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`FDA Approves IXEMPRA™ (Ixabepilone), a SemiSynthetic Analog of Epothilone B, for the Treatment of Advanced Breast Cancer | BMS Newsroom
`
`FDA Approves IXEMPRA™ (Ixabepilone), a Semi‐Synthetic
`Analog of Epothilone B, for the Treatment of Advanced Breast
`Cancer
`
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`Tuesday, October 16, 2007 8:00 am EDT
`
`PRINCETON, N.J.(BUSINESS WIRE)BristolMyers Squibb
`Company (NYSE: BMY) announced today that the U.S. Food
`and Drug Administration (FDA) has granted approval of
`IXEMPRA™ (ixabepilone) as monotherapy for the treatment
`of patients with metastatic or locally advanced breast cancer
`in patients whose tumors are resistant or refractory to
`anthracyclines, taxanes, and capecitabine. The FDA has also
`granted approval of IXEMPRA in combination with
`capecitabine for the treatment of patients with metastatic or
`locally advanced breast cancer resistant to treatment with
`an anthracycline, and a taxane, or whose cancer is taxane
`resistant and for whom further anthracycline therapy is
`contraindicated. IXEMPRA is a microtubule inhibitor belonging
`to a class of antineoplastic agents, the epothilones. Bristol
`Myers Squibb anticipates that IXEMPRA will be available within days.
`
`"Previously,
`patients with
`aggressive
`metastatic or
`locally advanced
`breast cancer no
`longer responding
`to currently
`available
`chemotherapies
`had limited
`treatment
`options"
`
`"Previously, patients with aggressive metastatic or locally advanced breast cancer
`no longer responding to currently available chemotherapies had limited treatment
`options," said Linda Vahdat, M.D., Associate Professor of Clinical Medicine and
`Associate Attending Physician, New YorkPresbyterian Hospital/Weill Cornell Medical
`Center. "The approval of IXEMPRA means that we now have an important new
`option for patients with metastatic breast cancer who have rapidly progressed
`through currently approved chemotherapies."
`
`"BristolMyers Squibb has a rich history in oncology spanning more than 40 years,
`and we are extremely proud that IXEMPRA has been approved as it is a significant
`addition to the BristolMyers Squibb oncology portfolio and addresses a serious
`unmet medical need in the treatment of patients with metastatic or locally
`advanced breast cancer," said Elliott Sigal, M.D., Ph.D., Executive Vice President,
`Chief Scientific Officer and President, Research and Development, BristolMyers
`Squibb.
`
`Registrational Trials
`
`The FDA reviewed the efficacy and safety of IXEMPRA based on the analysis of two
`multicenter, multinational trials that included 878 patients and evaluated IXEMPRA
`either as a monotherapy or in combination with capecitabine in patients with
`metastatic or locally advanced breast cancer.
`
`(Phase II, Monotherapy Trial: 081) The singlearm Phase II trial evaluated the
`efficacy and safety of IXEMPRA as a monotherapy. This study enrolled 126 patients
`with metastatic or locally advanced breast cancer resistant to three prior therapies
`(an anthracycline, a taxane and capecitabine). Resistance was defined as disease
`progression while on therapy in the metastatic setting (defined as progression
`while on treatment or within eight weeks of last dose) or recurrence within six
`months of the last dose in the adjuvant or neoadjuvant setting (only for
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`FDA Approves IXEMPRA™ (Ixabepilone), a SemiSynthetic Analog of Epothilone B, for the Treatment of Advanced Breast Cancer | BMS Newsroom
`12/18/2014
`anthracycline and taxane). HER2 positive patients must also have progressed
`during or after discontinuation of trastuzumab. The primary endpoint was objective
`response rate, which is an assessment of tumor shrinkage in response to
`treatment. Results determined by an independent radiology review (IRR) showed
`an objective partial response of 12.4% (95% CI, 6.919.9) in 113 response
`evaluable patients.
