Tetrathiomolybdate (DB05088): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Tetrathiomolybdate (TM) is an investigational, orally bioavailable small-molecule therapeutic agent primarily characterized by its potent and highly specific copper-chelating properties.[1] Its principal mechanism involves the reduction of systemic "free" copper—the non-ceruloplasmin-bound, biologically active form of the metal—through a dual-action process of inhibiting gastrointestinal absorption and forming inert complexes in the bloodstream.[3] This core function has positioned TM as a promising therapy for Wilson's disease, a genetic disorder of copper overload. Pivotal clinical trials have demonstrated its superiority over standard-of-care agents, such as trientine, in preventing the initial, often irreversible, neurological deterioration that can occur upon treatment initiation in affected patients.[5]

Beyond its application in Wilson's disease, TM has been the subject of extensive investigation across multiple therapeutic areas, including oncology and fibrotic diseases. In these contexts, its mechanism is understood to extend beyond simple metal sequestration. By depleting copper, TM inhibits a range of copper-dependent enzymes and signaling pathways critical to pathogenesis, such as those involved in angiogenesis (e.g., VEGF, bFGF), extracellular matrix remodeling (e.g., lysyl oxidase), and inflammation (e.g., NF-κB).[1] This positions TM not as a conventional cytotoxic or debulking agent, but as a modulator of the pathological microenvironment. Promising clinical data has emerged from its use as an adjuvant therapy to prevent recurrence in high-risk breast cancer.[9] Furthermore, recent research has uncovered a novel property of TM as a slow-release donor of hydrogen sulfide (

H2​S), a gasotransmitter with cytoprotective effects, suggesting potential applications in conditions such as ischemia-reperfusion injury.[10]

The safety profile of TM is intrinsically linked to its mechanism of action. The primary toxicities observed, including reversible anemia, neutropenia, and elevated liver transaminases, are direct consequences of excessive copper depletion and are generally manageable through careful dose titration guided by serum ceruloplasmin monitoring.[12] This predictable, mechanism-based safety profile contrasts favorably with agents that exhibit idiosyncratic or off-target toxicities.

Despite its strong scientific rationale and compelling clinical data in Wilson's disease, TM has faced a complex and challenging regulatory and development journey. A New Drug Application (NDA) for its use in Wilson's disease was met with a Refusal to File letter from the U.S. FDA in 2008.[14] Following this, the asset has passed through several corporate entities. Recent developments, including the acquisition of the late-stage bis-choline tetrathiomolybdate candidate (ALXN1840) by Monopar Therapeutics, signal renewed interest in navigating the regulatory pathway and finally realizing the therapeutic potential of this multifaceted compound.[15]

Drug Identification and Physicochemical Properties

Nomenclature and Identifiers

Tetrathiomolybdate is a small molecule identified by a comprehensive set of names and numerical codes across various chemical and pharmaceutical databases. Establishing these identifiers is crucial for accurate literature review and regulatory tracking. The generic name is Tetrathiomolybdate, which is also its common English name.[1] It is also referred to by several synonyms, including Thiomolybdate, Tiomolibdate ion, and Tiomolibdic acid.[1]

The compound has been assigned the DrugBank Accession Number DB05088 and the Chemical Abstracts Service (CAS) Registry Number 16330-92-0, which corresponds to the free acid or dianion form, 2−.[1] It is also cataloged under the FDA Unique Ingredient Identifier (UNII) 91U3TGV99T and the NCI Thesaurus Code C160684.[2] During its development, it has been known by the external ID ATN-224 and the investigational brand names Copexa and Coprexa.[1]

