CXA-10 (10-Nitrooleic Acid): A Comprehensive Pharmacological and Developmental Review of a Novel Endogenous Signaling Modulator

Executive Summary

CXA-10, known chemically as 10-Nitrooleic acid, is an investigational small molecule drug belonging to the class of nitro fatty acids (NFAs). It is an endogenous signaling molecule formed in the body under conditions of inflammation and nitrative stress.[1] The therapeutic rationale for CXA-10 was built upon a compelling and pleiotropic mechanism of action, positioning it as a potential treatment for a range of complex diseases characterized by oxidative stress, inflammation, and fibrosis.[3]

The primary mechanism of CXA-10 involves its function as an electrophilic signaling mediator. It modulates multiple fundamental cellular pathways, most notably through the potent activation of the cytoprotective Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the concurrent inhibition of the pro-inflammatory Nuclear Factor-kappa B (NF-κB) signaling cascade.[2] This dual action, which simultaneously enhances endogenous defense mechanisms while suppressing inflammatory damage, was supported by a robust body of preclinical evidence across various animal models of renal, cardiopulmonary, and metabolic diseases.

The clinical development program for CXA-10 began with a series of successful Phase 1 studies that established a generally safe profile, albeit with dose-related gastrointestinal side effects, and predictable, dose-proportional pharmacokinetics.[2] Based on this foundation, the developer, Complexa, Inc., advanced CXA-10 into two parallel Phase 2 programs targeting orphan diseases with high unmet need: Pulmonary Arterial Hypertension (PAH) and primary Focal Segmental Glomerulosclerosis (FSGS).[4] This stage marked a critical turning point in the asset's trajectory. The PAH program, comprising multiple clinical trials, was terminated due to a "negative study outcome," indicating a fundamental lack of efficacy in this indication.[5] In contrast, the Phase 2 FIRSTx study in FSGS was officially completed; however, the results were never publicly disclosed, creating a significant data gap that obscures the asset's true potential in renal disease.[5]

The clinical failure in PAH precipitated the financial collapse of Complexa, Inc., which ceased operations and sold its assets, including CXA-10, in 2020 for a nominal upfront payment of $75,000 to Imara Inc..[8] Following its own strategic shifts and a subsequent reverse merger, the asset is now held by Enliven Therapeutics, a precision oncology company for which CXA-10 is a non-core, non-aligned asset held for potential divestment.[10]

In its current state, CXA-10 represents a high-risk, potentially high-reward opportunity. Its strong scientific rationale and established early clinical safety profile are heavily counterweighted by a demonstrated clinical failure in a key indication, a critical lack of data in its most promising indication (FSGS), and a significantly deteriorated intellectual property portfolio with lapsed patents in major global markets.[12] Any potential revival of this asset is entirely contingent on the acquisition and positive re-analysis of the unpublished FSGS clinical trial data. Such an endeavor would require a low-cost acquisition and a meticulously designed clinical and regulatory strategy to navigate the asset's challenging history.

Compound Profile: Chemistry and Pharmacology

A precise understanding of the chemical and pharmacological identity of CXA-10 is fundamental to evaluating its properties and therapeutic potential. As an endogenous metabolite developed into a single-isomer therapeutic, its specific characteristics distinguish it from related compounds.

Nomenclature and Chemical Identity

The compound has been identified through a variety of names and unique codes across scientific literature, regulatory filings, and commercial databases.

• Primary Names: The most common names used in development and research are CXA-10 and its chemical name, 10-Nitrooleic acid.[1]
• Systematic (IUPAC) Name: The formal chemical name is (E)-10-nitrooctadec-9-enoic acid, also written as (9E)-10-nitrooctadec-9-enoic acid, which specifies the trans configuration of the double bond.[3]
• Synonyms: Additional synonyms include 10-nitro-9(E)-octadec-9-enoic acid, 10-Nitrooleate, and 10-nitro-9-trans-Octadecenoic Acid.[3]
• Unique Identifiers: The compound is cataloged under several key database identifiers:
• DrugBank ID: DB15026 [13]
• CAS Number: 875685-46-4 [1]
• FDA UNII (Unique Ingredient Identifier): 1N19AGY57Y [5]
• ChEMBL ID: CHEMBL561371 [16]

Physicochemical and Structural Properties

CXA-10 is a small molecule, classified as an endogenous metabolite, specifically a nitrated derivative of the common monounsaturated fatty acid, oleic acid.[1] Its physical and chemical properties are critical determinants of its formulation, pharmacokinetics, and biological activity.

