The History of Paxil
The following expose' was first published in May of 2004. It has recently been updated and edited. To date, it represents the most comprehensive and detailed history of Paxil known to the public.
What you are about to read is a distillation of several months worth of intensive Internet-based research completed using a high speed cable modem coupled with a Macintosh "G4" computer. Along the way the author, Rob Robinson, received a couple of crucial pieces of information from novelist (and Paxil survivor) Patricia Griffon, author of the Pulitzer-nominated Blind Reason along with a little help from "lady luck" herself. Robinson's travels whisked him through the Internet as if it were a 20th century version of "Alice In Wonderland's legendary looking glass" — tumbling head over heels into the hinterlands of cyberspace. Incredibly, it all began when he stumbled across a single record; one buried and long forgotten in a United States government cyber database almost 25 years ago.
Penetrating so many secrets we cease to believe in the unknowable.
But there it sits nevertheless, calmly licking its chops."
— H.L. Mencken
In the 1960's a small Danish company called Ferrosan entered into (according to their web site) a successful venture into CNS (Central Nervous System) research, which led to the discovery and launch of the antidepressant Paxil (a.k.a Seroxat), now owned by GlaxoSmithKline."
Ferrosan is almost always referred to as a Danish company — but in a document issued by the United States Federal Court of Appeals concerning a highly technical and convoluted patent dispute (SmithKline Beecham Corporation and Beecham Group, P.L.C. v. Apotex Corp., Apotex, Inc., and Torpharm, Inc.) relative to paroxetine — Ferrosan is referred to as "a British company." In any event, Ferrosan was a family owned enterprise; the Danish part of the group remained so until 1986 when it was acquired by Novo Industri A/S (now Novo Nordisk A/S). After the acquisition, the CNS (Central Nervous System) research activities, the distribution of prescription medicine, and the veterinary medicine activities were all merged into the corresponding divisions of Novo Industri A/S.] (The suit just mentioned was resolved on April 23rd, 2004 in favor of Apotex Corp., Apotex, Inc., and Torpharm, Inc.)
Leading the research team of Ferrosan was an individual, Dr. Jorgen Buus-Lassen, who supported the theory that the specific enhancement of serotonin might lift a depressive mood. But Dr. Buus-Lassen was not a doctor in the ordinary sense of the word, but rather a "DVM" or "Doctor of Veterinary Medicine." (In plain English: Buus-Lassen is licensed to be an animal doctor.) Buus-Lassen received his DVM credentials from the Royal School of Veterinary and Agriculture Science in Copenhagen. (Note: Buus-Lassen's first name sometimes appears as Joergen.)
Buus-Lassen and his associates at Ferrosan explored approximately 100 compounds before concocting the one that the world would come to know as "paroxetine" and, ultimately, Paxil in the United States.
Ferrosan filed a patent application (#598,146) with the United States Patent and Trademark Office on July 23rd, 1975. (A similar application was made in the UK on January 30th, 1973.) The U.S. application was a continuation-in-part of patent application #435,006, filed January 21, 1974 (now U.S. Pat. #3,912,743) relating to novel 3-substituted 1-alkyl-4-phenylpiperidines having interesting pharmacological properties which make them useful as antidepressants and anti-Parkinson agents. The Ferrosan patent record references two prior U.S. patents:
An application (with 10 claims) for a U.S. patent concerning "ethers of 2-piperidylphenylmethanols"
submitted on July 17th, 1958 (#749,075) by Robert Michel Jacob, Ablon-sur-Seine and Nicole Marie Joseph (Paris, France), assignors to Societe des Usines Chimiques Rhone-Polenc, Paris, France, a corporation of France. The application was approved, and U.S.Patent #2,976,291 was issued on March 21st, 1961. A "claims priority, application France August 1st, 1957 is noted.
An application (with 5 claims) for a U.S. patent concerning "2-benzyl-3-hyproxy and lower alkoxy piperidines" submitted on February 6th, 1963 (#256,536) by Robert L. Clarke, Bethlehem, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware. The application was approved, and U.S. Patent #3,178,438 was issued on April 13th, 1965.
The relevancy of these earlier patents has not been ascertained.
Jorgen Buus-Lassen's first paper on paroxetine was published in 1975.
U.S. patent #4,007,196 was issued by on February 8th, 1977 to Ferrosan. The 196' patent claims paroxetine and its salts and discloses their antidepressant properties.
