Copaxone's inventors hope for improved treatment

But Prof. Michael Sela and Prof. Ruth Arnon say it won't be easy to make a generic version of the multiple sclerosis drug.

Prof. Michael Sela and Prof. Ruth Arnon from the Weizmann Institute of Science discovered Copaxone for the treatment of multiple sclerosis while seeking to develop a product to induce the disease. The serendipitous discovery became the drug with the biggest sales by an Israeli pharmaceutical company. It would be no exaggeration to say that the discovery has even affected the Israeli economy.

Teva Pharmaceutical Industries Ltd. (NYSE: TEVA; TASE: TEVA) is expected to report $3.7-3.9 billion in Copaxone sales in 2013, after steady growth from $2.3 billion in 2008 to $4 billion in 2012.

Arnon and Sela have repeatedly said that they did not embark on their study to develop a drug. Sela told "Globes", "For me, curiosity is the determining factor; curiosity and truth. I am allergic to lies, but I can wake up at 2 am because something interests me. What interested me during the discovery of Copaxone was immunology - how the immune system works."

Arnon, who was Sela's doctoral student when Copaxone's development was initiated, has stressed that she was not seeking to develop a drug, but to complete a detective story to create understanding where previously there was only ignorance.

The year was 1967, and Arnon and Sela attempted to induce multiple sclerosis in animals to discover the causes of the disease and to create a model for understanding it.

Multiple sclerosis is caused when the immune system attacks and damages the fatty myelin sheaths of axons (nerve cells) in the brain and spinal cord. The process is often compared to damaging the plastic sheaths of electric cords, creating short circuits and preventing the transmission of data. The precise mechanism causing the immune system to go on the attack is not known, or why it targets myelin.

Arnon and Sela sought to investigate the immune response in general. Arnon told "Globes", "Another laboratory was working on a disease unique to lab animals called "experimental brain inflammation" by injecting a myelin-based substance taken from animals' spinal cord to see the response."

Arnon and Sela succeeded in developing a synthetic version of one of the proteins which induced the immune response. "The hypothesis was that because this protein had many positively charged amino acids, it connected with acidic fatty molecules to damage the myelin," says Arnon.

The results were disappointing the substance did not induce the disease, and not one of the test animals fell sick for a full year. At this point the researchers made the conceptual leap: if the morbidity rate was lower than expected, maybe something else was happening maybe the substance was preventing the disease.

"Globes": But how could that be?

Arnon: "Because there is a similar substance in the body which induces the disease, but our protein did not imitate it exactly, but only partially. It therefore competed for the active sites in the body, preventing emergence of the disease.

This is not the only mechanism which Copaxone affects MS. During its development, the precise way it worked was unknown, which hindered registering the product at the time. Today, however, this benefits Teva because the lack of clarity makes it difficult to bring generic versions of the product to market.

After achieving such impressive results on the model disease - experimental brain inflammation the question arose: could Copaxone cure the real disease, multiple sclerosis? The product worked in mice, albeit with side effects that were liable to stymie development at this stage, had the researchers not taken the risk of testing it on other animals. Ultimately, monkeys were tested.

"Were it not for the work on the monkeys, 250,000 people would not have our treatment today," says Sela. "We were lucky that we didnt have the contemporary hysteria around the issue".

Arnon says, "We then treated four patients in very serious shape who were willing to take the risk. We saw no deterioration in their condition, and no harm was caused, so we commenced a larger study to determine the optimal dosage."

It should be noted that for researchers to conduct a clinical trial for a product wholly owned by a university is considered highly unusual nowadays. Today, such a product would be commercialized at this stage to a small or large pharmaceutical company to conduct the trials - justifiably, as research institutes are less prepared to conduct large-scale clinical trials, which are not suitable for scientists.

Arnon has said in the past that a clinical trial without a discovery bores her.

Sela says, "We had a very important partner at this stage Dr. Murray Bornstein of Albert Einstein College of Medicine of Yeshiva University in New York. He strongly believed in the product, and begged for a few grams of the substance for treating the disease in 20 patients outside a clinical trial."

Arnon adds, "He then carried out a controlled study and the difference was huge: there were 60 relapses among the patients receiving the placebo during the study period, but only 26 cases among the patients receiving our product." She cites the numbers from memory, as if the study was conducted yesterday.

Sela says, "At this point, I contacted my friend, the late Eli Hurvitz, and told him, 'I'm coming with my wife for a light dinner. Prepare a slide projector because I want to show you something.'" He showed Hurvitz the results of the study, which were about to be published in the "New England Journal of Medicine". "Eli said, I'll take it," adds Sela.

