Survival Benefit With Syndax Pharmaceuticals' Entinostat Maintained in Women with Advanced Breast Cancer

--Seven-month survival advantage for exemestane plus entinostat treated patients--,
--Data presented at San Antonio Breast Cancer Symposium--,

WALTHAM, Mass., Dec. 7, 2011 -- WALTHAM, Mass., Dec. 7, 2011 /PRNewswire/ -- Syndax Pharmaceuticals, Inc. announced today that, with a 23-month patient follow up of ENCORE 301, a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of exemestane with and without entinostat in 130 patients with locally recurrent or metastatic estrogen receptor-positive breast cancer, the median overall survival of exemestane plus entinostat patients reached 26.9 months versus 19.8 months for exemestane plus placebo. This represents a 42% reduction (p=0.04) in the risk of dying for these patients. Previously presented data from ENCORE 301 demonstrated a near doubling in the progression-free survival (PFS) (4.3 vs. 2.3 months) with exemestane plus entinostat and the identification of a subset of these patients whose median PFS reached 8.5 months. The updated data is being presented today, December 7, 2011, at the San Antonio Breast Cancer Symposium in San Antonio, Texas.

"It is both exciting and encouraging to see after two years of follow up that patients treated with entinostat and exemestane benefited from an additional seven months of overall survival," said Denise A. Yardley, MD, breast program leader, senior investigator at the Sarah Cannon Research Institute and principal investigator of the study. "This encouraging signal of not only a progression-free survival advantage (4.3 months vs 2.3 months) but also of an overall survival benefit for this combination, coupled with an excellent safety and tolerability profile, provide the platform for the larger scale confirmatory, randomized, phase 3 study anticipated to begin enrollment in the first half of 2012."

Highlights of the data to be presented include:

• Overall survival: 26.9 months for exemestane + entinostat vs. 19.8 months for exemestane + placebo HR = 0.58 (95%CI: 0.34, 0.97) p = 0.04
• Progression-free survival: 4.3 months for exemestane + entinostat vs. 2.3 months for exemestane + placebo HR = 0.73 (95%CI: 0.49, 1.09) p = 0.06; 1-sided significance prospectively defined as  <0.10
• Progression-free survival of 8.5 months for exemestane + entinostat in subset of patients with increased protein acetylaton vs. 2.8 months in non acetylators HR = 0.32 (95%CI: 0.13, 0.79)
• Trend in improved progression-free survival in hormone-resistant vs. hormone-sensitive patients
• Exemestane combined with entinostat was well tolerated with the most frequent adverse events consisting of fatigue, gastrointestinal disturbances and hematologic abnormalities

"The continued survival benefit increases our confidence that entinostat will play a critical role in the treatment of women with estrogen receptor-positive metastatic breast cancer," said Joanna Horobin, MD, president and chief executive officer of Syndax.  "We look forward to moving entinostat into phase 3 clinical testing in 2012."
San Antonio Breast Cancer Symposium

Presentation Date/Time: Wednesday, December 7 from 5:00 PM - 7:00 PM
Poster Title: Entinostat, a Novel Histone Deacetylase Inhibitor, Added to Exemestane Improves PFS in Advanced Breast Cancer in a Randomized, Phase II, Double-Blind
Study Session: POSTER DISCUSSION I: Endocrine Resistance
Abstract Number: PD01-04
Location: Ballroom A

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.  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 (ERα). 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. The ability to target multiple mechanisms of resistance establishes entinostat as a promising candidate for preventing and overcoming aromatase inhibitor resistance through epigenetic modulation. In pre-clinical testing entinostat induced tumor regression when combined with an aromatase inhibitor after the development of hormone resistance.

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, late-stage, oncology-focused pharmaceutical company. The company 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. Syndax has worldwide rights to develop and commercialize entinostat which has shown promise in randomized clinical trials in solid tumors. Syndax is backed by top-tier venture capital firms Domain Associates, MPM Capital, Avalon, Pappas and Forward Ventures. Formed in 2005, Syndax'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.   For more information please visit www.syndax.com.

