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.

The CED, a private nonprofit in the Triangle that fosters entrepreneurism, announced Monday it had elected new officers for its board of directors, including executives from Pappas Ventures    and ChannelAdvisor.

The new chairman will be Eric Linsley, managing partner for Pappas Ventures, while David Spitz, president and COO of ChannelAdvisor, will serve as chairman-elect.

CED officers serve one-year terms.

The company elected 14 new members to the board, and had 13 members return for a second term. The full list is available here.

At this year’s ASCO meeting, researchers reported findings that mark the most encouraging clinical results in the history of RNAi therapeutic development. If later-stage clinical trials produce positive results as well, the data would vindicate small biotech companies that were abandoned by big pharma when times for RNAi-based drugs got tough.

These molecules initially generated enormous excitement in drug development circles, bolstered by the imprimatur of a Nobel Prize in physiology and medicine awarded to discoverers Andrew Z. Fire and Craig C. Mello. The hope was that synthetic siRNAs could shut off expression of disease-associated genes, providing therapies for previously untreatable human diseases ranging from cancer to genetic disorders.

Initially caught up in the excitement of access to an entirely new class of therapeutics to fill withering pipelines, pharma put serious money into RNAi programs. Leading the acquisition pack, Merck & Co. bought research company Sirna Therapeutics for $1.1 billion in 2006. Investment in RNAi was about $500 million between 2007 and 2010; RNAi pioneer Alnylam Pharmaceuticals alone recorded $57 million in research revenues from Roche.

Over the last couple of years, though, big pharma has bailed out of backing RNAi-based therapeutics. Mounting technical difficulties, especially delivery issues and immunogenicity, with the molecules were cited as the main reason. Clinical results making their way out of development programs may help assuage some of these concerns, as might the settlement of patent litigation involving Alnylam, Max Planck Society, the Whitehead Institute for Biomedical Research, and the University of Massachusetts (UMass).

To attract big pharma back, though, late-stage results will need to validate early clinical success. As the RNAi therapeutic field comes closer to reality, however, it will likely have to survive further lawsuits, as is the situation with the recently filed case against Alnylam by manufacturing partner Tekmira; Alnylam was among presenters at ASCO touting good news for RNAi with its candidate that uses Tekmira technology.

Big Pharma's Entry and Exit

As big pharma reconsidered its love affair with RNAi-based drugs, small companies cut back on programs and personnel. Five years after Merck’s mega purchase of Sirna, the biotech firm’s technology is being primarily used for laboratory studies rather than searching for the next blockbuster therapy.

Pharma’s attack of cold feet also hurt RNAi pioneer Alnylam Pharmaceuticals. The company said it planned to cut about 25 to 30 percent of its workforce as one of its pharma partners, Novartis, terminated a five-year alliance with it.

Last February Pfizer announced that it was dropping its therapeutic RNAi drug development work as part of a global R&D restructuring plan aimed at saving the company $1.5 billion. Also last year, in November, Roche said that it would close down RNAi research at three sites: Kulmbach, Germany; Madison, WI; and Nutley, NJ.

Roche had paid Alnylam $331 million in cash and equity for the Klumbach facility in 2007 as part of an agreement that included RNAi drugs for oncology and respiratory diseases. In 2008, Roche took over Mirus Bio for $125 million. The deal gave it the site in Madison, 20 employees, and an siRNA delivery system based on polyconjugate technology.

Then, in 2009, Roche paid $18.4 million up front to use Tekmira’s lipid nanoparticle (LNP) delivery technology to put its RNAi products into the clinic. The goal was to get its first RNAi-based product into the clinic by the end of 2010.

Instead, Roche is effectively out of the RNAi drug development business. The company said that there were ongoing challenges with cell-specific delivery and that the most promising indications for the technology were not part of its strategy.

Positive Early-Stage Data

Despite pharma’s defection from the space, small companies developing siRNA drug molecules are beginning to see glimmers of success, and business deals continue to go forward. As Pfizer left the space in 2010, Marina Biotech announced a product-specific development deal with Debiopharm.

The agreement covers a preclinical-stage bladder cancer program based on the topical delivery of LNP-siRNs. Marina will perform the early development work, funded by Debiopharm, and has the potential to earn milestone-based fees and royalties.

At the 2011 ASCO meeting, Silence Therapeutics reported positive data from its ongoing Phase I study of Atu027 in patients with advanced solid tumors. It is a liposomal siRNA formulation targeting PKN3, which is reportedly a key regulator of angiogenesis and lymphangiogenesis as well as metastasis and motility during pathological processes.