`
`Treatmentrelated nonhematological adverse events (greater than or equal to
`20%) included: peripheral sensory neuropathy 62% (Grade 3/4: 14%),
`fatigue/asthenia 56% (Grade 3/4: 13%), myalgia/arthralgia 49% (Grade 3/4: 8%),
`alopecia 48% (Grade 3/4: 0%), nausea 42% (Grade 3/4: 2%), stomatitis/mucositis
`29% (Grade 3/4: 6%), vomiting 29% (Grade 3/4: 1%), diarrhea 22% (Grade 3/4:
`1%), and musculoskeletal pain 20% (Grade 3/4: 3%). Treatmentrelated
`hematological adverse events (greater than or equal to 20%) included:
`neutropenia (Grade 3/4: 54%) and leukopenia (Grade 3/4: 49%).
`
`(Phase III, Combination Trial: 046) The randomized Phase III trial evaluated the
`efficacy and safety of IXEMPRA in combination with capecitabine in comparison with
`capecitabine as monotherapy. This trial included 752 patients who were previously
`treated with anthracyclines and taxanes, and whose tumors had demonstrated
`prior resistance to these therapies. Anthracycline resistance is defined as
`progression while on therapy or within six months in the adjuvant setting, or three
`months in the metastatic setting. Taxane resistance is defined as progression while
`on therapy or within 12 months in the adjuvant setting or four months in the
`metastatic setting. Evaluation of the primary endpoint demonstrated that IXEMPRA
`in combination with capecitabine resulted in a statistically significant improvement in
`progressionfree survival compared to capecitabine monotherapy median 5.7
`(95% CI, 4.86.7) vs. 4.1 months (95% CI, 3.14.3); P<0.0001, Hazard ratio=0.69
`(95% CI, 0.580.83).
`
`Treatmentrelated nonhematological adverse events (greater than or equal to
`20%) reported in patients treated with IXEMPRA in combination with capecitabine
`included: peripheral sensory neuropathy 65% (Grade 3/4: 21%), palmarplantar
`erythrodysesthesia (handfoot) syndrome 64% (Grade 3/4: 18%), fatigue/asthenia
`60% (Grade 3/4: 16%), nausea 53% (Grade 3/4: 3%), diarrhea 44% (Grade 3/4:
`6%), vomiting 39% (Grade 3/4: 4%), myalgia/arthralgia 39% (Grade 3/4: 8%),
`anorexia 34% (Grade 3/4: 3%), stomatitis/mucositis 31% (Grade 3/4: 4%), alopecia
`31% (Grade 3/4: 0%), abdominal pain 24% (Grade 3/4: 2%), nail disorder 24%
`(Grade 3/4: 2%), musculoskeletal pain 23% (Grade 3/4: 2%), and constipation 22%
`(Grade 3/4: 0%). Treatmentrelated hematological adverse events (greater than or
`equal to 20%) reported in patients treated with IXEMPRA in combination with
`capecitabine included: neutropenia (Grade 3/4: 68%) and leukopenia (Grade 3/4:
`57%).
`
`Comparative treatmentrelated nonhematological adverse events reported in
`patients treated with capecitabine alone included: peripheral sensory neuropathy
`16% (Grade 3/4: 0%), palmarplantar erythrodysesthesia (handfoot syndrome)
`63% (Grade 3/4: 17%), fatigue/asthenia 29% (Grade 3/4: 4%), nausea 40%
`(Grade 3/4: 2%), diarrhea 39% (Grade 3/4: 9%), vomiting 24% (Grade 3/4: 2%),
`myalgia/arthralgia 5% (Grade 3/4: <1%), anorexia 15% (Grade 3/4: 1%),
`stomatitis/mucositis 20% (Grade 3/4: 3%), alopecia 3% (Grade 3/4: 0%), abdominal
`pain 14% (Grade 3/4: 1%), nail disorder 10% (Grade 3/4: <1%), musculoskeletal
`pain 5% (Grade 3/4: 0%), and constipation 6% (Grade 3/4: <1%). Treatment
`related hematological adverse events of Grade 3/4 severity reported in patients
`treated with capecitabine alone included: neutropenia 11% and leukopenia 6%.