Various salt forms of tetrathiomolybdate have been utilized in preclinical and clinical research. The most frequently cited is Ammonium tetrathiomolybdate (ATTM), with CAS Number 15060-55-6.[18] More recent development has focused on bis-choline tetrathiomolybdate, also known as WTX101 or ALXN1840.[15] Other salt forms mentioned in chemical databases include the di-hydrochloride, dipotassium, and disodium salts.[2] The evolution from the ammonium salt to the bis-choline salt is a significant aspect of the drug's development history. This transition is not merely a chemical alteration but represents a strategic pharmaceutical maneuver. The free form of the compound is known to be prone to instability, making stable salt forms preferable for creating a viable drug product.[21] Pharmaceutical development of new salt forms is a common strategy to improve key properties such as chemical stability, solubility, and bioavailability, which can lead to an improved dosing profile (e.g., once-daily administration versus the frequent dosing required for earlier formulations) and secure new intellectual property.[22] This shift to the bis-choline salt likely reflects an effort to create a more robust and commercially attractive therapeutic agent.

Chemical Structure and Properties

The chemical formula for the tetrathiomolybdate anion is MoS4​.[1] Its average molecular weight is reported as 224.19 g/mol or 224.20 g/mol, with a monoisotopic mass of 225.794787 g/mol.[1] The anion possesses a tetrahedral geometry, with a central molybdenum atom bonded to four sulfur atoms. The corresponding Simplified Molecular-Input Line-Entry System (SMILES) notation is S=

Mo--;v8(=S)=S.

Physical Characteristics, Formulation, and Storage

In its solid state, tetrathiomolybdate is a dark brown powder. It exhibits high solubility in water, with values reported as

≥100 mg/mL, and is also soluble in organic solvents such as dimethyl sulfoxide (DMSO). The compound is hygroscopic, meaning it readily absorbs moisture from the air, which underscores the need for specific handling and storage conditions. To maintain product quality and stability, it should be stored under an inert atmosphere, with recommendations for refrigeration at -20°C for long-term storage. For clinical applications, tetrathiomolybdate is administered orally, typically formulated as capsules or coated tablets.

Table 1: Key Identifiers and Physicochemical Properties of Tetrathiomolybdate

Property	Value	Source(s)
Generic Name	Tetrathiomolybdate
DrugBank ID	DB05088
CAS Number (anion)	16330-92-0
CAS Number (Ammonium Salt)	15060-55-6
FDA UNII	91U3TGV99T
Chemical Formula	MoS4​
Average Molecular Weight	224.19 g/mol
Appearance	Dark brown powder solid
Water Solubility	≥100 mg/mL
Primary Route	Oral
Storage Conditions	-20°C, hygroscopic, store under inert atmosphere

Comprehensive Mechanism of Action

The pharmacological activity of tetrathiomolybdate is complex and multifaceted, extending well beyond simple metal chelation. Its diverse therapeutic potential across seemingly unrelated diseases—from genetic copper overload to cancer and ischemia—can be understood by examining three distinct but interconnected mechanistic pillars: (1) high-affinity systemic copper sequestration, (2) downstream inhibition of copper-dependent enzymes and signaling pathways, and (3) novel activity as a gasotransmitter donor. This integrated view provides a comprehensive framework for its broad biological effects.

Primary Mechanism: High-Affinity Systemic Copper Chelation

The foundational mechanism of tetrathiomolybdate is its function as a potent and highly specific anticopper agent. Its primary therapeutic goal is to lower the systemic concentration of "free copper"—the non-ceruloplasmin-bound copper that is biologically available and considered the principal mediator of toxicity in Wilson's disease. TM achieves this through a dual-site action that is dependent on its administration relative to food intake.

When administered with meals, TM acts within the gastrointestinal tract. It complexes with dietary copper as well as endogenously secreted copper present in saliva and gastric juices. This process forms large, insoluble tripartite complexes with food proteins, effectively preventing the absorption of copper from the gut. This action rapidly induces a negative copper balance in the patient.

Conversely, when administered in a fasted state between meals, TM is absorbed from the gut into the bloodstream. Once in circulation, it exerts its systemic effect by forming a highly stable, tripartite complex with free copper and serum albumin. This complex renders the copper biologically inert and unavailable for cellular uptake by tissues. The TM-copper-albumin complex is then slowly cleared from the body, primarily via biliary excretion and, to a lesser extent, in the urine.

