`Timeline
`
`Date
`
`1975
`
`1976
`
`1976
`
`1981
`
`1984
`
`1984
`
`1984
`
`1985
`
`1985
`
`1987
`
`1989
`
`Event
`Georges Köhler and César Milstein, scientists at the Medical Research Council, Laboratory
`of Molecular Biology (Cambridge, UK), discovered the potential of using antibodies in
`vitro to fight disease.
`The research of Michael Bishop and Harold Varmus at the University of California San
`Francisco showed that disturbances in one or more members of a family of genes can lead
`to the transformation of a normal cell into a cancer cell.
`Genentech was founded by venture capitalist Robert A. Swanson and biochemist Dr.
`Herbert W. Boyer.
`Genentech scientists John McGrath and Art Levinson cloned and sequenced a portion of
`the human HER2 gene for the first time.
`Robert Weinberg and his team of scientists at the Massachusetts Institute of Technology
`discovered an unusual mutant rat gene encoding a tyrosine kinase that produced cancer
`features in transfected cells and named it "neu."
`Georges Köhler and César Milstein win the Nobel Prize in Medicine, "for theories
`concerning the specificity in development and control of the immune system and the
`discovery of the principle for production of monoclonal antibodies."
`Genentech scientists Axel Ullrich and Peter Seeberg, in collaboration with Mike Waterfield
`at the Imperial Cancer Research Fund and Joseph Schlesinger at the Weizmann Institute,
`published the complete human EGF-R sequence in Nature.
`Following work that began in the early 1980s, a Genentech team of scientists, including
`Axel Ullrich and Art Levinson, clone the first full-length human HER2 gene. This
`achievement is described in a paper published in Science.
`Stu Aaronson at the National Institute of Health showed that the HER2/neu gene is
`frequently amplified in human breast tumors.
`Michael Shepard, Axel Ullrich and their teams at Genentech developed mouse 4D5, the
`parent of Herceptin, simultaneous with the discovery by Dr. Dennis Slamon at UCLA, and
`colleagues at the University of Texas Health Science Center, that linked HER2 over-
`expression with a more aggressive type of breast cancer found in approximately 25
`percent of patients. Further work by Shepard's group demonstrated that the 4D5 could
`suppress the growth of HER-over-expressing tumor cells, and also enhance their
`sensitivity to killing by the host immune system. Further proof of concept was the
`demonstration by the Genentech and UCLA teams that radio-labeled 4D5 could localize to
`HER2-overexpressing tumors in patients.
`Michael Bishop and Harold Varmus were awarded the Nobel Prize in Medicine for their
`discovery that normal cells contain genes capable of becoming cancer genes.
`
`https://www.gene.com/media/product-information/herceptin-development-timeline
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`Date
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`1990
`
`1992
`
`1993
`
`1995
`
`1996
`
`Event
`Len Presta, Paul Carter and Michael Shepard of Genentech create Herceptin by
`humanizing the 4D5 mouse antibody directed at HER2.
`Genentech filed an Investigational New Drug Application (IND) with the U.S. Food and
`Drug Administration (FDA) and Phase I clinical trials were initiated.
`Genentech initiated two Phase II clinical trials that evaluated the investigational anti-
`HER2 antibody as a single agent and in combination with chemotherapy in the relapsed
`setting.
`Genentech began enrollment of the Phase III pivotal trials for patients with HER2 over-
`expressing metastatic breast cancer.
`Pivotal trial 648, double-blind, placebo-controlled study of the investigational anti-
`HER2 antibody plus chemotherapy to include 450 women with newly diagnosed
`metastatic breast cancer
`Trial 649, study of the investigational anti-HER2 antibody as a single agent to
`include 200 women whose metastatic disease had failed to respond to one or two
`rounds of chemotherapy
`Trial 650, study of the investigational anti-HER2 antibody to include 200 women who
`had newly diagnosed metastatic breast cancer but did not want chemotherapy
`Genentech worked closely with breast cancer patient advocates to design an expanded
`access program to ensure the investigational agent is available to patients with no other
`therapeutic alternatives.
`
`Genentech advanced the construction of a new manufacturing facility that would produce
`the anti-HER2 antibody.
`
`Critical efforts are undertaken to enroll patients into the trials, including:
`Genentech clinicians and outside investigators spearheaded an amendment to the
`study protocol of pivotal trial 648 to include paclitaxel chemotherapy as an
`alternative to doxorubicin chemotherapy and traveled across the country to inform
`investigators to spur interest in the trial;
`Genentech and patient advocates worked together to publicize the trials to the breast
`cancer community.
