NEWS
A two-decade saga for prostate cancer vaccine PROSTVAC, starting with the now-defunct Therion Biologics, is paying off for Bavarian Nordic. The Kvistgaard, Denmark–based vaccine developer brokered a deal, potentially worth $975 million, with Bristol-Myers Squibb (BMS) of New York to complete phase 3 testing of the vaccine for treating castration-resistant prostate cancer. Developed at a time when the immunobiology of cancer vaccines was poorly understood, the therapy failed in clinical trials in the early 2000s. But by choosing different clinical endpoints, Bavarian Nordic, which picked up the program from the National Cancer Institute in 2008, reported positive phase 2 results (8.5-month survival benefit). Milestone payments are pegged to the results of an ongoing phase 3 trial known as PROSPECT—the greater the survival benefit over that reported in phase 2, the greater the payout. Bavarian Nordic’s vaccine (rilimogene galvacirepvec–rilimogene glafolivec) follows the prime/boost model. An initial prostate-specific antigen (PSA) with three costimulatory molecules (TRICOM) vacciniafowlpox priming is followed by PSA-TRICOM fowlpox boosting doses. The vaccine faces competition from several recent approvals in the indication (Johnson & Johnson’s Zytiga (abiraterone acetate) and Medivation–Astellas’ Xtandi (enzalutamide)). But the real excitement might come from combining Bavarian Nordic’s vaccine for prostate cancer with BMS’s immunotherapeutics Yervoy (ipilimumab, an antibody to CTLA4) or Opdivo (nivolumab, an antibody to PD-1).
20-year-old EMA’s birthday bash The European Medicines Agency (EMA) marked its coming of age on March 18 with a conference entitled “Patients at the heart of future innovation.” Guido Rasi, principal adviser in charge of strategy at EMA, welcomed regulators, advisers, drug developers, investors and policymakers from across the globe, including Margaret Hamburg of the US Food and Drug Administration (FDA); Elias Zerhouni, president of global R&D at Sanofi; and Mark Walport, chief scientific adviser to the UK government. Zerhouni credited the EMA for leading the way in clinical-trials transparency initiatives and the FDA for pioneering pathways to accelerate approvals for breakthrough drugs. But Zerhouni also remarked that the ultimate goal should not be to boost the number of drugs approved but to ensure drugs that affect great swathes of the population reach primary care, noting the trend toward approvals for rare disease therapies. The former NIH director also noted that regulatory convergence between agencies is sorely lacking. Despite efforts by the EMA and the FDA to collaborate, there is still a 22% discrepancy between the agencies’ decisions to approve or reject drugs. Harmonization should become a priority, he urged. After all, drug development is a global business. Imagine international air travel if every country had its own airspace rules, Zerhouni prompted: who would board that plane?
326
Nonbrowning GM apple cleared for market The US Department of Agriculture (USDA) on February 13 approved the first genetically modified (GM) apple developed to resist browning. The Arctic apple’s go-ahead is a notable achievement for Canadian firm Okanagan Specialty Fruits, as the small biotech is one of the few to have successfully moved a GM plant through the regulatory process on its own. Indeed, two weeks after the apple’s launch, Okanagan announced its acquisition by Germantown, Maryland– based Intrexon, a synthetic biology company. Okanagan’s stockholders will receive $10 million in upfront cash and $31 million in Intrexon common stock. Industry observers now question whether the Arctic apple will carve a niche in the fruit tree industry or get caught up in the GM labeling debate. Pre-cut fruit and vegetables are a growing trend in the food industry. “The [nonbrowning] trait will enable food service companies to cut and package the apples without adding browning inhibitors such as calcium ascorbate—an antioxidant that changes the flavor of the apple, says Neal Carter, founder of the Summerland, British Columbia–based Okanagan. About 22,000 trees will be planted in the US this spring, with the resulting fruit available in fall 2016 for product demonstration, he says. Okanagan has also applied for regulatory approval of its apple in Canada. Browning is caused by polyphenol oxidases (PPOs) naturally present in fruit and vegetables. When fruit is cut or bruised, these enzymes catalyze the oxidation of polyphe-
