A Comprehensive Monograph on Perflenapent (Dodecafluoropentane): Chemical Properties, Pharmacology, and Evolving Clinical Applications

1.0 Executive Summary

Perflenapent, a small molecule identified chemically as dodecafluoropentane, represents a unique perfluorocarbon (PFC) with a distinct and evolving history in clinical medicine. This report provides a comprehensive analysis of its chemical nature, dual pharmacological mechanisms, regulatory journey, and current investigational landscape. Initially developed by Sonus Pharmaceuticals as EchoGen®, an injectable emulsion, it gained marketing authorization in the European Union in 1998 as a phase-shift ultrasound contrast agent. Its mechanism in this role was predicated on the conversion of liquid nanodroplets into echogenic gas microbubbles upon entering the warmer physiological environment of the human body. Despite its European approval, EchoGen® failed to secure regulatory clearance in the United States and was subsequently withdrawn from the market, a decision attributed primarily to commercial and strategic factors rather than safety concerns.

In recent years, Perflenapent has been repurposed and is undergoing a clinical renaissance as a novel oxygen therapeutic, formulated as a dodecafluoropentane emulsion (DDFPe) and developed under the name NanO2™ by NuvOx Pharma LLC. This therapeutic application leverages the same fundamental physicochemical property that defined its function as a contrast agent: a boiling point of approximately 29°C. At physiological temperature (37°C), Perflenapent exists as a gas, a state in which it can dissolve and transport significantly more oxygen than liquid-phase PFCs. This property, combined with its chemical inertness and rapid, complete elimination from the body via pulmonary exhalation, confers a favorable safety and pharmacokinetic profile that circumvents the toxicity issues that plagued earlier-generation, high-boiling-point PFCs.

Currently, Perflenapent is being investigated in several high-unmet-need therapeutic areas. Clinical trials are exploring its potential as a neuroprotectant in acute ischemic stroke (NCT02963376), a radiosensitizer for the treatment of glioblastoma multiforme (GBM) by reversing tumor hypoxia (NCT03862430), and an oxygen-delivery agent for patients with mild respiratory distress (NCT06658535). The U.S. Food and Drug Administration has granted Orphan Drug Designations for its use in GBM and sickle cell disease, underscoring its potential in rare and serious conditions. This report synthesizes the complete trajectory of Perflenapent, from its chemical foundation to its past as a diagnostic agent and its promising future as a multi-indication therapeutic platform.

2.0 Identification and Physicochemical Properties

The foundation of Perflenapent's unique pharmacological behavior lies in its distinct chemical structure and resulting physical properties. A thorough understanding of its identity is essential for contextualizing its clinical applications.

2.1 Nomenclature and Chemical Identifiers

Perflenapent is known by a variety of names across chemical, pharmaceutical, and commercial contexts. Establishing a clear and consolidated list of these identifiers is crucial for accurate cross-referencing of scientific and regulatory literature. The compound's generic name is Perflenapent, while its preferred name under the International Union of Pure and Applied Chemistry (IUPAC) is dodecafluoropentane.[1] It should be noted that the prefix 'per-', while historically used, is no longer recommended by IUPAC for this class of compounds.[2] A comprehensive list of its identifiers is provided in Table 1.

Table 1: Nomenclature and Chemical Identifiers for Perflenapent

Identifier Type	Value	Source(s)
Generic Name	Perflenapent	1
IUPAC Name	Dodecafluoropentane	2
Common Synonyms	Perfluoropentane (PFP), Dodecafluoropentane emulsion (DDFPe)	1
Commercial/Code Names	NVX-108, FC 4112, FC 87, FLUORINERT, Flutec PP50	1
DrugBank ID	DB11625	1
CAS Number	678-26-2	1
UNII	483AU1Y5CZ	1
ChEBI ID	CHEBI:39428	2
PubChem CID	12675	2
InChI Key	NJCBUSHGCBERSK-UHFFFAOYSA-N	1
ATC Code	V08DA03	1

2.2 Molecular Structure and Chemical Classification

Perflenapent is a small molecule with the chemical formula $C_{5}F_{12}$.[1] Structurally, it is a saturated five-carbon alkane (pentane) in which every hydrogen atom has been replaced by a fluorine atom.[3] This complete fluorination is the defining feature of its chemistry.

