A Comprehensive Monograph on 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH): A Second-Generation Photosensitizer for Photodynamic Therapy

Executive Summary

2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a, commonly known by the abbreviation HPPH and the developmental name Photochlor, is an investigational small molecule belonging to the chlorin class of photosensitizers.[1] It has been developed as a second-generation agent for photodynamic therapy (PDT), a non-invasive therapeutic modality for cancer treatment. The central value proposition of HPPH lies in its significantly improved safety and tolerability profile compared to the first-generation, FDA-approved photosensitizer, porfimer sodium (Photofrin®). Specifically, HPPH is characterized by mild and rapidly resolving cutaneous photosensitivity, a side effect that severely limits the clinical utility of its predecessors.[3]

The mechanism of action of HPPH is consistent with the principles of PDT. Following intravenous administration, the molecule selectively accumulates in neoplastic tissues. Subsequent irradiation of the tumor with light at a specific wavelength—approximately 665 nm—excites the drug, leading to a photochemical reaction with molecular oxygen. This process generates highly cytotoxic singlet oxygen (1O2​), which induces oxidative damage, vascular shutdown, and direct tumor cell death via necrosis and apoptosis.[6] The molecule's photophysical properties are a key advantage; its long activation wavelength allows for deeper light penetration into tissue, enabling the treatment of larger and more deep-seated tumors than is possible with first-generation agents.[3]

Pharmacokinetically, HPPH is a highly lipophilic compound that is extensively bound to plasma proteins. It is cleared from the body without undergoing significant metabolism, which contributes to a predictable pharmacokinetic profile.[4] A critical feature is its differential clearance, where it is rapidly eliminated from the skin while being retained for longer periods in tumor tissue. This dichotomy between a very long plasma half-life and a short duration of skin photosensitivity is the pharmacological basis for its superior safety profile.[3]

The clinical development of HPPH has been extensive but complex. Early-phase clinical trials have demonstrated promising efficacy in a range of solid tumors, including non-small cell lung cancer, esophageal cancer, and head and neck squamous cell carcinoma, with notable complete response rates in certain settings.[10] However, the development pathway has been marked by challenges, including a number of withdrawn later-stage clinical trials and logistical issues such as drug supply shortages.[10] The majority of its development has been conducted under the aegis of a single academic institution, the Roswell Park Comprehensive Cancer Center, without the involvement of a major pharmaceutical partner to drive late-stage registration trials.[13]

In conclusion, HPPH represents a scientifically compelling and well-characterized second-generation photosensitizer that successfully addresses the primary clinical limitations of first-generation PDT. Despite its clear advantages in safety and photophysics, and the existence of a scalable manufacturing process, its progression toward regulatory approval has stalled. HPPH remains an investigational asset with significant, unrealized clinical potential, whose future advancement likely depends on overcoming strategic and commercial hurdles through partnership or acquisition.

Compound Profile: Chemical Identity and Physicochemical Characteristics

A comprehensive understanding of 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a begins with its precise chemical identity and the physicochemical properties that govern its behavior as a therapeutic agent. These foundational characteristics dictate its formulation, biological interactions, mechanism of action, and pharmacokinetic profile.

Nomenclature and Identifiers

To ensure clarity and precision, the compound is identified by a standardized set of names and registry numbers that are used consistently across scientific literature, clinical trial databases, and chemical registries.

• Generic Name: 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a.[1]
• Abbreviations: The most common abbreviation used in research and clinical contexts is HPPH.[1]
• Brand/Developmental Name: The compound is being developed under the brand name Photochlor.[1]
• IUPAC Name: The systematic name according to the International Union of Pure and Applied Chemistry (IUPAC) is (3S,4S)-14-Ethyl-9-[1-(hexyloxy)ethyl]-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid.[3]
• Other Synonyms: It is also referred to as Pyropheophorbide-α-hexyl-ether.[7]
• Registry Numbers:
• CAS Number: 149402-51-7.[1]
• DrugBank ID: DB15243.[2]
• ChemSpider: 4589621.[1]

Molecular Structure and Composition

The molecular architecture of HPPH is central to its function as a photosensitizer. It is a derivative of chlorophyll, belonging to the chlorin class of tetrapyrroles.

• Chemical Formula: The empirical formula for HPPH is C39​H48​N4​O4​.[1]
• Molecular Weight: The average molecular weight is consistently reported as 636.837 g·mol⁻¹.[1] Other sources provide closely matching values of 636.8 g·mol⁻¹ or 636.82 g·mol⁻¹.[3] The monoisotopic mass is 636.367556042 Da.[2]
• Structural Codes:
• SMILES: CCCCCCOC(C)C1=C2C=C3C(=C(C(=CC4=NC5=C(CC(=O)C5=C4C)C6=NC(=CC(=C1C)N2)[C@H]([C@@H]6CCC(=O)O)C)N3)CC)C.[1]
• InChI Key: PVXGCBZIVFCMJK-NMWXTPPCSA-N.[3]
• Appearance: In its solid state, HPPH is described as a black solid powder or a crystalline solid.[3]
• Purity: For research and preclinical use, HPPH is available at high purity, typically specified as ≥98% (as a mixture of epimers) or >90%.[3]

The structure of HPPH is a prime example of rational drug design for a second-generation photosensitizer. It is built upon a chlorin macrocycle, which is a porphyrin derivative where one of the peripheral double bonds in a pyrrole ring is reduced. This modification is fundamentally important, as it shifts the longest-wavelength absorption band (the Q-band) further into the red region of the spectrum, which is critical for its photodynamic activity. Attached to this core pharmacophore are several side chains, most notably the 2-(1-hexyloxyethyl) group. This substituent, which replaces the vinyl group of the parent pyropheophorbide-a molecule, consists of a six-carbon alkyl chain linked via an ether bond. This deliberate chemical modification dramatically increases the molecule's overall lipophilicity. This structural design—a photophysically active core combined with a lipophilicity-enhancing side chain—is not accidental. It is a calculated strategy to optimize the molecule's physicochemical properties to achieve a desired pharmacokinetic profile, namely enhanced association with plasma proteins and lipoproteins for transport, preferential accumulation in lipid-rich tumor microenvironments, and a differential clearance rate between tumor and normal tissues like skin.

Physicochemical Properties

The physical and chemical properties of HPPH directly influence its behavior in biological systems, from the challenges of pharmaceutical formulation to its distribution and interaction at the cellular level.