Data showed that nine of the 24 patients treated with the molecule achieved stable disease after repeated treatment. Six of these cases were confirmed at study end (three months after treatment initiation), and three other patients are continuing to receive treatment.

At the same meeting Alnylam reported results from a Phase I trial with its ALN-VSP, a systemically delivered RNAi therapeutic for the treatment of advanced solid tumors with liver involvement. Data showed that ALN-VSP was generally well tolerated, demonstrated evidence for anti-tumor activity, and was found to mediate RNAi activity in both hepatic and extra-hepatic tumors. The study demonstrated evidence of antitumor activity in heavily pretreated patients at doses of 0.7 mg/kg. Disease stabilization occurred in 64% (7 of 11) of patients who received the recommended Phase II dose of 1 mg/kg.

ALN-VSP comprises two siRNAs designed to target two genes required for the growth and development of cancer cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP), also known as eglin 5 (Eg5). The siRNA drug is formulated using a first-generation lipid nanoparticle developed by Tekmira Pharmaceuticals, Alnylam’s manufacturing partner for LNPs for RNAi drug delivery.

“At a high level, this was a first-in-human study in refractory cancer patients with metastatic disease, including liver involvement,” Akshay Vaishnaw, M.D., Ph.D., Alnylam’s svp of clinical research, pointed out to GEN. “The drug’s safety profile was very encouraging, but beyond safety, we got a lot of interesting mechanistic information.

“We did a series of DCE-MRI tests on the patients before and after treatment. This type of study allows visualization of blood flow through tumors. Since one of the drug components was an anti-VEGF siRNA, we wanted to monitor its effects. We found that 13 of the 28 study patients had a greater than 40 percent reduction in tumor blood flow, which is very comparable to other anti-angiogenic agents.”

Dr. Vaishnaw explained that the investigators also looked for evidence of specific mRNA cleavage in liver biopsies from patients taken before and after treatment. “We could show target mRNA cleavage in tumor biopsies that was present after but not before treatment,” he noted. “That is a very important molecular proof-of-concept for the field of RNAi therapeutics.”

Dr. Vaishnaw also commented on the lipid nanoparticles used in the drug formulation. “We have shown that LNPs provide a tractable way to achieve siRNA delivery. We think that bodes well for other areas of the platform, where we will use these particles for other siRNA applications.”

Alnylam’s drug candidate for transthyretin mediated amyloidosis, ALN-TTR01, uses the same LNP but has an siRNA directed against transthyretin. The company expects data from its Phase I study with ALN-TTR01 in the third quarter of this year. Finally, Alnylam has a Phase II-stage RNAi therapeutic called ALN-RSV01, which is being tested in lung transplant patients infected with respiratory syncytial virus.

Will Lawsuits Hamper R&D?

Alnylam, however, has more than just clinical development challenges on its plate. It will have to get through a lawsuit filed by Tekmira after having just settled another case regarding the Tuschl patents. The firm signed a global settlement agreement with Max Planck Society, Whitehead Institute, and UMass. MIT, formerly a party to the litigation, also agreed to the terms of the settlement.

As part of the settlement agreement, Max Planck, Whitehead, UMass, and MIT have agreed that future prosecution of the Tuschl I and Tuschl II patent families in the U.S. should be coordinated and led by a single party. Max Planck will assume that role, in addition to its ongoing leadership in the continued prosecution of the Tuschl II patent family outside the U.S. Importantly, UMass received the right to license Tuschl II to Merck/Sirna with certain limitations and to prosecute Tuschl I outside the U.S.

Now, however, Alnylam will have to contend with litigation around the LNP technology it uses to deliver its siRNA drugs. Tekmira said the suit was filed in response to “misappropriation and misuse of trade secrets, know-how and other confidential information, unfair and deceptive trade practices, unjust enrichment, unfair competition, and false advertising.”

Tekmira is seeking what could amount to more than $1 billion from Alnylam. Alnylam filed a legal response and counterclaim against Tekmira, saying that it plans to “fully defend itself.”

So while 2011 has looked like a validating year for RNAi technology, with the advent of clinical results and one major patent dispute getting settled, there is still concern over lawsuits that could crop up around enabling technologies. Additionally, small companies developing siRNA drug molecules or focused on delivery systems are trying to soldier on despite big pharma’s dysfunctional planning processes.

It is hoped that no one involved will get so distracted with all this tap dancing that much needed novel drug development fails to proceed, which would leave shareholders and patients alike holding a bag of hot air. Maybe pharma companies who bailed out saw it coming.

