Re: The Story of Gleevec

[Guest guest]

Hi Zavie,

& nbsp;

Thanks for this info - very interesting. Shortly after I completed my STI571

trial (Cape Town. South Africa) & nbsp;and Gleevec was registered, I was given

book by Novartis & nbsp;titled 'MAGIC CANCER BULLET' written by & nbsp;

Vasella (CEO Novartis) which tells & nbsp;how & nbsp;gleevec was researched and

finally approved & nbsp;- interesting read.

& nbsp;

Regards,

Shaun

swatts98@... & nbsp; & nbsp;

From: Zavie miller & lt;zmiller@... & gt;

Subject: [ ] The Story of Gleevec

Date: Wednesday, May 28, 2008, 4:01 AM

The Story of Gleevec

beth Buchdunger, Ph.D.

Juerg Zimmerman, Ph.D.

In 2001, the FDA approved Gleevec®, a groundbreaking drug for chronic myeloid

leukemia (CML). What makes this drug both powerful and gentle is that it focuses

on disrupting one specific protein that causes the cancer. This specificity

allows the medicine to be strong, while sparing other enzymes. Molecular

targeting, as this technique is known is a highly promising treatment that has

been called the " wave of the future "

by Secretary of Health and Human Services Secretary, Tommy . On a human

level molecular targeting means vastly reduced side effects and better chances

of survival.

The story of Gleevec began over four decades ago, in 1960 when scientists at the

University of Pennsylvania noticed chromosomal abnormalities in the blood of CML

patients. It wasn't until the 1980s with the advent of genetic mapping that

University of Chicago scientists determined that the chromosomal abnormality

produces a cancer-causing kinase enzyme. With this enzyme as a target, Novartis

researchers, led by Drs. Zimmerman and Buchdunger, created and tested 400

molecules to find one that would target this enzyme without disrupting any of

the hundreds of other similar enzymes in a healthy cell. After two years of

testing, they developed the molecule that would become Gleevec.

Following another eight years of safety testing and development, scientists were

ready to try the drug in patients and found dramatic results. Nearly every CML

patient who took the drug was responding and they reported only minimal side

effects. After taking the medicine, one patient said, " One minute I was looking

at death. The next I was looking at my whole life in front of me. " Novartis

expanded the clinical trials to make the drug available to more patients, while

the FDA put the drug on fast track to approval in 2001. The drug and the

molecular targeting approach have given back life to CML patients and brought

hope to patients with other cancers.

In early 1990, Dr. beth Buchdunger and Dr. Juerg Zimmerman, both of

Novartis, accepted a challenge from the leaders of the tyrosine kinase

inhibition team - Nick Lydon and Matter: Refine the lead compound that

blocks the enzyme that triggers chronic myeloid leukemia (CML) without harming

other members of the same family, called kinases, that are needed for the body

to function. Two years and some 400 molecules later, the researchers and their

colleagues came up with the molecule that became Gleevec®, a medicine that is

helping many patients with this debilitating and usually fatal disease and

giving hope to patients with other cancers.

The story of Gleevec actually began three decades earlier, in 1960, when

scientists at the University of Pennsylvania noticed that one chromosome in the

blood cells of many CML patients was shorter than normal - it was missing a big

chunk of its DNA. The stubby chromosome was nicknamed " the Philadelphia

chromosome " and marked the first time that a chromosomal defect was linked to

cancer.

Scientists now had a tantalizing clue, but they didn't yet have the tools needed

to use the clue to solve the mystery of CML. Another clue was revealed thirteen

years later, when a researcher at the University of Chicago discovered that the

missing end of the short chromosome had moved and fused with another chromosome.

By the 1980s, scientists were able to use genetic mapping to show that the two

ends of the broken chromosomes produced a cancer-causing protein, known as

Bcr-Abl. In 1986 and 1987, researchers writing in Science identified the protein

as a tyrosine kinase, a kind of enzyme that, among other things, helps regulate

cell growth and division. Bcr-Abl, the scientists wrote, changes the cell's

normal genetic instructions, jamming the signal that tells the body to stop

producing white blood cells. As a result, while a cubic millimeter of blood from

a healthy person contains 4,000 to 10,000 white blood cells, the same volume of

a CML patient's

blood contains 10 to 25 this number. The proliferating white blood cells cause

pain, debilitating illness, and, all too often, death. Only three out of ten CML

patients survive for even five years. Until Gleevec, which is a daily pill,

patients faced two daunting treatment options: high-risk bone marrow transplant

or daily infusions of interferon, with side effects that have been described as

" like having a bad case of the flu every day of your life. "

With the groundbreaking discovery that a single enzyme could cause CML, medical

researchers had a clear target. The search for a drug that could block the

tyrosine kinase known as Bcr-Abl was on.

