Phase 2 Studies With Torcetrapib/Atorvastatin Combination
Quelle: http://www.medscape.com/viewarticle/518571
Linda Brookes, MSc
The results of two phase 2 studies involving torcetrapib that established, respectively, the optimal dose to be combined with atorvastatin for development in clinical trials and cast further light on the mechanism of action of the investigational drug were presented during the AHA's 2005 Scientific Sessions. Torcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor currently in phase 3 clinical trials as a combination product with atorvastatin. CETP is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from high-density lipoprotein (HDL)-cholesterol to apolipoprotein B-containing lipoproteins. Humans with CETP deficiency have elevated levels of HDL-cholesterol and apolipoprotein A-I (apo-A1) -- a finding that led to the hypothesis that inhibiting CETP might raise HDL-cholesterol levels. This was subsequently confirmed in animal models and in healthy humans with normal HDL-cholesterol levels.
Early phase 2 data on torcetrapib, published in April 2004,[1] showed that in subjects with lower levels of cholesterol (< 40 mg/dL), inhibiting CETP with torcetrapib 120 mg/day produced significant increases in HDL-cholesterol when given alone (46%) as well as in combination with atorvastatin (61%), while also reducing low-density lipoprotein (LDL)-cholesterol by more than that achieved with atorvastatin alone. When the dosage of torcetrapib was increased to 240 mg/day, HDL-cholesterol increased by > 100%. Combination therapy appeared safe and well tolerated.
Data from additional phase 2 studies in patients with low HDL-cholesterol alone, presented earlier in 2005 at the American College of Cardiology's annual scientific sessions, showed that torcetrapib, both alone and on a background of atorvastatin, markedly raised HDL-cholesterol, but that consistent LDL-cholesterol lowering with torcetrapib was only seen in the patients taking background atorvastatin.[2] This provided the rationale for development of a fixed-combination of torcetrapib and atorvastatin rather than of torcetrapib alone as a monotherapy or as add-on therapy to any statin, to provide optimal lipid treatment for the majority of dyslipidemic patients.
Dose-Ranging Study
The study that compared the efficacy and safety of different doses of torcetrapib and atorvastatin, alone or in combination, in patients with elevated LDL-cholesterol but no overt cardiovascular disease was pivotal in the decision to move forward into phase 3 with torcetrapib 60 mg plus atorvastatin 10-80 mg. The data were presented by Tom Thuren, MD, PhD (Pfizer Global Research and Development, New London, Connecticut).[3] The safety profile of the combination appeared to be similar to that of atorvastatin alone, except for a slight increase in blood pressure occasionally associated with torcetrapib alone or in combination. This was reversible by discontinuation of treatment and is being further investigated.
The 12-week, randomized, double-blind (torcetrapib only), placebo-controlled, parallel-group study was carried out at 57 centers in the United States. The design was a 2-way factorial with equal allocation to 1 of 20 once-daily treatment regimens: torcetrapib 0, 30, 60, or 90 mg and atorvastatin 0, 10, 20, 40, or 80 mg. Eligible subjects were men and women aged 18-65 years with a body mass index ≤ 35 who were on statin treatment or eligible for drug treatment based on National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-cholesterol criteria. Two thirds of the subjects had hypertension (JNC 7 criteria) controlled on drugs or diet. A total of 493 subjects were randomized, of whom 432 completed the study.
A change in HDL-cholesterol levels produced by torcetrapib therapy was already apparent at Week 2, and it remained stable until the end of the study. Torcetrapib alone raised HDL-cholesterol by 26%-67%. All torcetrapib/atorvastatin combinations produced significant increases in HDL-cholesterol by Week 12 compared with atorvastatin alone. (P < .0001) (Table 1). The combinations of torcetrapib 60 mg with atorvastatin 10-80 mg raised HDL-cholesterol levels by 44%-66% (P < .0001 vs baseline), described by Dr. Thuren as a "very robust" result.
Table 1. Mean Percent Increase in HDL-Cholesterol
Atorvastatin Dose (mg) Torcetrapib Dose (mg)
0 (%) 30 (%) 60 (%) 90 (%)
0 1 26 45 67 §
10 6 39 53 61 §
20 3 35 44 76 §
40 4 29 50 59 §
80 2 42 66 72
§
Torcetrapib alone had only a small impact on LDL-cholesterol compared with atorvastatin alone, but all the torcetrapib/atorvastatin combinations were associated with greater decreases in LDL-cholesterol compared with atorvastatin alone (Table 2). The combinations of torcetrapib 60 mg with atorvastatin 10-80 mg significantly decreased LDL-cholesterol levels by 41%-60% (P < .0001 vs baseline).
