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Recycled drugs: failed antidepressants-- Stratera marketed for ADHD; Cymbalta for incontinence

Mon, 26 Apr 2004

A front page article in The Wall Street Journal (excerpt below) provides a roadmap of failed Eli Lilly drugs which the company repackaged for a different condition than the one for which the drugs had been tested in clinical trials, or to expand the market for drugs that don't bring in enough profits when marketed for a particular condition.

The Journal notes: "Lilly has long had a culture that looks at failure as an inevitable part of discovery and encourages scientists to take risks. If a new drug doesn't work out for its intended use, Lilly scientists are taught to look for new uses for a drug."

The Journal lists 8 failed Lilly drugs that were recycled or in the process of being recycled. Among the drugs that bombed are two antidepressants that have been repackaged.

Strattera and Cymbalta are antidepressants of the selective norepinephrine reuptake inhibitor (SNRI) class. In clinical trials Strattera had failed as an antidepressant, but is now a hot-selling drug euphemistically marketed as a "non-stimulant" treatment for ADHD.

Cymbalta (duloxetine), a potent dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine also failed in its original antidepressant trials. It is now being tested for incontinence at higher doses.

The recycling of these failed antidepressants raises concerns because of evidence-from previously concealed clinical trial data and from a large number of case reports--all indicating that the newer generation of antidepressants can trigger serious adverse symptoms that can lead to life-threatening behavior in some patients. These unwanted effects include: movement disorders, withdrawal symptoms, mania, depression, hallucinations, agitation, aggressiveness, anxiety, psychosis, akathisia, and violent or suicidal behavior.

The FDA had evidence of these drugs' adverse effects for years but failed to warn prescribing physicians and the public. For example, a "confidential" October 1996 memo FDA's Dr. Thomas Laughren referred to an analysis by Dr. James Knudsen, FDA's own medical officer of four Zoloft (sertraline) pediatric trials:

"Dr. Knudsen provided person-time data only for the sertraline exposed patients, yielding adjusted estimates of 0.035/ PEY [patient exposure years] for adults and 0.25 /PEY for pediatric patients. He commented on the 7-fold greater incidence of Suicidality in children taking sertraline compared to adults." In this memo (obtained under Freedom of Information) Dr. Laughren acknowledges that 6 children in those Zoloft trials who were on the drug became suicidal.

On March 22, 2004 the agency issued a warning advisory about antidepressant drug risks only after it was learned that senior FDA officials had suppressed the release of an analysis by FDA's leading expert. That report, by Dr. Andrew Mosholder, validates the safety concerns and the unfavorable risk / benefit ratio of antidepressants for children.

Strattera is an SNRI--the same class of drugs as Effexor, whose manufacturer, Wyeth, issued a clear warning about the suicidal risk, advising physicians not to prescribe Effexor for children. Since it's launching in December 2002, Strattera is the fastest growing ADHD drug, capturing 16.3% of the market share in just 9 months. The cumulative number of prescriptions written for Strattera doubled during the third quarter, from roughly 1 million in the first half of 2003 to more than 2 million by the end of September 2003. It is estimated that of 1.4 million individuals, 856,000 children are prescribed Strattera. See: Psychiatric News. Med Check Compiled by Jim Rosack December 5, 2003 Volume 38 Number 23 http://pn.psychiatryonline.org/cgi/content/full/38/23/22

The Alliance for Human Research Protection is concerned that children who are prescribed the failed antidepressant, Strattera, may be exposed to undisclosed serious risks of harm.

FDA's-approved label states: "STRATTERA was administered to 2067 children or adolescent patients with ADHD and 270 adults with ADHD in clinical studies. Yet, adverse effects analysis included only 427 children on Stattera, and reported withdrawal of only 15 of 427 children on Strattera compared to 4 out of 294 children given a placebo. See: http://www.fda.gov/cder/foi/label/2002/21411_strattera_lbl.pdf

What happened to the other 1,640 children who were administered Strattera?

AHRP questions FDA's inexplicable failure to include Strattera data in Dr. Andrew Mosholder's analysis of antidepressants-and we question the exclusion of Strattera from FDA's antidepressant drug advisory warning (March 22, 2004).

Surely FDA officials know that a drug described in FDA's approved Strattera label as a "selective norepinephrine reuptake inhibitor" is similar to several other SNRI drugs approved and marketed as antidepressants. Whether a drug is prescribed for children with depression or ADHD, the drug's potential adverse effects are the same. It is of particular note that neither diagnosis is determined by a scientifically verifiable diagnostic tool, but rather on the basis of subjective evaluation of behavioral "symptoms" which often undergo modidification.

Another failed antidepressant, Cymbalta, is in the SSNRI class and is currently in its second cycle of testing for incontinence and depression. Investigative press reports have revealed that there were 6 suicides in clinical trials testing Cymbalta at higher doses than the dose prescribed in the earlier failed clinical trials. Traci Johnson was a 19-year old healthy volunteer who had been prescribed higher doses of the drug was the sixth test subject to commit suicide during Cymbalta trials.

See: THE LOS ANGELES TIMES. A Godsend, Till a Life Unravels By Alan Zarembo and Benedict Carey, April 2, 2004 http://www.latimes.com/news/science/la-sci-humantest2apr02,1,6542363.story?coll=la-home-headlines

How does the FDA justify approval of high dose drug trials which put human subjects at increased risk of severe adverse effects--including the risk of suicide?

