Thyroid hormone beta receptor activation has additive cholesterol lowering activity in combination with atorvastatin in rabbits, dogs and monkeys

Abstract

Background and purpose: Thyroid hormone receptor (TR) agonists are in clinical trials for the treatment of hypercholesterolaemia. As statins are the standard of clinical care, any new therapies must have adjunctive activity, when given in combination with statins. As already known for the statins, the cholesterol lowering effect of TR activation involves increased expression of the low-density lipoprotein receptor. Using animal models, we tested whether TR activation would have additive cholesterol lowering activity in the presence of effective doses of a statin.

Experimental approach: We evaluated the activity of a liver-targeted prodrug, MB07811, of a novel TH receptor beta agonist, MB07344, as monotherapy and in combination with atorvastatin in rabbits, dogs and monkeys.

Key results: In rabbits, MB07344 (i.v.) decreased total plasma cholesterol (TPC) comparable to that achieved with a maximally effective dose of atorvastatin (p.o.). The addition of MB07344 to atorvastatin resulted in a further decrease in TPC. Similarly, the addition of MB07811 (p.o.) to atorvastatin treatment decreased TPC beyond the level achieved with either agent as monotherapy. In dogs and monkeys, atorvastatin and MB07811 were administered as monotherapy or in combination. Consistent with the rabbit studies, the combination treatment caused a greater decrease in TPC than either MB07811 or atorvastatin administered as monotherapy.

Conclusions and implications: We conclude that the effects of MB07811 and atorvastatin in lowering cholesterol are additive in animals. These results would encourage and support the demonstration of similarly improved efficacy of combination versus monotherapy with such agents in the clinic.

Figure 1

Dose-dependent effect of oral atorvastatin (AT) in normal rabbits. (A) Rabbits (n = 5 per group) on a normal chow (NC) diet. Shown are average total plasma cholesterol (TPC) values at baseline and following 2–3 weeks of treatment. The decrease in TPC produced by atorvastatin was similar at doses of 0.3 to 3 mg·kg⁻¹·day⁻¹. Values are mean ± SEM. *P < 0.05 for treatment vs. baseline.

Figure 2

Evaluation of activity of MB07344 as monotherapy and in combination with atorvastatin in normal rabbits. (A) Protocol scheme: Figure depicts the treatment timeline for the four experimental groups. In the combination group, adjunctive MB07344 treatment was added to atorvastatin after 2 weeks of atorvastatin treatment. (B) Average TPC in the vehicle control, atorvastatin alone and atorvastatin + MB0344 groups over the course of the protocol. Atorvastatin as monotherapy resulted in a significant (*P < 0.05) and stable reduction in TPC. The administration of MB07344 as an adjunct to atorvastatin starting at 2 weeks in the combination group resulted in a significant further decrease in TPC (**P < 0.05 vs. atorvastatin alone). Values are mean ± SEM. (C) Average TPC in the MB07344 monotherapy group: MB07344 treatment was associated with a significant reduction in TPC compared with baseline levels (*P < 0.05). Also depicted are the data for the Vehicle Control group for comparison. Values are mean ± SEM.

Figure 3

Activity of MB07811 on TPC in normal rabbits: average TPC data (% of baseline) in rabbits on normal chow in the vehicle and MB07811-treated groups. Oral MB07811 (10 mg·kg⁻¹·day⁻¹) resulted in a significant (*P < 0.05) reduction in TPC within 2 weeks of treatment. Values are mean ± SEM.

Figure 4

Additive effect of MB07811 in combination with atorvastatin in normal rabbits. Average % decrease in TPC from baseline in the MB07811 monotherapy group, and the atorvastatin ± MB07811 combination group (with atorvastatin alone and with MB07811 added). In the combination group, atorvastatin treatment alone resulted in a significant decrease in TPC (*P < 0.05 vs. baseline) which was further significantly decreased with the addition of MB07811 (**P < 0.05 vs. atorvastatin alone). Values are mean ± SEM.

Figure 5

Effect of atorvastatin and MB07811 in hypercholesterolaemic rabbits. (A) Effect of atorvastatin in hypercholesterolaemic rabbits on a 0.2% cholesterol diet. Shown are average TPC values of hypercholesterolaemic (HC) rabbits at baseline and after 6 weeks of treatment with various doses of atorvastatin. Animals in the atorvastatin (6–3) group did not tolerate the 6 mg·kg⁻¹·day⁻¹ dose and were switched to 1 mg·kg⁻¹·day⁻¹ for days 6–11 and then to 3 mg·kg⁻¹·day⁻¹ from day 11 to the end of the study. (B) Effect of MB07811 in hypercholesterolaemic rabbits on a 0.2% cholesterol diet. MB07811 treatment was associated with a significant reduction in TPC (*P < 0.05). Values are mean ± SEM.

Figure 6

Additive effect of MB07811 in combination with atorvastatin in normal dogs. (A) Animal-by-animal (n = 12) serum cholesterol at pre-dose (pre) and following 7 days of treatment (post) with MB07811, atorvastatin or atorvastatin + MB07811 in combination. Combined treatment resulted in a marked decrease in cholesterol regardless of baseline values in all animals. (B) Data shown are the average (n = 12) % changes in serum cholesterol following 7 days of treatment (post) compared with pre-dose levels taken just prior to the first dose of each cycle. Both MB07811 and atorvastatin given as monotherapy resulted in significant decreases in cholesterol compared with pre-dose levels (*P < 0.01). Notably, the combination treatment resulted in a significantly greater decrease in cholesterol compared with either MB07811 or atorvastatin given alone (**P < 0.01). Values are mean ± SEM.

Figure 7

Activity of MB07811 and atorvastatin as monotherapies and in combination in normocholesterolaemic monkeys. (A) Dose-response effects of MB07811 and atorvastatin. Both agents resulted in dose-related decreases in serum cholesterol after 7 days of treatment (*P < 0.05 vs. pre-treatment baseline). (B) Average pre- and post-treatment serum cholesterol in the three experimental groups. For all groups, post-treatment values were significantly decreased versus the pre-treatment level (P < 0.05). (C) Cholesterol levels expressed as % change from baseline. There was a significant decrease in cholesterol in the combination group compared with that achieved with either the MB07811 or atorvastatin monotherapy (*P < 0.05). Values are mean ± SEM.