The History of Human Insulin, Problems, and the Loss of Choice, 1980 to 1993

This press release is an announcement submitted by PR Newswire, and was not written by Diabetes Health.

| Jan 1, 2008

INDIANAPOLIS, July 21 - Eli Lilly and company today announced that it has begun limited testing in healthy human volunteers of biosynthetic human insulin produced by recombinant DNA technology.  The company also announced that it has started construction of the world’s first manufacturing facilities—at a cost of $40 million—to employ recombinant DNA technology to produce the biosynthetic human insulin.

In what is believed to be the first application of recombinant DNA technology to human health problems, Lilly began initial evaluation of the new insulin in humans.  The initial testing followed careful animal studies and extensive laboratory testing. 

Biosynthetic human insulin is identical to the insulin naturally made inside the human body and marks the first product development from Lilly’s major research program in recombinant DNA technology.  Although clinical evaluation will determine effectiveness, it is possible that this human insulin will lessen chances of allergic and other reactions that some diabetics experience from current insulin, which is made from animal pancreas glands.

The construction projects are under way at Lilly industrial centers in Indianapolis as well as at the company’s Dista Products Limited facility, near Liverpool, England.  The projects include various fermentation, purification, and technical support units.

In announcing these developments, Lilly board Chairman Richard D. Wood cautioned that considerable scientific work and necessary government approvals remain to be completed before supplies of biosynthetic human insulin are commercially available.

Mr. Wood noted that “it seems fitting for Lilly to pioneer this complex scientific field as further evidence of our long-standing commitment to the treatment of diabetes.”
Lilly developed the first commercial production of insulin from animal pancreas glands in 1923 and has been a major supplier since then.  Forecasts of long-range supplies of animal pancreas glands have suggested that animal insulin could likely be in very short supply in approximately 20 years.

“With the potential availability of Lilly biosynthetic human insulin,” Mr. Wood said, “we can now see the promise of a time when supplies of insulin will always be adequate to meet public needs.  Biosynthetic human insulin is an encouraging example of the way in which new scientific knowledge, such as recombinant DNA technology, can lead to products which serve the public interest.

Along with our investments in years of scientific research time, costing millions of dollars,” Mr Wood said, “our decision to make this major plant investment demonstrates that promising scientific breakthroughs can, at first, be costly.  However, such advancements offer the long-term benefit of adequate supplies of lifesaving insulin for a growing number of diabetics around the world.”
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The New York Times
July 24, 1980

LONDON, July 23 - Tests of insulin produced by bacteria that have been modified through techniques of recombinant DNA, or genesplicing, have begun at Guy’s Hospital here, scientists said today.

The new insulin is almost identical with that produced naturally in the human body by the pancreas. In diabetics the hormone is not made in amounts sufficient to break down sugar and other carbohydrates.  More than a million Americans suffering from diabetes rely on daily insulin injections to stay alive.  

Insulin currently used by diabetics is derived from the pancreas of animals, usually pigs or cows. In some cases, human patients can develop an infection with the animal insulins, a situation scientists hope can be avoided with the new insulin.

The first experiments have already been conducted on eight healthy volunteers who are members of the hospital’s staff. The tests consisted of injecting tiny amounts of both the new insulin and pig insulin at various sites on the body.  The results were assessed by doctors who did not know which type of insulin had been used at a given site. No local reactions or other side effects were detected at the sites where the new insulin was used.

Next, the ability of the new insulin to lower blood glucose levels will be tested on patients at the hospital.

Tests on Americans Planned

The insulin used by the hospital was provided by Eli Lilly & Company, the Indianapolis-based drug concern, the largest manufacturer of insulin. Early this week Eli Lilly announced that the new insulin would be tested on Americans before the end of the year.

Scientists have been trying to synthesize several medically useful products with recombinant DNA technology. They include interferon, a virus-fighting substance. DNA, or deoxyribonucleic acid, is the active substance of genes and the key chemical in heredity. Prof.  Harry Keen, director of the metabolic unit of Guy’s Hospital, described the new insulin as “the first major flower” of this type of research.

He said that two different methods would be used for the second stage of tests: injection under the skin, which is the usual way of giving insulin, and slow injection directly into the bloodstream, which is believed to mimic more  closely the body’s natural secretion of insulin.

Professor Keen expressed optimism about the role of insulin synthesized from bacteria. He said it should be available in much larger amounts than the previous type and that it might be possible to prepare a form of insulin that could be taken orally, eliminating the need for injections. He said he also believed the new insulin might help reduce the incidence of long-term complications of diabetes by controlling blood glucose levels more effectively.

In the meantime, Eli Lilly, which pioneered the commercial production of insulin almost 60 years ago, is moving ahead with a $40 million project to build plants here and in England where the hormone will be produced in quantity.

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PR Newswire
February 12, 1981


NEW YORK, Feb. 12 - Clinical evaluation of biosynthetic human insulin in diabetic patients began at medical centers today in Detroit, Philadelphia, and Trenton, N.J.


Announcing the start of clinical evaluation today were:

Dr. Fred W. Whitehouse, chief of the division of metabolic diseases at Ford Hospital, Detroit.

Dr. Theodore G. Duncan, director of the Diabetes Treatment and Education Center at Pennsylvania Hospital, Philadelphia. 

Dr. Arthur Krosnick, vice president of medical staff at Mercer Medical Center and chairman of the Diabetes Coordinating Council, Trenton.

Thorough evaluation of the new insulin must be conducted prior to application for the necessary government approvals required before the product is available for all diabetics.

Insulin-dependent diabetics currently rely on insulin produced from the pancreas glands of swine and cattle.  Biosynthetic human insulin is identical to insulin produced in the human body, but is made by means of recombinant DNA using a laboratory strain of common bacteria found in the body.  This is believed to be the first long-term application of recombinant DNA technology in the world.

Clinical evaluation in diabetics began in December, 1980, at the University of Kansas School of Medicine-Wichita.  Other centers in the United States and Canada will begin evaluation of the recombinant DNA-produced medicine in the near future, according to Eli Lilly and Company, manufacturer of the new insulin.  Lilly is a pioneer in the development of insulin.  The company developed the first commercial production of insulin in 1923 and has continued its efforts to improve the medicine.

