If those who do not learn from the past are condemned to repeat it, then Roche's extensive study of Pfizer's torcetrapib is the Swiss firm's attempt to avoid a repeat of the first cholesterol ester transfer protein inhibitor's performance.

Roche used the recent American College of Cardiology Scientific Sessions in Chicago to publicize data characterizing - and contrasting - torcetrapib and Roche's CETP inhibitor, R1658, in conjunction with the initiation of a Phase III outcomes trial.

"I would like to emphasize the message that our CETP inhibitor is a unique CETP," Roche's Life Cycle Leader for R1658 Fouzia Laghrissi-Thode told an April 2 teleconference. "The compound is clearly different from torcetrapib or any torcetrapib-related CETP inhibitors," she said.

Climbing Out Of Pfizer's Hole

Torcetrapib's failure left deep psychological wounds for the CETP inhibitor class. Pfizer had positioned the CETP inhibitor as a future blockbuster, supported by one of the most expensive clinical trials ever conducted. It was also the bedrock of the firm's evergreening strategy for the mega-blockbuster statin Lipitor (atorvastatin), which loses exclusivity in June 2011.

So when signs of elevated blood pressure and associated cardiovascular mortality resulted in the late 2006 termination of Pfizer's 15,000-patient ILLUMINATE trial (and torcetrapib development in general), the rest of the industry scrambled. Other CETP inhibitor programs were halted as sponsors scrutinized the torcetrapib situation.

Roche, which licensed R1658 (then JTT-705) from Japan Tobacco, and Merck are the only players left standing in the CETP arena. Both companies have made serious PR-style efforts to restore confidence in the class. Merck devoted a portion of its Dec. 11, 2007 R&D meeting to addressing torcetrapib's flaws and building up its own anacetrapib (¹ Pharmaceutical Approvals Monthly January 2008, p. 13), while Roche took a strong and public stand with a sideline event at the ACC meeting, with similar aims.

One troubling aspect of the legacy that torcetrapib left for the rest of the class is that it had paradoxical effects: as expected, the Pfizer drug raised HDL or "good" cholesterol, but at the same time it failed to affect atherosclerosis (the clinical improvement for which HDL elevation is thought to be a surrogate). This called into question the rationale behind development of new molecules designed to attack the HDL half of the cholesterol equation.

Still Trying To Rally Support For HDL Strategy

Speaking at Roche's ACC event, Roche R1658 advisor Philip Barter, director of the Heart Research Institute in Sydney, Australia, noted that the evidence of a protective effect of HDL in humans is strongly circumstantial. "We do know that treatment with drugs that raise HDL, such as niacin or fibrates, are associated with a slowing of progression of coronary heart disease and a reduction in cardiovascular events, but that doesn't tell us that it's HDL because these drugs have other effects that may contribute to the benefit."

The torcetrapib ILLUMINATE trial was "the first of the studies testing this [benefits of targeted HDL raising] hypothesis in humans," Barter said.

Torcetrapib "raised the HDL dramatically, it had additional lowering of LDL and, unfortunately, had no effect on atherosclerosis in three imaging trials," Barter said. "And in an endpoint trial it actually was harmful, increasing both mortality and major cardiovascular events." Pfizer's presentation of the torcetrapib imaging studies was one of the headline events of the 2007 ACC meeting (² Pharmaceutical Approvals Monthly May 2007, p. 5)

"After the torcetrapib discontinuation, we have conducted several investigations aiming to have a better understanding of the off-target toxicity related to torcetrapib," Laghrissi-Thode said. Roche concluded that torcetrapib's toxicity was related to its off-target effect on renin-angiotensin-aldosterone system gene expression. Data presented to ACC included a comparison of the hemodynamic effects of CETP inhibitors in rats and analyses of R1658 Phase II data.

