NEWS
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Celgene’s multibillion spree on Oncomed/NYC In December, Celgene, of Summit, New Jersey, signed a deal potentially worth a whopping $3.3 billion for options on up to six anti-cancer stem cell products from OncoMed Pharmaceuticals, of Redwood City, California. Celgene initially became interested in one of OncoMed’s lead products, demcizumab—a monoclonal antibody that targets Delta-like ligand 4, an activator of Notch signaling, known to be important in stem cells and cancer—because of its potential to work in combination with Celgene’s chemotherapy Abraxane (nab-paclitaxel). But George Golumbeski, senior vice president of business development at Celgene, says they soon realized OncoMed has “a wonderfully effective drug discovery group.” Wells Fargo analyst Brian Abrahams characterizes the up-front payment of $177.25 million, including a $22.25-million equity investment in OncoMed, as “substantial,” but notes that Celgene is getting multiple shots on goal for the initial payment. Although most of the deal is for preclinical compounds and only demcizumab is in phase 2b trials, Golumbeski defends the up-front payment, noting it’s “in line with what’s been paid for similar assets at similar stages.” The investment in OncoMed’s promising-but-unproven cancer stem cell targets highlights Celgene’s broader strategy of investing in innovation. In November, Celgene established a collaboration with Versant Ventures, of Menlo Park, California, to license or acquire products developed by Versant’s biotech incubator Blueline Bioscience, which will license technology in Celgene’s core focuses of oncology and inflammatory diseases out of research centers in Toronto. “We were really struck by how much good work is going on there,” Golumbeski says. In New York, Celgene seeded a fund to invest in startups with Eli Lilly, of Indianapolis, and GE Ventures, of Fairfield, Connecticut. The collaboration pools a total of $50 million from the three companies and the public-private New York Economic Development Corporation with another $50 million from venture capital partners. The funding doesn’t give Celgene rights to products developed by the startups, but comes with increased access to innovation at the New York medical centers where the startups will be spun out from. “With or without rights, that kind of closeness has always been to our advantage,” Golumbeski said. Celgene hasn’t acquired a marketed product since its 2010 acquisition of Los Angeles-based Abraxis BioSciences, but Golumbeski said the biotech has looked at late-stage compounds because, “The deals that get done tend to be more a function of what gets through our diligence Brian Orelli process.”
Master Protocol for squamous cell lung cancer readies for launch Five biopharma companies will soon be testing their lung cancer compounds in a very different type of clinical trial. The Lung Cancer Master Protocol will test multiple novel drugs simultaneously using a biomarker-driven protocol. The idea is to modernize clinical trial infrastructure by setting up a model of collaborative testing of drug candidates that saves much of the time and expense usually associated with clinical trials. The master protocol’s first focus is squamous cell lung cancer, and five investigational drugs from Amgen, AstraZeneca, Genentech, MedImmune and Pfizer will be tested (Table 1). Trials could begin in March 2014, according to Roy Herbst of the Yale Cancer Center in New Haven, who co-chairs the master protocol’s steering committee. Detailed plans of the protocol design were announced during the Friends of Cancer Research at the Brookings Institution Conference on Clinical Cancer Research, November 7, 2013, in Washington, DC. The master protocol is a “truly exciting development, one that will benefit industry and patients,” says US Food and Drug Administration (FDA) Commissioner Margaret Hamburg. “It vastly increases the chances of finding more and better treatments.” Although a concept paper from several years ago laid the groundwork, the
practical genesis of the master protocol was a brainstorming session early during 2012, according to oncologist David Gandara of the University of Davis, California, part of the steering committee whose members worked out details for the protocol. “We concluded the classic drug development paradigm needed to be revised because it takes seven and a half years to complete and has too many failures,” he says. Other biomarker-driven screening trials are already under way, such as I-SPY2 (Box 1) for breast cancer and BATTLE-2 for nonsmall cell lung cancer. But the master protocol is pioneering in that it aims to create an infrastructure that could be applicable to other types of cancer and other diseases as well. It also allows successful agents to be followed into phase 3, whereas experimental agents in I-SPY2 ‘graduate’ after phase 2. “We hope that this serves as a prototype,” says Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research. In the master protocol, initially, patients will be screened with a centralized genotypic test, probably using next-generation sequencing. Those with squamous cell lung cancer will then be sorted into one of multiple arms of a clinical trial. Each patient is assigned to a study arm matching tumor mutations to the hypothesized mechanism
Sebastian Kaulitzki
in brief
The first Master Protocol will test five experimental drugs for squamous cell lung cancer.