Its molecular weight is 288.036 g·mol⁻¹ (average) and 287.980837956 Da (monoisotopic).[1] The molecule is achiral and its structure is represented by the SMILES string FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[1]

Chemically, Perflenapent is classified within several hierarchical groups. It is an organofluoride, belonging to the broader class of organohalogen compounds.[1] More specifically, it is a fluoroalkane and a fluorocarbon.[3] Due to its industrial and biomedical applications, it is also categorized as a compound used in research, a diagnostic chemical, and a contrast agent.[1] The U.S. Environmental Protection Agency (EPA) and the Organisation for Economic Co-operation and Development (OECD) classify it as a per- and polyfluoroalkyl substance (PFAS).[7]

2.3 Physicochemical Characteristics and Biological Relevance

The pharmacological functions of Perflenapent are almost entirely dictated by its physical properties rather than by specific biochemical interactions like receptor binding. Its behavior in a biological system is a direct consequence of its chemistry, with its boiling point being the single most critical determinant of its clinical utility and safety profile.

At room temperature, Perflenapent is a colorless, odorless liquid.[7] A summary of its key physicochemical properties and their biological implications is presented in Table 2.

Table 2: Summary of Key Physicochemical Properties of Perflenapent

Property	Value	Biological Relevance	Source(s)
Boiling Point	28-29°C	Enables phase-shift from liquid to gas at physiological temperature (37°C). This drives both its mechanism as an ultrasound contrast agent and its high oxygen-carrying capacity as a therapeutic. It also facilitates rapid and complete elimination via pulmonary exhalation, preventing bioaccumulation and associated toxicity.	2
Physical State	Liquid at room temp. (25°C), Gas at body temp. (37°C)	Allows for formulation and administration as a liquid emulsion, which transforms into functional gas microbubbles in vivo.	10
Water Solubility	0.0383 mg/mL (Very low)	Dictates its formulation as a stabilized emulsion for intravenous administration. Its hydrophobicity is essential for maintaining discrete droplets in the bloodstream.	1
Density (liquid)	~1.63 g/mL at 25°C	High density relative to aqueous media.	2
Vapor Pressure	~84-86 kPa at 25°C	High volatility contributes to its efficient transition to a gaseous state and subsequent rapid clearance from the lungs.	2
Polar Surface Area	0 Ų	The molecule is completely non-polar, lacking any sites for hydrogen bonding, which contributes to its chemical inertness and low solubility in water.	1
logP	3.28 - 4.18	Indicates high lipophilicity. However, as a fluorocarbon, it is also lipophobic, a dual characteristic that prevents it from dissolving in either aqueous or lipid environments, allowing it to circulate as a discrete carrier.	1

The boiling point of Perflenapent, consistently reported at 28-29°C, is slightly below human physiological temperature.[2] This seemingly simple physical constant is the master variable governing its entire clinical story. This property enables a phase transition from a liquid to a gas upon intravenous administration, a phenomenon that is the explicit mechanism for its function as an ultrasound contrast agent (EchoGen®), where injected liquid nanodroplets vaporize into highly reflective gas microbubbles.[11] This same property is the key to its superior efficacy as an oxygen therapeutic (NanO2™). As a gas, Perflenapent can dissolve and deliver approximately 1000 times more oxygen by volume than a liquid perfluorocarbon.[10] Furthermore, this low boiling point is directly responsible for its enhanced safety profile compared to older PFCs. High-boiling-point PFCs (e.g., boiling points ≥140°C) remained liquid in the body, leading to long-term retention in the reticuloendothelial system and subsequent toxicity.[10] In contrast, gaseous Perflenapent is rapidly and completely cleared from the bloodstream via exhalation, preventing bioaccumulation.[10]

An interesting nuance of Perflenapent's chemistry is its dual hydrophobic and lipophobic nature. While standard chemical metrics like logP indicate it is lipophilic and its low water solubility confirms it is hydrophobic, expert analysis of fluorocarbons describes them as being simultaneously lipophobic.[1] This is not a contradiction. The unique properties of the carbon-fluorine bond create a molecule that is immiscible with both water and many non-polar lipids and organic solvents. This dual "phobia" is critical to its function, as it ensures that the emulsified droplets remain stable and discrete within the bloodstream, neither dissolving in the aqueous plasma nor partitioning into cell membranes or lipid deposits. This stability allows the droplets to function effectively as circulating carriers.

2.4 Safety, Handling, and Toxicology

In its pure chemical form, Perflenapent carries GHS hazard classifications indicating it may cause skin, eye, and respiratory irritation, with a corresponding signal word of "Warning".[2] It is stable under normal conditions but should be stored cold.[3] Its decomposition temperature is high, at approximately 400°C.[9]

