In the 1980s,
Then, in the 1990s, Lilly abandoned both its biotech and autoimmune efforts, only to watch biotech autoimmune medicines become some of the world's best-sellers.
So now, Lilly is trying to get back in the game.
As early as next month, Lilly will announce late-stage clinical trial results for two biotech drugs designed to slow the inflammation caused by autoimmune diseases, such as psoriasis and lupus, which occur when the body's immune system gets stuck in attack mode.
In addition, by the end of the year, Lilly will announce clinical trial results from a third non-biotech autoimmune medicine, for rheumatoid arthritis.
These drugs are Lilly's best shots at catching the second wave of autoimmune drugs. The first wave, which hit the market more than 15 years ago, produced four of the 10 best-selling drugs in the world. Humira, a biotech autoimmune drug made by
It's a drug Lilly would love have - in fact, a drug Lilly considered buying in the late 1990s. Humira this year will produce half as much revenue, by itself, as Lilly's entire business. Other drugs that are part of the first wave of autoimmune drugs, such as Enbrel and Remicade, had sales last year of nearly
"In hindsight, would we have liked to have been part of it? Yeah," said
A decade ago, Lilly acquired a company that has helped its researchers engineer the most complex proteins, called antibodies, into biotech drugs. Biotech drugs are made from proteins produced by strands of human DNA, and are often injected into patients. By contrast, the more common pill form of drugs are combined from various chemicals.
In the past five years, Lilly has invested billions of dollars and hired hundreds of scientists, clinicians and business personnel to ramp up an autoimmune business. Analysts aren't yet convinced the new generation of autoimmune drugs can match the spectacular sales of the older versions, like Humira. Two recent launches of autoimmune drugs -
Analysts say the autoimmune strategy makes sense for Lilly, which is searching high and low for drugs to replace Zyprexa and Cymbalta, which saw their main patents expire in 2011 and 2013. Each of those drugs had peak annual sales of
"Lilly, probably, will be a fast follower" in autoimmune drugs, said
In early, out early
That month, the
Also that year, Lilly started an autoimmune research group, to move past drugs like Oraflex - which helped relieve the symptoms of autoimmune disease - to medicines that actually slowed the progression of the disease.
But it wasn't to be.
Lilly had to pull Oraflex from the market after it was linked to dozens of deaths, and the company later pleaded guilty to criminal charges for failing to report the deaths to regulators.
Lilly executives urged their newly hired autoimmune researchers to find replacements for Oraflex, recalled
"We thought the science was breaking in the early 1980s," said Bumol, who is now Lilly's head of biotech and autoimmune research.
The research team tried hard for eight years to find non-biotech drugs to treat autoimmune diseases, but after no success the effort ended in the early 1990s, Bumol said.
In addition, despite several attempts, Lilly's biotech business never branched outside diabetes. Lilly paid
Hybritech alumni, many using the Lilly money the Hybritech sale brought them, went on to found at least 150 biotech companies, spawning the vibrant
But Lilly got little from the deal. It stopped researching biotech cancer drugs in 1991 and sold the Hybritech diagnostic business a few years later.
Instead, Lilly's executives streamlined their research and development efforts to focus on five areas: cardiovascular, cancer, neuroscience, diabetes and anti-infectives.
That focus was highly successful at the time, helping Lilly to launch blockbusters such as Gemzar, Zyprexa, Humalog and Evista.
Except for its diabetes research, Lilly continued to prefer drugs made from chemicals, also known as small molecules, rather than biotech drugs, which are also called biologics.
"Many people in Lilly, and in the industry, thought [in the early 1990s] that small molecules were the answer to all the problems," said Dr.
Roughly a year after Lilly halted its autoimmune research effort, researchers in
That breakthrough led to the first successful human trial of a biotech autoimmune drug, the results of which were announced in 1994 by
That drug, launched in 1998 as Remicade, became the first of the new wave of autoimmune drugs.
"That was the big tipping point, the big 'Aha!' moment," Bumol said of the work that led to Remicade.
Lilly had worked with Centocor to launch a cardiovascular biotech drug called ReoPro, in 1994. But the two companies never worked on autoimmune drugs.
