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Nobel Prize Winning Ubiquitin in Action

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Proteologics’ pioneers targeted drug development CEO Joshua Levin discusses the molecules being developed with Teva and GlaxoSmithKline.[Extracted from Globes, Israel]

The award of the 2011 Nobel Prize in Chemistry to Prof. Dan Schechtman, following the 2009 win by Prof. Ada Yonath, put the world of chemistry and Israel’s contributions to science that laypeople can barely understand in the limelight. Schechtman and Yonath have not yet turned their discoveries, of quasi-crystals and the mechanism of the ribosome, respectively, into commercial products, but their two Israeli predecessors, Prof. Aaron Ciechanover and Prof. Avram Hershko, the 2004 Nobel Laureates in Chemistry, have succeeded in doing so (or at least trying). They contributed their know-how and reputations to Proteologics Ltd. (TASE: PRTL).

Ubiquitin – the new buzzword

To understand what Proteologics is doing, it is necessary to go back to high school chemistry and the stubborn teacher who tried to explain what a protein is. The company is developing targeted therapeutics for the ubiquitin system, which regulates almost all aspects of eukaryotic cellular function, including cell cycle regulation, DNA repair, signal transduction, immune response, protein quality control and metabolism. The system comprises about 1,000 protiens.
Hershko and Ciechanover discovered the ubiquitin system in 1978, and jointly won the Nobel Prize in Chemistry in 2004 for the discovery. They are both members of Proteologics’ science advisory board.
Targeted medications are not regular drugs; as their name implies, they have just one specific target, and are consequently more effective, (improving a patient’s quality of life by reducing the side effects of treatment) and are more efficient for health funds by cutting costs. These drugs discover the proteins that play an important role in a disease, neutralizing which leads to improvement, even a cure, for the disease in question.
A ubiquitin is a small regulatory protein that can be attached to proteins and label them for destruction for the proper function of the cell. Ubiquitin tags can also direct proteins to other locations in the cell, where they control other protein and cell mechanisms. Disruption of the ubiquitin system is therefore liable to cause a wide range of diseases, including cancers, diseases of the nervous system such as Alzheimer’s or Parkinson’s, muscular dystrophy, and viral diseases.
Drug development is complicated, and the difficulties are compounded in the case of the ubiquitin system. It is a hierarchal cascade system with three levels: The E1 enzyme is a single protein, which can bind with the subordinate level, E2 enzymes (of which there are about 40), which in turn influence the more than 600 E3 enzymes.
This hierarchal cascade and the multiple E2-E3 connections complicates the drug development task. E3 enzymes directly transfer the signal to the protein, and this is where Proteologics finds the proteins that are the basis for its therapeutics. Any intervention higher up in the hierarchy is liable to cause harm rather than help.
Business model: spread the risk
Proteologics’ business model may prove in future to be much more effective than the models of other R&D companies. The drug development and approval process has three main stages. First is identification of the target and development of a suitable molecule, which is followed by preclinical and human clinical trials.
Proteologics only operates at the first and second stages, while the final stage, which requires more time and financial investment, is handled by the company’s big pharma partners – Teva Pharmaceutical Industries Ltd. (Nasdaq: TEVA; TASE: TEVA) and GlaxoSmithKline plc (NYSE; LSE: GSK).
In this way, Proteologics reduces its financial risk, as the clinical trial and most expensive stage is carried out by big pharma companies which bear the financial risk. Proteologics even receives advances for R&D costs, which are partly covered by its partners. The company also has an option for receiving milestone payments, and will receive generous royalties from sales, assuming that the drug is approved for marketing.
Until that day comes, if it ever does, Proteologics can use the milestone payments to pursue additional projects on the basis of the platform it developed for working with E3 enzymes with different tags. This enables the company to survive, in theory, for a long time as it expands its knowledge and its platform to create a large enough product base that will increase its chances of turning at least one of its drug candidates into a commercial product.
Proteologics CEO Joshua Levin says that it has been able to lower its risk profile by choosing two partners that complements each other, in both character and terms of the agreements signed with them. GlaxoSmithKline, a UK giant with a market cap of $117 billion, is developing with Proteologics six programs for the treatment of various cancers (each program is based on a different E3 enzyme). Teva is jointly developing three programs. Proteologics is also developing two programs independently, and will either continue to do so or find a partner.
“GlaxoSmithKline and Teva complement each other,” says Levin. “Teva is not an innovative company, which is why it chose to invest a little in us now, and give us a larger share of revenue from drug sales. GlaxoSmithKline, in contrast, chose to invest much more in us at the first and second stages, and took a greater share for itself when the drug reaches market.”
In the case of GlaxoSmithKline, which is the more important partner for Levin, each program could generate up to $176 million in royalties, or up to $1 billion altogether, but Levin is realistic about these numbers. “This isn’t a real number. There’s no chance that all six drugs will be commercialized,” he says.