• Solubility and Lipophilicity: HPPH is characterized as an extremely hydrophobic and lipophilic compound.[3] This property is a double-edged sword: it aids in membrane traversal and tumor accumulation but presents significant challenges for formulation.
• Water Solubility: The aqueous solubility is exceptionally low, measured at 0.0112 mg/mL.[2] This poor water solubility is a major obstacle that necessitates complex formulation strategies for intravenous administration and precludes any possibility of oral delivery.[6]
• Organic Solvent Solubility: In contrast, HPPH is soluble in various organic solvents, including dimethylformamide (DMF) at 10 mg/mL, dimethyl sulfoxide (DMSO) at 3 mg/mL, and ethanol at 0.33 mg/mL.[7] Clinical and preclinical formulations leverage this by using co-solvents and surfactants, such as DMSO, polyethylene glycol 300 (PEG300), and Tween-80, to create a stable solution for injection.[13]
• logP (Octanol-Water Partition Coefficient): This quantitative measure of lipophilicity confirms the molecule's hydrophobic nature. Reported values include 6.37 (calculated by ALOGPS) and a higher 7.53 (calculated by Chemaxon), both indicating a strong preference for lipid environments over aqueous ones.[2]
• Acid-Base Properties: The molecule contains both acidic and basic functional groups. The strongest acidic pKa is 3.75, attributed to the carboxylic acid on the propanoic acid side chain, while the strongest basic pKa is 5.04, associated with the pyrrole nitrogens. At physiological pH of 7.4, the carboxylic acid group is deprotonated, giving the molecule an overall physiological charge of -1.[2]
• Spectroscopic Properties: The electronic structure of the chlorin macrocycle gives HPPH a characteristic absorption spectrum. It displays multiple absorption maxima (λmax​), including peaks at 229, 266, 318, 407, and 660 nm.[7] The intense peak around 407 nm is the Soret band, common to all tetrapyrroles. The most therapeutically relevant peak is the Q-band in the far-red region of the spectrum, cited variously as 655 nm, 660 nm, or 665 nm.[7] It is the absorption of light at this wavelength that initiates the photodynamic process.
• Drug-Likeness Rules: Computational analysis shows that HPPH violates several empirical rules used to predict oral bioavailability, such as Lipinski's Rule of Five, the Ghose Filter, and Veber's Rule. Its predicted oral bioavailability is 0.[2] This is fully consistent with its development exclusively as an agent for intravenous administration.

Table 1: Summary of Chemical and Physical Properties of HPPH

Property	Value	Source(s)
Generic Name	2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a	1
Brand Name	Photochlor	1
CAS Number	149402-51-7	1
DrugBank ID	DB15243	2
Molecular Formula	C39​H48​N4​O4​	1
Average Molecular Weight	636.837 g·mol⁻¹	1
Appearance	Black solid powder / Crystalline solid	3
Water Solubility	0.0112 mg/mL	2
logP (Octanol-Water)	6.37 - 7.53	2
pKa (Acidic)	3.75	2
pKa (Basic)	5.04	2
Activation Wavelength (λmax​)	~660-665 nm (Therapeutic Q-band)	7
Key Organic Solubilities	DMF: 10 mg/mL; DMSO: 3 mg/mL	7

Mechanism of Action in Photodynamic Therapy

The therapeutic activity of HPPH is not inherent to the molecule itself but is conditionally activated by light, a hallmark of photodynamic therapy (PDT). The mechanism involves a precise sequence of physical and chemical events that culminate in localized cytotoxicity within the target tumor tissue.

Principles of Photodynamic Activation

PDT is a binary therapeutic modality that requires the confluence of three otherwise non-toxic components: a photosensitizer drug (HPPH), light of a specific wavelength, and molecular oxygen.[16] The process unfolds in a series of distinct steps:

1. Systemic Administration and Selective Accumulation: HPPH is administered systemically via intravenous infusion. Due to its lipophilic nature and the leaky, disorganized vasculature characteristic of solid tumors, HPPH preferentially extravasates and accumulates in malignant and premalignant tissues compared to most normal tissues.[3] A specific "drug-light interval" (typically 24-48 hours) is observed post-infusion. This period allows the drug concentration to reach an optimal ratio between the tumor and surrounding healthy tissues, particularly the skin, thereby maximizing therapeutic specificity and minimizing off-target damage.[3]
2. Photoexcitation: After the drug-light interval, the tumor is irradiated with non-thermal light from a laser source. For HPPH, the light is tuned to a wavelength that matches its Q-band absorption maximum, typically cited as 655 nm, 660 nm, or 665 nm.[7] Upon absorbing a photon of this specific energy, the HPPH molecule is promoted from its stable ground state ( S0​) to a highly energetic, short-lived singlet excited state (S1​).[18]
3. Intersystem Crossing: The molecule in the S1​ state is unstable and can rapidly decay back to the ground state. However, a significant fraction of these excited molecules undergoes a process called intersystem crossing, where the electron spin inverts, transitioning the molecule to a lower-energy but much longer-lived triplet excited state (T1​).[18] The relatively long lifetime of the triplet state (on the order of microseconds) is crucial, as it provides a sufficient window for the molecule to interact with its surroundings.

The choice of activation wavelength around 665 nm is a critical design feature and a major advancement over first-generation photosensitizers like Photofrin®, which is activated at 630 nm.[3] The "therapeutic window" for light in biological tissue lies in the red and near-infrared spectrum (approximately 600-900 nm), where absorption by endogenous chromophores such as hemoglobin and melanin is minimized. Within this window, longer wavelengths penetrate tissue more deeply because they are subject to less absorption and scattering. Therefore, the 665 nm light used to activate HPPH can reach tumors that are larger or more deeply seated than those treatable with the 630 nm light used for Photofrin®. This physical principle directly translates into a significant clinical advantage, expanding the potential scope of PDT to a broader range of solid tumors.[3]

Generation of Reactive Oxygen Species (ROS)

The core cytotoxic event in HPPH-mediated PDT is the generation of reactive oxygen species (ROS), primarily through a Type II photochemical reaction.

• Energy Transfer to Oxygen: The long-lived triplet state HPPH molecule (T1​) acts as an energy catalyst. It collides with ambient molecular oxygen (3O2​), which exists naturally in a triplet ground state, within the tumor tissue. During this collision, the HPPH molecule transfers its excess energy to the oxygen molecule, returning to its own stable ground state (S0​) where it can be re-excited by another photon.[18]
• Singlet Oxygen Formation: The energy transferred to the molecular oxygen promotes it from its stable triplet ground state to a highly reactive, electronically excited singlet state, known as singlet oxygen (1O2​).[6]
• Cytotoxicity of Singlet Oxygen: Singlet oxygen is an extremely potent and indiscriminate oxidizing agent. Due to its high reactivity, its radius of action is very short (estimated at <0.02 µm), meaning it exerts its cytotoxic effects only in the immediate vicinity of where it is generated. It rapidly reacts with and oxidizes essential biological macromolecules, including lipids in cell membranes, proteins (enzymes), and nucleic acids, leading to irreversible cellular damage and initiating cell death pathways.[6]

Cellular and Tissue-Level Effects

The localized burst of singlet oxygen production triggers a multi-pronged attack on the tumor, leading to its destruction through several complementary mechanisms.