At a more specific molecular level relevant to Wilson's disease, TM has been shown to interact directly with the defective ATP7B protein. It induces dimerization of the metal-binding domain of ATP7B by forming a unique sulfur-bridged molybdenum cluster (Mo2​S6​O2​), a highly specific interaction that contributes to its therapeutic effect in this condition.

Downstream Molecular Targeting and Pathway Modulation

The systemic depletion of bioavailable copper by TM has profound downstream consequences, leading to the inhibition of a wide array of copper-dependent enzymes and signaling pathways that are critical drivers of various pathologies.

• Anti-Angiogenesis: Copper is an essential cofactor for angiogenesis, the formation of new blood vessels required for tumor growth and metastasis. TM exerts a powerful anti-angiogenic effect by inhibiting multiple copper-dependent pro-angiogenic factors, including Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Interleukin-8 (IL-8). This approach is considered a "global" inhibition of angiogenesis because it targets a broad spectrum of cytokines simultaneously, a potential advantage over therapies that target only a single factor.
• Inhibition of Superoxide Dismutase 1 (SOD1): TM inhibits the activity of the copper-zinc enzyme Superoxide Dismutase 1 (SOD1) in both endothelial and tumor cells. Inhibition of SOD1 leads to an accumulation of intracellular superoxide anions. The cellular response to this oxidative stress is context-dependent: in endothelial cells, it results in the inhibition of Extracellular signal-regulated kinase (ERK) phosphorylation and attenuation of angiogenesis; in tumor cells, it is potent enough to induce apoptosis.
• Suppression of NF-κB Signaling Cascade: A central mechanism underlying TM's anti-cancer, anti-fibrotic, and anti-inflammatory effects is its ability to suppress the Nuclear Factor-kappa B (NF-κB) signaling cascade. NF-κB is a master transcriptional regulator that controls the expression of numerous genes involved in inflammation, cell survival, and angiogenesis. By inhibiting NF-κB, TM globally downregulates the production of its pro-pathogenic target genes.
• Inhibition of Lysyl Oxidase (LOX): The anti-fibrotic activity of TM is primarily attributed to its inhibition of the lysyl oxidase (LOX) family of enzymes (including LOXL2). These copper-dependent enzymes are essential for the cross-linking of collagen and elastin fibers in the extracellular matrix (ECM). By inhibiting LOX, TM prevents the excessive ECM stiffening that characterizes fibrotic diseases. This mechanism also has implications in oncology, as LOX activity is crucial for modeling the pre-metastatic niche that facilitates tumor cell invasion and metastasis.
• Other Copper-Dependent Targets: TM also inhibits the activity of several other key copper-containing metalloenzymes, including cytochrome C oxidase (essential for mitochondrial respiration), vascular adhesion protein-1 (VAP-1), the copper chaperone ATOX-1, and matrix metalloproteinase 9 (MMP-9).

Novel Mechanisms: Sulfide Donor Properties

Recent research has unveiled an entirely new dimension to tetrathiomolybdate's pharmacology, identifying it as a member of a novel class of slow-release hydrogen sulfide (H2​S) donors.

H2​S is an endogenous gasotransmitter, alongside nitric oxide and carbon monoxide, that plays critical roles in cellular signaling and cytoprotection. It is particularly important in mitigating ischemia-reperfusion injury, where it protects tissues by inhibiting mitochondrial respiration at complex IV (cytochrome C oxidase), thereby reducing the production of damaging reactive oxygen species (ROS) upon reoxygenation.