• Chemical Formula: $C_{18}H_{33}NO_4$ [1]
• Molecular Weight: The average molecular weight is 327.465 g/mol, with a monoisotopic mass of 327.240958547 g/mol.[1]
• Structure: The molecule's structure is defined by an 18-carbon fatty acid chain with a carboxylic acid head, a single double bond between carbons 9 and 10 in the trans (E) configuration, and a nitro group ($NO_2$) attached to carbon 10.
• SMILES: CCCCCCCC/C([N+]([O-])=O)=C\CCCCCCCC(O)=O [1]
• InChI Key: WRADPCFZZWXOTI-BMRADRMJSA-N [3]
• Physical Properties: At room temperature, CXA-10 is a colorless to light yellow liquid.[1]
• Solubility and Partitioning: The compound exhibits very poor water solubility at 0.000774 mg/mL, consistent with its long, lipophilic fatty acid chain. It is soluble in organic solvents such as ethanol.[3] Its high lipophilicity is reflected in its octanol-water partition coefficient (logP), with calculated values ranging from 5.26 to 5.97.[13]
• Acidity: The carboxylic acid group provides the molecule's principal acidic character, with a predicted pKa of approximately 4.77 to 4.99. This indicates that at physiological pH (~7.4), the molecule will exist predominantly in its deprotonated, anionic carboxylate form.[13]

These physicochemical properties, particularly the low aqueous solubility and high lipophilicity, present significant challenges for oral drug formulation and can influence absorption and distribution, likely contributing to the gastrointestinal side effects observed in clinical trials.

Property	Value	Source(s)
DrugBank ID	DB15026	13
CAS Number	875685-46-4	1
FDA UNII	1N19AGY57Y	5
Chemical Formula	$C_{18}H_{33}NO_4$	1
Average Molecular Weight	327.465 g/mol	13
Appearance	Colorless to light yellow liquid	1
Water Solubility	0.000774 mg/mL	13
logP	5.26 - 5.97	13
pKa (Strongest Acidic)	4.99	13
SMILES	CCCCCCCC/C([N+]([O-])=O)=C\CCCCCCCC(O)=O	1
InChI Key	WRADPCFZZWXOTI-BMRADRMJSA-N	13
Table 1: Consolidated Physicochemical and Structural Properties of CXA-10

Classification and Pharmacological Context

CXA-10 is a member of the nitro fatty acids (NFAs), a class of endogenous lipid signaling molecules.[2] These molecules are not typically stored but are formed de novo in environments of inflammation and oxidative/nitrative stress through the reaction of nitrogen-derived species with unsaturated fatty acids.[19] The nitration of oleic acid in vivo produces a mixture of two primary regioisomers, 9-nitro-oleic acid and 10-nitro-oleic acid, in roughly equal proportions.[2] The decision by Complexa, Inc. to develop CXA-10 as a single, purified 10-nitro isomer represented a specific therapeutic hypothesis that this particular isomer might possess an optimal efficacy and safety profile. Pharmacologically, it is categorized as an Anti-Inflammatory Agent and a Lipid.[13]

Mechanism of Action: A Multi-Pathway Signaling Modulator

The therapeutic rationale for CXA-10 is rooted in its ability to act as a pleiotropic signaling molecule, simultaneously modulating multiple pathways that are central to inflammation, oxidative stress, and cellular homeostasis. Unlike traditional drugs that bind non-covalently to a single receptor, CXA-10 functions as an electrophilic agent that covalently modifies key regulatory proteins, leading to a cascade of downstream effects.

Core Electrophilic Signaling

The key functional group responsible for the biological activity of CXA-10 is its nitroalkene moiety. The electron-withdrawing nitro group makes the double bond highly electrophilic, rendering it a potent Michael acceptor.[20] This chemical reactivity allows CXA-10 to undergo a Michael addition reaction, forming reversible covalent adducts with cellular nucleophiles. The primary biological targets of this reaction are the highly reactive thiol groups of cysteine residues within specific proteins.[3] This post-translational modification, termed "nitroalkylation," can alter the conformation and function of these target proteins, thereby transducing a biological signal. This positions CXA-10 not as a simple agonist or antagonist, but as a sophisticated modulator of cellular signaling networks.

