ICOS
Encyclopedia
Icos Corporation was the largest biotechnology
company in the U.S. state of Washington before it was sold to Eli Lilly and Company
in 2007. Co-founded in 1989 by George B. Rathmann, a pioneer in the industry and Chief Executive Officer (CEO) and co-founder of Amgen
, Icos focused on the development of drugs to treat inflammatory disorders. During its 17-year history, the company conducted clinical trial
s of twelve drugs, three of which reached the last phase of clinical trials. Icos also manufactured antibodies
for other biotechnology companies.
Icos is famous for tadalafil
(Cialis), a drug used to treat erectile dysfunction
. This drug was discovered by GlaxoSmithKline
, developed by Icos, and manufactured and marketed in partnership with Eli Lilly. Boosted by a unique advertising campaign led by the Grey Worldwide Agency, sales from Cialis allowed Icos to become profitable in 2006. Cialis was the only drug developed by the company to be approved. LeukArrest
, a drug to treat shock, and Pafase, developed for sepsis
, were both tested in phase III clinical trials, but testing was discontinued after unpromising results during the trials. Eli Lilly acquired Icos in January 2007, and most of Icos's workers were laid off
soon after. CMC Biopharmaceuticals, a Danish contract manufacturer
, bought the remnants of Icos and retained the remaining employees.
Icos was founded in 1989 by George Rathmann, Robert Nowinski, and Christopher Henney, each of whom had previously started another biotechnology company: Rathmann had created Amgen
; Nowinski had launched Genetic Systems, later sold to Bristol-Myers Squibb
; and Henney co-founded Immunex, later sold to Amgen
. Icos was formed with the goal of developing new drugs to treat the underlying causes of inflammatory diseases and halt the disease process in the early stages. The name Icos comes from icosahedron
, a 20-sided polyhedron
, which is the shape of many virus
es, and was chosen because the founders originally thought retrovirus
es might be involved in inflammation. The founders raised $33 million in July 1990 from many investors, including Bill Gates
– who at the time was the largest shareholder, with 10% of the equity
. The company initially had temporary offices in downtown Seattle, but moved to Bothell
in September 1990. Icos went public
on June 6, 1991, raising $36 million. George Rathmann, seen as a guiding father to Icos, left the company in February 2000, and was replaced as CEO and chairman by Paul Clark, a former executive at Abbott Laboratories
. A former Icos manager named short-sighted leadership by Clark as a factor in the failure of the company to develop any other successful drugs apart from Cialis.
(ED) and approved for pulmonary arterial hypertension (PAH). It is a phosphodiesterase type 5 (PDE5) inhibitor
, similar in function to Viagra
. In addition to ED and PAH, tadalafil has undergone clinical trials for the treatment of benign prostatic hyperplasia
and for female sexual dysfunction.
Tadalafil was initially formulated by Glaxo Wellcome (now GlaxoSmithKline
) under a new drug development partnership between Glaxo and Icos that began in August 1991. The drug was originally researched as a treatment for cardiovascular diseases such as hypertension and angina, but focus quickly shifted to ED with the success of another PDE5
inhibitor, sildenafil
(Viagra), which had been developed by Pfizer
. Icos began research on tadalafil in 1993, and clinical trials started two years later. Glaxo let the partnership with Icos lapse in 1996, including the company's 50% share of profits from resulting drugs, because the drugs in development were not in Glaxo's core markets. In 1998, Icos formed a 50/50 joint venture with Indianapolis
-based Eli Lilly
(Lilly Icos LLC) to develop and commercialize tadalafil as Cialis. The release of Cialis in the United States was delayed in April 2002 when the Food and Drug Administration (FDA) recommended that Icos perform more studies, improve labeling, and address manufacturing issues. Cialis was approved in Europe in November 2002 and in the United States a year later. The drug was approved for once-daily use for ED in Europe in June 2007 and in the United States in January 2008.