• Direct Tumor Cell Killing: The massive oxidative damage inflicted upon cellular components directly initiates cell death programs. Preclinical studies have identified both apoptosis (programmed cell death) and necrosis as key mechanisms of HPPH-mediated cytotoxicity.[6] High-intensity PDT tends to cause rapid necrosis, characterized by cell swelling and membrane rupture, which releases cellular contents and incites a strong inflammatory response. Lower-intensity PDT can favor apoptosis, a more controlled form of cell death.[19]
• Vascular Damage: A pivotal and often dominant mechanism of PDT is its effect on the tumor's blood supply. Endothelial cells lining the tumor vasculature readily take up HPPH. Upon light activation, the resulting photodamage to these cells leads to platelet aggregation, thrombus formation, and increased vascular permeability, ultimately causing a shutdown of blood flow to the tumor.[9] This vascular collapse starves the tumor of essential oxygen and nutrients, leading to widespread secondary tumor death.
• Immune System Activation: The acute inflammation triggered by PDT-induced necrosis and vascular damage serves as a powerful "danger signal" to the immune system. The release of damage-associated molecular patterns (DAMPs) and inflammatory cytokines attracts innate immune cells (such as neutrophils and macrophages) to the treated area. These cells can then process and present tumor antigens to the adaptive immune system, potentially leading to the development of a systemic, long-lasting anti-tumor T-cell response that can target residual or metastatic disease.[19]

The ultimate clinical outcome of HPPH-PDT is not merely a function of the administered drug and light doses. Sophisticated preclinical modeling has revealed that the total light fluence (measured in J/cm²) is an imperfect predictor of tumor response. A more accurate dosimetric quantity is the calculated mean reacted singlet oxygen ([¹O₂]rx), which integrates local drug concentration, light fluence rate, and, critically, the local oxygen concentration.[16] This finding underscores the profound importance of the tumor microenvironment. Since oxygen is a required substrate for the photochemical reaction, the efficacy of HPPH-PDT is fundamentally limited by tissue oxygenation. This implies that pre-existing tumor hypoxia, a common feature of solid malignancies, can be a major mechanism of treatment resistance. Consequently, treatment strategies that can modulate or overcome tumor hypoxia may be necessary to maximize the therapeutic potential of HPPH. This elevates the practice of PDT from a simple application of drug and light to a complex, multifactorial discipline requiring advanced dosimetry and a deep understanding of tumor biology.

Preclinical and Clinical Pharmacology

The pharmacological profile of HPPH, encompassing its absorption, distribution, metabolism, and excretion (ADME), as well as its pharmacodynamic effects, provides the scientific basis for its clinical use, dosing regimens, and safety profile. A comprehensive population pharmacokinetic study in cancer patients has provided robust data on its behavior in humans.[4]

Pharmacokinetics (ADME)

The journey of HPPH through the body is largely dictated by its extreme lipophilicity and lack of metabolic breakdown.

• Administration and Absorption: HPPH is formulated for intravenous (IV) administration, typically delivered as a 1-hour infusion.[4] This route ensures 100% bioavailability, bypassing the absorption phase entirely. Oral administration is not feasible due to its physicochemical properties and predicted lack of absorption from the gastrointestinal tract.[2]
• Distribution: Following IV infusion, HPPH rapidly partitions within the body according to a two-compartment model.
• Plasma Protein Binding: A defining characteristic of HPPH is its extensive and near-complete (almost 100%) binding to plasma proteins, such as albumin and lipoproteins.[4] This high degree of protein binding effectively sequesters the drug within the vascular compartment initially, leading to a relatively small initial volume of distribution.
• Volume of Distribution: In a human population study, the key mean distribution parameters, normalized to body surface area, were determined to be:
• Volume of the central compartment (Vc​): 2.40 L/m²
• Steady-state volume of distribution (Vss​): 9.58 L/m².[4]

The Vss​ is modest, consistent with a drug that is highly protein-bound and does not distribute extensively into all tissues, but rather concentrates in plasma and well-perfused organs.

• Tissue Distribution: Preclinical studies in murine models have mapped the tissue distribution of HPPH. The highest concentrations are found in the liver, the primary organ of clearance, followed by other highly perfused organs such as the adrenals, lungs, spleen, and kidneys. Conversely, uptake into the brain is very low, suggesting poor penetration of the blood-brain barrier.[9] This distribution pattern generally correlates with the relative blood flow to these tissues.
• Metabolism: A remarkable and clinically significant feature of HPPH is its apparent lack of metabolism.
• Analysis of serum from patients treated with HPPH using high-performance liquid chromatography (HPLC) failed to detect any circulating metabolites.[4]
• Furthermore, in vitro experiments incubating HPPH with human liver microsomal preparations, which contain the primary drug-metabolizing enzymes (e.g., cytochrome P450s), resulted in no production of metabolites or glucuronic acid conjugates.[4]

This metabolic stability is a highly advantageous property. Drug metabolism is a major source of inter-patient variability in drug response due to genetic polymorphisms in metabolizing enzymes. It can also lead to the formation of active or toxic metabolites that complicate the drug's profile. The absence of metabolism for HPPH means its pharmacokinetics are more predictable across the patient population, as noted in the conclusion of the population PK study: "HPPH pharmacokinetic profiles are readily predictable from the global population model".4 This also dramatically reduces the potential for drug-drug interactions with co-administered medications that induce or inhibit metabolic pathways, a crucial consideration in oncology patients who are often on complex polypharmacy regimens.

