Dreams, drugs and devices

Israel’s only hospital-affiliated biopark, located in Jerusalem, helps doctors conduct research and translate ideas into new drugs and medical devices.

By JUDY SIEGEL-ITZKOVICH
doctors operating room 311 (photo credit: HBL)
doctors operating room 311
(photo credit: HBL)
It’s a rare physician who can check up on his hospital-ward patients and then stroll down the road to a biopark and work on a new medical product  based on his own research. There are only 10 such medical bioparks on hospital campuses in the whole world, according to the Hadassah Medical Organization (HMO), which boasts that the year-old facility on its Jerusalem-Ein Kerem campus is the only one in Israel.
Until recently, physicians regarded getting their research published in a medical journal as one of the most prestigious accomplishments they could achieve. But today, developing an innovative medication, medical device or new use for existing drugs converted into a product to benefit patients’ health far surpasses that.
HMO, which has always viewed research as a major role, is now going farther than ever in getting medical products based on its busy staff’s knowhow to the patient’s bedside. Thanks to its biopark, constructed by an outside company that received the land free and a build-operate-transfer contract, HMO has become Israel’s medical center pioneer in “translational medicine.”
“Our doctors see patients and know what they need to get better, so I insist that all our research centers be headed by a physician,” declares HMO director-general Prof. Shlomo Mor-Yosef. “But doctors have little time to spend on the search for investors, establishment of startups, manufacture and commercial marketing, so our Hadasit biomedical technology transfer company run by business professionals assists them.”
He noted that medical researchers at the Weizmann Institute in Rehovot and even the Hebrew University of Jerusalem (which which HMO is affiliated for its professional schools) are different than Hadassah physicians, as they don’t see patients who get treatment based on their discoveries. “Physician-researchers are practical, know what questions have to be asked and are more focused on applications at the bedside,” Mor-Yosef added.
Many physicians are not oriented to business and don’t know on what door to knock to turn their research into a product, or how to raise money through the stock market. “A medical discovery may be very impressive, but not everything can be turned into a commercial product,” said the HMO director-general in an interview with The Jerusalem Post. “Knowing all this is the expertise of medical organizations’ research and development companies and bioholding companies. Our biopark presents to other companies the advantages of being on this campus, the infrastructure, services, consultations and interactions with researchers. It’s a boon, and we plan to build another three here in Ein Kerem.” It is true that not every good idea turns into a product, added Mor-Yosef. “But I am very optimistic that our doctors’ ideas will result in companies that go far to benefit health around the world.”
Hadasit CEO Dr. Einat Zissman says the new biopark is a “one-stop shop” for development, from lab animal studies to clinical testing of ideas developed in HMO institutions and on to preliminary “greenhouses” and startups that evolve into fully fledged companies. Imaging technology for lab animals, a cyclotron to follow the spread of drugs through the body, consultation with HMO experts and a wide variety of other infrastructure are there, open also to outside researchers. Zissman, successor to Dr. Rafi Hofstein – who envisioned such a biopark project – less than a year ago, explained that some of the would-be medical products belong only to Hadassah researchers, but others are being developed in cooperation with other universities and hospitals. “One has to find a commercial partner to push development. Dozens of startups have been set up by HMO researchers in the past decade – more than any other hospital’s – as are the number of patents and patent applications. But it’s hard for physicians to find time for this. Thus the advantage of startups is that they find a professional manager who is not an MD,” said Zissman, a trained pharmacist. “There’s a limit on how far a doctor can bring a product forward. Startups cover the gap between research and the point when big companies can get involved in the technology.”
Hadasit Bio-holdings – headed by Ophir Shahaf – works hand in glove with Hadasit to “package” the intellectual property of Hadassah researchers and find money for its development and expansion. After a business-minded CEO is appointed, a business plan with clear milestones and goals is prepared, and the long, expensive road of drug development begins. “Excellent science may be enough for an article in a prestigious [medical or scientific] journal but not enough for a real, revenue-generating business,” Shahaf said.
He noted that “from the glimmer in the scientist’s mind all the way to a prescription at your local pharmacy,” this road can be seven years long and cost $500 million. Thus, as not all succeed, this is a risky business, even without considering the regulatory authorities such as the strict and demanding US Food and Drug Administration or the European Union’s EMEA (European Medicines Agency).
HBL’s CHIEF notes that the risk can be minimized somewhat with the diversification of products and technologies, picking the right sectors in which HMO has centers of excellence and choosing drug candidates meant for markets where there is no current solution.
Funding is always the bottleneck. In the past four years, HBL has raised over $30 million from public investors; this funds the preparation for and execution of Phase I and Phase II studies at eight portfolio companies. “Established in 2005, it  commercializes intellectual property for Hadassah researchers, but we are also publicly traded in the Tel Aviv Stock Market (with the abbreviation HDST). No other company whose shares are sold on the stock market has such excellent raw material, infrastructure and innovation,” maintained Shahaf, who is a lawyer.
