What drugs are in development for Primary hyperoxaluria?

Overview of Primary Hyperoxaluria Primary hyperoxaluria (PH)) is a group of ultra‐rare, autosomal recessive metabolic disorders characterized by the overproduction of oxalate due to genetic defects in liver enzymes. This excessive oxalate leads to calcium oxalate crystal formation in the kidneys and other organs, ultimately resulting in nephrolithiasis, nephrocalcinosis, and potentially end‐stage renal disease. The three known subtypes—PH1, PH2, and PH3—arise from mutations in different genes, with primary hyperoxaluria type 1 (PH1) being the most common and severe form.

Definition and Causes
PH is defined by inherited enzyme deficiencies affecting the glyoxylate metabolism pathway in the liver. In PH1, a deficiency of alanine‐glyoxylate aminotransferase (AGT) leads to an accumulation of glyoxylate, which is then converted by lactate dehydrogenase (LDH) into oxalate. In PH2 and PH3, similar metabolic derailments occur due to mutations in glyoxylate reductase/hydroxypyruvate dehydrogenase and other related genes. The genetic causes lead to markedly elevated urinary oxalate excretion, precipitating oxalate deposition in the kidneys and other tissues, and ultimately causing systemic oxalosis.

Current Treatment Options
For many years the management of PH has been limited to conservative measures such as hyperhydration, the use of crystallization inhibitors (e.g., citrate preparations), and ultimately liver or combined liver–kidney transplantation for those reaching renal failure. Liver transplant addresses the underlying metabolic defect in PH1, while kidney transplantation manages end‐stage renal disease, though both options carry high morbidity and risks. The recent advent of RNA interference (RNAi) therapeutics has revolutionized treatment. For example, Oxlumo® (lumasiran) was the first approved RNAi therapy for PH1, significantly reducing urinary oxalate production by targeting the messenger RNA of hydroxyacid oxidase 1 (HAO1). Despite this breakthrough, the unmet need remains high, and several drug candidates are presently under development to address the spectrum of PH subtypes and improve long‐term outcomes, especially in pediatric populations.

Drugs in Development
While Oxlumo (lumasiran) is now available for PH1 treatment, several novel drug candidates are in various stages of development that target different aspects of oxalate overproduction and related metabolic pathways. The focus in drug development for PH is predominantly on RNAi therapeutics and bacteriotherapy, with some emerging small molecule agents that target enzymatic processes upstream of oxalate formation.

Drug Candidates and Mechanisms
•   Nedosiran:
Nedosiran is an RNA interference therapeutic developed primarily by Dicerna Pharmaceuticals and is being investigated as a treatment for PH. Unlike lumasiran (which targets HAO1 mRNA), nedosiran is designed to inhibit the hepatic lactate dehydrogenase enzyme—a common final step in oxalate production in all three PH subtypes. Preclinical and early-phase clinical data have highlighted nedosiran’s robust capacity to lower urinary oxalate excretion. In the pivotal PHYOX2 trial, nedosiran demonstrated statistically significant reductions in urinary oxalate levels compared to placebo, with many patients achieving sustained “normal or near-normal” values. However, the drug’s performance has shown some variability in patients with PH2, contributing to discussions on its differential efficacy among PH subtypes. This candidate is a promising example of how RNAi technology can be adapted to target enzymes beyond HAO1—thereby broadening the therapeutic application across PH subtypes.

•   Rivfloza™ (Novo Nordisk’s RNAi therapeutic):
Another product from Novo Nordisk, Rivfloza™, functions similarly to other RNAi therapeutics by targeting key liver enzymes implicated in oxalate overproduction. Based on the PHYOX™2 and PHYOX™3 extension data, Rivfloza™ has demonstrated marked reductions in 24-hour urinary oxalate excretion and has been positioned as a potential alternative for PH1 patients. Its mechanism centers on silencing the messenger RNA of an enzyme involved in the final conversion step leading to oxalate formation. Even though its recent approval signals an important advancement, clinical data continue to refine its dosing regimen, duration of efficacy, and patient subgroup analyses, including its impact in both pediatric and adult populations.