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The Economist
July 17, 1982

Eli Lilly; Painful Innovation- Eli Lilly, the biggest drug company in the United States and 10th largest in the world, is suffering unpleasant side-effects from its new anti-arthritic drug. Reports in British medical magazines have associated the drug, benoxaprofen, with illnesses and nearly 40 deaths.   

British health officials say they are watching the drug’s performance.

The problem surfaced in Britain just as the drug was being introduced in the United States. One American consumer group is already campaigning for its withdrawal. Doubts surrounding the drug have probably spiked Eli Lilly’s plans to compete on equal terms with Pfizer’s rival anti-arthritic drug, which could bring Pfizer sales of $200m this year.

Eli Lilly has a good reputation with the United States Food and Drug Administration. But this and other setbacks could delay approval of a second new drug which is important to the company, human insulin produced with genetic engineering techniques. Eli Lilly has applied for approval for its new insulin product in the United States, Britain and West Germany. The company hopes to get approval from one regulatory authority by the end of this year.

Eli Lilly and the specialist Danish company Novo are the largest producers of insulin, a business worth $400m a year. Both companies are invading each others’ markets, and also trying to capture sales in West Germany from Hoechst. Novo is waiting for approval for its human insulin in America, but already has permission to sell the new product in Britain.

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Washington News

October 29, 1982,
By Al Rossiter, jr., UPI Science Editor

The Food and Drug Administration Friday cleared synthetic human insulin made in genetically engineered “factories” of bacteria for sale to the public to treat diabetes.
It is the first human health-care product of the new gene-splicing technology okayed for commercial use. Approval took only five months - exceptionally fast for a new drug.  

The FDA told Eli Lilly & Co., which will market the insulin under the brand name of Humulin, that federal scientists had reviewed test results and found the synthetic insulin safe and effective for diabetes treatment.

Lilly spokesman Ronald Culp in Indianapolis said the company has sent letters and mailgrams to 260,000 doctors across the nation advising them of the FDA approval. He said the company plans a phased introduction of the product beginning later this year.

Lilly estimates there are 5 million diabetics in the world who require daily insulin injections to help their bodies deal with sugars and starches in food.

Insulin for humans who don’t make enough of the hormone themselves is now obtained from the pancreas of pigs and cattle after they are slaughtered. There is no shortage of animal glands to make insulin today, but some specialists believe one could develop in the next decade.

Production of insulin in bacteria promises to make endless quantities of the hormone. The synthetic insulin is identical to that produced by the human pancreas, but FDA spokeswoman Faye Peterson said the synthetic product has not been shown to have any therapeutic improvement over animal insulin.

Dr. Rachmiel Levine of the City of Hope Medical Center at Duarte, Calif., where some of the pioneering genetic engineering research on insulin was conducted, said the synthetic insulin has one distinct advantage over insulin now in use. Unlike the animal products, he said the human insulin is not likely to produce allergic reactions in patients.

Lilly first tested the human insulin in healthy volunteers and then in more than 1,000 diabetics around the world.

The cost of Humulin has not yet been established. The trade newspaper Genetic Engineering News quoted Dr. John A. Galloway, senior pharmacologist at Lilly, as saying Lilly’s initial price to wholesalers probably will be higher than the price of currently available purified pork insulin.

The approval of the synthetic insulin came four years after scientists at the City of Hope and Genentech Inc., in South San Francisco announced they had succeeded in producing bacteria that could manufacture insulin chemically identical to that produced by the human pancreas.

The technique is the product of gene-splicing technology developed in the 1970s. Genes that direct the pancreas to make insulin are artificially made in the laboratory and the inserted into bacteria. The organisms are thus “tricked” into making a protein for which they have no use.

The technology has developed quickly. The first artificial gene capable of working in a living cell was made in 1976 at the Massachusetts Institute of Technology.
Genentech president Robert Swanson said the FDA approval was a “tribute to the collaboration of two great teams of scientists, those of Eli Lilly and Genentech.”
He said the U.S. government approval followed by one month the approval of British regulatory authorities for introduction of synthetic human insulin in the United Kingdom.

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McGraw-Hill’s Biotechnology Newswatch
November 15, 1982
As Lilly’s synthetic insulin gets FDA OK, Novo, Biogen join to clone their own

DATELINE: BETHESDA, MD - Approval by the Food and Drug Administration here of bacterially cloned human insulin October 29 is being viewed by experts as a giant step for genetic engineering, but only a marginal advance for medical science. The synthesized hormone, first product of recombinant DNA ever cleared for human use, has been trademarked Humulin by its maker, Eli Lilly and Company of Indianapolis.

Doubt as to the benefit of Humulin over conventional insulin extracted from the pancreases of pigs and cows was cited by Dr. Solomon Sobell, director of
the FDA’s division of metabolism and endocrine drug products.  Sobell says that in clinical testing of the new product, human antibodies have formed despite expectations that the cloned hormone, being identical with the human molecule, would not cause an immune response.

“Further clinical studies,” he tells Newswatch, “will more clearly indicate whether there are any advantages to human insulin.” This testing period, he adds, could last for several years.

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The Washington Post
October 30, 1982
FDA Approves Insulin Made by Splicing Genes
By Cristine Russell, Washington Post Staff Writer

The Food and Drug Administration yesterday announced approval of synthetic human insulin, the first health care product made by gene-splicing to become commercially available.

The insulin, to be called Humulin, is expected to be phased into the marketplace later this year by manufacturer Eli Lilly & Co. of Indianapolis, the major producer of insulin from animal organs.  Government approval of a drug developed through the genetic “recombinant DNA” technology represents a major practical payoff for basic biological research that was touted as revolutionary when it was introduced in the mid-1970s.  

Approval of the new drug comes four years after California scientists at the City of Hope Hospital and the commercial firm Genentech Inc. announced that they had succeeded in creating synthetic human insulin in the laboratory. Eli Lilly then made an agreement for long-term development of the product.

Dr. Henry Miller, a medical officer with FDA’s National Center for Drugs and Biologics, said in an interview that the approval was “significant” because it “demonstrates the scientific and commercial viability of the technology” and “shows that FDA does not intend to place Draconian regulatory impediments in the path of approval of these products.”

