Enbrol is to inflammation as penicillin is to infection. Few realize the blockbuster drug was developed in Israel.

Israel has provided the global drug development pipeline with many well–known internationally successful medications including Copaxone, Rebif, Exelon, Doxil, Azilect and Gonal. In fact there is yet another well–known drug that is not very often associated with Israel – Enbrel, for the treatment of inflammatory diseases and probably the most successful Israeli drug that you do not recognize as Israeli.

The researchers, Prof. Dan Aderka and Prof. David Wallach, from Sheba Hospital, Tel Hashomer and the Weizmann Institute of Science, respectively, were the first to guess that a molecule such as Enbrel had to exist. They also were the first to patent the product, a patent that protected their developed product and which recently expired.

An additional patent is based on Enbrol, a molecule that when added to the drug makes it easier for the body to absorb, and this patent right was recently approved until 2026. “When rumors began to circulate about the extension of the patent, Amgen’s stock price rose from $70 to $110. The stock price hadn’t been so high for ten years,” said Aderka to clarify how significant the drug is to Amgen (Nasdaq: AMGN), currently traded around $90 with a market cap of $70 billion, making it the world’s largest independent biotech company.

Enbrel saw sales of $3.9 billion in 2012 making it the seventh best–selling drug in the US. This achievement was due to the fact that it is the most innovative treatment for inflammatory diseases that has come onto the market in recent years.

Aderka said, “Who knows, maybe this product deserves a Nobel Prize, since it completely changes the progress of the disease.” When the drug is administered at an early stage of arthritis, it inhibits the inflammation and prevents permanent damage to the joints, thus saving patients from short–term pain and slows down the process of permanent damage that can lead to disability – this certainly is a change. In addition to arthritis, it is also registered for use against psoriasis and inflammation of the spine.

There is no doubt that Israelis should be proud of the drug, but the story of Enbrel has other elements. It provides an insight into the obstacles in the path of inventors developing drugs and the lucrative nature of the business as well as the politics and organizational culture that can either help a drug or destroy it.

40 liters of urine

It all started in 1987. Aderka looked at an edition of the “Lancet,” one of the world’s top scientific journals. “They described a substance called TNF, tumor necrotic factor (a body that destroys tumor cells, which it was later discover did not have such a simple role), which appears in excess in people with septic shock, i.e. total system collapse resulting from excessive and disorderly behavior of the immune system. I immediately thought – if there is such a material acting so wildly in the patient’s body, there must be a substance that controls it in a healthy body.”

At the time, Aderka was an internal specialist at Ichilov Hospital as well as as a researcher in Wallach’s Weizmann Institute laboratory. (“In the morning I was a doctor and mainly at night I worked in a laboratory,” he explains.) He approached Wallach and offered to look for the substance in the blood in septic shock patients. Wallach suggested searching in patients’ urine, where it would be easier to isolate protein. Since Aderka was a doctor, he had no problem. He collected the urine from septic shock patients, and the researchers quickly found what they were looking for.

Wallach, by the way, has another story about how the substance was found, but he asked not to comment on this article.

Aderka said, “The idea first arose on April 15. By April 17 we had a datum indicating that this protein was active. This is something that could happen only to a doctor and a scientist together. The researcher recommends on the best research method and the doctor has access to secretions and is not afraid to get his hands dirty.”

When Aderka dripped the substance to cells in–vitro, the TNF, the same substance that is rampant in a septic shock attack, couldn’t hurt them. This attribute gave it the name “anti–TNF.”

To confirm the hypothesis that this substance is in the body of any human being, extracting the substance and trying to map the genetic sequence, we had to collect a lot of urine, not only from patients. “We hung a sign in Weizmann Institute toilets, and we put a bucket. We wrote, ‘please donate to the last drop’, and researchers donated generously”, says Aderka. Within a few days we’d collected 40 liters of urine.

Aderka went on to finish his postdoctoral work in the US and in the meantime Wallach and another researcher in the laboratory, Hartmut Engelmann, continued to work to find out the sequence of the substance, an endeavor that took almost two years. Meanwhile in the US, Aderka was intrigued to examine the effect of the drug on cancer. It turned out that cancer cells secrete anti–TNF, and when they do so, it’s hard to hurt them.