116
VOLUME 32 Number 2 FEBRUARY 2014 nature biotechnology
news Table 1 The first five squamous cell lung cancer treatment arms chosen for the master protocol launch Company/location
Compound
Target
MedImmune/Gaithersburg, Maryland MEDI4736
mAb targeting programmed cell death 1 ligand
AstraZeneca/London
Azd4547
Fibroblast growth factor receptor tyrosine kinase inhibitor
Amgen/Thousand Oaks, California
Rilotumumab
A mAb directed against hepatocyte growth factor
Genentech/S. San Francisco
Taselisib
Phosphoinositide-3 kinase inhibitor
Pfizer/New York
Palbociclib (pd-0332991)
A cyclin-dependent kinase (CDK)-4 and CDK6 inhibitor
npg
© 2014 Nature America, Inc. All rights reserved.
mAb, monoclonal antibody.
of action of a particular compound. Within each arm, patients would be randomized to an experimental drug or standard of care. Each arm will operate independently and be powered to demonstrate overall survival as the primary endpoint. Interim progression-free survival would be used to determine whether an experimental drug progresses from phase 2 to 3.
The core innovation in the master protocol is that multiple agents will be tested in several study arms in a single, ongoing, clinical trial. Another change is that testing patient DNA with next-generation sequencing can provide more diagnostic information than can be achieved with one test. This is a bold move away from testing each drug with its own companion diagnostic.
Box 1 First two drugs celebrate I-SPY2 graduation While the Friends of Cancer Research prepare to launch the Lung Cancer Master Protocol, sponsors of the landmark phase 2 I-SPY2 trial are celebrating the graduation of its first two candidates, AbbVie’s veliparib and Puma Biotechnology’s neratinib. Veliparib and neratinib were the first two drugs to enter into the trial, suggesting it can deliver on its promise of efficiently identifying which patients respond to which drugs. Across the Atlantic, in December, the European Union’s Innovative Medicines Initiative unveiled a €53 ($72.7)-million adaptive trial to test Alzheimer’s disease drug candidates. “These trials are the wave of the future,” says Hope Rugo, a trial investigator and oncologist at the University of California San Francisco School of Medicine. The I-SPY2 trial, which launched in 2010, tests multiple drugs, from multiple companies, in newly diagnosed breast cancer patients before they undergo surgery (Nat. Biotechnol. 28, 383–384, 2010). Investigators use up to ten biomarker signatures to stratify patients. They also feed early efficacy data into an adaptive randomization algorithm that enrolls patients into different treatment arms depending on how previous patients fare; the algorithm enrolls more patients into treatment arms when positive signals emerge, and fewer when negative signals emerge. AbbVie’s veliparib, a poly(ADP-ribose) polymerase inhibitor, graduated in triple-negative (HER2 negative, hormone receptor negative) patients, a particularly nonresponsive population. An estimated 62% of patients receiving veliparib had a pathologic complete response—no detectable tumor at the time of surgery—compared with 26% of patients receiving the standard of care, Rugo reported at the San Antonio Breast Cancer Symposium in December 2013. The most common adverse events were hematologic. Puma’s neratinib, a multi-tyrosine-kinase inhibitor, graduated in HER2 positive, hormone receptor–negative patients. Investigators will present pathologic complete response and adverse event data at a medical conference later this year. QuantumLeap Healthcare Collaborative, who are coordinating the I-SPY2 trial, are talking with AbbVie and Puma about launching I-SPY3, an adaptive collaborative follow-on to I-SPY2. “I-SPY3 will hope to be a nimble way to move these agents relatively quickly into a phase 3,” says Rugo, “but at the same time these agents might go in to company-sponsored trials.” I-SPY2 is still testing five more monotherapy or combinations treatments, and more arms can be added. No drugs have dropped out of the trial so far. In Europe, the biomarker-driven Alzheimer’s disease trial is expected to enroll about 1,500 patients. The project is a proof-of-concept trial that shares many of the I-SPY2 features. It is part of the EU’s Framework Programme 7 and applications are due April 8. Asher Mullard Ottawa, Ontario, Canada
