With a dearth of potential new drug candidates worldwide, Israel's biopharmaceutical and drug development companies provide the global pharmaceutical industry with a rich seam of new molecules. From personalized medicine and stem cell treatment to drug development in such areas as CNS, oncology and cardiology, investors in Israeli companies are hoping to reap high returns through investment, acquisitions and IPOs. Moreover, Israeli investors now realize that although biotech ideas may take longer to develop into marketable products than in other high-tech sectors, the rewards are bigger and last longer.

Teva Pharmaceuticals (NYSE: TEVA; TASE: TEVA) has proven this point in Israel through its blockbuster multiple sclerosis treatment Copaxone. The drugs patent has now expired with copycat competition set to drastically cut Copaxone's sales from $3.8 billion last year to just $1.8 billion in 2018. Nevertheless, between 2002 and 2017 Teva enjoyed accumulative Copaxone revenue totaling a stunning $42 billion. In recent years, the drug has consistently been one of the world's top 20 best selling treatments.
Teva remains the world's largest generic pharmaceutical manufacturer with overall annual revenue of over $20 billion, but with the global generics market suffering from pressure to reduce prices in the US, and the expiration of the Copaxone patent, Teva is a company in transition. In 2017, to help reduce the debt taken on to acquire Allergan's generics division Actavis for $40 billion in 2016, Teva announced a comprehensive streamlining program to lay off 14,000 employees worldwide including 1,750 in Israel.
With the patent for Parkinson's treatment Azilect also expired, Teva's worldwide sales in 2017 fell to $170 million from $450 million in 2016. Sales of other specialty medicines following the acquisition of US branded drug developer Cephalon for $6.8 billion in 2011 include leukemia treatment Treanda $658 million, sleep apnea treatment Nuvigil $61 million, and respiratory treatments ProAir $501 million, and Qvar $361 million. Teva is developing its branded drug capabilities and the hopes are that the new drug touted as a blockbuster replacement for Copaxone - Fremanezumab for treating migraine - will receive FDA approval within a year. In 2017, Teva received FDA approval for Austedo for treating chorea associated with Huntington's disease.
Israel's other major pharmaceutical companies include Taro Pharmaceuticals (NYSE: TARO), owned by India's Sun Pharmaceuticals. The company's plant is in Haifa and in 2017 it reported revenue of $640 million in generic, branded and OTC drugs. Agis Pharmaceuticals was acquired by US company Perrigo (NYSE: PRGO TASE: PRGO). With two plants in the Negev, and annual sales of about $400 million Perrigo Israel develops, manufactures and distributes over-the-counter (OTC) and generic prescription (Rx) pharmaceuticals, and nutritional products and has a specialty sciences business comprised of assets focused on the treatment of Multiple Sclerosis. In 2017, Perrigo Israel sold its Chemagis active pharmaceutical ingredients (API) operations to SK Capital for $110 million.

Another Israeli company with a pipeline of promising new drugs is Clal Biotechnology Industries (CBI) (TASE: CBI), controlled by Clal industries, which is itself controlled by US company Access Industries owned by Len Blavatnik. CBI’s portfolio includes 14 life science companies including nine drug development companies, five of them Israeli and four from the US. CBI’s portfolio companies include MediWound (Nasdaq: MDWD), which raised $70 million in its Wall Street IPO in 2014, and has received EMA approval for its burn and wound treatment product NexoBrid.. MediWound’s second innovative product candidate, EscharEx, currently in advanced clinical trials, is being developed for debridement of chronic and other hard-to-heal wounds.
Other portfolio companies include: CureTech, which is developing cancer lymphoma and colorectal cancer treatments and which Rehovot based Insight Tech recently agreed to buy for up to $500 million in milestone payments. Gamida Cell, which is developing a stem cell therapy cancer treatment, and received $35 million in investment from Novartis in 2014 for 15% equity has a drug for treating hematological malignancies in a Phase III clinical trial. CBI also has a stake in Biocancell, which is developing cancer treatments and its lead product for the treatment of bladder cancer in Phase III clinical trials, recently raised $23 million from private investors. Biokine Therapeutics is a biopharmaceutical company focused on developing novel therapeutics to treat cancer.
