• 11/22/2004
  • Dale Chenoweth

In recent years, knowledgeable biomedical researchers have sometimes wondered aloud whether the first approved gene therapy would come from a U.S. company, or instead from one in Europe or maybe even Britain. The answer, apparently, is none of the above.

China Steps Out Ahead
In March of this year the Chinese company Shenzhen SiBiono GeneTech Company, Ltd. began marketing in China a cancer gene therapy called Gendicine. The therapy was approved in October 2003 by China’s State Food and Drug Administration (SFDA) for use against squamous cell carcinoma of the head and neck (SCCHN), a category of solid tumors originating in such sites as the pharynx, larynx, oral cavity, and nose.

In a self-interview published online last May, the company’s founder and chair, Zhouhui Peng, MD, said several Phase II and III trials among 135 patients with advanced SCCHN showed 64 percent had a complete response (CR) to the adenovirus-p53 drug used in combination with radiotherapy, and 29 percent had a partial response (PR).

That’s significantly better than the response to chemotherapy and radiotherapy regimens that are now standard treatment in the U.S. and elsewhere.

Additional trials involving another 240 patients also were positive, said SiBiono, but their data was not released. In all the trials, the drug was given by direct injection into accessible tumors.

The easy accessibility of head and neck tumors for direct injection and their high incidence in China made SCCHN a good target disease, the company said. Over 1.6 million people worldwide currently have SCCHN diagnoses, with about 30,000 to 40,000 new cases annually in the U.S. alone.

Adenovirus Takes p53 Gene Into Malignant Cells
Many of the new molecular-target cancer drugs, such as Gleevec, Rituxan, and Iressa, as well as drugs for other diseases harness knowledge of how genes are related to diseases.

But Gendicine marks the first approval of what many in the field consider a true gene therapy: the therapeutic introduction into a cell of wild-type, working copies of a gene to do the work of a missing or mutated gene.

Gendicine uses a recombinant human adenovirus (serotype 5), engineered not to replicate, to carry into malignant cells working copies of the p53 tumor suppressor gene, a combination called an Ad-p53 construct.

The p53 gene is one of the most important tumor suppressor genes. When functional, it detects and forces into cell cycle arrest and/or apoptosis cells with DNA too damaged to be repaired, ideally before they become malignant. But the gene is missing or damaged in over 50 percent of all human tumors.

The p53 gene’s ability to force DNA-damaged cells into self-destruction attracts the attention of cancer researchers partly because both chemotherapy and radiation initiate cell killing by damaging DNA.

The gene also can up-regulate some anti-tumor genes, and down-regulate tumor-protective genes such as the multi-drug resistance (MDR) gene. Gendicine’s exogenous p53 also stimulates an immune response against malignant cells that over-express p53, a common phenomenon after transformation.

SiBiono says the drug may be effective against a wide range of other solid tumors, and such clinical trials are underway.

Little Data, Certainty, So Far Among Scientists in the West
Gendicine’s approval was well-celebrated in China, with a congratulatory ceremony attended by national and local government officials, according to the China Daily, the state-sanctioned newspaper.

But applause—or even recognition—so far seems to be muted or absent in much of the West, perhaps because of a paucity of verifiable data so far.

“They have not yet released any data in an internationally-accessible, peer-reviewed journal that would allow objective analysis or confirmation of the statistics they have offered,” says Marshall R. Posner, MD, Medical Director of the Head and Neck Oncology Program at Dana-Farber Cancer Institute, affiliated with Harvard Medical School.

Posner says as many questions as answers arise from the information the company has so far made public outside China.

“In one trial, 35 percent of their patients had advanced nasopharynx cancer and they compared their drug and radiotherapy to radiotherapy alone, and said patients who got RT alone had a complete response rate of about 19 percent. That is patently inferior to what you would get with this treatment, in any major center,” says Posner. “And we don’t know who these patients were, how old they were, or how they were randomized. We also don’t know if they biopsied to see if the virus actually got into the human tumors; we don’t know if the patients had pre-existing viral antibodies.”

