Youyou Tu wins 2015 Nobel Prize in Physiology or Medicine

Youyou Tu received the 2015 Nobel Prize in Physiology or Medicine. She became the first Chinese scientist who won the prize. In 1970s, Tu successfully extracted artemisinin from Artemisia annua with ether. At first, they failed to extract the compound with boiling water, because hot water had already damaged the compound.

Chinese investors may hype the concept as they always did in the past, though artemisinin suppliers such as Fosun Pharma (SSE: 600196) and KPC Pharmaceuticals (SSE: 600422) didn’t and will not earn much from the drug because of its low price. Chinese stock markets are filled with speculators and retail investors. We will see.

Chipscreen BioSciences surpasses Eddingpharm in breast cancer

In July 2015, Chipscreen BioSciences initiated a Phase III trial of chidamide in hormone receptor (HR) positive breast cancer (CTR20150456). It is the first Phase III trial to evaluate the efficacy and safety of HDAC inhibitor in Chinese patients with breast cancer.

Syndax Pharmaceuticals (NASDAQ: SNDX) is evaluating another HDAC inhibitor, entinostat, in breast cancer in a pivotal Phase III trial in breast cancer. Two years ago, the FDA granted Breakthrough Therapy Designation to the drug based on Phase IIb (ENCORE 301) results.

In September 2013, Eddingpharm licensed China rights to entinostat. Eddingpharm originally intended to participate in Syndax’s global Phase III trial. However, the IND wasn’t submitted to the CFDA until February 2015. If all goes well, Eddingpharm will commence clinical study of entinostat in 2016.

Syndax’s Phase IIb trial (NCT00676663) assigned 130 patients with HR positive breast cancer progressing on first-line therapies[1]. Patients were randomly assigned to exemestane + entinostat (EE) or exemestane + placebo (EP). Median overall survival was improved to 28.1 months with EE versus 19.8 months with EP (p=0.036).

The Phase IIb results appear encouraging, but I still have some doubts. There is no difference in response rate (6.3% vs. 4.6%). The median progression-free survival (mPFS) of 2.3 months in the EP group was lower than the 3.8-4.1 months observed in other similar trials[2,3]. The EE group had more Grade 3/4 adverse events (50% vs. 26%).

The FDA has approved everolimus plus exemestane for the second-line treatment of HR positive breast cancer. The combination of palbociclib with fulvestrant has also shown a marked benefit in second-line treatment in a Phase III trial. Entinostat, if approved, will have to compete with everolimus and palbociclib in the second-line settings.

Entinostat (MS-275) was discovered by Japanese scientists in Mitsui Pharmaceuticals in 1990s. European Patent EP0847992 which covers entinostat expires in 2017. The patent protection for the compound relies on WO2010022988 which covers a crystalline polymorph.

Syndax licensed the program from Bayer with an upfront fee of $2 million in April 2007. The company conducted a Phase II trial of entinostat plus erlotinib in non-small cell lung cancer, but failed. Fortunately, the Phase II trial in breast cancer succeeded.

Chipscreen’s chidamide is an anolog derived from entinostat. The CFDA has approved chidamide for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in December 2014. Chipscreen is likely to complete the breast cancer study in advance of Eddingpharm.

Chidamide

[1] J Clin Oncol. 2013, 31(17), 2128-2135.
[2] N Engl J Med. 2015, 373(3), 209-219.
[3] N Engl J Med. 2012, 366(6), 520-529.
[4] J Med Chem. 1999, 42(15), 3001-3003.

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Chipscreen grabs CFDA approval for chidamide

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.

Drug R&D in China: Top 10 most valuable Phase III drugs

Product Company Indication Class Phase III design
apatinib HengRui HCC VEGFR inhibitor NCT02329860: apatinib vs. placebo
NSCLC NCT02332512: apatinib vs. placebo
retagliptin HengRui T2DM DPP-4 inhibitor NCT01970033: retagliptin vs. placebo

NCT01970046: retagliptin+ metformin vs. placebo + metformin

PEX168 Hansoh T2DM GLP-1 (once a week) NCT02477969: PEX168 + metformin vs. placebo + metformin
albuvirtide Frontier HIV HIV fusion inhibitor NCT02369965: albuvirtide + Kaletra vs. TDF/3TC + Kaletra
PEG-Tα1 Hansoh HBV Tα1 (once a week) NCT02366247: Tα1 + adefovir vs. placebo + adefovir
fruquintinib Hutchison CRC VEGFR inhibitor NCT02314819: fruquintinib vs. placebo
flumatinib Hansoh CML Bcr-Abl inhibitor NCT02204644: flumatinib vs. imatinib
batifiban Bio-Thera thrombosis Gp IIb/IIIa inhibitor CTR20130814: batifiban vs. placebo
benvitimod TianJi psoriasis CTR20130379: benvitimod vs. calcipotriol
971 Green Valley AD oligomannurarate CTR20140274: 971 vs. placebo

Ref: (1) https://clinicaltrials.gov/ct2/home; (2) http://www.chinadrugtrials.org.cn/

Hua Medicine has yet to eliminate the biggest risk in the development of glucokinase activator

Here is an interview with Hua Medicine vice president Yi Zhang. According to Yi Zhang, sinogliatin (RO5305552) should be the best glucokinase activator or even the best anti-diabetic drug in the world. It’s not really all that good in my opinion.

Pharmaceutical companies have put hundreds of millions of dollars in the development glucokinase activators. Similar therapies from Merck, AstraZeneca and others never made it to market. The biggest problem is that glucokinase activators appear lack long-term efficacy.

