A Randomized Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Trabodenoson in Healthy Adult Volunteers

Abstract

Purpose: To investigate the safety, tolerability, and pharmacokinetics of trabodenoson, a highly selective adenosine mimetic targeting the adenosine A1 receptor.Methods: In Part 1, 60 healthy adult volunteers were randomized to 14 days of twice-daily topical monocular application of placebo or trabodenoson (200, 400, 800, 1,600, 2,400, or 3,200 μg). In Part 2, 10 subjects were randomized to placebo or 8 escalating doses of bilateral trabodenoson (total daily doses: 1,800–6,400 μg).Results: The incidence of treatment-related adverse events in Part 1 was similar in the trabodenoson (27.8%) and placebo (25.0%) groups. Most were mild in intensity. The most common adverse events (AEs) for trabodenoson and placebo were headache (25.0% vs. 33%, respectively) and eye pain (11.1% vs. 4.2%, respectively). Ocular AEs were infrequent (16.7% and 17.9%, respectively), were self-limited, lasted <24 h, and were typically mild in intensity. The most common ocular AE was eye pain (9.5% and 3.6%, respectively), with a single observation of ocular hyperemia (200 μg trabodenoson). Trabodenoson was rapidly absorbed [median time to maximum concentration (tmax): ∼0.08 to 0.27 h] and eliminated (t½: 0.48–2.0 h), with no evidence of drug accumulation. Systemic exposure to topical trabodenoson was dose related but not dose proportional, with a plateau effect at doses ≥2,400 mg per eye. No clinically significant treatment-related systemic AEs were observed, and increasing systemic exposure had no effect on heart rate or blood pressure.Conclusions: Ocular doses of trabodenoson up to 3,200 μg per eye were safe and well tolerated in the eye and resulted in no detectable systemic effects in healthy adult volunteers.

Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome

“…[21][22][23][24][25] Trabodenoson is an adenosine receptor agonist with a strong selectivity for A 1 R, 30 and an established safety profile that has demonstrated exceptional tolerability, including no significant burning or stinging, and no clinically significant treatment-related systemic adverse events. 19 Data from the present study support the notion that preconditioning of the A 1 R is a feasible therapeutic strategy to reduce DED-associated ocular inflammation and exerts anti-inflammatory and cyto-protective effects on the lacrimal gland and conjunctival goblet cells.…”

“…Trabodenoson is well-tolerated without instillation pain or irritation associated with currently approved therapies. 19 In DED is a common ocular surface inflammatory disease that results in eye discomfort and visual disturbance and can affect a patient's quality of life. Two major types of DED, as identified by the International Dry Eye Workshop are aqueous-deficient dry eye and evaporative dry eye.…”

“…Therefore, we tested the efficacy of the A 1 R agonist, trabodenoson, in a preclinical mouse model for DED. We chose trabodenoson (INO-8875) given its established safety and pharmacokinetic profile that was tested in several clinical trials, including a randomized Phase I dose-escalation study in healthy volunteers 19 as well as a Phase II study in adults with primary open-angle glaucoma and ocular hypertension. 20…”

Novel therapies for glaucoma: a patent review (2013-2019)

“…In a preliminary Phase 1 dose escalation study in 60 healthy adult volunteers, it was shown to be safe and well tolerated up to 3.2 mg per eye with no detectable systemic effects (14 days of twice-daily topical monocular application). It lowers IOP by augmenting the primary outflow pathway for aqueous humor through the trabecular meshwork [15]. , although it seems to be present in the retina and the anterior eye.…”

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

“…A 3 agonists reduce AH flow by inhibiting chloride ion channels in ciliary epithelial cells [165]. An A 1 agonist in phase III trials has demonstrated favorable toxicity profiles, possible neuroprotective effects, and efficacious IOP lowering [166]. Receptor activation has also been shown to induce the secretion of MMPs, particularly MMP-2, probably the cause of reduced outflow resistance [167,168].…”