Making transgenic animals to produce drugs has matured, but few products have come to market
A few years back, PharmAthene closed the site where it had made the recombinant enzyme Protexia in the milk of transgenic animals. Government support for the nerve agent countermeasure had waned because of budget constraints and efficacy concerns. Since then, the Maryland-based company has developed a new production method, and government interest has returned.
PharmAthene says its new mammalian-cell-culture route “offers significant advantages over the transgenic-goat-based approach,” including higher yield, easier scale-up, and lower costs. The firm says the platform also is “consistent with those used for other biotechnology products” and will lead to a “more traditional regulatory path to Food & Drug Administration licensure.”
With the shift, proponents of transgenic drug production must strike Protexia from the list of products they hoped would be made with the technology. The ability to generate transgenic biologic drugs has matured over two decades, but only two products have been approved in that time. Small companies committed to transgenics have had difficulty growing.
Even the marketers of the two approved products, U.S.-based GTC Biotherapeutics and the Dutch firm Pharming, are struggling. Both still assert that the technology can cost-competitively produce high-quality, complex proteins without capacity limitations. But the reality is that they have worked for many years on little-changed portfolios of candidates without much new nearing the market.
“The two products on the market show that the technology is commercially viable,” says Heiner Niemann, head of the Institute of Farm Animal Genetics at Germany’s Friedrich Loeffler Institute. “But they are not blockbusters, just ‘door openers,’ and the industry would probably need a blockbuster” to take off. When, or if, it will get to that stage is hard to assess, he adds.
Isolating and purifying proteins from transgenic animal milk is essentially the same as for cell-based approaches. And on the critical front end of the process, Niemann says, “the production of transgenic animals has much improved.” New technologies have made the process more efficient and cost-effective than in its early days, he adds. Other advances have addressed drawbacks in engineering large animals to correctly express proteins.
But as transgenics has evolved, so has the broader biopharmaceutical industry, says Angelika Schnieke, head of the livestock biotechnology group at the Technical University of Munich. She spent 11 years, some as assistant director of research, at the transgenics firm PPL Therapeutics in Edinburgh, Scotland, until it closed down in 2003.
When transgenic drug development emerged in the 1990s, it was met with “quite a bit of enthusiasm” by biotech customers looking for drug production sources, Schnieke says. “There was often a shortage of capacity, and if you wanted to have more products you had to build whole new facilities.” Transgenics firms thought they could solve the problem, but as they took time to work on it, the biopharma industry moved on to larger reactors and other production methods.
Transgenics found a foothold making products that were difficult to express in other systems, Schnieke explains. Companies already able to work in cell culture “knew they had a much easier way to get that product to the market” and wouldn’t look elsewhere, she says.
Finding or keeping pharmaceutical company partners has been challenging for transgenics firms, according to Jan De Kerpel, a stock analyst with Brussels-based KBC Securities who covers Pharming. Potential partners “are quite satisfied with the other technologies that they have, such as bacteria-, yeast-, or mammalian-cell-based methods, and clearly prefer these above transgenic-animal-based production.”
PPL, which focused on transgenic sheep, shut down after Bayer suspended a program for α1-antitrypsin after Phase II trials testing it as a respiratory therapy. In 2004, Pharming bought PPL’s patents related to several recombinant proteins, including blood-clotting factors and fibrinogen.
PharmAthene found itself in transgenics in 2005 when it bought Protexia from now-defunct Nexia Biotechnologies. Protexia fit well in the transgenics mold because the enzyme was hard to obtain from blood plasma or recombinant systems.
Meanwhile, GTC, a 1993 spin-off of Genzyme, was the first to get a transgenic drug approved. In June 2006, European regulators okayed ATryn, a human antithrombin protein made in goats’ milk, for treating a hereditary blood disorder. Fast-tracked by the agency because it targeted a rare disease, ATryn won FDA approval in February 2009.
Achieving this milestone was hard. Transgenic drug firms had to cope with a complete lack of experience on the part of regulators with the firms’ methods and products, Schnieke says. Early on, she recounts, companies had to help formulate rules on production, quality, and testing. After a decade of work, and just a month before approving the first product, FDA adopted guidelines regulating genetically engineered animals.
Meanwhile, the European Medicines Agency (EMA) is still publishing draft guidelines to ensure the quality of drugs produced in transgenic animals. In guidelines that came out in May, EMA called for vigilance with respect to transgenic-system-specific aspects because “experience with the technology is relatively limited.” Such aspects include animal production and maintenance, as well as product processing, purity, and contamination.
