BMN-255: An Investigational Glycolate Oxidase Inhibitor – Development and Discontinuation

I. Introduction to BMN-255

A. Overview of BMN-255 as an Investigational Therapeutic Agent

BMN-255 was an investigational, orally administered, small molecule therapeutic agent.[1] Its development program was primarily focused on addressing medical conditions characterized by the overproduction of oxalate, a metabolic end-product that can contribute to significant pathology, particularly in the renal system. The therapeutic strategy centered on modulating a key enzyme involved in oxalate synthesis.

B. Developer: BioMarin Pharmaceutical, Inc.

The development of BMN-255 was undertaken by BioMarin Pharmaceutical, Inc..[1] BioMarin is a biotechnology company recognized for its dedication to discovering, developing, and commercializing therapies for rare and genetic diseases, often with a focus on enzyme deficiencies and metabolic disorders.[4] This background provides context for the company's interest in a condition like hyperoxaluria, which can have genetic underpinnings or arise secondary to other metabolic disturbances.

C. Statement of Current Development Status (Discontinued)

It is important to establish at the outset that the clinical development of BMN-255 was discontinued by BioMarin Pharmaceutical, Inc..[1] This decision, announced in April 2024, marked the cessation of further investigation into this compound for its intended indications. The reasons and context surrounding this discontinuation will be detailed later in this report.

The discontinuation of BMN-255, despite early indications of positive pharmacodynamic activity, highlights the multifaceted nature of pharmaceutical development where scientific potential must be weighed against broader corporate strategies and resource allocation. BioMarin, managing a diverse portfolio that includes complex and high-investment gene therapies such as Roctavian (which itself encountered commercialization hurdles [1]), explicitly attributed the discontinuation of BMN-255 to "portfolio prioritization" rather than any emerging safety concerns with the drug candidate.[6] This suggests that factors such as market potential assessment, strategic alignment within the company's evolving research and development landscape, and the allocation of finite resources likely played a decisive role in the compound's fate.

BMN-255's focus on hyperoxaluria, particularly within the context of Nonalcoholic Fatty Liver Disease (NAFLD) or Metabolic dysfunction-associated steatotic liver disease (MASLD), represented an effort to address a comorbidity with significant unmet medical needs.[1] This approach appeared to leverage BioMarin's established expertise in metabolic and rare diseases, aiming to treat a specific consequence of these increasingly prevalent liver conditions.

II. Chemical Profile and Drug Class

A. Chemical Identity

BMN-255 is chemically identified as 5-[[trans-4-[4-(trifluoromethoxy)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4-carboxylic acid.[7]

• CAS Number: 2360927-98-4 [7]
• Molecular Formula: C16​H16​F3​N3​O4​ [7]
• Molecular Weight: 371.31 g/mol [7]
• Synonyms: BMN 255, BMN255 [7]

B. Drug Type

BMN-255 is classified as a small molecule drug.[1] It was specifically designed for oral administration, a route that generally offers advantages in terms of patient convenience and ease of use compared to injectable or infused therapies.[2] The choice of an oral small molecule approach is significant as it typically involves less complex manufacturing processes and potentially lower costs of goods compared to biologics or gene therapies, which also form part of BioMarin's broader portfolio. This makes the strategic decision to discontinue an oral small molecule with early positive signals particularly noteworthy, implying strong countervailing pressures from portfolio-wide considerations.

C. Pharmacological Class

The primary pharmacological class of BMN-255 is a glycolate oxidase inhibitor.[8] From a therapeutic area perspective, it was categorized under urologic agents and agents for digestive system disorders, reflecting its intended applications in conditions affecting the renal and hepatic systems.[1]

D. Chemical Structure

The chemical structure of BMN-255, 5-[[trans-4-[4-(trifluoromethoxy)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4-carboxylic acid, comprises several key functional groups including a triazole ring, a carboxylic acid moiety, and a fluorinated phenylcyclohexyl ether component.[7] Such structural features are common in medicinal chemistry and are typically selected and optimized during the drug discovery process to achieve specific target engagement (in this case, glycolate oxidase), favorable pharmacokinetic properties (such as oral bioavailability and metabolic stability), and an acceptable safety profile. While the detailed structure-activity relationship studies for BMN-255 are not extensively covered in the available materials, the presence of these motifs suggests a rational design approach aimed at producing an effective and drug-like molecule.