Former CBI portfolio companies include Avraham Pharmaceuticals, which is developing Logostigil, currently undergoing a three-year Phase II clinical trial on patients with mild cognitive impairment, to test whether the drug can delay, or prevent the onset of Alzheimer’s disease.
Protalix Biotherapeutics (NYSE: PLX) is working on Phase III trials with a Fabry disease treatment called PRX-102; PRX-106, an oral TNF blocker, which has been fast-tracked with orphan-drug status by the FDA. In November, the Karmiel based company signed a collaboration agreement with Chiesi Farmaceutici worth up to $370 million in milestone payments.
The company prewviously developed a Gaucher disease treatment Elelyso, which received FDA approval and commercialization rights were recently sold to Pfizer for $46 million. The drug, which was developed in cooperation with Pfizer, capitalizes on its proprietary biomanufacturing plant cell culture platform to develop biopharmaceuticals and biogenerics or biosimilar pharmaceutical proteins. It is the first drug of its kind in the world with such a platform to obtain FDA approval and the company says they have more products in the pipeline. The Gaucher drug has also received approval for Brazil and Israel.
Other Israeli companies include Chiasma (Nasdaq: CHMA), which develops oral versions of biological drugs, and raised $102 million in an IPO in 2015, shortly after raising $70 million in Series E funding. Prolor, which was acquired by Opko Health (NYSE: TASE: OPKO) for $480 million has successfully completed a Phase II trial for hGH-CTP, which treats growth hormone deficiency. Galmed Pharmaceuticals (Nasdaq: GLMD), which is developing a fatty liver treatment in Phase IIb trials, has raised $41 million on Nasdaq, while Enzymotec (Nasdaq: ENZY), which is developing lipid-based products and solutions for the nutritional and healthcare markets, raised $63.5 million before being acquired by Frutarom (TASE: FRUT; LSE: FRUT) for $290 million. Rare genetic disease treatment developer BioBlast Pharma (Nasdaq: ORPN), wound treatment company MacroCure (Nasdaq: MCUR) and cancer and inflammatory disease treatment developer VBL Therapeutics (Nasdaq: VBLX) all raised capital on Wall Street in recent years. Also raising money on Nasdaq recently was Foamix Pharmaceuticals (Nasdaq: FOMX), a clinical stage specialty pharmaceutical company focused on developing and commercializing proprietary topical foams to address unmet needs in dermatology, which drew a $16 million investment from OrbiMed earlier this year.
The most recent Nasdaq IPOs by Israeli companies include: Sol-Gel which is developing a non-antibiotic preparation for the treatment of acne that has already passed a Phase II trial and which raise $75 million at a company value of $225 million; and UroGen Pharma which is developing a product for drug delivery of a bladder cancer treatment and raised $105 million in two offerings. Intec Pharma (Nasdaq: NDEC TASE: NDEC), which has an Accordion Pill for treatment of Parkinson's Disease that is used for delayed release of the levodopa and carbidopa drugs at the entrance to the intestine, recently raised $35.4 million on Nasdaq. Intec Pharma's product is in Phase III clinical trials. ,
There are about 250 biotech, pharmaceutical and agbio companies in Israel. The country’s veteran biotech firm Bio-Technology General (BTG) is fully owned by Ferring Pharmaceuticals, which acquired the company from Savient Pharmaceuticals of the US in 2005 for $80 million. Operating from its cGMP plant in Beer Tuvia, BTG acts as one of Ferring’s R&D centers focusing on development and manufacture of recombinant bacterial and mammalian cell based products for the pharmaceutical and medical device industries.
Other veteran Israeli biotech firms that are further down the development road include Peptor, which a decade ago merged with the German firm Develogen. Peptor has also signed strategic agreements with major international players in developing its synthetic peptide-based pharmaceuticals. This includes a licensing agreement with Aventis for its diabetes drug and cooperation with Roche in the field of cancer treatment.
