News FocusCHINESE GENE THERAPY

Splicing Out the West?

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Science  24 Nov 2006:
Vol. 314, Issue 5803, pp. 1232-1235
DOI: 10.1126/science.314.5803.1232

Chinese researchers have been the first to put cancer gene-therapy products on the market, but critics question the data behind the success stories

Great leap forward.

With a boost from the government, SiBiono GeneTech in Shenzhen has jumped to the front ranks of China's biotech industry.

CREDIT: CAIO CAMARGO

BEIJING—Maria Corina Roman, a Danish surgeon, made international news when she decided to seek treatment for her breast cancer using the world's first commercial gene therapy. Disappointed with standard cancer treatment, Roman flew to China in 2004 to try Gendicine, a Chinese product that contains a virus with a human tumor suppressor gene (p53) spliced into its DNA. Just days after the first injection, Roman reported that she had regained energy and appetite. Gendicine's maker, SiBiono GeneTech Co. in Shenzhen, spread the word. Encouraging reports about this gene therapy appeared in the Financial Times, Business Week, and China Daily.

This fall, however, Roman's tumor has returned, SiBiono acknowledges. The company's chief executive, Peng Zhaohui, says nevertheless that the drug has proved to have “good efficacy,” adding that Roman, SiBiono's most famous client, “should continue to treat with Gendicine.”

Peng's advice is based on more than optimism; it reflects national policy. China's State Food and Drug Administration (SFDA) approved Gendicine for clinical use in October 2003 and licensed its commercial production in spring of 2004. Last year, SFDA approved a second genetically engineered anticancer product: a modified virus, dubbed H101, designed to infect and kill cells containing mutated versions of the p53 gene. The maker, Sunway Biotech Co. in Shanghai, says it expects to strike a licensing deal by the end of this year with Genzyme Corp. in Cambridge, Massachusetts, to run clinical trials of a Genzyme gene-therapy product in China and possibly test H101 in the United States.

As these projects advance in China, gene therapies in North America and Europe are struggling to complete premarket clinical tests. After a U.S. patient died in a 1999 genetherapy trial and two children in French trials developed leukemia in 2002, the U.S. Food and Drug Administration (FDA) tightened controls on experiments, says James Norris, head of the U.K.-based International Society for Cell & Gene Therapy of Cancer. Western companies say they are making progress but have not yet brought a single gene therapy to market.

Some see this as a sign that China is catching up with, or even surpassing, the West. “I think the future of gene therapy will be in China,” says Andre Lieber, a genetherapy researcher at the University of Washington (UW), Seattle. But he warns that recent claims of success should be read with caution. There is a “problem” with interpreting clinical studies done in China, Lieber says. Often the primary data are published only in Chinese—raising a barrier to nonspeakers—and even when they appear in English, critical information may be missing (see sidebar, p. 1233).

Intellectual-property rights may be problematic, too. Some researchers in the West have questioned claims of independent innovations made by Chinese drug companies; this could limit sales outside China. Finally, critics argue that the Chinese regulatory system is not rigorous and that Gendicine, for one, was approved with scant evidence of efficacy. With drugs to treat cancer, “the bar is a lot lower than in the United States to get approval,” says Frank McCormick, director of the University of California, San Francisco, Comprehensive Cancer Center.

High hopes

On a plot of land in the outskirts of Shenzhen stands an empty building with opaque windows, a site where owners hope a biotech bonanza will blossom. Starting next year, this newly constructed plant will begin producing 1.5 million vials of Gendicine per year, seven times the capacity of SiBiono's current facility, according to SiBiono's Peng. Science visited Peng in his office in May and spoke with him last month by phone.

A hallway at the company's headquarters is plastered with clippings from Chinese and international media describing how Gendicine has helped cancer patients. Peng said SiBiono aims to spearhead the sale of gene-therapy products in China with Gendicine. It was given its Chinese name—jin you sheng, “born again today”—by China's Vice President Zeng Qinghong when he made a ceremonial visit to the company a month before SFDA cleared the drug for market.