Both Merck’s MK-0941 and AstraZeneca’s AZD1656 failed in mid-stage trials. Although initially favourable plasma glucose reductions were observed, the efficacy was not sustained[1, 2]. Furthermore, MK-0941 was associated with elevated plasma triglycerides. Merck’s scientists even suggested

that continued activation of hepatic glucokinase has deleterious metabolic effects and that nonspecific activation of glucokinase may not be an appropriate approach for the treatment of type 2 diabetes.

Hua Medicine was founded by Li Chen, the former CSO of Roche’s R&D Center in China, with $50 million from a group of investors, including ARCH Venture Partners and WuXi PharmaTech. Hua Medicine licensed worldwide rights to sinogliatin from Roche in 2011. Roche bargained away the program more or less due to the failure of Merck and AstraZeneca.

Hua Medicine has completed a Phase Ib trial in which 53 patients just received 8 days of sinogliatin. The long-term efficacy and safety have not been assessed. It is too early to say Hua Medicine succeeded where Merck and AstraZeneca had failed.

[1] Diabetes Obes Metab. 2013, 15(10), 923-930.

[2] Diabetes Care. 2011, 34(12), 2560-2566.

Chipscreen grabs CFDA approval for chidamide

Chipscreen BioSciences announced that the CFDA had approved chidamide for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in December 2014. The drug and Hengrui’s apatinib were the only two NCEs launched by domestic drug makers last year.

Chidamide (CS055/HBI-8000) is a HDAC1/2/3/10 inhibitor derived from entinostat (MS-27-275)[1] which was first discoved by Mitsui Pharmaceuticals in 1999. Chipscreen holds worldwide IP rights to chidamide (patents: WO2004071400, WO2014082354).

Syndax Pharmaceuticals (NASDAQ: SNDX) is testing entinostat in breast cancer and NSCLC in pivotal trials. The FDA granted Breakthrough Therapy Designation to entinostat for advanced breast cancer in 2013. Eddingpharm in-licensed China rights to entinostat from Syndax in September 2013.

Chipscreen disclosed positive results from Phase II study of chidamide in relapsed or refractory PTCL at 2013 ASCO Annual Meeting[2]. Out of 79 evaluable patients in the trial, 23 patients (29.1%) had confirmed responses (8 CR, 3 CRu, and 12 PR). The most common grade 3/4 AEs were thrombocytopenia (24%), leucocytopenia (13%), neutropenia(10%).

The FDA has approved three HDAC inhibitors, known as Zolinza (vorinostat), Istodax (romidepsin) and Beleodaq (belinostat), for the treatment of PTCL. Celgene priced Istodax at $12000-18000/month and reported annual sales of $54 million in 2013. The efficacy and safety profile of chidamide compares favorably with romidepsin.

Although a dozen of companies are developing generic vorinostat and romidepsin, no chemical 3.1 NDA has been submitted to the CFDA so far. Chipscreen will be the only domestic maker of HDAC inhibitor in the coming two years. Moreover, the company is testing chidamide in NSCLC and breast cancer in early clinical studies.

[1] Proc Natl Acad Sci USA. 1999, 96(8), 4592-4297.

[2] J Clin Oncol 31, 2013 (suppl; abstr 8525).

Teach an old dog new tricks: the story of nitroxoline

Nitroxoline is a wide spectrum antibiotic that has been used in many countries (e.g., Germany, Taiwan, South Africa) for about fifty years. Recently, Asieris Pharmaceuticals (亚虹医药) initiated a Phase II trial (CTR20131716) to test nitroxoline (APL-1202) in non-muscle invasive bladder cancer. The NFPFC has granted Major Drug Invention Program of China’s 12th Five-year Plan designation to nitroxoline.

The antiangiogenic activity of nitroxoline was discovered by Jun Liu who received his undergraduate degree from Nanjing University in 1983 and now is a professor of pharmacology and molecular sciences at Johns Hopkins University. His research focuses on using old drugs to treat new diseases.

Jun Liu’s team identified nitroxoline as a MetAP2 inhibitor from a target-based high-throughput screen of 175000 compounds[1]. At the same time, they tested 2687 approved drugs (Johns Hopkins Drug Library) in HUVEC cells through a cell-based screening, and nitroxoline stood out again. Finally, Jun Liu concluded that nitroxoline inhibits HUVEC proliferation (IC50=1.9 μM) through dual inhibition of MetAP2 (IC50=54.8 nM) and SIRT1/2 (IC50= 20.2 μM, 15.5 μM).

The team tested nitroxoline in breast cancer (HCC1954) xenografts at the dose of 60 mg/kg. A 60% inhibition of tumor volume and a 43% inhibition of tumor weight were noted on day 30. Because more than 70% of nitroxoline was found in urine after oral dosing[2], they tested nitroxoline in mice with bladder cancer (KU7-luc) at the dose of 30 mg/kg. Nitroxoline showed a statistically significant inhibition of bladder tumor growth.

Actually, Jun Liu has designed and synthesized a series of derivatives derived from nitroxoline[3]. Several compounds inhibited HUVEC growth with sub-micromolar IC50, but did not affect MetAP2 or SIRT1, in contrast to the previous hypothesis. Asieris selected nitroxoline as clinical candidate without further optimization. Moreover, Kangrun Pharmaceuticals (康润医药) has filed a patent application (CN103319404) covering a list of nitroxoline derivatives.

The recommended dosage of nitroxoline in adults with urinary tract infections is 600 mg/day. At the dose of 400 mg/day, 10 µM of nitroxoline could be found in urine, which is high enough to inhibit angiogenesis in patients with bladder cancer. Asieris’ Phase II doses were 300-600 mg/day.

[1] J Natl Cancer Inst. 2010, 102(24), 1855-1873.

[2] Int J Clin Pharmacol Biopharm. 1979, 17(12), 476-481.

[3] Org Biomol Chem. 2012, 10(15), 2979-2992.