Survival Benefit With Syndax Pharmaceuticals' Entinostat Maintained in Women with Advanced Breast Cancer

--Seven-month survival advantage for exemestane plus entinostat treated patients--,

--Data presented at San Antonio Breast Cancer Symposium--,

WALTHAM, Mass., Dec. 7, 2011 -- WALTHAM, Mass., Dec. 7, 2011 /PRNewswire/ -- Syndax Pharmaceuticals, Inc. announced today that, with a 23-month patient follow up of ENCORE 301, a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of exemestane with and without entinostat in 130 patients with locally recurrent or metastatic estrogen receptor-positive breast cancer, the median overall survival of exemestane plus entinostat patients reached 26.9 months versus 19.8 months for exemestane plus placebo. This represents a 42% reduction (p=0.04) in the risk of dying for these patients. Previously presented data from ENCORE 301 demonstrated a near doubling in the progression-free survival (PFS) (4.3 vs. 2.3 months) with exemestane plus entinostat and the identification of a subset of these patients whose median PFS reached 8.5 months. The updated data is being presented today, December 7, 2011, at the San Antonio Breast Cancer Symposium in San Antonio, Texas.

"It is both exciting and encouraging to see after two years of follow up that patients treated with entinostat and exemestane benefited from an additional seven months of overall survival," said Denise A. Yardley, MD, breast program leader, senior investigator at the Sarah Cannon Research Institute and principal investigator of the study. "This encouraging signal of not only a progression-free survival advantage (4.3 months vs 2.3 months) but also of an overall survival benefit for this combination, coupled with an excellent safety and tolerability profile, provide the platform for the larger scale confirmatory, randomized, phase 3 study anticipated to begin enrollment in the first half of 2012."

Highlights of the data to be presented include:

• Overall survival: 26.9 months for exemestane + entinostat vs. 19.8 months for exemestane + placebo HR = 0.58 (95%CI: 0.34, 0.97) p = 0.04
• Progression-free survival: 4.3 months for exemestane + entinostat vs. 2.3 months for exemestane + placebo HR = 0.73 (95%CI: 0.49, 1.09) p = 0.06; 1-sided significance prospectively defined as  <0.10
• Progression-free survival of 8.5 months for exemestane + entinostat in subset of patients with increased protein acetylaton vs. 2.8 months in non acetylators HR = 0.32 (95%CI: 0.13, 0.79)
• Trend in improved progression-free survival in hormone-resistant vs. hormone-sensitive patients
• Exemestane combined with entinostat was well tolerated with the most frequent adverse events consisting of fatigue, gastrointestinal disturbances and hematologic abnormalities

"The continued survival benefit increases our confidence that entinostat will play a critical role in the treatment of women with estrogen receptor-positive metastatic breast cancer," said Joanna Horobin, MD, president and chief executive officer of Syndax.  "We look forward to moving entinostat into phase 3 clinical testing in 2012."

San Antonio Breast Cancer Symposium
Presentation Date/Time: Wednesday, December 7 from 5:00 PM - 7:00 PM
Poster Title: Entinostat, a Novel Histone Deacetylase Inhibitor, Added to Exemestane Improves PFS in Advanced Breast Cancer in a Randomized, Phase II, Double-Blind
Study Session: POSTER DISCUSSION I: Endocrine Resistance
Abstract Number: PD01-04
Location: Ballroom A

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.  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 (ERα). 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. The ability to target multiple mechanisms of resistance establishes entinostat as a promising candidate for preventing and overcoming aromatase inhibitor resistance through epigenetic modulation. In pre-clinical testing entinostat induced tumor regression when combined with an aromatase inhibitor after the development of hormone resistance.

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, late-stage, oncology-focused pharmaceutical company. The company 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. Syndax has worldwide rights to develop and commercialize entinostat which has shown promise in randomized clinical trials in solid tumors. Syndax is backed by top-tier venture capital firms Domain Associates, MPM Capital, Avalon, Pappas and Forward Ventures. Formed in 2005, Syndax'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.   For more information please visit www.syndax.com.

Female biotech executives have been key players in many of the biggest events in the industry this year--Takeda Pharmaceutical's buyout of Nycomed, the merger of Alkermes ($ALKS) and Elan Drug Technologies and the sale of Plexxikon to Daiichi Sankyo. Should we be surprised? No, women in this industry defy the odds when they rise to key positions in the male-dominated biotech game. Of course we're seeing them accomplish big things. But they deserve recognition.