•   Oxabact® OC5 (OxThera AB):
Distinguished from RNAi approaches, Oxabact® OC5 is a formulation based on the use of the gut bacterium Oxalobacter formigenes. This therapeutic candidate employs a probiotic mechanism whereby the administered bacteria degrade oxalate in the gastrointestinal tract, thereby promoting its removal from the body and reducing plasma oxalate concentrations. Clinical trials, including Phase II studies, have aimed to establish the long-term safety and efficacy of Oxabact OC5 in dialysis patients and others with PH. Data indicates that while plasma oxalate levels may decrease, a significant proportion of patients need to be closely monitored for gastrointestinal adverse events. Nonetheless, this bacteriotherapy approach presents an innovative biological strategy differing markedly from gene-silencing agents.

•   Preclinical Small Molecule Agents (e.g., INS-6015):
INS-6015 is a small molecule drug candidate developed by Inositec AG, which is currently in its preclinical stage. Although the exact mechanism remains under evaluation, INS-6015 is intended for congenital disorders and metabolic diseases, and it may act by modulating enzymatic activity or signal transduction pathways that influence oxalate synthesis. Due to its early-stage status, further studies are required to elucidate its potential benefits and safety profile in PH.

•   Collaborative RNAi Programs:
Several collaborations, notably between Alnylam Pharmaceuticals, Dicerna, and other biotech companies, have facilitated cross-licensing of intellectual property and concurrent clinical evaluations. These collaborations are specifically designed to develop next-generation RNAi molecules optimized for durability, dosing frequency, and efficacy across the PH spectrum. The collaborative efforts have resulted in multiple RNAi agents designed to target various points in the glyoxylate metabolism pathway with the ultimate aim of reducing systemic oxalate burden.

Collectively, these drug candidates represent a broad array of therapeutic strategies—from gene-silencing modalities (nedosiran, Rivfloza™) to bacteriotherapy (Oxabact® OC5) and potential small molecule inhibitors (INS-6015). Their mechanisms range from direct mRNA targeting and enzyme inhibition to altering gastrointestinal oxalate handling, thereby attacking the problem of oxalate overproduction from different angles.

Clinical Trial Phases and Progress
Drug development for PH is being pursued across various clinical trial stages:
• Nedosiran has progressed from early phase dose-escalation studies (Phase 1/2) to pivotal Phase 2 trials (PHYOX2) and even extension studies (PHYOX4 for PH3). Detailed pharmacokinetic and pharmacodynamic evaluations have confirmed its ability to consistently reduce urinary oxalate levels, although with some inconsistency in certain subtypes. The promising trial data have led to expectations for future regulatory submissions and potential approval in populations beyond PH1.

• Rivfloza™ from Novo Nordisk has successfully completed pivotal Phase 2 studies (PHYOX™2) with subsequent interim data from ongoing Phase 3 extension studies (PHYOX™3). The results indicate that patients maintain substantial reductions in 24-hour urinary oxalate excretion over extended periods, and the clinical outcomes support its continued advancement toward final regulatory approvals. The robust statistical significance (p<0.0001) of its primary endpoint underscores its potential as an alternative to existing therapies.

• Oxabact® OC5, focusing on bacteriotherapy, is undergoing controlled trials, typically in Phase 2 studies, to assess its long-term safety, reduction of plasma oxalate levels, and improvement in renal parameters in patients on dialysis and in earlier stages of PH. Although this approach is biologically distinct from RNAi, the clinical data gathered so far support its further investigation as an adjunct or alternative therapy for patients who cannot benefit fully from gene-silencing treatments.

• Preclinical candidates like INS-6015 are in the initial discovery phase, where in vitro and in vivo models are being used to validate their biological activity, dosing parameters, and safety profiles. The progress of such small molecule agents will determine whether they can enter first-in-human trials and subsequently be integrated into the overall treatment strategies for PH.

Overall, clinical trial data for these drugs demonstrate a robust and multi-phase development pipeline that is designed to address the complexity of PH. The development programs are carefully structured to include diverse patient populations (pediatric, adult, and varying PH subtypes), incorporate detailed pharmacodynamic endpoints (24-hour urinary oxalate levels measured by area under the curve analyses), and assess both short-term efficacy and long-term safety.

Challenges in Drug Development
Despite the encouraging progress, several scientific, technical, regulatory, and operational challenges continue to complicate drug development in primary hyperoxaluria.

Scientific and Technical Challenges
•   Heterogeneity of Patient Population:
PH is an extremely rare disease with three subtypes that vary in severity and presentation. The genetic heterogeneity and different enzyme deficiencies pose challenges to ensuring that a single therapeutic agent will be effective for all patients. For example, nedosiran has shown promising results in PH1, yet its efficacy in PH2 appears inconsistent, possibly due to differences in metabolic pathways.