Ciba-Geigy, the company that later became Novartis, already had an active

program of searching for molecules that inhibited cancer causing tyrosine

kinases, targeting breast cancer and various solid tumors.

Enter Dr. Zimmermann, a medicinal chemist, and Dr. Buchdunger, a cell biologist.

" From the existing kinase program we had a molecule that showed some activity

against the enzyme but was weak, non-selective, and toxic, "

says Dr. Zimmermann. " The toxicity supported the hypothesis that we shouldn't

inhibit all kinases. There are hundreds of kinases in a healthy cell, and many

are important for housekeeping, such as metabolism. We had to increase the

activity of the compound and fine-tune it so it wouldn't harm the good kinases. "

It was a team effort. Dr. Zimmermann and his colleagues would design and

synthesize a molecule, and Dr. Buchdunger and her colleagues would test the

molecule against the cancer-causing enzyme.

" She would tell us 'the compound is not selective' or 'it does not penetrate the

cell' and I'd have to come up will another, " recalls Dr.

Zimmerman. " I would change the molecule. It's similar to what a locksmith does

when he has to make a key fit. You change the shape of the key and test it. Does

it fit? If not, you change it again. The molecule has to fit into a pocket of

the enzyme.... We had to do it many times. That was frustrating, but it keeps

you up and running. For me personally, I would be bored if I only had to attempt

it once. You learn from your failures. You learn how you could do a better job. "

" You go from one step to the next, " says Dr. Buchdunger. " When you find a

compound that looks interesting in terms of specificity and potency, then you

test it for toxicity, and you hope and pray. You keep your fingers crossed that

it passes the next hurdle. "

In addition to finding a molecule that was both active and selective, the

scientists had to find one that could be taken orally, in pill form.

" Oral bioavailability was a big, big hurdle, " says Dr. Zimmermann. " For us, it

was a given. We wanted a breakthrough treatment where the patient could stay

home and doesn't have to go through all the side effects. We had to go back to

the lab to improve the uptake of the drug without losing activity and

selectivity. "

Novartis had been working with Dr. Druker, a haematologist and oncologist

with specific expertise in tyrosine kinases relative to CML and then of the

Dana-Faber Cancer Institute in Boston, to profile the lead compounds identified

by Buchdunger and Zimmerman. Dr. Druker's work highlighted one compound in

particular and his work enabled the company to focus on this one compound.

The compound that would become Gleevec was synthesized in 1992. For the next

several years, company and academic scientists conducted the additional research

and initial chemical and pharmaceutical development needed to start clinical

trials.

" So many things need to happen before you dare give the compound to a patient, "

explains Dr. Buchdunger.

The first Phase I study began in June 1998. The results of these preliminary

studies were dramatic. Nearly every CML patients who took the drug was

responding. Most patients experienced a significant reduction in the number of

white blood cells and a reduction or disappearance in the number of cells

containing the cancer-triggering chromosome. Moreover, the patients reported

only minimal side effects.

Word of the drug's effectiveness spread rapidly in the CML community - through

word of mouth and Internet patient chat groups. One of the patients who was

encouraged by the trial data was Suzan McNamara.

After being diagnosed with CML in March 1998, Ms. McNamara began her battle

against the disease with a combination therapy of hydroxyurea and interferon.

She began to experience debilitating side effects, including depression, weight

loss, hair loss, and fatigue so severe she had to stop working. She tried to

enroll in a Gleevec clinical trial, but, at that time, the supply was only

adequate for the limited number of patients needed for the Phase I Study.

Knowing what a difference the drug could make for her and others, Ms. McNamara

circulated a petition to members of the Internet support group, collecting some

4,000 signatures. The petition asked Novartis to move more quickly to develop

the drug. In October 1999 she sent the petition, along with a letter, to Dan

Vasella, M.D., Chief Executive Officer of Novartis. In the letter, Ms. McNamara

explained how encouraged CML patients were about the data generated by the

trials and asked that the studies be

expanded so that more patients could participate.

In fact, the company had already assigned the highest priority to the

development of Gleevec and was already expanding the larger clinical trials to

test the drug. Ms. McNamara, and thousands of other CML patients, gained access

to Gleevec through the trials. Says Ms.