Interestingly enough, Buus-Lassen was not listed as Paxil's (paroxetine) inventor; that was credited by Ferrosan to Jorgen Anders Christensen (Virum, DK) and Richard Felt Squires (Gl. Olstykke, DK). These individuals were Ferrosan associates of Buus-Lassen. Nevertheless, Buus-Lassen is considered the "father" of Paxil today. (Perhaps "grandfather" would be more appropriate.) Later though, Buus-Lassen was listed as "inventor" when Ferrosan applied (#804,810) to the USPTO on December 4th, 1985 (and in Britain on December 4th, 1984) to use Paxil (paroxetine) in the treatment of obesity. On May 17th, 1988 Ferrosan was accorded U.S. Patent #4,745,122 for that indication. (Ferrosan also lists Buus-Lassen as inventor for at least two more U.S. paroxetine-related patents: #4,585,777 on April 29, 1986 and #4,593,036 on June 3rd, 1986.
Ferrosan later developed a process to produce the crystalline hydrochloride salt of paroxetine, or paroxetine hydrochloride (PHC).
In 1980, Ferrosan licensed the #4,007,196 patent and its other "PHC-related technology" to SmithKline. SmithKline began manufacturing PHC in its Harlow plant in England.
In March 1985, a chemist in SmithKline’s Worthing, England laboratory, Alan Curzons, created a new crystalline form of PHC while attempting to improve PHC production. Curzons’ test results established that the new product was the hemihydrous form of PHC (PHC hemihydrate), while Ferrosan’s original form was anhydrous PHC (PHC anhydrate). PHC anhydrate comprises crystals of PHC without bound water molecules. PHC hemihydrate comprises PHC crystals with one bound water molecule for every two PHC molecules. PHC hemihydrate proved more stable and thus more easily packaged and preserved.
Further review of the SmithKline samples showed that the Harlow plant had unwittingly made PHC hemihydrate as early as December of 1984.
In May 1985, SmithKline began double-blind clinical tests in the United States to determine the "safety and efficacy" of PHC hemihydrate capsules to treat depression symptoms.
On October 25, 1985 SmithKline filed a patent application in the British Patent Office relating to “crystalline paroxetine hydrochloride, its preparation and its uses as a therapeutic agent.” The British application identified the invention as both the hemihydrate and the anhydrate form of PHC, as well as mixtures that contain a major portion of either form.
On October 23, 1986, SmithKline filed a U.S. application claiming priority to a British application that issued as the #4,721,723 patent in 1988. The ’723 patent does not claim PHC anhydrate and does not claim mixtures of the two PHC forms.
If you would like to peruse the U.S. patent records concerning paroxetine (Paxil) visit the USPTO web site.
In 1989 Buus-Lassen wrote a piece entitled "Introduction to the development of paroxetine, a novel antidepressant." The article was a terse four paragraphs. Of those, two were single sentences. At the bottom of the page were nine footnotes. [Acta psychiatr. scand. (1989) 80:13.]
In an April 28, 2002 interview with British newspaper "The Guardian" (see The Chemistry of Happiness) Buus-Lassen was quoted, saying It (paroxetine) didn't work with all patients. In most studies we could just show that we had about the same efficacy as the older tricyclic antidepressants. We didn't see a better effect."
SmithKline Beecham and "the Gates Of Hell"
Beecham — patent #4,007,196 licensing in hand from Ferrosan — after merging with another drug company called SmithKline & French (to become SmithKline Beecham a.k.a. SKB), would eventually become the company responsible for flinging wide the laboratory "gates of hell," thereby allowing Paxil to find its new home in the medicine cabinets of America (and the world.)
But before Paxil could be sold in the United States SKB had to gain approval from the Food And Drug Administration certifying Paxil as "safe and effective." So in the 1980's SKB undertook a series of Paxil human clinical trials. Although the drug was tried on SKB employees, most interesting were those conducted in Yugoslavia in the late 1980's. To SKB's dismay the Yugoslavia trials were an unmitigated disaster; the company was having a hell of a time coming up with tests they could present to the FDA demonstrating the drug was safe and effective. Billions of dollars in projected profits were imperiled. So what did SKB do? Using a bit of "the devil's math" they "fixed" the studies so Paxil would "wow" the FDA. (Which, many years later, led to the following lawsuit citing fraud by SKB (now GSK). It is believed that a small but critical change in Paxil's product information label came about as a result of this lawsuit being filed.)
