• Therapy extended median survival to 6.4 months.
• Two patients are alive four years after start of epigenetic treatment.

PHILADELPHIA — Patients with recurrent metastatic non-small cell lung cancer have a morbid prognosis, but a new epigenetic therapy may have potential for this population, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.

A research team at Johns Hopkins University tested a combination epigenetic therapy of azacitidine and entinostat among 45 patients with recurrent metastatic non-small cell lung cancer who had been heavily pretreated with other therapies but showed no response. Each patient received azacitidine on nine days and entinostat on two days per month. The trial had an “open-label” design, in which all patients received the treatment and there was no control group receiving a placebo.

Researchers found a median survival of 6.4 months with treatment, where the typical survival for this patient population is four months. Patients who showed signs of gene methylation reversal in at least two of four key genes had better survival than the rest, and two patients experienced dramatic tumor shrinkages.

Four of the 19 patients who received subsequent anticancer therapies had a major objective response to immediate subsequent treatment with other agents. Seven patients remain alive, including two who began treatment approximately four years ago.

“We are starting to show traction for epigenetic therapy for one of the most difficult-to-treat tumors,” said Stephen A. Baylin, M.D., professor and deputy director of the Kimmel Cancer Center at Johns Hopkins University and leader of the Stand Up To Cancer (SU2C) Epigenetics Dream Team. “This study appears to show the first durable successes in solid tumors with epigenetic therapy.”

This drug combination has previously shown efficacy among patients with leukemia.

“We hope these results lead to a larger, more definitive clinical trial of this drug combination,” said Charles Rudin, M.D., Ph.D., professor of oncology and director of the Upper Aerodigestive Cancer Program at Hopkins’ Kimmel Cancer Center. Rudin led the team of physicians and cancer biologists who conducted the study.

This research is funded in part by SU2C, a Specialized Programs of Research Excellence (SPORE) grant from the National Cancer Institute (NCI) and the Flight Attendant Medical Research Institute.

“This research would not have been possible, especially at this accelerated pace, without Stand Up To Cancer,” said Baylin. “Our SU2C Dream Team has benefitted enormously from the initiative’s vision and visibility. The funding helps leverage other support mechanisms, like our SPORE grant from the NCI, which could never separately fund a trial of this magnitude and scope. It has enabled incredibly fruitful collaborations and allowed us, most importantly, to make a real difference in peoples’ lives.”

Portions of this release have been provided by Johns Hopkins

Eric will join a panel discussion on the challenges facing personalized medicine at a featured Personalized Medicine Coalition event at the North Carolina Biotechnology Center on November 16.

Scott Weiner will participate on the panel “Can the Rest of the World Save the Private US Medical Device Industry?” at Medtech 2011 in Chapel Hill, NC on November 1.

Barry Myers will be speaking on a panel discussing trends in Biomedical Engineering at Medtech 2011 in Chapel Hill, NC on November 2.

Zelboraf, the most-recent Pappas Ventures-backed product to be approved by the FDA, has attracted worldwide media interest. Click here to see the ABC News report on how the melanoma drug, pioneered by Plexxikon, is providing new hope for patients who have this deadly disease.

The IPO market might be looking a little frosty, but the M&A market so far this year has been positive enough to warm VCs’ hearts.

The median selling price through September was nearly $71 million – four times the median amount invested prior to liquidity, according to Dow Jones VentureSource. That kind of multiple hasn’t been seen since 2000.

Because M&A is affected by the stock market, the pace is likely to fall in the fourth quarter, but the total raised is sure to exceed last year. VentureSource pegs the amount raised in the first nine months at $37.3 billion, only slightly behind the $39.42 billion for all of 2010, which was the best year since 2007. (VentureSource is owned by Dow Jones & Co., the publisher of this blog.)

