Ad blockers pt 4

Previously:

• Part 1
• Part 2
• Part 3

Despite evidence presented that Advexin was safe, gene therapy in general was described as cursed in this 2005 Nature Biotechnology piece

"Because gene therapy has such a nasty reputation, people tried to rename it or call it 'new and improved' to free themselves of the stigma," says Michael Zasloff, an analyst with Ferris, Baker Watts of Washington, DC. "That may fool the public, but the market sees through it," he says.

Nevertheless, Nature Biotech wrote:

The first gene therapy approved in the US will most likely be Austin, Texas−based Introgen's Advexin, which delivers normally functioning p53 to cells.

Advexin was safe, and was in phase 3 trials. As noted in part 3, Introgen was planning to submit Advexin to the FDA for approval in 2004. Those plans changed...Introgen finally submitted their BLA in 2008, a few weeks after announcing a joint venture with the Texas A&M System.

This followed presentation of long-awaited phase 3 trial data at a cancer conference, which MD Anderson headlined as

Gene Therapy Increases Survival for End-Stage Head and Neck Cancer

There was some fine print

The trial showed that p53 expression in the patient's tumor before treatment is a reliable biomarker for how to treat head and neck cancer. Patients with a favorable p53 profile who received Advexin® had a median survival of 7.2 months, compared with 2.7 months for those whose tumor expressed high levels of mutant p53 before treatment. Patients with this unfavorable profile were better off taking the chemotherapy drug methotrexate, resulting in median survival of 5.9 months.

Potbangers in the biotech stock analysis community were not impressed, and predicted that Advexin would not be approved. The market agreed, and Introgen's stock plummeted.

The potbangers were right this time. The FDA told Introgen its application was "incomplete". By the end of 2008, Introgen filed for bankruptcy and David Nance had stepped down as CEO. Since then, Nance resigned from the Introgen Board and has resurfaced at a nonprofit to promote high-tech business in Texas.

David Nance says Texas could do a far better job of creating high-tech jobs and companies if the state's fiercely competitive regions and universities had a better way to work together.

Vision 1920 points out that the agreement between Introgen Technical Services and the TAMU System doesn't involve paying ITS (now renamed Vivante) anything - it's just a memorandum of understanding to apply for grants together from the Emerging Technology Fund, the Texas Enterprise Fund and the Federal Government.

So, what's the problem?

Ad blockers pt 3

Previously:

• Part 1
• Part 2

In 1993, Jack Roth's group described the adenovirus p53 vector that would become Advexin in a short paper in the journal Biotechniques. The earliest clinical trials in the gene therapy trials database with p53-carrying Adenovirus vectors started in 1995, with Jack Roth as one of the PIs. Overall, the database lists 34 US clinical trials of Adenovirus vectors carrying p53 for cancer therapy. Some of these may have involved Introgen competitors, but many were for what would become known as Advexin. A 1997 press release describes the results of one set of Phase 1 trials, and a collaboration:

Introgen Therapeutics, Inc., an Austin-based company engaged in the development of cancer therapeutics, sponsors Drs. Roth and Clayman along with 25 other clinicians and researchers at M.D. Anderson Cancer Center. Introgen and RPR Gencell, the gene therapy division of Rhone-Poulenc Rorer, are collaborating to develop and commercialize gene therapy products based on the p53 pathway and k-ras oncogene inhibition.

Adenovirus vectors fell under a cloud in 1999 when an Arizona teenager died during clinical trial involving adenovirus vectors. This was not a trial involving Introgen, but all ad vectors were suspect. Even improved vectors were cause for worries:

Gene therapy researchers at the Baylor College of Medicine in Houston, Texas, who recently reported success with the 'gutless' adenoviral vector in animals may not get to test the vector in humans.

The pharmaceutical company, Merck, which owns the licence on a technique used to produce the vector, is refusing to extend its material transfer agreement (MTA) with Baylor, saying that it does not want to be liable for any problems the vector might cause in clinical trials.

How this affected the Introgen Adenovirus projects is not clear. Phase 1 and Phase 2 trials continued, and Introgen-sponsored scientists presented safety results at meetings. In 2002, the Ad5-p53 vector was trademarked as Advexin, and Introgen was telling the world to expect an approval application in 2004 (Biodrugs 17 (3): 216-222). Also from that review:

In April 2001, Aventis Gencell and Introgen restructured their existing collaboration agreement for p53 gene therapy products. Aventis Gencell indicated that p53 research had suffered from internal competition for resources and was pulling back from its development agreement with Introgen for p53 gene therapy products.

