Chapter 13. Pharmaceuticals and Vaccines
Israeli scientists are highly adept at making basic advances relevant
to therapeutics. Although new conventionally-synthesized or extracted pharmaceuticals may not be
"biotechnology" under some definitions, it is hard to ignore such recent Israeli advances as, for
example, the Weizmann Institute's:
COP-1, a new synthetic drug that successfully helped arrest the progress of multiple sclerosis in
recent Phase III clinical trials;
Vitamin-D derivatives that limit the effects of osteoporosis;
Synthetic vitamin-D derivatives that strengthen human bones weakened by kidney diseases and
prevents milk fever in cows;
Natural extract of egg lipids, which seems to strengthen the immune system in children with cystic
fibrosis and adults with AIDS; and
Microbial product that rapidly inhibits protein kinase C activity in guinea pig models and could
prevent anaphylactic shock.
Other examples include the discovery by Technion scientists (and their collaborators) that deprenyl,
an existing drug, can block the brain enzymes that destroy dopamine. Deprenyl treatment can thus
reduce the doses of L-dopa required by patients with Parkinson's disease and delay or eliminate the
serious side-effects of prolonged L-dopa use. Recently 28 laboratories participated in NIH-sponsored
clinical trials that showed that deprenyl indeed slows the progress of Parkinson's disease. The Israeli
investigators are now working on new deprenyl-like drugs with Teva Pharmaceuticals.
A joint Hebrew University-Weizmann Institute team has developed a new family of iron-binding
drugs that can control malaria resistant to standard drug therapy. Some 200-300 million people
contract (often fatal) malaria every year, worldwide. One such drug SF1-ileu, a ferrichrome "mimic,"
has been proven rapidly effective in vitro against all stages of parasite development in malaria strains
from three different continents, without damaging normal cells. U.S. and Israeli patents have been
Ben-Gurion University scientists have been developing new drugs for patients suffering from manic
depression, a psychiatric disorder affecting more than 20 million people a year. They have found and
tested an antibiotic derivative that controls mood swings in patients not responding to lithium, the
usual drug of choice. Like lithium, the new drug blocks inappropriate increases in cyclic-AMP (a
potent energy-related chemical), induced by the body's own noradrenaline.
Cancer chemotherapy with quinone-based drugs like Adriamycin and Daunomycin creates highly-reactive oxygen radicals that cause semi-random breaks in the DNA of cancer cells to stop their
proliferation. Weizmann scientists have successfully joined these drugs to DNA fragments that stick
to specific sites on the cancer cell's DNA. This targeting should lower the required doses and thus the
severe side-effects of these drugs.
These are a few of the recent Israeli contributions of modern pharmaceutics. Many Israeli drug
projects involve foreign collaborators, and almost all involve early licensing to large foreign firms
capable of funding large $100 million clinical trials. This reflects the comparatively small absolute
size (by international standards) of Israel's biomedical industry, investment resources and market, and
Israel's difficulty in meeting the FDA's requirements for clinical trials (Chapter 21). Thus, although
Israelis pioneer an impressive number of new pharmaceuticals, given the multi-million dollar
development and testing costs involved in bring a new drug to market, much of the final action occurs
elsewhere, in the U.S. or Europe.
Now let's look at some newer, biotechnology-derived approaches to
therapeutics, further back in the R&D pipeline, beginning with two YISSUM projects that show how
two traditionally-successful Israeli biotechnologies -- interferon production and monoclonal antibodies
-- have been given a new therapeutic twist. Additional examples will be found in Chapter 14
(Hormones) and Chapter 15 (Immunotherapy).
Interferons are protein messengers that can, among other things, help activate the body's own
antiviral defenses. Double-stranded RNA (ds-RNA) can induce the body to produce extra interferon
and boost the body's immune defense, but ds-RNA is toxic. The problem is that ds-RNA binds to,
and inactivates, eukaryotic initiation factor 2 (EIF-2), a protein essential to turning RNA "messages"
into protein (translation) in normal cells. Israeli investigators at the Hebrew University (HU)-Hadassah Medical School have securely attached ds-RNA to its EIF-2 target in the laboratory and
hope to use the resulting combination as a safe, potent interferon inducer. They have already
demonstrated the drug's safety and efficacy in saving mice infected with otherwise fatal doses of
In fact, the ds-RNA/EIF-2 combination is 10-times more potent than ds-RNA alone and, unlike
injections of a single externally-produced interferon, the body is induced to produce a full natural
range of different interferon and forms. Even better, this endogenous interferon is produced over
a period of several days, ensuring it reaches its target. In contrast, external interferon is cleared
within minutes, often without firing a shot. Finally, ds-RNA is relatively easy and inexpensive to
produce, compared to the recombinant interferons. Genes to produce the three subunits of EIF-2 have
already been cloned, and the production of recombinant EIF-2 should be feasible. In fact, the costs
may eventually be low enough to use ds-RNA/EIF-2 to treat viral infections in domestic animals, as
well as in man.
