By Jennifer Van Brunt

Editor

Of the 39 new medicines approved for sale in the U.S. by the FDA in 1998, nine were biologics Enbrel, Herceptin, Remicade, Simulect, Synagis, Thymoglobulin, Certiva, LYMErix and RotaShield. This means that close to one-quarter (actually, 23 percent) of new medicines entering the market are now biological products, the majority created via biotechnological means. That's even better than in 1997, when about 20 percent (10 of 49) of the new medicines approved by the FDA were biologics. By this point, there's little doubt that biotechnology has made its mark on modern medicine, whether those new products have been developed directly by biotech firms or whether they have been created by big pharmaceutical houses employing the various technologies. For instance, of the nine new biologics approved in 1998, six were sponsored by biotech firms and the remainder (Simulect, LYMErix and RotaShield) by big pharma.

London-based SmithKline Beecham plc's vaccine for Lyme disease, LYMErix, was approved in December. This preventive vaccine contains a recombinant outer surface protein (OspA) from Borrelia burgdorferi, the tick-borne bacterium that causes the infection. Novartis Pharmaceuticals Corp., of East Hanover, N.J. (a unit of Switzerland-based Novartis AG), received approval for Simulect in May. This product, a monoclonal antibody that blocks the receptor for interleukin-2, was approved for preventing acute rejection episodes after kidney transplantation. And Wyeth-Lederle Vaccines, of Philadelphia (a division of Wyeth-Ayerst Laboratories), gained marketing approval for it rotavirus vaccine, RotaShield, in August. The oral vaccine, which contains a live, tetravalent virus, is indicated for preventing rotavirus gastroenteritis, which causes severe and sometimes fatal diarrhea in children.

In fact, the first recombinant drug the FDA approved came from a big pharma company. In 1982, the agency approved Eli Lilly and Co.'s Humulin (recombinant human insulin) for treating diabetes but that product was the result of a partnership between the Indianapolis-based pharmaceutical giant and Genentech Inc., of South San Francisco. Between 1983 and 1995, the agency approved an average of one or two new biotech-derived biological entities annually. It wasn't until 1996 that the pace began to pick up, with three unique biologics (both Avonex, developed by Biogen Inc., of Cambridge, Mass., and Copaxone, developed by Jerusalem-based Teva Pharmaceutical Industries Ltd., for treating multiple sclerosis, as well as Gaithersburg, Md.-based MedImmune Inc.'s RespiGam for respiratory syncytial virus infection in young children).

According to a recent report (New Drug Approvals In 1998) from the Washington-based association Pharmaceutical Research and Manufacturers of America (PhRMA), the review times for the nine biologics approved in 1998 averaged out to 13.5 months. According to PhRMA, this is a little longer than the average of 11.7 months it took the agency to review new drugs, but much speedier than the 30 months it used to take the FDA to approve a new medicine before the establishment of the user fee program.

As usual, the FDA came through with a basketful of new product approvals in the waning days of the year, especially in December. However, of the new biotech company-sponsored products approved that month, some of which are listed below, not all qualify as biologics.

* Genzyme Corp.'s Thyrogen, a recombinant thyroid stimulating hormone, was approved for use in diagnostic procedures used to monitor patients for recurrence of thyroid cancer. Genzyme, of Cambridge, Mass., said it expects worldwide sales of $50 million to $75 million.

* Cephalon Inc., of West Chester, Pa., had its first new drug approved in the U.S. Provigil, or modafinil, is a synthetic compound that is thought to affect alpha-adrenergic receptors in the brain. The FDA approved the product for treating the excessive daytime sleepiness of narcolepsy. David Stone, managing director in the Boston office of SG Cowen Securities Corp., estimated Provigil sales of $12 million to $13 million in 1999; $50 million in 2000; and $90 million in 2001. Cephalon licensed the drug from Paris-based Laboratorie L. Lafon in 1993; that company has been selling the product in France since 1994 and Cephalon has been selling it in the U.K. since March 1998 (it was approved for marketing in the U.K. in October 1997).

* Laval, Quebec-based BioChem Pharma Inc.'s (NASDAQ:BCHE) popular AIDS drug Epivir (lamivudine) was also approved in the U.S. for treating chronic hepatitis B virus infection in adults. Epivir-HBV, an oral drug that contains a lower dose of the nucleoside analogue 3TC, will be marketed by BioChem Pharma partner Glaxo Wellcome plc, of London. This same drug, called by various other names, was also approved in Canada in 1998 (as Heptovir) and just received the regulatory nod from health authorities in the People's Republic of China (where it is called Heptodin). It's also been approved in the Philippines, New Zealand and Pakistan (under the trade name Zeffix).

* MedImmune's (NASDAQ:MEDI) intravenous immune globulin CytoGam, for prophylaxis against cytomegalovirus (CMV) disease associated with organ transplants, got approved for a second indication. CytoGam was first approved in 1990 for use in preventing CMV disease in kidney transplant patients, but now can be applied in lung, liver, pancreas and heart transplants as well. Sales of the product have been growing since initial product launch, reaching $20.3 million in 1997.