Exiting Yugoslavia (bogus studies in hand) SKB submitted Paxil's application to the FDA.
Through a combination of agency ineptitude and — to some what appears to be— collusion, Paxil was approved by the FDA for sale in the U.S. a few months subsequent to a October 5th, 1992 agency review of the drug.
Paxil's official FDA approval date is December 29th, 1992.
In 1993, SmithKline placed "its" antidepressant drug (with PHC hemihydrate as the active ingredient) on the market under the name Paxil. (For the record: Paxil was actually first sold in the UK, in 1991, under the trade-name "Seroxat.")
What has resulted is a mind-boggling swath of human misery cutting across the lives of countless thousands of individuals who took Paxil. Now, in 2005 and 13 years after Paxil was introduced in the U.S. it appears the carnage is far from over. For that the public can thank, in part, football legend Terry Bradshaw who was hired by GSK to aggressively promote Paxil. (Bradshaw has been called the "Pied Piper of Paxil" for his role in luring thousands of unsuspecting new victims over the edge and into depths of "the Paxilian abyss.")
But the real story of Paxil is only beginning. For reasons still not ascertained a trademark for Paxil was applied for on March 28th, 1980 with the United States Patent and Trademark Office (under "Goods & Services") as a hypnotic drug for human use. But not by Ferrosan or Beecham, but by a German drug company called Boehringer Ingelheim G.m.b.H. To view this U.S. government database record go to the this web page and
Click on Search Trademarks. A new window will appear.
Under the Select The Search Form click on New User Form Search (Basic).
A new web page will come up. Type the word "Paxil" in the Search Term field and click on the Submit Query button.
A new web page with records arranged in a grid format will appear. Scroll down the page to a record which displays serial number 73255881. Right of that is a registration number: 1170889. Click on the word "Paxil" just right of the registration number, and the full record will be retrieved.
Note: The official registration date for the Boehringer Ingelheim trademark is listed as September 29, 1981 and a "termination" date of April 7, 1988.
The existence of this seemingly (at first glance) "run of the mill" record educed an extraordinary question: Did Boehringer Ingelheim enter into a joint venture with Ferrosan in the 1960's — whereupon Jorgen Buus-Lassen was provided the (approximately) 100 compounds he and his associates tested — out of which came Paxil?" Ferrosan was a relatively small company. As such, it is unlikely the company produced the compounds, but rather obtained them "off the shelf" from a much larger company with the resources to make them — like Boehringer Ingelheim. What followed was, in all likelihood, an agreement whereby Boehringer Ingelheim told Ferrosan if it came up with anything marketable from the compounds they would handle the marketing and distribution.
If this is not the case, then why did Boehringer Ingelheim — and not Ferrosan, or Beecham (later merged with SmithKline to become SmithKline Beecham) — register Paxil on March 28th, 1980, with the United States Patent and Trademark Office? The only logical explanation it seems is Ferrosan and Boehringer Ingelheim had a business agreement regarding Paxil; one that apparently went "poof" the very same year Ferrosan licensed SmithKline the #4,007,196 U.S. patent, along with its other "PHC-related technology." Whatever the case, this Ferrosan—Boehringer Ingelheim connection warranted a closer look at the latter company.
But before doing that, there's a quite bit more to that Boehringer Ingelheim trademark registration worth considering:
Why did Boehringer Ingelheim classify Paxil as a "hypnotic" — and not an antidepressant? That was not a random designation; either Ferrosan or Boehringer Ingelheim, must have conducted research and studies that indicated this was the best way to, pharmacologically speaking, describe the drug's effect. (Where, one might wonder, is that data now? In GlaxoSmithKline's confidential company archives?)
Why did SKB begin selling Paxil in the United States as an antidepressant and not a hypnotic?
How was "Paxil the hypnotic" transformed by SKB into "Paxil the antidepressant"? After all, hypnotics are central nervous system (CNS) depressants. (Webster's dictionary defines a hypnotic as Any agent that produces, or tends to produce, sleep: an opiate; a soporific; a narcotic. (One medical dictionary simply defines a hypnotic as a "sleeping-tablet".) Does it matter? Perhaps not. However, sticking with the hypnotic label for Paxil might have prompted the FDA to classify the drug as a controlled substance. (Which Paxil should be.) Or, perhaps it would have made it impossible to position Paxil in the U.S. marketplace to compete with Lilly's multi-billion dollar Prozac profit engine ... which was being peddled as an antidepressant. Or maybe all of the above.