In a more speculative offering, other HU-Hadassah researchers have developed a series of monoclonal
antibodies against adhesion molecules on the surface of normal and cancer cells. They hope to
develop ways to prevent stray cancer cells from using adhesion molecules to invade other tissues
(metastasis) after tumor removal or irradiation. If successful, such an approach could markedly lower
At the other extreme, another HU-Hadassah team finds fault with the current subunit vaccines for
influenza. They produce a weak humoral antibody response compared to conventional killed-whole-virus (KWV) vaccines. They induce no cell-mediated immune response and are not really suited for
respiratory tract infections, in which secretory immunoglobulin-A (IgA) is the main protective
antibody. These investigators have developed an innovative new method for producing KWV
influenza vaccines that avoid the use of both -propiolactone (which is banned) and formalin (which
has safety problems). They have already prepared several such vaccines and successfully used them to
protect mice against the corresponding, representative strains of influenza. Millions of Americans
suffer each year from influenza. Even when not fatal, the economic losses (such as lost work hours)
can be staggering, and school absence rates can reach 40 percent or more during an epidemic. One
advantage of the new vaccine is it can be administered as a nasal spray, rather than as an injection.
Cardiovascular diseases, such as myocardial infarction ("heart
attacks") and stroke, are the leading killers in the developed countries of the Western World. Israeli
investigators are developing a wide range of innovative therapeutics for this major threat -- and
Platelets are small vesicles (they are not cells, since they have no nucleus) shed by special bone
marrow cells, called megakaryocytes. Platelets, clotting factors and calcium can trigger a chain
reaction in which prothrombin is converted into thrombin, which, in turn, converts soluble fibrinogen
into fibrin. Passing red blood cells are caught in a mesh of fibrin fibers to create a blood clot. This
self-sealing is an important response to external injury, but unwanted internal blood clots can lodge
in, and block, crucial blood vessels in the heart (myocardial infarction), brain (stroke) or arteries
Anticoagulants can inhibit the formation of thrombin and thus clot-forming fibrin. The standard
warfarin and heparin treatments have intrinsic limitations, and two newer treatments, low-molecular-weight heparin (sales already over $100 million/year) and hirudin can only be injected. A joint HU-Tel Aviv University (TAU) team has developed a completely new family of low-weight anticoagulants
(from nontoxic food ingredients) that can be administered orally as tablets. These new drugs also
prolong the thrombin time and inhibit thrombin-induced platelet aggregation. Other potential clinical
applications for the new drugs include improved blood collection, improved dialysis and heart-lung
machine operation and improved bone marrow transplantation procedures.
Many chemicals cause platelets to aggregate into tight clumps. One of the most powerful is human
platelet activating factor (PAF). PAF plays an important role in atherosclerosis-related problems, and
can also induce superoxide production (in neutrophils), bronchoconstriction, allergy and
inflammation. Several major drug companies have been trying to develop synthetic PAF-inhibitors.
HU investigators have, instead, turned to the humble leech, which needs to produce anticoagulants
and PAF-inhibitors to prevent clotting during its blood meals. The investigators have isolated and
patented (in the U.S. and Israel, patent-pending in Europe) a powerful, highly-specific low-molecular-weight inhibitor of PAF. It has tremendous potential as a drug for blood-clot-related conditions,
allergy and inflammation. The investigators are now chemically characterizing their leech-derived
PAF inhibitor, and studying other low-molecular weight, leech-derived materials which inhibit the
platelet aggregation caused by other factors, such as adenosine diphosphate (ADP), epinephrine and
Antisense oligomers are short peptide molecules that are complementary to (and hence can bind)
specific RNA sequences. A HU/TAU/Max Planck team has developed antisense oligomers that can
bind to the messenger-RNA's coding for two important enzymes, acetylcholinesterase (ACHE) and
butyrlcholinesterase (BCHE). The former greatly enhances the proliferation of blood-forming
precursors cells (stem cells) in the bone marrow. These, in turn, suppress the development of platelet-producing megakaryocyte cells. The compounds may be useful in treating diseases in which
megakaryocytes are overproduced -- such as polycythemia vera, megakaryocytic leukemia, ovarian
adenocarcinoma and lupus erythematosus -- or in which platelet functioning must be reduced
(thrombosis, atherosclerosis, post-M1 syndrome). Basic R&D on this approach is continuing in mice.
The final project in this series involves more basic research on the genes and gene products that affect
angiogenesis, the proliferation of existing blood vessels and their potential clinical applications.
Israel has a thriving pharmaceutical industry dominated by the highly successful Teva
Pharmaceuticals. Teva, Israel's 10th largest company, has over 3,000 employees, 200 of whom are
engaged in R&D. Teva sold over a half billion dollars of pharmaceuticals in 1993 (up 27 percent),
including $172 million of exports (up a dramatic 92 percent), and boasts a 25-35 percent growth rate.
