ReN-1869

ReN1869 (NNC 05–1869) is a novel, selective H1 receptor antagonist that has been developed for analgesic purposes. In a first human dose administration study, the safety and pharmacokinetics of seven single oral doses in the range of 3.5 to 95 mg ReN1869 were studied. The study was a randomized, double‐blind, placebo‐controlled, dose‐escalating study in 56 healthy subjects. No serious or severe adverse events were reported. After active doses, an average of 0.6 adverse events (AEs) was reported per subject in comparison to 0.5 AEs per subject after placebo, and the frequency of subjects reporting AEs was not related to dose level. The most frequently reported adverse events were dizziness, fatigue, and somnolence, and their occurrence was not proportional to dose. Vital signs, ECG recordings, and clinical laboratory results showed no changes of clinical relevance. During telemetric monitoring at all dose levels until 4 hours after dosing, no clinically relevant abnormalities were observed. A maximally tolerated dose was not identified. ReN1869 was rapidly absorbed after dosing. The overall mean value of t1/2 and oral clearance was 4.7 hours and 11.7 L/h, respectively. The parameters Cmax and AUC increased proportionally with dose level, whereas all other pharmacokinetic parameters were independent of the dose. In conclusion, single‐dose administration of ReN1869 in doses up to 95 mg exhibited very few adverse events and no clinically relevant effects on any of the observed safety parameters. The pharmacokinetics points to simple first‐order pharmacokinetics for ReN1869. All together, it makes ReN1869 a potential new drug candidate for the treatment of chronic pain and inflammatory conditions of neurogenic origin.

Extensive pre-clinical investigations have shown that the tricyclic compound ReN1869 ((R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid, CAS 170149-99-2) is a potent H1-antagonist with pronounced antinociceptive properties. In this human phase-I trial the effect of different acute and multiple doses of ReN1869 on capsaicin induced neurogenic inflammation and hyperalgesia was investigated. Twenty-one healthy male subjects were enrolled in this randomised, double-blind, three-period, crossover trial design--consisting of acute and one week b.i.d. oral administration of 25 and 50 mg doses of ReN1869 and matching placebo--separated by 3 week washout periods. Capsaicin solution (1%) (INCI: Capsicum frutescens--containing capsaicinoides from Capsicum annuum annuum, CAS 84603-55-4) was applied in an occlusive mode for 30 min on the skin of the back in all three acute and subchronic medication periods to induce neurogenic inflammation. When the nociceptive laser pulses were applied to the capsaicin pre-treated skin, ReN1869 exerted a highly significant reduction of the pain response--as predominantly detected by suppression of the (central) P2-component in the laser-induced somatosensory evoked potentials (LSEPs) from Vertex-EEG. The primary efficacy endpoint, the N1/P2 peak to peak amplitude, was significantly reduced with the administration of ReN1869--primarily by a suppression of the P2-component of the LSEP. This suppression was dose-dependent and was more pronounced after a one week treatment (subchronic mode) with ReN1869 than after the first dose (acute mode). In contrast to the (central) P2-component there was no significant effect on the (peripheral) N1-component of the LSEPs taken from capsaicin-treated skin. As ReN1869 had no significant effect when the laser pulses were applied to normal skin, and the compound's effect was mainly restricted to the (central) P2-component, when LSEPs were taken from capsaicin treated skin, it can be concluded that ReN1869 exerts its positive effect to reduce capsaicin-induced hyperalgesia by a primarily central mechanism.