Biotech
Onion (Allium cepa), a species within the Allium genus, is a vegetable cultivated and consumed globally, serving as a foundational ingredient in a vast array of culinary traditions.[1] Despite its ubiquity in the human diet, it is also a source of allergic reactions, which, while rare, can be severe.[1] The immunological response to onion is complex, capable of inducing both immediate (Type I) and delayed hypersensitivity reactions through various routes of exposure, including ingestion, direct skin contact, and inhalation of vapors during food preparation.[2]
To diagnose these allergic sensitivities, standardized allergenic extracts are employed in clinical settings. Onion Allergenic Extract (DrugBank ID: DB10548) is a non-standardized food allergenic extract derived from onion bulb tissue.[7] It is formulated for diagnostic use in skin testing to identify the presence of onion-specific immunoglobulin E (IgE) antibodies in sensitized individuals.[7] The extract is typically supplied in a phenol-preserved saline or glycerin-based solution for percutaneous or intradermal administration.[8] The diagnostic principle relies on the interaction between the allergenic proteins in the extract and IgE antibodies fixed to the surface of cutaneous mast cells. This interaction triggers mast cell degranulation, releasing histamine and other chemical mediators that produce a characteristic wheal-and-flare reaction, indicative of a positive test.[8]
True IgE-mediated allergy to onion is considered uncommon relative to other major food allergens.[4] However, epidemiological data suggest that sensitization is clinically relevant within specific populations. An observational cross-sectional study conducted in Spain, a region with high consumption of
Allium vegetables, evaluated 8,109 allergic patients. Among the 2,508 patients who reported food-related symptoms, hypersensitivity to garlic or onion was confirmed in 27 individuals, corresponding to a prevalence of 2.92% within this symptomatic subgroup.[10] Another study focusing on a cohort of 108 patients in Saudi Arabia with suspected food allergies found that 15 patients (13.8%) had detectable specific IgE antibodies to garlic and/or onion, with 12 of these patients showing co-sensitization to both.[13] A separate analysis of 8,109 general allergic patients identified sensitization to onion in approximately 1% of the cohort.[4] These findings collectively indicate that while onion is not a primary allergen on a population-wide scale, it is a significant sensitizer in certain regions and among individuals with a predisposition to atopic disease.
A critical aspect of diagnosing adverse reactions to onion is the differentiation between a true IgE-mediated allergy and a food intolerance or sensitivity. An allergy is an immune system response, where the body mistakenly identifies onion proteins as harmful and produces specific IgE antibodies, leading to the release of histamine and other mediators.[1] This response can range from mild cutaneous symptoms to severe, life-threatening systemic reactions known as anaphylaxis.[6]
In contrast, an onion intolerance or sensitivity does not involve the immune system in the same manner and is often related to the body's inability to properly digest certain compounds in the onion.[14] Symptoms of intolerance are typically confined to the gastrointestinal tract and may include bloating, stomach pain, gas, or diarrhea.[6] While uncomfortable, these symptoms are not life-threatening and do not carry the risk of anaphylaxis.[14] This distinction is paramount for accurate diagnosis, risk assessment, and patient management.
The allergenic potential of onion is attributed to several proteins that have been characterized and identified as capable of binding to IgE antibodies and triggering an allergic cascade. To date, three principal allergens have been described in scientific literature: All c 3, a lipid transfer protein; All c 4, a profilin; and a 56 kDa alliin lyase.[2] The specific protein to which a patient is sensitized can have significant implications for the clinical presentation of their allergy, including the severity of reactions and the pattern of cross-reactivity with other allergens.