McNamara, whose cancer is now in remission and who is studying to be a molecular

biologist: " One minute I was looking at death. The next, I was looking at my

whole life in front of me. "

Positive clinical trial results prompted the U.S. Food and Drug Administration

(FDA) to grant " fast track " designation to the drug. On May 10, 2001, only ten

weeks after the company submitted a New Drug Application, the FDA approved

Gleevec for the treatment with Philadelphia chromosome-positive CML in the blast

crisis, accelerated phase or in chronic phase after failure of interferon

therapy.

There's a disconnect between lab work and real life. When we heard from

patients, we could share the excitement. A gentleman from Texas wrote us that he

had sold his house. 'My doctor told me I was going to die,' he wrote. Now he

said his only problem is that the new owner won't sell him back the house. And

people told us that there were no side effects.

Before, we would just hypothesize about selectivity, but now we know from real

patients that selectivity means freedom from side effects. For scientists, it's

a dream come true: to do something in the lab and have it help in real life. "

*- Juerg Zimmerman, Ph.D.*

Gleevec was immediately hailed as a major breakthrough by officials and

scientists. Secretary of Health and Human Services Tommy called it " the

wave of the future. " Dr. Harmon Eyre of the American Cancer Society called it " a

huge breakthrough…a great drug, a great new discovery. " But for Dr. Buchdunger

and Dr. Zimmermann, the most important affirmation came from patients.

" When the data started to come in, it was hard to believe, " recalls Dr.

Buchdunger. " But it was obvious looking at the white blood cell counts that some

patients were experiencing absolute normalization of their blood counts. "

" There's a disconnect between lab work and real life, " says Dr.

Zimmerman. " When we heard from patients, we could share the excitement.

A gentleman from Texas wrote us that he had sold his house. 'My doctor told me I

was going to die,' he wrote. Now he said his only problem is that the new owner

won't sell him back the house. And people told us that there were no side

effects. Before, we would just hypothesize about selectivity, but now we know

from real patients that selectivity means freedom from side effects. For

scientists, it's a dream come true: to do something in the lab and have it help

in real life. "

" We have learned many lessons from this compound. The scientific community has

benefited from the idea of targeting. We have learned useful lessons for the

development of new drugs, not only for cancers but for other diseases.. "

*- beth Buchdunger, Ph.D.*

Gleevec is also helping real-life patients with another kind of cancer.

Because of the proven activity of Gleevec against tyrosine kinases,

Demetri, M.D. of the Dana-Farber Cancer Institute, developed and tested the

hypothesis that Gleevec could be effective as a therapy for gastrointestinal

stromal tumor (GIST), a rare solid tumor. After clinical trials, the FDA

approved Gleevec for GIST on February 1, 2002.

Now, even after more than four decades of discovery, trials and triumphs, the

Gleevec story is not over. Novartis, in conjunction with the National Cancer

Institute, is conducting studies on how the drug works, and on its long-term

effect on patients. Clinical trials are underway to study whether Gleevec works

against other cancers, including brain cancers and soft-tissue sarcomas. And

scientists in the pharmaceutical industry and in academia are conducting

intensive research to identify cancer-causing proteins in other tumors.

Says Dr. Klausner, director of the National Cancer Institute:

" Gleevec offers proof that molecular targeting works in treating cancer,

provided that the target is correctly chosen. The challenge now is to find these

targets. "

" We have learned many lessons from this compound, " says Dr. Buchdunger, who is

overseeing preclinical research on whether Gleevec might work against other

cancers. " The scientific community has benefited from the idea of targeting. We

have learned useful lessons for the development of new drugs, not only for

cancers but for other diseases. "

Zavie

Zavie (age 69)

67 Shoreham Avenue

Ottawa, Canada, K2G 3X3

dxd AUG/99

INF OCT/99 to FEB/00, CHF

No meds FEB/00 to JAN/01

Gleevec since MAR/27/01 (400 mg)

CCR SEP/01. #102 in Zero Club

2.8 log reduction Sep/05

3.0 log reduction Jan/06

2.9 log reduction Feb/07

3.5 log reduction Jan/08

3.6 log reduction Apr/08

e-mail: zmillersympatico (DOT) ca

Tel: 613-726-1117

Fax: 309-296-0807

Cell: 613-202-0204

ID: zaviem

YM: zaviemiller

Skype: Zavie