SFDA approved Gendicine as a treatment for head and neck cancer based on small clinical trials showing that more patients had tumors disappear with Gendicine plus radiotherapy (64%) than with radiotherapy alone (19%). Peng has called these “phase II/III” trials, an unusual term that combines safety (phases I and II) with proof of efficacy (phase III).

In 2005, SFDA approved Sunway's H101, also designed for treatment of head and neck cancer, after a 160-patient phase III clinical trial showed that 74% of patients receiving H101 plus chemotherapy experienced a reduction in the size of tumors compared to 40% of patients receiving chemotherapy alone.

Gendicine has now been given to more than 4000 patients to treat not just head and neck tumors but also 50 different cancers, Peng claims. The venture thus far has received about $6 million in grants and government start-up funds as well as $6 million from private investors.

Peng projected in 2004 that 50,000 patients would have received Gendicine treatment by the end of 2006. Demand is far short of that target, but if the drug works—and if patients can afford the high price of treatment, costing $1680 to $3360 per cycle—the market could eventually be huge. “Having 1.3 billion potential patients compared to 300 million in the United States makes a successful drug very lucrative in China,” says Norris.

Imitation or innovation?

Doubts persist, however, about China's future as a gene-therapy powerhouse. Some U.S. companies allege that China's commercial products are spinoffs of Western inventions with relatively minor modifications. Introgen Therapeutics in Austin, Texas, for example, claims that SiBiono's Gendicine is similar to its own experimental product, a recombinant adenovirus containing the human p53 gene (rAd-p53).

Wei-Wei Zhang, president and CEO of San Diego-based GenWay Biotech, published the first paper on rAd-p53 while working at the University of Texas M. D. Anderson Cancer Center in Houston in 1994. He holds U.S. patents on the viral construct and related processes. M. D. Anderson negotiated a license with Introgen, which has spent more than $70 million to develop a product based on Zhang's rAd-p53, trademarked Advexin. It has been in clinical trials since 1994. The company's ongoing phase III trial using Advexin to treat head and neck cancer is under review for “accelerated approval” by FDA.

Introgen's 106-patient phase II trial in 2005 showed a 10% “tumor response rate,” defined by at least 30% reduction in tumor size, in patients who received Advexin alone. Introgen Vice President Robert Sobol says phase III trials are going well.

Meanwhile, Introgen CEO David Nance claims that Gendicine is a “derivative” of his company's product. In an August 2006 filing with the U.S. Securities and Exchange Commission, Introgen claims that Gendicine infringes on a 1994 patent filed in China but concedes that “enforcement of patents in China is unpredictable, and we do not know if monetary damages could be recovered from SiBiono.”

Peng disputes these statements. In a phone interview, he said that Gendicine is “very different” from Introgen's product, and that the only similarity is the use of p53.

Sunway acknowledges that its product, H101, was inspired by U.S. research but says it developed H101 independently—a claim that is not disputed. According to Sunway officials and other observers, H101 is similar to a product called Onyx-015, made by Onyx Pharmaceuticals Inc. in San Francisco. Onyx-015 and H101 both use a modified adenovirus to target probable cancer cells that have a deficient or mutated p53 gene. This so-called oncolytic virus, which has been tested in U.S. phase I and II clinical trials, is designed to replicate in target cells and kill them.

Sheer numbers.

Companies that want to develop a new idea for treating cancer are attracted by China's low costs and huge market.

CREDIT: LOUIS-LAURENT GRANDADAM/GETTY IMAGES

Onyx never filed for a patent on Onyx-015 in China. Nevertheless, Sunway CEO Hu Fang says that in developing H101, “we followed almost everything Onyx did in clinical trials. … We modified the virus, very little, for patent purposes.”

Although Onyx-015 has shown in phase II trials that it also can achieve local shrinkage of head and neck tumors of about 60% to 70%, McCormick, a co-founder of Onyx, says this was not enough to win FDA approval. Regulators wanted more evidence, specifically data showing that Onyx-015 prolonged survival. Onyx ended a phase III trial when the main backer pulled out in 2005.