So, we're excited to bring our readers FierceBiotech's much-awaited-and belated-Women in Biotech feature. We had an overwhelming response to our call for nominations this year, with more than 130 great submissions and an amazing slate of candidates. True to our mission of providing readers the top news in biotech, many of the honorees here are women who drove some of the big stories we covered this year. We also wanted the women featured this year to represent the best of the global biotech industry, and you'll find women here who are making an impact for organizations based in Asia, Europe and here in the U.S.These women are inspiring, not just to women, but (at least speaking for the males on our team) men involved in the industry, too. Our profiles will bring you up to date with what each of these female movers in biotech are working on these days. Some are rallying scientists at young startups, gearing up for important late-stage trials or leading research of serious health concerns such as HIV. For each of the honorees, there are unique stories about how impressive women have gotten ahead in the competitive biotech field."

I think that the potential interesting little extra that you get from speaking to some of the women in biotech is we've probably been challenged with thinking a little bit more about how to cultivate our careers," said Abbie Celniker, chief executive of Eleven Biotherapeutics and one of this year's Women in Biotech. "As a result, we can be a tiny bit more self-reflective because we've had to do lots of course correction to make sure we could compete in the days when it was more predominately male."

Kathleen Sereda Glaub
President, Plexxikon

In the biotech business and at her home garden, Kathy Glaub likes to plant seeds and watch them grow. Of course, the seeds of biotech involve investments in R&D and carefully crafted financing strategies. In those regards, there's been a bumper crop this year at the drug discovery firm Plexxikon, and Glaub has been able to savor the fruits of her 10 years spent helping to shape the business strategy and firming up lucrative partnership deals.

Berkeley, CA-based Plexxikon has been a breakout success this year, during which the startup was sold to Japan's Daiichi Sankyo in a nearly $1 billion deal closed in April and its lead drug Zelboraf gained an FDA green light for treating melanoma. Glaub has been heavily involved in the action; she hammered out the details of the buyout pact with Daiichi, which has kept Plexxikon intact as an independently operating discovery and development shop. She also helped field a sales team this year for marketing Zelboraf, which is partnered with Swiss drug giant Roche.

Success like this is a rare thing in biotech, where even companies that raise gobs of cash and boast hot science often tank. So it's worth taking note of some of the moves Glaub and her colleagues made at Plexxikon. For one, the group brought more than $200 million in non-dilutive funding through a series of pharma collaborations, dwarfing the nearly $67 million in equity the firm sold to raise capital for its programs. The company has also kept a relatively lean team on its full-time roster, and the company's prudent fiscal management allowed it to operate in the black--and, yes, paying taxes--for several years before the approval of Zelboraf, Glaub said.

To come out on top at Plexxikon, Glaub has more than two decades in the biotech field, getting her start in the industry with Genentech during the mid-1980s. She rose to treasurer of the famous biotech (now a unit of Roche, of course) in 1988, managing the company's cash during a time when capital was scarce compared with reserves in later years. She then jumped aboard Cell Genesys, where she was financial chief from 1993 to 1998. (Cell Genesys, a therapeutic vaccine developer, was sold on the cheap in 2009 to BioSante after running into financial trouble.) Glaub's track record at Plexxikon speaks volumes for the wisdom she's gained and applied during her years in biotech.

"Wherever I have gone, I have placed my bets on the people I would be working with," Glaub said. "Secondly, I always ask how could we do something better, and why not? I have never been one to follow and rather enjoy bucking the trend or the models that people talk about. In part, that is how we were successful at Plexxikon."

Mary Lynne Hedley
President, CSO, Co-founder, Tesaro

Mary Lynne Hedley's latest biotech adventure has her exploring multiple paths to find and develop new therapies and supportive care drugs for cancer patients. Hedley, the president and chief scientist at Lexington, MA-based Tesaro, is now leading the company's excursion to gain FDA approval of its lead compound, rolapitant, which aims to prevent nausea and vomiting from chemotherapy and is ready for late-stage trials. At the same time, she's responsible for hunting for other drugs for cancer patients that fit the company's in-licensing strategy.

It's a big job, but that's part of the joy for Hedley. Rather than take a comfy post at an existing biotech after doing post-doctoral work at Harvard, Hedley and her colleagues decided to license technology from the venerable university and start their own company, Zycos, which focused on cancer and anti-viral drugs. She eventually became CEO of the venture-backed startup, leading the company through its sale to MGI Pharma. One of her proudest moments was handing nice bonus checks to her Zycos employees after the MGI buyout and a series of ups and downs that challenged the team, she said.