In 2006, Cialis generated $971 million in sales, leading Icos to post its first-ever quarterly profit in August. In May 2009, tadalafil, to be sold as Adcirca by United Therapeutics, was approved in the United States for the treatment of pulmonary arterial hypertension based on data from a pivotal study begun before the sale of Icos to Eli Lilly.
when the patent was issued. In the United States, Pfizer filed suit against Lilly Icos soon after receiving a broad US patent for PDE5 inhibitors in October 2002. The United States Patent and Trademark Office
ordered a reexamination of the patent, and, as in Britain, the examiner found that PDE5 inhibitors were not a new invention by Pfizer, voiding the patent. In Canada, Pfizer moved to block sales of Cialis five months after it was approved there, arguing that there could be consumer backlash against Pfizer should Cialis be pulled from the market months later as a result of an ongoing patent lawsuit. A federal judge refused, saying he could not "imagine demonstrations in the street or storming of the barricades because one impotence medicine is made unavailable".
, in 38 users of sildenafil and 5 users of tadalafil or vardenafil
(Levitra). Lilly Icos voluntarily amended the Cialis label to warn of the condition. The FDA was criticized for its handling of the matter, as an FDA safety officer had commented on unusual reports of blindness over 13 months before a journal article was published on the issue. United States Senator Chuck Grassley
wrote a letter to the FDA detailing his criticism, saying that the FDA's Office of New Drugs (OND) had taken no action "despite OND's knowledge of the blindness risks since January 2004 and general agreement among FDA staff last spring that the label should be updated". Grassley's letter also suggested that Pfizer resisted adding the blindness warning to Viagra's label. In July 2005, the FDA said that Viagra, Levitra, and Cialis labels would all carry warnings on the risk of sudden blindness, though it was unclear whether the drugs were actually causing the blindness.
Lilly Icos hired the Grey Worldwide Agency in New York, part of the Grey Global Group
, to run the Cialis advertising campaign. Cialis advertisements were described as being gentler, warmer and with a more relaxed feel than those of its rivals, to reflect the longer duration of the drug. (Tadalafil has a half-life
of 17.5 hours, compared to 3.5 for sildenafil and 4.5 for vardenafil.) Iconic themes in Cialis advertisements include couples in bathtubs and the slogan "When the moment is right, will you be ready?" Cialis advertisements were unique among those of ED drugs in that they went beyond describing ED and mentioning the drug's benefits. As a result, Cialis advertisements were also the first to describe side effects
, as the FDA requires advertisements in support of a specific brand name to mention side effects; ads for Levitra and Viagra did not mention the brand name of the drug, therefore circumventing this FDA requirement. One of the first advertisements for Cialis aired during the 2004 Super Bowl
; Lilly Icos paid more than $4 million for the one-minute ad. Just weeks before the game, the FDA required more possible side effects, including priapism
, to be listed in the advertisement. Although many parents objected to the ad being aired during the Super Bowl, Janet Jackson
's halftime "wardrobe malfunction
" overshadowed Cialis. In January 2006, a physician was added to the advertisements to describe side effects on-screen, and Icos began running advertisements only where more than 90 percent of the audience was made up of adults, effectively ending Super Bowl advertisements. In 2004, Lilly Icos, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively.
, multiple sclerosis
, ischemic stroke, heart attack, pancreatitis
, pulmonary arterial hypertension, chronic obstructive pulmonary disease
, interstitial cystitis
, psoriasis
, hemorrhagic shock, sexual dysfunction
, benign prostatic hyperplasia
, rheumatoid arthritis
, emphysema
, chronic bronchitis
, and acute respiratory distress syndrome
.
s to the site of inflammation. During testing, few patients were given the drug, because LeukArrest had to be administered within four hours of the injury and informed consent
was required; patients were often unconscious, and relatives had to be reached to give consent. In June 1998, Icos and many medical centers asked the FDA to waive consent requirements in situations where the patient was at high risk of dying and relatives could not be reached. While some medical ethicists opposed waiving consent, the FDA approved the proposal in August 1998 for five medical centers. Development of LeukArrest was halted in April 2000 when interim data from phase III clinical trials did not meet Icos's goals of significantly reducing the chance of multiple organ failure
and reducing the death rate from shock at 28 days. LeukArrest was also tested unsuccessfully for treatment of heart attack
, multiple sclerosis
, and stroke
.