Modulation of Key Inflammatory and Cytoprotective Pathways

Through its electrophilic signaling mechanism, CXA-10 exerts significant influence over several critical intracellular pathways.

• Nrf2 Pathway Activation: CXA-10 is a potent stimulant of the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.[23] Under normal conditions, Nrf2 is kept inactive in the cytoplasm by its repressor, Keap1. Electrophiles like CXA-10 are thought to modify specific cysteine residues on Keap1, causing it to release Nrf2. Once freed, Nrf2 translocates to the nucleus and initiates the transcription of a broad array of genes containing the Antioxidant Response Element (ARE).[21] This response upregulates the expression of numerous cytoprotective enzymes and proteins, including:
• Phase II Detoxification Enzymes: Heme Oxygenase-1 (HO-1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1).[1]
• Heat Shock Proteins: hsp27 and hsp70, which act as molecular chaperones to protect against cellular stress.[1]
• Glutathione Metabolism Enzymes: Glutathione-S-transferases (e.g., GSTA1-2, GSTA3, GSTA4), which are critical for detoxification and maintaining redox balance.1 This activation of the Nrf2 system is the core of CXA-10's proposed ability to bolster the body's own defense mechanisms against oxidative stress and tissue injury.3
• Inhibition of Pro-inflammatory Signaling: Concurrently with its cytoprotective effects, CXA-10 actively suppresses key pro-inflammatory pathways. It has been shown to inhibit the activity of Nuclear Factor-kappa B (NF-κB) and Toll-like receptor 4 (TLR4) signaling.[2] NF-κB is a master transcriptional regulator of inflammation, controlling the expression of a wide range of pro-inflammatory mediators. By inhibiting NF-κB, CXA-10 can prevent the production and release of cytokines such as Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-1 beta (IL-1β), as well as chemokines like Monocyte Chemoattractant Protein-1 (MCP-1).[2]
• PPARγ Agonism and Metabolic Effects: Nitro-oleic acid has been identified as an endogenous ligand and agonist for the Peroxisome Proliferator-Activated Receptor gamma (PPARγ).[15] PPARγ is a nuclear receptor that plays a crucial role in adipogenesis, lipid metabolism, and glucose homeostasis. Its activation is also associated with anti-inflammatory effects. This aspect of CXA-10's mechanism contributes to the metabolic benefits observed in preclinical studies, such as improved insulin sensitivity and reductions in circulating triglycerides and cholesterol.[3]

Integrated Mechanistic Synopsis

The therapeutic potential of CXA-10 arises from this unique, integrated mechanism. In a disease state characterized by a vicious cycle of inflammation and oxidative stress, CXA-10 is proposed to act as a homeostatic re-regulator. It simultaneously dampens the "fire" of inflammation by inhibiting NF-κB and TLR4, while also activating the cell's "fire department" and repair crews through the Nrf2 pathway. This dual action provides a powerful and elegant rationale for its investigation in complex, multi-factorial diseases where both processes are pathologically intertwined, such as FSGS and PAH.

The ability of CXA-10 to modulate multiple, fundamental biological pathways is simultaneously its most compelling feature and a significant developmental challenge. On one hand, this broad mechanism provides a strong scientific basis for its potential utility across a wide spectrum of diseases driven by inflammation and oxidative stress, as reflected in the diverse range of preclinical models in which it showed activity and the initial clinical targets selected by its developer.[2] On the other hand, this lack of a single, highly specific target can lead to a less predictable clinical profile and a higher risk of off-target effects. A molecule that influences numerous systemic processes may not achieve a sufficient therapeutic index, where the desired on-target benefits in a specific organ (e.g., the kidney or lung) can be realized at doses that do not cause undesirable systemic effects. The dose-related gastrointestinal adverse events, such as diarrhea and nausea, observed in Phase 1 trials are a likely manifestation of this broad, systemic activity and a potential harbinger of the challenges in finding this therapeutic window.[2]

Furthermore, the elegant and interconnected mechanism described in preclinical literature provides a compelling narrative that ultimately failed to translate into clinical success in PAH. Preclinical studies clearly demonstrated that CXA-10 could reduce inflammation, mitigate oxidative stress, and improve vascular function in rodent models of pulmonary hypertension.[3] The mechanism appeared perfectly suited to address the underlying pathology of the disease. However, the Phase 2 clinical program in human PAH was terminated due to negative outcomes.[6] This points to a significant translational gap between the animal models and the human disease state. The complexity of established human PAH, with its advanced and often irreversible vascular remodeling and severe right heart failure, may be too advanced or operate via pathways that are not sufficiently modulated by CXA-10 at tolerable doses. This suggests that while the mechanism is valid at a biological level, its therapeutic potency may be insufficient for such an advanced disease, a critical consideration for any future development efforts.