Whatever the case, one has to wonder if Paxil is soon destined to end up in the pharmaceutical trash-bin of history — just like another hypnotic, called Halcion did.
Boehringer Ingelheim: "Black Widow" At The Center Of The 'SSRI Web'?
Boehringer Ingelheim is one of the twenty largest drug companies in the world; it has strategic partnerships with many other multi-national pharmaceutical corporations, including SSRI giants GlaxoSmithKline and Eli Lilly — as well as a new company called NeuroSearch which is headed up by none other than the "father of Paxil" himself — Jorgen Buus-Lassen.
Probing the history of Boehringer Ingelheim, it was discovered the company had garnered some bad press after it was widely reported it, under the direction of Richard von Weizsacker, had supplied the United States government with large quantities of a highly toxic and dangerous herbicide called dioxin (a.k.a. "Agent Orange") during the Vietnam War. Weizsacker eventually left the company and went on to become president of the Federal Republic of Germany in 1984.
Interestingly, Weizacker's father, Baron Ernst von Weizsacker, served as state secretary in the foreign ministry of the German Republic from 1938-1943; in 1949 he was sentenced at the Nuremberg trials to seven years imprisonment for "crimes against humanity." Specifically, he was convicted for his use of diplomatic pressure to make possible the deportation of Slovakian and Italian Jews to Nazi death camps. His sentence was later commuted to "time served."
In the 1990's, a study published in the journal of the United States National Cancer Institute provided conclusive evidence of a direct relationship between industry and the cancer-causing effects of dioxin. Generally ignored by the mainstream press, the study revealed that many thousands of workers in the U.S. chemical industry died of various cancer-related illnesses as a result of exposure to dioxin. Pooling data from more than 5,000 workers from 12 different factories across the United States, the study found that workers with the highest dioxin exposure had a 60 percent greater risk of dying from cancer than the U.S. national average.
It turns out dioxin was discovered in Hamburg, Germany in 1954 — at the company of C.H. Boehringer — by a scientist named Karl–Heinz Schulz while conducting a series of experiments using "76 assorted Boehringer products." (The ultimate parent company of the Boehringer Ingelheim corporation is C.H. Boehringer Sohn. Boehringer Ingelheim GmbH, which is a subsidiary of C. H. Boehringer Sohn, is the central holding company for administrative purposes — the corporate central body which manages and directs the worldwide family of Boehringer Ingelheim companies and which delivers central services to all companies of the corporation. Click on this link for more information.)
Schulz's dioxin experiments used live rabbits. Schulz would rub the ears of a control group of the animals with one of the 76 Boehringer chemicals. A second group of rabbits — housed alongside the control group in open cages — was not treated with a test chemical. A few days after the first experiment commenced hideous boils appeared on the test rabbits' ears. Incredibly, the untreated rabbits in the cages next to the test rabbits were also affected — even though they did not come in direct contact with one of the chemicals. Instead, they began dying of liver necrosis (a condition whereby liver tissue practically rots). Schulz concluded the untreated rabbits were inhaling the chemicals applied to the control group rabbits. The one thing that all of the chemicals being tested had in common? They contained varying amounts of dioxin.
Subsequent to his rabbit experiments, Schulz reported to his employer that the compounds containing dioxin were, in his opinion, “too deadly” for any conceivable use.
What did Boehringer management make of Schulz's report? They didn't like it, because the company wanted to unload many of the compounds into the American market — so they hid the test results. Boehringer subsequently sold most of these compounds to Dow Chemical in, as best can be ascertained, 1960. One of the compounds sold to Dow Chemical was the isolate dioxin.