E. Table: Summary of BMN-255 Chemical Properties

Property	Detail	Reference(s)
Chemical Name	5-[[trans-4-[4-(trifluoromethoxy)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4-carboxylic acid	7
CAS Number	2360927-98-4	7
Molecular Formula	C16​H16​F3​N3​O4​	7
Molecular Weight	371.31 g/mol	7
Drug Type	Small Molecule, Oral	1
Pharmacological Class	Glycolate Oxidase Inhibitor	8

This table provides a concise summary of the fundamental chemical and pharmacological identifiers of BMN-255, consolidating key factual data into an easily accessible reference.

III. Mechanism of Action

A. Primary Mechanism: Glycolate Oxidase Inhibition

BMN-255 was developed as an inhibitor of the enzyme glycolate oxidase (GO).[8] Glycolate oxidase plays a critical role in hepatic metabolism, specifically catalyzing the oxidation of glycolate to glyoxylate.[11] Glyoxylate is a direct precursor to oxalate; thus, by inhibiting glycolate oxidase, BMN-255 aimed to reduce the downstream production of oxalate.

B. Pharmacodynamic Effects

The inhibition of glycolate oxidase by BMN-255 was expected to, and did, lead to specific measurable pharmacodynamic effects:

• Increased Plasma Glycolate: As a direct consequence of inhibiting its metabolizing enzyme, an accumulation of the substrate glycolate was anticipated. Early clinical studies in healthy human volunteers confirmed this: oral daily dosing of BMN-255 resulted in a "rapid and potent increase in plasma glycolate".[9] This elevation was sustained over a 14-day dosing period, serving as a direct and quantifiable pharmacodynamic biomarker of target engagement in humans.[9] This early validation is a crucial step in drug development, confirming that the drug reaches its intended molecular target and exerts the expected enzymatic inhibition in vivo.
• Predicted Reduction in Urinary Oxalate: The primary therapeutic goal of BMN-255 was to lower the levels of oxalate excreted in the urine. The observed sustained increases in plasma glycolate led to the prediction that this would translate into a "profound reduction in oxalate excretion in patients".[9] This prediction relies on the understanding that by blocking the conversion of glycolate to glyoxylate, the pool of precursor available for oxalate synthesis would be significantly diminished. The use of plasma glycolate as a surrogate biomarker in early development allowed for an anticipation of clinical efficacy with respect to oxalate reduction.

C. Rationale for Therapeutic Use

The rationale for using BMN-255 was to decrease the endogenous production of oxalate. By doing so, the drug aimed to alleviate the pathological conditions associated with hyperoxaluria, most notably the formation of calcium oxalate kidney stones and the potential for progressive renal damage.

The selection of glycolate oxidase as a therapeutic target is supported by other modalities. For instance, RNA interference (RNAi) therapeutics, such as lumasiran, also target glycolate oxidase (by reducing its expression) and have proven effective in treating Primary Hyperoxaluria Type 1 (PH1).[11] This external validation of the target enzyme underscores the scientific soundness of BMN-255's approach, even though BMN-255 employed a small molecule inhibition strategy rather than RNAi. Furthermore, focusing on the reduction of oxalate production via upstream enzyme inhibition represents a strategy to address the fundamental metabolic imbalance in hyperoxaluric states, as opposed to managing already formed oxalate or attempting to enhance its excretion. This upstream intervention, in theory, could offer more comprehensive control over the body's oxalate burden.

IV. Intended Therapeutic Indications

BMN-255 was investigated for several conditions linked by the common thread of oxalate dysmetabolism and its consequences.

A. Hyperoxaluria

The principal therapeutic target for BMN-255 was hyperoxaluria, a condition defined by abnormally high levels of oxalate in the urine.[1] This broad indication encompassed hyperoxaluria that could arise from various underlying causes, including those associated with chronic liver diseases.