Contact: Vera Hassner Sharav
Tel: 212-595-8974

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Wall Street Journal
Flop Factor: By Learning From Failures, Lilly Keeps Drug Pipeline Full; Dr. Nyikiza Uses Math Skills To Save Cancer Treatment; A Surprisingly Simple Fix; Lessons of an Antelope Hunt By Thomas M. Burton Apr 21, 2004 A.1

INDIANAPOLIS -- Five years ago, Eli Lilly & Co. had high hopes for an experimental chemotherapy drug called Alimta. But after three patients taking Alimta died suddenly in 1999, Lilly halted trials of the drug. It looked like a fatal blow for Alimta -- despite strong evidence that it could reverse tumor growth.

Paolo Paoletti, the Lilly doctor running the trials, begged for two weeks to save the drug. He teamed up with a Rwandan mathematician, Clet Nyikiza, whom Lilly keeps on staff largely to study drug failures. Dr. Nyikiza had been fascinated by why complex processes fail ever since his grandfather taught him as a boy in East Africa the telltale signs of an unsuccessful antelope hunt. By analyzing blood samples and medical records, Messrs. Paoletti and Nyikiza identified a surprising problem with an unexpectedly simple solution.

Today, Alimta is an approved treatment for mesothelioma, a rare type of cancer caused by exposure to asbestos. It's under Food and Drug Administration consideration as a treatment for lung cancer, a much more common ailment.

Alimta's resurrection helps illustrate why Lilly is coming out with a flood of new medicines even as many of its competitors struggle to replace blockbuster drugs coming off patent. Lilly has long had a culture that looks at failure as an inevitable part of discovery and encourages scientists to take risks. If a new drug doesn't work out for its intended use, Lilly scientists are taught to look for new uses for a drug. In the early 1990s, W. Leigh Thompson, Lilly's chief scientific officer, initiated "failure parties" to commemorate excellent scientific work, done efficiently, that nevertheless resulted in failure.

Other drug companies are also seeing the importance of tolerating - and learning from -- failure, a valuable strategy since about 90% of experimental drugs in the industry fail. For example, Pfizer Inc. originally developed the blockbuster impotence drug Viagra to treat angina, or severe heart pain.

Lilly has taken this approach to unusual lengths. It assigns someone --often a team of doctors and scientists -- to retrospectively analyze every compound that has failed at any point in human clinical trials. Blair Sheppard, a management professor at Duke University who's done Consulting work for Lilly and other pharmaceutical companies, says that Lilly developed "a formalized and thoughtful process in which it reviewed failures more honestly, more deeply and started the process sooner than anyone else."

Many Lilly drugs have risen from failure. Evista, now a $1 billion- a-year drug for osteoporosis, was a failed contraceptive. Strattera, a hot-selling drug for attention deficit/hyperactivity disorder, bombed out as an antidepressant.

A promising cardiovascular drug called a PPAR-alpha-agonist, which lowers fat levels in the blood, arose from a failed asthma project. The antidepressant Cymbalta, for which Wall Street has high hopes, failed in its original trials until a Lilly scientist upped the dosage.

In an industry where getting two new drugs approved by the FDA is considered a banner year, Lilly already has six approved so far in 2003 and 2004 combined and hopes to get another two approved by year- end. And it has another 11 promising drugs in the middle- to late- stage pipeline.

Still, Lilly's share price has been in the doldrums because of other factors. In August 2001, the company's patent exclusivity on the antidepressant Prozac expired and most of the $2.6 billion in revenue from the drug quickly evaporated. More recently, Lilly was hurt badly when the FDA blocked approval of some new drugs for more than a year because of quality and record-keeping problems at two Indianapolis Lilly plants. In addition, some of Lilly's drugs, including Evista, the osteoporosis medicine, have run into tougher-than-expected competition. Just last week, Smith Barney lowered its profit outlook for the drug maker.

Lilly sales rose to $12.58 billion in 2003 from $10 billion in 1999, including a 14% jump in 2003 from 2002. But earnings per share slipped some over the same period, to $2.37 a share in 2003 from $2.46 a share in 1999. Without one-time gains and charges, earnings per share rose to $2.58 in 2003 from $2.28 in 1999.

The pipeline of new drugs has helped keep Lilly's price-to-earnings ratio consistently at the high-end of the drug industry. Lilly traded yesterday in 4 p.m. composite trading on the New York Stock Exchange at $72.25 a share, down $1.15.

Second Chances
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Lilly drugs arising from earlier failures

DRUG: Strattera
STATUS: Marketed for ADHD treatment
HISTORY: Failed in depression studies

DRUG: Evista
STATUS: Marketed for osteoporosis
HISTORY: Failed for birth control

DRUG: Alimta
STATUS: Marketed for mesothelioma
HISTORY: Trial had been stopped

DRUG: Cymbalta
STATUS: Reviewed by FDA for depression
HISTORY: Failed at lower dose

DRUG: MEPM
STATUS: In trials for cancer
HISTORY: Failed for psoriasis

DRUG: Gemzar
STATUS: Marketed for cancer
HISTORY: Failed as antiviral agent

DRUG: PPAR-alpha agonist
STATUS: In trials for cardiovascular disease
HISTORY: Failed asthma trial

DRUG: Ghrelin blocker
STATUS: In preclinical trials for obesity
HISTORY: Failed frailty study

Sources: Eli Lilly; WSJ research

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