Chemotalk Newsletter

Chemotalk Newsletter, Vol. 66: October 1, 2013

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October. Say goodbye to watermelon until next spring...

 

LEUKEMIA DRUG WINS 'BREAKTHROUGH' STATUS

By John Carroll When Boehringer Ingelheim took volasertib into a Phase III study for ACUTE MYELOID LEUKEMIA earlier this year, the company claimed a pioneering role in advancing a promising cancer therapy that inhibits polo-like kinase--or Plk. The FDA agreed, offering to help speed development with its "breakthrough" therapy designation.

The BTD announcement marks another step forward in Boehringer's considerable effort to push a small group of late-stage cancer therapies into the market. In July the FDA approved afatinib for NON-SMALL CELL LUNG CANCER patients with EGFR mutations.

At ASCO last summer the company also reported positive--though slim--progression-free and overall survival data for nintedanib in a population of patients with advanced non-small cell lung cancer. Now another late-stage oncology program has stepped into the spotlight. Boehringer says it was one of the first groups to push a Plk drug into the clinic.

Volasertib inhibits Plk1, an enzyme that regulates cell division. By targeting the enzyme, the drug triggers apoptosis, blitzing cancer cells. "This FDA Breakthrough Therapy designation provides the opportunity to engage in an ongoing dialogue with the FDA to help expedite the development of volasertib as a potential treatment option for these patients with AML," said Sabine Luik, Boehringer's senior vice president of medicine and regulatory affairs.

Boehringer investigators barreled straight into Phase III in January after posting Phase II results on volasertib at the end of last year. Of the 42 patients who were ineligible for intensive remission induction therapy and treated with a combination of volasertib and LDAC, 13, or 31%, demonstrated a complete remission compared to 13% of the LDAC-only arm. The median event-free survival rate was 5.6 months in the combo group compared to 2.3 months in the chemo group.

All of Boehringer's cancer drugs are homegrown, stemming from a decision to start a cancer research division in Vienna 17 years ago. Now, that work is likely to bear fruit with some key approvals. There's still quite a bit of discussion about what the FDA's breakthrough drug status actually means. The FDA's cancer chief, Richard Pazdur, made a full-throated effort at ASCO to pledge the agency's assistance to hastening a final marketing decision on cancer drugs ushered into the BTD program. But it's early days yet, with little hard evidence available to demonstrate just how meaningful it is for developers.

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More good news:

CANCER DREAM TEAM

PHILADELPHIA, Sept. 27 -- The American Association for Cancer Research issued the following news release:

The American Association for Cancer Research (AACR) is now accepting submissions of ideas for the Stand Up To Cancer (SU2C)-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant, which will offer up to $8 million over a three-year period. The Lustgarten Foundation is providing $4 million in funding for this team. Collectively, the Fox Family Cancer Research Funding Trust and the Fox Family Foundation are making a $5 million gift to Stand Up To Cancer, $4 million of which is supporting this particular team.

Nobel laureate Phillip A. Sharp, Ph.D., describes convergence research as an exciting new approach that brings together the biological, computational, physical, and engineering sciences and entails not only collaboration among research groups, but also the integration of disciplinary approaches that were originally viewed as separate and distinct.

The grant provides three years of funding for research projects that must include therapeutic interventions for PANCREATIC CANCER and deliver near-term patient benefit through investigation by a multidisciplinary, multi-institutional convergence Dream Team of experts. The project must bring together biology (e.g. genomics, epigenetics, proteomics, and/or other biological fields) and at least one additional field of research such as physics, engineering, or immunology.

Proposals for the grant must describe plans indicating how the group will use a transformative and synergistic approach, and how the work will be translated into the clinic. To maximize creativity, innovation, and collaboration, the projects should span multiple disciplines and use modern scientific tools to attack research questions in a coordinated effort. In particular, the use of convergence research is required, which in addition to biology, aims to capitalize on a range of fields such as computer science, engineering design, immunology, and nanotechnology.

A SU2C-Lustgarten Joint Scientific Advisory Committee (JSAC) will conduct a unique, interactive, rapid, and rigorous evaluation of the applications via a multistep scientific review process. The JSAC is comprised of highly accomplished senior laboratory researchers and physician-scientists, as well as advocates.