There's no reward for her quite like seeing how the drugs she develops help patients. MGI, where she led R&D after the company bought Zycos, was sold to Eisai for a nifty $3.9 billion in 2008. While she was heavily involved in the deal, and upbeat about its outcome, a more personal triumph was listening to the stories of patients who benefited from MGI's drug Dacogen for myelodysplastic syndromes, she said.

Taking a drug all the way through clinical trials and regulatory reviews takes great stamina. "I like to do things that are extremely important and physically challenging," said Hedley, who, outside of her work in biotech, went with her family on a demanding trek down the Inca Trail to explore Machu Picchu in Peru this year and wants to climb Kilimanjaro next year.

"Reaching higher has been critical to my success [in biotech]," Hedley said. "Doing the hardest thing I could, meaning taking the hardest career path because I was going to learn the most. It's the biggest risk because you can fail and if you fail you fall really hard. But sometimes in failure you pull yourself back up. Trying again makes you stronger. And when you succeed you strengthen the belief and confidence in yourself to go to the next level."

Read more: FierceBiotech's 2011 Women in Biotech - FierceBiotech http://www.fiercebiotech.com/special-reports/fiercebiotechs-2011-women-biotech#ixzz1fO6GHEHISubscribe: http://www.fiercebiotech.com/signup?sourceform=Viral-Tynt-FierceBiotech-FierceBiotech

Perhaps the biggest personalized medicine breakthrough of 2011 was the progress of melanoma drug Zelboraf and its companion diagnostic, both of which sped through regulatory approval.

Clinical trials demonstrated that Roche‘s (OTC:RHHBY) Zelboraf was extremely effective in treating skin cancer. But the drug doesn’t work for everyone. Only patients whose tumors express a particular gene mutation respond to the drug. The companion diagnostic also developed by Roche identifies the appropriate patients for Zelboraf. Under priority review by the U.S. Food and Drug Administration, approval of that diagnostic was expected this November. The agency beat that target by nearly three months.

Not all personalized medicine drugs and diagnostics will have such a speedy path through the FDA. But the companies, academics and investors who have a stake in personalized medicine are working to smooth the path for future personalized medicine breakthroughs.

The Personalized Medicine Coalition has released a report “The Case for Personalized Medicine,” choosing Research Triangle Park, North Carolina, where the group has a large cluster of members, to formally announce the document. In addition to supporting personalized medicine education and innovation, the group is also pushing for new legislation that would go further than the Genomics and Personalized Medicine Act of 2007. Among the group’s goals are forging a more predictable regulatory path for personalized medicine products and getting Medicare coverage of personalized medicine diagnostics. PMC President Edward Abrahams discusses some of the group’s legislative goals here.

The coalition hosted a panel discussion at the North Carolina Biotechnology Center on the opportunities and challenges facing personalized medicine. Here are some highlights.

Personalized medicine’s promise: In the last quarter, Burlington, North Carolina laboratory services and diagnostics company LabCorp (NYSE:LH) has released two personalized medicine tests, one of them a companion diagnostic for Zelboraf. The other, an Abbott companion diagnostic for lung cancer patients, predicts patient response to the Pfizer (NYSE:PFE) drug Xalkori. LabCorp CEO David King said that at one time, personalized medicine was thought of primarily in terms of reproductive testing such as pre-natal and neo-natal testing. But the technology today has come far and it promises to go even further.

Dr. Amy Abernethy, director of the Duke Cancer Care Research Program, sees many of those tools in the clinic. The kinds of tests that are available for her to use to make diagnostic and treatment decisions are vast and they grow each year. “The way we’ve practiced medicine in the clinic has rocketed forward in the last decade,” Abernethy said.

The challenges: While Abernethy embraces the new diagnostic tools, she said she’s not sure when a new test will show up in an electronic system with a reimbursement code. Jonathan Roy, director of commercial diagnostics for GlaxoSmithKline Biologicals (NYSE:GSK), offered a different perspective on reimbursement. In the United States, a company might get reimbursed, but not at a level they’d like. “In the European market, you might not get reimbursed at all,” he said. Roy said the global regulatory environment is wildly inconsistent from one market to another. But in finding partners for companion diagnostics, GSK must think globally because its goal is to make a test and a treatment available to the largest number of people. LabCorp’s King also sees regulatory as well as cost challenges for companion diagnostics. But as these tests become more common, he also sees challenges for clinicians. Personalized medicine will mean the generation of an enormous amount of data and it will be a challenge to process it and manage it. King likened the challenge to standing on the beach staring at an approaching 60 foot tidal wave. “And there will be one every minute,” he said.

