Monthly Archives: March 2015

Nonbrowning GM apple cleared for market

Posted on by
Reply

appleThe 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 polyphenols 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, where they bound complementary RNA to 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 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 non-GM 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 

The Future of Sustainable Use Biodiversity in Brazil

Posted on by
1

webBrazil tried to lead the world in sustainable use of biodiversity over the last decades. It attracted the whole world for the RIO 92 summit and Eco 92. The most prominent authorities worldwide came to Rio and a host of countries signed the Biological Diversity Convention (BDC). The goal of the convention is the sustainable use of biological diversity and the fair and equitable sharing of benefits derived from the use of genetic resources, through the appropriate access to genetic resources and transfer of relevant technologies, taking into account all rights over these resources and technologies, and by means of appropriate funding – this is all in the first article of BDC.

More than two decades later, we unfortunately have to consider that the Convention failed to accomplish its first goal: conservation of the world biodiversity. Brazil fortunately did not lead this destruction but we must acknowledge that in the last three decades an area larger than Germany was devastated in the Amazon. Asia and Africa are even more drastic examples.

Also, the BDC never accomplished the equitable sharing of benefits derived from the use of genetic resources. This is mostly because benefits are protected by patents and there is no appropriate funding to assure technology transfer. Thus, I would have to say, unfortunately, that BDC was a big failure overall. But for Brazil? For Brazil it is even worse, because the principles advocated by the Convention were intended to be folded into national law, and this did not happen. These principles stated that one country could not benefit from the biodiverse richness of another without financial compensation. This is difficult because negotiations between countries in the subject of intellctual property rights are complex and results are hard to achieve.

In Brazil, the attempt to incorporate the principles of the BDC into law failed because sharing of benefits had to be exercised between scientists and indigenous people, and thus these actors had to deal with contracts in place before the benefits were known. The law (Provisional Measure 2186, 2001) concentrated the power for regulating access to genetic resources in the hands of the Ministry of Environment. It also created a council called CGEN (Conselho de Gestão do Patrimonio Genético) that controls the access to genetic resources in the worst way possible, and when Marina Silva was the Minister of Environment, she created an institution called Chico Mendes. A third actor in the process is IBAMA, which should be subordinated to the Minister of the Environment but in practical terms it is not.

The result is that all these actors did not work together and caused chaos. CGEN admitted that it does not know how to exercise the Provisional Measure, but continuously sued companies and scientists. It’s interesting to note that not one pharmaceutical product has been produced from Brazilian biodiversity (ACHEFLAN is the only exception, and it caused the company ACHE to be sued by CGEN). If one works at the Butantan Institute, home to a tremendous snake collection, and one wants to develop a pharmaceutical product from a snake poison, one must get an authorization from Instituto Chico Mendes. These authorizations take forever to be issued. Elibio Rech, a scientist from EMBRAPA, was sued because he wanted to work with spider genes encoding for important proteins. He was treated as if the spiders were going to disappear from the environment because of his experiments.

So what is the future of Brazil, the most biodiverse country in the world? A recent attempt to build a new law to replace the MP proposed by the government resulted in a version that is worse than the current. The CGEN is still there, and the control of genetic resources will be retained by the Ministry of Environment, even though there is opposition.

Attempts by scientist to go beyond science into technologies or products might still be possible. The Labor Party proposal lost and the “substitutive” won; the next step is that the “substitutive” will move to the Senate. It is still possible that some improvement will be introduced in the substitutive and improve the context greatly. Time will tell.

