Novel HDL-Targeted Therapies -- The Search Continues

Linda Brookes, MSc

Disclosures

June 12, 2007

In This Article

The Hypercholesterolemia Study

A total of 304 patients (50% men; mean age, 54 years) participated in the hypercholesterolemia study. All patients had:

  • LDL cholesterol 100-160 mg/dL on statins or 130-190 mg/dL if statin-naive; and

  • No diabetes or coronary disease.

Baseline levels of total and LDL cholesterol were raised (average, 248 mg/dL and 164 mg/dL, respectively). Following a 4- to 6-week washout period, patients were randomized to receive placebo or atorvastatin 10 mg or 40 mg for 4 weeks, after which they were randomized to 12 weeks of active treatment with LY518674 10 mcg or 50 mcg.

The primary endpoint of this study was percent change in LDL cholesterol, which was reduced by both doses of LY518674 monotherapy ( Table 2 ). LY518674 monotherapy also reduced levels of triglycerides and increased HDL cholesterol levels.

When added to either atorvastatin dose, LY518674 at both doses produced additional reductions in triglycerides and additional increases in HDL cholesterol, but did not produce any significant further reductions in LDL cholesterol beyond that produced by atorvastatin alone ( Table 3 ).

LY518674 and fenofibrate were generally well tolerated in both studies, but both drugs raised some safety concerns. In the dyslipidemia study, LY518674 (50 mcg and 100 mcg) and fenofibrate increased serum creatinine levels among patients with dyslipidemia, and many patients (31.4% to 38.0%) had increases in serum creatinine above the upper limit of normal. In the hypercholesterolemia study, 16.7% of patients on atorvastatin 40 mg plus LY518674 had alanine aminotransferase (ALT) levels 1.5-4 times the upper limit of normal.

"These results demonstrate the challenges in developing new PPAR agonists as therapeutic agents," said Dr Nissen. "The beneficial effects of PPAR activation appear to be associated with a variety of untoward effects, which may include oncogenesis, renal dysfunction, rhabdomyolysis, and cardiovascular toxicity. The promise of PPAR agonists stems primarily from the hope that more active agonists would produce more robust benefits. However, the current pair of studies do not support this hypothesis. Despite a potency approximately 10,000 times greater than fenofibrate and greater selectivity, LY518674 did not produce more favorable effects on lipoproteins compared with fenofibrate."

Early Phase 1 Study

Data from an earlier study of LY518674 showing that the agent reduces triglycerides, total cholesterol, LDL cholesterol, and ApoB and ApoC-III were presented at the meeting by Daniel C. Howey, MD (Eli Lilly, Indianapolis, Indiana).[4] The phase 1, randomized, placebo-controlled, dose-escalation study was carried out in 69 mildly obese (mean body mass index 31) but otherwise healthy subjects who were administered single and multiple doses of LY518674. Dose selections were based on safety assessments consisting of physical exams, subject interviews, and laboratory tests from prior doses. During single dosing, 32 subjects received placebo or LY518674 0.1 mcg, 1 mcg, 10 mg, 30 mcg, or 60 mcg. During multiple dosing, 35 subjects received placebo or LY518674: 0.025 mcg, 0.1 mcg, 1 mcg, or 10 mcg daily for 14 days.

Following the 30-mcg single dose, mild gastrointestinal symptoms occurred that increased in frequency and severity following 60 mcg. LY518674 affected fasting triglycerides and postprandial triglycerides in a dose-responsive fashion from 24 to 36 hours after administration. The maximum effect occurred between 1 mcg and 10 mcg. During multiple dosing, LY518674 was well tolerated up to 1 mg. After thirteen 10-mcg doses, 1 subject experienced rhabdomyolysis, detected by routing safety monitoring.

Blood pressure was reduced by 10% without orthostasis or symptoms. Blood pressure lowering was similar in both the earlier (2-12 hour post-dose) and later (16- to 24-hour postdose) periods of the day, consistent across all doses. This blood pressure effect was not seen in the phase 2 studies and could not be repeated in healthy volunteers, Dr. Howey reported.

LY518674 at doses up to 0.1 mcg reduced triglycerides up to 45.7%, total cholesterol up to 23.5%, LDL cholesterol by up to 28.6%, ApoB by up to 24.9%, and ApoC-III by up to 43.5%. ApoA-II showed a dose-response increase by 44.6% at 1 mcg/day. There was no effect on HDL or ApoA-I after 14 days.

A post hoc analysis of the increases in LDL cholesterol levels seen with LY518674 in the phase 2 atherogenic dyslipidemia study and in the phase 1 study showed that they correlated with baseline triglyceride levels. Baseline triglycerides were high in this study, whereas in the hypercholesterolemia study they were less high and LDL cholesterol was reduced by LY518674. Commenting on these results, Dr. Nissen noted that these increases in LDL cholesterol produced by LY518674 are clearly undesirable, and increases in ApoA-II, as seen in both studies, have been linked to adverse cardiovascular outcomes.

Dr. Howey noted that the future of LY518674 had not been decided by Eli Lilly at that time. "The drug has a very clean safety profile and there are still some clinical trials pending," he said. Another phase 2 study with LY518674 was completed in 2006 and is under analysis at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Daniel Rader, MD, and other investigators studied the effects of LY581674 100 mcg/day vs placebo for 8 weeks in 40 subjects with the metabolic syndrome. They also examined the effects on biomarkers of reverse cholesterol transport.

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