`
`IMPORTANT SAFETY INFORMATION
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`FDA Approves IXEMPRA™ (Ixabepilone), a SemiSynthetic Analog of Epothilone B, for the Treatment of Advanced Breast Cancer | BMS Newsroom
`12/18/2014
`TOXICITY IN HEPATIC IMPAIRMENT
`
`IXEMPRA (ixabepilone) in combination with capecitabine is contraindicated in
`patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk
`of toxicity and neutropeniarelated death.
`
`In combination with capecitabine, the overall frequency of Grade 3/4 adverse
`reactions, febrile neutropenia, serious adverse reactions, and toxicity related
`deaths was greater in patients with hepatic impairment.
`
`Caution should be used when using IXEMPRA as monotherapy in patients with AST
`or ALT > 5 x ULN. Use of IXEMPRA in patients with AST or ALT > 10 x ULN or bilirubin
`>3 x ULN is not recommended.
`
`With monotherapy, Grade 4 neutropenia, febrile neutropenia, and serious adverse
`reactions were more frequent in patients with hepatic impairment.
`
`CONTRAINDICATIONS
`
`IXEMPRA is contraindicated in patients:
`
` with a known history of a severe (CTC Grade 3/4) hypersensitivity reaction to
`agents containing Cremophor® EL or its derivatives such as polyoxyethylated
`castor oil.
`
` who have a baseline neutrophil count <1500 cells/mm3 or a platelet count
`<100,000 cells/mm3.
`
`PERIPHERAL NEUROPATHY
`
`Patients treated with IXEMPRA should be monitored for symptoms of neuropathy,
`such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort,
`or neuropathic pain. Patients experiencing new or worsening peripheral neuropathy
`may require changes in the dose or discontinuation of IXEMPRA. Neuropathy was
`the most frequent cause of treatment discontinuation due to drug toxicity. Caution
`should be used when treating patients with diabetes mellitus or existing moderate
`to severe neuropathy.
`
`MYELOSUPPRESSION
`
`Patients should be monitored for myelosuppression; frequent peripheral blood cell
`counts are recommended for all patients receiving IXEMPRA.
`
`Patients who experience severe neutropenia or thrombocytopenia should have
`their dose reduced. Neutropenia related deaths occurred in patients administered
`IXEMPRA and capecitabine (1.9% of 414 patients) and IXEMPRA alone (0.4% in 240
`patients).
`
`HYPERSENSITIVITY REACTION
`
`Premedicate with an H1 and an H2 antagonist approximately 1 hour before
`IXEMPRA infusion and observe for hypersensitivity reactions (e.g., flushing, rash,
`dyspnea, and bronchospasm).
`
`In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped
`and aggressive supportive treatment (e.g., epinephrine, corticosteroids) started.
`
`Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must
`be premedicated in subsequent cycles with a corticosteroid in addition to the H1
`and H2 antagonists, and extension of the infusion time should be considered.
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`IMMUNOGEN 2220, pg. 3
`Phigenix v. Immunogen
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`FDA Approves IXEMPRA™ (Ixabepilone), a SemiSynthetic Analog of Epothilone B, for the Treatment of Advanced Breast Cancer | BMS Newsroom
`12/18/2014
`PREGNANCY
`
`Women should be advised not to become pregnant when taking IXEMPRA. If this
`drug is used during pregnancy or the patient becomes pregnant, the patient should
`be apprised of the potential hazard to the fetus.
`
`CARDIAC ADVERSE REACTIONS
`
`Caution should be exercised in patients with a history of cardiac disease.