Interestingly enough, a year prior to the sale of the dioxin et. al. rights to DOW it was reported that a representative of the United States Army Chemical Corps traveled to Boehringer to see what he could find out about dioxin's potential use as a chemical weapon. Based on his report the U.S. military concluded dioxin was too dangerous to be handled safely, although it didn't stop them from using the chemical as a defoliant (sprayed from airplanes) to clear vast tracts of lush vegetation in Vietnam during the Vietnam war. Elsewhere, estimates were uncovered that suggest as many as one million Vietnamese died as a result of exposure to dioxin. Countless other Vietnamese were seriously poisoned — as were untold thousands of American soldiers. Little wonder the chemical was described as the most poisonous chemical in the world in a 1991 article that appeared in "The Mirror" in Germany. Dioxin, it seems, could (and perhaps should) be classified as a weapon of mass destruction.
Digging further into Boehringer Ingelheim's history an effort was made to ascertain what the company was doing in the 1930's and 1940's when Germany was controlled by the Nazi party. Specifically, what activities did Boehringer Ingelheim engage in during Hitler's reign that would prompt it — after the collapse of the Third Reich — to join the German Forced/Slave Labor Compensation Fund? Did it have anything to do (as reported by the Shoah Project) with Boehringer "Compound 2516" studies ordered by Heinrich Himmler and carried out under the aegis of "Dr." Claus Shilling at the Dachau concentration camp?
Go to the Google search engine and type in these three words: "dachau" "boehringer" and "2516". One of the first links that will appear should read "Shoah Project Dokumentation KZ Dachau." Immediately right of this phrase click on the text that reads Translate this page.
A new web page will appear with German text translated into (approximate) English. Scroll down to the bottom of the page to the following passage which reads (verbatim):
Professor Dr. Claus Schilling
a set of experiments with the malaria preparation Boehringer 2516 let
accomplish. None of the 1200 chose ever in agreement explained
themselves or freieillig announced themselves. For these attempts
clergyman were often selected. The prisoners were infected by the
injection of the mosquitoes themselves or by injections of Extracten
from the Schleimdruesen of the mosquitoes with malaria.
Further research led back to the late 1800's whereupon it was discovered (according to The Rise and Demise of Cocaine by Paul Gootenberg) that C.H. Boehringer & Sohn had "jumped into the cocaine trade" and were involved in the business for several decades (possibly well into 1940's through World War II.)
Leaping forward to modern times, it was discovered Boehringer Ingelheim is the manufacturer of an experimental AIDS drug called "Viramune" (nevirapine). The drug is being used in "clinical trials" involving infants and children at a place in New York's Washington Heights called "Incarnation Children's Services" — as well as at Columbia Presbyterian and, in fact, at hundreds of participating hospitals in pediatric AIDS clinics nationwide. Coincidentally, GlaxoSmithKline (formerly SKB) is participating in these "studies" with two of its drugs: Retrovir (AZT) and Epivir (3TC, lamivudine). Res ipsa loquitur: For further details visit The House That AIDS Built".
Cymbalta: Spawn of Boehringer Ingelheim and Eli Lilly
In November, 2002, Boehringer Ingelheim and Eli Lilly (Prozac's manufacturer) signed a long-term agreement to work together and develop the commercialized use of a compound called duloxetine hydrochloride. Duloxetine, (trademark named "Cymbalta") was developed as a "dual purpose" drug capable of treating "stress urinary incontinence" as well as depression. (Lilly and its stockholders are counting on Cymbalta to be its next blockbuster antidepressant, since Prozac has gone off patent and profits have gone "poof.") In late 2004 Cymbalta was approved by the FDA as "safe and effective." But how safe and effective? Read the following Philadelphia Inquirer article Suicide Of A Human Guinea Pig.
A Family Reunion of Sorts: Boehringer Ingelheim and Buus-Lassen
Boehringer Ingelheim is also heavily involved with Jorgen Buus-Lassen (formerly of Ferrosan, creator of Paxil) who is now head of his own company called NeuroSearch (a Danish biopharmaceutical company listed on the Copenhagen Stock Exchange: NEUS:CO)
For its part Boehringer Ingelheim is investing a total of DKK 680 million in exchange for sales rights to a drug for Alzheimer’s and Parkinson’s disease that NeuroSearch is developing. Boehringer Ingelheim has agreed to take on on the future development costs of the drug. According to Buus-Lassen: It (the agreement with Boehringer Ingelheim) is the most important agreement in NeuroSearch’s history. The cash injection ensures that we can develop the drug for the ever more prevalent Alzheimer’s and Parkinson’s disease and bring it to market.