Chicago-—They’re not cures, but two novel drugs produced unprecedented gains in survival in separate studies of people with melanoma, the deadliest form of skin cancer, doctors reported on Sunday. In one study, an experimental drug showed so much benefit so quickly in people with advanced disease that those getting a comparison drug were allowed to switch after just a few months.

The drug, vemurafenib, targets a gene mutation found in about half of all melanomas. The drug is being developed by Genentech, part of Swiss-based Roche, and Plexxikon Inc., part of the Dai-ichi Sankyo Group of Japan.

The second study tested Bristol-Myers Squibb Co.’s Yervoy, a just-approved medicine for newly diagnosed melanoma patients, and found it nearly doubled the number who survived at least three years.

“Melanoma has just seen a renaissance of new agents,” and more are being tested, said Dr. Allen Lichter, chief executive of the American Society of Clinical Oncology.

The new studies were presented recently at the oncology group’s annual meeting in Chicago and published online by the New England Journal of Medicine.

“This is really an unprecedented time of celebration for our patients,” said Dr. Lynn Schuchter, of the University of Pennsylvania’s Abramson Cancer Center. The new drugs are not by themselves cures, but “the future is going to be to build upon the success” by testing combinations of these newer drugs, she said.

Melanoma is on the rise. There were 68,000 new cases and 8,700 deaths from it in the United States last year, the American Cancer Society estimates. Only two drugs had been approved to treat it, with limited effectiveness, until Yervoy, an immune-system therapy, won approval in March.

The experimental drug, vemurafenib (vem-yoo-RAF-eh-nib), is aimed at a specific gene mutation, making it the first so-called targeted therapy for the disease. The drug got attention when a whopping 70 percent of those with the mutation responded to it in early safety testing.

The new study, led by Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York, was the key test of its safety and effectiveness. It involved 675 patients around the world with inoperable, advanced melanoma and the gene mutation. They received vemurafenib pills twice a day or infusions every three weeks of the chemotherapy drug dacarbazine.

After six months, 84 percent of people on vemurafenib were alive versus 64 percent of the others.

Less than 10 percent on the drug suffered serious side effects—mostly skin rashes, joint pain, fatigue, diarrhea and hair loss. About 18 percent of patients developed a less serious form of skin cancer. More than a third needed their dose adjusted because of side effects.

The study is continuing, and many remain on the drug, including one of Schuchter’s patients: Brian Frantz, a 50-year-old former firefighter from Springfield, Virginia.

Within a week or two of starting on the drug in September, “we noticed an improvement” and shrinkage in his many tumors, he said. “It was just a miracle.”

Schuchter said that’s typical of how patients have responded to the drug.

“Within 72 hours, their symptoms improve, pain medicines can be reduced,” she said.

The study is a landmark and the results are “very impressive” in people, who historically have not fared very well, said Dr. April Salama, a Duke University melanoma specialist.

The study was sponsored by the drug’s makers, and many of the researchers consult or work for them. The companies are seeking approval to sell the drug and a companion test for the gene mutation in the US and Europe. A Genentech spokesman said the price has not yet been determined.

The other new drug, Yervoy, is not a chemotherapy but a treatment to stimulate the immune system to fight cancer. Dr. Jedd Wolchok of Memorial Sloan-Kettering led the first test of it in newly diagnosed melanoma patients.

About 502 of them received dacarbazine and half also got Yervoy. After one year, 47 percent of those on Yervoy were alive versus 36 percent of the others. At three years, survival was 21 percent with Yervoy versus 12 percent for chemotherapy alone.

Side effects included diarrhea, rash and fatigue. More than half on the new drug had major side effects versus one quarter of those on chemotherapy alone.

Bristol-Myers Squibb paid for the study and many researchers consult or work for the company. Treatment with Yervoy includes four infusions over three months and costs $30,000 per infusion.

Understanding oncogenesis at the molecular level offers the prospect of tailoring treatments much more precisely for patients with advanced cases of this deadliest of skin cancers.

Syndax Pharmaceuticals, a clinical-stage epigenetics oncology company, announced the National Cancer Institute (NCI) will sponsor a multi-center phase 2 study of Syndax’s lead product entinostat, a novel inhibitor of histone deacetylases (HDAC), and anastrozole, an aromatase inhibitor, in postmenopausal women with operable triple negative breast cancer to evaluate biomarkers and surrogates for response. The trial, to be conducted under a Cooperative Research and Development Agreement (CRADA) executed between the NCI and Syndax, will investigate whether patient tumors can be reprogrammed to express estrogen receptor and render them to be sensitive to hormonal agents. This trial is based on animal data being published in the March 1, 2011, issue of Cancer Research.