The committee is chaired by Nobel laureate Phillip A. Sharp, Ph.D., institute professor at the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. It is co-chaired by William G. Kaelin, Jr., M.D., professor in the Department of Medicine at the Dana-Farber Cancer Institute, Harvard Medical School, and associate director of basic science at the Dana-Farber/Harvard Cancer Center; and David Tuveson, M.D., Ph.D., director for research of The Lustgarten Foundation Pancreatic Cancer Research Lab at Cold Spring Harbor Laboratory, and director of research for The Lustgarten Foundation.

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In case any of the readers of this newsletter are researchers who are not already familiar with this project and might be interested, read on:

Letters of Intent for SU2C-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant projects are due by noon ET on Nov. 7, 2013, via proposalCENTRAL.(https://proposalcentral.altum.com/)

For general information on eligibility criteria, the application process, and other details about this Dream Team grant, visit www.AACR.org/SU2CFunding. Inquiries may be directed to the AACR Scientific Review and Grants Administration Department at 267-765-1049 or su2c@aacr.org.

The SU2C-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant recipients are scheduled to be announced in spring 2014.

 

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IMMUNOTHERAPY SKIN CANCER TREATMENTS: A MELANOMA BREAKTHROUGH?

by KATE KELLAND

AMSTERDAM (Reuters) - A new generation of drugs designed to trigger the immune system to fight cancer is offering the prospect of a "clinical cure" for some MELANOMA skin cancer patients who until a few years ago were more likely to be facing a swift death. Cancer specialists gathering for a European conference said the so-called immunotherapy drugs, a class led by Yervoy, or ipilimumab, have transformed an area of oncology in which until recently doctors barely had time to get to know their patients.

Stephen Hodi, assistant professor of medicine at the Dana-Farber Cancer Institute in the United States, said he was cautious about using the term cure, but described recent advances as a "paradigm shift". At the least, he said, the success of this new generation of medicines means some melanoma patients would now be living with a chronic disease, rather than facing imminent death.

"This is a really amazing time ... A few years ago we could never have imagined using the C-word, cure, in melanoma, but we are headed that way. Ipilimumab opened a door, and now the field is moving extremely fast," he told Reuters at the European Cancer Congress (ECC) in Amsterdam.

Yervoy, approved by regulators in 2011, was hailed as a breakthrough treatment in melanoma after it became the first drug ever to extend survival in patients with advanced forms of the melanoma, the deadliest form of skin cancer. A type of drug known as a human monoclonal antibody, it activates the body's immune system to fight the cancer by targeting a protein receptor called Cytotoxic T-Lymphocyte Antigen 4, or CTLA-4.

On average, Yervoy added only about four months of life in pivotal trials, but around 20 percent of patients had an impressively durable response to the drug. Hodi presented new data at the ECC from the largest and longest study of overall survival for patients treated with Yervoy which showed some of them can survive for up to 10 years.

Alexander Eggermont of the Institut Gustave Roussy Comprehensive Cancer Center in France, who specializes in the treatment of melanoma, said Hodi's results suggested some patients could be effectively cured of their cancer - a concept known as a "clinical cure" - with the drug helping the immune system to keep the disease in check. "Patients apparently can keep residual tumors under control for a long time when the immune system is properly 'reset', and the concept of 'clinical cures' becomes a reality," he said in a statement to the conference.

And with a next generation of immunotherapy drugs - designed to disable proteins called PD1 and PDL1 that prevent the immune system from spotting and attacking cancer cells - already being tested alone and in combination with Yervoy, there is "tremendous promise" in the treatment of melanoma, said Hodi.

Bristol-Myers Squibb is conducting late stage trials of its next-generation drug, nivolumab, in advanced melanoma, while rival U.S. drugmaker Merck is developing a competitor, lambrolizumab, which in early-stage trials helped shrink tumors in 38 percent of advanced melanoma patients. Swiss drugmaker Roche's also has a leading contender - MPDL3280A - in this class.