Table 2. Mean Percent Decrease in LDL-Cholesterol
Atorvastatin Dose (mg) Torcetrapib Dose (mg)
0 (%) 30 (%) 60 (%) 90 (%)
0 0 26 10 15 §
10 37 39 41 44 §
20 43 35 50 59 §
40 50 29 58 54 §
80 49 42 60 60
§
As expected, levels of apolipoprotein ± 00 (apo ± 00), a marker for LDL and very low-density lipoprotein (VLDL) cholesterol were not reduced by torcetrapib alone in those subjects with high triglycerides (> 350 mg/dL at baseline). However, reductions in apo ± 00 with torcetrapib/atorvastatin were not dependent on triglyceride levels. The mean LDL-cholesterol/HDL-cholesterol ratio decreased in a dose-dependent manner with each drug and with all the combination doses. Torcetrapib did not affect the ability of atorvastatin to lower triglycerides, so the combination lowered triglycerides by the same magnitude (18%-31% in this study). Although torcetrapib alone does not reduce triglyceride levels, it induces a triglyceride distribution shift, which it is believed changes the particles so that they become more antiatherogenic.
Safety
The overall safety pattern with the torcetrapib/atorvastatin combinations was similar to that of atorvastatin alone. Discontinuations due to treatment-related adverse events were low for all the torcetrapib doses (15 across all groups), and they resolved without further intervention. No increase was seen in rates of hepatic or musculoskeletal adverse events. The only additional adverse event associated with torcetrapib was a 0.8- to 5.2-mm Hg increase in systolic blood pressure (SBP) detected as early as 2 weeks. Pooling the data from all 10 phase 2 studies showed that subjects who received the 60-mg dose of torcetrapib had a 2-mm Hg mean increase in SBP, and about 4% of subjects had an elevation in SBP of ≥ 15 mm Hg or discontinued treatment due to elevated blood pressure. In the 3 studies that measured 24-h ambulatory blood pressure, the mean SBP increase with torcetrapib 60 mg was 2.7 mm Hg. This blood pressure effect will be characterized more thoroughly in phase 3.
Effect of Torcetrapib on Cholesterol Efflux
A separate multicenter, placebo-controlled, double-blind, phase 2 study, reported by Mark J Bamberger, PhD (Pfizer Global Research and Development, Groton, Connecticut),[4] investigated how CETP inhibition affects the efflux of cellular cholesterol. Human subjects with low or high HDL-cholesterol (male < 44 or ≥ 44 mg/dL, female < 54 or ≥ 54 mg/dL; 40 subjects per stratum) were randomized to treatment with either placebo or torcetrapib at 120 mg daily for 8 weeks. Torcetrapib produced increases of 42%-58% in HDL-cholesterol in all subjects. Ratios of free cholesterol and cholesteryl esters to apolipoprotein-AI increased significantly by 17%-24% (P < .0001 and P < .0001, respectively), consistent with formation of larger HDL particles.
Among the known mechanisms of cholesterol efflux, torcetrapib treatment resulted in a small but significant increase in efflux mediated by adenosine triphosphate-binding cassette transporter A1 (ABCA1), but scavenger receptor type B1 (SR-B1)-mediated efflux increased to a greater extent as a result of torcetrapib treatment and was highly correlated with HDL constituents, including phospholipid, cholesterol, and apo-AI.
These results demonstrate that partial inhibition of CETP with torcetrapib does not compromise, and may even enhance, the cholesterol efflux potential of HDL. Studies of the effect of torcetrapib on cellular cholesterol efflux mediated by ABCG1 are under way.
Ongoing Development of Torcetrapib/Atorvastatin
The combination product of torcetrapib 60 mg and atorvastatin 10-80 mg is now in phase 3 clinical trials as part of a global development program. A wide range of approximately 12,000 patients at cardiovascular risk will be enrolled in trials to demonstrate improved efficacy and comparable safety of the torcetrapib/atorvastatin combination vs atorvastatin alone, other statins, and fibrates. The program includes comparative atherosclerotic imaging trials involving coronary intravascular ultrasound (IVUS) and carotid ultrasound technology, as well as a full range of blood-lipid efficacy studies.
One of the first trials, which enrolled its first patient in 2003, is a multicenter randomized trial that is comparing atorvastatin/torcetrapib combination therapy with atorvastatin alone in preventing progression of coronary atherosclerosis as measured by IVUS in about 1100 patients with nonobstructive coronary heart disease (20%-50% stenosis). Patients first receive atorvastatin to lower plasma LDL-cholesterol levels before randomization to combination therapy or atorvastatin alone. The lead investigator is Steven E. Nissen, MD (Cleveland Clinic Foundation, Cleveland, Ohio). Dr. Nissen has been a leader in the development of IVUS and its application to the diagnosis of coronary artery disease and has been at the forefront of research into the causes and treatments of coronary artery disease.
An additional 13,000 patients from 250 sites in Australia, Europe, and North America are expected to complete the Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE) trial, which began enrollment in 2004. ILLUMINATE is a multicenter, double-blind, randomized, parallel-group evaluation of the effect of torcetrapib/atorvastatin (atorvastatin 10-80 mg) vs atorvastatin alone on the occurrence of major cardiovascular events in subjects with coronary heart disease or risk equivalents. The trial is expected to run for 4-5 years. |
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