2012 is the critical year

Under Proteologics’ timetable, 2012 will be a critical year. Teva, which has undergone quite a few changes, mainly as a result of its acquisition of Cephalon, is scheduled to receive its first molecule from Proteologics within months, and will have to decide whether it wants to pursue development. If it chooses not to do so, Proteologics can continue development (a Phase I clinical trial) independently, or find another partner, without the need to start the development process from scratch.
Levin is not worried that either Teva or GlaxoSmithKline will return molecules to the company, but he is nonetheless doing everything to make sure that does not happen. In the case of GlaxoSmithKline, each program has a three-year timeframe, which means that in early 2013, Proteologics will have to hand over the first molecule to it and wait for a response.
Read full article at Globes

Nobel Prize Winning Ubiquitin in Action

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Proteologics’ pioneers targeted drug development CEO Joshua Levin discusses the molecules being developed with Teva and GlaxoSmithKline.[Extracted from Globes, Israel]

The award of the 2011 Nobel Prize in Chemistry to Prof. Dan Schechtman, following the 2009 win by Prof. Ada Yonath, put the world of chemistry and Israel’s contributions to science that laypeople can barely understand in the limelight. Schechtman and Yonath have not yet turned their discoveries, of quasi-crystals and the mechanism of the ribosome, respectively, into commercial products, but their two Israeli predecessors, Prof. Aaron Ciechanover and Prof. Avram Hershko, the 2004 Nobel Laureates in Chemistry, have succeeded in doing so (or at least trying). They contributed their know-how and reputations to Proteologics Ltd. (TASE: PRTL).

Ubiquitin – the new buzzword

To understand what Proteologics is doing, it is necessary to go back to high school chemistry and the stubborn teacher who tried to explain what a protein is. The company is developing targeted therapeutics for the ubiquitin system, which regulates almost all aspects of eukaryotic cellular function, including cell cycle regulation, DNA repair, signal transduction, immune response, protein quality control and metabolism. The system comprises about 1,000 protiens.
Hershko and Ciechanover discovered the ubiquitin system in 1978, and jointly won the Nobel Prize in Chemistry in 2004 for the discovery. They are both members of Proteologics’ science advisory board.
Targeted medications are not regular drugs; as their name implies, they have just one specific target, and are consequently more effective, (improving a patient’s quality of life by reducing the side effects of treatment) and are more efficient for health funds by cutting costs. These drugs discover the proteins that play an important role in a disease, neutralizing which leads to improvement, even a cure, for the disease in question.
A ubiquitin is a small regulatory protein that can be attached to proteins and label them for destruction for the proper function of the cell. Ubiquitin tags can also direct proteins to other locations in the cell, where they control other protein and cell mechanisms. Disruption of the ubiquitin system is therefore liable to cause a wide range of diseases, including cancers, diseases of the nervous system such as Alzheimer’s or Parkinson’s, muscular dystrophy, and viral diseases.
Drug development is complicated, and the difficulties are compounded in the case of the ubiquitin system. It is a hierarchal cascade system with three levels: The E1 enzyme is a single protein, which can bind with the subordinate level, E2 enzymes (of which there are about 40), which in turn influence the more than 600 E3 enzymes.
This hierarchal cascade and the multiple E2-E3 connections complicates the drug development task. E3 enzymes directly transfer the signal to the protein, and this is where Proteologics finds the proteins that are the basis for its therapeutics. Any intervention higher up in the hierarchy is liable to cause harm rather than help.
Business model: spread the risk
Proteologics’ business model may prove in future to be much more effective than the models of other R&D companies. The drug development and approval process has three main stages. First is identification of the target and development of a suitable molecule, which is followed by preclinical and human clinical trials.
Proteologics only operates at the first and second stages, while the final stage, which requires more time and financial investment, is handled by the company’s big pharma partners – Teva Pharmaceutical Industries Ltd. (Nasdaq: TEVA; TASE: TEVA) and GlaxoSmithKline plc (NYSE; LSE: GSK).
In this way, Proteologics reduces its financial risk, as the clinical trial and most expensive stage is carried out by big pharma companies which bear the financial risk. Proteologics even receives advances for R&D costs, which are partly covered by its partners. The company also has an option for receiving milestone payments, and will receive generous royalties from sales, assuming that the drug is approved for marketing.
Until that day comes, if it ever does, Proteologics can use the milestone payments to pursue additional projects on the basis of the platform it developed for working with E3 enzymes with different tags. This enables the company to survive, in theory, for a long time as it expands its knowledge and its platform to create a large enough product base that will increase its chances of turning at least one of its drug candidates into a commercial product.
Proteologics CEO Joshua Levin says that it has been able to lower its risk profile by choosing two partners that complements each other, in both character and terms of the agreements signed with them. GlaxoSmithKline, a UK giant with a market cap of $117 billion, is developing with Proteologics six programs for the treatment of various cancers (each program is based on a different E3 enzyme). Teva is jointly developing three programs. Proteologics is also developing two programs independently, and will either continue to do so or find a partner.
“GlaxoSmithKline and Teva complement each other,” says Levin. “Teva is not an innovative company, which is why it chose to invest a little in us now, and give us a larger share of revenue from drug sales. GlaxoSmithKline, in contrast, chose to invest much more in us at the first and second stages, and took a greater share for itself when the drug reaches market.”
In the case of GlaxoSmithKline, which is the more important partner for Levin, each program could generate up to $176 million in royalties, or up to $1 billion altogether, but Levin is realistic about these numbers. “This isn’t a real number. There’s no chance that all six drugs will be commercialized,” he says.