nature biotechnology VOLUME 32 Number 2 FEBRUARY 2014
in brief It’s official: biologics are pharma’s darlings Biologics have replaced small molecules as the dominant focus of big pharma’s pipeline, and a new analysis from the Tufts Center for the Study of Drug Development (Boston) has quantified the phenomenon. In 2012, about 40% of all biotech products in clinical development were being developed by big pharma, up from 15.2 % in 2000, according to Ron Evens, an adjunct professor at the University of the Pacific in Stockton, California, who conducted the study with Boston-based Tufts. And in an even more startling metric, biotech products accounted for only 7% of revenue generated by the top ten treatments worldwide in 2001, but made up 71% of that revenue in 2012. Over a similar period, biotech product sales more than quadrupled, financing of biotech research increased tenfold, and the amount invested in pharma-biotech research alliances increased sixfold. In fact, all parameters in the Tufts report point in the same direction: pharma has dramatically shifted its R&D strategy from an almost singular focus on small-molecule drugs in the early 1990s to a dominant focus on biotech products today. Driving the transformation are biotech products’ novel mechanisms of action and ability to command high prices, combined with the declining patent lives of small-molecule drugs, the report said. Biotechnology Industry Organization spokesperson Tracy Cooley says her organization agrees that the growth of biotech has been driven in part by those factors, though the shift “can be largely attributed to a natural evolution Emily Waltz of the industry.”
in their words “This is among the worst applications of biotechnology. They will increase the use of toxic pesticides in industrial agriculture while providing absolutely no benefit to consumers.” Andrew Kimbrell, executive director of the Center for Food Safety, heavily criticizes the USDA’s recommendation to deregulate Dow AgroSciences Enlist corn and soybean, which combines resistance to three herbicides, among them glyphosate and 2,4,D. (Reuters, 3 January 2014) “We lock up our refrigerator. We lock up our freezer. We lock up the pantry.” Mark Greenberg of Denver, a consultant to a hedge fund, whose son has Prader-Willi, a rare condition that results in uncontrollable hunger. Zafgen of Cambridge, Massachusetts, announced some positive phase 2a results in this indication with its anti-obesity drug beloranib, a METAP2 inhibitor. (New York Times, 14 January 2014)
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in brief
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Boston quartet revamps biopsies Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston Children’s Hospital and the Broad Institute, all in Boston, have launched the Joint Center for Cancer Precision Medicine, headquartered at Dana-Farber. The focus of this clinical cancer genomics center will be on sharing the partners’ huge resources in sequencing and new molecular profiling tools to help customize patients’ treatment. The initiative will see the creation of a computational biology working group spread across the partner institutions including biologists, bioinformaticians and software designers to develop algorithms aimed at interpreting genome sequencing data. The Joint Center is focused on more than cancer sequencing, says Barrett Rollins, Dana-Farber’s CSO. The pathology component is key to the project. Using sequencing, the Center will start with a well-characterized patient population, Rollins says, then follow disease progression and the effects of experimental drugs by watching how cancers respond or become resistant over time. The only way to do that, Rollins says, is to analyze tissue with advanced immunohistochemistry, sequencing, epigenetic analyses or proteomic profiling during treatment. “This is not part of routine clinical care. It’s not even part of routine clinical research for the most part,” he says. The pathology techniques themselves aren’t new, said Rollins, but the operational processes required to support multiple biopsies in a research capacity are. If this approach is successful, the center would “absolutely want to collaborate with as many groups as were interested.” Funding for the initiative is from Allison Proffitt local philanthropy.