•   Biomarker Validation and Endpoint Selection:
Accurate and reliable biomarkers—such as urinary oxalate excretion and plasma oxalate concentration—are critical in evaluating the efficacy of PH therapies. However, the lack of universally validated surrogate endpoints in PH trials is a significant hurdle. Novel RNAi therapies often rely on surrogate endpoints, and ensuring that these correlate with meaningful clinical outcomes (such as preservation of renal function) is essential for gaining regulatory approval.

•   Delivery and Durability of RNAi Agents:
For RNAi therapeutics such as nedosiran and Rivfloza™, efficient delivery to hepatocytes while maintaining potency and minimizing off-target effects is paramount. Although enhanced stabilization chemistry (ESC) and GalNAc conjugation have improved delivery, further optimization is needed to balance dosing frequency with efficacy. Additionally, long-term durability of the gene-silencing effect is critical in managing a chronic disease like PH.

•   Complexities in Bacteriotherapy:
With Oxabact® OC5, challenges arise in maintaining consistent colonization of the gastrointestinal tract, ensuring the bacterium retains oxalate-degrading activity, and dealing with issues related to immune modulation and safety in long-term use. Variability in gut microbiome composition among patients can also affect the therapeutic efficacy.

•   Preclinical-to-Clinical Translation for Small Molecules:
For preclinical candidates such as INS-6015, there is an inherent risk associated with translating in vitro data to human clinical response. Complexities in metabolic pathways, dosing challenges, and ensuring a favorable risk–benefit profile still need to be resolved through rigorous preclinical testing and iterative clinical trial design.

Regulatory and Approval Challenges
•   Small Patient Populations:
Individual PH subtypes affect only a few hundred to a few thousand patients worldwide, which makes it difficult to run large, adequately powered clinical trials. Regulators require robust statistical evidence of efficacy and safety, yet the limited patient numbers and geographic dispersion complicate this effort. This scarcity compels developers to utilize innovative and adaptive trial designs.

•   Regulatory Hurdles for Novel Modalities:
RNAi-based treatments, bacteriotherapy, and other novel therapeutic approaches often do not fit neatly into conventional regulatory frameworks. Companies must work closely with regulatory agencies to design trials with adaptive endpoints, justify surrogate endpoints, and clearly define risk–benefit profiles. Collaborations and early regulatory interactions have proven essential in de-risking these novel approaches.

•   Intellectual Property and Cross-Licensing Agreements:
The rapid development of gene-silencing technologies has led to a complex landscape of intellectual property rights. Cross-licensing agreements between companies such as Alnylam Pharmaceuticals and Dicerna can influence development strategies, market access, and ultimately the approval timelines of new drugs. Balancing competitive interests while ensuring patient access remains a regulatory and business challenge.

•   Differences in Global Regulatory Requirements:
Differences between regulatory requirements in the US, Europe, and other regions can lead to varied approval timelines and necessitate additional studies or data packages for each market. For instance, while Oxlumo has gained approval in the US and EU, similar therapies may face additional scrutiny in regions like Japan—prompting sponsors to conduct bridging or additional local studies.

Future Directions and Implications
The continuous evolution of precision medicine technologies and innovative clinical trial designs promises to reshape the therapeutic landscape for primary hyperoxaluria. Future research and development efforts will likely focus on refining drug delivery, understanding patient heterogeneity, and expanding treatment options across all PH subtypes.

Potential Impact on Treatment Landscape
•   Diversification of Therapeutic Options:
As new drugs such as nedosiran, Rivfloza™, and Oxabact® OC5 advance through clinical trials, the therapeutic landscape for PH will diversify significantly. This expansion will allow for more tailored treatment strategies, enabling clinicians to select therapies based on specific PH subtypes, patient age, and disease severity. The availability of multiple drugs with differing mechanisms of action—ranging from RNAi therapies to bacteriotherapy—will allow combination strategies that may improve overall outcomes and delay disease progression.

•   Improved Long-Term Outcomes and Quality of Life:
With earlier intervention via novel therapeutics, it is hoped that progression to end-stage renal disease and the need for transplantation can be significantly reduced. Sustained reductions in urinary oxalate and plasma oxalate levels, as observed in clinical studies for RNAi agents, indicate the potential for long-term stabilization of renal function. Moreover, the incorporation of non-invasive biomarkers and advanced imaging techniques in clinical trials will further support the reassessment of patient outcomes and enhance quality-of-life measures.

