Resverlogix's Phase IIb Results Good for 'Bromodomain' Drugs

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"Resverlogix's RVX-208, designed to increase levels of high-density lipoprotein cholesterol in patients with atherosclerosis, is hitting all of its marks."

Bromodomain

Resverlogix Corp. (RVX:TSX) reported success in a Phase IIb (SUSTAIN) trial of its small-molecule BET protein inhibitor, RVX-208, designed to increase levels of high-density lipoprotein cholesterol (HDL-C) in patients with atherosclerosis.

The Calgary, Alberta-based company took a beating on the Toronto stock exchange two years ago when top-line results for its ASSERT Phase II trial failed to reach statistical significance for increasing ApoA-1, even though it gave solid results for increasing HDL. (See BioWorld Today, Nov. 18, 2010.)

This time around, RVX-108 is hitting all of its marks, and the market responded with an increase of C18 cents. Resverlogix's stock (TSX:RVX) closed Tuesday at C$1.75 (US$1.77).

The news made a good birthday present for CEO Don McCaffrey, who joked that at age 54 he might soon be needing the drug that his company is developing. McCaffrey said he was particularly pleased with the safety results, which put to rest any concerns about elevated levels of alanine aminotransferase from previous trials.

"We showed any liver transaminases were indeed transient. We saw nothing from week 12 to the end of the trial," McCaffrey told BioWorld Today. "It's very reassuring that this drug possesses all of the capabilities for a chronic program."

SUSTAIN enrolled 176 patients with established atherosclerotic cardiovascular disease and low HDL in South Africa to receive therapy or placebo over a 24-week period. The enrollment criteria were based on the patient population with the largest response to RVX-208 in the ASSERT trial.

The study also met its secondary endpoints, increasing levels of Apo-A1 and large HDL particles. Concurrently with reporting the trial results, Resverlogix also secured a $25 million loan with Citibank N.A. to fund ongoing research and development, as well as for working capital and general corporate expenses.

RVX-208 is a product of the company's epigenetics-focused research platform. According to Resverlogix, it removes atherosclerotic plaque and increases production of ApoA-1, a building block of HDL, by targeting BET proteins, which read out epigenetic modifications in the DNA and recruit additional proteins to regulate gene activity.

RVX-208 has been erroneously compared with CETP inhibitors, such as Merck & Co. Inc.'s anacetrapib or Pfizer Inc.'s terminated drug torcetrapib. Development of torcetrapib was halted due to drug-associated deaths and heart attacks, while anacetrapib was shown to decrease LDL-C by 40 percent and increase HDL-C by 138 percent, compared to placebo, in an 18-month trial in 1,623 patients.

RVX-208 is distinct from that family of drugs because of its mechanism and its recruitment of the reverse cholesterol transport pathway to shuttle atherosclerotic plaque out of arteries and remove it from the body.

According to McCaffrey, the CETP inhibitors prevent HDL from leaving the system, which results in a large increase in HDL levels, but does not create new molecules.

McCaffrey said Resverlogix is the most advanced "bromodomain company." The next most advanced in that space is GlaxoSmithKline plc. Its drug, I-BET151 , is in development as a therapy for various types of leukemia.

GSK published research showing the potential of bromodomain drugs for mixed lineage leukemia in the Oct. 2, 2011 , edition of Nature. That compound has not yet entered clinical trials, however.

Other companies playing with bromodomains include Tensha Therapeutics, of Cambridge, Mass., and Constellation Pharmaceuticals Inc., also of Cambridge.

Tensha bagged a $15 million Series A financing to develop its bromodomain inhibitors for cancer last year. That program is at the preclinical stage. (See BioWorld Today, Sept. 13, 2011.)

Early this year, Constellation signed a $95 million collaboration agreement with Genentech Inc., a division of Roche, to develop therapies for cancer and other diseases based on epigenetics and chromatin biology. Constellation's most advanced programs target inhibitors of BET and EZH2 chromatin writer. (See BioWorld Today, Jan. 17, 2012.)

Although there's a great deal of interest in BET inhibitors in general, McCaffrey said there are no other companies developing one for cardiovascular disease.

Resverlogix has announced its intention to partner its technology, particularly in oncology and autoimmune disease. For its cardiovascular program, it will be waiting for data from its upcoming ASSURE trial.

ASSURE will seek to prove regression of plaques in the artery using intravascular ultrasound (IVUS) to directly assess those plaques. The 26-week, double-blind, randomized, placebo-controlled trial will enroll a total of 310 patients. Those in the active group will receive 100 mg twice daily. Two IVUS measurements, baseline and at 26 weeks, will be used to assess the change in percent atheroma volume in the artery.

"This is a very definitive proof-of-concept trial," McCaffrey said, noting that statin drugs, which have been billion-dollar blockbusters for the pharmaceutical industry, have not been able to show plaque reduction in that way. "That's a drug that can only create a status quo scenario, where they stop any further buildup of plaque," McCaffrey explained.

$25M Loan to Bridge Licensing Revenue

In an announcement unrelated to its clinical news, Resverlogix said it had taken out a $25 million loan with Citibank, repayable upon maturity on Aug. 24, 2017. For the first year, the interest rate on the loan is 4.5 percent per year, and thereafter will be the LIBOR swap rate plus 3. 14 percent.

The loan is secured by a $25 million standby letter of credit via Resverlogix investor Eastern Capital Ltd.

McCaffrey said it is normally difficult for biotech companies to take out loans. "The deal rates are so onerous, they are close to usury," he said. Most of those loans are offered at rates comparable to credit cards.

The letter of credit offered by Eastern Capital made it possible for Resverlogix to secure the coveted nondilutive financing.

McCaffrey said the company would like to use licensing deals to generate revenue to retire the loan.

"We literally have thousands of molecules that we've researched already," McCaffrey said. Those molecules fall into three categories: cardiovascular, oncology and autoimmune. "We're looking at various deal structures now, and anticipate over the next several months to do one or two different deals."

Catherine Shaffer
BioWorld

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