New safety data on CETP inhibitor RO4607381/JJT-705
Data presented at the American College of Cardiology Scientific Sessions, Chicago, March 20-April show that the new cholesteryl ester transfer protein (CETP) inhibitor RO4607381/JJT-705 is well tolerated with no indication of any treatment-related increase in blood pressure. As well, experimental studies in an animal model show that RO4607381/JTT-705 had no impact on blood pressure or rennin-angiotensin system gene expression.
Clinical development of the first of the CETP inhibitors, torcetrapib was halted in early December 2006 following evidence from an interim analysis of a statistically significant excess mortality in patients treated with the combination of torcetrapib and atorvastatin in the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact on Atherosclerotic Events) trial.1 Analyses showed an excess of major cardiovascular events (464 vs. 373, hazard ratio 1.25; 95%CI 1.09 to 1.44, p=0.001) and deaths (93 vs. 59, hazard ratio 1.58; 95%CI 1.14 to 2.19, p=0.006) in the torcetrapib-treated group. The excess of deaths included both cardiovascular and non-cardiovascular causes. This was despite evidence that torcetrapib increased HDL cholesterol by 72% and decreased LDL cholesterol by 25% over and above values achieved by treatment with atorvastatin alone.1
Subsequent analyses showed that torcetrapib o increased systolic blood pressure by 5.4 mmHg, decreased serum potassium and increased serum sodium, bicarbonate and aldosterone (p<0.001 for all comparisons). These data suggest that torcetrapib may have activated the renin-angiotensin-aldosterone system (RAAS), and that these off-target effects contributed to the increased rate of major cardiovascular events and death observed in ILLUMNATE.1
These findings highlight the need for safety data and confirmation that other CETP inhibitors currently in development do not share similar off-target effects as torcetrapib.
RO4607381/JJT-705 is a new CETP inhibitor in clinical development. Previous reports have shown that this CETP inhibitor increases levels of HDL cholesterol in patients with type III dyslipidaemia treated with pravastatin.2
Due to concerns about cardiovascular safety concerns, data from five phase II trials in patients with dyslipidaemia and at high risk of coronary heart disease were evaluated.3 The data included were from 4 phase phase II trials in 546 patients with type II hyperlipidaemia and coronary heart disease (CHD) or CHD risk equivalents (one in which patients received RO4607381/JJT-705 300, 600 or 900 mg daily or placebo for 4 weeks and three in which patients received RO4607381/JJT-705 300 or 600 mg daily or placebo in combination with atorvastatin, pravastatin or simvastatin for 4 weeks). In addition, data from one trial in 292 patients with dyslipidaemia and low to average HDL cholesterol levels treated for 12 weeks were analysed separately. Patient characteristics were generally well matched across the treatment groups.
The incidence of adverse events was similar for placebo and RO4607381/JJT-705. Cardiac and vascular adverse events occurred with similar low frequencies across the 4-week studies (Table 1). Vascular adverse events reported were 3 cases of hypertension and one of aggravated hypertension in the placebo group and two cases each of hypertension or aggravated hypertension in the RO4607381/JJT-705 group.
In the 12-week trial, there was a similar low incidence of cardiac adverse events in active and placebo groups. Three patients experienced vascular adverse events, one on placebo (hypertension) and two on RO4607381/JJT-705 (one patient each with hypertension or peripheral artery aneurysm). Only palpitations experienced by one patient on RO4607381/JJT-705 was considered possibly related to treatment.
Table 1. Cardiac and vascular adverse events (AEs) with RO4607381/JJT-705, pooled analysis
| Placebo | 300 mg | 600 mg | 900 mg | |
| 4-week studies | N=203 | N=101 | N=192 | N=50 |
| Any AE | 86 (42.4) | 50 (49.5) | 80 (41.7) | 29 (58.0) |
| Cardiac AE | 8 (5.2) | 2 (3.8) | 7 (4.8) | N/A |
| Vascular AE | 4 (2.6) | 0 | 2 (1.4) | N/A |
| 12-week study | N=74 | N=76 | N=68 | N=74 |
| Any AE | 39 (52.7) | 36 (47.4) | 38 (55.9) | 40 (54.1) |
| Cardiac AE | 1 (1.4) | 4 (5.3) | 3 (4.4) | 3 (4.1) |
| Vascular AE | 1 (1.4) | 2 (2.6) | 0 | 0 |
As well, blood pressure remained stable throughout these studies.
These data were complemented by an experimental study using normotensive Wistar rats which do not express CETP and spontaneously hypertensive (SH) rats as animal models to investigate the haemodynamic effects of different CETP inhibitors (torcetrapib and RO4607381/JJT-705).4
The investigators measured mean arterial pressure (MAP) and systolic and diastolic arterial pressure in the rats during 5 days treatment with torcetrapib (10, 40 or 80 mg/kg/day) or RO4607381/JJT-705 (100, 300, or 500 mg/kg/day), or placebo. The mechanism of blood pressure increase was investigated by analysing the expression of genes involved in blood pressure regulation, i.e. the RAS genes.
Torcetrapib transiently increased systolic pressure in normotensive rats (by about 5 mmHg). In SH rats, torcetrapib treatment led to dose dependent increase in systolic and diastolic pressure, which was significant in those treated with a dose of 40 mg/kg (increases of 7.3 mmHg and 5.3 mmHg, respectively, p<0.05). However, there was no significant change in arterial pressure with any of the doses of RO4607381/JJT-705. Compared with placebo, MAP was increased by 7.8 mmHg on torcetrapib but by only 0.8 mmHg on RO4607381/JJT-705.
Torcetrapib treatment also led to increased expression of several of the key genes of the RAS, including those responsible for expression of angiotensinogen, angiotensin receptor-1, angiotensin converting enzyme and endothelin 1, in the adrenals and the aorta (Figure 1). These data suggest that off-target toxicity of torcetrapib appears to be mediated by the adrenal glands. In contrast, there was no significant change in RAS-related gene expression in any of the tissue samples taken from rats treated with RO4607381/JJT-705.
Taken together, these findings indicate that RO4607381/JJT-705 does not appear to share off-target effects of torcetrapib on blood pressure mediated by the RAS.
References
1. Barter P, Caulfield M, Eriksson M et al. Effects of torcetrapib on morbidity and mortality in patients at high risk for coronary events. New Eng J Med 2007;357:2109-22.
2. Kuivenhoven JA, de Grooth GJ, Kawamura H et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol 2005;95:1085-8.
3. Steiner, G, Kastelein JJ, Kallend D, Stroes ES. Cardiovascular safety of the cholesteryl ester transfer protein inhibitor RO4607381/JJT-705: results from Phase 2 trials. Presented at the 57th Annual Scientific Session of the American College of Cardiology, Chicago, March 29-April 1, 2008.
4. Stroes ES, Kastelein JJ, Benardeau A et al. Absence of effect of RO4607381/JJT-705 on blood pressure and tissue expression of renin-angiotensin system-related genes in rats. Presented at the 57th Annual Scientific Session of the American College of Cardiology, Chicago, March 29-April 1, 2008.
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