. Pafase is the recombinant
form of platelet-activating factor acetylhydrolase (PAF-AH, also known as lipoprotein-associated phospholipase A2
), an enzyme
made naturally by macrophage
s and found in human blood. PAF-AH inactivates platelet-activating factor
, a phospholipid
that plays a role in the inflammation seen in sepsis. The enzyme was discovered in the mid-1980s by graduate student Diana Stafforini and researchers Steve Prescott, Guy Zimmerman, and Tom McIntyre at the University of Utah
. The gene
that codes for Pafase was discovered by Icos. Early trials for sepsis showed that the drug reduced the death rate after 28 days and patients were less likely to develop severe respiratory problems. Icos also tested Pafase for acute respiratory distress syndrome
(ARDS). In phase II trials for ARDS, Pafase reduced the death rate after 28 days and reduced the chance that the lungs of the patient would fail. However, Icos halted development in December 2002 when interim data from phase III trials for sepsis showed that the drug did not help patients survive. Scientists at Northwestern University
later studied Pafase for necrotizing enterocolitis
, and there is ongoing research on the enzyme for atherosclerosis
at the University of Utah.
s for use in the areas of pulmonary hypertension
and chronic heart failure. Two drugs, sitaxentan sodium (also spelled sitaxsentan) and TBC3711, were tested in clinical trials under the partnership. Sitaxentan was designed to treat pulmonary arterial hypertension, and TBC3711 was designed to treat cardiovascular disease
s such as hypertension. In April 2003, Icos sold its part of the 50/50 partnership, including any share of sitaxentan and TBC3711, to Texas Biotechnology for $4 million at closing and another $6 million within 18 months. Sitaxentan sodium was later approved in Europe, Canada, and Australia, and was marketed under the brand name Thelin. In 2010, Thelin was voluntarily withdrawn from the market worldwide due to concerns about irreversible liver damage.
to manufacture a class of GPC's antibodies that targeted B-cell lymphoma
s. In January 2002, Icos signed an agreement with Eos Biotechnology, under which Icos would produce Eos's most promising monoclonal antibody candidate, and Eos would have non-exclusive rights to Icos's CHEF1 enhanced mammalian protein expression
technology. Eos's antibody inhibited angiogenesis
(the formation of new blood vessel
s) and was being researched as a treatment for solid tumor
s. In October 2003, Icos partnered with Protein Design Labs to manufacture their M200 antibody.
After Icos's experimental drugs failed in clinical trials, Eli Lilly was in a prime position to purchase the company. In October 2006, Eli Lilly announced that it had reached terms to acquire Icos for $2.1 billion, or $32 a share. After receiving pressure from large institutional shareholders as well as proxy advisory firm Institutional Shareholder Services (ISS) suggesting the deal should be rejected, Lilly increased its offer to $2.3 billion or $34 per share, a 6% increase. Again, resistance was voiced by some large shareholders, and ISS advised shareholders against accepting the new offer, which it still deemed insufficient. On January 25, 2007, at a special meeting, 77% of the shareholders voted in support of the acquisition. Eli Lilly closed the transaction to acquire Icos for $2.3 billion on January 29, 2007.
As a result of the acquisition, Eli Lilly gained complete ownership of Cialis, and promptly shut down Icos operations and laid off Icos personnel, except for 127 employees working at the biologics facility. Icos was the largest biotechnology company in the state of Washington at the time of the acquisition, and employed around 700 people. In December 2007, CMC Biopharmaceuticals A/S
, a Copenhagen
-based provider of contract biomanufacturing services, bought the Bothell biologics facility and retained the existing 127 employees.
Senior executives at Icos received cash payments worth a combined $67.8 million for selling the company to Eli Lilly. Icos chairman, chief executive, and president Paul Clark received "a 'golden parachute
' worth $23.2 million in severance pay
, cashed-out stock options, restricted stock awards and other bonuses for retention and closing the deal." Nine senior Icos executives received similar packages, each worth more than $1 million.
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...
company in the U.S. state of Washington before it was sold to Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
in 2007. Co-founded in 1989 by George B. Rathmann, a pioneer in the industry and Chief Executive Officer (CEO) and co-founder of Amgen
Amgen
Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
, Icos focused on the development of drugs to treat inflammatory disorders. During its 17-year history, the company conducted clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s of twelve drugs, three of which reached the last phase of clinical trials. Icos also manufactured antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
for other biotechnology companies.