Non-clinical toxicology data show a median lethal concentration (LC50) from inhalation in rats of 120 gm/m³.[3] Preclinical studies conducted during the development of the EchoGen® emulsion in rodents and dogs revealed that adverse effects—such as transient changes in blood pressure, respiration rate, and hypoactivity—were dose-related and typically resolved without intervention.[12] The minimum lethal single intravenous dose in rats was found to be 4.0 ml/kg, approximately 80 times the recommended human dose for contrast imaging. A 14-day repeat-dose study in dogs identified left ventricular endocardial hemorrhages at high daily dose levels (0.4, 1.0, and 2.0 ml/kg/day), an effect not observed at lower doses or in single-dose studies.[12] Ecologically, the compound is not considered harmful to aquatic organisms and is not expected to cause long-term adverse effects in the environment.[9]

3.0 Pharmacology and Mechanism of Action

Perflenapent is a pharmacologically unique agent whose actions are driven by physical principles rather than biochemical interactions. Its utility stems from its ability to undergo a phase transition at physiological temperature and its high capacity to dissolve respiratory gases. These properties have enabled its development for two distinct clinical applications: diagnostic ultrasound imaging and therapeutic oxygen delivery.

3.1 Pharmacodynamics: A Dual-Mechanism Analysis

The pharmacodynamic effects of Perflenapent are best understood by separately analyzing its function in its two primary roles.

3.1.1 As an Ultrasound Contrast Agent (EchoGen®): The Phase-Shift Colloid

The mechanism of Perflenapent as a contrast agent is based on a physical process known as acoustic droplet vaporization, commercialized under the name PhaseShift™ technology.[2] The product, EchoGen®, is formulated as a stable emulsion of microscopic liquid droplets of dodecafluoropentane.[11] Following intravenous injection, these liquid droplets circulate in the bloodstream. Upon exposure to the body's temperature (37°C) and ambient pressure, the droplets, with their boiling point of 29°C, undergo a phase transition and vaporize into gas microbubbles.[11]

The resulting microbubbles are highly echogenic, meaning their surface strongly reflects ultrasound waves. This property dramatically increases the acoustic backscatter from blood compared to the surrounding tissues.[12] The pharmacodynamic effect is a significant enhancement of the ultrasound signal, leading to opacification of cardiac chambers and improved delineation of the endocardial border of the left ventricle. This allows for better visualization of wall motion and blood flow, which is particularly valuable in patients whose baseline, non-contrast echocardiograms are technically difficult or inconclusive.[12] The contrast enhancement is transient, with a duration of approximately four minutes for B-mode imaging of the heart and up to 13-20 minutes for color Doppler signal enhancement in the peripheral vasculature.[12]

3.1.2 As an Oxygen Therapeutic (DDFPe/NanO2™): A Novel Gas-Phase Delivery System

The repurposing of Perflenapent as a therapeutic agent leverages the inherent ability of perfluorocarbons to physically dissolve large quantities of respiratory gases, a property stemming from the high electronegativity of the fluorine atoms.[10] Unlike hemoglobin, which chemically binds oxygen, PFCs carry gases in physical solution. Perflenapent's key advantage over prior PFCs is its existence as a gas at body temperature. Gases can dissolve and deliver approximately 1000 times more oxygen by volume than their liquid counterparts, making Perflenapent a far more efficient oxygen carrier.[10]

The therapeutic formulation, known as DDFPe or NanO2™, consists of nanometer-sized droplets (approximately 250 nm in diameter) that are small enough to perfuse capillaries that may be constricted or blocked to larger red blood cells (approximately 8 microns in diameter), particularly in ischemic tissues.[16] The pharmacodynamic effect has two primary therapeutic applications:

1. Tissue Reoxygenation and Salvage: In conditions like acute ischemic stroke or respiratory distress, the DDFPe nanodroplets absorb oxygen in the lungs and transport it through the circulatory system. Upon reaching hypoxic tissues, they offload the dissolved oxygen, helping to restore cellular metabolism, reduce edema, and salvage tissue that is at risk of infarction.[10] DDFPe has a remarkably high oxygen-carrying capacity of 80% v/v, significantly greater than that of older PFCs like perfluorooctylbromide (50%) or perfluorodecalin (42%).[10] This allows it to be effective at gram-weight doses that are 200 to 1000 times lower than those required for previous PFCs, thereby avoiding the dose-limiting toxicities associated with overloading the reticuloendothelial system.[10]
2. Tumor Radiosensitization: Solid tumors, such as glioblastoma multiforme (GBM), are often characterized by significant regions of hypoxia. This lack of oxygen renders them resistant to radiation therapy, as the cytotoxic effect of radiation is largely mediated by the formation of oxygen-dependent free radicals. The proposed mechanism for Perflenapent in this context is to act as a radiosensitizer.[17] By efficiently delivering oxygen to the hypoxic core of the tumor, it is hypothesized to re-establish an oxygenated microenvironment, thereby restoring the tumor's sensitivity to standard radiation treatment.[18]

3.2 Pharmacokinetics: Distribution, Metabolism, and Pulmonary Clearance

The pharmacokinetic profile of Perflenapent is exceptionally straightforward and is a key differentiator from other PFCs, underpinning its favorable safety.