So far this year, six acquisitions of U.S.-based venture-backed companies have closed at $700 million or more. The biggest was Plexxikon, which Daiichi Sankyo bought for $805 million. The company, which is developing a treatment for melanoma, raised $67 million from investors including Advanced Technology Ventures, Alta Partners, Astellas Venture Capital, Pappas Ventures and Walden International. The deal includes an additional $130 million in potential milestone payments

Second place goes to another health-care company, medical device maker Ardian, which sold to Medtronic for $800 million after raising more than $66 million. Advanced Technology Ventures was an investor in that company, too, along with Emergent Medical Partners, Morgenthaler Ventures and Split Rock Partners. Medtronic also was a backer.

Those deals closed in the first half of the year. The action lately has been more on the tech side. The third-largest deal of the year – and largest of the third quarter – was the $750 million sale of PopCap Games to Electronic Arts. The price could climb by another $550 million if certain performance goals are met. PopCap raised a single round of $22.5 million led by Meritech Capital Partners.

Paul Madera, a Meritech managing director said that during the last two years, the late-stage venture investor has seen its best run of liquidity since its start in 1999. But with stock market volatility crimping IPOs, he expects corporate acquirers to become more cautious. “There isn’t as much urgency to get things done,” Madera said.

Still, large tech companies are sitting on piles of cash and competition is fierce. The most active acquirer through September was Google, which bought nine companies, three of them in the third quarter. Dell and Zynga each have made four acquisitions, tied for second on the list.

The IPO market might be looking a little frosty, but the M&A market so far this year has been positive enough to warm VCs’ hearts.

The median selling price through September was nearly $71 million – four times the median amount invested prior to liquidity, according to Dow Jones VentureSource. That kind of multiple hasn’t been seen since 2000.

Because M&A is affected by the stock market, the pace is likely to fall in the fourth quarter, but the total raised is sure to exceed last year. VentureSource pegs the amount raised in the first nine months at $37.3 billion, only slightly behind the $39.42 billion for all of 2010, which was the best year since 2007. (VentureSource is owned by Dow Jones & Co., the publisher of this blog.)

So far this year, six acquisitions of U.S.-based venture-backed companies have closed at $700 million or more. The biggest was Plexxikon, which Daiichi Sankyo bought for $805 million. The company, which is developing a treatment for melanoma, raised $67 million from investors including Advanced Technology Ventures, Alta Partners, Astellas Venture Capital, Pappas Ventures and Walden International. The deal includes an additional $130 million in potential milestone payments

Second place goes to another health-care company, medical device maker Ardian, which sold to Medtronic for $800 million after raising more than $66 million. Advanced Technology Ventures was an investor in that company, too, along with Emergent Medical Partners, Morgenthaler Ventures and Split Rock Partners. Medtronic also was a backer.

Those deals closed in the first half of the year. The action lately has been more on the tech side. The third-largest deal of the year – and largest of the third quarter – was the $750 million sale of PopCap Games to Electronic Arts. The price could climb by another $550 million if certain performance goals are met. PopCap raised a single round of $22.5 million led by Meritech Capital Partners.

Paul Madera, a Meritech managing director said that during the last two years, the late-stage venture investor has seen its best run of liquidity since its start in 1999. But with stock market volatility crimping IPOs, he expects corporate acquirers to become more cautious. “There isn’t as much urgency to get things done,” Madera said.

Still, large tech companies are sitting on piles of cash and competition is fierce. The most active acquirer through September was Google, which bought nine companies, three of them in the third quarter. Dell and Zynga each have made four acquisitions, tied for second on the list.

WALTHAM, Mass., Sept. 6, 2011 /PRNewswire/ -- Syndax Pharmaceuticals, Inc., a clinical-stage epigenetics oncology company, announced today that ENCORE 301, a randomized, placebo-controlled phase 2 study of exemestane with and without entinostat hit its primary endpoint of an improvement in progression-free survival (PFS).  The study showed that patients who received entinostat, a novel, oral small molecule inhibitor of class I histone deacetylases, with the hormone therapy exemestane, lived longer without their disease getting worse than people who received exemestane alone.   Safety and efficacy results from the trial will be presented in a poster and an oral presentation at the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium 2011 in San Francisco, CA this week.  