2012 is the critical year

Under Proteologics’ timetable, 2012 will be a critical year. Teva, which has undergone quite a few changes, mainly as a result of its acquisition of Cephalon, is scheduled to receive its first molecule from Proteologics within months, and will have to decide whether it wants to pursue development. If it chooses not to do so, Proteologics can continue development (a Phase I clinical trial) independently, or find another partner, without the need to start the development process from scratch.
Levin is not worried that either Teva or GlaxoSmithKline will return molecules to the company, but he is nonetheless doing everything to make sure that does not happen. In the case of GlaxoSmithKline, each program has a three-year timeframe, which means that in early 2013, Proteologics will have to hand over the first molecule to it and wait for a response.
Read full article at Globes

Making armor for the brain (The story of Moussa Youdim)

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[Jerusalem Post: 11/13/2010]

Iranian-born Technion pharmacologist Moussa Youdim has worked for decades on drugs for Parkinson’s and Alzheimer’s disease and even ALS. Judy Siegel-Itzkovich interviews him.

  

PROF. MOUSSA YOUDIM and his wife Fruma. ‘The Nobel



His father’s struggle with deep depression over business troubles in 1957 changed the course of Moussa Youdim’s life, from studying in medical school to going into pharmacology and discovering a cure for that psychiatric disorder. Many patients with Parkinson’s and other diseases are grateful for that shift in the life of this 70-year-old Jew, who as a very active emeritus professor at the Technion-Israel Institute of Technology will next week share with seven others the $1 million EMET Prize for Art, Science and Culture.

The EMET Prize, awarded annually since 2002 for excellence in academic and professional achievements that have far-reaching influence, is sponsored by the A.M.N. Foundation for the Advancement of Science, Art and Culture in Israel, under the auspices of the prime minister. Youdim will receive his prize for brain science in the category of life sciences.

With a surname that comes from the Hebrew word yod’im (know) as his family for over 400 years in Persia were known for their intellectual pursuits, Youdim was given the name Moussa after an official in Teheran’s American Hospital who mistook her for Muslim and told his mother that she must call him Ali. When she protested that she was Jewish, he instructed her to name him Moussa. Since then, even though he is sometimes mistaken for being a Muslim (especially by airport security personnel), he has refused to change it to Moshe.

Warm, outgoing, polite and a man of the world, Youdim holds more than 100 international patents in neuropsychiatric drug development and cardiovascular drugs. He acts as a consultant for several major international pharmaceutical companies, and serves on many national and international scientific and grant-giving committees.

