A breakthrough waiting to happen
Avraham Hochberg has created therapies for destroying cancer without side effects, but his rather unorthodox style may be hindering the road to formal approval
In a perfect world, Prof. Avraham Hochberg would now be courted by several multinational corporations. The company he founded, BioCancell, has developed a technology for destroying cancer cells in 33 forms of the disease, and its trials on human subjects have yielded good results.
But the world is not perfect, and neither is Hochberg, which may be why BioCancell is currently being traded at a value of only NIS 38 million - low for a company at an advanced stage of developing a cancer drug. Even Hochberg himself calls the company's condition "critical."
BioCancell was established in 2004, based on Hochberg's research as a professor at the Hebrew University of Jerusalem (HU). He succeeded in isolating a gene that is present at high levels in two types of cells, embryonic stem cells and cancerous tumors, which led him to deduce that the H19 gene played a part in the development of cancer. Later studies discovered that H19 is present in 33 kinds of cancer, apparently because it enables malignant cells to survive despite low levels of oxygen and blood serum. Based on these findings, BioCancell developed a drug that seeks to destroy the cancer cells using the activation mechanism of the diphtheria toxin, without damaging healthy cells.
"People compare our drug to drugs that are individually adapted to the patient and perform a targeted destruction of the cancer cells, like Herceptin, used for treating breast cancer. But we don't administer the drug to the body; we give the body the factory that manufactures the drug," Hochberg explains.
The manipulation of the diphtheria toxin to kill cancerous tumors is an innovative technology that thrills the imagination, but it has not made matters easy for Hochberg or BioCancell when it comes to dealing with the U.S. Food and Drug Administration (FDA). "Chemotherapy, the conventional treatment for cancer, succeeds in 30 percent of cases; in the rest, the patients die," Hochberg says. "The FDA is okay with this. But when you talk to them about using toxins, they categorize what you do as 'gene therapy,' although there is no similarity. I don't replace, fix or alter genes."
BC-819, BioCancell's flagship drug, began its long journey toward FDA approval 16 years ago, in Hochberg's HU laboratory. That is where he developed the technology for the targeted treatment of cancer. In 1998 he patented it through HU's Yissum Research Development Company, which handles the commercial side of the university's intellectual property.
In 1999, Yissum gave Keryx Biopharmaceuticals an exclusive license to develop the technology. The head of development at Keryx was Morris Laster, now CEO of the BioLineRx technological incubator. In 2004, when Keryx decided to focus on drugs at an advanced stage of development and to shut down its labs in Jerusalem, the development rights reverted to Yissum, and Hochberg was left without funding for ongoing development.
Avi Barak, then CEO of Yissum - now he holds the same position at BioCancell - decided to see to it personally that Hochberg's lab had the resources needed for its work. He founded BioCancell, owned jointly by Yissum and Hochberg. Barak was forced to leave Yissum in early 2006 after his relationship with Yissum chairman Giora Yaron deteriorated. Barak became CEO of BioCancell, but Hochberg found himself under pressure to release Barak from the company.
BioCancell's August 2006 IPO, which raised NIS 22 million, not only solved the problem of funding development for almost two years, but also allowed the company to break away from Yissum, thus ending an unpleasant and burdensome relationship. BioCancell designated the money it had raised from the public for the development of a drug for patients with superficial (early) bladder cancer, a decision that at first glance - and, according to some observers, at second and third glance as well - seems puzzling.
Not a favorite
Hochberg is a controversial figure both within and outside the academic world. His unorthodox views and blunt style have not made him a favorite of the scientific community. Nevertheless, the unique technology he developed for treating cancer is admired. Few people, however, can understand why BioCancell chose as the first target for its sophisticated weapon a seemingly lackluster kind of cancer, in which tumor cells develop in the cell layer covering the bladder. Fewer than half a million Americans have been diagnosed with this disease, so the economic potential of a drug to combat it is relatively limited. Bladder cancer "only" causes pain and horrible suffering; other forms of cancer are swift and brutal killers, so innovative drugs for them can command nearly unimaginable prices.
"A patient with bladder cancer doesn't die. He goes around with a bag. It's not heroic. But if you prolong the life of a patient with pancreatic cancer by one month, you have a blockbuster," Hochberg says, reflecting the difficult marketing situation in which he placed BioCancell when he chose to focus on bladder cancer.