The rat study sought to determine whether the increased blood pressure and cardiovascular events that doomed torcetrapib are a compound or a class effect, according to the study abstract. "In contrast with torcetrapib, Roche's CETP inhibitor is not associated with the off-target toxicity on rat [RAAS] gene expression," Laghrissi-Thode summarized. R1658 "does not increase blood pressure," she asserted.

Two separate analyses of R1658 Phase II adverse event data were included at ACC. Neither found evidence of increases in blood pressure, cardiovascular AEs or ECG results in R1658 patients compared with placebo.

Is The Outlook Getting Murkier?

But even if safety proves not to be an issue for R1658, or other CETP inhibitors, efficacy measures may present regulatory challenges. Recent developments in the cardiovascular space - including failed outcome trials, questions about surrogate endpoints, and unexpected "not approvable" letters - potentially indicate tougher times with FDA.

Since HDL elevation is a surrogate marker, and there is confounding evidence out there from torcetrapib, sponsors of CETP inhibitors or other HDL-elevating compounds may have problems with stricter standards.

Pfizer's ILLUMINATE raised concerns about the reliance on surrogate endpoints in cholesterol drug development, a concern that heated up after Merck/Schering-Plough's simvastatin and ezetimibecombination Vytorin stumbled in ENHANCE, a major outcomes trial, when the expected effect on a validated surrogate marker (LDL cholesterol lowering) failed to produce the expected impact on progression of atherosclerosis.

The ENHANCE results are "a paradox, at odds with our traditional understanding of LDL and athero-sclerosis," according to a New England Journal of Medicine editorial published to coincide with the presentation of the final data at this year's ACC.

Faced with such prominent trial failures, most analysts expect FDA to become increasingly cautious and risk-averse. In the dyslipidemia field, that theory is supported by Merck's surprising receipt of a "not approvable" letter for Cordaptive (laropiprant/niacin, also MK-0524A) April 28, and Isis' same-day announcement about conservative guidance from FDA regarding development of mipomersen.

Merck CEO Richard Clark reiterated support for MK-0524A, which pairs niacin with a compound to inhibit the flushing side effect, during the Morgan Stanley Global Healthcare Unplugged Conference May 1. "We believe there is a pathway forward," he said. The path will carry a new name: FDA also rejected the trade name Cordaptive, so Merck plans to rename the product Tredaptive . The product will be resubmitted pending a meeting with FDA to discuss the benefit/risk profile, Clark said.

Clark also reiterated Merck's intent to move forward with MK-0524B, a combination of Cordaptive and simvastatin. While MK-0524B had experienced formulation problems, they seem to have been resolved - MK-0524B is in Phase III and has a 2008 filing target.

Showing an acceptable balance of benefit and risk for laropiprant, the NME component of Cordaptive, could be problematic in an increasingly strict regulatory environment. Laropiprant does not offer an efficacy advantage, but must stand or fall on the potential for improved compliance based on reducing flushing associated with niacin - a side effect that in itself does not pose a significant health risk.

Isis and partner Genzyme are revising the development strategy for their antisense agent mipomersen, after FDA said that LDL reduction would be an acceptable surrogate endpoint only for accelerated approval for homozygous familial hypercholesterolemia.

The firms are now accelerating plans for a dyslipidemia outcomes trial. An outcomes trial will be needed both to support full approval in hoFH and to expand mipomersen's use to other patients with high cholesterol who are at high risk for CV events.

Benefiting From Barriers To Entry

Cautious regulators (and prescribers) could build high barriers to entry for novel HDL elevating drugs, leaving Roche and Merck dominant.

While smaller firms have largely abandoned the CETP arena, a new wave of early-stage therapies addressing HDL flux, instead of simply raising HDL levels, are emerging from small firms and biotechs, according to an April 2008 article in Pharmaceutical Approvals Monthly's sister publication Start Up.

"In the medium term," Roche Strategic Marketing Head of Metabolic Diseases and Anemia Luke Miels predicted at the ACC event, "we expect the [HDL market] growth to be mainly driven by the CETP class with their robust M&M [morbidity and mortality] data." There will be "limited late-stage competition in this area," he predicted.