Meanwhile, in the early 1990s, biotech drugs started to show they did not have to be merely niche products. In 1996, two biotech drugs sold by
The next year, Lilly relaunched its biotech effort, with Bumol, the autoimmune researcher, as its head.
Biotech drugs didn't attract as many patients as say, Prozac, Lilly's iconic anti-depressant. But they did command higher prices. Remicade, for example, costs typical patients more than
In the early biotech days, it wasn't clear that large numbers of patients and their insurance plans would pay such high prices.
That's why, when the company that created Humira - BASF Knoll - shopped it around to all the big pharma companies in the late 1990s, Lilly passed.
"We considered licensing Humira," recalled Dr.
But by 2004, the situation looked different. That year, Lilly paid
By that time, sales of the autoimmune drugs had done well. And scientists had made significant advances in understanding how the immune system works, which provided drug companies with lots of new ways to combat autoimmune diseases.
"It was realized that, although we were a biologics company, by dint of our insulins, we were at risk of really missing the boat on the biologics revolution," Paul said. While Lilly had worked with smaller proteins, called peptides, on its biotech insulin, it was not until the AME acquisition that it could work on the larger proteins, antibodies, which have become the most successful biotech drugs.
"We were a little late to the party, but I think we made up for it," Paul said, noting that more than half of the drugs in Lilly's pipeline today are biotechs.
One big advantage of biotech drugs is that they can be engineered to attach to specific targets in the body, increasing their effectiveness and decreasing side effects.
To fight autoimmune disease, drug companies try to attach biotech drugs to some of the myriad messenger molecules that help the body's white blood cells attack bacteria, fungi and other foreign substances.
The first wave of autoimmune drugs attached to an early messenger in the immune process, which is called tumor necrosis factor, or TNF. TNF helps white blood cells get out of the bloodstream and the lymphatic system, so they can attack infected cells. It also helps send out lots of other messengers to other cells to promote and coordinate an immune response.
Nearly all autoimmune patients have too much TNF, for reasons that are not well understood. The early drugs, by attaching themselves to TNF molecules, reduced the levels of TNF active in patients.
"The anti-TNF [drugs], they're a little bit more like carpet bombing, rather than going in and being more precise," said Dr. Eiry Roberts, Lilly's vice president of autoimmune product development,
That's why Humira, Remicade and their cousin drugs are effective in only about half the patients who take them.
The second-generation drugs Lilly and other companies are developing attach themselves to messengers in the immune system that act closer to the site of a disease.
For example, Lilly's drug for psoriasis, ixekizumab, attaches to a messenger protein called IL-17, which gets involved late in an immune response to a bacterial or fungal infection, and seems particularly active in skin cells.
Lilly's drug baricitinib attaches to molecules that help white blood cells translate the message delivered by a messenger. By blocking the translation, it blocks the immune response. Lilly is studying baricitinib for rheumatoid arthritis and diabetic kidney disease.
The company's third autoimmune drug in late-stage testing is tabalumab. It is being studied in patients with lupus, which causes inflammation all over the body and in various organs. The drug tries to slow this process by attaching to a key messenger involved in activating white blood cells produced in bone marrow.
Lilly thinks its drugs will help more patients and help them in more significant ways than early autoimmune drugs. For example, in previous tests, ixekizumab helped 80 percent of patients reduce the amount of inflammatory plaques on their skin by 75 percent.
Humira and Enbrel, by contrast, achieved that much reduction in 30 percent to 50 percent of patients.
"This is for real," said Ricks, Lilly's biomedicines executive. "This is a hg change."
The problem: Autoimmune diseases - such as rheumatoid arthritis, psoriasis, lupus, and Crohn's disease - occur when the body's a immune system stays in attack mode longer than it should.
How it happens: Anyone who survived high school biology knows white blood cells attack foreign substances that invade the body. These white blood cells use an elaborate array of messenger molecules to identify the correct attack site and which white blood cells should do the attacking, and to help those cells multiply rapidly. It's as if the U.S. military called in bomber strikes, not via satellite and radio signals, but using hundreds of couriers to tell bombers where to go, how many planes to send, and what kind of bombs to use.
The strategy: Drug companies are trying to control autoimmune diseases by attaching a drug to key messenger molecules. Because a courier with a drug attached has a different shape, it can no longer attach to other messengers, which breaks the communication chain.
Source: IBJ research
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