He said the approval took place in “record time,” only five months after it was submitted by the company last May.
Miller said, however, that “the advent of human insulin therapy is not likely to constitute a medical breakthrough for insulin-requiring diabetics.”

Diabetes is a complicated disease in which sugar cannot be broken down properly due to a lack of insulin, a pancreatic hormone. The most severely affected victims, about one-third of the 6 million Americans diagnosed as having the disease, are dependent on injections of insulin produced from the pancreases of pigs and cattle. The new genetically produced insulin is identical to that produced by the human body.

Both FDA and Eli Lilly said that tests thus far have not found the synthetic human insulin to have any therapeutic advantage over the most highly purified forms of animal insulin, despite some researchers’ claims that the new human insulin would be less likely to produce allergic reactions.

But the production of human insulin by bacteria that can copy it in huge amounts does have the advantage of offering a “virtually limitless supply of products unaffected by circumstances such as shortages of the animal organs used in making insulin,” said an FDA spokesman.

Theoretically, the new method should be cheaper in the long run. But an Eli Lilly spokesman said that the human insulin would initially cost about 50 cents a day, a cost comparable with that of highly purified pork insulin. A commonly used beef-and-pork combination form of insulin is cheaper.
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The New York Times
November 1, 1982
Market Place; Genentech’s Outlook Now
By Robert Metz

GENENTECH Inc. offers speculators the quintessential fad stock.  Genentech, the highly acclaimed leader in the promising field of genetic engineering, has carried a stratospheric price/earnings multiple since the public offering of 1.1million shares at $35 each in October 1981. Few would question that this tiny company, with revenues of $15 million last year, was overvalued at a P/E ratio of more than 100.

Now, after years of research and the apparent perfection of a major product, Genentech may soon experience its first exposure to the commercial market and - if all goes well - its first important earnings.  Humulin is Genentech’s human-derived insulin, artificially fabricated through gene-splicing techniques, and it received marketing approval from the Food and Drug Administration last week.

Eli Lilly & Company’s marketing of the substance will mean royalty income for Genentech. Lilly is to produce Humulin at two new facilities - one in Indianapolis, Lilly’s headquarters, and the other in Liverpool, England. The human-derived alternative to bovine and porcine insulin may prove attractive enough to stuff Genentech’s coffers with royalties.

Assuming this happens - and assuming investor expectations don’t soar unreasonably - the South San Francisco company’s price/earnings ratio may drop to a realistic level for the first time. Viewed in terms of current earnings, Genentech’s P/E appears to discount heavy competition from an aggressive foreign producer with an attractive insulin product of its own and from Eli Lilly itself.

In 1982 Genentech may earn 4 cents a share. That estimate by Standard & Poor’s was published in OTC Stock Reports in mid-June.  Genentech was up 1 ½ Friday at 47 ¾ bid, 48 asked in the overthe-counter market. That’s an indicated P/E ratio of 120.

It is arguable whether Humulin will forge major inroads in the insulin market for some time. The product will cost twice as much initially as the animal insulins used by an estimated two million of the ten million diabetics in theUnited States. Eli Lilly will begin marketing the new insulin through drugstores in 1983. It will be sold without prescription.

Eli Lilly is one of the giants of the ethical drug industry, with 1982 sales estimated at more at $3 billion. In 1922 Lilly became the first company to develop insulin for use by the public. Its insulin, like that of its competitors, has been derived from pigs and cows.  This product is highly purified and usually has no side effects.  Humulin would be of intense interest to the rare diabetic who develops insulin resistance through antibody formation. The F.D.A. warned that “any change in insulin should be made cautiously and under medical supervision,” in keeping with a general caution about switching insulins made from different animal species.

Then there are competitive factors. Eli Lilly has a dominant share - 85 percent - of the United States insulin market. Sales of Humulin in this country may cost Lilly some sales of its own. The potential impact on Lilly’s profits and on its stock price over the long term has yet to emerge.

Despite the appeal of a human-derived product, a major sales effort presumably would be required to persuade diabetics who ingest animal insulin without notable side effects to pay a premium for Humulin.

Novo Industri, a Danish company, is the world’s second-largest insulin supplier. Novo has about 25 percent of the world market.  Contrast the P/E ratio of this respected company with that of Genentech. Novo’s Class A American shares sold as high as 48 this year and closed Friday at 47 ½, up 5/8. On earnings of $2.23 a share, Novo thus sells at a price/earnings multiple of 21 times the indicated 1981 result. Novo is a strong competitor of Eli Lilly.

Genentech has not said what royalty it is to receive from Lilly.  Shirley Clayton, a spokesman for Genentech, did say last week that Humulin revenues go direct to the bottom line. “We don’t have expenses anymore on the insulin development,” she said.

In the first six months of this year, Genentech had net income of $131,000 on revenues of $14 million. In the corresponding period a year earlier, net income was $208,000 on sales of $9 million. “When several of our products reach the marketplace,” Miss Clayton said Friday, “we will begin to see significant earnings.”

That was suitably cautious. Speculators who buy Genentech shares at current levels will take comfort in remarks made last week by Dr.  Henry Miller, the medical officer in charge of Humulin at the F.D.A.. He said Humulin represented a major step in “the scientific and commercial viability” of recombinant DNA techniques. “We have now come of age,” he said.

Genentech will come of age when the marketability of its products is established against older, well-established products and when royalty income actually begins to flow in sufficient amounts to affect net income. But those who speculated on Genentech earlier can already say that their hopes are based on more solid prospects this time.

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McGraw-Hill's Biotechnology Newswatch
November 15, 1982
As Lilly's synthetic insulin gets FDA OK, Novo, Biogen join to clone their own

BETHESDA, MD - Approval by the Food and Drug Administration here of bacterially cloned human insulin October 29 is being viewed by experts as a giant step for genetic engineering, but only a marginal advance for medical science. The synthesized hormone, first product of recombinant DNA ever cleared for human use, has been trademarked Humulin by its maker, Eli Lilly and Company of Indianapolis.