Icos is famous for tadalafil
Tadalafil
Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
(Cialis), a drug used to treat erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
. This drug was discovered by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
, developed by Icos, and manufactured and marketed in partnership with Eli Lilly. Boosted by a unique advertising campaign led by the Grey Worldwide Agency, sales from Cialis allowed Icos to become profitable in 2006. Cialis was the only drug developed by the company to be approved. LeukArrest
Rovelizumab
Rovelizumab, also known as LeukArrest and Hu23F2G, is a humanized monoclonal antibody which was an experimental immunosuppressive drug. Rovelizumab was developed by Icos to treat patients suffering from haemorrhagic shock. The drug is a monoclonal antibody that suppresses white blood cells which...
, a drug to treat shock, and Pafase, developed for sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
, were both tested in phase III clinical trials, but testing was discontinued after unpromising results during the trials. Eli Lilly acquired Icos in January 2007, and most of Icos's workers were laid off
Layoff
Layoff , also called redundancy in the UK, is the temporary suspension or permanent termination of employment of an employee or a group of employees for business reasons, such as when certain positions are no longer necessary or when a business slow-down occurs...
soon after. CMC Biopharmaceuticals, a Danish contract manufacturer
Contract manufacturer
A contract manufacturer is a manufacturer that contracts with a firm for components or products. It is a form of outsourcing.-Business model:...
, bought the remnants of Icos and retained the remaining employees.
History
Amgen
Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
; Nowinski had launched Genetic Systems, later sold to Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
; and Henney co-founded Immunex, later sold to Amgen
Amgen
Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
. Icos was formed with the goal of developing new drugs to treat the underlying causes of inflammatory diseases and halt the disease process in the early stages. The name Icos comes from icosahedron
Icosahedron
In geometry, an icosahedron is a regular polyhedron with 20 identical equilateral triangular faces, 30 edges and 12 vertices. It is one of the five Platonic solids....
, a 20-sided polyhedron
Polyhedron
In elementary geometry a polyhedron is a geometric solid in three dimensions with flat faces and straight edges...
, which is the shape of many virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es, and was chosen because the founders originally thought retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
es might be involved in inflammation. The founders raised $33 million in July 1990 from many investors, including Bill Gates
Bill Gates
William Henry "Bill" Gates III is an American business magnate, investor, philanthropist, and author. Gates is the former CEO and current chairman of Microsoft, the software company he founded with Paul Allen...
– who at the time was the largest shareholder, with 10% of the equity
Ownership equity
In accounting and finance, equity is the residual claim or interest of the most junior class of investors in assets, after all liabilities are paid. If liability exceeds assets, negative equity exists...
. The company initially had temporary offices in downtown Seattle, but moved to Bothell
Bothell, Washington
Bothell is a city located in King and Snohomish Counties in the state of Washington. It is part of the Seattle metropolitan area. The population was 33,505 as of the 2010 census...
in September 1990. Icos went public
Initial public offering
An initial public offering or stock market launch, is the first sale of stock by a private company to the public. It can be used by either small or large companies to raise expansion capital and become publicly traded enterprises...
on June 6, 1991, raising $36 million. George Rathmann, seen as a guiding father to Icos, left the company in February 2000, and was replaced as CEO and chairman by Paul Clark, a former executive at Abbott Laboratories
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
. A former Icos manager named short-sighted leadership by Clark as a factor in the failure of the company to develop any other successful drugs apart from Cialis.
Cialis
Sold as Cialis and initially codenamed IC351, tadalafil is a drug prescribed for erectile dysfunctionErectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
(ED) and approved for pulmonary arterial hypertension (PAH). It is a phosphodiesterase type 5 (PDE5) inhibitor
PDE5 inhibitor
A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis...
, similar in function to Viagra
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
. In addition to ED and PAH, tadalafil has undergone clinical trials for the treatment of benign prostatic hyperplasia
Benign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....
and for female sexual dysfunction.
Tadalafil was initially formulated by Glaxo Wellcome (now GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
) under a new drug development partnership between Glaxo and Icos that began in August 1991. The drug was originally researched as a treatment for cardiovascular diseases such as hypertension and angina, but focus quickly shifted to ED with the success of another PDE5
CGMP specific phosphodiesterase type 5
cGMP-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina....
inhibitor, sildenafil
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(Viagra), which had been developed by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
. Icos began research on tadalafil in 1993, and clinical trials started two years later. Glaxo let the partnership with Icos lapse in 1996, including the company's 50% share of profits from resulting drugs, because the drugs in development were not in Glaxo's core markets. In 1998, Icos formed a 50/50 joint venture with Indianapolis
Indianapolis
Indianapolis is the capital of the U.S. state of Indiana, and the county seat of Marion County, Indiana. As of the 2010 United States Census, the city's population is 839,489. It is by far Indiana's largest city and, as of the 2010 U.S...
