Breakthrough Dividend
Chapter 13. Pharmaceuticals and Vaccines

Conventional Pharmaceuticals

. 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 filed.

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.

Biotechnological Therapeutics

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 Mengo virus.

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 cancer mortality.

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 Therapeutics

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 market.

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 (arterial thrombosis).

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 arachidonic acid.

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.

In Industry

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 agents including:

Burroughs Wellcome RTP Monoclonal antibody therapeutics
Demeter Biotechnologies RTP Peptide therapeutics
Glaxo RTP Medical therapeutics
ICAgen RTP Ion channel modulators
Macronex Morrisville Macrophage regulators
Medco Research RTP Medical therapeutics
Miles Clayton Blood products
Optiko RTP Ophthalmic drugs
Spart Pharm. RTP Anti-cancer, anti-viral drugs
Sphinx Durham Lipid second-messengers
Trimeris Durham Antiviral therapeutics.

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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