Plant-Made Pharmaceuticals (PMPs) Financial Risk Profile

Bill Freese, Research Analyst, Friends of the Earth
Richard Caplan, Food Safety Advocate, U.S. Public Interest Research Group
December 2005

Summary

Introduction

Biopharmaceuticals are proteins generated in living organisms that have medicinal properties. They were once obtained exclusively from animal or human tissues, such as insulin from pig pancreas or albumin from human blood. Although over 99% of biopharmaceuticals by weight are still obtained in this way from tissues, there is a growing trend to produce biopharmaceuticals in fermentation facilities employing genetically engineered (GE) animal cells, bacteria, yeast or fungi. With over 132 GE products, the global market in biopharmaceuticals was valued at $32 billion in 2003, with a high, though declining, growth rate.

Genetically engineered (GE) plants represent an experimental platform for production of these compounds (i.e. "plant-made pharmaceuticals," or PMPs). Factors driving the use of GE plants include anticipated reduction in production costs, ease of scalability, and storage cost savings vis-à-vis proven fermentation techniques. However, despite 15 years of open-air field experimentation and huge investments of time, money and scientific expertise, not a single PMP has passed FDA's drug review process. PMPs are failing for numerous reasons, including technical difficulties, food industry opposition, increasingly stringent and costly regulation, untenable liability, opposition from farming and consumer groups, and growing interest in alternate production platforms.

Interest in PMPs on decline

Experimental PMPs are grown primarily in GE corn, soybeans, tobacco and rice; outdoor plantings require permits from the USDA. According to USDA records, the number of authorizations issued for field trials of crops producing pharmaceutical and related compounds has fallen from a peak of 19 in 2001 to 7 in 2004 and 2005 (see graph). While corn represents 48% of all pharma crop permits historically, pharma corn permits have fallen from a peak of 13 in 2001 to just one in 2004 and 2005. Half of the field trials in 2004 and 2005 involved pharma tobacco. This move away from corn to non-food tobacco reflects concern over contamination of food with PMPs.

Technical obstacles

It has proven much more difficult than once imagined to produce human and animal biopharmaceuticals in GE plants. The human immune system can react to a plant-made "human" drug as foreign due to subtle differences in structure between the natural and plant-made versions of the "same" compound. Immune system attack can render the drug ineffective, trigger allergic reactions or even cause auto-immune disorders. Another difficulty is extraction of the PMP from thousands of plant constituents without damaging it. Finally, the technique is plagued with inconsistency in drug yields and quality in plants with different genetic backgrounds, and in identical plants grown in different environments. For instance, inconsistency in plant-to-plant vaccine levels has undermined hopes of delivering "edible vaccines" in raw fruit or vegetable form.

Food industry has "zero tolerance" FOR PMPs in food

Another important reason for declining interest in PMPs is the strong opposition of the $500 billion food industry due to concerns about liability arising from contamination of the food supply with drugs. Geneticists and agronomists believe such contamination is inevitable at commercial scale - especially with corn, a prolific pollinator that is also the favorite PMP host plant. Thus, some have called for establishment of tolerances (i.e. maximum permissible levels) to legalize PMP contaminants in food. Yet the USDA and FDA maintain a zero tolerance standard for PMPs. And the food industry, normally supportive of liability-easing tolerances, has unequivocally opposed tolerances for PMPs, no doubt fearful of consumer and export market backlash upon discovery of even low "legal" levels of drugs in the food supply. Food company attitudes towards PMPs are shaped profoundly by the StarLink GE corn debacle, which cost them millions of dollars through food recalls, in part because the EPA held firm to a zero tolerance standard for transgenic residues of StarLink in food. With both the food industry and the government dead set against tolerances, open-air PMP production in food crops involves huge, and ultimately untenable, exposure to liability for PMP companies as well as farmers, millers, food companies, etc. Former Kraft Foods CEO Betsy Holden singled out the issue of PMP contamination of foods as a threat to her company and the food industry as a whole. In 2005, Anheuser-Busch threatened to end all purchases of Missouri rice if Ventria Bioscience went forward with plans to grow its pharma rice in rice-growing southeastern Missouri. The proposed planting, which was also opposed by Missouri rice growers, never took place.