• Excretion and Half-Life: The elimination of HPPH from the body is characterized by a biexponential decay, indicating a rapid distribution phase followed by a very slow terminal elimination phase.
• Half-Lives: The estimated mean population half-lives in humans are:
• Alpha (distribution) half-life (t½α​): 7.77 hours (95% CI: 3.46–17.6 h)
• Beta (elimination) half-life (t½β​): 596 hours (95% CI: 120–2951 h).[4]
• The terminal elimination half-life of 596 hours, or approximately 25 days, is exceptionally long. This means that low but detectable concentrations of HPPH can persist in the plasma for several months following a single infusion.[4]
• Route of Excretion: Preclinical data from radiolabeled studies in mice indicate that fecal excretion is the primary route of elimination from the body, which is typical for large, lipophilic molecules that are not renally cleared.[9]

Table 2: Key Human Pharmacokinetic Parameters of HPPH

Pharmacokinetic Parameter	Mean Population Value / Description	Source(s)
Administration Route	1-hour Intravenous Infusion	4
Systemic Clearance (CL)	0.0296 L/h/m²	4
Volume of Distribution (Vss​)	9.58 L/m²	4
Alpha Half-Life (t½α​)	7.77 hours (95% CI: 3.46–17.6 h)	4
Beta Half-Life (t½β​)	596 hours (95% CI: 120–2951 h)	4
Plasma Protein Binding	Nearly 100%	4
Primary Excretion Route	Fecal (based on preclinical data)	9
Metabolism	No circulating metabolites detected; no in vitro metabolism	4

Pharmacodynamics

The pharmacodynamic profile of HPPH describes the relationship between drug concentration, light application, and the resulting biological effect.

• The antitumor effect is a function of both the HPPH dose (typically administered in mg/m²) and the light dose, or fluence (administered in J/cm²).[3]
• As previously discussed, the most precise predictor of the biological outcome is not the light dose alone but the calculated mean reacted singlet oxygen ([¹O₂]rx), which accounts for the interplay between drug, light, and tissue oxygen levels.[16]
• In preclinical settings, HPPH has demonstrated the potential for synergistic activity when combined with conventional chemotherapy. For instance, it has been shown to work synergistically with gemcitabine to induce cell death in various pancreatic cancer cell lines, suggesting potential for combination therapy regimens.[7]

A critical analysis of HPPH's pharmacology reveals a striking and counterintuitive disconnect between its pharmacokinetic profile and its primary pharmacodynamic side effect. A drug with an extremely long terminal half-life of 25 days would logically be expected to cause persistent, long-lasting side effects. For a photosensitizer, this would imply a need for prolonged and stringent avoidance of sunlight, a major drawback of first-generation agents like Photofrin®. However, the clinical data for HPPH unequivocally demonstrate that clinically significant skin photosensitivity is mild and resolves rapidly, typically within a few days.[3] The seminal human pharmacokinetic study explicitly notes that despite the long-term presence of HPPH in plasma, "no instances of cutaneous photosensitivity have been noted in these patients" in the long term.[4]

The only way to reconcile these two observations—a long plasma half-life and short-duration skin photosensitivity—is through a mechanism of differential clearance. This implies that HPPH is cleared from the skin at a much faster rate than it is from the plasma or, most importantly, from the tumor tissue. This selective retention in the tumor while clearing rapidly from the skin is the single most important pharmacological property of HPPH. It is the molecular basis for its classification as a superior second-generation agent, as it directly solves the primary dose-limiting and quality-of-life-impairing toxicity that plagued first-generation PDT.

Synthesis and Manufacturing

The transition of a drug candidate from a laboratory curiosity to a viable clinical asset is critically dependent on the development of a robust and scalable manufacturing process. The history of HPPH synthesis illustrates this evolution, moving from laborious, small-scale isolation methods to a streamlined, patented process suitable for large-scale production.

Historical Synthetic Route

The initial methods for preparing HPPH were suitable for producing small quantities for early preclinical research but were impractical for commercial-scale manufacturing. This multi-step process was inefficient and relied on natural product isolation.[22]

1. Isolation from Natural Source: The process began with the isolation of the starting material, methyl pheophorbide a, from the blue-green algae Spirulina platensis. This required cryogenic fracturing of the algal cells, followed by solvent extraction, extensive chromatographic purification, and recrystallization.[21]
2. Decarboxylation: The purified methyl pheophorbide a was then subjected to thermal decarboxylation by refluxing in a high-boiling solvent like collidine to yield methyl pyropheophorbide a.
3. Ether Formation: The resulting methyl pyropheophorbide a was treated with 1-hexanol in the presence of an acid catalyst to form the characteristic 1-hexyloxyethyl ether side chain.
4. Saponification: In the final step, the methyl ester at the C-17 propionic acid side chain was hydrolyzed (saponified) to the free carboxylic acid to yield the final HPPH product.

This four-step procedure was laborious and required multiple, time-consuming column chromatography purification steps, making it unsuitable for producing the multi-kilogram quantities of active pharmaceutical ingredient (API) needed for late-stage clinical trials and commercial supply.[22]

Modern, Scalable Synthetic Process (Patented)

Recognizing the limitations of the historical route, a more efficient and scalable synthetic process was developed and patented, designed specifically for large-scale production.[22] This improved synthesis starts from a different, more accessible precursor, chlorin e6 trimethyl ester.

1. Cyclization: The process begins by treating chlorin e6 trimethyl ester with a base in a high-boiling aromatic solvent. This step facilitates an intramolecular cyclization to form methyl pheophorbide a.
2. Decarboxylation and Saponification: Without isolating the intermediate, the reaction mixture is then heated. This single heating step efficiently effects both the thermal decarboxylation of the C-13 methoxycarbonyl group and the saponification of the C-17 methyl ester, yielding pyropheophorbide a in a more streamlined fashion.
3. Ether Addition: In the final step, the pyropheophorbide a is treated with an acid, followed by the addition of 1-hexanol under basic conditions. This sequence facilitates the Markovnikov addition of the alcohol across the C-3 vinyl group, forming the desired 1-hexyloxyethyl moiety and yielding the final HPPH product.

This streamlined, three-step "one-pot" style synthesis is significantly more efficient and avoids the need for multiple intermediate purifications, making it suitable for the multi-gram to multi-kilogram scale required for commercial drug production.[22] The development and patenting of this scalable process represents a critical milestone in the drug's development lifecycle. It signifies a successful transition from an academic research compound to a potential commercial product by addressing a major potential bottleneck in Chemistry, Manufacturing, and Controls (CMC). This achievement indicates that at a key point in its history, there was a clear strategic intent and the necessary technical capability to advance HPPH towards the market. This context makes the subsequent stalling of its clinical development more pointedly attributable to clinical, regulatory, or financial factors rather than fundamental manufacturing limitations.

