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NOVO NORDISK's NOVOSTASE RECOMBINANT FACTOR VIIA IN PHASE II: GLOBAL REGISTRATION IS PART OF INTERNATIONALIZATION AND DIVERSIFICATION EFFORTS

Executive Summary

Novo Nordisk's Novostase Factor VIIa recombinant blood- clotting agent is in Phase II trials in the U.S. and Europe, and the company intends to file for approval in those countries at about the same time, Biopharmaceuticals Division VP Ulla Hedner, MD/PhD, told a Novo Nordisk science press seminar at the company's Bagsvaerd, Denmark headquarters on April 30. First approvals are expected "by the mid-90s," she said. Factor VIIa is being tested as a clot-inducing treatment for hemophiliacs who develop antibodies to Factor VIII or Factor IX, the standard blood-clotting treatments. The incidence of the development of antibodies among hemophiliacs is 10%-15%, Hedner said. Hemophilia occurs in seven to eight people per 100,000 worldwide, she noted. The numbers work out to over 2,000 cases in the U.S. "We intend to treat about 200 bleeds," Hedner reported. "So far, we have included 60 bleeding episodes" in the trial and "we hope to finanize this study sometime at the end of the year." The product has been used to treat 43 patients under compassionate use protocols, which are ongoing in both the U.S. and Europe. Novostase is available free of charge to treat life- or limb-threatening bleeds and in conjunction with surgery. The results of Factor VIIa studies to date "are encouraging and no side effects unequivocally assigned to Factor VIIa have been seen," Hedner told the press briefing. No reports have been made of patients developing antibodies to the recombinant product. Hedner pointed out that ease and speed of delivery would be important. The product is intended for at-home use and can be given in "something like five minutes," she said. Novo Nordisk's global development and registration plans for Novostase is one example of the Danish company's goal to expand both globally and beyond diabetes care products. Novo Nordisk is the world's leading producer of insulin with 1990 insulin sales of $ 770 mil. Expanding its worldwide presence is a goal outlined by the Danish company in its recently-released annual report. The report notes that several joint ventures were terminated in 1990, including the Squibb-Novo insulin venture in the U.S., because the agreements "were an obstacle to realizing our goal of launching a broader product portfolio on the world market." Novo Nordisk also expanded its worldwide sales force from 1,000 to 1,500 in anticipation of a higher product profile. In lieu of the insulin production agreement with Squibb, Novo Nordisk announced in late February that it has established its own insulin production facility in the U.S. in Clayton, N.C. ("The Pink Sheet" March 4, In Brief). At the Bagsvaerd meeting, Novo Nordisk focused on the expansion of its worldwide R&D as a crucial element of its globalization efforts. "We need to internationalize our research," Chief Science Officer Ulrik Lassen, MD, said. "We have made it a strategic issue to expand [R&D spending] faster outside of Denmark than in." Last year, the company spent 1.2 bil. Dkr (about $ 200 mil.) on R&D, which was roughly 15% of sales, and had a research staff of 1,901 worldwide. Approximately 85% of that research and development activity was carried out in Denmark, Lassen said, with about 12% conducted in the U.S. and Canada and 1% each in Japan, Switzerland and the U.K. Any international expansion will be focused on "centers of excellence," Lassen said, rather than on specific target countries. In the U.S., Seattle-based ZymoGenetics handles Novo Nordisk R&D. That company's lead product, platelet derived growth factor for soft tissue repair, is expected to enter the clinic during the first half of 1991. Zymogenetics was acquired by Novo in May 1988, prior to its Jan. 1984 merger with Nordisk. Another proprietary product could reach the U.S. market ahead of Novostase: Norditropin human growth hormone already is marketed throughout Europe but is blocked from U.S. sale by Genentech's and Lilly's shared orphan exclusivity. That exclusivity provision expires in 1994. Two other Novo Nordisk products are under development in the U.S. through partnerships. An NDA for the antidepressant paroxetine (Aropax/Seroxat), licensed by SmithKline Beecham for marketing outside the Nordic countries, has been pending at FDA since November 1989. SB is predicting a 1992 or 1993 U.S. launch for the 5HT-uptake inhibitor. The anti-epileptic tiagabine (formerly No-05-0328) is just beginning U.S. clinicals by licensor Abbott ("The Pink Sheet" April 8, p. 9). Novo Nordisk is conducting Phase II trials in Europe under the joint development agreement. Paroxetine and tiagabine are lead compounds in a new area of research for Novo Nordisk: central nervous system disorders. The project began in 1984, and the company indicated that it will soon form a full CNS division within its Health Care Group. CNS Division President Claus Braestrup, PhD, told the April 30 meeting about an earlier stage research project, the company's glutamate antagonist work. Glutamate, the brain's primary excitatory neurotransmitter, has been implicated in post-ischemic brain damage. A lead compound, NBQX, is in toxicology studies after demonstrating efficacy in gerbils for prevention of brain damage when administered up to six hours after an ischemic event. Initially NBQX will be studied for treatment of stroke, Braestrup said. Cardiac arrest and other ischemic events will also be studied. As promising as initial results are, Braestrup cautioned, "these are only animal experiments." Availability of a product is "at least five years down the line," he noted. CNS research now receives 15% of Novo Nordisk R&D spending, Chief Science Officer Lassen said, about the same as blood products (16%), and more than growth products (11%) and gynecology products (9%). Only industrial enzymes and diabetes receive substantially more research dollars from the company: 19% and 22%, respectively. "Our CNS research compares to any other company by any standard," Braestrup said. Insulin research remains the number one priority of Novo Nordisk R&D. Lisa Heding, MD/PhD, told the seminar about the company's efforts to find easier methods of insulin administration and ways to make products act more like insulin does in non- diabetics. Two advancements in Phase II are a monomeric insulin and an insulin nasal spray. Monomeric insulin is a recombinantly created single isomer of the normally hexameric human insulin. The smaller molecule size is said to speed up the rate of absorption to more closely mimic the normal function of insulin in non-diabetics. Long-range goals are insulin with greater organ specificity and an oral insulin. Two Novo Nordisk research chemists described their ongoing work in these areas. Both said that while there are as yet no lead compounds, progress is being made in understanding insulin's activity in the body. Insulin with greater liver specificity will likely be the first fruit of the research, the two chemists said. "Natural insulin is 50% removed by the liver," Heding noted.
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