Compugen (Nasdaq: CGEN; TASE: CGEN) signed a $500 million agreement with Bayer Healthcare for the research, development, and commercialization of antibody-based therapeutics for cancer immunotherapy against two novel Compugen discovered immune checkpoint regulators. Other Israeli firms developing new chemical entities include Proteologics (TASE: PRTL), which specializes in the ubiquitin system. Based on research by Nobel Prize winner Prof. Aaron Ciechanover of the Technion, Israel Institute of Technology, the company develops a new class of small molecule drugs against major diseases based on ubiquitin ligase inhibitors. Proteologics has signed a commercialization deal with GSK to develop its promising cancer treatment molecules and recently reported positive results in animal trials on two anti-inflammatory treatments.

Other promising Israeli biotech companies traded on the TASE include Can-Fite BioPharma (TASE: CFBI), which is developing novel treatments for autoimmune and liver diseases, and cancer. Can-Fite’s lead drug CF101 successfully has progressed through Phase IIa trials for the treatment of rheumatoid arthritis and psoriasis. Another drug CF 102 for the treatment of liver diseases is currently in Phase II clinical trials. Its spin off OpththaliX Inc. (Bulletin Board: OPLI) is developing a treatment for glaucoma. Kamada (TASE: KMDA) is another of the few Israeli biotech companies to successfully complete Phase III clinical trials. The company received FDA approval in July 2010 for Glassia, its intravenous AAT treatment for congenital emphysema and has a distribution agreement with Baxter International. Kamada sees sales of $100 million in 2017. XTL Biopharmaceuticals (Pink Sheets: XTLBY; TASE: XTL) is developing a drug for the treatment of blood cancer, while RedHill Biopharma (Nasdaq: TASE: RDHL), which buys the rights for drugs in advanced clinical trials, recently began a Phase II study for Bekinda for the treatment of irritable bowel syndrome. Mapi Pharma recently sold rights to a slow-release form of Copaxone for treating multiple sclerosis to Mylan. Pluristem Therapeutics (Nasdaq: PSTI; TASE PSTI) is developing stem cell therapy to treat severe obstruction of arteries that can lead to amputation and is a global leader in placenta-based cell science to develop and manufacture safe and effective cell therapy products. Pluristem recently entered into a licensing agreement with TES Holdings Co. to obtain a key patent in Japan to cover the treatment of ischemic diseases with placental cell therapy.

Among innovative business structures, which are designed to overcome Israeli biotech’s difficulties in raising capital and lack of management know-how, is BioLineRX (Nasdaq and TASE: BLRX). BioLineRx is a drug development company bridging the gap between Israel’s enormous innovative R&D potential and global pharmaceutical marketing. The company raised a further $25 million on Nasdaq last year after acquiring Agalimmune for $6 million to accelerate its immune-oncology pipeline. The Jerusalem-based company's lead drugs include: BL-5010, a novel formulation for non surgical removal of skin lesions, which has been commercially launched; BL-8040, for acute myeloid leukemia (AML) and other hematological cancers (in midst of Phase II trial); AGI-134 for the treatment of solid tumors which is nearing clinical trials; BL-9020, for the treatment of Type I diabetes; and BL-1230 for dry-eye syndrome. ProCognia (TASE: PRCG) has developed a protein-based technology for analyzing blood sugar molecules (glycoanalysis), while Medgenics (NYSE: MDGC AIM: MDGC) has developed a proprietary biological platform, the Biopump, which allows patients to produce, within their bodies and on a long-term basis, their own natural human protein therapy for the treatment of a range of chronic diseases, such as anemia and hepatitis C. Nasvax (TASE: NSVX) has an agreement with Novartis to develop a family of improved vaccines. Insuline Medical (TASE: INSL) which has developed InsuPatch to reduce injected insulin uptake speed in diabetics by near 50%, has signed an MoU with J&J.
