Chronic inflammation is now understood to be a canonical disease mechanism that drives a broad range of conditions including infectious diseases, metabolic disorders, and multiple forms of CNS degeneration and organ failure associated with aging.  As an inflammation platform drug, aldehyde traps have the potential to become a standard of care in every condition with complications of inflammation. 

Depending on the priorities of corporate partners or investors, Oculogics can advance its preclinical next generation aldehyde traps to the clinic in oral tablets, eyedrops or both within two years of external financing or program acquisition.  Each program can have its own funding, financial exit, target indication(s) and exclusive rights to one novel drug structure from our drug series.

A recent study by a Nobel laureate at UCSF showed that lipid aldehydes irreversibly activate the proteins in peripheral nerves that initiate pain signaling (Zhao 2020, Nature 585:141).  These new findings make chronic pain a promising treatment area for aldehyde traps because they deactivate the very same lipid aldehydes.  Traps will reduce pain signaling in afflicted tissues, with high drug safety because traps will not block pain sensitivity elsewhere in the body, and have no complications of addiction like opioid pain killers or GI bleeding like NSAIDs. 

The findings of Zhao et al. are consistent with (1) preclinical data in mouse models of inflammatory pain where reproxalap reduced pain by trapping lipid aldehydes, thereby blocking their activation of the proteins that initiate pain signaling; and (2) the rapid pain relief observed in clinical studies of reproxalap in a painful inflammatory eye condition. 

With their higher potency and CNS exposure, next gen traps are expected to give even greater pain relief to patients suffering from chronic pain in diseases associated with chronic inflammation and aging.  An oral IND application can be submitted to the FDA for either chronic pain per se or an indication associated with chronic pain, such as painful diabetic neuropathy, other forms of painful neuropathy, degenerative disc disease, osteoarthritis, migraines, traumatic injury, cancer including complications of radio or chemo therapy, and others.

As an inflammation platform drug, traps can also reduce complications of inflammation that are disabling but not painful.  Independent studies have shown that inflammation is a serious complication that advances disease progression in neurodegenerative brain diseases, cognitive and behavioral impairments in psychiatric disorders, painless peripheral neuropathy, cardiovascular disease, chronic kidney disease, and liver disease among others.

A next-gen aldehyde trap formulated in eyedrops can be advanced to an FDA IND application for topical treatment of dry eye, anterior uveitis and other painful inflammatory conditions in the front of the eye.  With their higher potency than reproxalap and greater drug safety than current treatments, they have the potential to become a clinical standard of care in a multi-billion dollar market.

Inflammation platform drugs have multiple development options

Abca4 retinopathies such as dry AMD and Stargardt disease are a special case where aldehyde traps have dual targets.  These diseases of progressive blindness are associated with inflammation and also the accumulation of toxic vitamin A dimers called A2E.  A2E accumulates abnormally in patients who have disease mutations in their Abca4 gene.  Its gene product is a membrane transporter that returns retinaldehyde, the aldehyde form of vitamin A, to the visual cycle if it escapes during opsin release in photoreceptors.  As A2E accumulates, it injures retinal pigment epithelial (RPE) cells next to the retina that provide essential metabolic support and triggers inflammation (1). 

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In addition to Abca4, these retinopathies are clinically associated with two complications of inflammation: 

• Complement activation consistent with CFH  gene variants 

• Lipid aldehyde and oxysterol toxicities consistent with the elevated levels of lipid aldehyde adducts found in donor eyes (2).  Lipid aldehydes amplify inflammation in a positive feedback loop (3).  

Together, RPE cell failure and chronic inflammation cause disabling cell losses in the retina (atrophic lesions) and corresponding losses in visual field (scotomas, blind spots).