• Distribution: Following intravenous administration, the DDFPe emulsion rapidly distributes throughout the vascular space.[12]
• Metabolism: As a chemically and biologically inert fluorocarbon, Perflenapent is not metabolized by the body.[10] It does not undergo any enzymatic transformation.
• Elimination: The sole route of elimination for the active dodecafluoropentane molecule is exhalation via the lungs, a process analogous to the clearance of volatile anesthetics.[10] Its low boiling point and high vapor pressure allow it to efficiently partition from the blood into the alveolar air and be expelled with breath.

The kinetics of this pulmonary clearance have been characterized and conform to a two-compartment model. In healthy volunteers, the mean distribution half-life is approximately 0.4 minutes, and the mean elimination half-life is 11.0 minutes.[12] In cardiac patients, the elimination half-life was observed to be slightly longer, at approximately 17.0 minutes.[12] The half-life for elimination from the blood in healthy individuals is approximately 3.0 minutes.[12]

This pharmacokinetic profile is the fundamental enabling factor for Perflenapent's re-emergence as a therapeutic agent. The historical failure of earlier PFCs as "blood substitutes" was a direct consequence of their poor pharmacokinetics. Those high-boiling-point compounds were not volatile enough for pulmonary clearance. Instead, they were sequestered by the reticuloendothelial system (e.g., liver and spleen), where they persisted for extended periods, leading to bioaccumulation and dose-limiting toxicities.[10] Perflenapent's chemistry inherently solves this problem. Its rapid and complete clearance prevents tissue accumulation, allowing for consideration of repeat-dosing regimens (e.g., daily infusions prior to radiation therapy for GBM) and use in critically ill patients where organ function may be compromised.

The stabilizing excipient used in the EchoGen® formulation, a polyfluoroalkyl(polyoxyethylene) ethanol, was studied in rats and found to be eliminated via both renal (53%) and hepatic (28% excreted in feces) pathways, with over 75% of the dose eliminated within 24 hours. The pharmacokinetics of this excipient have not been studied in humans.[12]

4.0 Historical Development and Regulatory Journey: The EchoGen® Era

The initial clinical life of Perflenapent was as the active ingredient in the ultrasound contrast agent EchoGen®. This period, primarily in the 1990s, saw its development, European approval, and eventual market withdrawal, setting the stage for its later repurposing.

4.1 Development by Sonus Pharmaceuticals and PhaseShift™ Technology

EchoGen® was the principal product under development by Sonus Pharmaceuticals, Inc., a company focused on ultrasound contrast agents and drug delivery systems.[11] The product's mechanism was based on the company's proprietary PhaseShift™ technology, which leveraged the unique boiling point of dodecafluoropentane (DDFP) to convert intravenously injected liquid droplets into echogenic gas microbubbles in vivo.[11] Sonus held the patents for this technology and later worked on a new formulation named SonoGen.[21] The company's focus remained on diagnostics until 2008, when it completed a business combination with OncoGenex Technologies, Inc., changing its name to OncoGenex Pharmaceuticals and pivoting its corporate strategy entirely to the development of oncology therapeutics.[23]

4.2 European Regulatory Approval and Commercialization

Sonus Pharmaceuticals pursued regulatory approval for EchoGen® in Europe by submitting a Marketing Authorization Application (MAA) to the European Medicines Evaluation Agency (EMEA), the precursor to the modern European Medicines Agency (EMA), in November 1996.[11] The application was successful. In March 1998, the EMEA's Committee for Proprietary Medicinal Products (CPMP) issued a positive opinion recommending approval.[11] Subsequently, in July 1998, the EMEA granted a formal marketing authorization for EchoGen® across the 15 member states of the European Union.[11]

The approved indication was for its use as a "transpulmonary echocardiographic contrast agent for use in patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers, enhance left ventricular border delineation with resulting improvement in wall motion visualisation." The label specified that EchoGen® should only be used in patients where a study without contrast enhancement is inconclusive.[12] Sonus initially partnered with Abbott Laboratories for the commercialization of EchoGen® in the EU, though Sonus later reacquired the marketing rights from Abbott in April 2000.[11]

4.3 United States Regulatory Review and Non-Approval

In parallel with its European efforts, Sonus filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) in 1996 to market EchoGen® in the United States.[11] However, the U.S. regulatory process proved unsuccessful. In February 1998, the FDA issued an action letter indicating that the NDA was "not approvable" in its current form, citing certain deficiencies.[11] Sonus attempted to address these issues by submitting an amendment to the NDA later that year, which the FDA accepted for a new 180-day review cycle.[11] Despite these efforts, EchoGen® never received FDA approval for any indication.