nols to quinones, causing oxidative browning. The damage is superficial but can affect the taste and texture of the apple as well as its cosmetic qualities. In the Arctic varieties, the GM apples were genetically engineered with a transgene that produces specific RNAs to silence the expression of at least four browning PPO genes. The apple RNA sequences were introduced into Granny Smith and Golden Delicious varieties, to bind complementary RNA and form a double strand. As RNA is single stranded, the double-stranded sequence is read as a mistake, and the plant’s naturally occurring Dicer enzymes are sent to chop it up, resulting in no or significantly fewer PPO proteins being produced. RNA interference (RNAi) was also used by JR Simplot of Boise, Idaho to silence PPO production in nonbrowning potatoes, which were approved by the USDA in November (Nat. Biotechnol. 33, 12–13, 2015). For that product, fragments of a single potato PPO gene were re-introduced into potato, activating the RNAi pathway. But unlike the apple, the potato’s double-stranded RNA is formed by an inverted repeat transcribed in the tuber and processed into small interfering RNAs that ultimately silence their targets. JR Simplot’s crop was also modified to have reduced acrylamide, which was achieved by using RNAi to silence the asparagine synthetase-1 gene (ASn1). Apples that won’t brown could make them more appealing to consumers and could also reduce waste by minimizing discarded apple
Okanagan Specialty Fruits
npg
© 2015 Nature America, Inc. All rights reserved.
Bavarian Nordic’s prostate vaccine hits pay dirt
Apple grower Neal Carter founded Okanagan Specialty Fruits in 1996.
volume 33 NUMBER 4 APRIL 2015 nature biotechnology
npg
© 2015 Nature America, Inc. All rights reserved.
news due to bruising. But at least three growers associations urged US and Canadian regulatory agencies to reject Okanagan’s petitions for approval. Their objections were not made because of human health or safety concerns. In separate letters, the US Apple Association, the Northwest Horticultural Council and the BC Fruit Growers Association said GM apples may cause severe market disruptions, particularly in apple export markets averse to genetically modified organisms (GMOs). US Apple, however, changed its tune once USDA approval became imminent. “We are confident from the assurance we’ve received from Okanagan that they intend to stand by their pledge to clearly identify their apples in all marketing and packaging,” enabling consumers to choose between GM and nonGM apples, says Wendy Brannen, director of consumer health and public relations at US Apple. Okanagan’s apples will not be labeled ‘GM’, but packaging will include the ‘Arctic’ name and logo. “It will be highly recognized as a GM product, given the amount of media attention we’ve had,” says Carter at Okanagan. The company has not yet
decided whether the packaging will use other descriptive words, such as ‘nonbrowning’, which will partly depend on guidance from the US Food and Drug Administration, Carter says. The GM apple may get caught up in the GMO labeling debate and used as an example, given its cachet as a family friendly, wholesome food, says Chris Schlect, president of the Northwest Horticultural Council in Yakima, Washington. “Apples are a symbolic product. It’s a fruit that a mother gives to a child going to school,” he says. “It’s going to be used in the media and by Congress in issues over the national labeling initiative.” Indeed, the Washington, DC–based Environmental Working Group put out a press release in February saying the approval of Arctic apples “underscores the need for a transparent and consistent national labeling standard.” Other consumer groups argued against the safety of Okanagan’s apple. The Center for Food Safety (CFS) said USDA’s environmental assessment was inadequate—a complaint the Center has made for nearly every biotech crop assessment USDA has conducted
in recent years. In its 61-page comment, the Center said that proper characterization of the PPO genes, their functions and the impacts of silencing them in the apple tree as a whole was not conducted. “I was floored by that,” says Martha Crouch, former professor of biology at Indiana University in Bloomington and a consultant for CFS. “It seems like that would be the minimum you would want to know before you start an assessment.” The Center noted that PPO genes have been shown in other plants to be associated with pathogen resistance, and that silencing them could lead to more susceptibility to disease and pests. Okanagan says it conducted pest- and disease-resistance studies, and supplied the data to the USDA upon the agency’s request. “We have not seen any difference in disease susceptibility or plant pest risk between Arctic and control apple fruit or trees,” says Carter. “As summarized and analyzed in our petition document, we monitored all common orchard pests and diseases, including storage rot, over multiple years and multiple sites and saw no difference.” Emily Waltz Nashville, Tennessee
Around the world in a month CHINA
China’s State Council creates a $6.5-billion venture capital fund to invest in startups in emerging industries, including biotech— the latest step in the government’s two-year old strategy to let market forces eventually play a decisive role in China’s economy. The funding will come from existing government capital designated for expansion of emerging industries as well as state corporations and private partners.
