RASP (reactive aldehyde species) sequestering agent
- Aldehydes (e.g., malondialdehyde, 4-hydroxynonenal): ADX-102 covalently binds to these aldehyde species. [1]
Reproxalap sequesters reactive aldehyde species that are elevated under inflammatory conditions . RASP enhance NF-κB, inflammasome upstream pro-inflammatory signaling cascades by binding to amino and thiol groups on receptors and kinases, and can also bind to phosphatidylethanolamine, a key component for maintaining ocular surface moisture . By reducing pro-inflammatory RASP levels, reproxalap reduces PKCα activity and blocks caspase 3/7 activation .

ADX-102 is a novel small molecule that covalently binds aldehydes, including malondialdehyde and 4-hydroxynonenal, which have been shown to mediate inflammatory pain.[1]

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Reproxalap protects cells from the cytotoxicity of C18:0-al. In vitro, the compound reduces PKCα activity and blocks caspase 3/7 activation, thereby exerting anti-inflammatory and pain-relieving effects . Reproxalap has demonstrated the ability to trap free aldehydes, diminish inflammation, and protect key cellular constituents from aldehyde damage .

- In a carrageenan-induced acute inflammatory pain mouse model, ADX-102 mediated dose-dependent reductions in nociceptive behavior. [1]
- In a Complete Freund's Adjuvant (CFA)-induced acute inflammatory pain mouse model, ADX-102 mediated dose-dependent reductions in nociceptive behavior. The data imply that ADX-102 may differentially affect thermal and mechanical pain pathways. [1]
- In a Phase 2b clinical trial for dry eye disease (January – July 2018), reproxalap ophthalmic solutions demonstrated statistically significant improvements versus vehicle across multiple symptom and sign measures. Improvements in symptoms and signs were observed as early as two weeks. [2]
- In the Phase 2b trial, reproxalap (0.25%) improved the ocular dryness score (OD & 4-Symptom Questionnaire, scale 0-5) compared to vehicle in the total population (baseline average score = 3.1) and in the above-median baseline population (baseline average score = 3.6). [2]
- In the Phase 2b trial, reproxalap (0.25%) improved the overall ocular discomfort score (0-5) compared to vehicle in the total population (baseline average = 2.9) and above-median baseline population. [2]
- In the Phase 2b trial, reproxalap (0.25%) improved the ocular stinging score (0-5) compared to vehicle in the total population (baseline average = 1.4) and above-median baseline population. [2]
- In the Phase 2b trial, reproxalap (0.25%) improved the fluorescein staining score (nasal, 0-4) compared to vehicle in the total population (baseline average = 1.9) and above-median baseline population (baseline average = 2.3). Responder analyses demonstrated statistical superiority of reproxalap over vehicle for staining improvement and for combined improvement of both ocular dryness and staining. [2]

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In the CFA-induced pain model, treatment with 100 mg/kg QD or 100 mg/kg BID ADX-102 resulted in statistically significant reductions in thermal hypersensitivity as measured by the Hargreave’s plantar test (Figure 1). Only the 100 mg/kg BID dose of ADX-102 showed an effect on mechanical sensitivity, as assessed by the Von Frey force test (Figure 2). Paw thickness, a measure of swelling, showed a modest effect at the 30 and 100 mg/kg BID doses (Figure 3).[1]

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In the carrageenan-induced pain model, ADX-102 treatment resulted in statistically significant reductions in thermal hypersensitivity at ADX-102 doses of 30 mg/kg BID and 100 mg/kg BID (Figure 4), but did not affect mechanical hypersensitivity (Figure 5). Paw thickness, a measure of swelling, showed a modest effect at the 100 mg/kg QD dose (Figure 6). There were no changes in body weight as a result of treatment in any group.[1]

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In animal models, by blocking RASP, reproxalap has been shown to inhibit Th1- and Th2-mediated inflammation . In Phase III clinical trials for dry eye disease, patients receiving reproxalap showed significant reduction in ocular redness just 10 minutes after entering a dry eye chamber compared to vehicle control, with effects sustained through the last measured time point (90 minutes) . Among 132 participants, reproxalap was statistically superior to vehicle for relieving ocular discomfort (P=0.004), with 70% of patients showing response to reproxalap . Reproxalap also significantly reduced ocular redness and increased Schirmer scores (a measure of tear production) in patients .

The effect of ADX-102 on acute inflammatory pain was tested in the carrageenaninduced and Complete Freund’s Adjuvant (CFA)-induced models in mice [1].