All c 3, a 12 kDa protein, is classified as a non-specific lipid transfer protein (LTP) and is recognized as a major allergen in onion.[2] LTPs are a well-known family of plant pan-allergens, characterized by their robust structure, which makes them resistant to both heat and enzymatic degradation by pepsin.[2]
The thermostability of All c 3 is of profound clinical importance. Unlike many food allergens that are denatured by cooking, rendering them less allergenic, All c 3 retains its structural integrity and allergenic potential even after being heated.[2] This molecular property provides a clear explanation for the documented cases of severe systemic reactions, including anaphylaxis, that have occurred after the ingestion of cooked onions.[2] This phenomenon is often counterintuitive for patients, who may incorrectly assume that cooked foods are safe. Therefore, the identification of All c 3 as a heat-stable LTP is a critical insight for clinical practice. It mandates that patient counseling for onion allergy must explicitly state that both raw and cooked forms of onion, as well as products containing onion powder, pose a risk and must be avoided.[19] One case report detailed an anaphylactic reaction to cooked onion, and skin testing confirmed that while the allergenic activity of cooked onion was substantially reduced compared to raw onion, it was still sufficient to induce a valid cutaneous response.[2]
In addition to the heat-stable LTP, two other allergens have been identified in onion. All c 4 is a profilin, a type of protein that is highly conserved across the plant kingdom and is a well-known pan-allergen.[2] Sensitization to profilins is often associated with pollen-food allergy syndrome (PFAS), where individuals with pollen allergies experience oral allergy symptoms upon eating certain raw fruits and vegetables. The other characterized allergen is All c alliin lyase, a 56 kDa enzyme.[2] The presence of multiple distinct allergen types underscores the complexity of onion allergy. A patient's specific sensitization profile—for instance, sensitization to the high-risk, heat-stable All c 3 versus the more labile, cross-reactive All c 4—can significantly influence their clinical risk. Standard diagnostic tools, such as whole onion extracts, do not differentiate between these sensitizations. This highlights a potential area for improvement in diagnostics; the development and clinical application of component-resolved diagnostics (CRD) for specific onion allergens would allow for more precise risk stratification and tailored management advice for patients.
Allergenic cross-reactivity is a key feature of onion allergy, driven by the structural similarity of its allergenic proteins to those in other species.[6]
The following table summarizes the key allergenic proteins identified in Allium cepa.
Allergen Name | Protein Family | Molecular Weight (kDa) | Clinical Significance & Notes |
---|---|---|---|
All c 3 | Lipid Transfer Protein (LTP) | 12 | Thermostable; responsible for reactions to both raw and cooked onion. Major allergen implicated in systemic reactions/anaphylaxis.2 |
All c 4 | Profilin | - | Associated with cross-reactivity to pollens (pollen-food allergy syndrome). A pan-allergen.2 |
All c alliin lyase | Alliinase | 56 | Another characterized allergen in onion.2 |
Adverse reactions to onion can be triggered through multiple routes of exposure, including ingestion of the bulb, direct dermal contact, and inhalation of volatile compounds released during chopping.[1] The clinical presentation varies widely among individuals, from mild, localized symptoms to severe, life-threatening systemic reactions.[6]
The skin prick test (SPT) is a primary diagnostic tool for identifying immediate, IgE-mediated allergies.[21]
A specific IgE (sIgE) blood test, such as ImmunoCAP or the formerly used RAST, provides a quantitative measure of the onion-specific IgE antibodies circulating in the patient's blood.[1] This test confirms sensitization to onion and can be used when skin testing is contraindicated (e.g., in patients with severe dermatographism or those who cannot discontinue antihistamines).[26] In one reported case of anaphylaxis to onion, the patient's onion-specific IgE level was 3.99 kU/L.[2]
While SPT is generally a safe procedure, it is not without risk. Because the test involves introducing an allergen into the skin, there is a small but real risk of inducing a systemic allergic reaction, including anaphylaxis. For this reason, SPT must only be performed in a clinical setting where personnel are trained and equipped to manage such emergencies.[5] It is also crucial to recognize the limitations of allergy testing. Both skin and blood tests can yield false-positive results, where a patient shows sensitization (i.e., has specific IgE) but does not experience clinical symptoms upon exposure. Conversely, false-negatives can also occur.[23] Therefore, a positive test result confirms sensitization but must be interpreted in the context of a convincing clinical history to diagnose a true allergy.