`
`March 1996
`
`Researchers at Memorial Sloan Kettering co-authored a paper titled, "Phase II study of
`weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in
`patients with HER2-neu-overexpressing metastatic breast cancer," which showed that the
`antibody was clinically active in women with HER2-neu-overexpressing metastatic breast
`cancer who had received prior therapy. The study provided evidence that targeting growth
`factor receptors caused regression of human cancer.
`December 1996 Genentech initiated a partnership with diagnostics company DAKO to develop a
`commercial test to identify patients who overexpress the HER2 gene.
`Genentech completed enrollment of the Phase III pivotal trials for the anti-HER2 antibody
`(now known as Herceptin® (Trastuzumab)).
`
`March 1997
`
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`HOSPIRA EX. 1035
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`May 1998
`
`July 1998
`
`September
`1998
`
`Date
`May 1998
`
`Event
`Genentech submitted a biologic license application (BLA) for Herceptin, and DAKO
`submitted a pre-market approval (PMA) application to the FDA for approval of the
`diagnostic HercepTest . The FDA designated Herceptin as a "Fast Track" product for the
`treatment of metastatic breast cancer.
`Herceptin treatment can result in heart problems, including those w ithout
`symptoms (reduced heart function) and those w ith symptoms (congestive heart
`failure).
`Results from a Phase III investigational clinical trial of Herceptin were presented at the
`American Society of Clinical Oncology (ASCO) annual meeting. Results showed that
`Herceptin, in combination with chemotherapy, increased time to disease progression and
`response rates.
`Herceptin treatment can result in heart problems, including those w ithout
`symptoms (reduced heart function) and those w ith symptoms (congestive heart
`failure).
`Genentech and Roche signed a licensing agreement giving Roche exclusive marketing
`rights for Herceptin outside of the United States.
`Herceptin received FDA approval for use in women with metastatic breast cancer who
`have tumors that overexpress the HER2 protein. It is indicated for treatment of patients
`both as first-line therapy in combination w ith paclitaxel chemotherapy and as a
`single agent for those w ho have received one or more chemotherapy regimens.
`Dako's HercepTest is approved simultaneously to aid in the identification of patients for
`Herceptin treatment.
`Herceptin was the first therapeutic antibody targeted to a specific (HER2) cancer-related
`molecular marker to receive FDA approval.
`Herceptin treatment can result in heart problems, including those without symptoms
`(reduced heart function) and those with symptoms (congestive heart failure). The risk and
`seriousness of these heart problems were highest in people who received both Herceptin
`and a certain type of chemotherapy (anthracycline). Some patients have had serious
`infusion reactions and lung problems; fatal infusion reactions have been reported. In most
`cases, these reactions occurred during or within 24 hours of receiving Herceptin.
`Genentech issued a letter to healthcare providers about reports of serious adverse
`events, including hypersensitivity, infusion and pulmonary reactions.
`Some patients have had serious infusion reactions and lung problems; fatal
`infusion reactions have been reported. In most cases, these reactions occurred during
`or within 24 hours of receiving Herceptin.
`European Commission approved Herceptin for the treatment of HER2-positive metastatic
`breast cancer.
`December 2000 Enrollment of two Phase III clinical trials evaluating the potential use of Herceptin for the
`adjuvant treatment of early-stage HER2-positive breast cancer was initiated. Adjuvant
`therapy is given to women with early-stage (localized) breast cancer who have had initial
`treatment — surgery with or without radiation therapy — with the goal of reducing the risk
`of cancer recurrence and/or the occurrence of metastatic disease. The studies are
`sponsored by the National Cancer Institute (NCI), part of the National Institutes of
`Health, and conducted by a network of researchers led by the National Surgical Adjuvant
`Breast and Bowel Project (NSABP) and the North Central Cancer Treatment Group
`(NCCTG).
`
`May 2000
`
`August 2000
`
`https://www.gene.com/media/product-information/herceptin-development-timeline
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`HOSPIRA EX. 1035
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`Date
`March 2001
`
`Event
`Further data from a pivotal Phase III clinical trial were published in the New England
`Journal of Medicine (NEJM) that showed a significant increase in survival for women with
`HER2-positive metastatic breast cancer who received Herceptin and chemotherapy over
`chemotherapy alone.
`Herceptin treatment can result in heart problems, including those w ithout
`symptoms (reduced heart function) and those w ith symptoms (congestive heart
`failure). The risk and seriousness of these heart problems w ere highest in people
`w ho received both Herceptin and a certain type of chemotherapy (anthracycline).
`HERA, the third adjuvant trial of Herceptin, began enrollment.