Reproxalap has a molecular weight of 236.07, XLogP of 2.27, topological polar surface area of 59.14 Ų, 3 hydrogen bond acceptors, 2 hydrogen bond donors, 1 rotatable bond, and breaks 0 Lipinski's rules . In clinical studies, reproxalap is administered topically as a 0.25% ophthalmic solution, with rapid onset of action observed as early as 10 minutes after administration . Cross-over and parallel clinical trials evaluated efficacy data ranging from minutes to up to 12 weeks post-administration . Storage conditions: Powder is stable for 3 years at -20°C and 2 years at 4°C; solutions are stable for 6 months at -80°C and 1 month at -20°C .

- In the Phase 2b dry eye disease clinical trial (0.1% and 0.25% reproxalap ophthalmic solutions), no observed safety concerns were reported, and the drug was generally well tolerated. Predominantly mild instillation site irritation was reported. Discontinuation rates: 3/100 (3%) for 0.1% reproxalap, 12/100 (12%) for 0.25% reproxalap, and 1/100 (1%) for vehicle. These rates are consistent with recent Phase 2 dry eye disease clinical trials. [2]

[1]. Susan Macdonald, et al. ADX-102, a novel aldehyde trap, reduces nociceptive behavior in mouse models of carrageenan and CFA induced pain.https://ir.aldeyra.com/static-files/527c5795-0792-4322-9f47-69c79879415a
[2]. Reproxalap Phase 2b Dry Eye Disease Results.https://ir.aldeyra.com/static-files/c642ef41-fe14-47d1-ba0e-d2b6a90f6a57

- ADX-102 is a novel aldehyde trap that covalently binds aldehydes such as malondialdehyde and 4-hydroxynonenal, which mediate inflammatory pain. Aldehyde signaling represents a novel therapeutic target for pain treatment. [1]
- In the Phase 2b dry eye disease trial, the primary objective was achieved: endpoint selection and sample size powering were confirmed for Phase 3 clinical trials. The pathway to registration trials was confirmed with ocular dryness symptom score, ocular staining score, and 0.25% reproxalap dose. Aldeyra plans to discuss results with regulatory authorities and expects to initiate Phase 3 clinical trials in 2019. [2]
- Reproxalap has a novel mechanism of action with the potential to address the two major forms of dry eye disease. [2]
- Current prescription options for dry eye disease may take up to six weeks or longer to have an effect, whereas reproxalap showed early and consistent symptom improvements in Phase 2b trial. [2]
- Reproxalap is in late-stage development for dry eye disease and allergic conjunctivitis – two medical conditions with significant overlap. Anticipated milestones: dry eye disease Phase 3 program initiation in 2019; allergic conjunctivitis ALLEVIATE Phase 3 trial results in late 2018/early 2019. [2]
- Pipeline: Reproxalap ocular is in Phase 2/3 for dry eye disease, allergic conjunctivitis, and noninfectious anterior uveitis. Reproxalap dermal is in Phase 3 for Sjögren-Larsson Syndrome. [2]

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Reproxalap (formerly known as ADX 102 or NS-2) is a small molecule inhibitor developed by Aldeyra Therapeutics. It is currently being investigated for its efficacy in treating dry eye, allergic conjunctivitis, non-infectious anterior uveitis, and Sjögren-Larsson syndrome. NS-2 was granted orphan drug designation for its research in the treatment of Sjögren-Larsson syndrome.

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Mechanism of Action
Reproxalap inhibits reactive aldehydes (RASPs) and is currently being investigated for its efficacy in treating dry eye, allergic conjunctivitis, non-infectious anterior uveitis, and Sjögren-Larsson syndrome.

C12H13CLN2O

236.697421789169

236.071

C, 60.89; H, 5.54; Cl, 14.98; N, 11.84; O, 6.76

916056-79-6

16088030

Typically exists as Light yellow to yellow solid at room temperature

2.4

2

3

1

16

259

0

CC(C)(C1=C(C=C2C=C(C=CC2=N1)Cl)N)O

GUHFUVLKYSQIOQ-UHFFFAOYSA-N

InChI=1S/C12H13ClN2O/c1-12(2,16)11-9(14)6-7-5-8(13)3-4-10(7)15-11/h3-6,16H,14H2,1-2H3

2-(3-amino-6-chloroquinolin-2-yl)propan-2-ol

NS-2; NS2 NS 2; ADX-102; Reproxalap; 916056-79-6; 2-(3-amino-6-chloroquinolin-2-yl)propan-2-ol; ADX-102; Reproxalap [USAN]; NS-2; ALD-102; F0GIZ22IJH; ADX102; ADX 102,

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~422.48 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (10.56 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)