized as a bridge to combined liver-kidney transplantation, which can address both the enzymatic defect and the resultant kidney failure.

Limitations of Current Treatments
Despite these multifaceted approaches, the current standard treatments are associated with several limitations:
• Supportive measures do not directly address the underlying metabolic defect, thereby only mitigating symptoms rather than offering a curative solution.
• Pyridoxine responsiveness is limited to a subset of patients with specific mutations and the degree of urinary oxalate reduction can be variable.
• Liver-kidney transplantation, while curative for the enzymatic defect and renal failure, entails a major surgical procedure with significant risks including graft rejection, lifelong immunosuppression, considerable morbidity and mortality, and substantial healthcare costs.
• Dialysis, although life-sustaining, is burdensome and inefficient in clearing oxalate, especially once plasma oxalate levels exceed the solubility threshold leading to systemic deposition (oxalosis).

Clinical Trials for Primary Hyperoxaluria

Ongoing Trials
Recent years have seen significant momentum in clinical trials focused on targeting the underlying genetic and metabolic defects responsible for PH, transitioning from supportive care to targeted molecular therapies. A number of ongoing trials are evaluating RNA interference (RNAi) therapeutics, gene therapy approaches, and small molecule inhibitors to address the pathophysiology of this disease.

One of the most prominent ongoing clinical studies is the PHYOX™2 trial evaluating nedosiran—a GalXC™ RNAi therapeutic candidate developed by Dicerna Pharmaceuticals. In August 2021, positive top-line results from this pivotal study were announced, with nedosiran demonstrating a statistically significant reduction in urinary oxalate (Uox) excretion compared to placebo. The study met its primary endpoint and also achieved a key secondary endpoint with a significantly higher proportion of patients achieving normal or near-normal Uox levels sustained over time. These results support the progression towards regulatory filings as Dicerna prepares to submit a New Drug Application (NDA) based on the PHYOX2 data.

Beyond PHYOX™2, the PHYOX™3 trial is an open-label rollover extension study that seeks to evaluate long-term safety, efficacy, and the sustained effect of nedosiran in patients with PH not only limited to PH1, but also including PH types 2 and 3. Initial data from this trial indicate that nedosiran appears to be well tolerated with few injection-site reactions and a safety profile consistent with earlier phase studies. Patients enrolled in PHYOX3 have been receiving monthly doses, and the longest-treated patient has received up to seven monthly doses, indicating a substantial duration of exposure that is critical for evaluating long-term benefits and risks.

Further broadening the scope of nedosiran’s clinical investigation, recent updates indicate that additional nedosiran trials are in progress. The PHYOX7 trial is an open-label study recruiting patients with PH1 or PH2 who have severe renal impairment, including those on dialysis. This trial is designed to assess nedosiran’s efficacy, safety, and dosing adjustments in the context of advanced renal dysfunction. Similarly, the PHYOX8 trial is expected to enroll patients from infancy up to six years of age with PH1 or PH2, aiming to determine the treatment’s safety and efficacy in a pediatric population. These studies are particularly significant as they expand the potential indication of nedosiran to populations that have historically been underrepresented in clinical trials due to age or advanced disease status.

Several other clinical studies are being initiated or are in advanced stages regarding primary hyperoxaluria treatments. For instance, BridgeBio Pharma has announced plans to initiate a Phase 2/3 study in PH1 patients. This investigation intends to evaluate new oral therapies, with endpoints including changes in 24-hour Uox excretion and the proportion of patients achieving levels below the upper limit of normal. Although detailed results from this study have yet to be publicly released, these trials underscore the ongoing industry-wide efforts to expand therapeutic options for PH patients.

Furthermore, companies such as Alnylam Pharmaceuticals have continued their portfolio developments by ensuring competitive positioning for their RNAi therapeutic OXLUMO and by monitoring emerging investigational treatments. In their risk factors report, Alnylam acknowledges the presence of investigational agents like nedosiran and reloxaliase that may compete with their product in PH1, demonstrating the dynamic nature of the trial landscape and the importance of ongoing clinical research in this therapeutic space.

The clinical trials currently evaluating these novel treatments represent a promising shift from purely supportive management toward personalized, mechanism-based interventions that seek to correct the metabolic derangements at the heart of PH. The design of these trials typically involves careful dose escalation, multi-dose safety monitoring, and extended evaluation periods to assess long-term outcomes. The use of structured endpoints—such as absolute reduction in urinary oxalate excretion, normalization rates of Uox levels, and durability of response over extended periods—ensures that the therapeutic efficacy is measured in a rigorous and clinically meaningful manner.