The complement system, a part of the innate immune system, has been theoretically implicated in amplifying Type I allergic reactions through the generation of anaphylatoxins like C3a and C4a, which can degranulate mast cells.[28] This raises the question of whether measuring complement components like C3 and C4 could serve as diagnostic markers. However, studies in patients with allergic rhinitis have shown that C3 and C4 levels often remain within the normal range, even in individuals with detectable circulating immune complexes.[28] Therefore, while a mechanistic link is plausible, complement testing is not currently a standard or clinically useful tool for the routine diagnosis of IgE-mediated onion allergy.[29]
Onion extract is generally considered safe when consumed in typical food amounts.[32] When used medicinally, such as in topical gels for scar prevention, onion extract is rated as likely safe, though it may cause skin irritation or eczema in some individuals.[32] The primary safety concern relates to its use in diagnostic allergy testing. As with any allergen extract used for skin prick testing, there is a risk of inducing an allergic reaction, which in rare cases can be systemic and severe (anaphylaxis).[5] This risk underscores the necessity for such tests to be conducted by trained professionals in a controlled medical environment equipped to handle anaphylactic emergencies.[23]
Several potential interactions with onion extract used as a medicinal supplement have been noted:
It is also recommended that patients stop using onion as a medicinal supplement at least two weeks before a scheduled surgery due to its potential effects on blood clotting and blood sugar control.[32]
The cornerstone of managing a confirmed onion allergy is strict avoidance of onion and other cross-reactive Allium vegetables.[19] This requires diligent effort from the patient, as onion is a common ingredient in many processed foods, sauces, and restaurant dishes.[1]
The field of anesthesiology is in continuous pursuit of the ideal sedative-hypnotic agent. Such an agent would exhibit a rapid and predictable onset of action, a short duration of effect that allows for quick recovery after the procedure, and a wide therapeutic window with minimal side effects.[33] Key safety considerations include maintaining hemodynamic stability (i.e., avoiding significant changes in blood pressure and heart rate) and preserving respiratory function, which are known liabilities of many existing anesthetics like propofol.[35] The increasing number of procedures performed in outpatient settings further amplifies the need for agents that facilitate rapid recovery and discharge.[37]
Etomidate, a γ-aminobutyric acid type A (GABA-A) receptor agonist, has long been recognized for its uniquely favorable cardiorespiratory profile, causing minimal hemodynamic and respiratory depression compared to other induction agents. This stability makes it an attractive choice, particularly in critically ill or hemodynamically compromised patients.[38] However, etomidate's clinical utility is severely limited by a significant and well-documented side effect: suppression of adrenocortical steroid synthesis.[39] This effect is caused by the reversible inhibition of the mitochondrial enzyme 11β-hydroxylase, which is critical for the conversion of 11-deoxycortisol to cortisol.[42] Even a single bolus dose can suppress the adrenal response to stress for 6-8 hours, making it unsuitable for continuous infusion or for use in patients with sepsis, where a robust stress response is vital.[38]
ABP-700 (also known as cyclopropyl-methoxycarbonylmetomidate or CPMM) emerged from a rational drug design program aimed at creating an etomidate analog that would retain its beneficial hemodynamic properties while eliminating its adrenal toxicity. It was developed as a "soft drug," a compound designed to be metabolically labile. The key structural modification was the incorporation of an ester bond into the molecule.[33] This ester linkage was precisely engineered to be a substrate for rapid hydrolysis by non-specific tissue esterases, which are ubiquitous in the body. The hypothesis was that this rapid metabolism would break down the drug into an inactive carboxylic acid metabolite before it could accumulate to concentrations sufficient to inhibit 11β-hydroxylase, thus preserving adrenal function.
The primary mechanism of action of ABP-700 is identical to that of its parent compound, etomidate. It acts as a potent, positive allosteric modulator of the GABA-A receptor.[33] The GABA-A receptor is the principal inhibitory neurotransmitter receptor in the central nervous system. By binding to an allosteric site on the receptor, ABP-700 enhances the effect of the endogenous ligand, GABA, increasing chloride ion influx and causing hyperpolarization of the neuron. This neuronal inhibition produces the clinical effects of sedation and anesthesia.[34]
The defining feature of ABP-700's pharmacology lies in its metabolism. The engineered ester bond facilitates rapid hydrolysis by non-specific esterases found in blood and tissues, breaking the molecule down into an inactive carboxylic acid metabolite, known as CPM-acid.[33] This metabolic pathway proved highly effective at achieving the primary design goal: preventing adrenocortical suppression.