Doubt as to the benefit of Humulin over conventional insulin extracted from the pancreases of pigs and cows was cited by Dr. Solomon Sobell, director of the FDA's division of metabolism and endocrine drug products. Sobell says that in clinical testing of the new product, human antibodies have formed despite expectations that the cloned hormone, being identical with the human molecule, would not cause an immune response.

“Further clinical studies,” he tells Newswatch, “will more clearly indicate whether there are any advantages to human insulin.” This testing period, he adds, could last for several years.

Lilly is distributing its newly authorized Humulin to specialists at leading diabetology centers throughout the U.S. for free dispensing to selected patients. Full marketing will be phased in early next year, at prices yet to be fixed. An insulin-dependent diabetic, of which there are one million in the U.S. alone, spends from 28 to 35 cents daily for ordinary mixed beef-and-pork insulin, or 44 to 52 cents for the highly purified porcine hormone. Humulin, says a Lilly spokesman, will probably cost 50 to 55 cents for a daily dose.

Meanwhile, Squibb/Novo is expecting early FDA approval of its chemically modified product, which changes porcine to human insulin by replacing a single molecule (Newswatch, March 15, p. 7). But Squibb/Novo is hedging its bet by joining with Biogen, Inc., of Cambridge, Mass., to develop a recombinant-DNA human insulin that can compete with Lilly's. Biogen's president, Robert A. Fildes, disclosed this development to Newswatch but did not indicate when its new cloned hormone will be ready for testing.

Aside from its possible but still-unproved medical advantage over animal insulin, the cloned product provides assurance that if and when pig and cow pancreas supply is outstripped by the rising population of diabetics up 6% a year in the U.S. the drug will still be available. The FDA's Sobell says, “One worries about shortages of animal insulin, though we have not encountered one yet.”
And the clinical director of the National Institute of Arthritis, Diabetes, Digestive, and Kidney diseases, Dr. Phillip Gordon, warns that concern over restrictive supplies may be just a “smoke screen.” Though he grants that genetic engineering will now help guarantee a steady source, Gordon adds, I do not have the perception that we're running out of insulin.

FDA approval of Humulin came just six weeks after British authorities cleared it for human use in Britain, and four years after the hormone was first synthesized jointly by the City of Hope National Medical Center in Duarte, Calif., and Genentech, Inc., of San Francisco.
Biochemist Arthur D. Riggs, who led the team at Duarte that created the two-chain insulin genes for Genentech to clone, now tells Newswatch, “With the bacterial cells producing unlimited amounts of bona fide true human insulin, I think it's probably unnecessary to continue to extract it from animals.” Ten years from now, Riggs predicts, there will be several hundred of these peptide hormones being produced and eventually thousands for human and animal health care, food production, and so forth.

Once Lilly's Humulin is on the market, the company will pay licensing royalties to Genentech, which developed it, and to Stanford University for use of the basic Cohen-Boyer process patent that protects the invention of bacterial host-vector systems.

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McGraw-Hill, Inc. Chemical Week  March 2, 1983

Rushing with synthetic insulins

Eli Lilly's new bacterially cloned human insulin, Humulin, received Food and Drug Administration approval for marketing last October. The product, in which Lilly has invested $70 million, has not arrived in drugstores, and observers speculate that Lilly's one U.S. plant is not yet equipped to handle demand.

But even as Lilly gears up for production, set for later this year, it is being challenged by another synthetic human insulin product from Squibb-Novo. So, Lilly is trying to anchor its own product firmly in the diabetic-public's mind, observers note, before Squibb's product can be brought to market. The Squibb product would be the only other synthetic human insulin product to compete in the $100 million/year domestic insulin

Lilly's effort consists of a “physician experience program”, designed to familiarize doctors in the diabetology community with Humulin. Free samples are being supplied nation-wide to diabetes clinics and teaching facilities. The move is not a clinical trial, says Lilly, so the company doesn't expect physicians' clinical feedback. The program, claims a Lilly spokesman, “is merely an opportunity for [physicians] to familiarize themselves with an over-the-counter product that differs from most OTC products their patients can obtain.”

A better road

The move is, however, marketing-oriented. “And it's a logical strategy,” comments Dr. Edwin Fineberg, associate professor of medicine at the Indiana University Medical Center's diabetic clinic. Fineberg says the program allows diabetologists to use the insulin on the “appropriate patients”. That, he adds, is preferable to switching “en masse to Humulin once it hits the marketplace.”

One type of diabetic who may use Humulin, projects Fineberg, is the patient who has never before been treated with insulin. Many of these are new diabetics. Lilly estimates that the number of insulin-treated diabetics is growing at a rate of 5-6%/year, partially because more and more diabetics are being treated with insulin. But Lilly's initial target is the diabetic who is allergic to certain insulins, often the less-expensive beef and pork mixtures. Currently, 5% of the 2 million insulin-treated diabetics in the U.S. are allergic to these products. Diabetics who are allergic or resistant to treatments with beef and pork mixtures usually respond favorably to pure pork insulin. So too with Humulin, says Fineberg, who has conducted research on a variety of insulin products. But he believes that Humulin may be the superior treatment. Humulin, he says, appears to cause patients to recover more quickly from allergic symptoms “perhaps 20-30% faster.”

Worth it

Because of that effectiveness, Fineberg considers the expected price differential between Humulin and pure pork insulin to be insignificant. Humulin will probably cost about 5-10% more. But price considerations may play a more important role in the marketing of Squibb-Novo's new product, which is produced by adding a chemical step to the production process used to make pork insulin.

Essentially, Squibb changes porcine to human insulin by substituting one amino acid on the protein chain with another, namely threonine for alanine. Some analysts estimate the cost will be approximately 12% more than Humulin. Squibb-Novo, a joint venture of E. R. Squibb (Princeton, N.J.) and Danish drug maker Novo Industri, A/S, would not comment on its product, process, or production costs. But observers say Lilly's product may be less expensive because its recombinant DNA technology may provide economies of scale that would reduce costs eventually. And Lilly, which commands slightly more than 80% of the U.S. insulin market, already produces large volumes of the product.
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The Wall Street Journal
December 19, 1984
Denmark’s Novo Hits Trouble in Fast-Moving Biotechnology Industry, but Vows to Recoup
By Richard L. Hudson

BAGSVAERD, Denmark  –  In the futuristic lobby of Novo Industri AS sits a small computer. It is the Novo Professor, and at the press of a button its video screen tells about the company’s business, biotechnology, or its products, such as insulin.