`March 2001
`December 2001 Genentech received FDA approval to include, in the product label, data that showed an
`improved median overall survival for women with HER2-positive metastatic breast cancer
`treated initially with Herceptin and chemotherapy, compared to chemotherapy alone
`(median 25.1 months compared to 20.3 months).
`Worsening of low white blood cell counts associated with chemotherapy has also
`occurred. Herceptin can cause low amniotic fluid levels and harm to the fetus when taken
`by a pregnant woman. The most common side effects associated with Herceptin were
`fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough,
`headache, fatigue, shortness of breath, rash, low white and red blood cells, and muscle
`pain.
`December 2001 BCIRG 006, the fourth adjuvant trial of Herceptin, began enrollment.
`August 2002
`Genentech received FDA approval to include information about a breast cancer gene-
`detection test method called FISH (fluorescence in situ hybridization) in the Herceptin
`product labeling.
`Results from a joint analysis of the Phase III NSABP and NCCTG clinical trials evaluating
`the addition of Herceptin to standard adjuvant therapy for early-stage HER2-positive
`breast cancer were presented at the ASCO annual meeting. According to this 3-year
`planned joint analysis, Herceptin in combination with chemotherapy significantly reduced
`the risk of cancer recurrence.
`Some patients have had serious infusion reactions and lung problems; fatal
`infusion reactions have been reported. In most cases, these reactions occurred
`during or w ithin 24 hours of receiving Herceptin.
`Genentech issued a letter to healthcare providers informing them of updated
`cardiotoxicity information related to the use of Herceptin, obtained from the Phase III
`NSABP study (B-31).
`Herceptin treatment can result in heart problems, including those w ithout
`symptoms (reduced heart function) and those w ith symptoms (congestive heart
`failure). The risk and seriousness of these heart problems w ere highest in people
`w ho received both Herceptin and a certain type of chemotherapy (anthracycline).
`In one study with Herceptin and certain types of chemotherapy, an inadequate blood
`supply to the heart occurred.
`Based on results from the joint analysis of the NSABP and NCCTG trials, Genentech filed
`a supplemental Biologics License Application (sBLA) with the FDA for Herceptin for the
`adjuvant treatment of early-stage HER2-positive breast cancer.
`
`February 2006
`
`May 2005
`
`August 2005
`
`https://www.gene.com/media/product-information/herceptin-development-timeline
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`HOSPIRA EX. 1035
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`Date
`
`November
`2006
`
`June 2007
`
`January 2008
`
`Event
`The FDA approved Herceptin as part of a treatment regimen containing doxorubicin,
`cyclophosphamide, and paclitaxel for the adjuvant treatment of patients w ith
`early-stage HER2-positive, node-positive breast cancer based on the joint analysis
`of the NSABP and NCCTG studies.
`Herceptin can cause low amniotic fluid levels and harm to the fetus when taken by a
`pregnant woman. Patients should talk to their doctor if they are pregnant or become
`pregnant while taking Herceptin.
`December 2006 Genentech submitted an sBLA with the FDA based on the global HERA study to potentially
`expand Herceptin's use in the adjuvant treatment of early-stage HER2-positive breast
`cancer.
`Genentech submitted two sBLAs to the FDA based on the global BCIRG 006 trial to
`potentially expand Herceptin's use in the adjuvant treatment of early-stage HER2-positive
`breast cancer.
`Based on the HERA one-year data, the FDA approved Herceptin as a single agent for the
`adjuvant treatment of early-stage HER2-positive node-positive breast cancer or
`node-negative (ER/ PR-negative or w ith one high-risk feature) follow ing multi-
`modality, anthracycline-based therapy. Herceptin also may be administered as a
`single agent in an every-three-week dosing schedule for one year.
`Patients receiving their first dose of Herceptin may have chills and fever as well as
`nausea, vomiting, pain, headache, dizziness, shortness of breath, low blood pressure,
`rash, and weakness.
`Based on the results of the BCIRG 006 study, the FDA approved two new Herceptin-
`containing regimens for the adjuvant treatment of early-stage HER2-positive node-
`positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer.
`The first regimen is in combination w ith docetaxel and carboplatin, (also know n
`as TCH for Taxotere®, carboplatin, and Herceptin) w hich does not contain an
`anthracycline (doxorubicin) component.
`The second is part of a treatment regimen containing anthracycline
`(doxorubicin), cyclophosphamide, and docetaxel (AC-TH).
`
`May 2008
`
`October 2008
`
`October 2010
`
`In comparison to AC-TH, TCH provided a similarly effective treatment option.
`Worsening of low white blood cell counts associated with chemotherapy has also
`occurred.
`More than 420,000 women with HER2-positive breast cancer have been treated with
`Herceptin worldwide.