Luiz Antonio Barreto de Castro

$1-million price tag set for Glybera gene therapy

Posted on by
Reply
gene_Therapy

Gene therapy programs are generating much excitement, but there is little agreement about pricing and how payers will foot the bill. (Jim Dowdalls/Science Source)

The first gene therapy approved in the Western world is set to go on sale in Germany at a cost close to $1 million per treatment. The record-breaking price tag came to light in November 2014, when Amsterdam-based Uniqure and its marketing partner Chiesi, of Parma, Italy, filed a pricing dossier with German authorities to launch Glybera. A few weeks later, the focus on gene therapies sharpened further when Cambridge, Massachusetts–based Bluebird Bio presented striking early clinical data from four beta-thalassemia patients treated with its Lentiglobin BB305 gene therapy, at the American Society of Hematology meeting in San Francisco. Within three months, these patients had begun producing sufficient hemoglobin to reduce or eliminate the need for blood transfusions. Big pharma is taking notice; the most recent gene therapy deal signed in February, between Sanofi’s Genzyme unit and Third Rock Ventures’ Voyager Therapeutics, both in Cambridge, Massachusetts, is worth up to $845 million. But as gene therapies start to provide solutions for highly penetrant genetic diseases that had been intractable, the hand-wringing over their value and how government and private insurers around the globe will pay for them will likely begin.

“The pricing of specialty medicines has now caught everyone’s attention,” says Troyen Brennan, chief medical officer for the pharmacy benefit manager CVS Caremark, based in Woonsocket, Rhode Island. The pricing debate, sparked by Gilead Science’s hepatitis C virus drug regimen Sovaldi (sofosbuvir; Nat. Biotechnol. 32, 501–502, 2014), is set to intensify with the advent of these potentially curative—and very expensive—therapies for certain rare genetic diseases.

As the first and only approved gene therapy in Europe or the US, Glybera (alipogen tiparvovec) will likely become a bench-mark product. Glybera was recommended for approval by the European Medicines Agency in 2012 (Nat. Biotechnol. 30, 1153, 2012), and Chiesi plans to launch the product in Europe in early 2015, though it has yet to receive a nod from the US Food and Drug Administration (FDA). Glybera is used to treat adults with lipoprotein lipase (LPL) deficiency, an orphan disease which results in abnormally large particles of fat in the blood and causes inflammation of the pancreas. The therapy consists of LPL, encoded by an adeno-associated virus vector, administered through a series of intra-muscular injections. In addition to Germany, the company expects UK pricing March 1. So far, pricing discussions for gene therapy has remained “under the radar” for many payers in the US, says Brennan. “I’ve not seen the national health insurers talking much about this, but they will be sooner or later.” Glybera’s price depends on a patient’s weight, explained Uniqure CEO Jörn Aldag, at an investor meeting in early December. An average patient would need 19 vials of Glybera, he said, at a cost of nearly €44,000 (about $50,000) per vial. “Higher value to patients… should actually command a higher price,” Aldag noted. Uniqure has six-year follow-up data showing a 50% reduction in pancreatitis in Glybera-treated patients, he said, and dividing that up-front price by six years “you  get to a [per-year] price that’s actually lower than [typical] orphan drug pricing,” he said.

Pricing gene therapies might follow one of three general schemes. A classic up-front, one-time  payment,  such  that  Chiesi  and Uniqure are seeking for Glybera in Europe; an annuity model that spreads that payment over a number of years to lessen the cost-density burden on payers; and a pay-for-performance, risk-sharing model that tracks patient outcomes and rewards manufacturers for maintaining patients’ health over a period of time. Each of these schemes is likely to be used, depending on the specific attributes of any one therapy and specific negotiations between drug manufacturers and payers.

Rapid progress in the clinic may speed up such decisions. Bluebird’s therapy, was granted FDA’s  breakthrough therapy designation on Februar y 2, and  since the company’s December presentation at the hematology meeting, eight patients have been treated with the drug across two phase 1/2 clinical studies. Together, the two trials will enroll up to 22 patients with either beta-thalassemia major or severe sickle cell disease. BB305 treats those diseases by using a lentiviral vector to transfect a patient’s own hematopoietic stem cells ex vivo with a functional human beta-globin gene, then returning those cells to the patient.