Not only have the contributions of the leading pharmacology researcher been included in many standard text books, but he has published a stupendous 800 scientific articles, edited 45 books, served on the editorial boards of 44 international scientific journals, lectured around the globe and received many national and international awards and several honorary doctorates – most recently the European College of Neuropsychopharmacology LifeTime Achievement Award and election to the Leopoldina Germany Academy of Sciences.

HE GOT used to traveling and managing on his own from a young age. Around his 12th birthday, he was sent to a boarding school in the English city of Brighton, and from there left for Canada to study medicine at McGill University – until his businessman father took sick – when there were no safe medications for depression, Youdim recalls in an interview with The Jerusalem Post. His father was given electroshock treatments in England and felt better, but he had recurrent attacks and was never the same.

Youdim’s mother became the family breadwinner.

In 1960, the only existing antidepressant medication, iproniazid, had been meant for treating tuberculosis, but it was found to make people who took it happier. Yet, it killed some people who took it along with cheese or wine, launching a race to find a safe antidepressant.

After taking courses in bio- and neuro-chemistry, he became enthralled with the idea of understanding how the brain works, and wondered how to fix it. Graduating with a BSc and MSc and then his doctoral degree in biochemistry at McGill’s Allan Memorial Psychiatry Institute, he returned to England for post-graduate work at the University of London and taught at Oxford and at the College de France in Paris.

YOUDIM RECALLED that nearly 40 years ago, he heard a lecture by Holocaust survivor Joseph Knoll about work on an antidepressant called deprenyl. Unfortunately, it wasn’t effective, but it also was not harmful to people who drank wine or ate cheese. A few years later, Youdim and Prof. Peter Reiderer of Austria thought and demonstrated that deprenyl was effective in treating Parkinson’s, the degenerative disorder of the central nervous system that impairs motor skills, cognitive processes and other functions, and whose symptoms include tremor, rigidity and unstable posture, along with cognitive and neurobehavioral problems, dementia and sensory and sleep difficulties.

Deprenyl, later named selegiline in the US, became the first monoamine oxidase B inhibitor for the treatment of Parkinson’s disease. But they found that deprenyl may indeed have side effects; Youdim searched for a deprenyl-like drug that would be more effective. He finally stumbled upon a candidate drug that was in his possession; he developed it into rasagiline (now patented as Azilect and sold by the Israeli company Teva Pharmaceuticals).

Margaret Thatcher’s anti-Socialist tenure as British prime minister annoyed Youdim and other scientists no end – “she was called a ‘milk snatcher’ when she took away free milk supplies for schoolchildren – and though he was happy at Oxford, he became alienated from England.

Simultaneously, Youdim visited Israel (although most of his family ended up in Los Angeles) and was invited to see the Technion’s new medical school, where the dean offered him a job to establish and head a pharmacology department; the only one in Israel then was at the Hebrew University in Jerusalem. “I liked Europe, but I thought Israel would be exciting – and indeed it has been.”

ALTHOUGH ACADEMIC pharmacology is necessary to build the pharmaceutical industry, Israel had few prominent people in the field, and the Weizmann Institute of Science in Rehovot never set up its own pharmacology department because it didn’t regard it as pure but rather applied science. It is ironical that many people at Weizmann now consider themselves drug developers, he adds.

Although he had received enticing offers from the US and Iran, Youdim agreed to come to Haifa to live in 1977. “I had to recruit people for the department and was asked to go to ulpan to learn Hebrew, but I taught in English; I didn’t have the time to learn Hebrew. I was given five years, but I still don’t really speak it,” he admits with some amusement.

He and his first wife had three children – Shai, Tal and Avigail, none of whom went into science – and they later divorced. On a blind date 15 years ago, he met Fruma, a high-school English teacher and mother of two whose Holocaust-survivor parents moved from Austria to Israel when she was two years old. Moussa and Fruma married a decade ago, and – speaking Hebrew like a native and feeling “totally Israeli” – she makes up for his lack of fluency in the language. When not flying around the world together, they live in a penthouse on a hill in Haifa that overlooks much of the city and the sea. After chairing the pharmacology department at the Technion’s Rappaport Faculty of Medicine until 1994, he went on to direct the Technion’s Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Teaching.

ALTHOUGH HE says he has has never regretted becoming an Israeli, Youdim encountered roadblocks in the bureaucracy and the academic establishment.

“It’s a small country, with one pie, and everybody wants a piece of it. If you didn’t grow up here, you may have difficulty. Politics is important and intertwined with other things.” But, he says, all this can be overcome, and his own success story proves it.