At this point, Sunway obtained exclusive worldwide rights from Onyx to use the 015 modified virus in H101. “We bought the patent from Onyx because now we want to put our drug in Europe, the United States, and Japan,” says Hu. The distribution network will be ready soon, and Hu expects 2000 patients to sign up in the first year. The company is working on an improved version, H103, that includes a heat shock protein designed to attack metastatic tumors by inducing an immune response.

CREDIT: DATA COMPILED BY JERRY GUO AND HAO XIN

Different standards

The Chinese government is both an investor in and a regulator of biotech projects such as the ventures that produced Gendicine and H101. Some observers, including Norris, are concerned that the government's dual role could weaken its vigor as an enforcer of standards. He notes that “backers of these companies are high-level government officials.” From 2001 to 2005, the Ministry of Science and Technology (MOST) provided $106 million to innovative drug development, some of which went to SiBiono.

SiBiono's Peng also helped write a regulatory guidebook for SFDA on evaluating cancer gene-therapy products. Leaning forward in his executive chair, Peng proudly shows off a thin pamphlet. “It's the most systematic guidelines in the world, and I was the main framer,” Peng exclaims. There's an appearance of a conflict of interest in this, Norris says, although the government's acceptance of help with regulatory guidelines may reflect a wish to catch up quickly with standards in developed countries.

Peng acknowledges that SiBiono has government support and confirms that the application for Gendicine was sped “through a special channel.” The data from the Gendicine trials were submitted to SFDA in March 2003; the drug was approved 7 months later. Sunway also “pushed” to get its H101 application through in 10 months, Hu confirms. But companies can also apply for accelerated review at the U.S. FDA, and Peng argues that Chinese companies must comply with strict regulations, just like their counterparts in the West.

Yin Hongzhang, SFDA's chief of biological products, says the agency has “special policies” to approve a drug on the fast track if an initial technical review looks fine. “But we would require the manufacturer to do further research and collect more data on efficacy to submit” after approval, he says. Earlier this year, he asked SiBiono to send the required follow-up data; when he spoke with Science he was still waiting for the data.

China's regulatory framework differs in another way. Whereas the U.S. FDA often requires that novel cancer drugs extend the life of the patient to be judged a success, SFDA approved both Gendicine and H101 on the basis of tumor shrinkage.

Sunway's Hu says his company intends to show that H101 increases survival as well as shrinks tumors. “Survival time for patients is very important,” says Hu. In a retrospective study, he says the company has found that H101 can provide a 7-month survival benefit, but the results were not significant. They are now repeating phase III trials with a bigger sample size and more treatment cycles designed to maximize survival benefit.

There is good reason to expect that Chinese biotechnology will have a bright future. Companies in China “have excellent production facilities, a lot of money, and a lot of good people,” says UW's Lieber. Zhang adds that Chinese bioscientists deserve credit for picking up U.S. pioneers' work in cancer gene therapy.

At least a half-dozen Chinese gene-therapy drugs are in clinical trials at the moment, says Savio Woo, past president of the American Society of Gene Therapy. “Before the end of this decade, they should have more drugs. I will be surprised if they didn't,” he says. China also may draw significant outside investment to the field. Genzyme, for example, is negotiating to have Sunway run a phase II genetherapy clinical trial in China. The U.S. company is testing a modified adenovirus construct (Ad2/HIF-1α) to promote angiogenesis in patients with peripheral arterial disease, an immobilizing condition that decreases blood flow to the muscles. Already, Genyzme has enrolled 300 patients in Europe and the United States. “The climate in China is changing, with more innovative companies not just focused on manufacturing,” says Genzyme Vice President Earl Collier Jr. “We want to participate.”

Zhang nevertheless worries about “media hype” that could “mislead patients, officials, and investors and cause significant damage to the further development of China's biotech industry.” He hopes China can avoid repeating the mistakes that set back gene therapy in the West.

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