Solutions. There is no shortage of companies angling for financial backing of new therapies and diagnostics in personalized medicine. Durham venture capital firm Pappas Ventures, which focuses on life science investments exclusively, receives more than 1,000 proposals a year. The firm has made several investments in companies developing personalized medicine products. One of them, California biotechnology company Plexxikon, developed the drug that is now Zelboraf. Plexxikon was acquired by Japanese pharma company Daiichi Sankyo earlier this year in a deal valued at more than $935 million. Pappas Ventures saw a return greater than 10 times its original investment in the firm.

Pappas Ventures Managing Partner Eric Linsley said he’s an optimist who believes in personalized medicine. But he added that he’s paid by the firm’s limited partners to be a skeptic. Linsley said he believes solutions will come from innovation. But for that to happen, the FDA must encourage that innovation and payers must modernize how they reimburse new technologies.

Perhaps the biggest personalized medicine breakthrough of 2011 was the progress of melanoma drug Zelboraf and its companion diagnostic, both of which sped through regulatory approval.

Clinical trials demonstrated that Roche‘s (OTC:RHHBY) Zelboraf was extremely effective in treating skin cancer. But the drug doesn’t work for everyone. Only patients whose tumors express a particular gene mutation respond to the drug. The companion diagnostic also developed by Roche identifies the appropriate patients for Zelboraf. Under priority review by the U.S. Food and Drug Administration, approval of that diagnostic was expected this November. The agency beat that target by nearly three months.

Not all personalized medicine drugs and diagnostics will have such a speedy path through the FDA. But the companies, academics and investors who have a stake in personalized medicine are working to smooth the path for future personalized medicine breakthroughs.

The Personalized Medicine Coalition has released a report “The Case for Personalized Medicine,” choosing Research Triangle Park, North Carolina, where the group has a large cluster of members, to formally announce the document. In addition to supporting personalized medicine education and innovation, the group is also pushing for new legislation that would go further than the Genomics and Personalized Medicine Act of 2007. Among the group’s goals are forging a more predictable regulatory path for personalized medicine products and getting Medicare coverage of personalized medicine diagnostics. PMC President Edward Abrahams discusses some of the group’s legislative goals here.

The coalition hosted a panel discussion at the North Carolina Biotechnology Center on the opportunities and challenges facing personalized medicine. Here are some highlights.

Personalized medicine’s promise: In the last quarter, Burlington, North Carolina laboratory services and diagnostics company LabCorp (NYSE:LH) has released two personalized medicine tests, one of them a companion diagnostic for Zelboraf. The other, an Abbott companion diagnostic for lung cancer patients, predicts patient response to the Pfizer (NYSE:PFE) drug Xalkori. LabCorp CEO David King said that at one time, personalized medicine was thought of primarily in terms of reproductive testing such as pre-natal and neo-natal testing. But the technology today has come far and it promises to go even further.

Dr. Amy Abernethy, director of the Duke Cancer Care Research Program, sees many of those tools in the clinic. The kinds of tests that are available for her to use to make diagnostic and treatment decisions are vast and they grow each year. “The way we’ve practiced medicine in the clinic has rocketed forward in the last decade,” Abernethy said.

The challenges: While Abernethy embraces the new diagnostic tools, she said she’s not sure when a new test will show up in an electronic system with a reimbursement code. Jonathan Roy, director of commercial diagnostics for GlaxoSmithKline Biologicals (NYSE:GSK), offered a different perspective on reimbursement. In the United States, a company might get reimbursed, but not at a level they’d like. “In the European market, you might not get reimbursed at all,” he said. Roy said the global regulatory environment is wildly inconsistent from one market to another. But in finding partners for companion diagnostics, GSK must think globally because its goal is to make a test and a treatment available to the largest number of people. LabCorp’s King also sees regulatory as well as cost challenges for companion diagnostics. But as these tests become more common, he also sees challenges for clinicians. Personalized medicine will mean the generation of an enormous amount of data and it will be a challenge to process it and manage it. King likened the challenge to standing on the beach staring at an approaching 60 foot tidal wave. “And there will be one every minute,” he said.

