Hepalink acquires a resveratrol derivative from Canada

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[1]. 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[2]

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.

[1] Proc Natl Acad Sci USA. 2013, 110(49), 19754-19759.
[2] N Engl J Med. 2014, 371(3), 271-273.

Five Prime Therapeutics bets $452.5 million on novel immune checkpoint antibodies

Five Prime Therapeutics (NASDAQ: FPRX) announced a license agreement with Inhibrx for novel GITR antibodies on Thursday. Under the terms of the agreement, Five Prime will pay Inhibrx a $10 million license fee and up to $442.5 million milestone payments.

Inhibrx was co-founded by Dr. Quinn Deveraux who leads the R&D for the company. Prior to founding Inhibrx, Deveraux spent 10 years at the Genomics Institute of the Novartis Research Foundation. In 1997, Deveraux revealed the mechanism of IAP (inhibitor of apoptosis protein)[1], the first known cellular inhibitor of caspases.

Inhibrx’s lead candidate, INBRX-103, was licensed by Celgene for 500 million in June 2012. The mAb targets CD47 on cancer cells. CD47 interacts with SIRPα on macrophages and sends a “don’t eat me” signal. INBRX-103 has entered clinical studies in early 2015.

Back to the topic, GITR (also known as TNFRSF18) is a member of the TNF receptor superfamily. The protein is mainly expressed on regulatory T cells (Tregs, CD4+CD25+) that suppress immune responses. GITR agonists suppress Tregs and thereby enhance immune responses.

Thirteen years ago, Japanese immunologists first found that activation of GITR abrogated Tregs-mediated immune suppression[2]. GITR Inc. (Tolerx Inc.) is developing a first-in-class GITR agonist called TRX518 in melanoma. The Phase I trial of TRX518 was initiated in 2010, but it is still recruiting patients at present.

Inhibrx believes its INBRX-110 is the best-in-class GITR antibody. Based on Inhibrx’s multivalent antibody technology, INBRX-110 activates GITR independent of Fc binding. This is in contrast to conventional GITR antibodies.

Genentech, Bristol-Myers Squibb, and AstraZeneca are developing co-stimulatory antibodies that target other members of the TNF receptor superfamily such as CD40 (TNFRSF5), OX40 (TNFRSF4), 4-1BB (TNFRSF9). It is commonly believed that adding co-stimulatory antibodies to anti-PD1 therapy can enhance the antitumor immunity.

[1] Nature. 1997, 388(6639), 300-304.
[2] Nat Immunol. 2002, 3(2), 135-142.

The role of CD95 in cancer: promoter or suppressor?

CANbridge Life Sciences, a Beijing-based biotech company, in-licensed China rights to Apogenix’s lead candidate, APG101. The drug is a fusion protein that consists of the extracellular domain of CD95 and the Fc domain of IgG1 and blocks the interaction between CD95 and its ligand. Apogenix has completed a Phase II trial in patients with recurrent glioblastoma[1].

What interests me is the exact function of CD95 in cancer. CD95 (also known as Fas receptor) is a death receptor on the surface of cells that mediates apoptosis. Cancer cells often downregulate CD95 to evade apoptosis. Thus CD95 agonists were considered to kill cancer cells[2]. However, severe liver toxicity was observed in mice due to CD95-mediated apoptosis of hepatocytes.

In 2010, scientists from the University of Chicago speculated that CD95 could actually promote the growth of tumors[3]. The discovery seems unbelievable because CD95 had previously been defined as a tumor suppressor.

APG101 indeed showed a clinical benefit in patients with relapsed glioblastoma in the Phase II trial. PFS rates at 6 months were 20.7% for reirradiation + APG101 and 3.8% for reirradiation alone (p=0.048). Median PFS was 4.5 months vs. 2.5 months (p=0.0162). Median OS for both two arms were 11.5 months.

In the Phase II trial, there was no difference  in median OS. Many scientists still believe CD95 is a tumor suppressor[4,5]. Apogenix announced Phase II results in March 2012, but Phase III study hasn’t been initiated until now. The median OS of 11.5 months in second-line setting is not that attractive.

[1] Clin Cancer Res. 2014, 20(24), 6304-6313.
[2] Brain Pathol. 1998, 8(2), 285-293.
[3] Nature. 2010, 465(7297), 492-496.
[4] J Immunol. 2012, 188(9), 4441-4449.
[5] J Biol Chem. 2012, 287(30), 25530-25540.

Afferent Pharmaceuticals raises $55 million to develop cough and pain killer

Afferent Pharmaceuticals completed a $55m Series C financing. The round was led by Fidelity Management & Research Company, with participation from other crossover funds. The company was founded by the biotech foundry Third Rock Ventures in December 2009.

Dr. Anthony Ford, the founder and chief scientific officer of Afferent, was previously a scientist at Roche Bioscience. About 15 years ago, Ford found that the ATP receptor P2X3 is critical for peripheral pain responses[1]. P2X3 knock-out mice have reduced pain-related behavior in response to injection of ATP.

Abbott Laboratories reported a non-nucleotide antagonist of P2X3 receptor called A-317491 in 2002[2]. At that time Ford led the P2X3 discovery program at Roche. Afferent in-licensed the P2X3 program form Roche.

Afferent is developing its lead candidate, AF-219, for the treatment of cough and bladder pain. Results from a proof-of-concept study in chronic cough patients have been published in The Lancet[3]. The drug reduced cough frequency by 75% compared to placebo.

Kathleen Glaub joined the company as CEO in August 2014. She was one of the Top 10 Women in Biotech[4] in 2011 when her company Plexxikon was sold to Daiichi Sankyo in a $935 million deal. Plexxikon’s Zelboraf (vemurafenib) gained an FDA green light for treating melanoma that year.

[1] Nature. 2000, 407(6807), 1011-1015.
[2] Proc Natl Acad Sci USA. 2002, 99(26), 17179-17184.
[3] Lancet. 2015, 385(9974), 1198-1205.
[4] http://www.fiercebiotech.com/special-reports/fiercebiotechs-2011-women-biotech