Preclinical Evidence and Therapeutic Rationale

The advancement of CXA-10 into clinical trials was underpinned by a substantial body of preclinical research, including in vitro cell-based assays and in vivo studies in various animal models of human disease. These studies provided proof-of-concept for the drug's mechanism of action and demonstrated its potential therapeutic efficacy.

In Vitro Studies

Cell-based experiments were crucial for confirming that CXA-10 could engage its intended molecular targets and elicit the expected biological responses at a cellular level. In a key study using mouse keratinocytes, treatment with CXA-10 at concentrations ranging from 5 to 25 μM led to the upregulation of mRNA and protein expression for a suite of stress-response and antioxidant genes. These included Heme Oxygenase-1 (HO-1), heat shock proteins 27 and 70 (hsp27, hsp70), and cyclooxygenase-2 (Cox-2).[1] This result provided direct evidence of Nrf2 pathway activation and confirmed that the compound was biologically active in a relevant concentration range.

In Vivo Animal Model Efficacy

The therapeutic potential of CXA-10 was most convincingly demonstrated in a wide array of animal models that recapitulated key aspects of human inflammatory, fibrotic, and metabolic diseases.

• Renal Protection: A significant portion of the preclinical work focused on kidney disease, which formed the basis for the initial clinical programs.
• In rodent models of acute kidney injury (AKI), including those induced by ischemia-reperfusion, CXA-10 administration proved to be highly protective. It significantly reduced renal tubular damage, lowered serum creatinine levels by up to approximately 40% compared to vehicle-treated animals, and preserved overall renal function.[3]
• In a chronic model of nephropathy induced by deoxycorticosterone acetate (DOCA)-salt, CXA-10 was also shown to be renoprotective, suggesting its utility in both acute and chronic settings.[3]
• Mechanistically, these protective effects were associated with a reduction in proinflammatory cytokines within the kidney tissue. This strong preclinical data package provided the primary rationale for initiating human trials in AKI and later, in the chronic kidney disease FSGS.[25]
• Cardiopulmonary Disease (PAH): The potential for CXA-10 in pulmonary arterial hypertension was supported by efficacy in relevant animal models.
• In rodent models of PAH, treatment with CXA-10 reduced the expression of proinflammatory cytokines and markers of oxidative damage within the pulmonary vasculature, leading to improved vascular function.[3]
• In a distinct model where high-fat diet-induced obesity leads to the development of pulmonary hypertension, the parent compound nitro-oleic acid (OA-NO2) was shown to ameliorate both the metabolic dysfunction (glucose intolerance) and the associated pulmonary hypertension.[24] This data directly supported the strategic decision to pursue PAH as a key orphan disease indication in Phase 2.[4]
• Metabolic Syndrome: The PPARγ agonist activity of CXA-10 was explored in models of metabolic disease.
• In obese and insulin-resistant mice, administration of CXA-10 led to improved insulin sensitivity, a reduction in inflammation within adipose tissue, and a decrease in circulating levels of triglycerides and cholesterol.[3]
• Similarly, in obese Zucker rats, a genetic model of metabolic syndrome, nitro-oleic acid demonstrated beneficial metabolic effects.[15] These findings highlighted a potential alternative development path in metabolic diseases like nonalcoholic steatohepatitis (NASH).
• Other Inflammatory Conditions: The broad anti-inflammatory and immunomodulatory mechanism of nitro-oleic acids was demonstrated in a variety of other disease models, including atherosclerosis, inflammatory bowel disease, psoriasis, and inflammatory arthritis.[20] This extensive body of work underscored the fundamental nature of the pathways modulated by CXA-10 and its potential applicability to a wide range of human ailments.

Translational Bridge

The consistent and robust positive data generated across these multiple, mechanistically-related animal models created a strong and compelling translational rationale for advancing CXA-10 into human clinical trials. The evidence suggested that by targeting the fundamental pathological processes of inflammation and oxidative stress, CXA-10 could be a disease-modifying agent in complex conditions like AKI, PAH, and FSGS. However, as the clinical program would later reveal, this strong preclinical foundation did not guarantee success in human studies.

