Hepalink Pharmaceutical (SHE: 002399) has closed a license agreement and entered into a stock purchase agreement with Resverlogix Corp. (TSX: RVX). Under the terms of the agreement, Hepalink purchased 12.63% of Resverlogix common shares for $27 million. Hepalink will develop and commercialize Resverlogix’s lead candidate apabetalone (RVX-208) in China. Resverlogix will be eligible to receive sales-based milestone payments ($5-90 million) and royalties (6%).
RVX-208 is a derivative of resveratrol, an antioxidant that is commonly found in the skin of grapes. As you may have known, Resverlogix’s name is derived from resveratrol. Recently, RVX-208 was identified as a BET inhibitor specific for BRD2, with an IC50 value of 0.51 μM. The compound was designed to raise HDL-C, the so-called good cholesterol.
In April 2008, GlaxoSmithKline paid $720 million to acquire Sirtris Pharmaceuticals (NASDAQ:SIRT) and its special formulation of resveratrol known as SRT501. However, the Phase II trial of SRT501 was halted in November 2010, because several patients in the trial developed kidney failure.
Resverlogix has completed two Phase IIb trials known as SUSTAIN (24-week, 176 patients), and ASSURE (26-week, 324 patients). In the pooled data analysis, RVX-208 significantly increased HDL-C levels by 7.69%. RVX-208 decreased the incidence of major adverse cardiac events (MACE) by 55%, and lowered MACE by 77% in patients with a history of diabetes.
While I am supportive of phase III trials with RVX-208, I think it involves great risks. It was commonly believed that raising HDL-C should lower cardiovascular risk. However, recent studies have called the HDL hypothesis into question. CETP inhibitors and niacin raised HDL-C levels but failed to reduce cardiovascular risk.
Dr. Donald Lloyd-Jones, a well-known cardiologist, suggested that
the HDL cholesterol level has a role solely as a risk marker and not a risk factor that merits intervention to reduce cardiovascular events. Although higher HDL cholesterol levels are associated with better outcomes, it is time to face the fact that increasing the HDL cholesterol level in isolation seems unlikely to offer the same benefit.
Resverlogix believes RVX-208 is different. RVX-208 helps the body to create new HDL particles which are more effective in pulling cholesterol out of plaques. However, the ASSURE trial did not meet its primary endpoint of plaque regression as a result of unexpected strong placebo results.
The Phase IIb trials were directed by Dr. Steven Nissen, one of the world’s most eminent cardiologists. However, the Phase IIb trials were conducted outside the US. These early and small trials are not enough to prove that RVX-208 really could reduce MACE. To prove this, a large Phase III trial involving 20,000+ patients is warranted.
Take Orexigen Therapeutics’ (NASDAQ: OREX) 9,000-patient LIGHT trial as an example. The first 25% interim analysis suggested Contrave not only helped patients lose weight but also prevented MACE (55 vs. 35). However, the next 25% of data showed that 43 patients in the placebo group had MACE compared to 55 on Contrave.
Resverlogix is planning a Phase III clinical trial known as BETonMACE in high-risk cardiovascular disease patients with diabetes. Hepalink will be responsible for the Phase III costs in China. If all goes well, Resverlogix will launch the drug in 2020.
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 N Engl J Med. 2014, 371(3), 271-273.