But on one point, the Novo Professor is mute: What is wrong at Novo Industri?

After five years of rapid expansion, this Danish biotechnology company has hit rough sailing. Its sales growth, formerly averaging 28% annually, has slowed this year to 10%. Its market share  –  a third of the non-Communist world’s insulin sales, and more than 50% of industrial enzymes  –  is threatened by competitors. And its stock, once a favorite in New York and London hi-tech portfolios, has languished.

“It takes a brave man to buy” Novo’s stock nowadays, says Robin Gilbert, an analyst at James Capel & Co., a London brokerage house. ( Novo, whose price on the New York Stock Exchange peaked last year at $72.75 a share, closed yesterday at $24.375.)

What happened to Novo is common in the boom-and-bust biotechnology world. There are, by some estimates, about 200 companies that splice genes, manipulate microbes, or try in other ways to convert the biochemical and genetic discoveries of the past few decades into cash. Novo was one of the few European companies in the field to prosper. Last year, its pre-tax profit margin hit 28% of its approximately $300 million sales, and analysts forecast a glowing future.

But sustained success in biotechnology depends on being first. Novo, for once, was caught flat-footed. Its arch-competitor, Eli Lilly & Co. of Indianapolis, rushed out a new, genetically engineered insulin and poured on the marketing muscle, snatching sales. At the same time, Novo lost its edge in another market, when a major customer, Archer-Daniels-Midland Co., in Decatur, Ill., beat Novo at its own game and devised a way of making an industrial enzyme that ADM formerly bought from Novo.

Sales suffered, and Novo officials now predict pre-tax profit this year will only approximate last year’s, which soared 57% to about $86 million. (Net income was $63.5 million).

Novo says it isn’t out of the game. “We saw our growth checked this year very much due to some very specific problems” says the president, Mads Ovlisen, referring to Lilly and ADM. “There’s a lot of competition out there, and we intend to meet that competition.”

New products are in the works: a cheaper formula for insulin, tools to diagnose diabetes, a way to make better margarine. Novo also is broadening its business lines, and trying to polish its tarnished image in the stock market. Last month, top officers went on the road to court big investors and analysts in London and New York.

Whether Novo can rebound is important to Europe’s future in biotechnology. The company, begun in 1925 to manufacture a newly discovered hormone, insulin, is Europe’s biggest contender in a field dominated by such American companies as Genentech Inc. While some of the most important scientific discoveries behind biotechnology came from Europe, most of the products are from the U.S. The reasons are complex, but they include lack of funding for entrepreneurially minded scientists in Europe, and a longstanding aversion among many European researchers to big business.

Novo prospered by eluding such obstacles. When its growth was threatened by lack of funding in Denmark, it went elsewhere  –  first to London and the Eurobond market, then to the New York Stock Exchange, where it got its securities listed in 1981.

Novo also puts extra effort into luring good researchers. About 900 of its 4,200 employees are in research and development. It offers generous fringe benefits to all: free legal aid, free classes in English and public speaking, stock-purchase plans  –  even cut-rate rentals of about 30 vacation cottages around Denmark, Germany, Norway and Sweden.

More important, Novo bridges the social divide between scientists and marketers, focusing research on money-making products. It encourages its reseachers to jet around the world, visiting clients and discussing their needs. It offers courses in financial planning, to encourage bottomline thinking. When developing a product, it combines its researchers with marketers and production experts, in “ad hoc committees” that meet regularly to keep work focused. Novo even gets researchers, eager for promotion, money, or just a change of pace, to join the marketing staff  –  rare in Europe.

Rapid growth brought problems – burgeoning bureaucracy and management difficulties among them. Whatever the reasons, Novo was caught off-guard last year by setbacks in its insulin business, which accounted for 45% of total sales.

In 1982, Novo became the first company to mass-produce human insulin. Until then, almost all insulin administered to diabetics was extracted from pork or beef pancreas; some patients were allergic to the foreign substance. Novo developed an elegant technique using enzymes to convert pork insulin into human insulin, and it teamed up with Squibb Corp., of Princeton, N.J., to push the product in the big U.S. market. It was gaining fast on Eli Lilly, the dominant U.S. insulin maker.

Then Lilly introduced its own human insulin, a technologically more exotic product. At the same time, Lilly intensified its marketing efforts, snatching some hospital business. The result: the U.S. sales growth of Novo insulin slowed. Novo now “will have much greater difficulty maintaining its market share,” says David Dible, an investment analyst at Wood, Mackenzie & Co., an Edinburgh brokerage house.

But Novo hasn’t conceded defeat. It has applied for U.S. government approval to market another insulin type, and it is busy perfecting a third product that it claims will use an even more elegant  –  and less expensive  –  genetic process than Lilly.

But Novo also has problems in its second major business, industrial enzymes. In 1973, Novo developed a low-cost method to coax bacteria into secreting a special enzyme used in the soft-drink industry; the enzyme helps convert corn syrup into a sweetener cheaper than sugar. Although European sales of the sweetener were stifled by regulations protecting sugar growers, the product became a hit in the U.S.

When one of Novo’s biggest customers, ADM developed its own enzyme-making process, its purchases from Novo dwindled. Other companies still buy from Novo, and Mr. Ovlisen says he doesn’t plan to stop selling the enzyme or trying to improve it. But ADM’s move  –  which happened faster than Novo had anticipated  –  has lent extra urgency to Novo’s efforts to find new cash cows. New products, says Mr. Dible of Wood, Mackenzie, is now “the name of the game” for Novo.

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The Guardian, UK
March 22 1989
By James Erlichman

Human insulin may hold risks for diabetics

Human insulin, the first genetically engineered drug, is no better than conventional insulin treatment and may hold dangers for diabetics, says a government sponsored safety bulletin. The warning was published yesterday in Drug and Therapeutic Bulletin, a newsletter distributed to doctors by the Consumers’ Association.