In a 2004 review of gene therapy skepticism about the Advexin approach appeared:

Results published to date have been disappointing. Phase I trials for recurrent glioma reported only modest survival benefit and expression of adenoviral derived p53 only a short distance from the site of virus administration.¹¹⁵ Phase II/III trials for ovarian cancer failed to show treatment benefit with intraperitoneal administration of adenovirus expressing p53 with chemotherapy after debulking surgery.¹²⁰ Finally, Swisher et al published antitumour effects associated with the treatment of non-small cell lung cancer; however, no comparable control group was described in their report.¹¹⁶

That last bit is harsh. The author is not just saying the results were disappointing; he's calling the quality of the studies into question.

The potbanging would get worse.

To be continued...

Ad blockers pt 2

Prof Jack Roth and David Nance formed Introgen based on an idea for using gene therapy a cure for cancer, but like all gene therapies, they needed a way to deliver the genes to cells. That's what viruses do, and Adenovirus seemed like a good choice as a delivery vehicle, not just to Introgen, but to many in the growing field of gene therapy.

Adenoviruses are a large family of DNA viruses that infect humans and animals. They are relatively easy to manipulate by genetic engineering, they're stable, and infected cells express large amounts of the delivered gene product. Unlike retroviruses and adeno-associated viruses, Adenoviruses don't integrate their DNA into the host, which makes them less likely to cause cancer as a side effect - something that has been seen in gene therapy trials with the other delivery systems. This lack of integration is a problem for gene therapies that need long-term maintenance of the delivered gene, as is the case for genetic diseases where you want to fix lots of normal cells. But for cancer, this is not a problem. You don't care if p53 is stable in the cancer cells, because you expect p53 to kill them quickly. Unstable expression in the normal cells that also get infected is also OK; they already have their own good copies of p53.

Normal adenoviruses cause disease, but most adenoviral disease is relatively mild and most humans have already been exposed to adenoviruses. The disease-causing parts of the adenovirus can be removed by genetic engineering, and the adenoviruses can even be crippled so that they can only grow in the special cells in the lab. All these reasons led people to think that adenovirus vectors (gene delivery systems) would be safe and efficient - at least compared to the available alternatives.

So, Introgen had their anticancer magic bullet (p53) and their delivery system (modified adenovirus) back in the mid 1990s. By 1994, Introgen was starting Phase I clinical trials. The idea of p53-adenovirus anticancer gene therapy was so obviously good, the Chinese stole it! Science magazine wrote in 2006:

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."

Gendicine beat Advexin to the punch in China, but Introgen still held the patents for the US and European markets. The silver lining was that Gendicine's Chinese approval in 2003 was another piece of evidence that Advexin would work.

To be continued...

Ad blockers

The potbangers keep bringing up Introgen (see the comments on this story in the Eagle, for example). So Vision 1920 will retell the tale of Introgen, even if it mans having to get faculty input again.

As noted in an earlier post, Mr. David Nance, formerly of Introgen, is a biotech expert who has been advising the Governor for years. His company, Introgen, was founded on the work of Dr. Jack Roth of M.D. Anderson

Advexin, which expresses the tumor-suppressing p53 gene, is the first gene therapy to succeed in a U.S. phase III clinical trial for cancer. Jack A. Roth, M.D., a professor in the Department of Thoracic and Cardiovascular Surgery, invented the therapy and co-founded Introgen Therapeutics, Inc., the company that makes Advexin.

“The p53 protein,” Dr. Roth said, “is called ‘the guardian of the genome’ because it protects against damage to the cell. We are all constantly exposed to agents such as sunlight or tobacco smoke that can cause gene mutations. When the gene is functioning normally, p53 can actually help facilitate repair of those mutations or eliminate the damaged cell.”

In most cancers, however, p53 is defective. The thinking behind the Advexin protocol was to take a normal p53 gene and put it into p53-defective tumor cells to cause apoptosis—death—of the cancer cells but not of normal cells. According to Dr. Roth, “When the p53-expressing adenovirus is injected directly into tumors, it causes the tumors to shrink or to stop growing. And in a few cases, there are very dramatic responses where the tumors disappear completely.”

If you can inject something directly into a tumor, why not just kill it directly instead of using this p53-whatsit to turn on a program that kills the cell? Here's why: Traditional cancer therapy is known as slash, burn, and poison. You cut out the cancer, but you might miss some and it comes back. Same if you burn it out with radiation. Chemotherapy poisons the cancer but it poisons everything else in the body at the same time; that's why chemo patients lose their hair, lose their appetites, and are prone to infections. Unless you can deliver the poison only to the cancer cells, what you want is something that's a poison to the cancer cell but not to the patient's normal cells... and that's how p53 is supposed to work.

Introgen was based on the idea that you could deliver p53 everywhere. When it hit a normal cell, nothing would happen because there was already normal p53 there. when it hit a cancer cell that lacked p53, the incoming p53 would detect that the cell had problems and tell it to commit suicide (apoptosis means programmed cell death).

To implement this strategy, Introgen needed a delivery system. Back when they started, the delivery system of choice was Adenovirus.

To be continued...