-based Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
(Lilly Icos LLC) to develop and commercialize tadalafil as Cialis. The release of Cialis in the United States was delayed in April 2002 when the Food and Drug Administration (FDA) recommended that Icos perform more studies, improve labeling, and address manufacturing issues. Cialis was approved in Europe in November 2002 and in the United States a year later. The drug was approved for once-daily use for ED in Europe in June 2007 and in the United States in January 2008.
In 2006, Cialis generated $971 million in sales, leading Icos to post its first-ever quarterly profit in August. In May 2009, tadalafil, to be sold as Adcirca by United Therapeutics, was approved in the United States for the treatment of pulmonary arterial hypertension based on data from a pivotal study begun before the sale of Icos to Eli Lilly.
Lawsuits with Pfizer
Pfizer and Lilly Icos have filed many lawsuits against each other in various countries over Cialis and Viagra. Pfizer was given a broad patent on PDE5 inhibitors in Britain in 1993. Lilly Icos filed a complaint in a London court in September 1999, and the patent was overturned in November 2000 on the grounds that Pfizer's patent was based on information already in the public domainPublic domain
Works are in the public domain if the intellectual property rights have expired, if the intellectual property rights are forfeited, or if they are not covered by intellectual property rights at all...
when the patent was issued. In the United States, Pfizer filed suit against Lilly Icos soon after receiving a broad US patent for PDE5 inhibitors in October 2002. The United States Patent and Trademark Office
United States Patent and Trademark Office
The United States Patent and Trademark Office is an agency in the United States Department of Commerce that issues patents to inventors and businesses for their inventions, and trademark registration for product and intellectual property identification.The USPTO is based in Alexandria, Virginia,...
ordered a reexamination of the patent, and, as in Britain, the examiner found that PDE5 inhibitors were not a new invention by Pfizer, voiding the patent. In Canada, Pfizer moved to block sales of Cialis five months after it was approved there, arguing that there could be consumer backlash against Pfizer should Cialis be pulled from the market months later as a result of an ongoing patent lawsuit. A federal judge refused, saying he could not "imagine demonstrations in the street or storming of the barricades because one impotence medicine is made unavailable".
Blindness warning on label
In May 2005, the FDA began investigating reports of sudden blindness in users of sildenafil (Viagra). The FDA said it had received reports of the condition, a permanent blindness in one eye known as non-arteritic anterior ischemic optic neuropathyAnterior ischemic optic neuropathy
Anterior ischemic optic neuropathy is a medical condition involving loss of vision due to damage to the optic nerve from insufficient blood supply. AION is generally divided into two types: arteritic AION and non-arteritic AION...
, in 38 users of sildenafil and 5 users of tadalafil or vardenafil
Vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
(Levitra). Lilly Icos voluntarily amended the Cialis label to warn of the condition. The FDA was criticized for its handling of the matter, as an FDA safety officer had commented on unusual reports of blindness over 13 months before a journal article was published on the issue. United States Senator Chuck Grassley
Chuck Grassley
Charles Ernest "Chuck" Grassley is the senior United States Senator from Iowa . A member of Republican Party, he previously served in the served in the United States House of Representatives and the Iowa state legislature...
wrote a letter to the FDA detailing his criticism, saying that the FDA's Office of New Drugs (OND) had taken no action "despite OND's knowledge of the blindness risks since January 2004 and general agreement among FDA staff last spring that the label should be updated". Grassley's letter also suggested that Pfizer resisted adding the blindness warning to Viagra's label. In July 2005, the FDA said that Viagra, Levitra, and Cialis labels would all carry warnings on the risk of sudden blindness, though it was unclear whether the drugs were actually causing the blindness.
Marketing
Grey Global Group
Grey Group is a global advertising and marketing agency, whose slogan is providing solutions - with headquarters in New York City, and 432 offices in 96 countries, operating in 154 cities — organized into four geographical units: North America; Europe, Middle East & Africa, Asia-Pacific and Latin...