Formulation for Clinical Use

Due to its extreme hydrophobicity and negligible aqueous solubility, HPPH cannot be simply dissolved in saline for intravenous administration. It requires a specialized formulation to create a stable, injectable solution. While the exact composition of the final clinical formulation is proprietary, formulations used in preclinical and research settings provide insight into the strategies employed. These typically involve using a system of co-solvents and/or surfactants to solubilize the drug. Examples include:

• A mixture of 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline.
• A simpler mixture of 10% DMSO and 90% corn oil for animal studies.[13]

The final clinical product would be a sterile, filtered solution based on similar principles, designed to be safe and stable for intravenous infusion in patients.

Clinical Development and Investigational Use

The clinical development of HPPH has been driven by a clear rationale: to create a second-generation photosensitizer that retains the efficacy of earlier agents while overcoming their most significant clinical liability—prolonged, severe skin photosensitivity. Its investigational history spans more than two decades and a variety of solid tumor indications, characterized by promising early results but a challenging path toward late-stage development.

Developmental Rationale

HPPH was rationally designed to improve upon the first-generation photosensitizer, Photofrin®. The key objectives were to address Photofrin®'s main drawbacks:

1. Prolonged Cutaneous Phototoxicity: Photofrin®'s slow clearance from the skin necessitates that patients avoid sunlight and bright indoor light for 30 to 90 days post-treatment, a significant burden on quality of life.[20] HPPH was designed to clear more rapidly from the skin, reducing this period of photosensitivity.[3]
2. Suboptimal Activation Wavelength: Photofrin®'s activation at 630 nm limits its tissue penetration. HPPH's chlorin structure shifts this absorption to ~665 nm, allowing light to penetrate deeper into tissues, thereby enabling treatment of larger or thicker tumors.[3]
3. Chemical Purity: HPPH is a single, well-defined chemical entity, whereas Photofrin® is a complex and poorly characterized mixture of porphyrin oligomers, which is a disadvantage from a regulatory and manufacturing perspective.[4]

Review of Clinical Trials by Indication

HPPH has been evaluated in Phase I and Phase II clinical trials across several cancer types, with most of the research spearheaded by the Roswell Park Comprehensive Cancer Center.

• Non-Small Cell Lung Cancer (NSCLC):
• HPPH-PDT has been investigated for early-stage and obstructive lung cancers. A Phase II trial for patients with advanced NSCLC causing airway obstruction was scheduled to run from 2007 to 2011.[1]
• A key Phase I dose-ranging study (NCT01668823) focused on treating carcinoma in situ (CIS) and microinvasive bronchogenic carcinoma of the central airways. The study successfully determined the maximally tolerated light dose and demonstrated impressive efficacy, achieving a pathological complete response (CR) rate of 82.4% at the 1-month follow-up. The investigators concluded that HPPH-PDT is a safe and potentially effective treatment for these early-stage lung lesions.[2]
• Esophageal Cancer and Barrett's Esophagus:
• This was one of the earliest indications explored for HPPH, with a Phase I/II clinical trial (NCT00060268) for partially obstructive esophageal tumors initiated as early as 1997.[1]
• The drug was also evaluated in patients with high-grade dysplasia arising from Barrett's esophagus, a precancerous condition of the esophagus.[4]
• Head and Neck Squamous Cell Carcinoma (HNSCC):
• A significant portion of HPPH's clinical investigation has been in HNSCC, targeting various early-stage or recurrent cancers of the oral cavity, oropharynx, and larynx.[2]
• A notable study by Rigual et al. in patients with T1 squamous cell carcinoma of the oral cavity demonstrated a high complete response rate of 82%. However, the same study found that the response in premalignant lesions (dysplasia and CIS) was lower (46% CR) and less durable, suggesting the therapy is more effective against invasive cancer.[11]
• Despite these promising early results, the development path for this indication has been fraught with difficulty. A large number of Phase II trials targeting various stages of oral and oropharyngeal cancer, including the multi-indication trial NCT02119728, were ultimately withdrawn before completion.[12]
• Other Cancers:
• Early Phase I trials also included patients with multiple basal cell carcinomas of the skin.[4]
• Preclinical research has shown potent antitumor activity in animal models of glioma and pancreatic cancer, though it is unclear if these findings were translated into clinical trials.[7]

Table 3: Chronological Overview of Major Clinical Trials for HPPH

NCT Identifier	Trial Phase	Indication(s)	Start Date	Status	Key Findings/Reference
NCT00060268	I/II	Obstructive Esophageal Cancer	Jan 1997	Completed	One of the earliest trials establishing feasibility 1
NCT00017485	I	Non-melanomatous Skin Cancer	Jan 2000	Completed	Included patients with basal cell carcinoma 4
NCT01668823	I	Early-Stage NSCLC (CIS/Microinvasive)	Feb 2004	Terminated	82.4% pathological CR at 1 month; established max tolerated light dose. Terminated due to drug supply issues 2
NCT00528775	II	Advanced NSCLC (Airway Obstruction)	Aug 2007	Unknown	Scheduled to run 2007-2011 1
NCT02119728	II	Recurrent/Stage I-IV HNSCC	N/A	Withdrawn	A major multi-indication trial for oral/oropharyngeal cancers that was withdrawn 12
NCT03090412	II	Stage I/II Oral Cavity SCC	Mar 2018	Unknown	A follow-up trial to earlier promising HNSCC studies 13

Regulatory Status

Despite decades of research and clinical investigation, HPPH remains an investigational drug.[2] It has not received marketing approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any clinical indication. A review of publicly available regulatory communications from these agencies reveals no specific filings, reviews, or guidance documents pertaining to HPPH or Photochlor.[28] The absence of such documentation confirms its status as a compound that has not yet advanced to the stage of a New Drug Application (NDA) or Marketing Authorisation Application (MAA).

The clinical development history of HPPH provides a case study in the challenges of advancing a drug from academic discovery to commercial reality, a journey often referred to as crossing the "valley of death." The vast majority of clinical trials have been sponsored and conducted by a single academic institution, the Roswell Park Comprehensive Cancer Center, often with support from the National Cancer Institute (NCI).[10] While this environment is ideal for innovative, early-phase proof-of-concept studies, academic centers often lack the extensive financial resources, global operational infrastructure, and dedicated regulatory expertise required to conduct the large, multi-center, pivotal Phase III trials necessary for regulatory approval. The pattern of promising Phase I/II results followed by withdrawn Phase II trials and the explicit mention of one trial's termination due to "delays in HPPH supply" strongly suggest that the development of HPPH has been constrained by logistical, financial, and strategic limitations rather than a definitive failure on grounds of safety or efficacy.[10] This situation presents a classic scenario of a promising therapeutic asset that has stalled for non-clinical reasons, representing a potential opportunity for a commercial partner to acquire the asset and provide the necessary resources to complete its development.