Recent Findings
Recent updates from these clinical trials have provided robust evidence supporting the efficacy and safety of novel RNAi therapies:

• In the PHYOX™2 pivotal trial, nedosiran achieved a statistically significant reduction from baseline in Uox excretion compared to placebo (p<0.0001), and a significantly higher proportion of patients maintained Uox at normal or near-normal levels after Day 90 (p=0.0025). This finding is crucial because sustained normalization of Uox is associated with a decreased likelihood of stone formation and progression to ESRD, directly addressing one of the key limitations of current supportive treatments.

• Data from the open-label rollover extension study (PHYOX™3) have provided key insights into the long-term tolerability and optimization of dosing regimens. Early analysis shows that nedosiran was well tolerated, and no significant drug-related severe adverse events or injection-site reactions were observed over cumulative exposure spanning nearly two years among several patients. The consistency of these findings across different patient populations, including those with PH2 and PH3, hints at the broad applicability of this RNAi approach.

• The expansion into additional trials targeting specific patient subsets—PHYOX7 for those with severe renal impairment and PHYOX8 for pediatric patients—reflects a trend towards personalized medicine in this field. These trials are designed to answer critical questions regarding dosing, safety, and efficacy in populations that differ significantly in terms of age and disease severity. Their outcomes are anticipated to inform broader labeling strategies and to potentially enable an earlier intervention in the disease progression, which is key to improving long-term outcomes.

• Notably, the integration of these findings with real-world healthcare utilization data suggests that delayed diagnosis and mismanagement of PH result in high healthcare costs and increased rates of dialysis initiation. The promising results from nedosiran trials not only indicate a reduction in urinary oxalate but also offer hope in mitigating these downstream negative effects, thereby providing a comprehensive clinical benefit beyond biochemical markers.

Future Directions and Innovations

Emerging Therapies
The landscape of primary hyperoxaluria treatment is evolving rapidly with a focus on targeting the molecular defects directly. Several cutting-edge approaches are either entering clinical stages or are in advanced pre-clinical investigations:

• RNA Interference (RNAi) Therapies:
 – Nedosiran has emerged as a frontrunner in this category with renewed emphasis on its ability to significantly reduce Uox levels and maintain these at near-normal ranges. Its advanced clinical trial stages, including PHYOX2, PHYOX3, PHYOX7, and PHYOX8, provide a comprehensive evaluation across various patient demographics.
 – Other RNAi candidates, such as GalXC-Plus extrahepatic programs mentioned by Dicerna, are slated for introduction in early 2022. These may expand the treatment paradigm to target non-hepatic pathways that contribute to oxalate burden.

• Gene Therapy:
 – Gene therapy approaches aiming to correct the underlying mutation in the AGXT gene or otherwise restore enzyme activity are under development. Although still in the pre-clinical or early clinical phases, these therapies hold promise for a one-time curative treatment by directly addressing the enzyme deficiency responsible for the disease.

• Small Molecule Inhibitors:
 – Novel small molecule inhibitors, such as those targeting lactate dehydrogenase (LDH), are being explored to prevent the conversion of glyoxylate to oxalate. These compounds represent an attractive option due to their oral route of administration and potential for improved pharmacokinetic properties compared to biologics.
 – Recent patents detail methods and compositions for targeting the HAO1 gene (encoding glycolate oxidase) with RNAi agents, further diversifying the pool of therapeutic candidates.

• Bacteria-based and Enzyme Replacement Therapies:
 – Investigational therapies based on oxalate-degrading intestinal bacteria (e.g., Oxabact) and enzyme replacement strategies are also under exploration. Although earlier trials for these modalities have faced challenges, refinements in formulation and delivery systems (such as encapsulated enzyme preparations) continue to hold potential as adjunct or alternative therapies.

• CRISPR-Cas9 Gene Editing:
 – Early-stage research into CRISPR-based gene editing technologies offers the prospect of permanent correction of the genetic defect in liver cells. While the clinical application of this technology in PH is still at a nascent phase, the preclinical data are encouraging and suggest that this approach may become an integral part of the therapeutic armamentarium for PH in the future.

Potential Impact on Treatment Landscape
The ongoing clinical trials and emerging therapies in primary hyperoxaluria represent a paradigm shift from symptom management to the possibility of curative interventions. The potential impacts include:

• Improved Long-term Outcomes:
 – Therapies that reduce urinary oxalate excretion can prevent the cascade of events leading to nephrocalcinosis, recurrent kidney stones, and ultimately ESRD. Consequently, timely intervention can reduce the need for invasive procedures such as liver-kidney transplantation and dialysis.
 – Data from nedosiran trials suggest that robust oxalate lowering can delay or even prevent the systemic deposition of oxalate (oxalosis), thereby potentially preserving multisystem function and improving patient quality of life.