“Human” insulin, made in fermentation vats by organisms inserted with the human insulin gene, was hailed as a breakthrough when launched in 1982.

The 250,000 diabetics in Britain were told they would suffer fewer allergic reactions if they switched to it from their conventional insulins derived from pigs and cattle. But Doctor Andrew Herxheimer, editor of the bulletin and a clinical pharmacologist at Charing Cross Hospital, West London, says additives to the human insulin can cause similar reactions.

Human insulin may also eliminate “early warning symptoms”, such as sweating, pins and needles and heart palpitations, which signal to diabetics that their blood sugar level is too low. This condition, called hypoglycaemia, is caused when the injected insulin works too well and reduces the sugar in a diabetic’s blood too quickly. With clear warning signals a diabetic can avert trouble by swallowing sugar quickly; without them the diabetic may suddenly become unconscious. 

Makers of genetically engineered human insulin are required to include a warning of this risk with each insulin vial sold in the United States but no warning is required in Britain.

Most diabetics have now been switched to human insulins by doctors who have been lobbied by the drug makers, Eli Lilly, Nov and Nordisk-Wellcome. The companies have spent millions of pounds investing in the product. Dr Herxheimer concludes, however, that “a general changeover to human insulins is inappropriate.”

The British Diabetic Association said it had received many reports of hypoglycaemia attacks from patients who had switched to human insulin. “We deplore the fact that a number of patients have been switched without their knowledge or consultation,” a spokesman said.
A spokesman for Eli Lilly, the largest insulin maker, said the company needed more time to respond to the claims.

- - - - -
The Economist
October 14, 1989





Eli Lilly woes

THINGS could hardly be worse of Eli Lilly, an American drug giant that makes genetically engineered human insulin, a drug for treating diabetes.  Reports by British doctors have associated at least 17 deaths among Britain’s 200,000 diabetics with such drugs, which are made by several manufacturers.  British health officials have put out a warning, but it is still unclear whether the drug may have to be withdrawn. 

Eli Lilly is not the only maker of this drug, but it is extremely bad news for the company.  Most of the adverse reactions to the human insulin were spotted in one produced by rival firm Novo/Nordisk.  Humulin, the brand name for Lilly’s version of the drug, accounts for only around 10% of the company’s $ 4 billion annual sales, but it hoped that the product would turn into a big earner.  Eli Lilly has been planning to build two new Humulin plants, one in America and the other in Europe, representing a $200 million capital investment.

Eli Lilly has few other potential block-buster products, apart from an anti-depressant known as Prozac.  In 1982 the company was forced to withdraw its anti-arthritic drug, Opren, after nearly 100 deaths among patients who had taken it.  Lilly is only now settling the liability claims that arose from the incident.

It is still not clear why Humulin may be harming diabetic patients.  One possibility is that the human form of insulin promotes a peculiar reaction in the diabetic patients.  But why, no one knows.  Another possibility is that the human insulin preparation is impure. 

Such a finding would do the company no favours.  Last month, America’s Food and Drug Administration (FDA) sharply criticised Eli Lilly for its quality control procedures and shut down a manufacturing plant at its headquarters in Indianapolis.  Ten of Eli Lilly’s drugs, which were made at the plant, have also been recalled.  Three other manufacturing plants are under FDA investigation.  Eli Lilly blames technical aberrations. 

The drugs industry is already going through a massive bout of reorganisation.  If Lilly’s share price falls too far it could find itself the next takeover target.
- - - - -
The Economist
October 21, 1989


Artificial insulin is now available as an alternative to insulin from animals

There are around 80 million people who suffer from diabetes. Insulin can keep them healthy. Artificial human insulin is now available as an alternative to insulin from animals. But is it a good alternative?

DR PATRICK TOSELAND, a senior and well-respected biochemist at Guy’s Hospital in London, believes he has made an alarming discovery. In the past 18 months he has been asked to investigate the deaths of 19 young diabetics. The deaths were unusual. They all happened suddenly. They all appeared to follow a rapid decline in blood sugar levels, known as hypoglycemia. It seems that all the diabetics had been using human insulin.

Death is all too frequent among diabetics. But Dr Toseland thinks that this sort of sudden hypoglycemic death in young diabetics is something new. Experts are beginning to wonder whether they should advise patients using human insulin to change their treatment. Patients have complained to the British Diabetic Association (BDA) that with human insulin the warning symptoms of hypoglycemia are lessened. The BDA is beginning a clinical investigation to find out what is going on.

In diabetes the mechanisms that control sugar levels in the blood go awry. Healthy people’s blood-sugar levels are balanced with the help of insulin, a hormone made from a short chain of molecules called amino acids. The insulin is produced by the pancreas and then passed to the liver. From the liver, a signal is passed to tissues elsewhere in the body, telling them to absorb sugar from the blood. Diabetics cannot make insulin, or they make it in insufficient amounts, or they make insulin that does not work. That is why many must inject themselves regularly with the hormone. Without it they would die.

Pigs and cattle used to be the source of insulin. Animal insulin is almost identical to human insulin: the two hormones differ in only one of their 51 amino acids. In 1982 Eli Lilly, the American pharmaceutical giant, marketed insulin made by bacteria which had a gene describing the human amino-acid sequence engineered into them. It was the first genetically engineered drug to reach the market. Novo-Nordisk, a company based in Denmark which has been making human insulin by a chemical transmutation of pig insulin, now also makes a genetically engineered insulin.

Human insulin offered three advantages. It provided a reliable supply; it was argued that with the growing numbers of diabetics, animal supplies would run out. It promised relief for those allergic to animal insulin. And it might curb the nasty reactions that occur during long-term treatment, side-effects which include blindness and sometimes death. These may be explained by the fact that the body’s immune system recognises the animal insulin as being foreign, and attacks it with antibodies.

Human insulin is now widely prescribed. In Britain about 80% of diabetics are now on the new drug, though since insulin is available over the counter some may have made the change without medical advice. The figure in America is around 60%. That is why Dr Toseland’s findings have caused such alarm.