4.4 Market Withdrawal and Discontinuation Analysis

Although approved in Europe, EchoGen® was eventually withdrawn from the market. DrugBank and other databases list Perflenapent's regulatory status as "Withdrawn".[1] The specific reasons for this withdrawal are not explicitly detailed in a public assessment report within the provided documentation. However, a logical inference can be drawn from the available facts. Drug withdrawals can be initiated by regulators for safety or efficacy reasons, or by the marketing authorization holder for commercial reasons, with the latter being the most common cause.[27]

Several pieces of evidence point toward a commercial, rather than safety-driven, withdrawal for EchoGen®. First, the product failed to gain approval in the lucrative U.S. market, which would have severely limited its global commercial viability.[11] Second, the developing company, Sonus, underwent a complete strategic transformation in 2008, merging to become an oncology-focused company and divesting itself of its prior diagnostic focus.[23] Third, and most importantly, the extensive clinical data from the EchoGen® era, involving over 1,800 patients, consistently demonstrated a favorable safety profile with adverse event rates comparable to placebo.[11] Had the withdrawal been due to significant safety concerns, a public notification and detailed assessment report from the EMA would be expected, none of which are present in the available materials.[30] Therefore, the most plausible conclusion is that the withdrawal of EchoGen® was a business decision driven by the lack of U.S. approval and a subsequent shift in corporate strategy. This distinction is critical, as it signifies that the molecule does not carry a legacy of safety failure, a fact that has undoubtedly facilitated its redevelopment for new therapeutic indications.

5.0 Contemporary Investigational Applications: The Re-emergence as NanO2™

Building on the well-characterized physicochemical properties and favorable safety profile of Perflenapent, NuvOx Pharma LLC is spearheading its redevelopment as a therapeutic agent, formulated as a dodecafluoropentane emulsion (DDFPe) and branded as NanO2™.[32] This modern era of development leverages the molecule's potent oxygen-carrying capacity to address critical unmet needs in oncology, neurology, and critical care medicine.

5.1 Rationale for Repurposing: From Diagnostic Imaging to Therapeutic Intervention

The scientific rationale for repurposing Perflenapent is a direct extension of the properties that made it a viable, albeit commercially unsuccessful, contrast agent. Its low boiling point, high oxygen-dissolving capacity, and clean pharmacokinetic profile of rapid pulmonary clearance are the key attributes that make it a potentially superior oxygen therapeutic compared to its failed PFC predecessors. By avoiding the bioaccumulation and toxicity that plagued older, high-boiling-point PFCs, DDFPe can be developed for indications requiring safe and efficient oxygen delivery to hypoxic tissues.[10]

5.2 Application in Ischemic Stroke

In the context of acute ischemic stroke (AIS), the therapeutic goal is to deliver oxygen to the ischemic penumbra—the area of brain tissue at risk of infarction—thereby acting as a neuroprotectant and potentially extending the narrow therapeutic window for recanalization therapies like mechanical thrombectomy.[16] Preclinical animal models of AIS demonstrated strong positive effects with DDFPe administration.[16] This led to a Phase 1b/II clinical trial (NCT02963376) to evaluate the safety and preliminary efficacy of DDFPe in patients with AIS.[35] Following the completion of this study, a Phase 2/3 trial for this indication has been planned but is listed with a status of "Not Yet Recruiting".[36]

5.3 Application in Glioblastoma Multiforme (GBM) as a Radiosensitizer

The rationale for using Perflenapent in GBM is to combat tumor hypoxia, a key driver of resistance to radiation therapy.[18] By delivering oxygen specifically to the hypoxic tumor microenvironment, NanO2™ is intended to act as a radiosensitizer, enhancing the cytotoxic efficacy of standard-of-care radiation treatment.[17] Recognizing the high unmet need in this patient population, the U.S. FDA has granted Perflenapent an Orphan Drug Designation for its use as a "Radiosensitizer to be used during radiation treatment of glioblastoma multiforme (GBM)".[17] This indication is currently being investigated in the RESTORE trial (NCT03862430), a recruiting Phase 2, randomized, double-blind, placebo-controlled study combining NanO2™ with standard radiation and temozolomide chemotherapy in patients with newly diagnosed GBM.[18]

5.4 Application in Respiratory Distress

Leveraging its primary function as an oxygen therapeutic, Perflenapent is also being developed for patients with mild respiratory distress who are at risk of progressing to mechanical ventilation.[32] The goal is to supplement oxygen delivery and improve oxygenation in patients with compromised pulmonary function. A Phase 1b dose-escalation study, known as EXTEND-1b (NCT06658535), is planned to evaluate the safety and tolerability of NanO2™ in this population and to establish appropriate dosing for a subsequent Phase 2 trial.[32]