, to run the Cialis advertising campaign. Cialis advertisements were described as being gentler, warmer and with a more relaxed feel than those of its rivals, to reflect the longer duration of the drug. (Tadalafil has a half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of 17.5 hours, compared to 3.5 for sildenafil and 4.5 for vardenafil.) Iconic themes in Cialis advertisements include couples in bathtubs and the slogan "When the moment is right, will you be ready?" Cialis advertisements were unique among those of ED drugs in that they went beyond describing ED and mentioning the drug's benefits. As a result, Cialis advertisements were also the first to describe side effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
, as the FDA requires advertisements in support of a specific brand name to mention side effects; ads for Levitra and Viagra did not mention the brand name of the drug, therefore circumventing this FDA requirement. One of the first advertisements for Cialis aired during the 2004 Super Bowl
Super Bowl XXXVIII
Super Bowl XXXVIII was an American football game played on February 1, 2004 at Reliant Stadium in Houston, Texas to decide the National Football League champion following the 2003 regular season....
; Lilly Icos paid more than $4 million for the one-minute ad. Just weeks before the game, the FDA required more possible side effects, including priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
, to be listed in the advertisement. Although many parents objected to the ad being aired during the Super Bowl, Janet Jackson
Janet Jackson
Janet Damita Jo Jackson is an American recording artist and actress. Known for a series of sonically innovative, socially conscious and sexually provocative records, as well as elaborate stage shows, television and film roles, she has been a prominent figure in popular culture for over 25 years...
's halftime "wardrobe malfunction
Super Bowl XXXVIII halftime show controversy
Super Bowl XXXVIII, which was broadcast live on February 1, 2004 from Houston, Texas on the CBS television network in the United States, was noted for a controversial halftime show in which Janet Jackson's breast, adorned with a nipple shield, was exposed by Justin Timberlake for about half a...
" overshadowed Cialis. In January 2006, a physician was added to the advertisements to describe side effects on-screen, and Icos began running advertisements only where more than 90 percent of the audience was made up of adults, effectively ending Super Bowl advertisements. In 2004, Lilly Icos, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively.
Miscellaneous drugs
Icos developed several drugs whose purpose was to disrupt the process of inflammation in the body. The research program focused on the underlying causes of inflammation rather than specific disorders. The compounds developed by Icos were tested in clinical trials in the areas of sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, ischemic stroke, heart attack, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
, pulmonary arterial hypertension, chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...
, interstitial cystitis
Interstitial cystitis
Interstitial cystitis or bladder pain syndrome is a chronic, oftentimes severely debilitating disease of the urinary bladder...
, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, hemorrhagic shock, sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
, benign prostatic hyperplasia
Benign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....
, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
, chronic bronchitis
Chronic bronchitis
Chronic bronchitis is a chronic inflammation of the bronchi in the lungs. It is generally considered one of the two forms of chronic obstructive pulmonary disease...
, and acute respiratory distress syndrome
Acute respiratory distress syndrome
Acute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
.
LeukArrest
Rovelizumab, trade-named LeukArrest and also known as Hu23F2G, was developed to treat patients suffering from hemorrhagic shock, which is caused by massive blood loss. The drug is a monoclonal antibody that inhibits the recruitment of white blood cellWhite blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s to the site of inflammation. During testing, few patients were given the drug, because LeukArrest had to be administered within four hours of the injury and informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...
was required; patients were often unconscious, and relatives had to be reached to give consent. In June 1998, Icos and many medical centers asked the FDA to waive consent requirements in situations where the patient was at high risk of dying and relatives could not be reached. While some medical ethicists opposed waiving consent, the FDA approved the proposal in August 1998 for five medical centers. Development of LeukArrest was halted in April 2000 when interim data from phase III clinical trials did not meet Icos's goals of significantly reducing the chance of multiple organ failure
Multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome ', previously known as multiple organ failure or multisystem organ failure , is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis...
and reducing the death rate from shock at 28 days. LeukArrest was also tested unsuccessfully for treatment of heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
.