"These (Yervoy) survival results could even double or triple with anti-PD1/PDL1 monoclonal antibodies, and metastatic melanoma could become a curable disease for perhaps more than 50 percent of patients over the coming five to 10 years," Eggermont said.

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Finally... Long piece, published in June, just too good to postpone any longer. From The New York Times:

BREAKING THE SEAL ON DRUG RESEARCH

Researchers are pushing Big Pharma to disclose all clinical results the pediatrician's question, Dr. Jefferson realized that there was a flaw: they relied too heavily on the assumption that the articles published in journals accurately represented the results of all clinical trials that had been conducted.

As he tried to track down the authors of the Kaiser study and the two published trials, Dr. Jefferson said he hit dead ends: One author said he had noved offices and no longer had the files; another said he had never seen the primary trial data, instead relying on a summary analysis provided by Roche. All the authors suggested that he contact the company.

"We took it on faith -- on trust," Dr. Jefferson, 59, said recenty in a phone interview. Dr. Hayashi's question had tested that faith. Dr. Jefferson began typing each new discovery in a private journal he called Hayashi's Problem, which, he said, "charted my transformation from Dr. Jekyll to Mr. Hyde."

Dr. Doshi said that medicine "relies on hierarchies of trust." He added: "A patient is not going to be in a position to review the entire evidence base themselves. But they trust that there is a watchdog out there."

As they dug into the Tamiflu research, Dr. Doshi said, he realized that such a watchdog didn't exist. Instead, he said, "we have partial watchdogs who see part of the full picture." It became his mission to see the full picture.

Having struck out with the authors of the disputed Kaiser paper and the two other published trials, Dr. Jefferson approached Roche itself, asking for the underlying data from the missing trials. But when he declined to sign a confidentiality agreement, Roche decided not to cooperate with the researchers.

Without more complete data about the clinical trials, the Cochrane group decided that it could not include the disputed study that summarized those results. In December 2009, the team reported that Tamiflu could not be shown to reduce complications like pneumonia or hospitalizations.

The British Medical Journal, which printed the team's conclusions, also published its own investigation, showing that Roche had hired ghost writers to author some of the articles involving Tamiflu, and that those writers had said they were under pressure to highlight positive messages about the drug. Roche responded that hiring such writers was common industry practice at the time of the articles, sand it rejected the idea that they had been pressured to write positively about the drug.

The articles in the British journal created a sensation, and the Cochrane Collaboration's efforts became a cause celebre. "Everyone knows about publication bias," said Dr. Steven Woloshin, a professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice and an advocate of more widespread sharing of clinical trial data. "But they just had so much energy and they brought so much attention to it."

The group's efforts seemed to make a difference: After the articles in the British journal, Roche turned over partial copies of study reports, amounting to a little more than 3,000 pages. Then, in 2011, the European Medicines Agency turned over more than 22,000 pages of documents for 19 trial reports to Dr. Jefferson and his team.

The door had been opened. As they read through the records, the researchers discovered the importance of documents called clinical study reports, which are thousands of pages long ad contain details as varied as descriptions of trial protocol and design and the ingredients of the placebo pills.

"We used to know that there was a published paper and there were data behind it," said Dr. Fiona Godlee, the editor of the British Medical Journal. "But people haven't talked about these things, like clinical study reports, that are now being talked about a great deal." Last fall, the journal said it would publish gthe results of clinical trials only if drug companies and researchers agreed to provide data upon request.

In April, Roche said it would make available to the Cochrane researchers clinical study reports for all Roche-sponsored trials of Tamiflu. Dr. Jefferson, Dr. Doshi and their colleagues hope to complete another update to their review of the drug by year-end.

Some said it was a shame that it took this long for the company to relent. "All these years later, and we still don't know if Tamiflu is effective," said Dr. Harlan Krumholz, the Yale cardiologist who oversaw the review of Medtronic's bone treatment. "It's perplexing to have a billion-dollar drug, and you're still not willing to share everything you've got to know whether this thing is effective and safe."

Though the Tamiflu question is not yet resolved, the Cochrane researchers have succeeded in a bigger way: by helping to change the conversation around companies' responsibility to reveal drug trial data.