Safety, Tolerability, and Risk Profile

The safety and tolerability profile of HPPH is arguably its most compelling feature and the primary driver behind its development as a second-generation photosensitizer. The clinical data consistently highlight a significant improvement in the main dose-limiting toxicity of PDT—cutaneous photosensitivity—while demonstrating that its on-target effects are potent and require careful clinical management.

Cutaneous Photosensitivity: The Primary Safety Advantage

The defining characteristic of HPPH's safety profile is its dramatically reduced and transient skin phototoxicity when compared to first-generation agents like Photofrin®.[3]

• Comparison with First-Generation Agents: Whereas treatment with Photofrin® necessitates strict avoidance of sunlight and other sources of bright light for extended periods, often 30 to 90 days, to prevent severe sunburn-like reactions, the photosensitivity induced by HPPH is both milder and much shorter in duration.[20]
• Clinical Observations: A dedicated study on skin photosensitivity in patients treated with clinically effective antitumor doses of HPPH found that the side effect was mild and declined rapidly over a few days.[3] In this study, the most severe skin reaction observed was limited to mild erythema (redness) without edema (swelling), and this occurred in only a small subset of patients exposed to the highest tested doses of artificial solar-spectrum light. The peak skin response was observed when light exposure occurred 1 day after the HPPH infusion, with sensitivity decreasing significantly by day 2 and even more so by day 3.[3]
• Pharmacokinetic Correlation: This clinical observation is supported by the comprehensive pharmacokinetic study, which noted that despite the drug's very long persistence in the plasma, no instances of delayed or prolonged cutaneous photosensitivity were reported among the study participants.[4] This confirms that the concentration of HPPH in the skin falls below a clinically relevant threshold for photosensitivity much more quickly than it is cleared from the circulation.

Adverse Event Profile from Clinical Trials

Aside from the minimized systemic photosensitivity, the adverse events associated with HPPH-PDT are primarily localized to the treatment area and are a direct consequence of the intended therapeutic mechanism of action.

• Local Tissue Effects: The most commonly reported adverse events are pain and edema at the tumor site.[24] These are expected outcomes resulting from the acute inflammatory response triggered by the photodynamic destruction of tissue. In clinical trials for oral cancer, pain typically peaked about one week after treatment and could persist for up to four weeks, while edema was also a common finding.
• Dose-Limiting Toxicity (DLT): The potency of the local reaction can, in certain circumstances, become a dose-limiting toxicity. In a Phase I trial for oral cancer, one DLT was observed in a patient with pre-existing severe trismus (lockjaw) who had also received prior radiotherapy. This patient developed Grade 3 edema following PDT, which led to respiratory distress requiring a temporary tracheostomy.[24] This event underscores that the potent local inflammatory response can be dangerous in anatomically constrained areas and highlights the importance of careful patient selection.
• Systemic Toxicity: Apart from transient skin photosensitivity, HPPH appears to have an excellent systemic safety profile. No evidence of systemic organ toxicity has been reported in either preclinical or clinical studies, consistent with a drug that is metabolically inert and whose activity is confined to areas exposed to light.[5]

Risk Mitigation

The predictable nature of the local adverse events allows for effective risk mitigation strategies to be employed.

• Prophylactic Medication: The management of treatment-site pain and edema can be handled proactively. In clinical trials, this was successfully achieved with a tapering course of steroids to control inflammation and a multi-modal analgesic regimen including fentanyl patches and oral narcotics to manage pain.[24]
• Patient Selection: Careful patient selection is crucial to avoid severe complications. Following the observation of the DLT, the protocol for the oral cancer study was amended to exclude patients with severe trismus, demonstrating that risk can be managed by identifying and avoiding treatment in high-risk individuals.[24]

It is essential to draw a distinction between the systemic safety profile of HPPH and its local, on-target toxicity. The primary advantage of HPPH is its systemic safety, specifically the dramatic reduction in off-target cutaneous photosensitivity. This is a property derived from its favorable differential pharmacokinetics. However, this systemic safety should not be conflated with a lack of local potency. The on-target effects of HPPH-PDT are, by design, highly destructive to tissue. The potent cell-killing and vascular damage that lead to high efficacy rates will invariably produce a strong local inflammatory response, resulting in pain and swelling. The observed DLT was not a systemic toxicity but rather an exaggerated, on-target pharmacodynamic effect in a patient with compromised anatomy. Therefore, HPPH is not "safer" because its therapeutic action is weaker; it is safer because its off-target effects are minimized. The potent on-target effects remain a core feature of the therapy and require diligent clinical management of light dosimetry, patient selection, and supportive care to ensure tolerability.

Comparative Analysis and Strategic Outlook

To fully appreciate the clinical and commercial potential of HPPH, it must be evaluated within the competitive landscape of photosensitizers used in photodynamic therapy. A comparative analysis against the first-generation standard-of-care, Photofrin®, and another prominent second-generation agent, Foscan®, highlights its distinct profile and strategic positioning.

HPPH in the Context of Other Photosensitizers

HPPH was developed to be a "best-in-class" photosensitizer by systematically addressing the known deficiencies of its predecessors.

• vs. Photofrin® (porfimer sodium, First Generation): The comparison with Photofrin® clearly positions HPPH as a superior agent across multiple critical parameters.
• Safety: This is the most significant differentiator. HPPH's mild and transient cutaneous photosensitivity (lasting a few days) is a transformative improvement over the prolonged (30-90 days) and potentially severe photosensitivity associated with Photofrin®.[3] This has profound implications for patient quality of life and the overall feasibility of treatment.
• Efficacy and Physics: HPPH's longer activation wavelength (~665 nm) compared to Photofrin®'s (~630 nm) allows for significantly deeper light penetration into tissue. This physical advantage enables the effective treatment of larger and thicker tumors that would be inaccessible to Photofrin®-PDT.[3]
• Chemical Nature: HPPH is a single, pure chemical compound with a well-defined structure and molecular weight. In contrast, Photofrin® is a complex and poorly defined mixture of porphyrin oligomers, which presents challenges for manufacturing consistency and regulatory characterization.[4]
• vs. Foscan® (temoporfin, mTHPC, Second Generation): As both are potent, single-molecule chlorin-based photosensitizers, the comparison is more nuanced, but a safety advantage for HPPH remains apparent.
• Safety: While both agents are highly potent, Foscan® is also associated with prolonged skin phototoxicity (requiring 2-4 weeks of light avoidance) and has been linked in some reports to severe local tissue necrosis and scar formation, particularly in the treatment of HNSCC.[24] Clinical studies with HPPH have emphasized good tissue healing with minimal scarring, which is attributed to its lack of retention in fibroblasts.[24] This suggests HPPH may offer a more favorable local tissue-sparing effect and a better overall safety profile.
• Efficacy: Both HPPH and Foscan® are highly effective photosensitizers. They are activated by light of similar, deep-penetrating wavelengths (HPPH at ~665 nm, Foscan at ~652 nm) and have demonstrated comparable complete response rates in studies of head and neck cancer.[11] The choice between them may therefore hinge more on their respective safety and tolerability profiles.