Two years after his arrival, he suggested to Teva – then a small generic medicine producer – that they offer a deal for rasagiline, but officials turned him down. But in 1987, as Teva was beginning to develop original drugs such as Copaxone for multiple sclerosis, Youdim got a call, this time to invite him to establish a unit to work on his Parkinson’s drug along with Technion colleague Prof. John Finberg.

Today, approved by the US Food and Drug Administration, it offers hope to millions of Parkinson’s patients (1.5 million Americans and four million Chinese alone). With annual sales worth $400 million and royalties earned by the Technion and the scientists, Azilect is now being marketed worldwide; it is considered the first neuroprotectivedisease modifying drug for Parkinson’s.

Azilect does not cure the disease, says Youdim, but it has been shown to slow the degenerative process in the brain and has been found in lab studies to actually improve damaged neurons. “The jury is still out. I have nothing to do with clinical studies, but all reports show it helps and has no more side effects than a placebo. There are patients who have been taking it for six or seven years and still benefit from it.”

There are also signs, he says, that a derivative of rasagiline named Cardiamit would help patients suffering from cardiovascular disease, and this is about 20 times more common than Parkinson’s; he has conducted research in this with Technion physiologist Prof. Ofer Binah. This drug is being developed at the Technion’s Alfred Mann Institute.

Asked about implants of electrodes in the brain to alleviate tremors, Youdim says those are not the solution for the large numbers of Parkinson’s patients. A drug is their only hope, as you can’t perform such operations on everyone, he adds.

Youdim has an even bigger target – Alzheimer’s disease. Working with Hebrew University pharmacology Prof. Marta Weinstock-Rosin and Teva, he has developed a new type of drug called Ladostigil (TV 3326), which is now entering Phase II clinical trials in Europe. It integrates rasagiline’s anti-Parkinson benefits with the anti-Alzheimer effects of Weinstock- Rosin’s drug rivastigmine. This is natural, he says, as many Parkinson’s patients also suffer from this dementia disease. The exclusive commercial rights for Ladostigil, which is already the first multi-functional anti-Alzheimer’s drug to reach clinical trials, have been granted to Avraham Pharmaceuticals by the technology transfer arms of the Technion and HU. If everything works out, he believes that Ladostigil will be his second original drug to be put on the market.

Youdim has established the importance of monoamine oxidase and brain iron metabolism for brain function that can lead to cognitive impairments and neurodegenerative diseases. Excessive iron produces oxygen free radicals, which cause degeneration and aging, including brain damage.

Alzheimer’s, he notes, is a very complex, multifactorial disease. “It is not purely neurological; there are probably also some psychiatric aspects, as many patients also have a predisposition to depression.”

More recently he has developed with Prof. Mati Fridkin of Weizmann Institute novel multifunctional iron chelators with monoamine oxidase and cholinesterase inhibitory activity for treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig disease, a form of which afflicts British theoretical physicist Prof. Stephen Hawking and many others around the world) as well as Lewy Body disease and Type 2 diabetes. “We’ve already published a paper on it, and are working on Huntington’s as well – the familial [genetic] degenerative neurological disease that is even more terrible. I work harder than ever before, even though officially I am retired.” He has been invited twice to Beit Hanassi to see President Shimon Peres, who has asked a group of Israeli neuroscientists to advise him on the establishment of a virtual neuroscience institute linking via Internet a number of research institutions that would collaborate on developing novel approaches to treat neuropsychiatric disorders and benefit the Israeli economy.

As for his native country of Persia, Youdim recalls that in 1978, when he was in Israel, the Shah of Iran invited him to Teheran, decorated Youdim on the monarch’s birthday and gave him a royal medal. “The Soviet Union fell, so fundamentalist Iran could as well. If I were one day invited back, I would visit. It’s a beautiful country.”

Youdim says he hasn’t even asked how much money his share of the EMET Prize will be, but “I don’t care about money; we have enough. I have received so many honors in Israel and abroad that a Nobel Prize is not my goal. There are so many brilliant scientists who have not become Nobel laureates. What is important to me are the many e-mails and phone calls I receive from grateful patients who have been helped by rasagiline. One example was a woman who called at 4 a.m. from Dallas to thank me because her husband had responded to the drug.”

But he will be excited and moved at the EMET Prize ceremony, he concludes. “I will surely think of my father and mother, who meant so much to me. They would certainly be proud.”