"Entinostat combined with exemestane prolonged progression-free survival, reducing the risk of disease progression by 27% and showing an improvement in overall survival for post-menopausal women with estrogen-receptor positive metastatic breast cancer," said Denise A. Yardley, MD, breast program leader, senior investigator at the Sarah Cannon Research Institute and principal investigator of the study. "Furthermore, in a subset of patients evaluated for a pharmacodynamic measure of entinostat's effect, we demonstrated for the first time with this class of agents evidence of an association of protein lysine hyperacetylation with clinical outcome. I am extremely excited to be able to work with Syndax to validate the findings from this randomized phase 2 blinded, placebo-controlled trial with the development of a larger phase 3 confirmatory trial in hormone receptor-positive advanced breast cancer patients."

ENCORE 301 (ENtinostat Combinations Overcoming REsistance) was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of exemestane with and without entinostat in 130 postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer, progressing on treatment with the non-steroidal aromatase inhibitors anastrozole or letrozole.  The primary endpoint of the study was progression-free survival.  Other endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and safety and tolerability.  All patients had received prior hormonal therapy (1 prior line 42%; >1 prior line 58%), and 33% had received prior chemotherapy in the advanced breast cancer setting.  The results of this study with well-balanced arms included the following:

In the intent-to-treat population progression-free survival was significantly longer (defined prospectively as 1-sided p <0.10) with exemestane plus entinostat than with exemestane plus placebo (4.28 versus 2.27 months, respectively; hazard ratio (HR) = 0.73; p=0.06);

In the intent-to-treat population, with a median follow-up of 18 months, overall survival was significantly longer with exemestane plus entinostat than with exemestane plus placebo (26.94 versus 20.33 months, respectively; hazard ratio (HR) = 0.56; p=0.027);

In the subset of entinostat patients with protein acetylation data (n=27), median PFS increased to over six months in the patients exhibiting protein lysine hyperacetylation;

Entinostat combined with exemestane was well tolerated with the most frequent adverse events (AE) consisting of fatigue, gastrointestinal disturbances and hematologic abnormalities; and

Serious AE rate was similar for exemestane plus entinostat (13%) and exemestane plus placebo (12%).

"Delaying disease progression and improving survival, combined with an attractive safety profile, makes entinostat and exemestane an exciting option for patients with advanced ER-positive breast cancer," said Kathy D. Miller, MD, associate professor at Indiana University and trial investigator.  "Hormone therapy remains the mainstay of treatment for patients with hormone-sensitive disease. These clinical results provide hope to clinicians and patients that we may be able to delay resistance and increase the time to disease progression, maintaining women longer on hormone-based therapy with fewer side effects than chemotherapy." 

ENCORE 301 data will be presented in a poster session on Friday, September 9 from 4:30 to 5:45 PM PT and during an oral session on Saturday, September 10 from 10:00 to 11:30 AM PT in San Francisco, CA during the ASCO Breast Cancer Symposium 2011.  

"Based on the positive results from ENCORE 301 and the enthusiasm of the breast cancer community, we plan to enroll the first patient into a global, pivotal phase 3 study in early 2012," said Joanna Horobin, MD, president and chief executive officer of Syndax.  "While epigenetic drugs are approved for hematologic malignancies, if entinostat proves successful in this breast cancer setting, this  would be the first epigenetic therapy to benefit patients with solid tumors, representing not only an important contribution to the treatment of breast cancer but a significant commercial opportunity."

Breast Cancer and Hormone Therapy

Approximately 230,000 new cases of invasive breast cancer are diagnosed in women annually in the United States and there are approximately 150,000 women living with metastatic breast cancer (MBC).  Over 70 percent of women with breast cancer have estrogen receptor-positive (ER+) breast cancer.  The most effective cancer treatments target the underlying biology and in breast cancer the most common oncogenic driver is estrogen receptor signaling.  Blocking estrogen activity with aromatase inhibitors represents an effective treatment for most ER+ MBC patients, however acquired drug resistance to aromatase inhibitors leads to disease progression, ultimately requiring less effective, more toxic chemotherapies.(1)   Delaying resistance and disease progression represents a significant unmet need that could prolong survival while decreasing health care costs associated with chemotherapy and hospitalization.

