Objective: TD-9855 is a novel NET inhibitor (1) being studied for the treatment of symptomatic nOH. The objective of the present study was to characterize the cardiovascular (CV) effects of TD-9855 in rats and relate them to plasma drug exposure and peripheral NET target engagement assessed through inhibition of tyramine pressor responses.

Background: nOH and its symptoms originate from sudden reduction in blood pressure that occurs upon standing and is caused by impaired activation of post-ganglionic sympathetic neurons innervating the vasculature. Augmentation of norepinephrine release at the vascular sympathetic neuroeffector junction, through inhibition of NET, is a potential approach for treating the symptoms of nOH in patients with primary autonomic failure (2).

Methods: Normotensive male Sprague Dawley rats were anesthetized with thiobutabarbital and instrumented to enable intravenous (IV) dosing and direct measurement of mean arterial pressure (MAP) and heart rate (HR). Following a stabilization period of 60 minutes, animals were dosed intraperitoneally with either vehicle or a single dose of TD-9855 (ranging from 0.01 – 30 mg/kg). The intrinsic CV effects of vehicle or TD-9855 were recorded for 25 mins. Each animal was subsequently challenged IV with bolus ascending doses of tyramine (ranging from 0.03 – 1 mg/kg) at 5 minute intervals. In a separate group of animals, blood samples were collected at 15 and 60 minutes post-TD-9855 dosing to assess drug exposure.

Results: TD-9855 produced dose-dependent increases in MAP and HR in anesthetized rats (peak changes from baseline were 13.2 mmHg and 28.1 bpm, respectively). At doses which evoked CV effects, TD-9855 also produced dose-dependent and complete inhibition of tyramine-induced pressor responses, consistent with NET target engagement. The plasma unbound TD-9855 concentration, at 60 mins post-dose, producing 50% inhibition of tyramine pressor responses was 0.86 nM (95% CI of 0.58 – 1.27) which is similar to the molecule’s potency for rat native NET (IC50 = 1.3 nM) and human recombinant NET (IC50 =2.5 nM).

Conclusions: The findings of this preclinical study are consistent with TD-9855 facilitating sympathetic neurotransmission in cardiovascular tissues via a NET inhibitory mechanism and support clinical investigation of this molecule as a potential therapy to treat symptomatic nOH.

References: 1. Smith et al. (2015). Int. J. Neuropsychopharmacology, 18: 1-11. 2. Ramirez et al. (2014). Hypertension, 64:1235-40.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preclinical-cardiovascular-sympathoexcitatory-effects-of-td-9855-a-novel-norepinephrine-transporter-net-inhibitor-in-development-for-the-treatment-of-symptomatic-neurogenic-orthostatic-hypotension/