Food industry drives stricter, more costly, regulation

In the fall of 2002, two high-profile contamination episodes catapulted "biopharming" onto CBS Evening News (11/13/02). The culprit was ProdiGene, Inc., a privately-held Texas firm that was once the leader in development of corn-based PMPs. One incident involved the USDA-mandated destruction of 500,000 bushels of contaminated soybeans in Nebraska and $3.5 million in liability for ProdiGene. In a similar incident in Iowa, USDA ordered the destruction of 155 acres of field corn potentially contaminated with ProdiGene's pharm variety via cross-pollination. Food companies and consumer groups outraged by these episodes lobbied the USDA for stricter regulation of PMP field trials, which came in early 2003 in the form of greater isolation distances, dedicated harvesting equipment and more inspections. Later in 2003, the USDA acknowledged 113 other violations by GE plant field trial operators, raising serious questions about the biotech industry's ability and/or willingness to prevent contamination.

PMP production may be uninsurable

As part of the settlement imposed on ProdiGene for these violations, USDA is requiring the company to post a $1 million bond before any more field trials to cover damages from any future contamination episode. The North American Millers' Association demands that all PMP producers be required to obtain insurance coverage to indemnify everyone downstream in the food chain. But would insurers provide such coverage? According to Robert Hartwig, chief economist for the Insurance Information Institute: "Genetically engineered foods are among the riskiest of all possible insurance exposures that we have today." The amount of coverage available to biotech firms in general has declined in recent years, perhaps in part due to a $110 million settlement reimbursing non-StarLink growers for economic losses due to the StarLink corn contamination debacle. If insurance companies are increasingly leery of insuring even garden-variety GE crops, then their disinclination to cover companies whose operations threaten to put drugs and industrial chemicals in the food supply will be still greater.

Big players leery of PMPs

Swiss-based Novartis Pharma, the global leader in biopharmaceuticals, is skeptical of the GE plant platform and recently committed $6 billion to further development of conventional fermentation systems. Ag biotech industry leader Monsanto (MON) announced closure of its biopharm subsidiary, Integrated Protein Technologies (IPT), in October 2003 due to "uncertainty of the longer-term reward from a highly capital-intensive business." DuPont (DD) and its subsidiary Pioneer currently have an internal policy to forego PMP development. According to USDA data, neither Bayer CropScience (BAY) nor Syngenta (SYT) has conducted a single outdoor field trial of a drug-producing plant, though both companies have entered into joint ventures with biopharm dot.coms. Their strategy seems to be to avoid the financial risk associated with contamination episodes while at the same time keeping some irons in the fire. Of the five largest ag biotech companies, only Dow Chemical (DOW) is pursuing PMPs, but by its own admission is having considerable technical difficulties with its plant-made monoclonal antibodies.

Biopharm dot.coms not delivering

Efforts to develop PMPs are led by small firms such as ProdiGene, Epicyte, CropTech, Large Scale Biology and Ventria Bioscience. Despite $6 million in subsidies from an Iowa state economic development fund, ProdiGene has delivered nothing to Iowa's economy, and in fact was nearly sued by the Iowa Attorney General's office for defrauding farmers with its "get rich quick with pharm crops" ploy. ProdiGene, unable to pay USDA-imposed penalties (see above), was saved from bankruptcy through a no-interest loan from USDA and a buyout by Stine Seed Company.

In 2004, San Diego-based Epicyte Pharmaceutical, another pharma corn leader, shut down and sold its assets to Biolex of North Carolina. Epicyte's closure is the latest in a series of San Diego biotech company failures, dashing the city's dream of becoming the 'Silicon Valley of ag biotech.' Epicyte's collapse was due to technical difficulties in development of monoclonal antibodies and concern in the investment community about liability should the company's pharmaceuticals contaminate the food supply. Significantly, Epicyte's purchaser Biolex produces monoclonal antibodies "in regulatory-compliant, contained and controlled bioprocessing facilities" utilizing the aquatic plant duckweed.

CropTech was a privately-held Virginia company once considered the leader in development of PMPs in tobacco. In the ten years of CropTech's existence, it received over $12 million in state and federal subsidies. After failing to raise $6 million from struggling VA tobacco growers to stay afloat, the company sought financing from North and South Carolina, but filed for bankruptcy before it could take advantage of South Carolina's incentive package.

California-based Large Scale Biology (LSBC) conducted the first outdoor field trial of a pharmaceutical-producing plant (viral-vectored tobacco) in 1991. Fourteen years later, it has still not commercialized a single PMP. After going public at over $20/share in mid-2000, the company's share price has fallen steadily, ranging from $0.70-$2.50 in 2004 and from $0.25-$1.50 in 2005. LSBC had an operating loss of over $17 million in 2004, and has been rated a strong sell throughout 4Q 2005.

As of December 2005, Ventria Bioscience's planned move from California to Missouri is stalled. MO state legislators are balking at a ballooning subsidy package demanded by Ventria as a condition for it to set up shop at Northwest Missouri State University. Originally asked to provide $10 million, MO officials are now being asked to pony up $23 million in subsidies for the project, which includes a PMP education facility.