About Entinostat

Syndax's lead product entinostat is a novel, oral small molecule inhibitor of class I histone deacetylases, key enzymes that alter the structure of chromatin to control gene expression. Entinostat is differentiated from other members of the class through its unique selectivity profile, pharmacokinetic properties and safety profile. Entinostat has been studied in more than 600 cancer patients where objective tumor responses have been observed in both solid and hematologic malignancies.

WALTHAM, Mass., Aug. 17, 2011 /PRNewswire/ -- Syndax Pharmaceuticals, a clinical-stage epigenetics oncology company, today announced allowance by the European Patent Office for the patent application titled "N-(2-AMINOPHENYL)-4[N-(PYRIDINE-3-YL) - METHOXYCARBONYL - AMINOMETHYL]-BENZAMINE (MS-275) POLYMORPH B." This allowance follows the recent US issuance which was granted in June adding to the extensive patent estate for the Company's lead product, entinostat.

The patent covers the novel polymorph form B of the oral histone deacetylase inhibitor, entinostat, which is the specific polymorph being developed by Syndax for combination therapy with aromatase inhibitors for metastatic breast cancer and epidermal growth factor receptor tyrosine kinase inhibitors for advanced non-small cell lung cancer.

"This European allowance combined with the recent US issuance provides a strong patent position for entinostat, our lead product candidate, as we move forward into phase 3 testing for women with metastatic breast cancer," said Joanna Horobin, MD, president and chief executive officer of Syndax. "We look forward to presenting the results from our randomized phase 2 placebo-controlled study in metastatic breast cancer at the ASCO 2011 Breast Cancer Symposium in September. We believe entinostat may help address the significant need to improve outcomes for the thousands of women in the United States living with metastatic breast cancer by extending the benefit of hormone therapy and delaying initiation of chemotherapy."

About Entinostat

Syndax's lead product entinostat is a novel, oral small molecule inhibitor of class I histone deacetylases, key enzymes that alter the structure of chromatin to control gene expression. Entinostat is differentiated from other members of the class through its unique selectivity profile, pharmacokinetic properties and safety profile. Entinostat has been studied in more than 600 cancer patients where objective tumor responses have been observed in both solid and hematologic malignancies.

Breast cancer animal models demonstrated that resistance to aromatase inhibitors occurs through up-regulation of growth factor signaling pathways and down-regulation of estrogen receptor-alpha (ER). Entinostat effectively down-regulates growth factor signaling in breast cancer cells where these pathways are active. Entinostat also up-regulates the expression of ER in breast cancer cells which have negligible or undetectable levels of ER. In pre-clinical testing entinostat induced tumor regression when combined with an aromatase inhibitor after the development of hormone resistance. The ability to target multiple mechanisms of resistance establishes entinostat as a promising candidate for preventing and overcoming aromatase inhibitor resistance through epigenetic modulation.

Additional phase 2 studies with entinostat have demonstrated promising results in combination with the EGFR-TKI erlotinb (ENCORE-401) in non-small cell lung cancer and as a single agent in Hodgkin's lymphoma (ENGAGE-501). Results from the ENCORE clinical program have provided the basis for moving entinostat in pivotal, phase 3 testing across a platform of breast and lung cancer indications.

About Syndax

Syndax Pharmaceuticals, Inc. is a Waltham, MA-based, oncology-focused pharmaceutical company. Syndax is building a portfolio of new oncology products to extend and improve the lives of patients by developing and commercializing novel cancer therapies in optimized, mechanistically driven combination regimens. Formed in 2005, the company's intellectual property is based on work from scientific founder Ronald Evans, Ph.D., recipient of the 2004 Albert Lasker Prize for Basic Medical Research, a Member of the National Academy of Sciences, a professor at the Salk Institute for Biological Studies and a Howard Hughes Medical Institute Investigator. Syndax has worldwide rights to develop and commercialize entinostat and is backed by top-tier Venture Capital firms: Domain Associates, MPM Capital, Avalon, Pappas and Forward Ventures. For more information please visit www.syndax.com.