B. Nonalcoholic Fatty Liver Disease (NAFLD) / Metabolic dysfunction-associated steatotic liver disease (MASLD) / Nonalcoholic Steatohepatitis (MASH)

A significant focus of the BMN-255 development program was its use in participants diagnosed with NAFLD (now often referred to as MASLD) or MASH, who concurrently exhibited hyperoxaluria.[1] It is important to note that BMN-255 was not primarily designed to treat the underlying liver steatosis, inflammation, or fibrosis characteristic of NAFLD/MASH. Instead, its role in this patient population was to manage the associated hyperoxaluria, a recognized metabolic complication that can occur in individuals with liver dysfunction. This specific targeting of hyperoxaluria within the NAFLD/MASH population suggests an appreciation of a complex patient subgroup where impaired liver function may contribute to or exacerbate oxalate dysmetabolism. This represents a nuanced approach compared to broadly targeting NAFLD/MASH with agents aimed at liver-specific pathologies.

C. Nephrolithiasis (Kidney Stones)

A direct and anticipated benefit of reducing urinary oxalate levels was the prevention of nephrolithiasis, specifically the formation of calcium oxalate kidney stones.[1] Kidney stones are a common and painful consequence of hyperoxaluria. Thus, while "kidney stones" was listed as an indication, it is more accurately viewed as a clinical outcome that BMN-255 aimed to prevent by addressing the upstream metabolic defect of oxalate overproduction.

D. Chronic Kidney Diseases (CKD)

Chronic Kidney Diseases were also noted as an (inactive) indication for BMN-255 in one source.[1] This likely reflects the understanding that sustained hyperoxaluria and recurrent nephrolithiasis can lead to progressive kidney damage, contributing to the development or worsening of CKD. Oxalate nephropathy, resulting from the deposition of calcium oxalate crystals within the renal parenchyma, is a known cause of acute kidney injury and can progress to chronic kidney disease. Therefore, effective management of hyperoxaluria could potentially offer a renoprotective benefit in the long term.

V. Preclinical and Early Clinical Development (Healthy Volunteers)

A. Healthy Volunteer Studies

Prior to investigating BMN-255 in patient populations, BioMarin conducted and completed a multi-ascending dose (MAD) study in healthy human volunteers.[9] The U.S. Food and Drug Administration (FDA) had granted permission for BioMarin to proceed with this MAD portion of the early human studies.[17]

B. Key Findings from Healthy Volunteer Studies

The studies in healthy volunteers yielded important early data regarding the pharmacodynamics and safety of BMN-255:

• Pharmacodynamics: A key finding was that oral daily administration of BMN-255 led to a "rapid and potent increase in plasma glycolate".[9] This effect was observed to be sustained with 14 days of continuous dosing.[9] This increase in plasma glycolate served as a critical early signal of successful target engagement and proof of mechanism in humans, indicating that BMN-255 was effectively inhibiting glycolate oxidase in vivo.
• Predicted Efficacy: Based on the observed sustained elevations of plasma glycolate, it was "predicted to have a profound reduction in oxalate excretion in patients".[9] This highlights the utility of surrogate biomarkers in early drug development to project potential clinical efficacy. Directly measuring significant changes in 24-hour urinary oxalate might be more complex in short-term healthy volunteer studies; plasma glycolate, as an immediate upstream metabolite, offered a more direct and rapidly assessable indicator of enzyme inhibition, allowing for a scientifically grounded prediction of the downstream impact on oxalate levels.
• Safety: Across all tested dose levels, 14 days of oral daily dosing with BMN-255 was reported to be "safe" in these healthy volunteers.[9]

C. Significance of Early Findings

The positive pharmacodynamic results, coupled with an acceptable safety profile in healthy volunteers, were crucial for BioMarin. These findings provided the necessary scientific rationale and regulatory support to advance BMN-255 into clinical trials involving patients with the targeted conditions.[9] Establishing safety across multiple dose levels in healthy individuals is a prerequisite for obtaining regulatory approval to proceed with studies in patient populations, who inherently present more complex health profiles.

VI. Clinical Development Program in Patients (NCT06138327)

Following the encouraging results from healthy volunteer studies, BMN-255 advanced into a clinical trial designed to assess its effects in patients.

A. Overview of Clinical Trial NCT06138327

The primary clinical trial for BMN-255 in a patient population was registered under the identifier NCT06138327.