Clinical Development and Human Studies

The clinical development of CXA-10 progressed from a comprehensive Phase 1 program that established its basic human pharmacology to a targeted Phase 2 program in two distinct orphan diseases. The trajectory of this program, marked by early promise followed by significant setbacks, is critical to understanding the asset's current value and future potential.

Phase 1 Program Analysis

Complexa, Inc. conducted a thorough Phase 1 program to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of CXA-10 in humans. These studies utilized both intravenous and oral formulations and were conducted in diverse populations, including healthy volunteers, obese male subjects, and individuals with chronic kidney disease.[2]

• Study Designs: The program included several key trials: a first-in-human study of an intravenous emulsion (NCT02127190), a study in subjects with chronic kidney injury (NCT02248051), and multiple studies of an oral formulation, including single and multiple ascending dose studies in healthy and obese subjects (NCT02313064, NCT02460146) and a drug-drug interaction study (NCT02547402).[5]
• Safety and Tolerability: Across these studies, CXA-10 was found to be generally safe and well-tolerated. The most frequently reported adverse events (AEs) were dose-related and predominantly gastrointestinal in nature. Diarrhea, abdominal pain, and nausea were reported in over 10% of subjects receiving the drug.[2] No other clinically significant abnormalities on physical examinations, vital signs, laboratory tests, or electrocardiograms were reported, indicating a lack of major organ toxicity at the doses studied.[2]
• Human Pharmacokinetics (PK): Following oral administration, CXA-10 exhibited predictable and favorable pharmacokinetic properties. Plasma exposure, as measured by both peak concentration ($C_{max}$) and area under the curve (AUC), increased in a dose-proportional manner after both single and multiple ascending doses.[2] This linear PK profile simplified dose selection for subsequent Phase 2 trials.
• Pharmacodynamics (PD) and Biomarker Results: The Phase 1 studies successfully demonstrated target engagement in humans. Consistent with its proposed mechanism of action, treatment with CXA-10 led to a decrease in circulating biomarkers associated with inflammation and metabolic stress.[2] A particularly noteworthy finding emerged from study CXA-10-202, where the 150 mg dose produced a consistent decrease from baseline in levels of leptin, triglycerides, cholesterol, MCP-1, and IL-6. Intriguingly, this effect was not observed at the lower 25 mg dose or the higher 450 mg dose.[2] This observation suggests a potential bell-shaped or U-shaped dose-response curve, where the optimal biological effect occurs within a specific concentration range. This is a complex but not uncommon phenomenon for molecules that modulate broad biological networks and hints at a specific therapeutic window that must be achieved for efficacy.

Phase 2 Program: A Tale of Divergent Outcomes

Based on the promising Phase 1 data and strong preclinical rationale, Complexa launched an ambitious Phase 2 program focused on two orphan diseases: Focal Segmental Glomerulosclerosis (FSGS) and Pulmonary Arterial Hypertension (PAH). The outcomes of these programs diverged dramatically and ultimately determined the fate of the company and the asset.

