Abbott's Phase III success with its triple-lipid therapy ABT-335 added new color to a scientific panel's call for a return to statins, two of which were combined with the fenofibric-acid molecule - the next generation of Tricor - tested in almost 2,700 patients.

But results with ABT-335, which Abbott aims to market as TriLipix , did not impress Decision Resources analyst Donny Wong.

"I'm not surprised by any of the data I see here," he told "The Pink Sheet" DAILY, since statins do not improve triglyceride levels or HDL cholesterol much, but fenofibrates do.

A better test would match ABT-335 combined with statins against Tricor when used the same way, he said, though "it's not likely [Abbott] will do a head-to-head trial, because they could potentially be eating away at their own sales," Wong noted.

Abbott keeps rights to certain dosing methods, though Tricor has lost patent protection.

The late-stage news with TriLipix put an especially positive spin on the firm's efforts with London-based AstraZeneca to develop a single-pill, fixed-dose therapy pairing it with the latter's rosuvastatin, sold as Crestor (¹ Also see "Abbott, AstraZeneca To Combine Next-Generation Fenofibrate With Crestor In Phase III" - Pink Sheet, 31 August, 2007.).

Wong estimated such a drug could sell as much as $750 million annually - not much, considering the $28 billion market in lipid-lowering therapies as of 2006, but still important.

AstraZeneca had news with Crestor recently, stopping its JUPITER study early, after the drug reduced cardiovascular morbidity and mortality in patients with elevated C-reactive protein (² Also see "Stars Align For AstraZeneca In JUPITER Trial" - Pink Sheet, 31 March, 2008.).

When New York-based Pfizer's Lipitor (atorvastatin) goes off patent in the next few years, most statins other than Crestor will become available as generics.

For most patients, statins are enough to drop LDL cholesterol, the main goal in lipid therapy. "The market's becoming mature," Wong said.

Two Phase III studies with Abbot's drug met their primary endpoints, significantly improving HDL and triglycerides in patients with multiple blood-fat problems when combined with Lipitor and Zocor (simvastatin), from Whitehouse Station, N.J.-based Merck & Co., compared to statin therapy alone.

Data from the two studies were offered March 31 at the annual American College of Cardiology conference in Chicago, where a panel of scientists the previous day proposed a return to the use of statins in dyslipidema (³ Also see "ACC Meeting ENHANCE Panel Calls For Return To Statins" - Pink Sheet, 30 March, 2008.).

The panelists' opinion followed data from a study called ENHANCE that unexpectedly showed that the blockbuster Vytorin failed to stop the progress of atherosclerosis in patients with familial hypercholesterolemia.

Vytorin pairs Zocor with Zetia (ezetimibe), the cholesterol absorption blocker from Schering-Plough, of Kenilworth, N.J.

Using a stronger statin might beat an add-on drug's benefit

RBC Capital Markets analyst Phil Nalbone, in a March 31 research note, hailed TriLipix's "timely appearance" after ENHANCE data, but Wong said the media overplayed the trial's "failure."

Vytorin patients, Wong pointed out, already were taking Zocor - a very good and rather potent statin - and the situation that "makes it very difficult to look for any incremental benefit" from Zetia in what amounts to a "fairly niche population."

Also, ENHANCE was an imaging rather than outcome-based trial, he said.

"In reality, it was just inconclusive," Wong told the DAILY. "At the end of the day, were patients able to lower their LDL by adding Zetia? The answer to that is yes," but whether this knocked down their risk of heart attack and stroke remains unclear.

"Perhaps it's not just the level of LDL, but how you achieve it that makes the difference" in preventing serious cardiovascular trouble, Wong said. That is, using a more potent statin might provide a better outcome than adding Zetia to a weaker one.

Abbott Park, Ill.-based Abbott's two 12-week Phase III trials with TriLipix, reported at the ACC meeting, make up much of a three-study package that also includes a 52-week open-label extension study of 1,911 patients. The third study involved Crestor.

Those enrolled in the studies arrived with an LDL greater than 130 mg/dL and triglycerides greater than 150 mg/dL, with an HDL less than 40 mg/dL for men and less than 50 mg/dL for women.

The Lipitor and Zocor studies randomized 613 and 657 patients respectively to either TriLipix (135mg) combined with either 20mg or 40mg of the corresponding statin; TriLipix alone (135mg); or statin monotherapy (20mg, 40mg or 80mg).

Abbott included the 80mg statin monotherapy arm to judge safety and adverse events, but not in the statistical analysis, and all combinations beat monotherapies. More details - including those from the Crestor trial - will be disclosed in scientific forums during the year.

Though not thrilled by the TriLipix results known so far, Wong said Abbott is "in a good place" with its lipid portfolio.

Novel approaches to lipid lowering include Carlsbad, Calif.-based Isis Pharmaceuticals' mipomersen, the subject of a $1.9 billion licensing deal with Genzyme, of Cambridge, Mass.

The drug has "very potent effects, even on top of a statin background," Wong said. "The problem is, it's going to be injectable, very expensive, and likely to be approved for people with familial hypercholesterolemia."

Osaka, Japan-based Takeda had a "fairly promising" late-stage lipid therapy in TAK-475 (lapaquistat), Wong said. The firm stopped development March 28, about five months after FDA recommended suspending higher-dose trials (⁴ Also see "Takeda Discontinues Development Of Cholesterol Compound" - Pink Sheet, 28 March, 2008.).

- Randall Osborne (r.osborne@elsevier.com)

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