He can explain his choice, however: "There are three institutions that are difficult to change: religion, the military and medicine. When I came to the Helsinki Committee, which approves requests for tests on human subjects, with the plasmid, the biological material containing the instructions for manufacturing the diphtheria toxin, they thought the plasmid would turn into a frog and leap into the patient's pancreas. We needed to go with a good, simple indicator that would be a springboard for developing drugs for lethal forms of the disease, such as pancreatic, ovarian and liver cancer."
BioCancell's main problem, says Barak, is that the drug it has developed is not delivered to the bloodstream - in a tablet, for example. "On the other hand, it was relatively easy to explain the treatment to urologists, since the current treatment, the BCG vaccine, is also given by local injection into the bladder."
The results have been good so far. Fifty-six percent of the subjects in BioCancell's second trial completed the round with no new tumors; in 44 percent of the participants, their tumors disappeared or shrank by at least 50 percent. The success of the trial raises the question of whether BioCancell would do better to join forces with some pharmaceutical giant that could assume the remainder of the development process and pay the company a handsome one-time sum as well as royalties for drug sales, if development goes well and the drug is approved for sale.
Barak says that despite the promising indicators, pharmaceutical companies are not beating a path to BioCancell's door. "A few weeks ago we made a visit to Sanofi-Aventis. They don't understand that the reason why there are no side effects is a result of how the drug itself was created. They say to us, 'Come back in two or three years, after another stage of trials,' and they say to themselves, 'What's the hurry? So, instead of paying a few tens of millions of dollars, we'll pay a few hundreds of millions of dollars.' It doesn't really matter to them. Money is not a problem."
The second phase of the second human clinical trial of the bladder cancer drug is approaching. BioCancell's decision earlier this month to sell a five-percent stake in the company to Clal Biotechnology, in a private issue, left it with cash reserves of about NIS 13 million.
"We have enough money for the second phase, and then, if the results are good, I imagine there will be buyers for the drug," says Hochberg. "But for us this is a critical stage for the two goals that interest us - [treating] ovarian cancer and pancreatic cancer."
In December 2007, BioCancell showed good results in a trial for the treatment of ovarian cancer. It launched a strategic partnership with the Virginia Biosciences Development Center to perform a clinical trial in pancreatic cancer and received a promise of $1 million in funding from the U.S.-Israel Binational Industrial Research and Development Foundation. In light of the high costs involved and the company's current status, however, unless BioCell enters into a merger, takes on a new partner or sells the rights, it will not be able to go through the long and expensive trial process that might lead it to the holy grail - a drug that will attempt to poison two fatal types of cancer, ovarian and pancreatic.
"When it comes to developing the drug for these, we are at a critical stage. We need $6 million. There is really a major breakthrough to be made, and it's not a lot of money," Hochberg says. Still, the question remains whether Hochberg's difficult personality and temperament, the clashes with Yissum and the fact that he has retained control of a relatively large part of the startup (17 percent) have hindered good scientific work from making its way to patients and improving their condition, if not saving their lives.
"I'm an odd duck," Hochberg admits. "I see things differently. Nothing I have done has been normal, and everything I have done has gotten messed up, but I'm willing to reduce my holdings in the company to nothing and I'll do everything in my power to get this drug to the patients."
"At the end of the day, people want to work with people they're comfortable with. Avraham is not an easy man, and he pays the price," Barak says.
"And with pleasure," Hochberg adds.
Throughout his long career in research and in human and animal experiments, Hochberg has not limited himself to purely scientific activities. He headed the Turkey desk at the Neot Hakikar tourism company, which later merged with Geographical Tours, and wrote a book about his travels through Turkey with a local driver. He has a bachelor's degree in archaeology and has built dozens of model sailboats out of matchsticks.
Hochberg does not think the lack of focus has hurt his scientific work. "I believe that science is an art, not a job. You need your brain and soul to be free and open to other things. My science is not damaged by my other pursuits. I've had some of my best ideas while gluing matchsticks onto my boats. These pursuits have given me the strength and patience to do science. Science was never only work to me, I still love it and I haven't burned out. That's why my science is reaching its peak when I am close to 70."
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