The release of sulfide from TM is not uncontrolled; it is a regulated process dependent on environmental factors such as temperature, pH, and the presence of thiols (like glutathione). This suggests a targeted drug delivery mechanism, where sulfide release would be enhanced in pathological environments that are often acidic (ischemic) and rich in intracellular thiols. Furthermore, studies have shown that cellular uptake of TM is mediated by the anion exchanger-1 (AE-1) protein in erythrocytes, pointing to a specific, channel-dependent intracellular mechanism of action rather than passive diffusion. This intrinsic chemical property, independent of its copper-chelating function, provides a strong rationale for investigating TM in acute conditions like myocardial infarction, stroke, and hemorrhagic shock.

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion)

The pharmacokinetic profile of tetrathiomolybdate has been characterized primarily through preclinical studies, which reveal an orally bioavailable compound with significant inter-species variability.

• Absorption: TM is orally bioavailable, particularly when administered in a fasted state, which allows it to be absorbed systemically rather than acting solely within the GI tract. A study in dogs determined the average oral bioavailability to be 21%, though with high variability (standard deviation of 22%).
• Distribution: Following intravenous administration in sheep, the distribution of TM was best described by a two-compartmental open model. The steady-state volume of distribution (Vdss​) was calculated to be 0.8 L/kg. A key finding from studies in Long-Evans cinnamon (LEC) rats, an animal model for Wilson's disease, showed that TM uptake into the liver was 13-fold higher than in healthy control rats. This suggests that TM preferentially distributes to tissues with high pathological copper accumulation, targeting the primary site of disease.
• Metabolism: The provided data do not detail specific metabolic pathways for TM. Its primary biochemical fate in the body is the formation of the stable tripartite complex with copper and albumin, which is considered biologically inert.
• Excretion: The TM-copper-albumin complex is slowly eliminated from the body, with clearance occurring through both bile and urine. Studies in sheep demonstrated a significant increase in the fecal excretion of molybdenum within 24 to 48 hours of intravenous administration, consistent with biliary clearance.
• Half-life: The elimination half-life of TM shows marked variation across different animal species. In sheep, the intravenous elimination half-life was determined to be 396.8 minutes (approximately 6.6 hours). In contrast, studies in dogs revealed a much longer terminal elimination half-life of 27.7 hours following intravenous administration and 26.8 hours after oral administration. This significant inter-species variation in pharmacokinetics represents a considerable challenge for preclinical-to-clinical translation. The discordance in half-life between common preclinical models makes it difficult to accurately predict human pharmacokinetics and to establish an optimal dosing regimen. This uncertainty likely contributed to the challenges encountered in early clinical trials for indications outside of Wilson's disease, where finding the precise balance within the narrow therapeutic window between efficacy and mechanism-based toxicity is paramount.

Pharmacodynamics

The pharmacodynamic effects of tetrathiomolybdate are directly related to its copper-depleting mechanism and can be monitored using specific biomarkers.

• Biomarker of Activity: The primary pharmacodynamic marker used to guide dosing and assess the biological effect of TM is the serum concentration of ceruloplasmin. Ceruloplasmin is the main copper-carrying protein in the blood, and its levels serve as a reliable surrogate for the body's total copper status. Clinical trials with TM have consistently defined a target range for ceruloplasmin (e.g., 5–15 mg/dL or 8–17 mg/dL) to ensure adequate copper depletion for therapeutic effect while avoiding excessive depletion that could lead to toxicity.
• Effect on Free Copper: The most critical pharmacodynamic effect, particularly in the context of Wilson's disease, is the rapid and substantial reduction of toxic free copper levels. The ability of TM to quickly control free copper is believed to be the key mechanism by which it prevents the initial neurological worsening often seen with other decoppering agents.
• Effect on Other Biomarkers: In oncology trials, the pharmacodynamic activity of TM has been confirmed by measuring its impact on components of the tumor microenvironment. In a breast cancer study, successful copper depletion (indicated by lower ceruloplasmin levels) correlated significantly with a reduction in circulating endothelial progenitor cells (EPCs) and levels of the pro-fibrotic enzyme LOXL-2, providing direct evidence of TM's anti-angiogenic and matrix-modulating effects. However, the relationship between biomarkers and clinical outcomes can be complex. In a trial for advanced kidney cancer, while TM effectively depleted copper, the corresponding changes in serum levels of pro-angiogenic factors like IL-6, IL-8, VEGF, and bFGF did not correlate with clinical activity (disease stability) in the small patient cohort.