Both preclinical and clinical studies unequivocally demonstrated the adrenal safety of ABP-700. In beagle dogs, infusions of etomidate caused profound and durable adrenal suppression, whereas infusions of ABP-700 and propofol did not; adrenal responsiveness in the ABP-700 and propofol groups was normal and indistinguishable within 1.5 to 3 hours post-infusion.[44] In Phase 1 human trials, adrenocorticotropic hormone (ACTH) stimulation tests confirmed that ABP-700 did not cause adrenal suppression at any dose tested, with cortisol responses similar to those seen with placebo.[48] This successful uncoupling of the desired hypnotic effect from the undesired endocrine side effect was a significant achievement of rational drug design.
The rapid metabolism of ABP-700 endowed it with a favorable pharmacokinetic profile for an anesthetic agent. Phase 1 studies in healthy volunteers demonstrated linear, dose-proportional pharmacokinetics.[50] Following a single intravenous bolus, the time to maximum plasma concentration (Tmax) was rapid, ranging from 1.6 to 3.6 minutes. The drug was characterized by small volumes of distribution and rapid clearance, with a short terminal elimination half-life (
t1/2) of approximately 10.5 to 18.7 minutes in humans.[39] This profile is consistent with a drug that has a rapid onset of action and allows for a quick and predictable recovery, as the drug is cleared from the body swiftly after administration is stopped.
The development of ABP-700 is a compelling illustration of how targeted molecular modification can successfully address a specific, well-understood liability of a parent compound. The primary limitation of etomidate was its inhibition of 11β-hydroxylase, leading to adrenal suppression. By introducing a metabolically labile ester linkage, the designers of ABP-700 created a "soft drug" that was rapidly inactivated by ubiquitous esterases, preventing it from reaching concentrations sufficient to cause the unwanted endocrine effect. This was a clear success. However, this success in solving the primary problem unmasked a secondary pharmacological property—the propensity to cause excitatory phenomena—which ultimately became the new dose-limiting toxicity and the reason for the program's termination. This demonstrates a common and challenging theme in drug development: solving one problem can reveal another, and the overall clinical viability of a drug depends on the totality of its pharmacological profile, not just the successful optimization of a single parameter.
The following table provides a comparative overview of the key pharmacological features of etomidate, propofol, and ABP-700, contextualizing the rationale for ABP-700's development and the factors that led to its discontinuation.
Feature | Etomidate | Propofol | ABP-700 |
---|---|---|---|
Primary Mechanism | GABA-A Receptor Positive Allosteric Modulator | GABA-A Receptor Positive Allosteric Modulator | GABA-A Receptor Positive Allosteric Modulator |
Metabolism | Hepatic Esterases | Primarily Hepatic | Non-specific Blood and Tissue Esterases |
Hemodynamic Profile | Generally Stable | Causes Hypotension | Generally Stable |
Adrenal Suppression | Yes (Significant and Prolonged) | No | No |
Key Adverse Events | Adrenal Suppression, Involuntary Muscle Movements | Hypotension, Respiratory Depression, Propofol Infusion Syndrome | Involuntary Muscle Movements (IMM) |
Despite successfully avoiding adrenal suppression, the clinical development of ABP-700 was ultimately halted by a different adverse effect profile. Across multiple Phase 1 studies, the most consistently reported treatment-related adverse event was involuntary muscle movements (IMM), also described as myoclonus or excitatory phenomena. These events were dose-dependent, becoming more frequent and extensive at higher doses.[48] While also a known side effect of etomidate, the issue appeared prominent enough with ABP-700 to be a matter of clinical concern.[48] In one study, IMM was among the most common adverse events, occurring in over 5% of subjects.[35] Another study reported that premedication with fentanyl or midazolam could reduce the incidence and intensity of IMM, suggesting a potential mitigation strategy.[53]
Toxicology studies in dogs at supra-therapeutic doses (~10x clinical) revealed that ABP-700 could induce not only IMM but also electroencephalographically distinct seizures.[49] The high plasma concentrations of the CPM-acid metabolite achieved in these animal studies were found to inhibit both GABA-A and glycine receptors, providing a plausible mechanism for the observed seizures.[49] However, these inhibitory effects occurred at concentrations one to two orders of magnitude higher than those achieved in human clinical studies, suggesting the seizure risk was not directly translatable to the clinical setting.[48]
The development program for ABP-700 was officially discontinued by The Medicines Company in 2017. The stated reason was the frequent occurrence of "excitatory phenomena and abnormal involuntary muscle movement excitation at clinical doses". This indicates that the therapeutic window was unacceptably narrow; the doses required to achieve reliable procedural sedation were too close to the doses that caused disruptive and undesirable muscle movements.
