At their previous company (1), the founders of Oculogics pioneered a new drug class called aldehyde traps that are designed to treat all diseases associated with chronic inflammation. These diseases cause lifetime disabilities and over 50% of global deaths (2). Aldehyde traps safely block chemical damage by toxins that surge during chronic inflammation. Depending on the type of inflammatory disease, these toxins cause cellular injuries in the affected organ, tissues or joints, or in the brain, spinal cord or retina. This chemical damage increases inflammation and advances the severity and progression of each such disease.
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Reproxalap (3), a first generation trap we developed at our previous company (4), has clinical proof of concept in a painful condition of ocular inflammation. It matched the potency of steroids without any of their safety risks (5). Our next generation traps at Oculogics are now over 500 times more potent with optimal oral availability and CNS exposure. This enables them to be more effective in a broader range of diseases and administered by safe oral dosing.
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This drug class pioneers a novel therapeutic strategy. The biology and chemistry of free aldehydes have been studied for years. Now it is possible to block their toxicities in the clinic and spare patients from the harmful effects of their chemical damage.
Introducing
next generation
aldehyde traps
(1) Neuron Systems at founding, changed to Aldeyra Therapeutics at IPO (ALDX); (2) Furman 2019, Nature Med 10.1038/s41591-019-0675-0; (3) aka NS2, ADX-102; (4) Jordan et al., US Patent 7,973,025; (5) Mandell (2020) J Ocul Pharm Ther 10.1089/jop.2020.0056
Clinical proof
of concept
Higher potency,
oral availability,
CNS exposure
Most drugs have protein targets. Aldehyde traps have a novel design paradigm: small molecule drugs with small molecule targets. Their targets are lipid and oxysterol aldehydes that form when cell membranes and cholesterol are oxidized during inflammation. These toxins cause chemical damage that injures cells and amplifies inflammation.
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Inflammation is a complex process that involves hundreds of interacting genes (1). Briefly, it is triggered by microglial cells that act as sentinels by monitoring neighboring cells for distress due to infection, injury or disease. When they detect distress, they release two types of protein signals: chemokines that recruit white blood cells from circulation, and cytokines that activate inflammatory responses in the recruited cells, in the distressed cells, and in glial cells that sustain and amplify this signaling. Depending on where the distressed cells are located, this initiates neuroinflammation in the nervous system, visceral inflammation in organs or somatic inflammation elsewhere in the body.
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Inflammation evolved as a protective response that helps cells recover from distress and then shuts down. In some cases, however, it advances to chronic inflammation that injures or kills the distressed cells it evolved to protect. Chronic inflammation drives a broad range of diseases that cause lifetime disabilities and over 50% of global deaths (2). These include type 2 diabetes and metabolic syndrome, cardiovascular disease, autoimmune diseases and chronic kidney disease (3), and neurodegenerative diseases (4-6). Chronic inflammation is also associated with disabling conditions such as psychiatric disorders (7-8), brain fog following infection or immunotherapy (9-11), chronic pain and spinal and peripheral neuropathy (12-14), and retinal diseases that cause progressive blindness.
Inflammation is called a “canonical disease mechanism” because it contributes to so many different types of disease. Aldehyde traps are an “inflammation platform drug” because they are designed to treat this canonical disease mechanism in every inflammatory disease.