Clinical Efficacy and Investigational Use

Wilson's Disease: Primary Indication

Tetrathiomolybdate's most well-defined clinical application is as an initial therapy for Wilson's disease, a genetic disorder caused by mutations in the ATP7B gene, leading to impaired biliary copper excretion and subsequent toxic copper accumulation in the liver, brain, and other tissues. TM is particularly indicated for patients presenting with neurological symptoms, a population highly vulnerable to treatment-induced paradoxical worsening with traditional chelators.

Pivotal clinical evidence for TM's efficacy comes from a series of studies in this patient population. An open-label trial involving 55 neurologically presenting patients demonstrated the remarkable ability of TM to stabilize neurological function. During the initial 8-week treatment period, only one or two patients (3.6%) experienced any neurological deterioration, a stark contrast to historical rates with other agents. Following this initial TM therapy, patients transitioned to long-term maintenance with zinc and showed good to excellent neurological recovery over the subsequent years.

The superiority of TM was definitively established in a landmark randomized, double-blind, controlled trial that compared it directly against trientine, another commonly used chelating agent. The results, summarized in Table 2, were unequivocal. The primary endpoint, neurological worsening, occurred in only 1 of 25 patients (4%) in the tetrathiomolybdate arm, whereas 6 of 23 patients (26%) in the trientine arm experienced deterioration (

p<0.05). This clinically significant difference was underpinned by a clear pharmacodynamic mechanism. In patients receiving TM, serum free copper levels were rapidly and effectively controlled. In contrast, patients in the trientine arm exhibited an average

increase in free copper levels, and those who worsened neurologically had significant spikes in free copper that temporally correlated with their clinical decline. This provides a compelling biological rationale for TM's superior neuroprotective effect. While not tested in a head-to-head trial, TM is considered a much safer initial option than D-penicillamine, which is known to cause neurological worsening in up to 50% of patients. The standard regimen for this indication involves an 8-week course of TM, typically dosed at around 120 mg per day, followed by a transition to lifelong maintenance therapy with an agent like zinc acetate.

Table 2: Comparative Efficacy in Neurologically Presenting Wilson's Disease (TM vs. Trientine)

Study	Treatment Arm	Number of Patients (N)	Neurological Worsening Rate	Free Copper Control	Source(s)
Brewer et al. 2006	Tetrathiomolybdate + Zinc	25	4% (1/25)	Rapid and strong reduction
Brewer et al. 2006	Trientine + Zinc	23	26% (6/23)	Mean levels increased; spikes correlated with worsening
Brewer et al. 2009	Tetrathiomolybdate	55 (open-label)	N/A	Reduced to ~25% of baseline
Brewer et al. 2009	Trientine (from 2006 study)	23	N/A	Mean levels increased

Investigational Oncology Applications

The rationale for using tetrathiomolybdate in oncology is fundamentally different from that of traditional chemotherapy. The strategy is not to directly kill tumor cells but to modify the tumor microenvironment to inhibit angiogenesis and prevent metastasis, thereby controlling the disease and preventing recurrence. This approach is based on the critical role of copper in activating pathways (NF-κB, SOD1) and enzymes (LOX) necessary for neovascularization and the formation of a pre-metastatic niche.

The history of TM's clinical investigation in cancer reveals a crucial evolution in understanding its proper application. Early trials in patients with advanced, bulky tumors, such as kidney cancer and colorectal cancer, produced disappointing results. These trials were designed to measure traditional endpoints like tumor response (shrinkage), which do not align with TM's anti-angiogenic and anti-metastatic mechanism. The drug's true potential is not in debulking established tumors but in preventing dormant micro-metastases from developing the blood supply needed to grow into clinically significant disease.