• Full Title: "A Phase 1b, Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, 2-Period Crossover Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of an Oral Administration of BMN 255 in Participants With Non-Alcoholic Fatty Liver Disease (NAFLD) And Hyperoxaluria".[1] Other sources confirm the study's focus on NAFLD and hyperoxaluria.[3]
• Registration Number: NCT06138327.[1]
• Sponsor: BioMarin Pharmaceutical, Inc..[1]

B. Study Design and Phase

• Phase: The trial was designated as Phase 1b.[1] Some sources refer to it more generally as Phase 1 [1]; however, Phase 1b is a more precise classification for a study conducted in patients following initial safety and tolerability assessments in healthy volunteers.
• Design: The study employed a randomized, double-blind, placebo-controlled, 2-period crossover design.[1] The term "sponsor-open" likely refers to the sponsor's awareness of treatment allocation for operational purposes, not an unblinding of investigators or participants during the active conduct of the trial periods. The selection of a crossover design is an efficient method for early-phase patient studies, as it allows each participant to serve as their own control, thereby reducing inter-patient variability and potentially increasing statistical power with a smaller number of subjects. The "2-Period Crossover" design means that participants would receive both BMN-255 and placebo during different treatment periods within the study.

C. Study Objectives

The primary objectives of NCT06138327 were:

• Primary Safety Objective: To assess the safety and tolerability of daily oral doses of BMN 255 in adult participants diagnosed with NAFLD and concurrent hyperoxaluria.[10]
• Primary Efficacy/Pharmacodynamic Objective: To evaluate the effect of daily oral doses of BMN 255 on 24-hour urinary oxalate levels, corrected for Body Surface Area (BSA).[10] This endpoint directly measures the intended therapeutic effect of reducing oxalate production and is more clinically relevant in a patient study than plasma glycolate alone. Secondary objectives likely included the assessment of BMN-255 pharmacokinetics (PK) and further exploration of pharmacodynamic (PD) markers, such as plasma glycolate and plasma oxalate levels.[1]

D. Target Patient Population and Key Eligibility Criteria

• Conditions: The study targeted adult participants with Non-Alcoholic Fatty Liver Disease (NAFLD) who also exhibited hyperoxaluria. The conditions are also listed under related terms such as Kidney Stone, Nephrolithiasis, and Metabolic dysfunction-associated steatotic liver disease (MASLD).[1]
• Age Range: Participants were required to be between 18 and 70 years of age.[10]
• Key Inclusion Criteria:
• A documented history of NAFLD, confirmed by a liver fat content of ≥8.0%, as determined by Fibroscan (transient elastography) or magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) during the screening period.[10]
• Confirmed hyperoxaluria, defined as a 24-hour urinary oxalate excretion of ≥45 mg/24 hours/1.73m2 based on two independent assessments during screening.[10]
• A history of at least one kidney stone prior to screening.[10]
• Key Exclusion Criteria:
• A clinical history (including family history) or genetic analyses consistent with primary hyperoxaluria (Type 1, Type 2, or Type 3).[10] This criterion is significant as it indicates BMN-255 was being developed for secondary or enteric forms of hyperoxaluria, rather than the primary genetic forms for which other specific therapies (e.g., lumasiran) are available or in development.
• History or current evidence of inflammatory bowel disease (such as Crohn's disease, ulcerative colitis, or celiac disease/gluten-sensitive enteropathy) or evidence of chronic fat malabsorption (steatorrhea) due to any cause (e.g., pancreatic insufficiency).[10]
• A confirmed diagnosis of Nonalcoholic Steatohepatitis (NASH) or evidence of hepatic cirrhosis, based on clinical assessment, historical liver biopsy, other prior imaging studies, or a liver stiffness value ≥14 kPa during the Fibroscan examination at screening.[10]

E. Interventions

The study involved two intervention arms:

• Drug: BMN 255, administered orally.[1]
• Drug: Placebo, administered orally.[1]

F. Study Timelines and Status

• First Posted Date: The trial was first posted on clinical trial registries on November 18, 2023.[14] The study start date is listed as September 26, 2023.[16]
• Original Anticipated Study Completion Date: March 25, 2024.[16]
• Last Update Posted: June 11, 2024.[14]
• Status: The trial status is Withdrawn.[1] This indicates that the study was terminated before its planned completion, a direct consequence of BioMarin's strategic decision to discontinue the BMN-255 development program. The trial was last updated in June 2024, following the discontinuation announcement in April 2024.[1]