Solutions. There is no shortage of companies angling for financial backing of new therapies and diagnostics in personalized medicine. Durham venture capital firm Pappas Ventures, which focuses on life science investments exclusively, receives more than 1,000 proposals a year. The firm has made several investments in companies developing personalized medicine products. One of them, California biotechnology company Plexxikon, developed the drug that is now Zelboraf. Plexxikon was acquired by Japanese pharma company Daiichi Sankyo earlier this year in a deal valued at more than $935 million. Pappas Ventures saw a return greater than 10 times its original investment in the firm.

Pappas Ventures Managing Partner Eric Linsley said he’s an optimist who believes in personalized medicine. But he added that he’s paid by the firm’s limited partners to be a skeptic. Linsley said he believes solutions will come from innovation. But for that to happen, the FDA must encourage that innovation and payers must modernize how they reimburse new technologies.

ScienceDaily (Nov. 13, 2011) — Clinical benefit from use of a novel histone deacetylase inhibitor drug may be determined by examining blood cells days after a patient receives treatment. The drug, entinostat, is the first histone deacetylase inhibitor successfully tested in a randomized, placebo-controlled study in metastatic breast cancer -- and is the first to show that clinical outcome can be predicted shortly after administration.

The findings, reported at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held Nov. 12-16, 2011, represent an advance in the goal to offer patients only those therapies that will help treat cancer effectively, the researchers said.

"The ability to have a marker of benefit within the first several weeks of using this drug represents an exciting advance in personalized medicine," said lead researcher Peter Ordentlich, Ph.D., executive director of translational science and a founder of Syndax Pharmaceuticals Inc. in Waltham, Mass. Syndax Pharmaceuticals developed entinostat, an oral small-molecule drug that inhibits enzymes that alter the packaging of DNA inside the nucleus, which controls gene expression.

"The goal of entinostat in breast cancer is to extend the benefit of hormone therapy and delay the time that patients will need to use chemotherapy," said Ordentlich. More than 160,000 women are diagnosed each year with estrogen receptor (ER)-positive invasive breast cancer, and many are treated with agents that block the hormone. But most women become resistant to these therapies, and entinostat, combined with antihormone agents, is meant to extend their benefit, he said.

To test that strategy in ER-positive metastatic breast cancer, Syndax Pharmaceuticals conducted ENCORE-301, a randomized, placebo-controlled, phase 2 study (n=130) testing the use of exemestane, an aromatase inhibitor, with either entinostat or placebo.

Results of the clinical trial, released in September, showed that the combination therapy delayed cancer progression by 27 percent (4.3 vs. 2.3 months) compared with exemestane treatment alone. At a median follow-up of 18 months, overall survival was also significantly longer with exemestane plus entinostat than with exemestane plus placebo (26.9 vs. 20.3 months).

In this subset analysis, researchers examined blood samples from 49 patients (27 received combination therapy) to evaluate whether changes in circulating blood cells that reflected the activity of the histone deacetylase (HDAC) inhibitor could be detected. Researchers measured protein lysine acetylation, a biological marker of entinostat activity, in B cells, T cells and monocytes in blood samples taken at pretreatment and one, eight and 15 days after therapy with entinostat, which is taken once a week.

While levels of lysine acetylation after one day were not linked to clinical benefit, levels measured eight and 15 days after therapy were related to clinical benefit, Ordentlich said. Researchers found that patients with elevated levels of protein lysine acetylation had a 68 percent reduced risk for disease progression compared with those patients who did not have sustained elevated levels.

Researchers found that hyperacetylation was also associated with longer median progression-free survival across cell lines: B cells, 8.5 vs. 1.9 months; T cells, 6.6 vs. 1.8 months; and monocytes, 6.2 vs. 1.9 months. "Those patients who were able to maintain acetylation did well," Ordentlich said.

He added that entinostat's long half-life and unique pharmacology allow researchers to quickly gauge the agent's activity. In this way, "we gain insight into how to use HDAC inhibitors, as a class of cancer drugs, in a variety of solid tumors," he said.

The study was funded by Syndax Pharmaceuticals. Co-authors include investigators from the National Cancer Institute, who developed the assay used to test protein lysine acetylation in patient blood samples.