"All About NeuroSearch"
NeuroSearch was founded in April of 1989 by Buus-Lassen and five fellow researchers (Asger Aamund, Jørgen Drejer, Frank Wätjen, Leif Helth Jensen, Henrik K. Moltke and Peter Wulff) who left Ferrosan and struck out on their own, pledging their homes to get a startup loan. They first opened shop in a cellar at Danochemo (which specializes in laboratory medical equipment) based in Ballerup, Denmark. They obtained private financing in the amount of DKK 29.7 million for start up capital.
For a timeline of Neurosearch's history click on this link.
Today, Neurosearch is still located in Ballerup, Denmark (between the Copenhagen (DK) area and Skania in Sweden) in the so-called "Medicon Valley" which, as of October, 2002, was home to 26 hospitals and 12 universities with 4,000 researchers and 135,000 students. The area provides over 30,000 jobs in more than 160 biotechnology companies.
NeuroSearch's goal is to become an international leader in pharmaceutical research and development, with an intense focus on the central nervous system. The company intends to develop each of its compounds "in-house" to maximize the opportunity for potential profits. In other words: It won't buy bulk compounds "off the shelf" to experiment with — like Ferrosan did in the 1960's.
Typically, NeuroSearch tries to broker agreements with large pharmaceutical companies to "optimize development and/or marketing." At the same time NeuroSearch seeks to preserve commercial rights for its compounds in the Nordic and Baltic countries "with the possibility of expanding these primary markets to larger parts of Europe."
NeuroSearch operates under an "in-house as long as possible followed by collaboration" model based on the following concepts:
"Collaborations established during the late clinical phases of a compound's development are generally more profitable than those started during the initial stages."
"A gradual increase in NeuroSearch's capabilities in the areas of drug development, manufacturing of compounds on a larger scale for extended clinical trials and, in the long term, sales of marketable products."
NeuroSearch currently has agreements not only with Boehringer Ingelheim and GSK (as noted above) but also Abbott Laboratories, along with partnerships enjoining Pharmexa and Pierre Fabre, and equity interests in eight biotech companies, including Bavarian Nordic A/S, NsGene A/S, and Sophion Bioscience A/S.
"The SSRI Ties That Bind": NeuroSearch, Buus-Lassen and GSK
NeuroSearch's first accord involving GlaxoSmithKline came (see Neurosearch history link above) in 1993 with then Glaxo Group Research Ltd.
Ten years later and on December 13th, 2003, NeuroSearch and GlaxoSmithKline (which remember, now owns the patent for Paxil — first licensed to SKB from Ferrosan — the company Buus-Lassen used to work for) announced a landmark five-year research and development alliance. The alliance comprises a number of research programs, including the treatment of purported "diseases" of the central nervous system.
NeuroSearch compound NS2710, intended to treat the "disease of anxiety," was originally slated for distribution by pharmaceutical giant Pharmacia & Upjohn; however, "problems" arose during the clinical "Phase II" human trials. Not that the compound wasn't "effective" according to NeuroSearch, but rather some patients experienced sedation or an allergic reaction (i.e. NS2710 knocked them out or made them sick.) The disclosure of these problems was serious enough that Pharmacia & Upjohn immediately ended the partnership. (Perhaps NS2710 has been relegated to "veterinary use only." Or perhaps a variation of it will turn out to be GSK's "new Paxil.")
For the "disease of depression" GSK and NeuroSearch were, until March of 2002, banking on the success of compound NS2389 hyped as a "triple action," or "mixed monoamine re-uptake inhibitor." Recently though, abnormal cell growth (i.e. cancer) observed in experiments on rats and dogs scuttled further development.
The world will likely be hearing much more hype about mixed monoamine re-uptake inhibitors (MMRI's for short) in the near future. In a 2002 interview with the Guardian, a British newspaper, Buus-Lassen spoke of early clinical studies that suggest MMRI's work on some patients who do not respond to "serotonin enhancement" alone. But we still have to learn and see if this is right, he says. Until we've had a full program, it's still a kind of prediction. We have many pieces, but we don't know why not all patients are being cured. Several pieces we do not understand. (Cured? By a Buus-Lassen drug?)
What Buus-Lassen didn't mention in his interview with the Guardian is the fact that an older class of antidepressants, commonly referred to as "tricyclics," also inhibit monoamine re-uptake. And it was SSRIs, like Paxil that were — according to drug company propaganda — a great leap forward over the tricyclics in efficacy. The world now knows this is not the case.