in their words “Are universities checking to make sure that students have a support network at home to help them cope with bad news? And are the students really prepared to assess a risk that might not become important to them until long after the course is over?” Shawneequa Callier, a bioethics specialist at George Washington University in Washington, DC, questions the practice of offering free genome sequencing as a teaching tool at universities. The Mount Sinai School of Medicine started offering whole genome sequencing to medical and graduate students last fall. (New Scientist, 9 January 2014) “To those seniors who really do want one [penis pump], just buy it yourself. You don’t need to send the bill to your fellow Americans.” Ben Domenech of the Heartland Institute, upon hearing that Medicare overpaid by a factor of two for the over 400,000 claims for penis pumps approved from 2006 to 2011. (Huffington Post Business, 13 January 2014)
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In this protocol, five different agents will As the trial continues, it will become possible be tested against different mutations. The to “set up combinations,” whereas candidate common screening platform means it will drugs that are seen as not meeting end points be possible to identify and accrue patients may be dropped. Each of the arms within the with mutations that occur in very small master protocol is “totally separate,” accordnumbers. If a trial arm is testing a compound ing to Roy Herbst of Yale Cancer Center in that could be effective in a small subset of New Haven, who co-chairs the protocol. “So patients, screening may find a mutation that we won’t be comparing companies’ drugs.” would otherwise not be targeted. Not only Instead, each candidate drug will be comthose patients who have an appropriate bio- pared to the same standard-of-care control marker will be included in one particular arm. Even so, he adds, “We’ll have the biggest arm] Instead, researchers will be aiming for data set to see which antigens drive the [lung a 60/40 split, with the majority of patients cancer] process.” As the steering committee labored through chosen as appropriate and specific for a particular therapy in each of the trial arms, but much of the past year to transform the masthe rest of them not specifically linked to a ter protocol concept into reality, its members realized that they “had to choose drugs that particular biomarker. “This is the age of molecular profiling, and were ready” for inclusion in phase 2 clinical we’re moving full bore into that era,” says trials, Herbst says. Once added to the protoJeff Abrams of the National Cancer Institute col, each of the treatments will be evaluated on the basis of “progress(NCI). “We want these free survival” over three meds to get to patients, months, with each arm and with this trial we can “This is not easy powered to detect a tworeach out to the com- and could be rough fold increase, says statistimunity.” By community, because we’ve not cian Mary Redman of the he is alluding not only to the formal cancer trials done it before; it takes Fred Hutchinson Cancer Research Center in Seattle. network overseen by NCI pioneers,” says FDA’s For phase 3, the primary but also SWOG, one of the Woodcock. outcome shifts to overall largest cancer clinical trisurvival over a median of als cooperative groups in North America. Patients with advanced-stage eight months, and each arm is expected to squamous-cell lung cancer who seek to enroll include about 300 patients, she says. Other companies were contacted and their will have access to more than 300 clinical sites across North America, all following the same candidate treatments considered before the protocol and thus improving patient access committee whittled its list to five, Herbst to the several experimental therapies being says. However, among other promising treatment categories, none of the companies evaluated. Because the master protocol will be “bio- developing monoclonal antibody inhibitors marker driven,” says the other protocol of PD-1 was willing to participate, in part, co-chair, Vali Papademitrakopoulou of the because several such products are expected University of Texas MD Anderson Cancer to gain FDA approval soon and thus are furCenter in Houston, “all patients can be eli- ther along than would be appropriate for gible” and “no patient should be wasted,” evaluation under the new protocol. That sketch of the treatment-selection she says. For a drug to run in the trial, the one stipulation is that it has its own “suitable process hints at the looming challenges to and analytically validated biomarker.” Each be faced in implementing this new vision for treatment arm is independent of the others conducting clinical trials. Not all candidate within the master protocol, but they each drugs fit the model, not all companies will accrue appropriate numbers of patients, all want to join in such a complicated, multiwith advanced-stage disease, meaning the partnered enterprise, and patients, too, can experimental treatments are being consid- be expected to balk over some of its complexities. “This is not easy and could be rough ered as “second-line therapies.” This first trial for squamous cell lung can- because we’ve not done it before; it takes piocer following the master protocol will aim neers,” says FDA’s Woodcock. “But there’s an to enroll between 500 and 1,000 patients ethical imperative that we try this because it a year into four to six arms that will open offers the best hope for patients.” simultaneously, Papademitrakopoulou says. Jeffrey L Fox Washington, DC Corrected after print 29 May 2014
VOLUME 32 Number 2 FEBRUARY 2014 nature biotechnology
e r r ata
Erratum: Master Protocol for squamous cell lung cancer readies for launch Jeffrey Fox Nat. Biotechnol. 32, 116–118 (2014); published online 7 February 2014; doi:10.1038/nbt0214-116b; corrected after print 29 Month 2014
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In the version of this article initially published, Genentech’s compound Taselisib was incorrectly labeled as Pictilisib in Table 1. The error has been corrected in the HTML and PDF versions of the article.
nature biotechnology
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© 2014 Nature America, Inc. All rights reserved.
