A cancerous tissue inside the human body is a hungry one. It grows rapidly, and so it needs a constant supply of food and oxygen, meaning more and more blood vessels. The larger and more aggressive the growth becomes, the faster the blood vessels surrounding it need to develop. If the development of the blood vessels were to be stopped, the cancer could be stopped from spreading too.
"The idea of attacking the blood vessels leading to the cancer, instead of trying to attack the cancerous cells themselves, developed parallel to the understanding that cancerous cells tend to undergo rapid genetic changes, and develop resistance to any drug that is targeted at them," says Prof. Shmuel Ben-Sasson, chief scientist and founder of Jerusalem-based biotech start-up Tiltan Pharma Ltd.. "So this led to the idea of attacking instead the cancer's supply chain, the blood vessels. In adults, other tissues aside from the cancerous ones usually do not need any new blood vessels, and the idea was that if we could find a way of preventing the creation of new blood vessels, we would then be able to halt the growth and even strangle it and kill it off."
This idea is not new, and in recent years experimental drugs based on a blood vessel creation mechanism have occasionally surfaced. But while they worked fine under laboratory conditions or in animal testing, all these molecules were found to be either inefficient, or had too many side effects when tested on humans. To date, no satisfactory molecule has yet been found.
A partial breakthrough came with the launch of Avastin (the subject of the recent public campaign by colon cancer patients). This was the first example, the only one so far, of a drug whose action is based on the blood-vessel creation mechanism. "Avastin is like the Wright brothers' aircraft - the first evidence of the feasibility of an idea that not everyone believed in, certainly not after all the failures," says Tiltan Pharma CEO Yigal Stav. "But just as the Wright brothers' aircraft could stay airborne for just 20 minutes before it crashed, Avastin can prolong life by four to five months only. We know that this can be extended."
Tiltan Pharma believes that it is the company that will show how this can be achieved. The defining characteristic of the drug it has developed is that it is based on four ingredients instead of one. All the ingredients in Tiltan Pharma's drug are already known, but the company believes that the combination of all four creates an effect that is a far more significant than the sum of the parts. "When we saw that molecules that worked in laboratory tests and on animals did not work on humans, we realized that the single ingredient approach, as successful as it might be, would never be capable of dealing with blood vessels. The blood vessel building process is one that is basic to the existence of the body, and in basic processes such as these, the body is unwilling to rely on one mechanism only. It always prepares back-ups. We also noticed in Avastin, which blocks a specific growth factor, that the growth continues to create new blood vessels, using another growth factor instead," says Ben-Sasson.
"We said to ourselves, that if the process uses several mechanisms, we could also attack it through several mechanisms simultaneously, and achieve an attack that has greater force," Ben-Sasson adds. "It's like stopping a car - you take your foot off the gas, you press the brakes and also change down gear.
"With this understanding in mind, we studied all the available research on the creation of new blood vessels in order to find active ingredients. We located four ingredients, all of them small molecules (that is to say, ones that can be ingested orally, and do need to be administered intravenously), that already have US Food and Drug Administration (FDA) approval, but that no one thought of using together. Our patent is on the combination of these ingredients, their drug formulation, and the protocol, meaning which ingredients are given when and in what dosages."
Assuming that the product works, it will clearly have several advantages. While cancerous cells are constantly changing, cells that create new blood vessels are fairly stable genetically, so the chance that they could develop resistance is small. The drugs can be taken orally, as opposed to most of the newer cancer drugs (including Avastin), which are administered by injection. All the drugs already have FDA approval, so the likelihood of side effects is minimal. Another advantage is that there is nothing to prevent the integration of further ingredients in the drug, alongside the existing ones, as soon as research shows them to be connected with the new blood vessel creation mechanism.
Tiltan Pharma has almost completed a preliminary trial at the Sheba Hospital at Tel Hashomer. "The doctors were a bit skeptical at first," says Stav. "They've seen so many drugs that were supposed to treat cancer through the blood vessel mechanism, and were a failure. After a while, we got back to them and they all said how amazed they were that the side effects were fairly minimal."
Ben-Sasson: "What were the complaints about? That the drug had a bitter taste. We eventually dealt with that, and then they said it was too sweet."
Stav: "We'll deal with that too."
Ben-Sasson: "So far, 46 patients have completed the trial, and 60% of them presented a positive response, the halting of the development of the growth, and even a partial remission. In one patient who had a growth that really was malignant, the growth disappeared and did not return, and she has now been undergoing treatment for 20 months."
Tiltan Pharma's trial was not conducted under the auspices of the FDA, but it produced sufficient data in order to file an application with the FDA for the start of an official Phase II trial on a small group. The company has already begun discussions with the FDA on the details of the trial. The types of cancer that the trial will test are prostate cancer, which is insensitive to hormonal treatment, and pancreatic cancer, for which there are currently no treatments.
Tiltan Pharma was founded within the Yissum Technology Transfer Company of the Hebrew University of Jerusalem, on the basis of Ben-Sasson's research at the university. Stav previously served as CEO at drip irrigation technology company Netafim Ltd., and he currently sits on the boards of several companies. The company was financed through a seed investment from Yissum and the Boston Children's Hospital, and it later received an additional $2.1 million in investment from Israeli and Canadian investors, including the owners and manager of a Canadian pharmaceutical company. It is now seeking further investment from angels and investment institutions, principally to finance the clinical trial, which is due to get under way later this year.
"We wanted to call the drug 'four by four', but potential investors and customers said the name was too aggressive and advised us to opt for something that was more refined. So we chose Tiltan. After all, Tiltan is the Hebrew word for the clover with four leaves that brings luck. When we met investors from the US they said, 'Ah, Tiltan. You're tilting, that is to say you're moving the angiogenesis mechanism- the process of developing new blood vessels,' so that's Tilt-An.' We said, fine, Ok, if you say so."
Tiltan has already developed a compound with five ingredients and has successfully tested it on mice, but it will require additional finance to continue development. It is also developing an additional drug with five ingredients plus one upgraded component. "We've called them 'Hamsa', and 'Hamsa plus,'" says Ben-Sasson.
Published by Globes [online], Israel business news - www.globes.co.il - on April 11, 2007
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