NIGERIA
The Nigerian Senate adopts a key joint committee report establishing the National Biosafety Management Agency, which will regulate the safe use, handling and transport of genetically modified organisms and products in the country. Its sponsors had argued that the absence of a biosafety law has made it difficult for the agency to effectively perform its statutory functions and bring the benefits of the technology to Nigeria. A similar bill is being considered in the Nigerian House of Representatives.
URUGUAY
Uruguay’s Parliament approves legislation to promote its biotech sector, including the formation of a capital fund for startups and a national register of biotech developments to help the disbursement of possible new tax benefits and incentives. The new law will allow greater private sector participation in the country’s biotech R&D, innovation and tech transfer.
BANGLADESH
TANZANIA
The government finalizes environmental regulations to allow biotech research. Earlier this year, President Jakaya Kikwete challenged Tanzanian scientists to establish the practicality of agbiotech research, eliminating obstacles such as a clause in the 2009 biosafety regulations sanctioning technology developers, financial backers and even sales outlets should anything go wrong in the development and use of agbiotech.
nature biotechnology volume 33 NUMBER 4 APRIL 2015
Dhaka-based Incepta Pharmaceuticals is offering an unlicensed, generic version of Gilead’s blockbuster hepatitis C drug Sovaldi (sofosbuvir) for $10 a day, beating to market several Indian companies licensed by Gilead to produce the drug for 91 developing countries. Incepta is also in talks with the World Trade Organization to prequalify its version of Sovaldi as eligible for purchase by international aid agencies and countries. Gilead says it is “focused on enabling our 11 Indian generic partners to launch their authorized generic versions as soon as possible.”
327
A two-decade saga for prostate cancer vaccine PROSTVAC, starting with the now-defunct Therion Biologics, is paying off for Bavarian Nordic. The Kvistgaard, Denmark–based vaccine developer brokered a deal, potentially worth $975 million, with Bristol-Myers Squibb (BMS) of New York to complete phase 3 testing of the vaccine for treating castration-resistant prostate cancer. Developed at a time when the immunobiology of cancer vaccines was poorly understood, the therapy failed in clinical trials in the early 2000s. But by choosing different clinical endpoints, Bavarian Nordic, which picked up the program from the National Cancer Institute in 2008, reported positive phase 2 results (8.5-month survival benefit). Milestone payments are pegged to the results of an ongoing phase 3 trial known as PROSPECT—the greater the survival benefit over that reported in phase 2, the greater the payout. Bavarian Nordic’s vaccine (rilimogene galvacirepvec–rilimogene glafolivec) follows the prime/boost model. An initial prostate-specific antigen (PSA) with three costimulatory molecules (TRICOM) vacciniafowlpox priming is followed by PSA-TRICOM fowlpox boosting doses. The vaccine faces competition from several recent approvals in the indication (Johnson & Johnson’s Zytiga (abiraterone acetate) and Medivation–Astellas’ Xtandi (enzalutamide)). But the real excitement might come from combining Bavarian Nordic’s vaccine for prostate cancer with BMS’s immunotherapeutics Yervoy (ipilimumab, an antibody to CTLA4) or Opdivo (nivolumab, an antibody to PD-1).