Celgene’s multibillion spree on Oncomed/NYC In December, Celgene, of Summit, New Jersey, signed a deal potentially worth a whopping $3.3 billion for options on up to six anti-cancer stem cell products from OncoMed Pharmaceuticals, of Redwood City, California. Celgene initially became interested in one of OncoMed’s lead products, demcizumab—a monoclonal antibody that targets Delta-like ligand 4, an activator of Notch signaling, known to be important in stem cells and cancer—because of its potential to work in combination with Celgene’s chemotherapy Abraxane (nab-paclitaxel). But George Golumbeski, senior vice president of business development at Celgene, says they soon realized OncoMed has “a wonderfully effective drug discovery group.” Wells Fargo analyst Brian Abrahams characterizes the up-front payment of $177.25 million, including a $22.25-million equity investment in OncoMed, as “substantial,” but notes that Celgene is getting multiple shots on goal for the initial payment. Although most of the deal is for preclinical compounds and only demcizumab is in phase 2b trials, Golumbeski defends the up-front payment, noting it’s “in line with what’s been paid for similar assets at similar stages.” The investment in OncoMed’s promising-but-unproven cancer stem cell targets highlights Celgene’s broader strategy of investing in innovation. In November, Celgene established a collaboration with Versant Ventures, of Menlo Park, California, to license or acquire products developed by Versant’s biotech incubator Blueline Bioscience, which will license technology in Celgene’s core focuses of oncology and inflammatory diseases out of research centers in Toronto. “We were really struck by how much good work is going on there,” Golumbeski says. In New York, Celgene seeded a fund to invest in startups with Eli Lilly, of Indianapolis, and GE Ventures, of Fairfield, Connecticut. The collaboration pools a total of $50 million from the three companies and the public-private New York Economic Development Corporation with another $50 million from venture capital partners. The funding doesn’t give Celgene rights to products developed by the startups, but comes with increased access to innovation at the New York medical centers where the startups will be spun out from. “With or without rights, that kind of closeness has always been to our advantage,” Golumbeski said. Celgene hasn’t acquired a marketed product since its 2010 acquisition of Los Angeles-based Abraxis BioSciences, but Golumbeski said the biotech has looked at late-stage compounds because, “The deals that get done tend to be more a function of what gets through our diligence Brian Orelli process.”
Master Protocol for squamous cell lung cancer readies for launch Five biopharma companies will soon be testing their lung cancer compounds in a very different type of clinical trial. The Lung Cancer Master Protocol will test multiple novel drugs simultaneously using a biomarker-driven protocol. The idea is to modernize clinical trial infrastructure by setting up a model of collaborative testing of drug candidates that saves much of the time and expense usually associated with clinical trials. The master protocol’s first focus is squamous cell lung cancer, and five investigational drugs from Amgen, AstraZeneca, Genentech, MedImmune and Pfizer will be tested (Table 1). Trials could begin in March 2014, according to Roy Herbst of the Yale Cancer Center in New Haven, who co-chairs the master protocol’s steering committee. Detailed plans of the protocol design were announced during the Friends of Cancer Research at the Brookings Institution Conference on Clinical Cancer Research, November 7, 2013, in Washington, DC. The master protocol is a “truly exciting development, one that will benefit industry and patients,” says US Food and Drug Administration (FDA) Commissioner Margaret Hamburg. “It vastly increases the chances of finding more and better treatments.” Although a concept paper from several years ago laid the groundwork, the
practical genesis of the master protocol was a brainstorming session early during 2012, according to oncologist David Gandara of the University of Davis, California, part of the steering committee whose members worked out details for the protocol. “We concluded the classic drug development paradigm needed to be revised because it takes seven and a half years to complete and has too many failures,” he says. Other biomarker-driven screening trials are already under way, such as I-SPY2 (Box 1) for breast cancer and BATTLE-2 for nonsmall cell lung cancer. But the master protocol is pioneering in that it aims to create an infrastructure that could be applicable to other types of cancer and other diseases as well. It also allows successful agents to be followed into phase 3, whereas experimental agents in I-SPY2 ‘graduate’ after phase 2. “We hope that this serves as a prototype,” says Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research. In the master protocol, initially, patients will be screened with a centralized genotypic test, probably using next-generation sequencing. Those with squamous cell lung cancer will then be sorted into one of multiple arms of a clinical trial. Each patient is assigned to a study arm matching tumor mutations to the hypothesized mechanism
Sebastian Kaulitzki
in brief
The first Master Protocol will test five experimental drugs for squamous cell lung cancer.