The journey of ABP-700 began at Annovation Biopharma, a company founded on technology licensed from Massachusetts General Hospital.[37] The Medicines Company acquired Annovation in February 2015, gaining the rights to ABP-700 and its portfolio.[37] The acquisition was driven by the potential of ABP-700 to transform surgical and procedural care as a novel, rapidly reversible intravenous anesthetic.[37] Following the acquisition, The Medicines Company initiated the "VERONA" Phase 2/3 development program to advance the asset.[56]
An extensive Phase 1 program involving over 300 healthy volunteers established the initial safety, pharmacokinetic, and pharmacodynamic profile of ABP-700.[57] These studies confirmed the drug's rapid onset and offset, dose-dependent sedative effects, and lack of adrenal suppression.[50] However, these early trials also consistently identified involuntary muscle movements as a key adverse event.[51]
In June 2016, The Medicines Company announced the initiation of a Phase 2 trial (NCT02800590).[56] This was a single-blind, dose-finding study designed to evaluate the safety and efficacy of three different two-stage infusion regimens of ABP-700 for procedural sedation in 75 adult patients undergoing elective colonoscopy at three sites in the Netherlands.[61] All patients were to receive concomitant remifentanil, an opioid analgesic.[61] The primary efficacy endpoint was the rate of successfully completed procedures without the need for rescue sedation or the occurrence of significant respiratory depression.[61]
The clinical trial record for NCT02800590 shows a last update in February 2018 and lists the trial's status as "Completed".[59] However, no results from this study have ever been formally published in a peer-reviewed journal, a conspicuous absence for a completed Phase 2 trial.[48] The program was discontinued in 2017, citing the unacceptable incidence of involuntary muscle movements at clinical doses.
While the clinical safety profile was the proximate cause for termination, the decision must also be viewed through the lens of The Medicines Company's concurrent corporate restructuring. In late 2015, the company announced a major strategic shift to unlock shareholder value by narrowing its operational focus and divesting non-core assets.[66] Throughout 2016 and 2017, the company systematically sold off its hemostasis and non-core cardiovascular product lines to focus resources on a few high-potential "blockbuster" assets, most notably the investigational cholesterol-lowering drug inclisiran.[37] By 2018, investor communications were almost exclusively centered on the development of inclisiran.[70]
In this context, the ABP-700 program, an anesthesia asset with a challenging side-effect profile, was a clear candidate for discontinuation. The high cost and risk associated with conducting large Phase 3 trials to prove its safety and efficacy in the competitive anesthesia market likely did not align with the company's new, streamlined focus on cardiovascular disease. The challenging clinical profile of ABP-700 made it an easy program to cut as the company pivoted its entire corporate strategy. The lack of a formal publication for the completed Phase 2 trial further suggests that the results were likely not compelling enough to justify continued investment, especially for a company moving in a different therapeutic direction.
The story of ABP-700 is a salient case study in the complexities and risks inherent in pharmaceutical development. The drug represents a clear success in rational drug design, as its creators successfully engineered a molecule that retained the desirable hemodynamic stability of etomidate while completely avoiding its dose-limiting adrenal suppression. This was achieved through the clever incorporation of a metabolically labile ester linkage, a testament to a deep understanding of structure-activity relationships.
However, the resolution of this primary liability only served to unmask a secondary one: the propensity to induce involuntary muscle movements at clinically relevant doses. This secondary pharmacology ultimately defined the drug's therapeutic window, which proved to be too narrow for practical clinical use. The doses required for adequate sedation were inextricably linked to an unacceptable incidence of excitatory side effects. This challenge, compounded by a shifting corporate strategy at The Medicines Company that de-prioritized non-cardiovascular assets, led to the program's termination in 2017. The case of ABP-700 serves as a crucial reminder that the viability of a new therapeutic agent is a multifactorial equation, dependent not only on its efficacy against a specific target but also on the totality of its safety profile, its competitiveness within the existing market, and its alignment with the strategic priorities of its developer.
Published at: June 24, 2025
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