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
1. Chronic pain secondary to inflammation
2. Painless but disabling complications of inflammation
3. Painful ocular inflammation
4. Dry AMD and Stargardt Disease
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:
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Complement activation consistent with CFH gene variants
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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).
There are no approved treatments for dry AMD or Stargardt disease whose etiology is multi-factorial, not monogenic. Recent experimental treatments target CFH with gene therapy or protein inhibitors, or use visual cycle inhibitors to induce a local vitamin A deficiency in the eye, because A2E is a retinoid dimer and with less retinaldehyde, less A2E can form.
Aldehyde traps use a novel mechanism to block A2E formation in Abca4 knockout mice (4) more effectively than visual cycle inhibitors and with much greater safety:
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Traps have dual targets in these diseases, by design: lipid aldehydes that injure cells and amplify inflammation (5), and free retinaldehyde that forms A2E. Visual cycle inhibitors have one target, proteins that regulate retinaldehyde delivery to the retina.
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Traps have no adverse effects on vision because of their mechanism of action, as reviewed by the FDA (6). Visual cycle inhibitors always cause night blindness and other visual losses in a dose dependent manner. Their side effects do not limit their drug efficacy in mouse studies. They do limit efficacy in patients because clinical doses are lowered to reduce safety risks and legal liabilities of the side effects. No side effects, no efficacy, due to their mechanism of action.
Why will aldehyde traps be better than visual cycle inhibitors?
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Dual drug targets, by design
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More effective in mice
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No vitamin A deficiency
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No side effects on vision
(1) Sparrow (2012), Prog Ret Eye Res 31:121; (2) Hu (2020), Redox Biol 37:101787 Fig 6B; see also Dhooge (2021), Redox Biol 45:101957; (3) Spite (2009), Br J Pharmacol 158:1062; (4) a validated mouse model of Stargardt disease invented by Dr. Gabriel Travis; (5) Spite (2009), Br J Pharmacol 158:1062; (6) Jordan (2009), FDA IND #104497; (7) Ahmad (2021), Aust Prescr 44:129
Convenient oral dosing
Drug delivery to the back of the eye is challenging because retinal drugs administered by eye drops have never shown clinical efficacy. Intravitreal injections are unpopular with patients, associated with risks and not ideal for an early onset genetic disease such as Stargardt disease.
The higher potency, oral availability and retinal exposure of our next gen traps now make oral dosing feasible for retinopathies associated with Abca4 and inflammation. Many oral drugs are known to reach the retina, as shown functionally by the efficacy of oral steroids and antivirals in certain retinal indications and by the retinal adverse effects of other oral drugs for non-ocular indications (7).
Which experimental treatment could be best for me?
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A treatment with only one target may have limited benefits.
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Combination therapy can be a wise treatment decision for a multi-factorial disease if both treatments are safe and have no adverse effects on vision.