G. Study Locations (United States)

The NCT06138327 trial was planned to be conducted at multiple sites within the United States:

• University of Alabama - Department of Urology, Birmingham, Alabama.[10]
• ProSciento, Inc., Chula Vista, California.[10]
• Georgia Clinical Research, LLC, Lawrenceville, Georgia.[10]
• Medpace Clinical Pharmacology Unit, Cincinnati, Ohio.[10]
• Centricity Research, Columbus, Ohio.[10]
• Prolato Clinical Research Center, Houston, Texas.[10]

H. Table: Detailed Overview of Clinical Trial NCT06138327 for BMN-255

Feature	Details	Reference(s)
NCT Identifier	NCT06138327	1
Full Study Title	A Phase 1b, Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, 2-Period Crossover Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of an Oral Administration of BMN 255 in Participants With Non-Alcoholic Fatty Liver Disease (NAFLD) And Hyperoxaluria	1
Phase	Phase 1b	1
Current Status	Withdrawn	1
Sponsor	BioMarin Pharmaceutical, Inc.	1
Study Design	Randomized, Double-Blind, Placebo-Controlled, 2-Period Crossover	1
Target Conditions	Non-Alcoholic Fatty Liver Disease (NAFLD) with Hyperoxaluria, Kidney Stone, Nephrolithiasis, Metabolic dysfunction-associated steatotic liver disease (MASLD)	1
Key Interventions	BMN 255 (oral), Placebo (oral)	1
Primary Outcome Measures	Safety and Tolerability of BMN 255; Change in 24-hour urine oxalate levels	10
Key Inclusion Criteria	Age 18-70; NAFLD with liver fat ≥8.0%; Hyperoxaluria (≥45 mg/24h/1.73m2); History of ≥1 kidney stone	10
Key Exclusion Criteria	Primary hyperoxaluria (Types 1, 2, or 3); Inflammatory bowel disease; Chronic fat malabsorption; Confirmed NASH or cirrhosis	10

This table summarizes the critical aspects of the primary patient trial for BMN-255, offering a quick understanding of its objectives and design before its discontinuation.

VII. Discontinuation of Development

A. Announcement and Timing

BioMarin Pharmaceutical, Inc. announced the discontinuation of the BMN-255 development program in April 2024. This decision was communicated as part of the company's first-quarter 2024 financial results and followed a strategic review of its research and development assets.[1]

B. Stated Reason for Discontinuation

The explicitly stated reason for halting the development of BMN-255 was portfolio prioritization.[2] BioMarin clarified that this decision was part of a strategic move to focus its resources on other programs within its pipeline. Crucially, the company emphasized that none of the programs discontinued at that time, including BMN-255, were stopped due to safety signals emerging from their development.[6]

C. Context of Discontinuation

The discontinuation of BMN-255 was not an isolated event but occurred within a broader strategic realignment at BioMarin.

• BMN-255 was one of four programs that BioMarin ceased to develop; the others included BMN 331 (a gene therapy for hereditary angioedema), BMN 355 (a preclinical antibody for long-QT syndrome), and BMN 365 (a preclinical gene therapy).[1]
• This portfolio adjustment was driven by the company's new Chief Executive Officer with the aim of maximizing profitability and concentrating R&D investments on programs deemed most promising or strategically aligned.[2]
• A planned reduction in operating expenses was an anticipated outcome of these discontinuations, with estimated net reductions of $35 million to $40 million in 2024 operating expenses.[6]
• This strategic shift also occurred during a period when BioMarin was navigating challenges related to the commercial uptake and revenue generation of its approved gene therapy, Roctavian.[1] The financial pressures and learnings from Roctavian's launch may have influenced the company's risk appetite and investment criteria for its broader pipeline.