5.5 Other Designated and Potential Indications

The therapeutic potential of Perflenapent extends beyond the indications currently in active clinical trials. The FDA has also granted it an Orphan Drug Designation for the "Treatment of sickle cell disease," suggesting a potential role in mitigating the vaso-occlusive crises and ischemia associated with this condition.[17] Additionally, broader biomedical applications have been described, including its use as a safe propellant in pressurized metered-dose inhalers and in novel therapeutic strategies such as occlusion therapy via acoustic droplet vaporization, where focused ultrasound is used to trigger the phase transition of droplets for targeted embolotherapy.[2]

6.0 Clinical Trial Synopsis and Safety Profile

The clinical profile of Perflenapent is built upon decades of research, from the large-scale studies of the EchoGen® era to the targeted therapeutic trials of the modern NanO2™ programs. This consolidated body of evidence provides a robust understanding of its safety and emerging efficacy.

6.1 Summary of Key Clinical Trials

The current clinical development pipeline for Perflenapent as a therapeutic agent is focused on three primary indications. A synopsis of these major trials is provided in Table 3.

Table 3: Synopsis of Major Clinical Trials for Perflenapent (as DDFPe/NanO2™)

NCT Identifier	Trial Name/Acronym	Indication	Phase	Status	Intervention	Key Objectives/Endpoints
NCT02963376	N/A	Acute Ischemic Stroke	1b/2	Completed	DDFPe vs. Placebo (Dose Escalation)	Primary: Safety, Maximum Tolerated Dose (MTD). Secondary: Change in NIHSS score, 30/90-day mRS.
NCT03862430	RESTORE	Glioblastoma Multiforme (GBM)	2	Recruiting	NanO2™ vs. Placebo + Standard of Care (Radiation + Temozolomide)	Primary: Progression-Free Survival (PFS). Secondary: Overall Survival (OS), Objective Response Rate (mRANO).
NCT06658535	EXTEND-1b	Mild Respiratory Distress	1b	Not Yet Recruiting	Dodecafluoropentane (Dose Escalation)	Primary: Incidence of Treatment-Emergent Adverse Events (TEAEs). Secondary: Change in ROX Index, WHO ordinal scale.

6.1.1 Detailed Trial Analysis: NCT02963376 (Ischemic Stroke)

This Phase 1b/II study was a randomized, placebo-controlled, blinded, dose-escalation trial designed to determine the safety and MTD of DDFPe in patients with acute ischemic stroke.[33] The trial is now complete.[35] The key findings from the study have been published and provide the first modern clinical data on the agent.[16] The study concluded that intravenous DDFPe was safe and well-tolerated at all three tested dose levels (0.05, 0.10, and 0.17 mL/kg). No dose-limiting toxicities were encountered, and an MTD was not defined. The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) were similar between the DDFPe and placebo groups. Although the study's small sample size limited the statistical power for efficacy endpoints, it revealed promising signals of clinical benefit. Patients who received DDFPe treatment earlier after stroke onset showed a better response in their National Institutes of Health Stroke Scale (NIHSS) scores. Furthermore, 30- and 90-day modified Rankin Scale (mRS) scores, which measure functional outcome, suggested significant clinical improvement in the high-dose cohort.[16]

6.1.2 Detailed Trial Analysis: NCT03862430 (Glioblastoma)

The RESTORE trial is an ongoing Phase 2, double-blind, randomized, placebo-controlled study evaluating NanO2™ as a radiosensitizer in patients with newly diagnosed GBM.[18] The study, which is actively recruiting, randomizes patients on a 2:1 basis to receive either NanO2™ or saline placebo infusions immediately prior to each fraction of standard-of-care radiation therapy, which is given concurrently with temozolomide.[18] The primary endpoint is Progression-Free Survival (PFS), with key secondary endpoints including Overall Survival (OS) and objective response rate.[18]

Early safety data from the trial, presented at the 2024 Society for Neuro-Oncology Annual Meeting based on the first 22 treated patients, are consistent with the agent's known safety profile.[39] The most common non-serious AEs were related to the nervous system, gastrointestinal system, and skin. Several serious TEAEs were reported; however, after review by both site investigators and a medical monitor, the vast majority were determined to be unrelated or unlikely to be related to the study drug (NanO2™). The trial continues to enroll, with an estimated completion date in 2025.[39]

