Mitigating free aldehyde toxicity:
A new approach for inflammation and inborn errors of aldehyde metabolism.
At Aldeyra, we’ve targeted aldehydes as a novel approach to the treatment of inflammatory conditions as well as rare diseases where genetic mutations lead to inability to metabolize aldehydes. Our first approach is to diminish aldehyde load with a novel platform of small-molecule traps.
Specifically formulated to lower free aldehyde levels, this platform of drug candidates offers broad therapeutic promise across diseases characterized by inflammation and genetic diseases caused by inborn errors of aldehyde metabolism. For these conditions, we believe the administration of our aldehyde trap therapies has the potential to treat, prevent, and slow the progression of disease.
Initial success with ADX-102: our lead compound.
In the first quarter of 2016, we announced positive data from our Phase IIa clinical trial of ADX-102 ophthalmic solution in patients with allergic conjunctivitis. Relative to baseline, the data indicated that ADX-102 clinically improved ocular itching and tearing scores after acute administration and after 14 days of dosing. These data represented the first time an aldehyde trap has demonstrated the potential to ameliorate human disease and suggest that aldehydes are important targets in inflammation.
In the second quarter of 2016, we announced positive data from our Phase II clinical trial of ADX-102 opthalmic solution in patients with noninfectious anterior uveitis. ADX-102 reduced cell count in a manner comprable to standard-of-care topical corticosteroids, which are effective but toxic, leading to glaucoma and cataracts in many patients. Together with the positive data in allergic conjunctivitis, these results suggest that ADX-102 could be active in a broad array of inflammatory ocular diseases.
Additional observations on tolerance and efficacy.
To our knowledge, Aldeyra’s aldehyde trap program represents the first concerted pharmaceutical effort to lower aldehyde levels. Aldehydes activate a number of intracellular inflammatory factors including NF-kB, a prominent protein in the inflammatory response. Our lead compound, ADX-102, has been shown to bind and trap aldehydes more rapidly than aldehydes bind cellular constituents, such as proteins, lipids, carbohydrates and DNA.
Evidence also suggests that, when ADX-102 binds to free aldehydes, the resulting covalent ADX-102-aldehyde adducts are found in lysosomes soon after formation where the adduct is degraded within hours. Outside the lysosome, the adduct is remarkably stable, meaning the ADX-102-aldehyde bond is essentially irreversible in vivo. This evidence clearly supports our characterization of ADX-102 as an aldehyde trap with the potential to substantially lower aldehyde levels.