The timing of BMN-255's discontinuation in April 2024, relatively shortly after the initiation of its Phase 1b patient trial (NCT06138327) in late 2023, suggests that the decision was likely a component of a pre-determined strategic review rather than a direct response to emergent negative data from that specific trial. Given the typical timelines for patient enrollment, dosing, and data collection in clinical studies, particularly crossover designs, it is improbable that definitive negative efficacy or new safety signals from NCT06138327 would have been fully analyzed to trigger discontinuation within such a short timeframe, especially considering the positive safety and pharmacodynamic data from earlier healthy volunteer studies. The broader context of a new CEO and a comprehensive portfolio review supports the interpretation of a top-down strategic decision.[2]

The choice to discontinue an oral small molecule like BMN-255, which generally presents a less complex and costly development and manufacturing pathway compared to gene therapies (a core area of BioMarin's expertise), might indicate a particularly high threshold for projected return on investment or a significant shift in the company's therapeutic area focus. It could imply that the anticipated market size for BMN-255's specific indications was deemed insufficient relative to other opportunities, or that alternative programs within BioMarin's portfolio were perceived to offer a substantially greater potential impact or return, thereby justifying the reallocation of resources.

VIII. Discussion and Conclusion

A. Summary of BMN-255's Development Trajectory

BMN-255 emerged as an investigational, orally bioavailable, small molecule inhibitor of glycolate oxidase. Its development was founded on a strong scientific rationale: by inhibiting this key enzyme, BMN-255 aimed to reduce the endogenous production of oxalate, thereby addressing conditions such as hyperoxaluria, particularly in the context of NAFLD/MASH, and preventing complications like nephrolithiasis. Early studies in healthy volunteers were promising, demonstrating good safety and clear pharmacodynamic evidence of target engagement through a rapid and potent increase in plasma glycolate, which predicted a subsequent reduction in urinary oxalate excretion in patients.[9] This led to the initiation of a Phase 1b clinical trial (NCT06138327) designed to evaluate BMN-255 in patients with NAFLD and hyperoxaluria.[1] However, despite these positive early steps, the development of BMN-255 was discontinued in April 2024 due to a strategic decision by BioMarin to prioritize other assets in its portfolio; importantly, this discontinuation was not attributed to any safety concerns with BMN-255 itself.[6]

B. Potential of the Mechanism and Unmet Needs

The mechanism of glycolate oxidase inhibition remains a valid therapeutic strategy for reducing oxalate production. This is evidenced by the success of other therapeutic modalities, such as the RNAi agent lumasiran, which also targets glycolate oxidase (albeit through a different mechanism of action – reducing enzyme expression) and is approved for Primary Hyperoxaluria Type 1.[11] There remains a significant unmet medical need for effective and convenient treatments for various forms of hyperoxaluria and its complications, including recurrent kidney stones and the potential progression to chronic kidney disease. This need is particularly acute in complex patient populations, such as individuals with NAFLD/MASH who may develop secondary hyperoxaluria.

C. Implications of Discontinuation

The discontinuation of BMN-255 has several implications. For patients who might have benefited from an oral therapy for certain types of hyperoxaluria, it represents one less potential treatment option in an area where choices are often limited. For the broader field of metabolic and urologic drug development, the BMN-255 story underscores the inherent challenges in bringing new therapies to market, even those with a clear scientific rationale and promising early data. It also highlights how strategic business decisions, resource allocation, and the competitive landscape within a pharmaceutical company's portfolio can significantly influence the trajectory of individual drug candidates.

The development of BMN-255 specifically for hyperoxaluria in the context of NAFLD/MASH [3] brought attention to the interplay between liver disease and oxalate metabolism. While BMN-255 itself will not advance, the clinical questions surrounding the management of hyperoxaluria in patients with hepatic comorbidities remain pertinent and represent an area for future investigation.

D. Concluding Remarks

The development and subsequent discontinuation of BMN-255 illustrate the complex journey of an investigational drug. While its novel mechanism as an oral glycolate oxidase inhibitor showed early scientific promise for addressing hyperoxaluric conditions, strategic corporate decisions ultimately led to the cessation of its development. The fact that BMN-255 was an oral small molecule targeting an enzyme also addressed by other modalities suggests that its development path might have differed under a different corporate owner with an alternative portfolio focus or risk-reward assessment. Although BMN-255 will not reach patients, the knowledge gained from its preclinical and early clinical evaluation, and the further validation of glycolate oxidase as a therapeutic target, may still contribute to and inform future research efforts aimed at developing new treatments for disorders of oxalate metabolism.