Pafase
Pafase, also known as rPAF-AH, was developed to treat severe sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
. Pafase is the recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
form of platelet-activating factor acetylhydrolase (PAF-AH, also known as lipoprotein-associated phospholipase A2
Lipoprotein-associated phospholipase A2
Lipoprotein-associated phospholipase A2 also known as platelet-activating factor acetylhydrolase is a phospholipase A2 enzyme that in humans is encoded by the PLA2G7 gene. Lp-PLA2 is a 45-kDa protein of 441 amino acids.- Function :In the blood it travels mainly with low-density lipoprotein...
), an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
made naturally by macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s and found in human blood. PAF-AH inactivates platelet-activating factor
Platelet-activating factor
Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC is a potent phospholipid activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis...
, a phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
that plays a role in the inflammation seen in sepsis. The enzyme was discovered in the mid-1980s by graduate student Diana Stafforini and researchers Steve Prescott, Guy Zimmerman, and Tom McIntyre at the University of Utah
University of Utah
The University of Utah, also known as the U or the U of U, is a public, coeducational research university in Salt Lake City, Utah, United States. The university was established in 1850 as the University of Deseret by the General Assembly of the provisional State of Deseret, making it Utah's oldest...
. The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that codes for Pafase was discovered by Icos. Early trials for sepsis showed that the drug reduced the death rate after 28 days and patients were less likely to develop severe respiratory problems. Icos also tested Pafase for acute respiratory distress syndrome
Acute respiratory distress syndrome
Acute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
(ARDS). In phase II trials for ARDS, Pafase reduced the death rate after 28 days and reduced the chance that the lungs of the patient would fail. However, Icos halted development in December 2002 when interim data from phase III trials for sepsis showed that the drug did not help patients survive. Scientists at Northwestern University
Northwestern University
Northwestern University is a private research university in Evanston and Chicago, Illinois, USA. Northwestern has eleven undergraduate, graduate, and professional schools offering 124 undergraduate degrees and 145 graduate and professional degrees....
later studied Pafase for necrotizing enterocolitis
Necrotizing enterocolitis
Necrotizing enterocolitis is a medical condition primarily seen in premature infants, where portions of the bowel undergo necrosis .-Signs and symptoms:...
, and there is ongoing research on the enzyme for atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
at the University of Utah.
Sitaxentan sodium and TBC3711
In June 2000, Icos and Texas Biotechnology formed a 50/50 partnership to research endothelin receptor antagonistEndothelin receptor antagonist
A endothelin receptor antagonist is a drug that blocks endothelin receptors.Three main kinds of ERAs exist:* selective ETA receptor antagonists , which affect endothelin A receptors....
s for use in the areas of pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
and chronic heart failure. Two drugs, sitaxentan sodium (also spelled sitaxsentan) and TBC3711, were tested in clinical trials under the partnership. Sitaxentan was designed to treat pulmonary arterial hypertension, and TBC3711 was designed to treat cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
s such as hypertension. In April 2003, Icos sold its part of the 50/50 partnership, including any share of sitaxentan and TBC3711, to Texas Biotechnology for $4 million at closing and another $6 million within 18 months. Sitaxentan sodium was later approved in Europe, Canada, and Australia, and was marketed under the brand name Thelin. In 2010, Thelin was voluntarily withdrawn from the market worldwide due to concerns about irreversible liver damage.
Other drugs tested in clinical trials
Icos tested many other drugs that were not approved. They are:- ICM3, an antibodyAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
blocking ICAM-3ICAM3Intercellular adhesion molecule 3 also known as CD50 , is a human gene.-Interactions:ICAM3 has been shown to interact with EZR and Moesin.-Further reading:...
, designed to treat psoriasisPsoriasisPsoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
. - IC14, an antibody blocking CD14CD14Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form...
, designed to treat sepsisSepsisSepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
. - IC747 and IC776, two LFA-1 antagonists, designed to treat psoriasis.
- ResiniferatoxinResiniferatoxinResiniferatoxin is a naturally occurring, ultrapotent capsaicin analog that activates the vanilloid receptor in a subpopulation of primary afferent sensory neurons involved in nociception...
(RTX), a naturally occurring capsaicinCapsaicinCapsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
analog, designed to treat interstitial cystitisInterstitial cystitisInterstitial cystitis or bladder pain syndrome is a chronic, oftentimes severely debilitating disease of the urinary bladder...
