Argentina a Return to Future Success Zyprexa

8/10/2019 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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Argentina a Return to Future Success Zyprexa

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