At their previous company (1), the founders of Oculogics pioneered a novel treatment approach for inflammation called aldehyde trap therapy. Aldehyde traps are a new class of small molecule drugs that protect cells from harm caused by lipid aldehyde toxicities that surge during inflammation in disease and after surgery or traumatic injury.
Lipid aldehyde toxicities are a new area of medicine. Their biology and chemistry are well studied and widely published, but prior to aldehyde traps, it was not possible to block these toxicities in patients suffering from diseases associated with aging and inflammation.
Reproxalap (2,3 ), the first-in-clinic aldehyde trap, was advanced to the clinic for topical use in an eye drop formulation. Topical reproxalap recently met its primary endpoints in its Phase 3 registration studies in dry eye (4), a painful ocular condition associated with inflammation and aging. The FDA is now reviewing an NDA application for its commercial release. Topical reproxalap also matched the efficacy of prednisolone in another inflammatory ocular indication where steroids are a standard of care but with multiple safety risks (5).
The inventors of aldehyde trap therapy are now developing a novel series of next generation traps at Oculogics with over 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) www.aldeyra.com
(5) Mandell (2020), J Ocul Pharm Ther 36:732
Aldehyde traps deactivate naturally occurring toxins called lipid aldehydes which form spontaneously during inflammation as cell membranes are oxidized. They are toxic because they injure cells by attacking their proteins, DNA and RNA (1). These injuries degrade cell function and cause cell death, which then amplifies inflammation in a positive feedback loop. When lipid aldehydes are trapped, their toxicities are blocked.
Lipid aldehyde levels increase during aging (2) and can surge over 1000 fold during inflammation (3) which overwhelms natural defense mechanisms at inflamed tissue sites. Traps also deactivate another class of free aldehydes in the eye that form oular toxins which cause progressive blindness in multiple forms of retinal disease (4).
Aldehyde traps deactivate both targets by a potent chemical reaction that blocks their toxicities safely by trapping their harmful chemical group. Once trapped, the drug and its deactivated target are both cleared safely. In chemical terms, traps pull their targets into a thermodynamic sink as symbolized by the company logo, a Flamm paraboloid.
As reviewed by the FDA (5), 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) Zhang (2021), Arch Biochem Biophys 699:108749; (3) Dasuri (2013), Free Radic Res 47:8; (4) Sparrow (2012), Prog Ret Eye Res 31:121; (5) Jordan (2009), FDA IND #104497
As lipid aldehydes surge during inflammation, their concentrations can overwhelm the natural defense mechanisms that normally protect us against aldehyde toxicities. These defenses are extensive and highly evolved as they include a combination of superfamilies of reducing enzymes, small peptides and nucleophilic lipids (1).
The scale, diversity, and metabolic expense of these defense mechanisms indicate how harmful aldehyde toxicities are. Like all proteins, protective enzymes can be impaired by aldehyde attacks (2) and some inactivate as aldehyde concentrations increase (3). Patients can also differ in how protective their enzyme defenses are due to other factors which include aging, genetics, medical history, diet and lifestyle.
Aldehyde traps are designed to supplement these defenses potently and safely with no reliance on protein targets that can differ in patients. Such differences can compromise treatment efficacy when drugs target proteins.
(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
Novel Paradigm:
Small Molecule Drugs
with
Small Molecule Targets
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 are being developed to stop inflammation by promoting its resolution by protein and lipid cellular mediators (1,2), but clinical study results have been negative so far. Neither approach resolves the original cause of inflammation, nor does aldehyde trap therapy.
Aldehyde trap therapy uses a different treatment approach. As lipid aldehydes surge, it protects cells and tissues from aldehyde toxicities with the efficay of steroids (3) but none of the safety risks. In doing so, it supplements natural defense mechanisms against aldehyde toxicity that are overwhelmed or genetically impaired, and it suppresses feedback loops that amplify inflammation by multiple known mechanisms.
Aldehyde toxicities are so prevalent in inflammation that traps can treat a broad spectrum of inflammatory diseases even when their detailed mechanisms are disease specific (1) and vary with patient age, genetics and other factors. Aldehyde traps are an inflammation platform drug accordingly (4). The safety of aldehyde traps also allows patients to benefit from combination therapy, e.g. with another drug that resolves the original cause of inflammation if known and such a drug is available.
(1) Schett (2018), Nature Comm 9:3261; (2) Serhan (2018), J Clin Invest 128:2657; (3) Mandell (2020), J Ocul Pharm Ther 36:732; (4) A drug that can treat different diseases because they share an underlying mechanism of disease progression
High Drug Safety,
by Design
Inflammation
Platform Drug
The targets limit drug activity to inflamed sites
Higher drug potency and oral availability can increase the efficacy and broaden the potential use of aldehyde trap therapy. Oculogics is now extending its capabilities with a next generation drug series that has:
-
over 500 times more potency in a validated neurocellular assay
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oral or topical delivery as appropriate for each indication
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exemplary pharmacological properties
-
high CNS exposure for oral treatment of neuroinflammation in age-related diseases or following brain or spinal injury and surgery.
We achieved this increase in potency by optimizing drug structure with computational methods of quantum mechanics (density functional theory, DFT) that calculate the free energy (ΔG) of drug-target reactions. Our calculated ΔG results are predictive of experimental results in cellular assays and mouse studies.
High drug potency is important in both oral and topical delivery. For example, many studies have found that most of the drug in an eye drop drains into nasal cavities which lowers the effective dose to the eye.
All traps in our 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.
Improved Potency,
Oral Exposure and
CNS Penetration