On the other hand, the Ad-p53 idea has compelling logic, and for that reason has been the subject of studies at Dana-Farber and other institutions, yet for many types of p53 therapy, significant challenges remain to be met, noted Posner.

If and when more data are released, there are key positives to look for that could indicate real progress, Posner says. “If they really have a slightly different preparation of the virus in terms of its ability to be disseminated and to infect cells in the tumor, that would be a plus.”

“If they’ve demonstrated they can give it intravenously, that would be a plus, because intra-tumoral injection typically is useless in most cancers because some of the tumors may not be detected or accessible,” he adds.

Posner says until more data are presented, it’s likely that medical scientists’ acceptance of any medical benefit of the drug could remain limited outside China.

Medical Tourism Begins
Standard treatment with Gendicine consists of once-weekly injections directly into the tumor(s) for four to eight consecutive weeks, at a cost under $4,000 (USD), according to the drug’s developer.

At this time, Gendicine is available only in China, according to SiBiono, but hundreds of patients abroad have traveled to China so far to receive the drug.

SiBiono says it is seeking strategic partnerships to aid with distribution and marketing, and that it expects to have a global impact on human health.

Many wonder if U.S. or European companies that have spent millions developing patented Ad-p53 constructs could find their drugs, if approved, competing with similar gene therapy drugs – possibly too similar – being offered at a fraction of the cost, in China or in nations where IP rights are not currently enforced, perhaps close to the Western companies’ own shores.

China’s membership in the World Trade Organization (WTO) obligates it to enforce in China IP protections granted in other signatory nations. But it’s not WTO’s job to decide pro-actively when a violation of WTO IP agreements might occur or has occurred, says Peter Ungphakorn, Information Officer at the WTO headquarters in Geneva.

“That can only be established if member governments bring a dispute to the WTO for settlement under the legal process,” says Ungphakorn.

One U.S. gene therapy company, Introgen Therapeutics, has a series of patents it characterizes as broadly covering Ad-p53 constructs and many processes related to them. It has Ad-p53 constructs in two Phase III trials, the final stage before application for FDA approval. One of those drugs, Advexin, is farthest along of any U.S. gene therapy in trials.

In an August quarterly earnings conference call, Introgen’s President and CEO, David Nance, was asked if Introgen has taken any action to protect its IP rights to adenovirus p53 constructs.

“Yes, we have,” said Nance during the call. “The company controls two patents owned by the University of Texas that have issued in China and we have experienced those patents as a topic of discussion at a recent international trade forum sponsored by the US Department of Commerce.”

“We’re happy those cases were elevated to discussion by the government, and we may meet with the company,” said Nance, leaving unmentioned that such talks can be a prelude or prerequisite to initiation of more formal legal actions by governments, in some cases.

In a November 15, 2004 conference call response to this reporter’s questions, Nance said talks with SiBiono have taken place, but that Introgen will focus mainly on U.S. and European markets at least initially, where it does not see Gendicine as a potential threat.

Nance noted that results released by SiBiono were consistent with expectations for patients treated with Ad- p53 and radiotherapy.

Gene Therapy Steadily Progressing in U.S.
Meanwhile, gene therapy trials progress in the U.S. and abroad, with 18 NCI cancer gene therapy clinical trials underway in the U.S. as of mid-November, 2004.

Introgen expects to begin filing this year a “rolling application” for approval of Advexin, in which the FDA will look at data as it comes in, rather than beginning the review only after trials are over. With completion of the application expected by 2005’s end, approval could come as soon as mid-2006, says the company.

With publication of more data on Gendicine due in December 2004, according to SiBiono, the field of gene therapy appears to at last be bearing fruit.

So whether SiBiono’s Gendicine, or Introgen’s Advexin—or another compound—ends up with the laurels for “world’s first approved gene therapy” to be shown effective, one thing seems certain: the time when such an advance seemed always to recede into the future may s