Drug companies do not always credit the Cochrane Collaboration. In February, Roche followed Glaxo's lead and announced that it, too, would release detailed clinical data to outside researchers, upon request. But Daniel O'Day, chief operating officer of pharmaceuticals at Roche, denied that its pledge had ben motivated by the Tamiflu experience. He said Roche has provided data to "thousands" of researchers.

Mr. O'Day said "there were probably errors on both sides" in how the Cochrane researchers and Roche communicated with each other, and said the relationship deteriorated after Dr. Jefferson refused to sign a confidentiality agreement. He said the company was trying to rebuild its relationship with the Cochrane researchers, but that it stood by the safety and efficacy of Tamiflu.

Andrew Witty, Glaxo's C.E.O., said in an interview that his promise to provide detailed clinical data had grown out of a companywide effort, initiated soon after he became chief in 2008, that would "really ensure that we were more in step with where I thought, frankly, society and the world was moving."

Glaxo, moreover, was in need of a image rehabilitation. Ast year, it pleaded guilty to criminal charges and agreed to pay $3 billion in fines after the Uited States Justice Department accused the company, based in London, of failing to report safety data about its diabetes drug Avandia, and of publishing misleading information about Paxil, the antidepressant, in a medical journal. The settlement, which also included covil penalties over marketing of other drugs, was the largest ever involving a pharmaceutical company.

"We don't see any reason for this information to be held out of the public domain," Mr. Witty Said, "provided the people who are interrogating the information are legitimate researchers with a legitimate question to ask,."

In a twist, Roche now finds itself in the same side as the Cochrane researchers -- and against many in its own industry -- in a debate over what kind of data the European Medicines Agency should be making public. The agency released a draft policy, expected to take effect next year, in which it would release clinical trial data whenever it approved a new drug. While Roche and Glaxo have supported the policy, the Pharmaceutical Research and Manufacturers of America, a major industry group, and other drug companies have opposed it.

John J. Castellani, chief executive of PhRMA, said the industry had championed open-source efforts to develop better methods for testing CANCER drugs, for example. But proposals like those from the Cochrane team and the European agency go too far, he said.

"If you dump onto the sidewalk all the data and you include commercially protected information," he said, "then you're essentially giving to competitors what we invested billions of dollars in."

Others warned that such a policy could discourage drug companies from investing in Europe. "If you, on the other hand, say, 'You guys are bad actors, we want to cut your prices, we want to take your confidential data and share it with any one of your competitors, you don't get the same feeling of encouragement," Christopher A. Viehbacher, C.E.O. Of the French pharmaceutical company Sanofi, told reporters in Brussels, according to Reuters.

Industry officials and regulators in the United States say the public already has access to vast amounts of information about clinical trials. The basic results of all clinical trials must now be registered in a federal clearinghouse, for example, and the Food and Drug Administration publishes staff reviews and other documents when it approves a new drug. The F.D.A. has said that it is monitoring the developments in Europe but that federal laws in the United States restrict what types of information ca be released, particularly data that could reveal personal or commercially confidential information.

Cochrane group members point to the Medtronic study as an example of the value of a neutral perspective.

In 2011, Medtronic awarded a $2.5 million grant to Yale and asked it to oversee a detailed review of trial data for Infuse, a bioengineered material in spinal fusions to treat back pain. The company was facing claims that it had published misleading information about the treatment, and it turned over its data in an effort to address those criticisms. Two teams that examined the data came to similar conclusions: Infuse appeared to be no better than an older treatment, and may pose added risk.

A few months ago, Dr. Doshi opened what he hopes will be a new chapter in his quest for greater understanding of clinical trials. He and several other researchers published what ammounted to an ultimatum to rug companies: publish your data, or we'll do it for you.

Under the plan, researchers would publish articles summarizing trial results in cases where the underlying data has already been released. In isolated cases, such information has been made public through litigation and Freedom of Information Act requests.

"It's realy neat to see a larger opportunity for a larger impact," he said. Tamifluy just happened to be the lever that opened that door."

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Stay tuned .....

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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