His work has its problems. Hypoglycemia is difficult to detect in dead bodies; the sugar in the blood is rapidly destroyed. Dr Toseland has satisfactory blood-sugar data for only two of his 19 cases. In the others, he has had to rely on secondary signs of hypoglycemia such as acetone, which is produced when a sugar-starved body turns to fats and proteins for energy. And he does not include in his statistics cases where insulin concentrations in the blood are high; diabetics have died of hypoglycemia following insulin overdoses, both deliberately and by accident. He thinks that his findings give cause for concern.

The BDA points out that death among diabetics is quite common, and hypoglycemic deaths may have long gone by unnoticed. They may still be doing so. Only four other unexplained sudden deaths have been reported to the BDA this year. One case was reported several years ago in Switzerland. None has been seen in America.

Dr Toseland’s findings may reflect a change in the practice of British pathology. Post-mortems used to be conducted by a disparate group of clinical pathologists, but in the last few years the Home Office has preferred to use only a few, who are therefore in a better position to pick up disturbing trends. So Dr Toseland may have spotted a trend already there before human insulin came along. Or he may have spotted a new trend, but one which is not linked to the type of insulin used. Anyway, with so few people now using animal insulin, it will be hard to prove that the increase in deaths – if it really is occurring – is a problem exclusive to human insulin.

Novo-Nordisk believes an increase in deaths from sudden hypoglycemia might reflect changing practices among diabetics. Diabetics whose blood-sugar levels fluctuate widely seem more prone to long-term side-effects than those whose blood-sugar levels are maintained at concentrations found in healthy people. So doctors now recommend that diabetics try to control their blood-sugar levels more tightly, by having insulin steadily infused rather than injected, or by increasing the number of injections. When this is done the average concentration of glucose in the blood is kept low.

Recent research in West Germany has shown that patients are twice as likely to have a hypoglycemic attack if they are trying to regulate their blood-sugar levels particularly closely, presumably because they have smaller margins of error. With doctors’ help, patients can be taught to recognise a few tell-tale symptoms, such as sweating, which enable them to take timely action against hypoglycemia attacks.

Human, all too human

If it turns out that human insulin is more dangerous than the animal sort, scientists will probably reach for one of two theories. It may be that the antibodies with which the body reacts to animal insulin actually have a beneficial effect. In healthy people most of the insulin produced in the pancreas remains confined in the portal system of the liver, a fine network of blood capillaries. The hormone is rapidly soaked up, so it never reaches high levels elsewhere in the system. When insulin is injected, it floods the blood vessels in unnatural quantities. The antibodies might act to mitigate the effects of this insulin surge, toning it down. In a few patients antibodies are known to blunt the activity of insulin. The antibody response to human insulin is much smaller.

The second theory is more straightforward; the different properties could be the result of different chemistry. The amino acid which human insulin has and animal insulin lacks is attracted to water. It might make the hormone enter the body tissues more quickly than the animal sort does. That, too, could make the human insulin surge quicker and thus more dangerous.

Neither theory is compelling. Yet a case can be made for withdrawing the drug from the mass market where alternatives are available, albeit temporarily. According to Novo-Nordisk, recent research has shown that human insulin in fact offers no clinical benefits over the porcine and bovine sorts. Sugar levels, not antibodies, determine how healthy a diabetic will be. If the only benefit, then, of human insulin is to provide a reliable source of supply, doctors could shift back to prescribing animal insulin whilst data on the human sort are thoroughly sifted. That would hurt Eli Lilly and Novo-Nordisk, which have both made large investments in human insulin.

Whatever course of action the BDA and the Committee on the Safety of Medicines, Britain’s drug regulatory authority, eventually pursue, there is a more pressing problem. Frightened parents, on hearing reports of the deaths, threatened to stop injecting their children with the drug – thus putting them in mortal danger. This is why for the moment diabetics have been told to stick with their therapy.

- - - - -
The Wall Street Journal
October 30, 1989

Reports of Deaths Among U.K. Diabetics Using Human Insulin Stir Concern Here
By Bill Richards

Federal drug regulators, concerned over British reports that diabetics have died after shifting from animal to human-based insulin, say they are considering a study to see if similar deaths have occurred here.

The United Kingdom reports came from Dr. Patrick Toseland, head of clinical chemistry at Guy’s Hospital in London. In a telephone interview Friday, Dr. Toseland said the number of sudden, unexplained deaths of diabetics he had seen this year was 17 compared with just two in 1985. At least six of the deaths occurred among relatively young diabetics who had switched from animal to human insulin within the past year, he said.

Dr. Solomon Sobel, director of metabolism and endrocrine drug products for the U.S. Food and Drug Administration, said FDA officials have discussed Dr. Toseland’s findings “fairly intensively.” While there have been no reports of similar sudden unexplained deaths among diabetics in the U.S., Dr. Sobel said the FDA plans to examine Dr. Toseland’s evidence and is considering its own study here.

Dr. Toseland, a toxicologist, said he was preparing an article for a British forensic medical journal raising the possibility that the deaths may have occurred after human insulin blunted critical warning signs indicating hypoglycemia, or low blood sugar, which can kill diabetics.

The usual warning signs of hypoglycemia include sweating, anxiety and cramps. With proper warning, diabetics can easily raise their blood sugar to safe levels by eating sugar or sugary food. “The anecdotal data certainly shows that some of the people were not aware of the rapid onset of hypoglycemia,” Dr. Toseland said.

At the U.S. National Institutes of Health, Dr. Robert E. Silverman, chief of the diabetes program branch, said no evidence of unexpected deaths from hypoglycemia had shown up in a study of 1,500 diabetics that has been under way at NIH for five years. However, he said officials conducting the study hadn’t been looking for signs of problems related to hypoglycemia unawareness. “We are now monitoring for it much more closely,” he said.

“We do know there are slight differences in the way human and animal insulins drive down blood sugar,” Dr. Sobel said. The human-based drug starts the blood sugar dropping sooner and drives it down faster, he said. “But we don’t believe there is enough of a difference to be clinically significant,” Dr. Sobel said.

Reports of Dr. Toseland’s findings in the British press have triggered widespread concern among diabetics there. Both the British Diabetic Association and the Committee on Safety in Medicines  –  Britain’s equivalent of the U.S. FDA  –  recently issued statements noting the lack of hard scientific evidence to support Dr. Toseland’s findings. On Friday, the American Diabetes Association issued a similar statement urging the six million U.S. diabetics not to overreact to the British report.