AG groups divided on PMPs

While some agribusiness groups like the National Corn Growers Association support PMPs, farmer organizations like the American Corn Growers Association and National Family Farm Coalition are firmly opposed due to concern over liability to farmers from contamination. The Rocky Mountain Farmers Union (RMFU), Western Colorado Congress and 40 other rural & environmental groups have called for a moratorium on outdoor PMP experimentation, and were instrumental in stopping a proposed 2003 trial of pharma corn by Meristem Therapeutics. Farmer-led opposition in California and Missouri stopped proposed field trials of pharmaceutical rice by Ventria Bioscience in both states in 2004 and 2005, respectively. The opposition in Missouri included two major rice producer trade groups, USA Rice Federation and US Rice Producers Association. The flax industry is fighting attempts by a startup called Agragen to develop pharmaceutical flax due to contamination concerns.

Scientific and public interest groups opposed to PMPs

Two committees of the National Academy of Sciences have warned of the potential for contamination of food crops with PMP traits, and associated human health risks. The editors of Nature Biotechnology, the industry's leading journal, recently issued a scathing critique of PMP production in food crops, comparing it to a drug company "packaging its pills in candy wrappers or flour bags or storing its compounds or production batches untended outside the perimeter fence." A growing list of environmental, consumer protection and public interest science organizations are also opposed to open-air PMP production, especially in food crops. These include Friends of the Earth, Consumers Union, U.S. Public Interest Research Group and Physicians for Social Responsibility of Oregon, among others.

Alternate production platforms

In 2003, the Scripps Institute announced promising results from engineering algae to produce a range of biopharmaceuticals. Applied Phytologics (now Ventria Bioscience) has produced an experimental biopharmaceutical to treat cystic fibrosis in a contained fermentation system based on rice cell culture. Another promising experimental technique is rhizosecretion (engineering plants to secrete biopharmaceuticals from their roots) conducted hydroponically.

Conclusion

The $32 billion biopharmaceutical industry is based on proven fermentation systems employing various types of cell cultures. While this technique involves large capital start-up costs, it offers three crucial advantages over the experimental GE plant platform. It works, while GE plants have not. GE drug traits are contained, with virtually no possibility of contaminating the food supply, while 100% containment is impossible with GE plants. And precise control over production conditions facilitates a high level of consistency in drug quality and yield, which is not possible with plants grown out-of-doors exposed to a broad range of environmental conditions. Thus, further refinements to traditional fermentation techniques (e.g. Novartis' path) or development of alternate techniques like plant cell culture and rhizosecretion that offer the advantages of containment and control appear to be more promising than the GE plant platform in the future development of the biopharmaceutical industry.

Biotech Company Closes After Running Out of Cash

By Andrew Pollack
The New York Times
December 24, 2005

In a setback for a controversial area of biotechnology, the company that led the way in trying to produce pharmaceuticals in genetically modified crops ran out of money and shut its doors yesterday.

The company, the Large Scale Biology Corporation, based in Vacaville, Calif., said in a statement Thursday that all of its approximately 70 employees had been let go.

Large Scale was founded in 1987 as Biosource Genetics and was apparently the first company to try to produce protein-based drugs and industrial chemicals in genetically engineered plants.

Such production, it argued, would be faster and far less expensive than using genetically engineered bacteria or animal cells, which is the usual method of producing pharmaceutical proteins like insulin and growth hormone.

But environmental groups and food companies have expressed opposition to pharmaceutical-producing crops, saying that drugs might accidentally end up in the food supply, causing health problems and forcing costly product recalls.

Large Scale used tobacco, a nonfood crop, so its technology was somewhat less controversial than that of companies using corn or rice. And under the method used by the company, the genes put into the tobacco plant could not be spread by pollen.

Still, controversy over agricultural biotechnology in general has made it difficult for small companies in that business to raise money.

Robert L. Erwin, a founder and the chairman of Large Scale, said the bigger problem for his company was the reluctance of drug companies to have their products developed in crops.

Since there are no crop-produced pharmaceuticals on the market yet, he said, drug companies do not know how easy it will be to win approval for such drugs from the Food and Drug Administration.

"Everybody wants to be the second one out," Mr. Erwin said. "There are very few corporate executives willing to bet on an unproven process."

Moreover, he said, pharmaceutical crop developers are wrong in assuming that lower production costs are an important consideration for drug companies.

With high prices for their drugs, Mr. Erwin said, "cost is not really an issue for them."

Large Scale's demise is a blow to Owensboro, Ky., in the heart of tobacco country, where Large Scale has a factory to extract drugs from the tobacco.