“Ultimately, where industry needs to go is true pay for performance,” says Bluebird COO Jeff Walsh. But for such a model to work, the product would have to have “transformative data” and endpoints that can both be measured and have a direct correlation with disease. Bluebird’s BB305 may be among the first products that meet those criteria. The impact of the company’s gene therapy on beta-thalassemia patients who would otherwise require chronic blood transfusions is “measurable, with the ability to track on a patient-by-patient basis their level of hemoglobin, which has a direct correlation to whether they’re anemic,” says Walsh. “These are incredibly trackable outcomes and might be a perfect case study” for a pay-for-perfor- mance model, he says.

Spreading out the cost of therapy is likely to be important to insurance providers, especially private payers in the US who may have a patient for only a few years.“If I was working for a carrier right now, I’d be very eager to be pushing for some solutions that are not going to entail bearing the entire cost, just because I have a particular patient’s beta thalassemia this year,” says CVS’s Brennan. Now that insurers can’t reject patients based on pre-existing conditions, or limit lifetime benefits, and may be required to offer gene therapies that become standards of care as parts of minimum essential benefits packages (all of which came into law as part of the Patient Protection and Affordable Care Act in 2010), the environment for annuity-style payments for gene therapies is in place, he says (Nat. Biotechnol. 32, 874–876, 2014).

And for diseases with very clear cost off-sets—in beta-thalassemia, for example, the cost of chronic blood transfusions and disease complications—payers will be more likely to see gene therapies as being cost effective, says Roger Longman, CEO of Real Endpoints, a New York–based information and analytics company focused on pharmaceutical reimbursement. And at the same time, “companies can make a bunch of money without gouging the system,” he says.

Bluebird’s Walsh agrees that the efficacy and safety of a gene therapy and the cost savings for the overall healthcare system are the most important elements of pricing drugs in this space. In addition, he says, “quality of life is another major component of value,” in particular when you think about how a one-time treatment can replace a lifetime of medical interventions. And lastly, he says, “if a patient is having challenges maintaining an education or a job, and a curative therapy alters that equation, there’s societal value” to the therapy as well. The onus is on the drug developer to paint that picture on behalf of its therapy, says Walsh. “If we went to [payers] with a product that had incremental value, we wouldn’t be having the same dialogue,” says Walsh. “They realize there is a lot of value here for this patient population, one that has significant unmet medical need. That opens the door, and we’re starting to have really interesting discussions about their challenges, our challenges, and [finding] common ground,” he says.

Investors  are  clearly  excited  about  the potential for multibillion-dollar gene therapy products. As of early February the small biotech Bluebird was valued at more than $3 billion. Voyager is only a year old but its deal with Genzyme brought in a $100 million upfront payment to advance its adeno-associated virus gene therapy programs in Parkinson’s disease, Friedreich’s ataxia and Huntington’s disease, among other central nervous system disorders. In exchange for that upfront payment and future milestones and royalties, Genzyme will have the option to license multiple Voyager programs at the proof-of-concept stage. Voyager retains US rights to  some programs and global rights to its amyotrophic lateral sclerosis program. Another player in the space, Philadelphia-based Spark Therapeutics, went public on January 29 raising more than $130 million. Spark is developing gene therapies for hemophilia, inherited retinal dystrophies and neurodegenerative disorders, based on technologies developed at the Children’s Hospital of Philadelphia. The company’s lead product, RPE65, delivered by means of adeno-associated virus for inherited retinal dystrophies, received a breakthrough therapy designation in November 2014. The therapy is in a fully enrolled 28-patient phase 3 trial, and the company expects to  announce results later in 2015. Spark doubled in value on its first day of trading, to more than $1 billion.

All gene therapies are unlikely to be deemed equal in the eyes of payers—and Walsh’s four-part value equation hints at measuring what is, in some cases, unmeasurable. But curative products that are safe and have meaningful cost offsets, particularly in rare diseases, are likely to command record prices in the not-too-distant future.

Chris Morrison Yardley, Pennsylvania