This hypothesis was borne out in a Phase II trial that tested TM in a more appropriate setting: as an adjuvant therapy for patients with breast cancer at high risk for recurrence (i.e., after completion of primary therapy). In this study, TM was safe and well-tolerated. More importantly, the survival outcomes were highly promising for this poor-prognosis population. The two-year event-free survival (EFS) was 91% for patients with Stage II-III disease and 90% for those with adjuvant triple-negative breast cancer (TNBC). With a median follow-up of 6.3 years, the EFS for patients with Stage IV disease but no evidence of disease (NED) at enrollment was a remarkable 67-69%. These results suggest that TM, when used in the correct clinical context, may be a highly effective agent for preventing cancer recurrence.

Investigational Anti-Fibrotic Applications

Tetrathiomolybdate has also been investigated as a therapeutic agent for fibrotic diseases, which are characterized by the excessive accumulation and cross-linking of collagen in the extracellular matrix. The primary rationale for its use is its potent inhibition of the copper-dependent lysyl oxidase (LOX) enzymes, which are essential for collagen maturation and matrix stiffening. More recent research has also implicated cuproptosis—a form of programmed cell death induced by copper overload—as a contributor to fibrotic pathogenesis, providing another potential target for TM's copper-modulating effects.

In preclinical models of pulmonary fibrosis (PF), typically induced by bleomycin in mice, TM has consistently demonstrated efficacy. Treatment with TM has been shown to significantly reduce collagen deposition, attenuate the progression of fibrosis, and decrease the expression of LOX and other key fibrotic mediators. These strong preclinical results led to clinical investigation. A Phase I/II trial in patients with idiopathic pulmonary fibrosis demonstrated clinical efficacy, prompting the U.S. FDA to grant TM Orphan Drug status for this indication, although it has not yet proceeded to approval. The anti-fibrotic potential of TM may be broad, as preclinical studies have also shown positive effects in animal models of liver fibrosis and inflammatory conditions with a fibrotic component, such as adjuvant-induced arthritis.

Table 3: Overview of Key Investigational Trials in Oncology and Fibrosis

Indication	Trial Phase	Key Findings / Outcome	Status	Source(s)
Oncology
Breast Cancer (High-Risk Recurrence)	Phase 2	Safe and well-tolerated. Promising EFS: 91% (Stage II-III) and 90% (TNBC) at 2 years.	Completed
Advanced Kidney Cancer	Phase 2	Well-tolerated, effective copper depletion. No CR/PR; Stable Disease in 31% of patients.	Completed
Non-Small Cell Lung Cancer (NSCLC)	Phase 1	Studied in combination with Carboplatin/Pemetrexed.	Completed
Malignant Breast Tumor	Phase 2	Trial was terminated.	Terminated
Metastatic Colorectal Cancer	Pilot Study	Combination with IFL was well tolerated. RR 25%, median TTP 5.6 months.	Completed
Fibrosis & Other
Idiopathic Pulmonary Fibrosis	Phase 1/2	Demonstrated efficacy. Granted FDA Orphan Drug status.	Completed
Alzheimer's Disease	Phase 2	Trial was ongoing at time of publication.	Ongoing (at time of source)
Primary Biliary Cirrhosis	Phase 3	Trial was ongoing at time of publication.	Ongoing (at time of source)

Safety, Tolerability, and Risk Profile

The safety profile of tetrathiomolybdate is well-characterized and is notable for being almost entirely mechanism-based. Its toxicity is a direct extension of its therapeutic action—the depletion of systemic copper—which makes its adverse effects predictable and manageable. This contrasts favorably with drugs that have idiosyncratic or off-target toxicities.

