Resverlogix Thinks RVX-208 Can Succeed At Reducing Arterial Plaque Where Pfizer's Torcetrapib Failed

Resverlogix believes its small-molecule drug RVX-208 delivers on a key goal in cardiovascular drug development - the ability to clear life-threatening plaque out of arteries - setting the firm up to succeed with its first-in-class agent where others have failed and to write its own ticket in the $35 billion cholesterol market.

RVX-208 is a reverse cholesterol transport drug that offers the potential to increase high-density lipoprotein cholesterol in a unique way. The Canadian biotech doesn't have much data in hand yet to support its lofty aims, but it has a sound strategy and has already attracted interest.

Resverlogix reported data from a successful Phase Ib/IIa double-blind safety and tolerability study in September. A month later, at the company's Oct. 16 annual meeting, CEO Donald McCaffrey laid out a Phase II clinical plan, with studies to be conducted under the auspices of the Cleveland Clinic - a not insignificant factor in the CV community.

At the American College of Cardiology meeting in March, Steve Nissen, who heads up the clinic's Department of Cardiovascular Medicine, remarked that "increasing [apolipoprotein] A-1 production is kind of a Holy Grail."

"If you can make more A-1 and more lipid-poor, pre-beta discoidal HDL … [that] is the one mechanism that is likely to work," said Nissen, who went on to call the Resverlogix drug "pretty interesting."

Raising HDL Still An Untapped Market

"We believe we are entering a very, very special market," McCaffrey said in an interview. "Statins are a wonderful class of drugs that will stay around because lowering LDL is important. But they've built an … industry out of being able to stop further build-up of plaque in the arteries, while they are unable to remove it."

The landmark Framingham heart study revealed that for every one mg/dL rise in high-density lipoprotein in blood plasma, the risk of cardiovascular disease is reduced by 2 percent to 3 percent, but drug makers so far have been unable to find the magic bullet that can safely elevate HDL levels and at the same time allow the complicated fragments to function properly in the blood.

The Phase III blow up of Pfizer's cholesteryl ester transfer protein inhibitor torcetrapib, the vaunted follow-on to blockbuster Lipitor (atorvastatin), is a spectacular case in point. Where the Pfizer drug went wrong, explained McCaffrey, is in attempting to raise serum HDL levels by trapping the HDL particles in circulation, unaware that torcetrapib was thwarting the transport work HDL does. Pfizer announced it was terminating the torcetrapib program in December 2006 because of an imbalance in deaths between the two arms of a placebo-controlled Phase III study (¹ (Also see "Pfizer Terminates Torcetrapib Program" - Pink Sheet, 3 Dec, 2006.)).

Though Pfizer's failure chilled the CETP field, other firms remain at work on that approach to HDL. Merck is boldly betting on a CETP drug, anacetrapib, which it says induced favorable lipid changes in Phase II with none of the off-target effects that scuttled torcetrapib (² (Also see "Merck Taking Aggressive Approach To Cardiovascular Development" - Pink Sheet, 5 Jan, 2009.)). Roche, too, has a CETP candidate, dalcetrapib (R1658), in Phase III studies, that it claims is different from torcetrapib or any other CETP for that matter (³ Pharmaceutical Approvals Monthly May 2008).

But no other company appears to be working on an RCT drug. Former Pfizer play Esperion pursued a recombinant injectable ApoA-1, called Milano, at one time, but shelved the molecule (⁴ (Also see "Pfizer Spins Off Esperion While Retaining Former Subsidiary’s Top Compounds" - Pink Sheet, 1 May, 2008.)). Jan Johansson, who is now Resverlogix Senior VP-Medical Affairs, developed that technology, McCaffrey said, noting the compound had good intravascular ultrasound (IVUS) data that showed proof-of-concept that atherosclerosis can be reversed. Pfizer ultimately gave up on it because of cost and manufacturing issues in growing up the recombinant protein, but "it was good of them to do the proof of concept for us," he quipped.

McCaffery is also confident that the reverse transport cholesterol approach will trump the CETP attempt.

Where Their Approach To HDL Differs

Newer science has revealed that high levels of HDL alone aren't what decreases CV risk. HDL, it seems, acts as a plaque garbage truck. Torcetrapib blocked the liver's B-1 receptors, so the loaded HDL fragments were forced to stay in circulation, but they were unable to either dump their plaque load or gather more.

Resverlogix's drug, RVX-208, instead is aimed at increasing serum levels of apolipoprotein A-1, a building block that makes up 70 percent of HDL cholesterol, therefore creating more serum HDL that is ready to function as transport. "What we've been able to do is turn on the gene that makes Apo-A1 in very selective fashion," McCaffrey explained.

With RVX-208, new "empty, flat discoidal HDLs and pre-HDL disks" flow through arteries filling up with plaque and taking it to the liver, where they work through the scavenger receptor B-1 to dump their load, which is then flushed out of the body.

The promise of the RVX-208 approach is already drawing significant interest from the rest of the pharmaceutical industry.

