DT120 (LYSERGIDE, LSD): ASSESSING THE POTENTIAL RISK OF CARDIAC VALVULOPATHY AFTER CHRONIC DOSING IN RATS

Background

DT120 (lysergide D-tartrate, LSD, MM120) is under development as a potential treatment for generalized anxiety disorder and major depressive disorder. DT120 may elicit profound changes through interaction with 5-HT2A, 2B, and 2C receptors, among others. Activation of 5-HT2B receptors is linked to changes causing the valvular heart disease. We studied the effect of administration of DT120 in several chronic studies in rats.

Methods

(Study 1) Male (M) and female (F) rats were dosed with 0, 0.5, 2 and 6 mg/kg daily (QD) or 6 mg/kg weekly (QW) for 13 weeks. (Study 2) M and F rats dosed QW with 0, 0.5, 2 and 6 mg/kg of DT120 for 26 weeks with a 4-week recovery. Toxicity (clinical observations, body weights (BW), food consumption (FC), clinical, anatomic pathology and toxicokinetics were assessed in both studies. At necropsy the heart was assessed macroscopically both externally and internally, having opened all four heart chambers, before fixation. The samples that included the atria and aorta were bisected to include the left atrioventricular valve and the aortic valve in the same plane. Hematoxylin and eosin-stained sections were examined microscopically and graded using a 5-point grading system from minimal to severe.

Results

(Study 1) Exposure of DT120, measured by maximum observed concentration (Cmax) and area under the concentration time curve (AUC0-24), generally increased and was dose proportional in F and < dose proportional in M, with Cmax achieving 108 ng/ml in M and 249 ng/ml in F 6 mg/kg QW group on day 85. QD dosing resulted in some accumulation, while QW did not. DT120-related changes in the BW were in animals in 6 mg/kg QD, but not in the QW group. Lower FC was in M in 6 mg/kg QD group. No DT120-related heart weight differences or macro-or microscopic findings were noted for animals administered 6 mg/kg/occasion QW, and no DT120 related findings were noted in the valves of animals administered 0.5, 2, or 6 mg/kg/occasion QD or QW. (Study 2) Following DT120 administration, LSD was measured in the plasma on Day 1, 29, 92, 155 (Group 4 females only) and 176. Sex differences in LSD Cmax and AUC0-24 values were generally > 2-fold, with higher exposure observed in F, compared with M. Exposure generally increased with the increase in dose with Cmax achieving 345 ng/mL in M and 112 ng/mL in F on Day 176 at 6 mg/kg. BW and FC were slightly changed in M and F in 6 mg/kg groups with full recovery. No DT120-related macro-or microscopic finding in the myocardium or the heart valves were recorded.

Conclusions

Following chronic QD and QW administration of DT120, no DT120-related heart weight or heart weight ratio differences, macroscopic or clear microscopic observations in the myocardium, aortic and mitral valves were noted. Together with the toxicokinetic results, these data provide no evidence of ventricular or valvular remodeling associated with prolonged administration of DT120 in rats.