At their previous company (1), the founders of Oculogics pioneered a new drug class called aldehyde traps to treat diseases associated with inflammation and aging. Aldehyde traps are small molecule drugs that are specifically designed to protect cells from chemical damage by lipid aldehydes and oxidized cholesterol that surge during inflammation secondary to disease or infection, and after traumatic injury or surgery.
The toxicities of lipid aldehydes and oxidized cholesterol are a new area of medicine. Their biology and chemistry are widely published but prior to invention of aldehyde traps, it was not possible to block their toxicities safely and potently in patients.
Reproxalap (2,3), the first-in-clinic aldehyde trap, was advanced to the clinic for topical use in an eye drop formulation. It achieved clinical proof of concept in a Phase 2 trial of anterior uveitis, a painful condition of ocular inflammation. With no adverse effects, topical 0.25% reproxalap safely matched the efficacy of topical 1% prednisolone, a steroid standard of care treatment with multiple safety risks (4).
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The inventors of aldehyde trap therapy are now developing a novel series of next generation traps at Oculogics with over 500 times more potency to treat a broader range of inflammatory diseases more effectively and either orally or topically, as appropriate.
Introducing
Next Generation
Aldehyde Traps
(1) Neuron Systems at founding, changed to
Aldeyra Therapeutics at IPO (ALDX)
(2) aka NS2, ADX-102
(3) Jordan et al., US Patent 7,973,025
(4) Mandell (2020), J Ocul Pharm Ther 36:732
Aldehyde traps deactivate naturally occurring toxins called lipid aldehydes that form spontaneously during inflammation by oxidation of cell membranes, and oxidized cholesterol (oxysterols) that form under the same conditions. Both targets are toxic because they chemically damage proteins, DNA and RNA (1). Chemical damage, a primary driver of aging (2), degrades cell function and can lead to cell death, which in turn amplifies inflammation in a positive feedback loop.
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The levels of these targets increase during aging (3) and can surge over 1000 fold during inflammation (4) which overwhelms natural defense mechanisms at inflamed tissue sites. Traps also deactivate a third target, a special class of free aldehydes in the eye which form ocular toxins that cause progressive blindness in multiple forms of retinal disease (5).
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Aldehyde traps deactivate their targets by trapping them and converting their aldehyde groups covalently 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.
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Traps do not deactivate biologically essential aldehydes because they are sequestered continuously inside proteins where traps have no access. As reviewed by the FDA (6), aldehyde traps have never caused any adverse effects to date in clinical and preclinical studies, even at maximum feasible oral dose, i.e. full stomach capacity in lab animals.
(1) Negre-Salvayre (2008), Br J Pharmacol 153:6; (2) Gladyshev (2021), Nature Aging 1:1096; (3) Zhang (2021), Arch Biochem Biophys 699:108749; (4) Dasuri (2013), Free Radic Res 47:8; (5) Sparrow (2012), Prog Ret Eye Res 31:121; (6) Jordan (2009), FDA IND #104497 and subsequent clinical study reports.
Most approved drugs have protein targets. Aldehyde traps are a novel paradigm in which small molecule drugs have small molecule targets, namely the lipid aldehydes and oxysterols that chemically damage proteins, nucleic acids and other biomolecules.
Mammals have evolved an extensive set of highly evolved defenses against chemical damage by free aldehydes. They consist of multiple superfamilies of reducing enzymes as well as small peptides and nucleophilic lipids (1). The scale, diversity, and metabolic cost of these defenses indicate how harmful these toxicities are.
Unfortunately, these defenses are not always reliable. Like all proteins, the enzymes that protect us from aldehyde damage can themselves be disabled by chemical damage (2) and their enzyme activity can inactivate as aldehyde concentrations increase (3). Moreover patients can differ in how protective their enzymes are because of genetics, medical history, aging, diet and lifestyle.
In contrast, aldehyde traps are not chemically damaged as lipid aldehydes surge, do not rely on protein activity, always retain their full potency and are not compromised by patient variability.
Novel design paradigm
Natural defenses against chemical damage by
free aldehydes
(1) Aldehyde dehydrogenases, alcohol dehydrogenases, aldo-keto reductases, glutathione/glyoxalases, glutathione S-transferases, glutathione peroxidases, glutathione reductases, glutaredoxins, superoxide dismutases, heme oxygenases, peroxiredoxins and thioredoxins; carnosine, a dipeptide enriched in muscle cells; and phosphatidylethanolamine, an amino lipid; (2) Negre-Salvayre (2008), Br J Pharmacol 153:6; (3) Doorn (2006), Chem Res Toxicol 19:102
Inflammation has two roles in disease. It can be a driver (primary cause) of some diseases, or a complication of others that increases patient distress and prolongs recovery. In either case, when inflammation becomes chronic, it can damage or even destroy the afflicted organ or tissue site. Moreover it can spread to other organs or tissue sites when pro-inflammatory signals are released at the afflicted site and circulate to other sites in blood vessels or cerebrospinal fluid.
Current drugs treat inflammation by suppressing its further activation, which is helpful in some cases but too weak or too dangerous (e.g., metabolic disease, cytokine storms) in others. Experimental drugs that attempt to stop inflammation by promoting its resolution by novel mediators (1) have failed in the clinic. Neither approach resolves the original cause of inflammation, nor does aldehyde trap therapy.
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Aldehyde trap therapy uses a different treatment approach. As lipid aldehydes and oxysterols surge, it protects cells and tissues from chemical damage with the efficay of steroids (2) but none of the safety risks. In doing so, it also suppresses multiple feedback loops that amplify inflammation by known mechanisms.
Chronic inflammation is a canonical disease mechanism that many diseases share in common, even when they differ in their detailed disease mechanisms and vary with patient age, genetics and other factors. Because of that, traps are an inflammation platform drug (3). The safety of aldehyde traps also allows patients to benefit from combination therapy, e.g. with another drug that targets specific disease mechanisms if such a drug is available.
(1) Schett (2018), Nature Comm 9:3261; (2) Mandell (2020), J Ocul Pharm Ther 36:732; (3) A drug that can treat different diseases that share an underlying mechanism of disease progression
Traps are an
inflammation
platform drug
The targets limit drug activity to inflamed sites
Traps block chemical damage by lipid aldehydes
By design, Oculogics' next generation traps have:
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over 500 times more potency in a validated neurocellular assay
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extremely high oral availability
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exemplary pharmacological properties
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high CNS exposure for treatment of neuroinflammation in age related diseases, or after brain or spinal injury or surgery.
Drug potency was achieved by optimizing drug structures with computational methods of quantum mechanics (density functional theory, DFT) for maximal free energy (ΔG) of drug-target reactions. Computational parameters are calibrated by experimental data and results in silico are predictive of results in cells and animal studies.
Higher drug potency increases treatment efficacy and broadens the potential use of aldehyde trap therapy. High drug potency also benefits topical delivery because most of the drug delivered in eye drops drains into nasal cavities which lowers the effective dose in the eye.
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All traps in this novel drug series are patentably distinct and share multiple branch points in their synthetic route to facilitate the efficient synthesis of different analogs for different indications or financial exits.
Next gen traps:
greater potency,
oral availability and
CNS exposure