TULIP: Novel CETP Inhibitor Appears Safe, Effective in Lowering LDL-C in Patients With Dyslipidemia

Deborah Brauser

August 04, 2015

AMSTERDAM, THE NETHERLANDS — The novel cholesterol esterase transfer protein (CETP) inhibitor TA-8995 (Dezima) may provide a safe and effective option for modifying lipids in adults with dyslipidemia, suggests new research[1].

TA-8995 in Patients with Mild Dyslipidemia (TULIP) is a phase 2 randomized, parallel-group trial of 364 total participants from Denmark and the Netherlands. It showed that LDL-C was reduced by 27% to 45% for those receiving TA-8995 in doses ranging from 1 mg to 10 mg for 12 weeks vs those receiving placebo.

The reduction were even greater when the drug was combined with statins. The participants receiving 10 mg of TA-8995 plus 10 mg of rosuvastatin (Crestor, AstraZeneca) had a mean reduction in LDL-C of 63% vs the placebo group, while those receiving 10 mg of the active drug plus 20 mg of atorvastatin had a mean reduction of 68% (both P<0.0001).

In addition, all doses of TA-8995 assessed significantly increased HDL-cholesterol levels (by 76% to 179%).

The researchers, led by Dr G Kees Hovingh (University of Amsterdam, the Netherlands), note that the findings show that this new CETP inhibitor is a "potent" treatment for this patient population—as monotherapy or with a statin. However, "the translation of the antiatherogenic potential of TA-8995 . . . warrants formal testing in a cardiovascular-outcomes trial."

The study was published in the August 1, 2015 issue of the Lancet.

Effective, Safe

In TULIP, dyslipidemic patients between the ages of 18 and 75 years (mean age 65 years) were enrolled at 17 sites between August 2013 and January 2014. All had fasting LDL-C levels from 2.5 to 4.5 mmol/L and HDL-C levels from 0.8 to 1.8 mmol/L. Their triglyceride concentrations were less than 4.5 mmol/L.

Nine randomly selected, treatment-based subgroups were created. This included those receiving 1, 2.5, 5, or 10 mg of TA-8995 once daily for 12 weeks or matching placebo. Other participants were randomly assigned to receive 10 mg of rosuvastatin or 20 mg of atorvastatin alone or with 10 mg of TA-8995. Each group included 40 or 41 patients.

The group receiving a 1-mg daily dose of the novel drug had a 27.4% mean reduction in LDL-C at the end of treatment vs the group receiving placebo. There were also reductions of 32.7% in the 2.5-mg–dose group and 45.3% in both the 5-mg and 10-mg–dose monotherapy groups compared with the placebo group (all P<0.0001).

A total of 95% of both the 5-mg and 10-mg groups were able to achieve LDL-C levels lower than 2.5 mmol/L at study's end, with 65% of the 5-mg group and 63% of the 10-mg group achieving levels lower than 1.8 mmol/L.

The group receiving only atorvastatin had a 45.4% decrease in LDL-C vs placebo, but the decrease was 68.2% when atorvastatin was combined with 10 mg of TA-8995. The reductions for rosuvastatin monotherapy and combined therapy were 45.3% and 63.3%, respectively.

HDL-C levels were increased by 75.8%, 124.3%, 157.1%, and 179% for the groups receiving 1, 2.5, 5, and 10 mg of TA-8995, respectively, vs placebo (all P<0.0001). Increases of 152.1% and 157.5% were found in the groups receiving TA-8995 plus atorvastatin or rosuvastatin, respectively.

Secondary efficacy measures showed significant increases in apolipoprotein A-1 (apoA-1) levels for all monotherapy doses of TA-8995 (from 31.2% to 63.4%). Significant decreases in apoB levels ranged from 20% to 33.7% for the monotherapy groups vs placebo; the decreases were 50.1% and 46.3% for those receiving TA-8995 plus atorvastatin or rosuvastatin, respectively.

There were no significant effects on blood pressure, aldosterone, or cortisol.

Of 127 adverse events reported, 122 were considered to be mild or moderate. Nasopharyngitis and headache were the most common events cited. None of the serious adverse events reported "were deemed treatment-related," report the investigators. "TA-8995 seems to be free of the adverse effects of torcetrapib."

PCSK9 Alternative?

In an accompanying editorial[2], Dr Kausik K Ray (Imperial College London, UK) and Dr Antonio J Vallejo-Vaz (St George's University of London, UK) note that the findings suggest the study drug is currently the "most potent CETP inhibitor"—and is comparable to data available for subcutaneous proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.

"This makes TA-8995 a potentially viable, and likely cheaper, oral alternative," write the editorialists. "If improvements in HDL function of roughly 37% do indeed contribute meaningfully to cardiovascular disease risk reduction, as suggested by recent epidemiology, then TA-8995 might just offer the medical community a powerful new compound . . . to further reduce [CV] disease."

Drs Ray and Vallejo-Vaz conclude that the "impressive" findings now warrant a phase 3 outcomes study. "If such a trial is successful, an ideal therapeutic agent could result."

The study was funded by Dezima and "undertaken by Xention." Hovingh reports institution funding from Dezima, Amgen, Pfizer, Sanofi, Regeneron, AstraZeneca, Genzyme, Cerenis, Synageva, Roche, ISIS Pharmaceuticals, Kowa, and Merck and consulting fees from Amgen, Pfizer, Roche, and Sanofi. Disclosures for the coauthors are listed in the article. Ray reports receiving honoraria from Roche and Lily. Vallejo-Vaz reports no relevant financial relationships.

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