`The FDA approved Herceptin in combination with cisplatin and capecitabine or 5-
`fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or
`gastroesophageal junction adenocarcinoma, who have not received prior treatment for
`metastatic disease.
`
`Important Safety Information and Serious Side Effects
`
`https://www.gene.com/media/product-information/herceptin-development-timeline
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`HOSPIRA EX. 1035
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`Important Patient Safety Information
`
`Possible Serious Side Effects With HERCEPTIN
`
`Not all people have serious side effects, but side effects with HERCEPTIN therapy are
`common.
`
`Although some people may have a lifethreatening side effect, most do not.
`
`Your doctor will stop treatment if any serious side effects occur.
`
`HERCEPTIN is not for everyone. Be sure to contact your doctor if you are
`experiencing any of the following:
`
`HEART PROBLEMS
`
`These include heart problems—such as congestive heart failure or reduced heart function
`—with or without symptoms. The risk for and seriousness of these heart problems were
`highest in people who received both HERCEPTIN and a certain type of chemotherapy
`(anthracycline). In a study of adjuvant (early) breast cancer, one patient died of
`significantly weakened heart muscle. Your doctor will check for signs of heart problems
`before, during, and after treatment with HERCEPTIN.
`
`INFUSION REACTIONS, including:
`
`Fever and chills
`Feeling sick to your stomach (nausea)
`Throwing up (vomiting)
`Pain (in some cases at tumor sites)
`
`Headache
`
`Dizziness
`Shortness of breath
`
`These signs usually happen within 24 hours after receiving HERCEPTIN.
`
`Be sure to contact your doctor if you:
`
`Are a woman who could become pregnant, or may be pregnant
`
`https://www.gene.com/media/product-information/herceptin-development-timeline
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`HOSPIRA EX. 1035
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`HERCEPTIN may result in the death of unborn baby and birth defects. Birth control should
`be used while receiving HERCEPTIN after your last dose of HERCEPTIN. If you are exposed
`to HERCEPTIN during pregnancy or within 7 months of becoming pregnant, you are
`encouraged to enroll in the MotHER Pregnancy Registry by contacting 18006906720 or
`visiting http://www.motherpregnancyregistry.com/ and report HERCEPTIN exposure to
`Genentech at 18888352555.
`
`Have any signs of SEVERE LUNG PROBLEMS, including
`
`Severe shortness of breath
`Fluid in or around the lungs
`
`Weakening of the valve between the heart and the lungs
`Not enough oxygen in the body
`Swelling of the lungs
`Scarring of the lungs
`
`Your doctor may check for signs of severe lung problems when he or she examines you.
`
`Have LOW WHITE BLOOD CELL COUNTS
`
`Low white blood cell counts can be life threatening. Low white blood cell counts were seen
`more often in patients receiving HERCEPTIN plus chemotherapy than in patients receiving
`chemotherapy alone.
`
`Your doctor may check for signs of low white blood cell counts when he or she examines
`you.
`
`Other Important Information
`
`Before taking HERCEPTIN, you must have a HER2 test to determine if your cancer is
`HER2-positive. This is because the benefit of treatment with HERCEPTIN has been shown
`only in patients whose tumors are HER2positive.
`
`Side Effects Seen Most Often With HERCEPTIN
`
`Some patients receiving HERCEPTIN for breast cancer had the following side effects:
`
`https://www.gene.com/media/product-information/herceptin-development-timeline
`
`
`
`Fever
`Feeling sick to your stomach (nausea)
`Throwing up (vomiting)
`Infusion reactions
`
`Diarrhea
`
`Infections
`Increased cough
`
`Headache
`Feeling tired
`Shortness of breath
`
`Rash
`Low white and red blood cell counts
`
`Muscle pain
`
`Some patients receiving HERCEPTIN for metastatic stomach cancer had the following side
`
`effects:
`
`Low white blood cell counts
`
`Diarrhea
`Feeling tired
`Low red blood cell counts
`
`Swelling of the mouth lining
`Weight loss
`Upper respiratory tract infections
`
`Fever
`Low platelet counts
`
`Swelling of the mucous membranes
`Swelling of the nose and throat
`Change in taste
`
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`
`
`
`You should contact your doctor immediately if you have any of the side effects listed
`above.
`
`You are encouraged to report side effects to Genentech and the FDA. You may report side
`effects to the FDA at 1–800–FDA–1088 or http://www.fda.gov/medwatch. You may also
`report side effects to Genentech at 1–888–835–2555.
`
`Please see additional select Important Safety Information throughout, and the full
`Prescribing Information, including Boxed WARNINGS.
`
`https://www.gene.com/media/product-information/herceptin-development-timeline