Suitable quality and control systems are needed, according to the guidelines, because standard Good Manufacturing Practices can’t practically be applied to the animal side of the equation. For downstream processing, GMP conditions will apply, EMA says, “since it is expected that a protein that is produced by a transgenic animal, and its quality attributes, would follow the same standards as a protein produced in mammalian cells in a fermentation system.”
EMA approved the second transgenic product, Pharming’s Ruconest, in June 2010. Produced in the milk of transgenic rabbits, the C1 inhibitor is used to treat hereditary angioedema (HAE) and is sold in Europe by Swedish Orphan Biovitrum. Pharming also filed for FDA approval in late 2010 but was rebuffed. It hopes that results of a Phase III trial now under way will soon support a new application.
If the trial end point is met, Pharming’s North American partner, Santarus, will pay it $10 million. Another $5 million will come if FDA accepts a new filing. Until then, with just over $4 million in the bank, Pharming has been trying to hang on financially and is drawing on up to $13 million in funding from investors. For the first six months of 2012, the firm had revenues of $2.4 million and lost $21 million.
Pharming just implemented a cost-savings plan that will cut at least 20 jobs. As of May it had 75 employees. It closed its Wisconsin cattle research operations in June and sold the facility to a livestock firm. Pharming says the decision reflected the declining importance of transgenic cattle research and legacy proteins such as fibrinogen, lactoferrin, and collagen to its future strategy.
That strategy centers on advancing Ruconest, called Rhucin in the U.S., and Factor VIII through its transgenic rabbit platform. According to Chief Executive Officer Sijmen de Vries, Pharming wants to move away from its internal research focus to a “market-driven, externally focused, collaborative R&D model.” It will maintain enough capabilities to pursue partnerships and transfer its technology and processes.
Roth Capital Partners analyst Joseph Pantginis told clients in a recent report on Pharming that he’s optimistic about approval chances in the U.S. He sees the potential for Rhucin to capture “a significant share of the HAE market, given its low cost of goods, allowing for competitive pricing, safety, convenience, and potentially higher efficacy.”
KBC’s De Kerpel isn’t as bullish. In orphan diseases, it is important to be the first on the market, and Pharming will face at least three competitors if it wins approval. “Pharming really completely lost the competitive battle,” he says.
Ruconest “commercially isn’t a success, and it’s not related to the fact that it is being produced in transgenic animals,” De Kerpel adds. Indeed, the technology’s drawn-out history and social stigma seem not as much of a problem as the products the companies chose to produce with it.
Pharming’s lactoferrin, for example, “has been extremely difficult to partner or to make any money out of,” De Kerpel says. Both Pharming and GTC are also working on blood-clotting factors, believing they can fulfill an unmet supply need. But even if these products make it through development, they will face an extremely competitive market that “is not standing still,” he adds.
Commercial success has also eluded GTC, which had U.S. revenues of about $6.4 million last year, mainly from ATryn sales. In June 2010, GTC was down to just $6 million in cash. It took a $7 million loan from French partner LFB Biotechnologies, the second loan that year, and cut about 50 staff. That December, LFB acquired GTC for about $18 million.
GTC had about 39 employees as of the end of 2011, according to LFB. With the changes, the U.S. firm is focused on improving the financial performance of ATryn, developing Factor VIIa, and producing generic biologic drugs, or biosimilars, with LFB.
Transgenics firms see potential in biosimilars because many blockbuster biologics will soon lose patent protection. GTC believes it can deliver improved versions of monoclonal antibodies (MAbs) at lower cost and with greater manufacturing flexibility than other production systems. It has begun raising production animals for MAbs similar to adalimumab (Abbott Laboratories’ Humira), cetuximab (Bristol-Myers Squibb and Eli Lilly & Co.’s Erbitux), and trastuzumab (Genentech’s Herceptin).
LFB and GTC have licensed rights to ublituximab to TG Therapeutics, an LFB spinout. The cancer-treating MAb has targets similar to Rituxan, sold by Biogen Idec and Genentech. Although LFB currently makes ublituximab in mammalian cells, the firms say they will explore a transgenic method.
Moving transgenic biosimilars ahead will take at least a few more years. The companies involved have spent decades proving the technology works and then showing they can make it through the development and regulatory process. But given their lack of commercial success so far, it’s uncertain how much longer they can keep their businesses going.