`Discontinuation of IXEMPRA should be considered in patients who develop cardiac
`ischemia or impaired cardiac function due to reports of cardiovascular adverse
`reactions (e.g., myocardial ischemia, superventricular arrhythmia, and ventricular
`dysfunction). The frequency of cardiac adverse reactions (myocardial ischemia and
`ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine
`(1.9%) than in the capecitabine alone (0.3%) treatment group.
`
`POTENTIAL FOR COGNITIVE IMPAIRMENT FROM EXCIPIENTS
`
`IXEMPRA contains dehydrated alcohol USP. Consideration should be given to the
`possibility of central nervous system and other effects of alcohol.
`
`ADVERSE REACTIONS
`
`The most common adverse reactions (greater than or equal to 20%) reported by
`patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia,
`myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and
`musculoskeletal pain. The following additional events occurred in greater than or
`equal to 20% in combination treatment: palmarplantar erythrodysesthesia (hand
`foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. Drug
`associated hematologic abnormalities (>40%) include neutropenia, leukopenia,
`anemia, and thrombocytopenia.
`
`Please see accompanying full Prescribing Information including boxed WARNING
`regarding hepatic impairment.
`
`About BristolMyers Squibb
`
`For more than 40 years, BristolMyers Squibb has been committed to building a
`unified vision for the future of cancer treatment. With expertise, dedication and
`resolve, that vision led to the development of a diverse global portfolio of anti
`cancer therapies that are an important cornerstone of care today. Hundreds of
`scientists in BristolMyers Squibb's Research & Development organization are
`studying ways to improve current cancer treatments and identify better, more
`effective medicines for the future. BristolMyers Squibb is a global pharmaceutical
`and related health care products company whose mission is to extend and enhance
`human life.
`
`For more information regarding IXEMPRA, please call 1888IXEMPRA (1888493
`6772) Monday through Friday 8:00 am5:00 pm ET or visit
`http://www.ixempra.com/.
`
`This press release contains "forwardlooking statements" as that term is defined in the
`Private Securities Litigation Reform Act of 1995. Such forwardlooking statements are
`based on current expectations and involve inherent risks and uncertainties, including
`factors that could delay, divert or change any of them, and could cause actual outcomes
`and results to differ materially from current expectations. No forwardlooking statement
`can be guaranteed. Among other risks, there can be no guarantee as to when IXEMPRA
`(ixabepilone) will be commercially available. Forwardlooking statements in this press
`release should be evaluated together with the many uncertainties that affect Bristol
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`http://news.bms.com/pressrelease/fdaapprovesixempraixabepilonesemisyntheticanalogepothilonebtreatmentadvanced
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`IMMUNOGEN 2220, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
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`FDA Approves IXEMPRA™ (Ixabepilone), a SemiSynthetic Analog of Epothilone B, for the Treatment of Advanced Breast Cancer | BMS Newsroom
`12/18/2014
`Myers Squibb's business, particularly those identified in the cautionary factors
`discussion in BristolMyers Squibb's Annual Report on Form 10K for the year ended
`December 31, 2006 and in our Quarterly Reports on Form 10Q. BristolMyers Squibb
`undertakes no obligation to publicly update any forwardlooking statement, whether as
`a result of new information, future events or otherwise.
`
`SOURCE: BristolMyers Squibb Company
`
`CONTACT: Media, Madeline Malia, Communications, +16092523347, or
`
`mobile, +16096511323, madeline.malia@bms.com, or Tony Plohoros,
`
`Communications, +16092527938, or +12125464379, or mobile,
`
`+19085912839, tony.plohoros@bms.com, or investors, John Elicker, Investor
`
`Relations, +12125463375, john.elicker@bms.com, all of BristolMyers Squibb
`
`Web site: http://www.bms.com/
`
`http://www.ixempra.com/
`
`Business Wire NewsHQ℠
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`IMMUNOGEN 2220, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
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