Teva, which is based on generics, had less than $100 million in sales and a few million dollars in profits at the time. It decided to assume the huge project of developing a new treatment for multiple sclerosis, a mysterious disease which was not well understood, for which there few available therapies. Hurvitz and Teva gambled tens of millions of dollars on the product. The gamble paid off handsomely, and changed the face of Teva.

29 years in development

The process was lengthy. Arnon says, "We started with a theoretical study in 1967. Our results, including on the monkeys, were published in 1975. We then conducted the first clinical trial, which was published in 1977.

"In 1987, Teva assumed development of the product, which was approved in 1996. 29 years from the initial research. Developing a drug requires immense patience and a long life."

In 1998, Sela and Arnon won the Wolf Prize, one of Israel's most prestigious awards in science, and which is considered a precursor for a Nobel Prize.

Sela says, "At this point, I became vice president of the Weizmann Institute, effectively running it. This was the end for me, because while I've done some research since then, I've been busy with administration, and most of my work has been handed over to Ruth, who did a wonderful job. We've now resumed working on the subject together."

"Globes": Was there a dilemma in collaborating with Teva, which had no experience in the field?

Arnon: "Not really. It wasnt as if other companies were waiting by my door. At the time, I had ties with scientists at several companies, but they werent happy bringing outside products to their management. What, they'd reveal to their superiors that in-house R&D wasnt good enough? At Teva, Michael had a direct relationship with the company's management, and it didnt have an in-house innovative R&D department anyway.

"We worked very closely with them, and they ultimately received a product after a controlled human study. It was a gamble for them, but a calculated one."

In exchange, Teva promised to pay the Weizmann Institute relatively high royalties on sales, apparently around 8-10%, compared with the usual 4%.

There is a claim that Teva pays the Weizmann Institute exorbitant royalties.

Arnon: "Teva got an advanced product. They've profited handsomely from it."

Sela: "Our agreement ultimately went to arbitration. I know that I'm right, and that the royalties should be from the top line of sales to patients, as is written in the contract, even if Teva sells the product to its distributor at a discount. Judge Meir Shamgar ruled 100% in our favor on what was written in the contract. Everyone was astonished how Eli and I remained friends throughout this."

The friendship stayed solid. Sela later served as a director at Teva and as a member of its scientific committee. Both he and Arnon invested in Pontifax, the venture capital fund that Hurvitz founded in 2000. After Hurvitz's death, Sela was appointed Pontifax's chairman.

On the basis of the royalties that Teva pays on the huge Copaxone sales, Sela and Arnon have presumably earned tens of millions of dollars, possibly even hundreds of millions. The Weizmann Institute, which the main beneficiary of Copaxone, invested little in its development. "Where would the institute have had the money back then?" says Arnon. "We received a grant from the US National Institutes of Health."

When the product became a medication, Sela and Arnon became more interested in how it helped patients. This was now more than just curiosity. Arnon says, "Once, a diagnosis of multiple sclerosis was a terrible sentence of doom. Young people lost their jobs and spouses. It was a cruel fate. Today, most multiple sclerosis patients are treated at an early stage. I've met many patients, and they still visit and write me. Just a short time ago, I received a note from a scientist who was diagnosed with the disease, who investigated the product she was taking, and wished to thank me. To hear something like this from a peer is especially emotional."

Arnon and Sela are still studying Copaxone's action. Sela says, "It seems that, in addition to the product's first hypothesized active mechanism, it also causes other cells to excrete brain derived neurotropic factors, which prevents damage to the myelin sheath, and maybe even rebuilds it. The drug also apparently disrupts the continuity of events in which the immune systems' T-cells identify myelin as a foreign substance. Copaxone also encourages the replication of another kind of immune cell, control cells, which control the immune system's activity. Through these two mechanisms, the drug has succeeded in moderating the over destructive effect of T-cells."

Sela believes, however, that Copaxone, has already had its run. "40% of multiple sclerosis patients receive Copaxone, justifiably, but we're talking about an product that is injected daily, and there are now oral treatments, one by Teva. There are also products under development which may be better than our product.

"I would not replace Copaxone for people who have taken it for 8-9 years, but I hope that new patients will benefit from new products in the coming years. 20-30 years have passed since we discovered the product, and I hope that something better will arrive."

Published by Globes [online], Israel business news - - on March 28, 2013

Copyright of Globes Publisher Itonut (1983) Ltd. 2013

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