He said: you are wrong

At this stage, there was a conceptual breakthrough for the group – the recognition that an inhibiting substance can also be part of the receptor on the cell. What does that mean? When a substance wants to enter the cell or affect the cell, it does so through receptors that serve as a “lock”. Only a substance that fits the lock by structure may change the cell or enter the cell.

These receptors are placed in the cell, so they’ll have a “tail” in the cell, a “body” in the cell’s membrane and a “head” outside the cell. The head is used as a lock, where the key could fit. The discovery was exciting, that sometimes the “head” detaches, separates from the cell and circulates in the bloodstream.

This mechanism is great because it allows the body to regulate the activity of the substances. When it wants it to receive certain substances in to the cell (let’s say – TNF) it grows receptors for that substance on the cells. It’s fed up with this substance? No problem. It sends a message to the cells to shed the “head” of the receptors from the cell. Now, not only doesn’t the cell have a door that cannot be entered, but all the molecules of that substance, are absorbed and neutralized by the “fictitious locks” that float in the bloodstream.

Aderka said, “I was excited right away – this is the receptor! Wallach is a scientist. He said – this is definitely a possibility, but we’ll see, we’ll check it out”. At this point, the substance was isolated in Wallach’s laboratory, and in 1989 Aderka returned to Israel, to Wallach’s laboratory.

At this phase in the substance’s life, it was licensed by Yeda, the Weizmann Institute technology transfer company, to Serono (later it moved on to Imuneks and from there to Amgen).

Aderka said, “At this stage, an amazing thing occurred – I took the TNF, integrated it with my own receptor, which we already then we called anti–TNF, and I saw that it actually preserves its activity. Not anti at all! I told David about the result and he said, ‘You are wrong, repeat the experiment’, but I wasn’t wrong. And it took us years to understand why.”

Meanwhile, the product was about to be commercialized to treat sepsis and Aderka feared it would worsen the condition of patients. “In a conference in Japan in 1992, I said that the ‘anti–TNF’ will not help sepsis, but the companies were angry at me and wanted to silence me, because it was a product under development. How could I, the scientist who co–invented it, tell those guys that it would not work? But in 1996–1997, the product developers also realized it would not work, and they went back for another attempt to treat arthritis, just as we proposed in 1992.”

So why doesn’t the product work with sepsis? Apparently, the same receptor “head” that circulates in the blood to catch TNF molecules and prevent them from entering the cell, grabs them, but then releases them, that is, the process is reversible. This is where the patent part stops coming from Israel – a modification of the substance allowing grabbing the TNF, i.e. irreversibly, without releasing it.

The Enbrel drug for rheumatoid arthritis was released in 2000. Aderka received only part of the credit for his invention, and only part of the money. “Although I gave the thread, I wasn’t in the country when most of the work on protein sequencing was done and it was divided accordingly,” he says resignedly.

Despite everything Aderka is pleased. “Previously, there was no significant drug for the treatment of arthritis, except steroids. The reason you have not heard about the Israeli connection is probably Prof. Wallach’s modesty. For patients with arthritis, this is an invention on the scale of penicillin.” The drug is approved in the Israeli government’s health basket.

Aderka said, “The idea came in the most innocent and simple way and was realized in the most sophisticated way, using the excellent team of a doctor and scientist.”

Aderka chose to continue working as a doctor. “It’s my soul. I come from a family of doctors, but I dream that when I retire, I will return to being a researcher, perhaps even at the Weizmann Institute, and promote the development of Enbrel for the treatment of cancer.”

What significant insights did you get from this process?

He said, “Anything is possible, and what is important is to believe in what you see with your own eyes, and be free from prejudiced scientific beliefs, even if you have to admit a mistake. Adherence to prejudices and norms, or even to names such as ‘anti–TNF,’ are the ones that disrupt the progress of science. We need to look at science through the eyes of a child”.

Israel Rheumatology Association chairman and Head of the Rheumatology Outpatient Unit at the Sourasky, Ichilov Tel Aviv Medical Center Prof. Ori Elkayam said, “Enbrel and other biological medicines changed the face of rheumatology. Previously, we feared the effects of these drugs, but today, after 20 years of experience, it has been proven that the benefits are much larger than the possible harm. There is huge impact on patients and many of them divide up their lives into before the biological drugs and after them. In light of the therapeutic success, we are committed to diagnose the disease in its early stages and treat accordingly to stop the inflammatory process and prevent the damage caused by the chronic disease to patients.”

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