• Expanded Patient Access:
 – The initiation of trials in pediatric populations (PHYOX8) and in patients with advanced renal impairment (PHYOX7) highlights a move towards inclusivity in clinical research. If successful, these studies would allow earlier identification and intervention in PH, thereby addressing the delayed diagnosis issue that has historically plagued this disorder.
 – By demonstrating efficacy and safety across age groups and disease severities, new therapies could be rapidly incorporated into clinical practice, reducing the burden of frequent hospital visits, dialysis sessions, and high-cost interventions.

• Economic and Healthcare Utilization Benefits:
 – Real-world data indicate that delayed diagnosis and mismanaged disease progression lead to significant healthcare expenditures, increased hospitalization rates, and higher overall morbidity.
 – A therapy that effectively lowers urinary oxalate levels and slows disease progression could reduce healthcare resource utilization, lower costs associated with advanced renal replacement therapies, and ultimately improve the overall economic burden borne by patients and the healthcare system.

• Enhanced Quality of Life and Personalized Medicine:
 – With the advent of targeted therapies, treatment regimens could be personalized based on the patient’s genotype, disease stage, and responsiveness to therapy. For example, patients who are responsive to pyridoxine might still benefit from RNAi therapies that further reduce oxalate production, while non-responders could be managed with alternative modalities.
 – The incorporation of remote monitoring technologies and virtual assessments, as observed in some clinical trial designs, might further enhance adherence and patient engagement, contributing to better clinical outcomes and higher-quality care.

• Scientific and Regulatory Advances:
 – The positive outcomes in pivotal trials such as PHYOX2 have set precedents for regulatory approvals in ultra-rare diseases. The robust design of these trials—including the implementation of co-primary endpoints that measure both biochemical and clinical outcomes—provides a framework that can be applied to future studies in orphan diseases.
 – Continuous scientific investment, as demonstrated by the collaborative efforts between academic institutions and industry (e.g., Dicerna’s advances with nedosiran), is expected to pave the way for next-generation therapies. These efforts contribute not only to new treatment options but also to improvements in clinical trial design, endpoint selection, and patient safety monitoring.

Conclusion
In summary, the latest updates on ongoing clinical trials for primary hyperoxaluria reveal a dynamic and rapidly evolving landscape characterized by groundbreaking advances in RNAi therapeutics, gene-based interventions, and small molecule inhibitor strategies. The pivotal PHYOX™2 trial for nedosiran has garnered significant attention by demonstrating robust, statistically significant reductions in urinary oxalate excretion, thereby offering hope for a move away from purely supportive therapies towards a disease-modifying intervention.

The expansion of clinical studies to include long-term extension trials (PHYOX™3), as well as targeted studies in vulnerable populations such as pediatric patients (PHYOX8) and those with severe renal impairment (PHYOX7), underscores the commitment to addressing the unmet needs of all patient subsets affected by PH. Other investigational approaches, including gene therapy and small molecule inhibitors, are actively researched and may further transform the treatment landscape by providing options that are both less invasive and potentially curative.

From a broader perspective, these advancements signal a paradigm shift in the management of primary hyperoxaluria by integrating personalized medicine with innovative clinical trial design. The ongoing trials incorporate rigorous endpoints that assess both biochemical markers (such as Uox normalization) and clinical outcomes (such as reduced progression to ESRD), combining short-term efficacy with long-term safety profiles. The consolidation of these efforts is poised to not only alleviate the significant morbidity associated with PH but also reduce healthcare burdens and improve patient quality of life.

In conclusion, the latest updates from clinical trials in primary hyperoxaluria suggest a very promising future driven by advanced RNAi therapies, strategic expansion into diverse patient populations, and emerging gene-based and small molecule approaches. The comprehensive efforts of companies like Dicerna, BridgeBio Pharma, and Alnylam—supported by robust trial designs and encouraging preliminary results—are reshaping the therapeutic paradigm and hold the potential to revolutionize the treatment landscape for this ultra-rare and challenging metabolic disorder. Continued innovation, rigorous clinical evaluation, and collaborative research will be essential in ensuring that these emerging therapies deliver sustained benefits and ultimately reduce the burden of primary hyperoxaluria for patients around the world.