Table 4: Comparative Profile of HPPH vs. Key Photosensitizers

Feature	Photofrin® (porfimer sodium)	Foscan® (temoporfin)	HPPH (Photochlor)
Generation	First	Second	Second
Chemical Nature	Complex mixture of porphyrin oligomers	Single pure chlorin molecule	Single pure chlorin molecule
Activation Wavelength	~630 nm	~652 nm	~665 nm
Tissue Penetration Depth	Lower	Higher	Higher
Efficacy (General)	Effective for approved indications	Highly potent	Highly potent, comparable to Foscan®
Duration of Skin Phototoxicity	Prolonged (30-90 days)	Prolonged (2-4 weeks)	Mild and transient (a few days)
Key Adverse Events	Severe, prolonged photosensitivity; stenosis	Prolonged photosensitivity; severe local necrosis/scarring reported	Local pain and edema (manageable); minimal skin photosensitivity
Regulatory Status	FDA/EMA approved for specific cancers	EMA approved for palliative HNSCC	Investigational only

Strengths, Weaknesses, and Future Directions

A strategic assessment of HPPH reveals a profile of significant strengths offset by developmental weaknesses.

• Strengths:
• Superior Safety Profile: The minimal and transient cutaneous photosensitivity is a paradigm-shifting advantage over other approved photosensitizers.
• Favorable Photophysics: The long activation wavelength allows for the treatment of larger, deeper tumors, expanding the potential clinical utility of PDT.
• Predictable Pharmacology: The lack of metabolism simplifies its pharmacokinetic profile and reduces the risk of drug-drug interactions.
• Manufacturing Readiness: A scalable, patented manufacturing process has been established, removing a major potential barrier to commercialization.
• Demonstrated Efficacy: Early-phase trials have shown promising complete response rates in several solid tumor types, particularly early-stage HNSCC and NSCLC.
• Weaknesses:
• Stalled Development: The most significant weakness is that its clinical development has largely stalled. The pattern of withdrawn clinical trials and reliance on a single academic center has created a bottleneck, preventing its advancement to pivotal registration studies.
• Inconsistent Efficacy: Efficacy appears to be lower and less durable in premalignant lesions (e.g., dysplasia) compared to invasive carcinomas, which may limit its use in chemoprevention settings.
• Lack of Commercial Partner: The absence of a major pharmaceutical or biotechnology partner has deprived the program of the financial resources and operational expertise needed for late-stage development and commercialization.
• Future Directions: The most logical path forward for HPPH involves strategic commercial partnership or acquisition. A commercial entity could:

1. License the Asset: Acquire the rights to the compound from its academic developers.
2. Optimize CMC: Secure and potentially optimize the manufacturing and supply chain to ensure a reliable drug supply for large-scale trials.
3. Strategic Trial Design: Design and fund a well-controlled, multi-center pivotal Phase III trial in a carefully selected indication. Based on existing data, promising targets would include early-stage HNSCC or early-stage endobronchial NSCLC, particularly in patients who are poor candidates for surgery or radiation, where a repeatable, tissue-sparing therapy would have a high unmet medical need.
4. Explore Novel Formulations: Investigate advanced drug delivery systems, such as liposomal or nanoparticle formulations, to further enhance tumor targeting, improve solubility, and potentially modulate the pharmacokinetic profile.[5]

Conclusion

In summary, 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH/Photochlor) is a well-characterized, scientifically robust second-generation photosensitizer that represents a significant advancement in the field of photodynamic therapy. Through rational chemical design, it successfully addresses the most critical clinical limitation of first-generation PDT: prolonged and severe cutaneous photosensitivity. Its pharmacological profile is defined by a unique and highly favorable differential clearance mechanism, allowing for rapid elimination from the skin while maintaining therapeutic concentrations in tumor tissue. This, combined with its superior photophysical properties that enable deeper tissue treatment, positions HPPH as a potentially superior therapeutic agent to the current standard-of-care, Photofrin®, and a potentially safer alternative to other potent second-generation agents like Foscan®.

However, the trajectory of HPPH from the laboratory to the clinic is a poignant illustration of the challenges inherent in academic drug development. Despite a strong scientific foundation, a scalable manufacturing process, and a portfolio of promising early-phase clinical data, its progression has been impeded by logistical and strategic hurdles. The lack of a dedicated commercial partner has left this promising asset in a state of developmental arrest, unable to cross the "valley of death" to pivotal trials and regulatory submission.

HPPH remains a compound with substantial untapped clinical potential. It offers a solution to a long-standing problem in PDT and could provide a valuable, repeatable, and tissue-sparing treatment option for patients with a variety of solid tumors. Its future, however, is contingent upon a strategic intervention by a commercial entity with the resources, expertise, and vision to guide it through the final, demanding stages of clinical development and regulatory approval. As it stands, HPPH is a compelling opportunity—a de-risked asset with a clear value proposition awaiting the right partner to carry it forward to the patients it was designed to help.