Works cited

1. BMN-255 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 3, 2025, https://synapse.patsnap.com/drug/4aee424a0100401f8dd5039efdb802fa
2. New BioMarin CEO Prioritizes Three Programs, Axes Four Others - Global Genes, accessed June 3, 2025, https://globalgenes.org/raredaily/new-biomarin-ceo-prioritizes-three-programs-axes-four-others/
3. Nonalcoholic Fatty Liver Disease Archives - BioMarin Clinical Trials, accessed June 3, 2025, https://clinicaltrials.biomarin.com/api-condition/nonalcoholic-fatty-liver-disease/
4. BioMarin to Present Innovative Pipeline at R&D Day on September 12th in New York, accessed June 3, 2025, https://www.biomarin.com/news/press-releases/biomarin-to-present-innovative-pipeline-at-rd-day-on-september-12th-in-new-york/
5. 2023 Proxy Statement - SEC.gov, accessed June 3, 2025, https://www.sec.gov/Archives/edgar/data/1048477/000130817923000635/bmrn_courtesy-pdf.pdf
6. BioMarin Reports Record Financial Results for the First Quarter 2024 - PR Newswire, accessed June 3, 2025, https://www.prnewswire.com/news-releases/biomarin-reports-record-financial-results-for-the-first-quarter-2024-302125449.html
7. 5-((TRANS-4-(4-(TRIFLUOROMETHOXY)PHENYL)CYCLOHEXYL)OXY)-1H-1,2,3-TRIAZOLE-4-CARBOXYLIC ACID - GSRS, accessed June 3, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/WC82E7HRU5
8. BMN 255 - AdisInsight - Springer, accessed June 3, 2025, https://adisinsight.springer.com/drugs/800061907
9. BioMarin Announces Record Breaking First Quarter 2023 Results, Including 15% Year-over-year Growth of Total Revenues, accessed June 3, 2025, https://www.biomarin.com/news/press-releases/biomarin-announces-record-breaking-first-quarter-2023-results-including-15-year-over-year-growth-of-total-revenues/
10. A Study of BMN 255 in Participants With Non-Alcoholic Fatty Liver Disease And Hyperoxaluria | Clinical Research Trial Listing - CenterWatch, accessed June 3, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06138327/a-study-of-bmn-255-in-participants-with-non-alcoholic-fatty-liver-disease-and-hyperoxaluria
11. An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria - PubMed, accessed June 3, 2025, https://pubmed.ncbi.nlm.nih.gov/27432743/
12. Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias - PMC, accessed June 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7912158/
13. BioMarin Announces Record Breaking First Quarter 2023 Results, Including 15% Year-over-year Growth of Total Revenues, accessed June 3, 2025, https://investors.biomarin.com/news/news-details/2023/BioMarin-Announces-Record-Breaking-First-Quarter-2023-Results-Including-15-Year-over-year-Growth-of-Total-Revenues-04-26-2023/default.aspx
14. BMN-255 - MedPath, accessed June 3, 2025, https://trial.medpath.com/drug/52fcb94d0f1e427a
15. Success for YolTech's hyperoxaluria in vivo gene therapy in early-stage trial, accessed June 3, 2025, https://www.clinicaltrialsarena.com/news/success-for-yoltech-hyperoxaluria-in-vivo-gene-therapy-in-early-stage-trial/
16. BMN-255 - Drug Profile | Trials & News - ngram, accessed June 3, 2025, https://www.ngram.com/drugs/NGDB16913
17. Document - SEC.gov, accessed June 3, 2025, https://www.sec.gov/Archives/edgar/data/1048477/000104847722000025/earningsrelease-03aug22ex9.htm
18. Fatty Liver Disease, Nonalcoholic Withdrawn Phase 1 Trials for 5-[[trans-4-[4-(trifluoromethoxy)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4-carboxylic acid (DB18067) - DrugBank, accessed June 3, 2025, https://go.drugbank.com/indications/DBCOND0039812/clinical_trials/DB18067?phase=1&status=withdrawn
19. Kidney Stones (DBCOND0032121) | DrugBank Online, accessed June 3, 2025, https://go.drugbank.com/conditions/DBCOND0032121
20. Error | ClinicalTrials.gov, accessed June 3, 2025, https://clinicaltrials.gov/study/NCT06138327