Clinical Adverse Events

The most common and clinically significant adverse events reported in trials are hematological and hepatic. Bone marrow suppression, manifesting as anemia, neutropenia, or leukopenia, is frequently observed. In a Phase II trial in kidney cancer, Grade 3-4 granulocytopenia was the most common reason for dose reduction, though it was typically of short duration and was not associated with febrile complications. Elevations in liver transaminases are also a common finding. In one study, approximately 15% of patients experienced these mild, mechanism-based side effects. Other less severe adverse events that have been reported include sulfurous eructation (belching) and fatigue.

Toxicity Management and Drug Interactions

A key feature of TM's safety profile is that its adverse effects are generally reversible and can be effectively managed by adjusting the dose or temporarily suspending treatment. Clinical protocols are designed to titrate the dose of TM based on serial monitoring of serum ceruloplasmin levels to maintain copper depletion within a therapeutic window, thereby minimizing the risk of toxicity from excessive copper removal. At particularly high doses, there is a theoretical risk of forming an insoluble copper-TM complex that could deposit in the liver and cause hepatotoxicity, underscoring the importance of careful dosing.

Several potential drug interactions have been identified:

• Methemoglobinemia: The risk of this rare blood disorder can be increased when TM is co-administered with a variety of local anesthetics (e.g., lidocaine, prilocaine, cocaine) and other agents like capsaicin and meloxicam.
• Thrombosis: An increased risk of thrombosis may occur when TM is combined with the erythropoiesis-stimulating agent peginesatide.
• Immunosuppression: The risk of immunosuppression may be increased when TM is combined with etrasimod.

Non-Clinical Toxicology

As a chemical substance, tetrathiomolybdate has defined handling hazards. It is classified as a skin irritant (Category 2), a serious eye irritant (Category 2), and may cause respiratory irritation upon inhalation (Category 3). Environmental assessments indicate that it is harmful to aquatic life with long-lasting effects. In ruminant animals like sheep and cattle, high dietary intake of molybdenum compounds in the context of low copper intake can lead to a syndrome of copper deficiency known as molybdenosis, characterized by weight loss, changes in hair/wool, and reduced fertility.

Regulatory and Development History

The path of tetrathiomolybdate from a promising academic discovery to a potential commercial therapeutic has been long and fraught with significant regulatory and corporate challenges. Its history is a case study in the difficulties of developing drugs for rare diseases, where strong clinical data may not be sufficient to ensure a smooth path to approval.

U.S. FDA Status

Tetrathiomolybdate is not currently approved by the U.S. Food and Drug Administration (FDA) for any indication. The most significant event in its regulatory history occurred in January 2008, when Pipex Pharmaceuticals, the sponsor at the time, received a "Refusal to File" letter from the FDA for its New Drug Application (NDA) for Coprexa (oral tetrathiomolybdate). This decision, which applied to the indication of initially presenting neurologic Wilson's disease, meant that the FDA did not consider the application sufficiently complete to begin a formal review. A refusal to file can be due to a range of issues, from administrative incompleteness to perceived deficiencies in the data package, and it represented a major setback for the drug's development.

Despite this, TM has received some positive regulatory feedback. The FDA granted it Orphan Drug Designation for the treatment of idiopathic pulmonary fibrosis based on promising early clinical data. The bis-choline salt of TM was also granted orphan status for Amyotrophic Lateral Sclerosis (ALS) in 2017, although this designation was later withdrawn in 2022. More recently, in June 2022, ammonium tetrathiomolybdate was nominated and discussed for inclusion on the 503A Bulk List, which would allow it to be used by compounding pharmacies for Wilson's disease and various cancers.

EMA Status (European Medicines Agency)

Similar to its status in the U.S., tetrathiomolybdate is not approved by the European Medicines Agency (EMA). The regulatory activity in Europe has centered on a Paediatric Investigation Plan (PIP) for bis-choline tetrathiomolybdate for the treatment of Wilson's disease. A PIP is a mandatory component of drug development in the EU to ensure that the needs of pediatric populations are considered. The EMA accepted a modification to the agreed PIP in May 2022. However, in a subsequent strategic shift by the sponsor, a notification for the discontinuation of this pediatric development program was published in November 2023, halting that specific line of investigation.