The benefit of HDL elevation "is an evolving hypothesis" and a non-validated surrogate marker, Miels stated. "In contrast to LDL, health authorities, of course, are requiring M&M data for this surrogate."

The R1658 Phase III program consists of one morbidity-mortality study. "The reason we have opted to do an M&M is because it's the only way to truly evaluate the cardiovascular benefits of CETP inhibition," Laghrissi-Thode explained. She also acknowledged that "this is the only route for approval for a CETP today."

"The compound will be investigated looking at risk reduction in a high-risk population," she said. The Phase III study will enroll 15,600 patients considered to be stable after recent acute coronary syndrome events, randomized to placebo or active treatment and receiving "optimized background therapy to make sure that we assess the real effects of raising HDL."

The event-driven trial started in April. At its most recent earnings presentation, on April 17, Roche projected filing an NDA for R1658 in 2012 or later.

The pivotal trial plan includes a "stepwise risk mitigation plan that will include a futility analysis halfway through Phase III," Roche Holding Head of Investor Relations Karl Mahler said during the April 2 call.

"We believe there are clear decision points where we can make a decision on further investment," Miels said. "These points will be data driven, some of them will be based on efficacy, some will be based on safety and others on a combination of both."

Mechanistic Studies Will Complement M&M

On top of the morbidity-mortality study, Roche plans to conduct two exploratory studies "to give us more insight into these targets," Laghrissi-Thode said.

A two-year Phase II trial assessing progression or regression of atherosclerotic plaque started in March. According to www.clinicaltrials.gov, the trial will enroll 100 patients with coronary heart disease. The primary outcome measures are change from baseline of MRI plaque size/burden and of "target (plaque) to background (blood) ratio from an index vessel."

A larger Phase II trial of R1658's effect on vascular function is slated to start in May. The 450 CHD patients to be enrolled will receive R1658 or placebo for 36 weeks. The primary endpoints for measuring endothelial function will be flow-mediated dilatation and blood pressure monitoring. A secondary endpoint will assess CETP mass and activity.

Anacetrapib Plays Tortoise To Cordaptive's Hare

In contrast to Roche's push with R1658 unveiled at ACC, Merck has proceeded more cautiously with its CETP candidate anacetrapib (MK-0859). Where Roche is proceeding with mechanistic studies and its outcomes trial in parallel, Merck is describing its anacetrapib pivotal program as a "sequenced" effort that will start this year.

"We are in the process of initiating a careful and sequenced Phase III program," Merck VP-Clinical Research Richard Pasternack told a Lehman Brothers conference March 18. "We're doing this out of extreme caution."

"Some of the mechanistic arguments that go on about whether CETP inhibition is absolutely favorable or not continue to be debated, so we want to make very sure that in a very careful and measured fashion that we test this agent … in a safe and responsible fashion," Pasternack explained.

Merck hopes to obtain additional clinical experience in patients before initiating an outcomes study, according to materials from the December business briefing. Merck will "evaluate effects on key safety parameters (blood pressure, electrolytes, aldosterone) with longer patient exposures" in the first part of the sequenced Phase III program.

A cardiovascular outcomes study for anacetrapib is expected to start as early as 2009.

Merck's sequenced anacetrapib plan stands in contrast to its diving-in approach to an outcomes trial for Cordaptive. "We took the approach of a very large outcomes study very early in our clinical program," Pasternack recalled. Instead of waiting for it to be a Phase IV requirement, Merck initiated the 20,000-patient THRIVE study comparing Cordaptive to simvastatin in patients with active coronary artery disease. As of March, THRIVE was half randomized.

- Bridget Silverman (b.silverman@elsevier.com)

Roche Exorcizes Torcetrapib’s Ghost: CETP Candidate Starts Phase III

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