• Focal Segmental Glomerulosclerosis (FSGS):
• Trial Design: The FIRSTx study (NCT03422510) was a Phase 2, multicenter, open-label, randomized trial designed to investigate two different dose titration regimens of oral CXA-10. The study planned to enroll approximately 30 adult subjects with biopsy-confirmed primary FSGS and significant proteinuria.[5]
• Primary Outcome: The key efficacy endpoint was the reduction in proteinuria, as measured by the percent change from baseline in the urine protein-to-creatinine ratio (UPCR) after 3 months of treatment.[7]
• Status and Results: The trial is officially listed in the ClinicalTrials.gov registry as Completed.[5] However, in a critical failure of transparency and a major blow to the program, no results from this study have ever been posted to the registry or published in peer-reviewed literature. The last update to the trial record was made in August 2020, and the data remains a "black box".[7] This lack of data is the single most significant issue affecting the current valuation and future potential of the CXA-10 asset. A company would not typically withhold positive or even neutral data, which strongly implies the results were negative or inconclusive. However, it is also possible that the company's collapse occurred before the data could be fully analyzed and disseminated. Without access to this dataset, any assessment of CXA-10's potential in renal disease is purely speculative.
• Pulmonary Arterial Hypertension (PAH):
• Trial Program: A comprehensive program was initiated to evaluate CXA-10 in PAH patients who were already on stable background therapy. The cornerstone of this program was the PRIMEx study (NCT03449524), a multicenter, placebo-controlled trial, along with an open-label extension study (NCT04053543) and a smaller investigator-sponsored trial (NCT04125745).[5]
• Status and Reason for Termination: In stark contrast to the FSGS trial, the outcome of the PAH program is known. All three major PAH trials are listed as Terminated.[5] Crucially, the reason cited for the termination of the investigator-sponsored trial was a "negative study outcome from Complexa's multicenter clinical trial".[6] This is a clear and unambiguous statement that the primary PRIMEx study failed to demonstrate efficacy. The termination was explicitly noted to be unrelated to safety issues, with "no safety concerns" reported.[6] This indicates that the drug, at the doses tested, was tolerable but simply ineffective in altering the course of human PAH. This efficacy failure was a fatal blow to the program and likely the primary catalyst for the company's subsequent demise.
• Other Exploratory Indications: Efforts to explore CXA-10 in asthma were initiated but did not advance meaningfully. One trial (NCT03680976) was withdrawn before enrolling patients, while another (NCT03762395) has a listed start date that is inconsistent with the developer's operational timeline, suggesting it never proceeded.[5]

NCT ID	Phase	Indication	Status	Sponsor	Key Notes
NCT02127190	1	Acute Kidney Injury	Completed	Complexa, Inc.	First-in-human study, IV emulsion.
NCT02248051	1	Chronic Kidney Injury	Completed	Complexa, Inc.	IV emulsion in CKD patients.
NCT02313064	1	Healthy Volunteers	Completed	Complexa, Inc.	Oral formulation, SAD/MAD study.
NCT02460146	1	Healthy Obese Males	Completed	Complexa, Inc.	Oral formulation, PK/PD study.
NCT02547402	1	Healthy Males	Completed	Complexa, Inc.	Drug-drug interaction study with statins.
NCT03422510	2	Focal Segmental Glomerulosclerosis (FSGS)	Completed	Complexa, Inc.	FIRSTx study. CRITICAL: No results ever posted or published.
NCT03449524	2	Pulmonary Arterial Hypertension (PAH)	Terminated	Complexa, Inc.	PRIMEx study. Parent trial that failed for efficacy.
NCT04053543	2	Pulmonary Arterial Hypertension (PAH)	Terminated	Complexa, Inc.	Open-label extension of PRIMEx. Terminated as a result of parent study failure.
NCT04125745	2	Pulmonary Arterial Hypertension (PAH)	Terminated	Mark Gladwin, MD	Investigator-sponsored trial. Terminated due to "negative study outcome" of Complexa's trial.
NCT03680976	2	Asthma	Withdrawn	Sally E. Wenzel MD	Withdrawn before patient enrollment.
NCT03762395	2	Asthma / Obesity	Recruiting	U. of Colorado	Unlikely to be active given sponsor history; likely not updated.
Table 2: Comprehensive Summary of CXA-10 Clinical Trials

Corporate History, Intellectual Property, and Asset Trajectory

The commercial and corporate history of CXA-10 is a cautionary tale of a promising scientific platform that failed to navigate the immense challenges of late-stage clinical development. The trajectory from a well-funded startup to corporate dissolution and the subsequent fire-sale of its lead asset provides critical context for any future valuation.

The Rise and Fall of Complexa, Inc.

Complexa, Inc. was a privately held, clinical-stage biopharmaceutical company founded in 2008 with headquarters in Pennsylvania.[25] The company's scientific platform was built on the research and development of endogenous nitro fatty acids (NFAs) as a novel class of therapeutics for a range of inflammatory, fibrotic, and metabolic diseases.[25]

The company successfully attracted significant venture capital investment to advance its lead candidate, CXA-10. Key funding rounds included a $13 million Series B financing in June 2014 to support the initial Phase 1 trials and the development of an oral formulation.[32] This was followed by a substantial $62 million Series C financing in July 2017, which was explicitly raised to fund the pivotal Phase 2 proof-of-concept trials in FSGS and PAH.[4]

The failure of the PAH clinical program in 2020 proved to be an insurmountable obstacle for the company. Lacking a clear clinical success to attract further investment or partnership, Complexa, Inc. ceased operations. Its corporate website became inactive in mid-2022, and business intelligence platforms list its official status as "Out of Business" as of June 9, 2022.[8]

Asset Disposition and Current Ownership

Following its operational collapse, Complexa's assets were handled through an "Assignment for the Benefit of Creditors," a state-level legal process for winding down an insolvent company.