Some civic leaders in Owensboro had been hoping that pharmaceutical production would be a source of income for tobacco farmers and the basis for a local biotechnology industry.

A recent study by Robert Wisner, a professor of economics at Iowa State University, said that benefits to farmers and rural economies from pharmaceutical crops were likely to be modest. The report was sponsored by the Union of Concerned Scientists, which is critical of agricultural biotechnology.

Large Scale was selling one tobacco-produced protein for use by research laboratories and industry. It was working on producing enzymes to treat rare diseases, a cancer treatment and vaccines.

In the company's statement, the chief executive, Kevin J. Ryan, said that Large Scale was "taking steps to preserve our assets for the benefit of our creditors and stockholders."

The company said it was still in talks with potential collaborators on deals that could raise money and is also talking with potential acquirers.

The company went public at $17 a share in 2000, the year of a biotech investing frenzy in which dozens of companies issued stock.

Even after a recent reverse split aimed at building up the price per share by reducing the number of shares, the stock closed at 19 cents on Friday. That will be its last day of trading on a Nasdaq market because the company said it would not appeal a decision by Nasdaq to delist it.

GE Trees at the Meeting in Vitoria
December 23, 2005

By Anne Petermann and Orin Langelle, Global Justice Ecology Project

The United Nations Food and Agriculture Organization (FAO) reports outdoor field trials of GM trees worldwide in 16 countries. While the majority are located in the United States, there are also GE tree test plots in France, Germany, Britain, Spain, Portugal, Finland, Sweden, Canada, Australia, India, South Africa, Indonesia, Chile and Brazil. China is the only country known to have developed commercial plantations of GM trees, with well over one million trees planted throughout ten provinces.

Most of the research is being focused on Poplars (47%), Pines (19%) and Eucalyptus (7%). The main traits being studied are herbicide tolerance, insect resistance, wood chemistry (including reduction of lignin content), and fertility.

The projected social and environmental impacts from the release of GE trees commercially include the increased native forest conversion to plantations; the increased use of toxic herbicides and pesticides; and the loss of wildlife and water sources. Additionally, the contamination of native forests with engineered pollen from GE trees is predicted to lead to impacts such as the increased susceptibility of native forests to disease, insects and environmental stresses like wind and cold; disruption of forest ecosystems which depend on insects; the exacerbation of global warming due to increased forest mortality; and the loss of forest-based foods, medicines, fuel and traditional cultures. Scientists at Duke University in North Carolina in the US have created pollen models that demonstrate tree pollen traveling for over 1,000 km. Because scientists admit that 100% guaranteed sterility in GE trees is impossible, if GE trees are released into the environment, the widespread contamination of native forests cannot be prevented.

With the exception of China, the most rapid advancement toward GE tree commercialization seems to be taking place in the Americas: in the US, Chile and Brazil.

In Chile, research is being carried out on radiata pine to engineer it for insect resistance by inserting the gene for Bt production. Pine plantations currently comprise 80% of Chile's plantations and the area of land covered by plantations in Chile continues to grow. Industry in Chile has projected a release of Bt radiata pine by 2008. Monsanto Corporation predicted that Chile would be the first country to commercialize GE trees, although China has won that race. Because many of the plantations in Chile are concentrated on the traditional lands of the Mapuche indigenous people, there are widespread health problems in Mapuche communities due to the chemicals used on the plantations and also due to the very heavy pollination from the pine plantations, which completely encircle some Mapuche villages. The introduction of Bt pines into these plantations will greatly exacerbate these health problems.

In Brazil, Aracruz Cellulose and Suzano are involved in research into GE trees. Suzano, which manages over 3,000 square km of timberland in Brazil is partnered with Israel-based CBD Technologies on a project to increase the growth rate of eucalyptus trees. "Regular eucalyptus trees are usually cut down after seven years, during which they grow to a height of 20 meters. Trees treated with CBD can reach that height in 3 years or less," stated Dr. Seymour Hirsch, CEO of CBD Technologies. CBD and Suzano plan to set up a joint company to market their GE eucalyptus following the completion of their field trials. CBD also insists its fast-growing GE trees will help stop global warming. "A one hectare forest consumes 10 tons of carbon annually from the CO2 that the trees breathe. Clearly a forest that grows twice as fast consumes twice as much and contributes to the shrinking of the hole in the ozone." [sic]

International Paper, which has 200,000 hectares of land in Brazil is also involved in GE tree experimentation there. In addition, IP is a partner in Arborgen, the world's leading GE tree corporation. The other two partners are Rubicon, based in New Zealand, and US-based MeadWestvaco. Arborgen recently announced that it was shifting its focus from research and development to the marketplace. Specifically, Spokesperson Dawn Parks said Arborgen will be looking to hire a handful of engineers and production workers to design and run machinery capable of turning out larger quantities of the lab-altered seedlings the firm has developed.