116
VOLUME 32 Number 2 FEBRUARY 2014 nature biotechnology
news Table 1 The first five squamous cell lung cancer treatment arms chosen for the master protocol launch Company/location
Compound
Target
MedImmune/Gaithersburg, Maryland MEDI4736
mAb targeting programmed cell death 1 ligand
AstraZeneca/London
Azd4547
Fibroblast growth factor receptor tyrosine kinase inhibitor
Amgen/Thousand Oaks, California
Rilotumumab
A mAb directed against hepatocyte growth factor
Genentech/S. San Francisco
Taselisib
Phosphoinositide-3 kinase inhibitor
Pfizer/New York
Palbociclib (pd-0332991)
A cyclin-dependent kinase (CDK)-4 and CDK6 inhibitor
npg
© 2014 Nature America, Inc. All rights reserved.
mAb, monoclonal antibody.
of action of a particular compound. Within each arm, patients would be randomized to an experimental drug or standard of care. Each arm will operate independently and be powered to demonstrate overall survival as the primary endpoint. Interim progression-free survival would be used to determine whether an experimental drug progresses from phase 2 to 3.
The core innovation in the master protocol is that multiple agents will be tested in several study arms in a single, ongoing, clinical trial. Another change is that testing patient DNA with next-generation sequencing can provide more diagnostic information than can be achieved with one test. This is a bold move away from testing each drug with its own companion diagnostic.
Box 1 First two drugs celebrate I-SPY2 graduation While the Friends of Cancer Research prepare to launch the Lung Cancer Master Protocol, sponsors of the landmark phase 2 I-SPY2 trial are celebrating the graduation of its first two candidates, AbbVie’s veliparib and Puma Biotechnology’s neratinib. Veliparib and neratinib were the first two drugs to enter into the trial, suggesting it can deliver on its promise of efficiently identifying which patients respond to which drugs. Across the Atlantic, in December, the European Union’s Innovative Medicines Initiative unveiled a €53 ($72.7)-million adaptive trial to test Alzheimer’s disease drug candidates. “These trials are the wave of the future,” says Hope Rugo, a trial investigator and oncologist at the University of California San Francisco School of Medicine. The I-SPY2 trial, which launched in 2010, tests multiple drugs, from multiple companies, in newly diagnosed breast cancer patients before they undergo surgery (Nat. Biotechnol. 28, 383–384, 2010). Investigators use up to ten biomarker signatures to stratify patients. They also feed early efficacy data into an adaptive randomization algorithm that enrolls patients into different treatment arms depending on how previous patients fare; the algorithm enrolls more patients into treatment arms when positive signals emerge, and fewer when negative signals emerge. AbbVie’s veliparib, a poly(ADP-ribose) polymerase inhibitor, graduated in triple-negative (HER2 negative, hormone receptor negative) patients, a particularly nonresponsive population. An estimated 62% of patients receiving veliparib had a pathologic complete response—no detectable tumor at the time of surgery—compared with 26% of patients receiving the standard of care, Rugo reported at the San Antonio Breast Cancer Symposium in December 2013. The most common adverse events were hematologic. Puma’s neratinib, a multi-tyrosine-kinase inhibitor, graduated in HER2 positive, hormone receptor–negative patients. Investigators will present pathologic complete response and adverse event data at a medical conference later this year. QuantumLeap Healthcare Collaborative, who are coordinating the I-SPY2 trial, are talking with AbbVie and Puma about launching I-SPY3, an adaptive collaborative follow-on to I-SPY2. “I-SPY3 will hope to be a nimble way to move these agents relatively quickly into a phase 3,” says Rugo, “but at the same time these agents might go in to company-sponsored trials.” I-SPY2 is still testing five more monotherapy or combinations treatments, and more arms can be added. No drugs have dropped out of the trial so far. In Europe, the biomarker-driven Alzheimer’s disease trial is expected to enroll about 1,500 patients. The project is a proof-of-concept trial that shares many of the I-SPY2 features. It is part of the EU’s Framework Programme 7 and applications are due April 8. Asher Mullard Ottawa, Ontario, Canada