Works cited

1. 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a - Wikipedia, accessed September 6, 2025, https://en.wikipedia.org/wiki/2-(1-Hexyloxyethyl)-2-devinyl_pyropheophorbide-a
2. 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a: Uses ..., accessed September 6, 2025, https://go.drugbank.com/drugs/DB15243
3. Photochlor | HPPH | CAS#149402-51-7 | Photosensitizer | MedKoo ..., accessed September 6, 2025, https://www.medkoo.com/products/4723
4. Population pharmacokinetics of the photodynamic therapy agent 2 ..., accessed September 6, 2025, https://pubmed.ncbi.nlm.nih.gov/12702566/
5. Mild skin photosensitivity in cancer patients following injection of Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a; HPPH) for photodynamic therapy | Request PDF - ResearchGate, accessed September 6, 2025, https://www.researchgate.net/publication/7743474_Mild_skin_photosensitivity_in_cancer_patients_following_injection_of_Photochlor_2-1-hexyloxyethyl-2-devinyl_pyropheophorbide-a_HPPH_for_photodynamic_therapy
6. Chemical structure of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)., accessed September 6, 2025, https://www.researchgate.net/figure/Chemical-structure-of-2-1-hexyloxyethyl-2-devinyl-pyropheophorbide-a-HPPH_fig3_258056612
7. HPPH (Photochlor, Pyropheophorbide-α-hexyl-ether, 2-[1 ..., accessed September 6, 2025, https://www.caymanchem.com/product/20611/hpph
8. HPPH | CAS 149402-51-7 | Cayman Chemical | Biomol.com, accessed September 6, 2025, https://www.biomol.com/products/chemicals/biochemicals/hpph-cay20611-1
9. Murine pharmacokinetics and antitumor efficacy of the ... - PubMed, accessed September 6, 2025, https://pubmed.ncbi.nlm.nih.gov/8229470/
10. A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1 ..., accessed September 6, 2025, https://pubmed.ncbi.nlm.nih.gov/26718878/
11. Current state and future of photodynamic therapy for the treatment of head and neck squamous cell carcinoma - PMC, accessed September 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5376070/
12. 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a Withdrawn ..., accessed September 6, 2025, https://go.drugbank.com/drugs/DB15243/clinical_trials?conditions=DBCOND0028812%2CDBCOND0028814%2CDBCOND0029507%2CDBCOND0154103%2CDBCOND0037028%2CDBCOND0037032%2CDBCOND0030141%2CDBCOND0030142%2CDBCOND0037045%2CDBCOND0028768%2CDBCOND0028770%2CDBCOND0029517%2CDBCOND0029847%2CDBCOND0029848%2CDBCOND0029851%2CDBCOND0029854%2CDBCOND0029855%2CDBCOND0029858%2CDBCOND0029838%2CDBCOND0029839%2CDBCOND0029842&phase=2&purpose=treatment&status=withdrawn
13. HPPH (Photochlor) | Photosensitizer - MedchemExpress.com, accessed September 6, 2025, https://www.medchemexpress.com/HPPH.html
14. 149402-51-7(14-Ethyl-9-(1-(hexyloxy)ethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbine propanoic acid) - ChemicalBook, accessed September 6, 2025, https://m.chemicalbook.com/ProdSupplierGWCB31238726_EN.htm
15. Highly Efficient Water-Soluble Photosensitizer Based on Chlorin ..., accessed September 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8033774/
16. Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling - PubMed, accessed September 6, 2025, https://pubmed.ncbi.nlm.nih.gov/27653233/
17. Photodynamic Therapy | Frontier Specialty Chemicals, accessed September 6, 2025, https://frontierspecialtychemicals.com/photodynamic-therapy/
18. Photodynamic therapy: A hot topic in dermato-oncology (Review), accessed September 6, 2025, https://www.spandidos-publications.com/10.3892/ol.2019.9939
19. Photodynamic Therapy Review: Principles, Photosensitizers ..., accessed September 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8470722/
20. Photodynamic Therapy for Cancer: What's Past is Prologue - PMC, accessed September 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7282978/
21. Phototoxic effects of pyropheophorbide-a from chlorophyll-a on ..., accessed September 6, 2025, https://www.researchgate.net/publication/262188794_Phototoxic_effects_of_pyropheophorbide-a_from_chlorophyll-a_on_cervical_cancer_cells
22. WO2004005289A2 - Efficient synthesis of pyropheophorbide a and ..., accessed September 6, 2025, https://patents.google.com/patent/WO2004005289A2/en
23. Efficient synthesis of pyropheophorbide a and its derivatives - Justia Patents, accessed September 6, 2025, https://patents.justia.com/patent/7053210
24. Photodynamic Therapy with 3-(1'-hexyloxyethyl ... - AACR Journals, accessed September 6, 2025, https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-13-1735/2101032/1078-0432_ccr-13-1735v1.pdf
25. 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a | MedPath, accessed September 6, 2025, https://trial.medpath.com/drug/c84387e6dd289374?page=1
26. Recurrent Squamous Cell Carcinoma of the Larynx | DrugBank Online, accessed September 6, 2025, https://go.drugbank.com/indications/DBCOND0028811
27. Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity | DrugBank Online, accessed September 6, 2025, https://go.drugbank.com/indications/DBCOND0028812
28. Human Foods Program - FDA, accessed September 6, 2025, https://www.fda.gov/about-fda/fda-organization/human-foods-program
29. HFP Constituent Updates - FDA, accessed September 6, 2025, https://www.fda.gov/food/news-events-hfp/hfp-constituent-updates
30. Human Food Program (HFP) FY 2025 Priority Deliverables - FDA, accessed September 6, 2025, https://www.fda.gov/about-fda/human-foods-program/human-food-program-hfp-fy-2025-priority-deliverables
31. Substances Added to Food (formerly EAFUS) - FDA, accessed September 6, 2025, https://www.fda.gov/food/food-additives-petitions/food-additive-status-list
32. Regulatory Information - FDA, accessed September 6, 2025, https://www.fda.gov/regulatory-information
33. FDA Provides Update on Proposal for Unified Human Foods Program, including New Model for the Office of Regulatory Affairs, accessed September 6, 2025, https://www.fda.gov/news-events/press-announcements/fda-provides-update-proposal-unified-human-foods-program-including-new-model-office-regulatory
34. Direct healthcare professional communications (DHPC) | European Medicines Agency (EMA), accessed September 6, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/direct-healthcare-professional-communications-dhpc
35. Demand for AI-integration propelling mass spectrometry growth, accessed September 6, 2025, https://www.europeanpharmaceuticalreview.com/news/265163/demand-for-ai-integration-propelling-mass-spectrometry-market-growth/
36. Merck's health business gains new Global Head of R&D - European Pharmaceutical Review, accessed September 6, 2025, https://www.europeanpharmaceuticalreview.com/news/265153/merck-health-business-research-medical-head-david-weinreich/
37. Human regulatory: overview | European Medicines Agency (EMA), accessed September 6, 2025, https://www.ema.europa.eu/en/human-regulatory-overview
38. Regulatory News - PHAGECON, accessed September 6, 2025, https://www.phagecon.pt/noticias.php
39. EMA warns consumers about 'sharp rise' in counterfeit versions of Novo, Lilly weight loss drugs, DrugsControl Media Services, accessed September 6, 2025, https://drugscontrol.org/news-detail.php?newsid=43085
40. Photodynamic Therapy for Barrett's Esophagus and Esophageal Carcinoma - Clinical Endoscopy, accessed September 6, 2025, https://www.e-ce.org/upload/pdf/ce-46-30.pdf
41. Advancements in photodynamic therapy of esophageal cancer - Frontiers, accessed September 6, 2025, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1024576/full