Prof. Benjamin Reubinoff, a Hadassah University Medical Center gynecologist and one of the world’s leading experts in human embryonic stem cells (hESCs), will soon direct clinical trials at the biopark’s CellCure Neurosciences Ltd. on victims of the common “dry type” of age-related macular degeneration (AMD), the Western world’s main cause of vision loss in people over 50. This painless disease occurs when pigmented cells at the center of the retina break down and die, destroying sharp central vision. Working with Hadassah ophthalmologist Prof. Eyal Banin, Reubinoff has created unique retinal pigment cells from hESCs. Reubinoff is director of Hadassah’s Human Embryonic Stem Cell Research Center at the Goldyne Savad Institute of Gene Therapy, while Banin is director of the Center for Retinal and Macular Degeneration in Hadassah’s ophthalmology department. One injection into the eyes of rats succeeded in halting damage to the retina, the “screen” on which images are displayed and translated into vision by the retina’s photoreceptor cells.
“We set up company cellcure about four years ago in Ein Kerem, based on inventions developed over years of hESC work in Hadassah. We’re now at the stage of translating information from our lab animals into the development of cells to be used – subject to regulatory approval – in phase 1 clinical trials. These should take two years,” said Reubinoff, who added that there is currently no effective treatment to halt the degenerative process. “We hope our injectible cell replacement therapy for the dying layer will halt disease progression and even improve patients’ sight. We have already shown proof of concept, and there is a potential market of many millions of AMD patients. It will be one of the first applications of hESCs in the clinic, certainly at Hadassah and probably one of the first in the world.”
Prof. Yaron Ilan, director of Hadassah’s internal medicine department and chairman of the Israeli Association to the Study of the Liver, has initiated two public companies. One is Exalenz, which produced a noninvasive device to accurately assess liver function in people of all ages – even week-old newborns believed to have liver disease – merely by breathing into it. The other is Immuron, which produces antibodies named Travelan from cows for the treatment of travelers’ diarrhea; clinical trials using Travelan are being carried out against liver disease and type 2 diabetes, and new drugs for HIV will follow. Immuron, whose products also target a huge market, is already traded on the Australian stock market
Exalenz is running clinical trials in major liver centers in US and Europe, and the drug is expected to get final FDA approval soon.
Veteran internal medicine specialist Prof. Yaakov Naparstek set up ProtAb, a startup for the development of injected antibodies to treat rheumatoid arthritis as well as a number of other autoimmune diseases such as irritable bowel disease and psoriasis. Another startup to his credit is Verto, which is developing a membrane to filter out damaging antibodies that cause lupus erythematosus, an autoimmune disorder affecting many bodily systems mostly in young women. Naparstek’s third product, developed with Hebrew University biochemist and drug developer Prof. Yechezkel Barenholz, is a new delivery system for corticosteroids to better treat inflamed arthritic joints.
“We are big believers in the role of the hospital as a center for translational research. We noticed that there are types of rodents that don’t develop rheumatoid arthritis; they have something that protects them,” said Naparstek. “We discovered protective antibodies that increase the level of anti-inflammatory factors, so we developed a monoclonal antibody, made it suitable for humans using molecular biology and are manufacturing it at ProtAb. Investors joined, and the antibody will be tested for a year, leading, we hope, to clinical trials. We believe it will be curative, or at least alleviate the autoimmune disease for a long time.” The injected antibody is unique,” he continued, because “it takes advantage of a natural process.”
Research by Prof. Dror Mevorach, chairman of a third Hadassah internalmedicine department, led to the establishment of Enlivex, which fightsgraft-versus-host-disease (GVHD) – the main cause of death in cancerpatients who receive bone marrow transplants. “I have spent 15 years onapoptosis, which is programmed cell death,” he said. “There is cellturnover. Millions of cells in a human body die within 24 hours, but itwas not clear how it occurs. When the body collects dead cells, itdownregulates inflammation. If bacteria enter the body and causeinflammation, the immune system fights them. When they start to die,the inflammation is quietly resolved.”
So Mevorach took this physiological phenomenon to produce an injectionfor GHVD, which is a big problem in bone marrow transplant patients.“We can suppress or create immune tolerance and reduce the phenomenonof GVHD. It worked in mice and in human cells, leading to a clinicaltrial on two GVHD patients who had bone-marrow transplants for cancerand are now in very good condition. We hope to treat 12 more in thenext stage.”
Given the Hadassah professors’ and and the biopark’s initial success,surely other other leading Israeli medical centers are eyeing thefacility’s progress and considering the model for themselves.