•   Personalized and Precision Medicine Approaches:
Advances in genetic screening, biomarker development, and patient stratification will likely pave the way for more personalized treatment regimens in PH. Tailoring therapy based on a patient’s genotype or specific metabolic profile can optimize efficacy and reduce the risk of adverse events—especially in a heterogeneous disease setting where one treatment may not be optimal for all patients.

Research and Development Trends
•   Continued Innovation in RNAi Technology:
The success of Oxlumo has spurred significant interest in RNAi-based therapies. Future developments will likely focus on optimizing dosing regimens, improving delivery mechanisms (for example, through next-generation conjugation strategies), and extending the application of RNAi agents to other aspects of hepatic metabolism disorders. The continued evolution of this modality provides hope for more effective and less frequently dosed therapies.

•   Expansion of Adaptive and Innovative Clinical Trial Designs:
Given the challenges associated with conducting large-scale clinical trials in rare diseases, researchers are increasingly adopting innovative study designs, including adaptive trials and Bayesian statistical methods. These approaches allow for modifications based on interim analyses and can better account for inter-patient variability. By integrating advanced pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation techniques, future trials are expected to be both more efficient and predictive, thereby accelerating the development timeline.

•   Collaborative Research Networks and Global Consortia:
The rarity of PH necessitates collaborative research efforts that span multiple institutions and countries. Global consortia and patient advocacy groups are playing a pivotal role in patient recruitment, natural history studies, and the validation of clinical endpoints. Such collaborations increase the statistical power of clinical studies and streamline regulatory submissions by generating comprehensive datasets across diverse populations.

•   Utilization of Digital Health and Real-World Evidence:
To supplement traditional clinical trials, there is an emerging trend in leveraging digital health platforms and real-world evidence to monitor treatment outcomes, adherence, and safety in routine practice. Longitudinal registries and remote monitoring technologies can capture timely data, aid in the rapid identification of adverse events, and allow for dynamic adjustments in treatment protocols. These innovations are expected to further de-risk clinical development and provide regulators with robust evidence for decision-making.

•   Targeting Ancillary Pathways and Combination Therapies:
Research is also focusing on ancillary pathways that influence oxalate metabolism, such as factors involved in gut microbial composition or upstream regulatory pathways that affect hepatic enzyme expression. Future therapies may combine RNAi agents with probiotics or other small molecules to achieve synergistic effects. These combination strategies are at the forefront of translational research and may offer additional avenues for patients who do not respond adequately to a single-agent therapy.

Conclusion
In summary, the drug development landscape for primary hyperoxaluria is evolving rapidly with multiple innovative therapeutic candidates in the pipeline. RNAi therapeutics such as nedosiran and Rivfloza™ are at advanced stages of clinical evaluation, offering promising alternatives to currently approved treatments like Oxlumo® (lumasiran). In parallel, biologic approaches such as Oxabact® OC5 harness bacteriotherapy by using Oxalobacter formigenes to degrade oxalate in the gut, thus providing a complementary strategy. Early-stage small molecule candidates like INS-6015 underscore the diverse mechanisms being explored, while extensive collaborative efforts and adaptive clinical trial designs help overcome the intrinsic challenges of developing drugs for an ultra‐rare disorder.

The challenges in drug development for PH span scientific aspects like patient heterogeneity and biomarker validation, as well as regulatory hurdles due to small patient populations and novel therapeutic modalities. However, through rigorous clinical trial design, global collaboration, and the integration of modern digital health tools, these challenges are being actively addressed.

Looking toward the future, the expanding pipeline—bolstered by technological advances in RNAi, adaptive trial designs, and personalized medicine—has the potential to significantly alter the treatment paradigm for primary hyperoxaluria. With multiple candidates targeting different metabolic steps, the possibility to tailor therapy for individual patients and even combine different modalities offers hope for improved long-term outcomes, reduced progression to renal failure, and enhanced quality of life for those affected by this devastating disorder.

Ultimately, the convergence of robust clinical data, innovative delivery methods, and strategic regulatory collaborations will be critical in ensuring that these new drugs reach the patients who need them most. The sustained research and development efforts in this field, as reflected by the numerous studies and clinical trials, are paving the way for a new era of precision therapeutics in primary hyperoxaluria, potentially transforming the management and prognosis of the disease for future generations.