20-year-old EMA’s birthday bash The European Medicines Agency (EMA) marked its coming of age on March 18 with a conference entitled “Patients at the heart of future innovation.” Guido Rasi, principal adviser in charge of strategy at EMA, welcomed regulators, advisers, drug developers, investors and policymakers from across the globe, including Margaret Hamburg of the US Food and Drug Administration (FDA); Elias Zerhouni, president of global R&D at Sanofi; and Mark Walport, chief scientific adviser to the UK government. Zerhouni credited the EMA for leading the way in clinical-trials transparency initiatives and the FDA for pioneering pathways to accelerate approvals for breakthrough drugs. But Zerhouni also remarked that the ultimate goal should not be to boost the number of drugs approved but to ensure drugs that affect great swathes of the population reach primary care, noting the trend toward approvals for rare disease therapies. The former NIH director also noted that regulatory convergence between agencies is sorely lacking. Despite efforts by the EMA and the FDA to collaborate, there is still a 22% discrepancy between the agencies’ decisions to approve or reject drugs. Harmonization should become a priority, he urged. After all, drug development is a global business. Imagine international air travel if every country had its own airspace rules, Zerhouni prompted: who would board that plane?
326
Nonbrowning GM apple cleared for market The US Department of Agriculture (USDA) on February 13 approved the first genetically modified (GM) apple developed to resist browning. The Arctic apple’s go-ahead is a notable achievement for Canadian firm Okanagan Specialty Fruits, as the small biotech is one of the few to have successfully moved a GM plant through the regulatory process on its own. Indeed, two weeks after the apple’s launch, Okanagan announced its acquisition by Germantown, Maryland– based Intrexon, a synthetic biology company. Okanagan’s stockholders will receive $10 million in upfront cash and $31 million in Intrexon common stock. Industry observers now question whether the Arctic apple will carve a niche in the fruit tree industry or get caught up in the GM labeling debate. Pre-cut fruit and vegetables are a growing trend in the food industry. “The [nonbrowning] trait will enable food service companies to cut and package the apples without adding browning inhibitors such as calcium ascorbate—an antioxidant that changes the flavor of the apple, says Neal Carter, founder of the Summerland, British Columbia–based Okanagan. About 22,000 trees will be planted in the US this spring, with the resulting fruit available in fall 2016 for product demonstration, he says. Okanagan has also applied for regulatory approval of its apple in Canada. Browning is caused by polyphenol oxidases (PPOs) naturally present in fruit and vegetables. When fruit is cut or bruised, these enzymes catalyze the oxidation of polyphe-
nols to quinones, causing oxidative browning. The damage is superficial but can affect the taste and texture of the apple as well as its cosmetic qualities. In the Arctic varieties, the GM apples were genetically engineered with a transgene that produces specific RNAs to silence the expression of at least four browning PPO genes. The apple RNA sequences were introduced into Granny Smith and Golden Delicious varieties, to bind complementary RNA and form a double strand. As RNA is single stranded, the double-stranded sequence is read as a mistake, and the plant’s naturally occurring Dicer enzymes are sent to chop it up, resulting in no or significantly fewer PPO proteins being produced. RNA interference (RNAi) was also used by JR Simplot of Boise, Idaho to silence PPO production in nonbrowning potatoes, which were approved by the USDA in November (Nat. Biotechnol. 33, 12–13, 2015). For that product, fragments of a single potato PPO gene were re-introduced into potato, activating the RNAi pathway. But unlike the apple, the potato’s double-stranded RNA is formed by an inverted repeat transcribed in the tuber and processed into small interfering RNAs that ultimately silence their targets. JR Simplot’s crop was also modified to have reduced acrylamide, which was achieved by using RNAi to silence the asparagine synthetase-1 gene (ASn1). Apples that won’t brown could make them more appealing to consumers and could also reduce waste by minimizing discarded apple
Okanagan Specialty Fruits
npg
© 2015 Nature America, Inc. All rights reserved.
Bavarian Nordic’s prostate vaccine hits pay dirt
Apple grower Neal Carter founded Okanagan Specialty Fruits in 1996.
volume 33 NUMBER 4 APRIL 2015 nature biotechnology
npg
© 2015 Nature America, Inc. All rights reserved.
