Argentina a Return to Future Success Zyprexa
Transcript of Argentina a Return to Future Success Zyprexa
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T H E P 1 P B L I N B
Lilly is redefining the way it bringsproducts to market.
And olanzapine, the company'santipsychotic drug in development for thetreatment of schizophrenia and otherpsychotic disorders, is forging newground-from process definition toclinical trial studies to global marketing
strategies."We are blazing a new trail in how
we develop products at Lilly," said Beth S.Morris, manager of development projectsmanagement.
In fact, Morris describes the
changes in chemistry, manufacturing, andcontrol CM&C as a "quantum leap" forthe company. CM&C is the part of thedrug development process that includesthe process development and characterization of a new drug substance and thedevelopment of analytical methods,dosage formulations, and supportingstability data for registration and marketing requirements.
Early validationA key strategy recently introduced
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in chemistry, manufacturing, and controlis the early validation of bulk and productprocesses. Historically, the company hasmanufactured separate lots for stabilitystudies and full-scale validation. In thepast, stability lots were manufactured atpilot scale to ensure that when the processor product was taken to full-scale
production, it would remain stable i.e.,potency of bulk drug substance or tablet,shelf life, etc.. The data generated fromthese lots were used for regulatorysubmission. Full-scale validation lots atthe manufacturing site were not com
pleted until after regulatory submissionand often right before product launch.
"Under the previous system, wedidn't know if the process parametersused for stability studies and regulatorysubmission would reflect what the processor product would do when it went to full-scale production," Morris said. "With that
kind of system, it's possible to find yourselfliving with a suboptimal process that waslocked in at the time of submission."
Employing the new strategy with
olanzapine as the pioneer, Lilly completed
validation of the bulk drug substance atKinsale, Ireland, in late 1993. The
company recently completed validation of
full-scale tablet lots in Puerto Rico. Seerelated story on page 8. In addition, full-scale production of granules was c om
pleted at Basingstoke, England, inSeptember.
The greatest advantage of early
validation is that the process for full-scalemanufacturing is fully defined andoptimized at the time of regulatorysubmission. According to Morris, it's asignificant strategic investment that
contributes to the company's qualityspeed initiative.
Dedicated core teamMorris is one of eight members of
the olanzapine dedicated core team, a
pilot effort in which the central-nervous-system CNS compound is serving as amodel for other Lilly products. While the
core team concept is not new at Lilly,previous core team members worked onseveral projects simultaneously. The
concept of the dedicated core team is to
Focus
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Operator Israel Gonzalez and production leader Betsy Galarza of the dry products plant inPuerto Rico inspect a granulator used in the manufacture of validation lots f or olanzapine.
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focus all team members' efforts on only
one compound."1 think the dedicated core team is
the first step in an interesting evolution inthe project team structure at UIly," said
Jeffrey S. Kasher, Ph.D., manager ofpharmaceutical projects. "If you look atcompanies outside the pharmaceuticalindustry you'll see that this is how they'regetting things done."
Representing pharmaceutical
projects management, central-nervous-
system global business unit, medical, anddevelopment projects management, theolanzapine core team has project responsibility solely for this compound.
"While there are others working onolarizapine, the core team is looking at theoverall strategy and focusing exclusivelyon this one compound," Kasher said."That focus allows the team to anticipate
possible issues and to react more quickly.The team is in a better position to keepthe project on track. And olarizapine is aproject which can't afford delays of weeksor months."
A drug in demand
If anything, the market already hasbeen waiting too long for a drug likeolanzapine. A central-nervous-systemdisorder whose causes are not completelyunderstood, schizophrenia afflicts morethan 5 million people worldwide. In theUnited States, schizophrenia is thenumber one mental illness in terms ofpatients who are hospitalized. Andexperts estimate that one-third of thenation's homeless suffer from schizophrenia. The disease severely impairs aperson's ability to reason and to feelemotion, leading the individual down aspiral of devastating despair.
"Schizophrenia is truly a malignant
disease whose signs and symptoms are farfrom everyday human experience," saidCharles M. Beasley,Jr., M.D., a seniorclinical research physician.
Symptoms include hallucinationsand delusions, called positive symptoms,as well as social withdrawal, apathy, and
an emotionless demeanor. Referred to asnegative symptoms, these latter manifestaOcro9ffR 2994
tions are perhaps the most debilitating
and most difficult to treat.Antipsychotic drug therapy for
treating schizophrenia has been available
for decades. The conventional
antipsychotics, however; treat only thepositive symptoms. And the tradeoff for
controlling the hallucinations and
delusions often includes severe side
effects, such as a Parkinson's disease-like
syndrome and tardive dyskinesia, an
involuntary writhing of the muscles. Such
side effects, along with persisting negative
If anything,market
v !aas beentoo long
symptoms, make it almost impossible fora person with schizophrenia to resume a
normal life.
In past years, the focus of therapy
has moved to a new class of medicinescalled atypical antipsychotics. These drugs
not only suppress the positive and
negative symptoms of schizophrenia, but
do so with a relative reduction in thesevere side effects of traditionalantipsychotics. Currently, the "gold-
standard" among atypical antipsychotics
for the treatment of schizophrenia is
clozapine, which, like olanzapine,
interacts at a diverse array of neurotrans
mitter receptors, including receptors for
dopamine, serotonin, and acetylcholine.
Marketed by Sandoz Pharmaceuticals,clozapine is the only approved drug
believed to control both the positive and
negative symptoms of schizophreniawithout the extrapyramidal side effects of
other neuroleptics. But treatment is not
without a cost.Clozapine is an older compound
that initially was removed from development because it was linked to a potentially
fatal condition called agranulocytosis, aprecipitous loss of white blood cells thatcan lead to a fatal infection. Today, patientswho use clozapine must have their bloodtested regularly to monitor their white
blood cell count, a test that is both time-
consuming and expensive. For this reason
alone, clozapine will probably never be a
first-line treatment for schizophrenia.Although the drug boasts a high success
rate in treating both positive and negative
symptoms, its potentially fatal side effect,along with other less serious but uncomfortable side effects, has made clozapine atreatment of last resort, especially forpatients who haven't responded adequately
to other antipsychotics.The market is looking for a safe
clozapine, and Lilly's drug candidate
olanzapine looks like it might "fit the bill.""Preliminary study data are highly
encouraging regarding the safety profile of
olanzapirie," said Gary D. Tollefson, M.D.,
Ph.D., executive director of clinicalinvestigation and regulatory affairs. "[The
datal suggest that the compound maysuccessfully differentiate itself fromclozapine."
Targeted for worldwide regulatory
submission in 1995, olanzapine has been
shown to suppress both the positive and
negative symptoms of the disease. Inaddition, more than 2,500 patients have
been given the investigational drug in
clinical trials, and no cases of
agranulocytosis have been reported.A Phase II placebo-controlled study,
using haloperidol a common neuroleptic
as an active comparator, showed olanza
pine to be statistically superior to both
placebo and haloperidol. Data from additional Phase II studies will be presented tothe European and American Colleges of
Neuropsychopharmacology by year-end.
Enrollment in a 2,000-patient
international Phase III trial was completed
in August, reflecting another innovativestep in the development of olanzapine.
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