• Asset Sale to Imara Inc.: On October 19, 2020, an asset purchase agreement was executed between the assignee for Complexa and Imara Inc..[9] The terms of this sale are highly revealing of the asset's perceived value at the time. Imara acquired the specified assets of Complexa for a remarkably low upfront payment of just $75,000, with additional undisclosed contingent payments based on future milestones.[9] This "fire-sale" price indicates that the asset was considered to have very little immediate value, likely reflecting the definitive failure in PAH and presumed negative or inconclusive data from the FSGS trial. The acquisition was likely a low-cost bet on the intellectual property, remaining drug substance, and the clinical trial database.
• Status within Imara and Merger with Enliven: Imara Inc. was a clinical-stage company focused on rare blood disorders, with its own lead asset, tovinontrine (IMR-687), for sickle cell disease and beta-thalassemia.[34] Within Imara's pipeline, CXA-10 was likely designated with the internal code IMR-261.[6] After Imara's own lead program also faced clinical setbacks, the company underwent a strategic shift.[11] In a transaction that closed in February 2023, Imara executed a reverse merger with Enliven Therapeutics.[10]
• Current Ownership and Status: The newly formed public company, Enliven Therapeutics, Inc., is a precision oncology company focused on developing a pipeline of small molecule kinase inhibitors.[37] The CXA-10/IMR-261 asset, which targets inflammatory and fibrotic pathways, is entirely outside of Enliven's new strategic focus. Consequently, the asset is being held solely for divestment. The terms of the Imara-Enliven merger included the issuance of a Contingent Value Right (CVR) to pre-merger Imara stockholders. This CVR grants them the right to receive payments from any potential future sale or licensing of IMR-261.[10] The use of a CVR structure is a standard strategy for handling high-risk, non-core assets that an acquiring company does not wish to invest in but from which it hopes to extract some potential future value. This confirms that CXA-10 is an orphaned asset awaiting a third-party buyer.

Intellectual Property Landscape

A robust intellectual property (IP) portfolio is essential to justify the significant investment required for late-stage drug development. An analysis of the patent estate for CXA-10 reveals a significant and concerning deterioration.

• Core Patent Filings: The primary patent family covering the use of CXA-10 for treating diseases like FSGS and PAH is represented by international application WO2017059451A1 and its national phase entries, such as Canadian application CA3000842A1.[12] These patents claim methods of treating various diseases by administering 10-nitro-9(E)-octadec-9-enoic acid.
• Deterioration of Patent Status: A detailed review of the legal status of this patent family across global jurisdictions reveals a critical weakness. Patent applications in numerous key pharmaceutical markets—including Canada, Europe, Australia, Japan, and Korea—are listed with a status of "Abandoned," "Withdrawn," or "Ceased".[12] This strongly suggests that during Complexa's financial distress and subsequent dissolution, the necessary actions and fee payments to maintain and prosecute these applications were not made. This has resulted in a severely compromised global patent portfolio. While some protection may remain in the United States, the lack of broad international exclusivity presents a major barrier to commercialization and dramatically reduces the asset's value. Any potential acquirer would face the daunting prospect of generic competition in major markets shortly after launch, making it difficult to recoup development costs. A new IP strategy, potentially focused on novel formulations or new methods of use, would be essential but may not fully substitute for the loss of core compound-of-use protection.

Synthesis, Strategic Analysis, and Future Outlook

A comprehensive evaluation of CXA-10 reveals an asset with a profound disconnect between its strong scientific rationale and its challenging clinical and commercial history. Its future potential is contingent on resolving the critical uncertainties that led to its current status as an orphaned drug candidate.

Integrated Risk-Benefit Assessment

The investment profile of CXA-10 is characterized by a high-risk, high-reward dynamic, with significant factors weighing on both sides of the ledger.