. - IC485, a PDE4 inhibitorPDE4 inhibitorA phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 on cyclic adenosine monophosphate . It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in...
, designed to treat emphysemaEmphysemaEmphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
, chronic bronchitisChronic bronchitisChronic bronchitis is a chronic inflammation of the bronchi in the lungs. It is generally considered one of the two forms of chronic obstructive pulmonary disease...
, chronic obstructive pulmonary diseaseChronic obstructive pulmonary diseaseChronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...
, and rheumatoid arthritisRheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. - IC83, a CHK-1CHEK1Serine/threonine-protein kinase Chk1 is an enzyme that in humans is encoded by the CHEK1 gene.Chk1 is a kinase that phosphorylates cdc25, an important phosphatase in cell cycle control, particularly for entry into mitosis. Cdc25, when phosphorylated on serine 216 by chk1 becomes bound by an adaptor...
inhibitor, designed to enhance chemotherapyChemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
Manufacturing
Icos manufactured many antibodies for various companies. In August 2001, the company partnered with Seattle Genetics to manufacture a component of their top experimental antibody drug SGN-15. In November 2001, Icos signed a production agreement with GPC BiotechGPC Biotech
GPC Biotech is a German biopharmaceutical company. The company's mission statement reads "... to discover, develop and commercialize new anticancer drugs."...
to manufacture a class of GPC's antibodies that targeted B-cell lymphoma
B-cell lymphoma
The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph glands. They develop more frequently in older adults and in immunocompromised individuals ....
s. In January 2002, Icos signed an agreement with Eos Biotechnology, under which Icos would produce Eos's most promising monoclonal antibody candidate, and Eos would have non-exclusive rights to Icos's CHEF1 enhanced mammalian protein expression
Protein expression
Protein expression is a subcomponent of gene expression. It consists of the stages after DNA has been translated into polypeptide chains, which are ultimately folded into proteins...
technology. Eos's antibody inhibited angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
(the formation of new blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s) and was being researched as a treatment for solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s. In October 2003, Icos partnered with Protein Design Labs to manufacture their M200 antibody.
Acquisition by Eli Lilly
As a result of the acquisition, Eli Lilly gained complete ownership of Cialis, and promptly shut down Icos operations and laid off Icos personnel, except for 127 employees working at the biologics facility. Icos was the largest biotechnology company in the state of Washington at the time of the acquisition, and employed around 700 people. In December 2007, CMC Biopharmaceuticals A/S
Aktieselskab
An aktieselskab is the Danish name for a stock-based corporation. An aktieselskab can be both publicly traded and private.-Liability:...
, a Copenhagen
Copenhagen
Copenhagen is the capital and largest city of Denmark, with an urban population of 1,199,224 and a metropolitan population of 1,930,260 . With the completion of the transnational Øresund Bridge in 2000, Copenhagen has become the centre of the increasingly integrating Øresund Region...
-based provider of contract biomanufacturing services, bought the Bothell biologics facility and retained the existing 127 employees.
Controversy
In addition to the layoff of Icos employees, other aspects of the acquisition were equally controversial, such as assertions that Icos was being sold too cheaply and that conflicts of interest existed. The latter related to Icos senior executives, who – despite poor stock performance, in part from failed clinical development programs and an inability to successfully license drugs over the preceding years – were to be massively compensated upon a successful acquisition.Senior executives at Icos received cash payments worth a combined $67.8 million for selling the company to Eli Lilly. Icos chairman, chief executive, and president Paul Clark received "a 'golden parachute
Golden parachute
A golden parachute is an agreement between a company and an employee specifying that the employee will receive certain significant benefits if employment is terminated. Sometimes, certain conditions, typically a change in company ownership, must be met, but often the cause of termination is...
' worth $23.2 million in severance pay
Severance package
A severance package is pay and benefits an employee receives when they leave employment at a company. In addition to the employee's remaining regular pay, it may include some of the following:* An additional payment based on months of service...
, cashed-out stock options, restricted stock awards and other bonuses for retention and closing the deal." Nine senior Icos executives received similar packages, each worth more than $1 million.
See also
- Drug developmentDrug developmentDrug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
- Eli Lilly controversiesEli Lilly controversiesEli Lilly and Company is a global pharmaceutical company and one of the world's largest corporations. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
- Pharmaceutical industry