nature biotechnology VOLUME 32 Number 2 FEBRUARY 2014
in brief It’s official: biologics are pharma’s darlings Biologics have replaced small molecules as the dominant focus of big pharma’s pipeline, and a new analysis from the Tufts Center for the Study of Drug Development (Boston) has quantified the phenomenon. In 2012, about 40% of all biotech products in clinical development were being developed by big pharma, up from 15.2 % in 2000, according to Ron Evens, an adjunct professor at the University of the Pacific in Stockton, California, who conducted the study with Boston-based Tufts. And in an even more startling metric, biotech products accounted for only 7% of revenue generated by the top ten treatments worldwide in 2001, but made up 71% of that revenue in 2012. Over a similar period, biotech product sales more than quadrupled, financing of biotech research increased tenfold, and the amount invested in pharma-biotech research alliances increased sixfold. In fact, all parameters in the Tufts report point in the same direction: pharma has dramatically shifted its R&D strategy from an almost singular focus on small-molecule drugs in the early 1990s to a dominant focus on biotech products today. Driving the transformation are biotech products’ novel mechanisms of action and ability to command high prices, combined with the declining patent lives of small-molecule drugs, the report said. Biotechnology Industry Organization spokesperson Tracy Cooley says her organization agrees that the growth of biotech has been driven in part by those factors, though the shift “can be largely attributed to a natural evolution Emily Waltz of the industry.”
in their words “This is among the worst applications of biotechnology. They will increase the use of toxic pesticides in industrial agriculture while providing absolutely no benefit to consumers.” Andrew Kimbrell, executive director of the Center for Food Safety, heavily criticizes the USDA’s recommendation to deregulate Dow AgroSciences Enlist corn and soybean, which combines resistance to three herbicides, among them glyphosate and 2,4,D. (Reuters, 3 January 2014) “We lock up our refrigerator. We lock up our freezer. We lock up the pantry.” Mark Greenberg of Denver, a consultant to a hedge fund, whose son has Prader-Willi, a rare condition that results in uncontrollable hunger. Zafgen of Cambridge, Massachusetts, announced some positive phase 2a results in this indication with its anti-obesity drug beloranib, a METAP2 inhibitor. (New York Times, 14 January 2014)
117
NEWS
in brief
npg
© 2014 Nature America, Inc. All rights reserved.
Boston quartet revamps biopsies Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston Children’s Hospital and the Broad Institute, all in Boston, have launched the Joint Center for Cancer Precision Medicine, headquartered at Dana-Farber. The focus of this clinical cancer genomics center will be on sharing the partners’ huge resources in sequencing and new molecular profiling tools to help customize patients’ treatment. The initiative will see the creation of a computational biology working group spread across the partner institutions including biologists, bioinformaticians and software designers to develop algorithms aimed at interpreting genome sequencing data. The Joint Center is focused on more than cancer sequencing, says Barrett Rollins, Dana-Farber’s CSO. The pathology component is key to the project. Using sequencing, the Center will start with a well-characterized patient population, Rollins says, then follow disease progression and the effects of experimental drugs by watching how cancers respond or become resistant over time. The only way to do that, Rollins says, is to analyze tissue with advanced immunohistochemistry, sequencing, epigenetic analyses or proteomic profiling during treatment. “This is not part of routine clinical care. It’s not even part of routine clinical research for the most part,” he says. The pathology techniques themselves aren’t new, said Rollins, but the operational processes required to support multiple biopsies in a research capacity are. If this approach is successful, the center would “absolutely want to collaborate with as many groups as were interested.” Funding for the initiative is from Allison Proffitt local philanthropy.
