Gendicine again in Nature this week..thanks to microcapfun at YMB..[they are up to 3500 Gendicine patients]
Controversial Chinese gene-therapy drug entering unfamiliar territory
Experience in clinic is raising issues that Western researchers will not have seen before
Hepeng Jia
[Zhaohui Peng, Chairman and Chief Executive of SiBiono says Gendicine has proved to be safe and effective in around 3,500 patients in the clinic.]
The first gene-therapy treatment to enter the market should have received a tremendous reception, but the fact that it was approved in China provoked a mixed response.
Chinese scientists and the government hailed the approval of Shenzhen SiBiono GenTech's Gendicine for head-and-neck squamous cell carcinoma (HNSCC) as illustrating how China is at the forefront of gene-therapy technology. Foreign researchers in the field, meanwhile, greeted the news with indifference, if not scorn, claiming the approval was more indicative of China's permissive regulatory system.
Two years after Gendicine was launched, what have we learnt about the drug? Western researchers still think that more data are needed to satisfy their concerns. But by virtue of being in the clinic, Gendicine is providing a window into a world of gene-therapy treatments that Western researchers have never seen before. The experience with Gendicine could teach other companies valuable lessons on what to expect if their gene-therapy drugs reach the market.
Gendicine is a recombinant adenovirus containing the tumour-suppressor gene p53. The combination of a vector often used in gene-therapy trials and a gene long studied in the prevention of cancer should make the approval of Gendicine a significant medical achievement, as it is "a true hybrid of the biotech age", says Sheldon Krimsky, Vice-Chair of the Council for Responsible Genetics Board of Directors, based in Cambridge, Massachusetts (Krimsky, S. GeneWatch 18, 10–13; 2005).
Western researchers, however were concerned about how the drug was tested. In the only English-speaking article published containing clinical trial data, Gendicine combined with radiotherapy showed a threefold effect in complete tumour regression compared with a group on radiotherapy alone (Peng, Z. Hum. Gene Ther. 16, 1016–1027; 2005).
The data, however, came from 120 patients, far less than for a rigorous Phase III trial in Europe or the United States, says Krimsky.
Jack Roth, Chairman of thoracic and cardiovascular surgery at the MD Anderson Cancer Center says "the results that SiBiono reported are very similar to what was observed in Phase II trials of Advexin in 217 patients with head-and-neck cancers." Advexin is another p53-based gene-therapy drug that the Texas-based company Introgen Therapeutics licensed from MD Anderson and is currently in Phase III trials.
Gendicine is providing a window into a world of gene-therapy treatments that Western researchers have never seen before.
Chinese researchers say that follow-up findings seem to reinforce the original data. At the Conference of the International Society for Cell and Gene Therapy of Cancer, held in Shenzhen in December last year, the lead researcher of the Phase I trial, Demin Han of Beijing Tongren Hospital, reported that 11 of the 12 HNSCC patients in the trial were still alive at the end of November 2005. The trial began in 1999, and the American Joint Committee on Cancer states that the 5-year survival rate for head-and-neck cancers is 60–70%.
According to Shanwen Zhang of Peking University's School of Oncology, follow-up data from the Phase II and III trials showed that the 3-year survival rate for HNSCC patients on Gendicine and radiotherapy was 14.4% higher than the radiotherapy-only group.
Gendicine has performed well in around 3,500 patients in the clinic for various indications, says Zhaohui Peng, Chairman and Chief Executive of SiBiono. "In terms of tumour regression, it has also shown some good therapeutic effect in other cancers, such as liver, breast, lung and stomach cancers," says Peng, although data have only been published in Chinese (for instance, Weng, Z. Shenzhen J. Integr. Tradit. Chin. West. Med., 14, 206–210; 2004 and Zhang, S. Chin. J. Phys. Med. Rehabil., 24, 489–491; 2002).
Safety does not seem to be a concern, according to Peng. "So far, no side effects have been reported, other than common cold phenomena, such as self-limiting fever."
This differs markedly from the experience outside China. Many countries have been nervous about gene therapy ever since the death of Jesse Gelsinger during a US trial in 1999, and after two children developed leukaemia in trial in France in 2003. Peng thinks the type-5 adenovirus vector used for Gendicine could explain the better safety profile. Patients are given Gendicine at around 1/100 of the dose given to Gelsinger, to avoid the strong immune reaction thought to be linked with his death, says Peng. And SiBiono used an adenovirus vector as it is not known to integrate into the human genome to produce adverse effects such as leukaemia, unlike the retrovirus used in the French trial.
Because we are still not very clear about the mechanism of gene delivery and because of the limit of Gendicine's authorized indication, we are very cautious in using this medicine.
But without hard evidence to support these hypotheses, more basic studies on the vector are needed, says Chen Lin of the Chinese Academy of Medical Sciences. "We do not clearly understand the receptors of different tumour cells to type-5 adenovirus, or whether the type-5 adenovirus vector has particularly stronger capacity to infect cells (to deliver p53) than those type-5 viruses naturally existing in human bodies." A study is needed to assess the antibody level of the average Chinese against type-5 adenovirus, says Lin.
There is a paucity of information on Gendicine — at least in the English-language-publishing world. But, Chinese doctors at the bedside say issues are being raised that foreign researchers are unlikely to have considered — issues that could help develop more successful treatments.
For instance, adoption of Gendicine in the clinic has not been as fast as expected, admits Peng. Cost is a big deterrent. Gendicine is not covered by medical insurance, and costs 3,380 Yuan (US$420) per dose. With around eight doses per period of treatment, many patients can't afford to take Gendicine. Peking University's Zhang says only four of his head-and-neck cancer patients can afford to take Gendicine each week — that's around 20% of his HNSCC patients.
Many Chinese doctors are wary about using Gendicine after a lawsuit in October 2004. Relatives of a late-stage liver cancer patient sued Zhang because they said the off-label use of Gendicine caused the patients' death. In January this year, however, a medical accident appraisal committee in Beijing judged that the patient's death had nothing to do with the off-label use. Since October, though, Zhang's hospital has stopped the off-label use of Gendicine.
Uncertainty about how the treatment works is also an issue. Yongsong Guan, a radiotherapist at Chengdu-based West China Hospital, Sichuan University, says he only gives Gendicine to around 10% of his patients. Although Guan says that patients do respond well to the treatment, he admits that "because we are still not very clear about the mechanism of gene delivery and because of the limit of Gendicine's authorized indication, we are very cautious in using this medicine."
It is a wake-up call to US gene therapy researchers.
Slowly, but surely, though, doctors are uncovering clues about how the treatment works best. Doctors say that Gendicine works better when injected directly into the tumour. Homing in on the tumour minimizes any immune reaction against the adenovirus vector and improves the efficiency of p53 delivery.
Other doctors say that the patient's condition is a big factor. "We observe an effect only in patients whose life expectance is longer than half a year," says Dinggang Li, director of the Gene Therapy Cancer Treatment Centre at Beijing Haidian Hospital. Of Li's 110 patients so far on Gendicine — who notably are mainly foreigners — only 30% meet the half-year life expectance. According to Li, the vast majority of this subset of patients have seen partial or complete regression of their tumours.
Resolving these issues is crucial, as the number of gene-therapy treatments being developed in China is escalating (Figs 1, 2). Hopefully this explosion in activity could have a knock-on effect in other countries, says Mark Kay, director of the Program in Human Gene Therapy at Stanford University. "It is a wake-up call to US gene-therapy researchers. Gendicine can stimulate renewed interests in the field, as long as we can reproduce its data, no matter where they are made." |