Industrial Biotech and Agro-Bio In industrial biotechnology, Bio Dalia Technologies manufactures and markets Bacillus thuringiensis bioinsecticides and is active in contract manufacturing of biochemicals by fermentation, industrial bioprocess development and R&D. In Agro-Bio Hazera and Zeraim Gedera are world leaders in seed technology, while Rahan Meristem has developed tissue culture plants for the diagnosis of plant pathogens and recombinant vaccines for veterinary purposes. Among promising projects being developed by Gavish Bio Applications in the Galilee is a post-harvest preservation and protection of fruits and genetically modified plants, which raise the nutritional quality of animal feed and food for human consumption. AgroGreen, a member of MINRAV GROUP, provides “green” and friendly solutions for agricultural problems and demands. AGROGREEN focuses its development efforts on biological pesticides. BioFeed has developed a device that is an environmentally safe for controlling the Mediterranean fruit fly (Medfly), in which no chemicals come into contact with the fruit, while Biomor is devoted to developing a biocide based on Tea Tree Oil extract.
Evogene (NYSE: TASE: EVGN) is a crop genetics company, a spin-off of Compugen, which is focused on the improvement of high commercial value key traits in important crops through gene discovery, genome remodeling and advanced breeding techniques. Evogene and French biotech firm Biogemma SAS recently reported success in the first year field trial of high-yield drought resistant corn developed with genes located by Evogene. FertiSeeds is an agro-biotechnology company offering a novel, universal solution for low cost production of hybrid seeds based on molecular genetic technology, while Virumar develops an innovative platform technology and vaccine against Marek’s disease in poultry. Rosetta Green (TASE: RSTG), which uses unique genes named microRNAs to develop plants and algae with improved traits was acquired by Monsanto for $35 million.

Israeli biotech was given a boost by the establishment of a $250 million VC fund which is being managed by OrbiMed Advisors, the largest healthcare investment fund in the world. The fund was initiated by an Israeli government tender and investment of $40 million and reflects the feeling that the country’s biotech industry is only scratching the surface of its potential. OrbiMed followed this up last year by closing a $307 million second Israel biomed investment fund. In addition to its investments in BioLineRX and RedHill, OrbiMed's investments include Otic Pharma, which is developing novel formulations for ear antibiotics, RDD Pharma, which is developing drug-device combinations for the treatment of ano-rectal diseases, Atox Bio, which develops novel immunomodulators, LogicBio, which develops gene therapy vectors for previously incurable genetic and infectious diseases and Nutrinia, which treats rare diseases of the GI tract by developing encapsulated oral insulin gut maturation, focusing on dual orphan indications - premature infants and short bowel. OrbiMed is also a partner in the FuturX incubator in Ness Ziona with Japan's Takeda and J&J. The eleven portfolio companies include Protekt Therapeutics, which is developing a drug for enhancing the long-term memory of those suffering from mild cognitive impairment (MCI) and ICE Therapeutics, which is developing proprietary small molecules for treating lower urinary tract disorders and neuropathic pain associated with cold intolerance. Other startups include Ayala Pharmaceuticals, which recently raised $17 million to develop two Bristol Myers Squibb oncology drug candidates, Azura Ophthalmics, which raised $16 million to develop a treatment for eye gland dysfunction, Pharma Two B, which raised $30 million last year for the Parkinson's treatment it is developing, and Drug delivery co SteadyMed, which recently raised $30m to develop Trevyent for the treatment of Pulmonary Arterial Hypertension. DreaMed Diabetes is developing automatic regulation of insulin release and has partnered with Medtronic. Pancreatic cancer drug treatment company Tiltan Pharma raised $1.5 million for a Phase II clinical trial of TL-118. Tilatan is a portfolio company of Integra Holdings, the biopharmaceutical company of Hebrew University tech transfer company Yissum. Enlivex Therapeutics is developing cell immunotherapy treatments for Graft versus Host Disease and is a portfolio company of Hadasit Bioholdings, a unit of the tech transfer company of Hadassah Medical Organization.