in their words “Are universities checking to make sure that students have a support network at home to help them cope with bad news? And are the students really prepared to assess a risk that might not become important to them until long after the course is over?” Shawneequa Callier, a bioethics specialist at George Washington University in Washington, DC, questions the practice of offering free genome sequencing as a teaching tool at universities. The Mount Sinai School of Medicine started offering whole genome sequencing to medical and graduate students last fall. (New Scientist, 9 January 2014) “To those seniors who really do want one [penis pump], just buy it yourself. You don’t need to send the bill to your fellow Americans.” Ben Domenech of the Heartland Institute, upon hearing that Medicare overpaid by a factor of two for the over 400,000 claims for penis pumps approved from 2006 to 2011. (Huffington Post Business, 13 January 2014)
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In this protocol, five different agents will As the trial continues, it will become possible be tested against different mutations. The to “set up combinations,” whereas candidate common screening platform means it will drugs that are seen as not meeting end points be possible to identify and accrue patients may be dropped. Each of the arms within the with mutations that occur in very small master protocol is “totally separate,” accordnumbers. If a trial arm is testing a compound ing to Roy Herbst of Yale Cancer Center in that could be effective in a small subset of New Haven, who co-chairs the protocol. “So patients, screening may find a mutation that we won’t be comparing companies’ drugs.” would otherwise not be targeted. Not only Instead, each candidate drug will be comthose patients who have an appropriate bio- pared to the same standard-of-care control marker will be included in one particular arm. Even so, he adds, “We’ll have the biggest arm] Instead, researchers will be aiming for data set to see which antigens drive the [lung a 60/40 split, with the majority of patients cancer] process.” As the steering committee labored through chosen as appropriate and specific for a particular therapy in each of the trial arms, but much of the past year to transform the masthe rest of them not specifically linked to a ter protocol concept into reality, its members realized that they “had to choose drugs that particular biomarker. “This is the age of molecular profiling, and were ready” for inclusion in phase 2 clinical we’re moving full bore into that era,” says trials, Herbst says. Once added to the protoJeff Abrams of the National Cancer Institute col, each of the treatments will be evaluated on the basis of “progress(NCI). “We want these free survival” over three meds to get to patients, months, with each arm and with this trial we can “This is not easy powered to detect a tworeach out to the com- and could be rough fold increase, says statistimunity.” By community, because we’ve not cian Mary Redman of the he is alluding not only to the formal cancer trials done it before; it takes Fred Hutchinson Cancer Research Center in Seattle. network overseen by NCI pioneers,” says FDA’s For phase 3, the primary but also SWOG, one of the Woodcock. outcome shifts to overall largest cancer clinical trisurvival over a median of als cooperative groups in North America. Patients with advanced-stage eight months, and each arm is expected to squamous-cell lung cancer who seek to enroll include about 300 patients, she says. Other companies were contacted and their will have access to more than 300 clinical sites across North America, all following the same candidate treatments considered before the protocol and thus improving patient access committee whittled its list to five, Herbst to the several experimental therapies being says. However, among other promising treatment categories, none of the companies evaluated. Because the master protocol will be “bio- developing monoclonal antibody inhibitors marker driven,” says the other protocol of PD-1 was willing to participate, in part, co-chair, Vali Papademitrakopoulou of the because several such products are expected University of Texas MD Anderson Cancer to gain FDA approval soon and thus are furCenter in Houston, “all patients can be eli- ther along than would be appropriate for gible” and “no patient should be wasted,” evaluation under the new protocol. That sketch of the treatment-selection she says. For a drug to run in the trial, the one stipulation is that it has its own “suitable process hints at the looming challenges to and analytically validated biomarker.” Each be faced in implementing this new vision for treatment arm is independent of the others conducting clinical trials. Not all candidate within the master protocol, but they each drugs fit the model, not all companies will accrue appropriate numbers of patients, all want to join in such a complicated, multiwith advanced-stage disease, meaning the partnered enterprise, and patients, too, can experimental treatments are being consid- be expected to balk over some of its complexities. “This is not easy and could be rough ered as “second-line therapies.” This first trial for squamous cell lung can- because we’ve not done it before; it takes piocer following the master protocol will aim neers,” says FDA’s Woodcock. “But there’s an to enroll between 500 and 1,000 patients ethical imperative that we try this because it a year into four to six arms that will open offers the best hope for patients.” simultaneously, Papademitrakopoulou says. Jeffrey L Fox Washington, DC Corrected after print 29 May 2014
VOLUME 32 Number 2 FEBRUARY 2014 nature biotechnology
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Erratum: Master Protocol for squamous cell lung cancer readies for launch Jeffrey Fox Nat. Biotechnol. 32, 116–118 (2014); published online 7 February 2014; doi:10.1038/nbt0214-116b; corrected after print 29 Month 2014
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In the version of this article initially published, Genentech’s compound Taselisib was incorrectly labeled as Pictilisib in Table 1. The error has been corrected in the HTML and PDF versions of the article.
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