news due to bruising. But at least three growers associations urged US and Canadian regulatory agencies to reject Okanagan’s petitions for approval. Their objections were not made because of human health or safety concerns. In separate letters, the US Apple Association, the Northwest Horticultural Council and the BC Fruit Growers Association said GM apples may cause severe market disruptions, particularly in apple export markets averse to genetically modified organisms (GMOs). US Apple, however, changed its tune once USDA approval became imminent. “We are confident from the assurance we’ve received from Okanagan that they intend to stand by their pledge to clearly identify their apples in all marketing and packaging,” enabling consumers to choose between GM and nonGM apples, says Wendy Brannen, director of consumer health and public relations at US Apple. Okanagan’s apples will not be labeled ‘GM’, but packaging will include the ‘Arctic’ name and logo. “It will be highly recognized as a GM product, given the amount of media attention we’ve had,” says Carter at Okanagan. The company has not yet
decided whether the packaging will use other descriptive words, such as ‘nonbrowning’, which will partly depend on guidance from the US Food and Drug Administration, Carter says. The GM apple may get caught up in the GMO labeling debate and used as an example, given its cachet as a family friendly, wholesome food, says Chris Schlect, president of the Northwest Horticultural Council in Yakima, Washington. “Apples are a symbolic product. It’s a fruit that a mother gives to a child going to school,” he says. “It’s going to be used in the media and by Congress in issues over the national labeling initiative.” Indeed, the Washington, DC–based Environmental Working Group put out a press release in February saying the approval of Arctic apples “underscores the need for a transparent and consistent national labeling standard.” Other consumer groups argued against the safety of Okanagan’s apple. The Center for Food Safety (CFS) said USDA’s environmental assessment was inadequate—a complaint the Center has made for nearly every biotech crop assessment USDA has conducted
in recent years. In its 61-page comment, the Center said that proper characterization of the PPO genes, their functions and the impacts of silencing them in the apple tree as a whole was not conducted. “I was floored by that,” says Martha Crouch, former professor of biology at Indiana University in Bloomington and a consultant for CFS. “It seems like that would be the minimum you would want to know before you start an assessment.” The Center noted that PPO genes have been shown in other plants to be associated with pathogen resistance, and that silencing them could lead to more susceptibility to disease and pests. Okanagan says it conducted pest- and disease-resistance studies, and supplied the data to the USDA upon the agency’s request. “We have not seen any difference in disease susceptibility or plant pest risk between Arctic and control apple fruit or trees,” says Carter. “As summarized and analyzed in our petition document, we monitored all common orchard pests and diseases, including storage rot, over multiple years and multiple sites and saw no difference.” Emily Waltz Nashville, Tennessee
Around the world in a month CHINA
China’s State Council creates a $6.5-billion venture capital fund to invest in startups in emerging industries, including biotech— the latest step in the government’s two-year old strategy to let market forces eventually play a decisive role in China’s economy. The funding will come from existing government capital designated for expansion of emerging industries as well as state corporations and private partners.
NIGERIA
The Nigerian Senate adopts a key joint committee report establishing the National Biosafety Management Agency, which will regulate the safe use, handling and transport of genetically modified organisms and products in the country. Its sponsors had argued that the absence of a biosafety law has made it difficult for the agency to effectively perform its statutory functions and bring the benefits of the technology to Nigeria. A similar bill is being considered in the Nigerian House of Representatives.
URUGUAY
Uruguay’s Parliament approves legislation to promote its biotech sector, including the formation of a capital fund for startups and a national register of biotech developments to help the disbursement of possible new tax benefits and incentives. The new law will allow greater private sector participation in the country’s biotech R&D, innovation and tech transfer.
BANGLADESH
TANZANIA
The government finalizes environmental regulations to allow biotech research. Earlier this year, President Jakaya Kikwete challenged Tanzanian scientists to establish the practicality of agbiotech research, eliminating obstacles such as a clause in the 2009 biosafety regulations sanctioning technology developers, financial backers and even sales outlets should anything go wrong in the development and use of agbiotech.
nature biotechnology volume 33 NUMBER 4 APRIL 2015
Dhaka-based Incepta Pharmaceuticals is offering an unlicensed, generic version of Gilead’s blockbuster hepatitis C drug Sovaldi (sofosbuvir) for $10 a day, beating to market several Indian companies licensed by Gilead to produce the drug for 91 developing countries. Incepta is also in talks with the World Trade Organization to prequalify its version of Sovaldi as eligible for purchase by international aid agencies and countries. Gilead says it is “focused on enabling our 11 Indian generic partners to launch their authorized generic versions as soon as possible.”
327