Arborgen, headquartered in Summerville, North Carolina in the southeast US, is focusing much of its attention to eucalyptus in Brazil, which Arborgen considers to be its "most important geography." Arborgen has established a Brazilian office and previously projected that they would have full field-testing in place in Brazil by 2005 on customer land.

In 2002 Arborgen hired former Monsanto executive Barbara H. Wells as their new chief executive. She had previously been the vice president for Latin America for Emergent Genetics and prior to that had been commercial biotechnology manager in Brazil, which may explain why Arborgen moved its field trials from New Zealand to Brazil after Wells came on board.

Arborgen is working to develop "improved pulping" [i.e. low-lignin] eucalyptus as well as cold-tolerant eucalyptus. Development of cold-tolerant eucalyptus is of interest for plantations in both Chile and the Southeast US.

Rubicon CEO Luke Moriarity in his July 2005 address to shareholders emphasized the critical role Brazil plays in Arborgen's commercialization of GE trees. He emphasized the potential of GE low-lignin eucalyptus plantations in Brazil. "…by reducing the amount of lignin actually produced by the tree itself, a huge reduction in the total cost of wood-pulping can be achieved. Pulp operators can be expected to pay a significant premium for successful low-lignin treestocks."

He went on to calculate the potential profit that could be made, "the value accruing annually to the treestock provider is [projected to be] some 38 million US dollars post tax. Repeating this level of sales year after year, without any assumed growth in market share, or penetration into other markets, translates into a value for this one product of some 475 million US dollars post tax."

He continued in this vein, "however when you begin to look at the possibilities more closely you can see that the value potential is actually huge. Rather like human health, although much lower profile, the annual unit sales of forestry seedlings are well into the billions, recur every year, and span the globe. And unlike human health, where competition is intense, there are no global competitors to ArborGen in this space. Of course, ArborGen is still some years away from selling commercial product, so naturally the equity market discounts this prospective value fairly aggressively at present. However, as the chart behind me illustrates, as ArborGen continues successfully along the commercialisation path - as it has done to date - we can expect this "time to market" discount to decrease, and the value of ArborGen to ramp up accordingly."

In conclusion he stated, "So I hope that illustrates the nature of this undertaking, and gives you some insight into its huge potential. As the saying goes - "it is only a matter of time."

Researchers working on genetic modification of trees surveyed for their opinions about risks associated with GM trees raise two concerns most often: environmental threat of escape of GM pollen or plants into native ecosystems and forests and their impacts on non-target species; and negative public perceptions of GM trees. This well-founded concern about public reaction to GE trees provides an important strategic opening for the campaign to stop GE trees.

In the US and Canada, thirteen national, regional and local organizations have come together as the STOP GE Trees Campaign, whose goal is to ban genetically engineered trees. To accomplish this goal, the group builds economic disincentives, social pressures and legal barriers against GE trees. Their activities include public education, community organizing, media outreach and distribution of a new documentary video on GE trees ("A Silent Forest: The Growing Threat, Genetically Engineered Trees"), narrated by Dr. David Suzuki.

Global Justice Ecology Project is also reaching out to organizations and movements around the globe who are fighting plantations in regions where GE research and development is occurring, in order to provide information about this looming threat and offer support for efforts to prevent the introduction of GE trees into plantations. GJEP has established its first pilot program in Chile with the Mapuche group Konapewman that coordinates efforts to reclaim traditional Mapuche lands and oppose threats such as industrial timber plantations and GE trees. GJEP plans to use the experiences from this pilot program in their effort to reach out to additional communities and groups in other regions threatened by GE trees.

Internationally GM tree and forest protection groups have spoken at United Nations meetings around the world about the threat from GM trees. Groups such as the Peoples Forest Forum of Finland, Global Justice Ecology Project of the United States, World Rainforest Movement and Friends of the Earth International have spoken at the UN Forum on Forests in both Geneva and New York City to inform delegates of the dangers GM trees pose to native forests around the world.

With little to no indication of help, however, from either the UN Forum on Forests or the U.N Convention on Climate Change, the international GE trees campaign is now turning to the United Nations Convention on Biological Diversity (CBD) to see what kind of international regulations on GM trees might be achieved through the CBD.

Even the UN Food and Agriculture Organization seems to be in favor of such international regulations. Their July, 2005 report on GM trees concludes,

Internationally renowned geneticist Dr. David Suzuki points out that

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