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Abstract Background

Oculogics can advance its 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 for IND approval, 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 cell membranes 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 would prevent them from initiating pain signaling in afflicted tissues, and with high drug safety because traps would not block pain sensitivity elsewhere in the body. These findings are consistent with the rapid pain relief seen in clinical studies of reproxalap in painful ocular inflammation.   

 

With their greater potency and high CNS exposure, next gen traps are expected to benefit patients suffering from chronic pain in multiple diseases associated with chronic inflammation.  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, degenerative disc disease, osteoarthritis, migraines, traumatic injuries, cancer including complications of radio or chemo therapy, and other painful diseases associated with inflammation. 

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

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). 

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

  • Complement activation consistent with CFH  gene variants 

  • Lipid aldehyde 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 lead to disabling cell losses in the retina (atrophic lesions) and corresponding losses in visual field (scotomas, blind spots).

Abstract Background

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:

  • 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.

  • 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?

  • Dual drug targets, by design

  • More effective in mice

  • No vitamin A deficiency

  • 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?

 

  • A treatment with only one target may have limited benefits.

  • 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. 

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