• Strengths:
• Compelling Mechanism of Action: The drug's ability to simultaneously activate the cytoprotective Nrf2 pathway and inhibit pro-inflammatory NF-κB signaling is well-defined and scientifically elegant. This dual mechanism remains highly relevant for a multitude of diseases driven by oxidative stress and inflammation.
• Extensive Preclinical Package: A robust collection of in vivo data demonstrates clear efficacy in multiple relevant animal models of kidney, lung, and metabolic diseases.
• Established Human Safety Profile: The Phase 1 program successfully established a tolerable safety profile in humans, with predictable, dose-proportional PK and known, manageable gastrointestinal side effects.
• Weaknesses:
• Confirmed Clinical Efficacy Failure: The termination of the entire Phase 2 PAH program due to a "negative study outcome" represents a definitive and significant clinical failure.
• Critical Data Gap: The complete absence of any published or reported data from the completed Phase 2 FIRSTx trial in FSGS creates a massive uncertainty that overshadows the entire asset.
• History of Corporate Failure: The asset is tainted by the bankruptcy of its original developer, Complexa, Inc., and its subsequent low-value sale.
• Severely Compromised IP Portfolio: The abandonment and lapse of patent applications in key international markets presents a major barrier to future commercial viability.

Analysis of Development Setbacks

The failure in PAH was the pivotal event that led to the asset's downfall. This outcome suggests that the systemic anti-inflammatory and anti-fibrotic effects of CXA-10, when delivered orally at tolerable doses, were insufficient to meaningfully alter the course of advanced human PAH, a disease characterized by severe and often fixed vascular remodeling and right ventricular failure. This raises substantial questions about the drug's potency and its potential utility in other severe, systemic fibrotic conditions. It underscores a common and difficult challenge in drug development: the translational gap between promising results in simplified animal models and the complex, multifactorial nature of chronic human disease.

Unrealized Potential and Key Unknowns

Despite its history, the future of the CXA-10 asset hinges almost entirely on a single, critical unknown: the results of the completed FIRSTx trial (NCT03422510) in FSGS. FSGS remains a devastating kidney disease with a high unmet medical need and few effective therapeutic options.[39] If the data from that trial, which is currently sequestered, were to show a positive signal—even a modest reduction in proteinuria or a benefit in a specific patient sub-population—it could provide a basis for a renewed and highly focused development effort. Without access to and analysis of this data, the asset's clinical potential is purely hypothetical and its value is minimal.

Recommendations and Future Pathways

Based on this comprehensive analysis, a clear and stepwise strategic path for any party interested in acquiring and reviving CXA-10 can be delineated.

• Primary Recommendation: Data Acquisition and Due Diligence. The absolute first and most critical action is to conduct due diligence to determine if the complete raw clinical trial data package from the NCT03422510 (FIRSTx) study can be acquired from Enliven Therapeutics. This is the sole gating item for any further consideration.
• Scenario 1: FSGS Data is Negative or Unobtainable. If the data confirms a lack of efficacy, or if the data package is incomplete or cannot be acquired, the asset holds negligible value for further development. The combination of two Phase 2 failures (one confirmed, one presumed) and a severely weakened IP portfolio makes any future investment unjustifiable. The project should be abandoned.
• Scenario 2: FSGS Data is Positive or Shows a Signal of Activity. If a thorough re-analysis of the FIRSTx data reveals a clinically meaningful benefit, a high-risk but potentially viable development path could be considered. This pathway would require:

1. Low-Cost Acquisition: Negotiating the purchase of the asset, including all data, IP, and remaining drug substance, from Enliven Therapeutics for a price that reflects its high-risk profile, likely structured with minimal upfront payment and significant back-end milestones.
2. IP Rehabilitation: Engaging patent attorneys to assess the remaining IP estate and develop a new strategy to build protection, potentially through novel formulations (e.g., delayed-release to mitigate GI effects), specific method-of-use patents derived from the FSGS data, or combination therapies.
3. Regulatory Engagement: Meeting with regulatory agencies (e.g., the FDA) to present the re-analyzed Phase 2 data and collaboratively design an efficient and well-defined pivotal Phase 3 trial, potentially leveraging orphan drug designations.

• Alternative Strategies: Should the FSGS path prove unviable, the broad mechanism of CXA-10 could theoretically be applied to other, less-explored indications. A strategy focused on local delivery could potentially maximize efficacy at the target site while minimizing the systemic exposure that leads to GI side effects. This could include developing topical formulations for inflammatory skin diseases like psoriasis or inhaled formulations for allergic airway diseases. However, this would represent a much earlier-stage, higher-risk proposition, as it would require new preclinical proof-of-concept work and would essentially reset the development clock.

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