The New Partnering Reality: Pharmacoeconomics

The firm is working with due diligence teams from several pharma companies. One team actually lent Resverlogix its 12-member clinical design team to help design the RVX-208 program all the way through to Phase III so it would match their in-house techniques in case a deal is made. "I found that very encouraging," McCaffrey said.

Resverlogix hired pharma industry consultants Destum Partners to conduct a marketing survey of 15 top cardiologists and internists in the U.S. with an eye toward using the information in dealings with potential partners.

That yielded some intriguing results - McCaffrey said he was "quite surprised" how the physicians said they would use the drug in diabetes practice. But one of the most encouraging findings was that nearly all of the physicians surveyed said that with a 1 percent regression in plaque they would make RVX-208 a mandatory addition to second-line treatment with statins, and if it resulted in a 3 percent or greater reduction in plaque volume, they would make it primary care. "That makes this potential huge."

Suitors May Have IVUS Study Data In 12 Months

When it comes to exit strategies and deal structures, the technological ability in the CV field gives those agents a clear advantage over therapies like oncologics, which must have robust Phase III data to attract attention, McCaffrey said. IVUS gives them the ability to stick a camera in the heart, take pictures and physically show that the drug is working - that "puts pharma in a whole different frame of mind as far as wanting to deal," he said.

Resverlogix should have that sort of data in about a year. The firm is set to start dosing in a 60-patient IVUS study in February at the Cleveland Clinic, under the oversight of principal investigator Stephen Nicholls, IVUS medical director at the clinic.

Two clinical studies are to proceed in parallel; all patients in both must be on standard therapy for 13 weeks beforehand. The first is the pilot IVUS study with one dose in 60 acute coronary syndrome patients to examine early lipid effects and atheroma plaque characterization of the coronary vessel wall.

The second is a three-month pre-IVUS dose ranging study to be followed by a 12-month IVUS study. It will examine lipid changes in 280 stable cardiovascular patients on standard of care therapy, including statins.

As with its earlier studies, Resverlogix plans to test its therapy in patients who already are on statin therapy to be sure RVX-208 doesn't interfere. "We use simvastatin because it's considered the dirtiest of the statins. It has a lot more potential for drug-drug interaction at the CYP3A4 receptor, so if you're clean with simva, you're probably clean with all the rest," McCaffrey said. As an effective generic option, simvastatin is also a relevant choice for the market.

IVUS images are coded to show definition of plaque composition very clearly from the hard calcium or the soft fibrosis to the lipid core, McCaffrey explained. "We can see exactly how our drug is not only reducing the percent of thromba volume, but also the safety profile in hopefully showing the dangerous lipid core [dissolving to reveal] to a more solid base as we decline. "

The Data In Hand

The already-completed double-blind safety and tolerance Phase Ib/IIa study tested RVX-208 in 72 subjects for 28 days in three 24-subject dosing arms: low dose, dose-escalation and a high dose. The company expects to present more data at the American College of Cardiology meeting in March.

About half of the subjects had low levels of baseline HDL, and their performance exceeded expectations. In all subjects in all doses plasma ApoA-1 increased compared to placebo from 5.1 percent to 10.4 percent at days 8 and 28 respectively. At the lowest dose of 1 mg/kg twice daily, subjects with low levels of HDL-cholesterol/plasma ApoA-1 had statistically significant increases of 5.7 percent (p<0.05) at day 8 and 7.8 percent (p<0.05) at day 28.

In addition to the primary endpoint of increased production of plasma apoA-1, the study looked at early makers for reverse cholesterol transport, such as ApoA-1, HDL-c, pre-beta HDL and alpha HDL subparticles. A critical marker for the mechanism, alpha-1 HDL particles, showed high statistical significance, with an increase of 46.7 percent (p<0.004), in all subjects, and 57.2 percent (p<0.02) in the low dose arm over placebo at day 28.

While earlier trials confined patients to a clinical center, a capsule formulation now allows them to be treated at home, a savings in trial costs, McCaffrey told analysts in September. The drug currently is dosed twice daily, but Resverlogix hopes the cost of reformulating it for once-daily dosing can be shared with a partner further down the development path.

Other Pipeline Projects Re-initiated

While working with Medtronics to develop a next-generation drug for drug-eluting stents, Resverlogix became interested in inflammation, McCaffrey said, adding that "unfortunately that happened about three months before the drug-eluting stent industry kind of popped." Nonetheless, Resverlogix put a lot of time on inflammation until about January of this year.

That inflammation research led to an interest in rheumatoid arthritis that has produced an investigational small-molecule therapy with potential to replace big-dollar biologics, he said. Now that RVX-208 is moving into the next phase, Resverlogix is reinitiating other programs and "cranking up inflammation in particular."

The stent program? "If our plaque regression works, we're going to kind of flatten the rest of the stent industry. Why treat the condition in millimeters at a time when you can do it systemically?"

- Shirley Haley ( ⁵ [email protected] )