6.1.3 Detailed Trial Analysis: NCT06658535 (Respiratory Distress)

The EXTEND-1b study is a planned Phase 1b, open-label, non-randomized, dose-escalation trial designed to establish the safety, tolerability, and appropriate dosing of NanO2™ for a future Phase 2 study in patients with mild respiratory distress.[32] The study will use a sequential assignment design to test three escalating dose cohorts (0.025, 0.032, and 0.050 mL/kg).[32] The primary outcome measure is the cumulative incidence of TEAEs and SAEs over a 28-day period. Secondary outcomes will explore preliminary signals of efficacy, including changes in the Respiratory Rate Oxygenation (ROX) Index and the WHO 8-point ordinal scale for clinical status.[32] The study is listed as not yet recruiting.[32]

6.2 Preclinical Toxicology Profile

The preclinical safety of Perflenapent was established during the development of EchoGen®. Acute and subacute toxicology studies were conducted in both rodents and dogs. These studies showed that observed adverse effects, such as changes in blood pressure, respiration, and activity levels, were dose-related, transient, and self-resolving. A notable finding from a 14-day repeat-dose study in dogs was the occurrence of left ventricular endocardial hemorrhages at high daily doses, an effect that was not seen in single-dose studies or at lower repeat doses.[12]

6.3 Consolidated Clinical Safety and Tolerability

A consistent and favorable safety profile for Perflenapent has been demonstrated across decades of clinical investigation and for multiple distinct indications.

During the EchoGen® era of the 1990s, data were collected from over 1,800 patients.[11] A pivotal multicenter, placebo-controlled trial involving 151 patients concluded that adverse effects associated with perflenapent emulsion were "few and mostly mild, occurred within 30 minutes, and resolved without treatment".[15] A larger safety assessment involving 818 patients further confirmed this, finding no clinically significant abnormalities in laboratory tests, vital signs, or electrocardiograms, with overall adverse event rates being comparable to those seen with a saline placebo.[29]

This robust historical safety database provides strong support for the current development programs. The modern clinical trials of NanO2™ have independently corroborated these earlier findings. The Phase 1b/II stroke trial (NCT02963376) found no dose-limiting toxicities and an adverse event profile similar to placebo, even in a critically ill patient population.[16] Similarly, early safety data from the ongoing Phase 2 GBM trial (NCT03862430) suggest an acceptable safety profile, with most serious adverse events being attributed to the underlying disease, standard chemoradiation, or other factors rather than the investigational agent.[39] This consistent safety record across different formulations, patient populations, and decades of study is a significant asset. It is rooted in the molecule's fundamental properties: its chemical inertness and its rapid, complete pulmonary clearance, which prevents the bioaccumulation that caused toxicity with other perfluorocarbons. This well-characterized and benign safety profile substantially de-risks the ongoing clinical development of Perflenapent for its new therapeutic roles.

7.0 Regulatory Status and Global Approvals

The regulatory history of Perflenapent is complex, marked by an early approval in Europe, a non-approval in the United States, a subsequent market withdrawal, and a recent re-emergence as an investigational agent with special regulatory designations.

7.1 European Union (EMA)

• Status: Approved, then Withdrawn.
• Details: Perflenapent, under the trade name EchoGen®, received a centralized marketing authorization from the EMEA in July 1998 for use as an ultrasound contrast agent.[11] This authorization was valid across all EU member states. However, the marketing authorization was later withdrawn by the company. As analyzed previously, this withdrawal was likely for commercial and strategic reasons rather than due to safety or efficacy concerns identified by regulators.[28] Perflenapent is not currently an approved medicinal product in the European Union.

7.2 United States (FDA)

• Status: Investigational; Not Approved.
• Details: The New Drug Application (NDA) for EchoGen® was not approved by the FDA in the late 1990s.[11] Perflenapent has never held a marketing approval in the United States. It is currently in clinical development as an investigational new drug, NanO2™/DDFPe, for multiple indications under active Investigational New Drug (IND) applications, such as IND #131594 for the stroke program.[16] Importantly, the FDA has granted Perflenapent multiple Orphan Drug Designations, which provide incentives for the development of treatments for rare diseases. These designations include its use as a radiosensitizer for the treatment of glioblastoma multiforme (GBM) and for the treatment of sickle cell disease.[17]

7.3 Australia (TGA)

• Status: Not Registered.
• Details: The Australian Register of Therapeutic Goods (ARTG) is the public database of all therapeutic goods that can be legally supplied in Australia.[40] A review of the provided documentation, which describes the function of the ARTG, reveals no specific entry for Perflenapent or dodecafluoropentane.[40] Based on the available information, there is no evidence that Perflenapent has been registered with the Therapeutic Goods Administration (TGA) for supply in Australia.