Most of Teva's success is in generic drugs for the U.S. market, usually through Teva's wholly-owned
U.S. subsidiary, the Lemmon Company. Teva is traded on both the NASDAQ and Tel Aviv
Exchanges. Lemmon now accounts for over half of all Teva sales (and 90 percent of its generic
sales). Teva recently purchased a third of a French firm, Prographarm, which specializes in time-release formulations. Teva also represents Baxter-Travenol in the Israeli market.
Though Israel has 17 domestic drug companies, and several major foreign ones, Teva and its ABIC
subsidiary (veterinary drugs and vaccines) account for approximately 40 percent of all sales. Besides
its generic and traditional pharmaceuticals, Teva does develop and test new drugs based on Israeli
biomedical advances, such as the vitamin-D analog drugs they have developed (with Weizmann
Institute scientists) to treat osteoporosis. These not only stop the wasting of bone, but can actually
reverse the trend, increasing bone mass. Osteoporosis affects over 25 million Americans a year,
especially post-menopausal women.
Teva's most recent new product, a drug (copolymer-1, COP-1, copaxone) that successfully fights
multiple sclerosis, was a long time in the making. It is also a good example of what Israeli scientists
and their local partners face in getting a new drug to market.
Around 1970, Weizmann Institute scientists synthesized COP-1 as a chemical model for "basic
protein," a major component of the fatty myelin sheath that surrounds and insulates the signal-transmitting axons of mammalian nerve cells. In multiple sclerosis, this protective coating is slowly
but inexorably lost. Eventually muscular (and often emotional) control is lost. There is no known
cure. Subsequent research in animal models showed that COP-1 could block the cells that destroy the
myelin sheath by inducing the activity of suppressor T lymphocytes. The Weizmann Institute's
commercialization unit, Yeda R&D, licensed COP-1 to Teva Pharmaceuticals in 1987.
The initial trials of COP-1 were held at the Hadassah Hospital in Jerusalem, at first in patients with
extreme multiple sclerosis symptoms, and then in less-affected patients. Later, preliminary trials were
conducted at the Albert Einstein College of Medicine in New York. COP-1 slowed or halted the
progression of the disease, especially in patients with exacerbating/remitting (ER) multiple sclerosis
(MS). A two-year American double-blind, controlled phase-II clinical trial followed. The frequency
of relapse was markedly decreased in 25 COP-1-treated patients. Finally, Teva initiated a full phase-III clinical trial at 11 U.S. medical centers. These fully confirmed previous results, and Teva is in the
process of filing new drug applications with the FDA and its European and Israeli counterparts.
If Teva files with the FDA in late 1994, as planned, it could have the required approvals as early as
1996. Even better, since the FDA has already declared Copaxone an "orphan drug" -- a move
designed to encourage the development of drugs for less common (and profitable) diseases -- Teva
would have a U.S. monopoly on Copaxone for seven years. The total world market for multiple
sclerosis pharmaceuticals is around $2-3 billion a year, and the share of a drug like Copaxone (Teva's
name for COP-1) could easily be in the $100-300 million range annually. If these rosy predictions are
realized, Copaxone alone could be worth as much as Teva's entire generic drug market.
Despite the hype, and Copaxone's very real success (as a palliative, if not a cure), its likely future is
far more complex. It provides, however, another important caveat to keep in mind when reading this
report. Israel is not alone, and its successes do not occur in isolation. They are part of a very dynamic
and competitive environment. Teva announced the initial results of its Phase III trials in July 1994,
but so did Biogen (USA), which has a similar, some say slightly superior, product. Biogen's entry
reduces the recurrence of ER/MS attacks 31 percent (compared to Teva's 24 percent), slowed the
development of the disease 75 percent. (Teva has made no such claims) and apparently has fewer
side-effects. Both companies are rushing to market in a dead-heat race, and both should come away
with something very worthwhile (even $20-50 million sales a year would make Copaxone a financial
success). Still, Israel faces sizable risks, and immense potential benefits, when it plays in this highly-competitive international arena.
In addition to a variety of small companies concentrating on new formulations and delivery systems
for existing drugs (e.g., BioDar), Israel also has several smaller companies developing new human
therapeutic agents (Appendix C). Life Science Research has sales of over $3 million a year. Pharmos,
which has developed interesting "soft" Ophthalmic drugs, has acquired a small Florida firm and is
now legally its overseas subsidiary. Biotechnology General and Interpharm and their therapeutic
products are discussed in Chapters 14 and 15 respectively.
North Carolina, has several companies specializing in new drug formulations (e.g., Protein Delivery,
Inc.), including hormone polymers. It also has several companies developing new human therapeutic
||Ion channel modulators
||Anti-cancer, anti-viral drugs
Although several Israeli and North Carolina pharmaceutical firms (e.g., Chaitech and Trimeris,
Pharmos and Optiko) seem to have somewhat similar interests, these fields are too broad to make
definitive statements based on available information.
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