Development and Commercial Landscape

The development of tetrathiomolybdate was pioneered by academic researchers, primarily at the University of Michigan, who established its efficacy in Wilson's disease. The commercial rights and development responsibilities have since been transferred through a series of corporate entities. After the NDA setback with Pipex Pharmaceuticals, the asset was associated with Wilson Therapeutics and later Alexion Pharmaceuticals (subsequently acquired by AstraZeneca), which advanced the more stable bis-choline salt, ALXN1840, through Phase 1, 2, and 3 clinical trials for Wilson's disease.

This long and complex journey illustrates how commercial and strategic factors, beyond pure clinical merit, heavily influence a drug's fate. The frequent corporate handoffs and shifting development priorities have delayed its availability to patients. However, the story of TM may be entering a new chapter. In 2023, Monopar Therapeutics acquired the late-stage candidate ALXN1840 from Alexion. This move signals a renewed commitment to bringing a form of tetrathiomolybdate to market, with Monopar stating its intention to pursue regulatory discussions with the FDA, potentially focusing on patients with severe symptoms of Wilson's disease. This represents a potential "third act" for a drug whose scientific promise has remained intact despite its challenging development history.

Synthesis and Future Outlook

Tetrathiomolybdate (TM) stands as a compound of significant pharmacological interest and unfulfilled clinical promise. Its profile is defined by a unique, multi-modal mechanism of action that has demonstrated compelling efficacy in specific, well-defined clinical contexts. The synthesis of available evidence leads to several key conclusions regarding its established role and future potential.

First, for the initial treatment of neurologically presenting Wilson's disease, tetrathiomolybdate has established itself as the superior therapeutic option based on high-quality, comparative clinical trial data. Its ability to rapidly control toxic free copper and, consequently, prevent the initial neurological worsening that plagues treatment with agents like trientine and D-penicillamine addresses a critical and high-stakes unmet medical need. The fact that it remains unapproved for this indication represents a significant gap in the therapeutic armamentarium for this rare and devastating disease.

Second, the investigational history of TM in oncology and fibrosis offers a crucial lesson in aligning therapeutic strategy with biological mechanism. Its failure in trials targeting bulky, advanced tumors and its concurrent success in preventing recurrence in high-risk breast cancer patients highlight its true potential. TM is not a traditional cytotoxic agent but a microenvironment modulator. Its future in these fields, if any, lies in carefully designed trials for the adjuvant or maintenance setting, where its anti-angiogenic, anti-metastatic, and anti-fibrotic properties can be leveraged to prevent disease progression or relapse. Biomarker-driven patient selection will be essential to identify populations most likely to benefit.

Third, the discovery of TM's properties as a slow-release hydrogen sulfide donor opens an entirely new and exciting frontier for research. This mechanism, distinct from its copper-chelating activity, provides a strong rationale for its investigation in acute settings of ischemia-reperfusion injury, such as myocardial infarction and stroke. This potential is nascent but could dramatically expand the compound's therapeutic scope.

Looking forward, the stewardship of the late-stage asset ALXN1840 by Monopar Therapeutics is a pivotal development. The primary challenge will be to successfully navigate the FDA regulatory process, addressing any deficiencies that led to the 2008 Refusal to File and presenting a compelling case based on the robust existing data for Wilson's disease. The opportunity lies in finally delivering a clinically superior drug to a vulnerable patient population. Future research should continue to explore its potential in oncology and fibrosis through mechanistically appropriate trial designs and should vigorously pursue the novel applications suggested by its sulfide-donor properties. Ultimately, the successful development of tetrathiomolybdate will depend on a focused strategy that fully appreciates and exploits its multifaceted pharmacology.

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