“A loss of the warning symptoms of hypoglycemia is a complex problem that is very unlikely to be due simply to the type of insulin used,” the American association said.

The FDA already requires drug manufacturers to include warnings with insulin products that symptoms of hypoglycemia are less pronounced with human insulin than with animal-based products.

Eli Lilly & Co., the Indianapolis-based drug manufacturer, dominates the U.S. human insulin market with its product known as Humulin. Lilly is building plants to make the insulin in Indianapolis and Fagershein, France. In its latest annual report, Lilly said Humulin sales have shown “excellent growth.”

Lilly officials said they had seen reports of hypoglycemic unawareness among some patients making the shift from animal to human insulin, but didn’t know if the problem had caused any deaths. Dr. Leigh Thompson, a Lilly group vice president, said the company’s clinical trials of both its animal and human-based insulins indicated no difference in the level of hypoglycemia between users of either product.

Dr. Toseland said most of the British diabetics who died had been taking a human-based insulin made by Novo /Nordisk, a Danish manufacturer. None of the diabetics were using Lilly’s insulin.
- - - - -

The Washington Post
November 7, 1989

Concern in Britain About Human Insulin; U.S. Experts Wary of Diabetic Danger Reports
By Judith Randal

For the minority of diabetics who require insulin to control their blood sugar, the question is whether synthetically produced human insulin is better than insulin from pigs or cattle.

That question took on renewed urgency after reports from Britain potentially linking a small but sudden increase in deaths among diabetics to human insulin.

Pork insulin differs slightly from human insulin -by a single amino acid, a chemical building block of protein-and beef insulin differs by three amino acids. Logically, therefore, human insulin would seem to be the best choice. However, biochemist Patrick Toseland, director of clinical chemistry at Guy’s Hospital in London, has doubts.

Toseland investigates the deaths of diabetics at the request of pathologists throughout Britain. He became concerned when, in a recent 10-month period, there were seven sudden deaths in diabetics younger than 35, whereas four years earlier there had been no such deaths in this age group.

“Experienced pathologists were making comments to me like, ‘These are the first sudden deaths in young diabetics I’ve heard of in 30 years,’” Toseland recalled in an interview. “So I had to wonder if something unusual wasn’t happening.”

In 1987, Toseland found a Swiss study of human insulin reported in The Lancet, a British medical journal. The Swiss study caught his eye because the seven young British diabetics who had suddenly died had all recently switched from animal to human insulin. The Lancet article reported that 66 of 176 Swiss diabetics who had made the same switch had developed a condition known as “unaware hypoglycemia”.

Hypoglycemia means low blood sugar. Ordinarily, its onset is heralded by telltale symptoms such as hunger, anxiety, sweating, confusion, palpitations and poor coordination. Diabetics learn to correct it by promptly consuming glucose tablets or a sugar-rich juice, soft drink or food. But in the “unaware” variety, they may become comatose or even die because the warning signs of the attack are blunted or missing, giving them no chance to ward it off.

There is no hard proof, Toseland emphasized, that human insulin is any more likely than animal insulin to result in unaware hypoglycemia, but the timing of the seven sudden deaths of the young diabetics-besides some who were older-aroused suspicions.

As recently as 1985, more than 90 percent of the insulin sold in England was animal insulin, but at least three quarters of it is now human. That gave the recent deaths potentially more significance in Toseland’s view.

At the Food and Drug Administration, Solomon Sobel, director of metabolism and endocrine drug products, said that human insulin drives blood sugar levels down faster than animal insulin, which may explain the sudden deaths in England. But he said he does not know of any similar deaths in this country.

The FDA became aware of a potential problem, he added, when the Lancet article appeared in 1987. Last month, another article on the subject appeared in the British Medical Journal, intensifying the agency’s concern.

“We have now met with our epidemiologists,” said Sobel. “They and our biostatisticians will be analyzing several data bases so that we hope to have some idea by the end of the year of whether there is a real hazard {associated with human insulin }. If this doesn’t give us an answer, we may have to go to further studies.

“Toseland’s cases have attracted a good deal of attention from the British press, but they may be falsely alarming.”

One of the factors that complicates getting at the truth, said Sobel, is that sugar in blood and other tissues is rapidly destroyed after death. This can make it impossible to be sure that the sudden death of a diabetic was caused by hypoglycemia.

Further adding to the confusion is that suicides by deliberate overdoses of insulin, which induce hypoglycemia, are not unknown. Indeed, Toseland said, in the last 10 months four more young British diabetics who had been on human insulin died suddenly, but he excluded them from his statistics because of evidence suggesting that their deaths may have been intentional.

Perhaps most confusing of all is that the use of insulin has been changed in both Britain and the United States by a growing practice known as “tight control,” which consists of either steady infusions of insulin by an automatic pump or more frequent injections than were usual in the past.

Tight control evens out swings in a diabetic’s blood sugar levels, which are thought to contribute to the loss of vision, kidney failure, poor nerve function and blood vessel damage that are frequent long-term complications of the disease. A study of more than 1,400 patients in the United States and Canada is under way to determine whether the advantages of tight control as demonstrated by animal experiments also benefit people who have diabetes.

According to Robert Silverman, director of the diabetes program branch at the National Institutes of Health, which is funding the study, its results won’t be known until at least 1992. But it is already “well documented,” he said, “that some patients on tight control regimens become more prone to hypoglycemia, regardless of what type of insulin they take.”

So far, said Silverman, “there is no evidence from the study that human insulin contributes disproportionately to hypoglycemia, with or without warning signs. But since the study was begun in 1984-well before Toseland raised the issue-it was not designed to answer that question anyway.”

Silverman explained that the study focuses on blood sugar levels so that its patients have not been grouped by the kind of insulin they use. Indeed, the insulin regimens of many of them frequently change. “We’ve taken a preliminary look at our data and will be reviewing it more intensively in the next few weeks,” he said. “But I don’t think this will tell us definitely whether there is a problem with human insulin o

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Posted by Anonymous on 10 February 2009

This article only runs to 1989, not 1993

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