8.0 Synthesis and Future Outlook

Perflenapent (dodecafluoropentane) stands as a compelling example of how fundamental physicochemical properties can define a molecule's entire clinical lifecycle, enabling its resurrection from a withdrawn diagnostic agent into a promising, multi-indication therapeutic platform. Its journey offers valuable lessons in drug development, regulatory strategy, and the enduring importance of basic science.

8.1 Integrated Analysis: Connecting Physicochemical Properties to Clinical Promise

The entire clinical narrative of Perflenapent can be traced back to a single, critical physical constant: its boiling point of 29°C. This property is the master variable that dictates its mechanism, pharmacokinetics, safety, and ultimately, its potential.

1. Mechanism: The phase transition from liquid to gas at body temperature was the direct mechanism for its function as the ultrasound contrast agent EchoGen®. This same phase transition ensures it exists as a gas in vivo, which is the key to its superiority as an oxygen therapeutic, allowing it to carry up to 1000 times more oxygen than liquid-phase PFCs.
2. Pharmacokinetics and Safety: The high volatility resulting from its low boiling point enables rapid and complete clearance via pulmonary exhalation. This "clean" pharmacokinetic profile prevents the tissue bioaccumulation and reticuloendothelial system overload that led to the clinical failure of first-generation, high-boiling-point PFCs. This inherent safety has been consistently demonstrated in clinical trials spanning three decades and is the bedrock upon which its current therapeutic development is built.

The story of Perflenapent is thus one of a molecule whose time has come twice. The very properties that made it a viable contrast agent in the 1990s are the same ones that now position it as a next-generation oxygen therapeutic, capable of addressing pathologies of hypoxia and ischemia in ways its predecessors could not.

8.2 Challenges and Opportunities in Clinical Development

Despite its promising profile, the path forward for Perflenapent is not without challenges.

• Challenges:
• Manufacturing: The production of a stable, sterile, and consistently sized nano-emulsion is a complex manufacturing challenge that must be addressed for commercial scale-up.
• Clinical Efficacy: The indications being pursued—glioblastoma and acute ischemic stroke—are notoriously difficult to treat, and demonstrating a statistically significant and clinically meaningful benefit will be a high bar. For GBM, ensuring adequate penetration of the blood-brain barrier and sufficient oxygen delivery to the tumor core will be critical for success.
• Regulatory Scrutiny: As a member of the PFAS class of chemicals, it may face increased regulatory and public scrutiny, although its rapid elimination from the body distinguishes it from persistent environmental PFAS.
• Opportunities:
• Strong Safety Profile: The extensive historical and contemporary safety data significantly de-risk its clinical development and may provide a smoother regulatory path.
• Novel Mechanism of Action: As a physical oxygen carrier, its mechanism is agnostic to the genetic mutations or acquired resistance pathways that limit the efficacy of many targeted therapies and chemotherapies. This makes it an ideal candidate for combination therapy.
• High Unmet Need: The target indications (GBM, stroke, respiratory distress, sickle cell disease) represent areas of profound unmet medical need, where even modest improvements in outcome could have a major clinical impact.
• Regulatory Incentives: The multiple Orphan Drug Designations granted by the FDA provide significant benefits, including market exclusivity, tax credits, and regulatory support.

8.3 Recommendations for Future Research and Development

Based on the current body of evidence, several avenues for future research and development appear warranted:

1. Mechanism Confirmation: Continue to pursue mechanistic confirmation in human trials, such as the planned use of TOLD MRI in the RESTORE trial to directly visualize tumor re-oxygenation, which would provide invaluable proof-of-concept data.[18]
2. Expansion into Other Hypoxic Conditions: Explore the potential of Perflenapent in other ischemic and hypoxic conditions. Its neuroprotective effects in stroke suggest potential utility in traumatic brain injury or cardiac arrest. Its role as an oxygen carrier could be investigated in acute myocardial infarction, peripheral artery disease, or as an adjunct to preserve organs for transplantation.
3. Synergistic Combinations: Investigate its potential synergy with other cancer therapies that are known to be limited by tumor hypoxia, such as certain classes of immunotherapy (e.g., checkpoint inhibitors) where an oxygenated microenvironment is crucial for immune cell function.
4. Human Pharmacokinetics of Excipients: Address the data gap identified in the original EchoGen® studies by formally characterizing the pharmacokinetics of the emulsion's stabilizing excipients in humans, which will be necessary for a complete regulatory submission.[12]

In conclusion, Perflenapent is a molecule of significant renewed interest. Its unique, physically-driven pharmacology and excellent safety profile make it a compelling candidate for addressing some of medicine's most challenging hypoxic and ischemic diseases. The success of its ongoing clinical trials will determine whether this repurposed agent can finally fulfill its therapeutic potential.

9.0 References

[1]

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