According to Dr. Robert Temple, Associate Director for Medical Policy United States Food and Drug Administration who (on Monday, September 11th, 2000, during the course of a public hearing conducted under cover of the FDA Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee) said ....the new antidepressants do not differ in effectiveness from the old antidepressants.
It appears GSK and NeuroSearch are simply "recycling" tricyclics and repackaging them as "new and improved." (Triple action, no less!)
GSK-NeuroSearch's NS2359 is intended for the treatment of "Attention Deficit Hyperactivity Disorder," or ADHD. In a number of pre-clinical models, NeuroSearch's scientists claim to have shown NS2359 "improves" the function of the neurotransmitters dopamine, nor-adrenaline and serotonin. On the basis of these pre-clinical (and clinical Phase I results) NeuroSearch anticipates NS2359 will provide a better "therapeutic effect" in the treatment of patients (mostly children) purported to have ADHD.
NS2359 has been tested in 125 healthy volunteers in five Phase I clinical studies, and is alleged to be "well tolerated." In another study involving 54 volunteers (carried out by Professor K. Wesnes, Cognitive Drug Research Ltd.) it was "proven" NS2359 increases attention and improves the ability to recall verbal information.
NeuroSearch initiated a Phase II study with NS2359 at three clinical centers in the U.S. The study included 100 adult (so called) "ADHD patients," of which 50 were treated with a half milligram of NS2359 once a day, while the other 50 received placebo. The stated goal of the study was to gauge the efficacy of NS2359 in the treatment of ADHD symptoms as well as its "tolerability." The treatment period was eight weeks, and the study was expected to be finalized in 2004.
NS2359 has also been studied in cocaine addicts in collaboration with the United States National Institute on Drug Abuse.
Watching Every Neurosearch-GSK Move: "Eli Lilly on the Prowl"
Undoubtedly pharmaceutical giant Eli Lilly is watching this development very carefully, because if NS2359 eventually passes the cursory FDA "sniff test" then its own ADHD drug "Strattera" might have a new competitor to deal with — one backed by GSK's own mega marketing machine.
Strattera is a selective nor-epinephrine re-uptake inhibitor (SNRI). To see the sales pitch for Strattera visit the Lilly web site. In 2004, visitors were welcomed to the Strattera web site by three smiling girls leaning on one another's shoulder in a sort of "Norman Rockwell" knock-off pose. One presumes they were taking the drug — and loving it. (Or maybe they were just models.) Visitors are provided an "opportunity" to find out if they are "living with ADD" by taking an online "screening test." Strattera is "approved by the FDA" for use in children and adolescents — as well as adults who Lilly further targets using glitzy TV "infomercials" and glossy full-page magazine ads under cover of seeking to educate the public about the "grown up" version of ADHD, or Adult "Attention-Deficit Disorder." According to Lilly, many adults have been living with the condition — but don't recognize it Because its symptoms are often mistaken for a stressful life. Lilly suggests: If you've felt this type of frustration most of your life, you may have Adult ADD; a condition your doctor can help diagnose and treat. (After what — a five minute visit with a doctor — one hounded by a Lilly professional sales rep to prescribe Strattera?)
Back to the NeuroSearch-GSK Hydra
Before heading too far off on a tangent (albeit one that might lead to yet another equally interesting inquiry) let's revisit that corporate Hydra borne of GSK and NeuroSearch: Under the terms of the five-year agreement NeuroSearch will receive some "triple action" funding — a total of EUR 82 million (DKK 610 million) in guaranteed payments from GSK. NeuroSearch will further receive EUR 46.8 million (DKK 348 million), comprising EUR 29.1 million (DKK 217 million) of up-front and research payments, and EUR 17.7 million (DKK 132 million) for 616,000 new NeuroSearch shares to be issued to GSK. The shares correspond to an 8.7% increase of the share capital equal to GSK having a strategic equity interest in NeuroSearch of 8.0% after the capital increase. The purchase price of DKK 214 per share of DKK 20 represents a 30% premium to the average market price over thirty days before the agreement was signed. For new development candidates selected by GSK, the terms of the agreement continue until the patents regarding the selected candidates expires. The agreement may only be terminated by GSK in case of NeuroSearch's insolvency, material breach or in case the controlling interest in NeuroSearch is transferred to a new owner.