* SangStat Medical Corp.'s (NASDAQ:SANG) polyclonal antibody Thymoglobulin, a pasteurized anti-thymocyte rabbit immunoglobulin, was approved for reversing acute organ rejection in kidney transplant recipients. Analyst William Tanner, with Vector Securities International Inc. in Chicago, estimated sales of Thymoglobulin of $15 million in 1999, increasing to $56 million in 2002. SangStat, of Menlo Park, Calif., also received FDA approval in November 1998 for SangCya, an oral cyclosporine product for preventing solid organ transplant rejection

Many other products developed by biotech companies also got the FDA's seal of approval in 1998. A selected list follows below.

* MedImmune's Synagis, a humanized monoclonal antibody to respiratory syncytial virus (RSV), was approved in June for preventing serious RSV disease in children and infants.

* GelTex Pharmaceuticals Inc. (NASDAQ:GELX), of Waltham, Mass., and Genzyme Corp. received marketing approval in November for RenaGel Capsules for controlling elevated phosphorus levels in patients with end-stage renal disease. The product consists of a non-absorbed polymer-based compound that binds to and eliminates target substances from the intestinal tract.

* Immunex Corp., of Seattle (NASDAQ:IMNX), won FDA approval for the rheumatoid arthritis drug Enbrel, a biological response modifier, in November. The product, a recombinant, soluble tumor necrosis factor receptor linked to an immunoglobulin molecule (the Fc portion of human IgG1), is indicated for reducing the signs and symptoms of moderate to severe rheumatoid arthritis in patients who have an inadequate response to one or more standard antirheumatic drugs. It can also be used in combination with methotrexate in patients who don't respond well to that drug alone.

* Collagenex Pharmaceuticals Inc., of Newtown, Pa. (NASDAQ:CGPI), won marketing approval in October for Periostat, an orally administered drug consisting of a subantibiotic dose of doxycycline. It's indicated as an adjunct to scaling and root planing for treating moderate to severe periodontitis in adults.

* Genentech's (NYSE:GNE) Herceptin, a humanized monoclonal antibody to the HER2 growth factor receptor, won marketing approval in September. It is indicated for treating HER2-overexpressing metastatic breast cancer, as a single agent in second-line and third-line therapy and in combination with paclitaxel in first-line therapy.

* Londenderry, N.H.-based Diatide Inc.'s (NASDAQ:
DITI) in vivo imaging agent AcuTect for acute deep vein thrombosis was cleared for marketing in September. The technetium-99m-labeled product consists of a small-molecule synthetic peptide designed to adhere to the GPIIb/IIIa receptors on activated platelets.

* Isis Pharmaceuticals Inc. (NASDAQ:ISIP), of Carlsbad, Calif., and marketing partner Ciba Vision Corp., of Atlanta (a unit of Swiss pharmaceutical giant Novartis AG), won approval for Vitravene in August. The antisense inhibitor of cytomegalovirus (CMV) replication was cleared for treating newly diagnosed and advanced CMV retinitis in AIDS patients.

* Malvern, Pa.-based Centocor Inc.'s (NASDAQ: CNTO) Remicade, for treating moderate to severe Crohn's disease in patients for whom conventional therapy is inadequate, was approved in August. The product is a chimeric monoclonal antibody to tumor necrosis factor-alpha. In January 1999, Centocor submitted a supplemental biologics license application to the FDA requesting approval of Remicade for treating rheumatoid arthritis.

* North American Vaccine Inc. (AMEX:NVX), located in Beltsville, Md., won approval in July for Certiva, a combined diphtheria, tetanus and acellular pertussis (whooping cough) vaccine. It was approved for active immunization in infants and children.

* Warren, N.J.-based Celgene Corp. (NASDAQ:CELG) received approval in July for Thalomid, its version of the controversial drug thalidomide. The drug, which is thought to act by modulating levels of tumor necrosis factor-alpha, is indicated for treating erythema nodosum leprosum, a severe condition associated with leprosy.

* Cor Therapeutics Inc. (NASDAQ:CORR), of South San Francisco, and marketing partner Schering-Plough Corp., of Madison, N.J., received approval in May for Integrilin, a small-molecule synthetic compound that inhibits the GPIIb/IIIa receptor that mediates platelet aggregation. It was approved for reducing death, heart attack and other complications of percutaneous transluminal coronary angioplasty as well as in acute coronary conditions (unstable angina and non-Q-wave myocardial infarction).

* Cleveland-based Gliatech Inc.'s (NASDAQ:GLIA) Adcon-L, a semisynthetic carbohydrate gel that acts as an anti-adhesion barrier following surgery, was approved in May. It's indicated for inhibiting postoperative adhesions involving spinal cord and nerve roots and to improve patient outcome following lumbar disc surgery.

* Organogenesis Inc. (AMEX:ORG), of Canton, Mass., and partner Novartis AG got the FDA's blessing in May for Apligraf for treating venous leg ulcers. The product is a human skin equivalent consisting of living human keratinocytes and fibroblasts (epidermis and dermis, isolated from human foreskin) and cultured in a three-dimensional system

* Chiron Corp. (NASDAQ:CHIR) got approval in January for Proleukin, a recombinant human interleukin, for treating metastatic melanoma, an expanded indication. The Emeryville, Calif., company received approval in Canada for this indication a year later, in January 1999. *

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