Novel design
paradigm
Inflammatory signaling
Inflammation
platform drug
(1) Zhao 2016 Molec Biosystems 10.1039/c6mb00240d; (2) Furman 2019, Nature Med 10.1038/s41591-019-0675-0; (3) Chen 2017 Oncotarget 10.18632/oncotarget.23208; (4) Cagle 2019 Curr Opin Toxicol 10.1016/j.cotox.2018.12.002; (5) Zhang 2023 Signal Transduc Targ Ther 10.1038/s41392-023-01486-5; (6) Giri 2024 Intl J Molec Sci 10.3390/ijms25073995; (7) Guo 2023 Transl Psychiatry 10.1038/s41398-022-02297-y; (8) Dunn 2020 Pharmacol Biochem Behav 10.1016/j.pbb.2020.172981; (9) Geraghty Cell 2025 10.1016/j.cell.2025.03.041; (10) Braga 2023 JAMA Psychiatry 10.1001/jamapsychiatry.2023.1321; (11) Monje & Iwasaki 2022 Neuron 10.1016/j.neuron.2022.10.006; (12) Albrecht 2018 Pain 10.1097/j.pain.0000000000001171; (13) Schomberg 2012 Annals Neurosci 10.5214/ans.0972.7531.190309; (14) Ellis & Bennett 2013 Br J Anaesth 10.1093/bja/aet128
Chronic
inflammation
Free aldehydes, the toxic targets of aldehyde traps, form naturally when stressed mitochondria leak superoxide, an unstable free radical of molecular oxygen. Superoxide converts rapidly to hydrogen peroxide, which oxidizes membrane lipids to lipid aldehydes such HNE, a clinical biomarker (1), and cholesterol to oxysterols (2) that isomerize to aldehydes. These aldehydes attack proteins and DNA, forming adducts that damage their structure, impair their function and injure cells (3,4). Lipid aldehydes surge a thousand-fold during inflammation (5), and as their concentrations increase, so does their chemical damage (6) that amplifies inflammation in positive feedback loops. This chemical damage is associated with all inflammatory and age-related diseases (7).
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The toxicities of free aldehydes are so harmful that we evolved a multi-tiered set of natural defenses to protect us from their chemical damage. These defenses consist of three different chemical classes: nucleophilic lipids, peptides, and proteins that include superfamilies of reducing enzymes and membrane transporters. Unfortunately they can be compromised by genetic variability, by their own susceptibility to chemical damage, and inactivated or overwhelmed at high concentrations (8).
Aldehyde traps supplement natural defenses by a distinct mechanism. They are not chemically damaged as free aldehydes surge, do not rely on protein activity, are not compromised by patient variability and are always active at full potency. They deactivate free aldehydes by two chemical reactions. The first reaction traps the aldehyde group and the second converts it to a safe reaction product that is rapidly cleared. In chemical terms, traps pull their targets into a thermodynamic sink as symbolized by the company logo, a Flamm paraboloid.
Free aldehydes cause
chemical damage
Natural defenses
can fail, but not
aldehyde traps
(1) Ellis & Bennett 2013 Br J Anaesth 10.1093/bja/aet128; (2) Sanotra 2022 Clin Biochem 10.1016/j.clinbiochem.2021.12.005;
(3) Kulig 2016 Chem Phys Lipids 10.1016/j.chemphyslip.2016.03.001; (4) Dasuri 2013 Free Radical Res 10.3109/10715762.2012.733003;
(5) Negre-Salvayre 2008 Br J Pharmacol 10.1038/sj.bjp.0707395; (6) Gladyshev 2021 Nature Aging 10.1038/s43587-021-00150-3;
(7) Zhang 2021 Arch Biochem Biophys 10.1016/j.abb.2020.108749; (8) Doorn 2006 Chem Res Toxicol 10.1021/tx0501839
Drug safety has been a top priority in the invention and development of the aldehyde trap drug class. This goal has been achieved, based on the high drug safety found in all preclinical and clinical studies to date. Traps act only where they are needed at sites with high levels of reactive aldehydes, their drug structures are hardened to block the formation of toxic metabolites during clearance, and their chemical reaction mechanisms have been calibrated carefully to avoid toxic off-target reactions. They have none of the serious and sometimes fatal side effects of other drugs that target the complicated gene and protein networks that mediate inflammation.
Traps cannot deplete biologically essential aldehydes, such as the aldehyde forms of vitamins A (retinaldehyde) and B6 (pyridoxal) which they are sequestered safely inside proteins where traps cannot reach them. As reviewed by the FDA (1), aldehyde traps have never caused any symptoms of vitamin A or B6 depletion in preclinical studies, even at maximum feasible dose (drug powder packed to full stomach capacity).
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Oculogics' next generation traps have over 500 times more potency in a validated neurocellular assay. Drug potency was increased by optimizing drug structures with computational methods of quantum mechanics (density functional theory, DFT) to achieve maximal chemical drive (free energy of reaction, ΔG) in the deactivation of drug targets.
Traps act safely
only where needed...
and with high
drug potency
(1) Jordan 2009 FDA IND #104497