Perhaps this deal is, in an oblique manner and after the fact, a way for GSK to say "thank you!" to Buus-Lassen for inventing Paxil which last year earned GSK several billion dollars — just like it has for many years now.
Regarding the GSK-NeuroSearch agreement Dr. Tadataka Yamada, Chairman of Research and Development at GlaxoSmithKline, fawned: Diseases of the central nervous system are particularly debilitating and represent a massive unmet medical need. Combining the skills and resources of GSK and NeuroSearch will accelerate and augment our current efforts to make effective new treatments available to patients as quickly as possible. GSK particularly values the collaborative culture at NeuroSearch, which bodes well for the success of our alliance.
Dr. Yamada, by the way, was one of the top GlaxoSmithKline executives deposed in the 2001 Donald Shell Paxil homicide/suicide case — which GlaxoSmithKline lost in spectacular fashion. Here's just a smattering of what Yamada had to say (in this instance about drug warning labels) when questioned under oath by Houston attorney Andy Vickery:
Dr. Yamada: ....We also have the pressure to understand that our (GlaxoSmithKline's) drugs aren't safe and that every drug — although every drug — every drug has potential complications but the benefits outweigh the risks.
Andy Vickery: And in that context, what is the importance of proper labeling as a means to accommodate these two competing interests? We need to get this drug out there on the one hand to people but the drug might hurt some people. Can that be ameliorated in some degree by proper labeling?
Dr. Yamada: That is the hope. That is the hope. It's not — it's not always been borne out, and so the FDA is rethinking about what they want to do, how they actually control the physician. I mean one of the problems is that — Maybe I'm saying too much here, Chuck. (Note: "Chuck" is GSK's counsel.)
Andy Vickery: I can't ask you what he said yesterday, but I bet one of them was just answer his questions. But I appreciate your helpfulness.
Dr. Yamada: It's like a pack of cigarettes. You see on there Surgeon General's warning.
Andy Vickery: Right.
Dr. Yamada: Nobody pays any attention to it.
Andy Vickery: Right.
And another excerpt from the Yamada deposition:
Andy Vickery: Dr. Yamada, as a physician, clinician, academician who not only practiced medicine but taught other doctors how to practice medicine for many years, would you agree that as a general proposition that if language appears in the warnings section in boldface that it is more likely that doctors will take heed of that information than if it's put back in the post-marketing surveillance section and it's not in boldface?
Dr. Yamada: Well, my experience would be that doctors just don't look at the label, period. Now, it could be because I was in an academic institution and that's what we did. Maybe we felt that we were more up-to-date and therefore we didn't need no label. I don't know, but my experience is that most physicians don't look at the label very carefully. And I'm not certain — I personally am not certain whether it would make a difference whether something was in a black box or in a warning section or in a precaution section, and if you would ask 20 young physicians, I'm not sure they could tell you the difference between those three.
Andy Vickery: Do you know that in the information disseminating process one of the truly important ways that your company communicates both the indications and the side effects of your medications to doctors is through the — I forget what title we were using about the detail men, as I call them, the people that call on doctors?
Dr. Yamada: Yes.
Andy Vickery: That's a very important conduit for information; isn't it?
Dr. Yamada: I believe it is, yes.
Andy Vickery: And do you know that your people are trained, your salespeople that call on doctors are trained to emphasize and reemphasize information that is in the warning section of the labels to doctors for the very reasons that you talk about?
Dr. Yamada: I believe so, but I don't know for a fact.
Andy Vickery: Okay, sir. How are you doing comfort wise?
Dr. Yamada: I'm fine. I'm fine.
Andy Vickery: Any time you want to take a break —
It seems fitting to conclude the history of Paxil by closing with a quote from Jorgen Buus-Lassen, the "father" of Paxil. Doing business (again) with Boehringer Ingelheim. Now head of his own company, NeuroSearch, and joined at the hip with GSK — which owns Paxil.
I am pleased that we were able to conclude this important strategic alliance with GSK as our two companies have had a well-functioning and trustful partnership within depression research for three years. I have a strong expectation that this extended partnership will be a major success for both companies. This agreement is one of the most important milestones in our history and is a major recognition of NeuroSearch's competencies within research and development. The agreement significantly increases the generation of value in NeuroSearch and strengthens our financial resources considerably.
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