5.5 Venous Thromboembolic Events
`An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see Adverse
`Reactions (6.1)]. In Study GOG-0240, Grades 3-4 VTE occurred in 11 % of patients receiving Avastin with
`chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of
`Grades 3-4 VTE was 5% in patients receiving A vastin with chemotherapy compared to 2% in patients receiving
`chemotherapy alone.
`
`Discontinue A vastin in patients with a Grade 4 VTE, including pulmonary embolism.
`
`5.6 Hypertension
`Severe hypertension occurred at a higher incidence in patients receiving A vastin as compared to patients
`receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-4 hypertension ranged from
`5% to 18%.
`
`Monitor blood pressure every two to three weeks during treatment with A vastin. Treat with appropriate
`anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular
`intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuing Avastin. Withhold
`A vastin in patients with severe hypertension that is not controlled with medical management; resume once
`controlled with medical management. Discontinue in patients who develop hypertensive crisis or hypertensive
`encephalopathy.
`
`5.7 Posterior Reversible Encephalopathy Syndrome
`Posterior reversible encephalopathy syndrome (PRES) was reported in <0.5% of patients across clinical studies.
`The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES is a neurological disorder
`which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic
`disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm
`the diagnosis of PRES.
`
`Discontinue Avastin in patients who develop PRES. Symptoms usually resolve or improve within days after
`discontinuing A vastin, although some patients have experienced ongoing neurologic sequelae. The safety of
`reinitiating A vastin in patients who developed PRES is not known.
`
`5.8 Renal Injury and Proteinuria
`The incidence and severity of proteinuria was higher in patients receiving A vastin as compared to patients
`receiving chemotherapy. Grade 3 (defined as urine dipstick 4+ or> 3.5 grams of protein per 24 hours) to Grade
`4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies. The overall incidence of
`proteinuria (all grades) was only adequately assessed in Study BOl 7705, in which the incidence was 20%.
`Median onset ofproteinuria was 5.6 months (15 days to 37 months) after initiating Avastin. Median time to
`resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median
`follow-up of 11.2 months and required discontinuation of A vastin in 30% of the patients who developed
`proteinuria [see Adverse Reactions (6.1)].
`
`In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving
`A vastin with chemotherapy experienced Grades 2-4 ( defined as urine dipstick 2+ or greater or > 1 gram of
`protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2-4 proteinuria resolved in 74% of patients.
`Avastin was reinitiated in 42% of patients. Of the 113 patients who reinitiated Avastin, 48% experienced a
`second episode of Grades 2-4 proteinuria.
`
`N ephrotic syndrome occurred in < 1 % of patients receiving A vastin across clinical studies, in some instances
`with fatal outcome. In a published case series, kidney biopsy of 6 patients with proteinuria showed findings
`consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who received
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Avastin with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of
`elevated serum creatinine levels (between 1.5 to 1.9 times baseline levels) in patients who received Avastin.
`Serum creatinine levels did not return to baseline in approximately one-third of patients who received A vastin.
`
`Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial
`urinalyses during A vastin therapy. Patients with a 2+ or greater urine dipstick reading should undergo further
`assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per
`24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic
`syndrome.
`
`Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine
`Ratio) and 24-hour urine protein [Pearson Correlation 0.39 (95% Cl: 0.17, 0.57)].
`
`Infusion-Related Reactions
`5.9
`Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension,
`hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3
`hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions
`
`I with the first dose occurred in <3% of patients and severe reactions occurred in 0.4% of patients.
`
`Decrease the rate of infusion for mild, clinically insignificant infusion-related reactions. Interrupt the infusion in
`patients with clinically significant infusion-related reactions and consider resuming at a slower rate following
`resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriate
`medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).
`
`5.10 Embryo-Fetal Toxicity
`Based on its mechanism of action and findings from animal studies, A vastin may cause fetal harm when
`administered to pregnant women. Congenital malformations were observed with the administration of
`bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10
`mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female
`reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential
`risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with
`Avastin and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)}.
`
`5.11 Ovarian Failure
`The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving Avastin with
`chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After
`discontinuing A vastin, recovery of ovarian function at all time points during the post-treatment period was
`demonstrated in 22% of women receiving A vastin. Recovery of ovarian function is defined as resumption of
`menses, a positive serum ~-HCG pregnancy test, or an FSH level < 30 mIU/mL during the post-treatment
`period. Long-term effects of A vastin on fertility are unknown. Inform females of reproductive potential of the
`risk of ovarian failure prior to initiating Avastin [see Adverse Reactions (6.1), Use in Specific Populations
`(8.3)}.
`
`5.12 Congestive Heart Failure (CHF)
`A vastin is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade 2:. 3 left
`ventricular dysfunction was 1 % in patients receiving Avastin compared to 0.6% of patients receiving
`chemotherapy alone. Among patients who received prior antbracycline treatment, the rate of CHF was 4% for
`patients receiving Avastin with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone.
`
`In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left
`ventricular ejection fraction (L VEF) were increased in patients receiving A vastin with antbracycline-based
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`chemotherapy compared to patients receiving placebo with the same chemotherapy regimen. The proportion of
`patients with a decline in LVEF from baseline of2'.: 20% or a decline from baseline of 10% to< 50%, was 10%
`in patients receiving A vastin with chemotherapy compared to 5% in patients receiving chemotherapy alone.
`Time to onset of left-ventricular dysfunction or CHF was 1 to 6 months after the first dose in at least 85% of the
`patients and was resolved in 62% of the patients who developed CHF in the Avastin arm compared to 82% in
`the placebo arm. Discontinue A vastin in patients who develop CHF.
`
`6 ADVERSE REACTIONS
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`• Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1)}.
`• Surgery and Wound Healing Complications [see Warnings and Precautions (5.2)}.
`• Hemorrhage [see Warnings and Precautions (5.3)}.
`• Arterial Thromboembolic Events [see Warnings and Precautions (5.4)}.
`• Venous Thromboembolic Events [see Warnings and Precautions (5.5)].
`• Hypertension [see Warnings and Precautions (5.6)].
`• Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5. 7)].
`• Renal Injury and Proteinuria [see Warnings and Precautions (5.8)}.
`•
`Infusion-Related Reactions [see Warnings and Precautions (5.9)}.
`• Ovarian Failure [see Warnings and Precautions (5.11)}.
`• Congestive Heart Failure [see Warnings and Precautions (5.12)].
`
`6.1 Clinical Trials Experience
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not
`reflect the rates observed in practice.
`
`The safety data in Warnings and Precautions and described below reflect exposure to A vastin in 4463 patients
`including those with mCRC (A VF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101),
`mRCC (BOl 7705), cervical cancer (GOG-0240), epithelial ovarian, fallopian tube, or primary peritoneal cancer
`(MO22224, AVF4095, GOG-0213, and GOG-0218), or HCC (1Mbrave150) at the recommended dose and
`schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving
`A vastin as a single agent or in combination with other anti-cancer therapies at a rate > 10% were epistaxis,
`headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back
`pain, and exfoliative dermatitis.
`
`Across clinical studies, A vastin was discontinued in 8% to 22% of patients because of adverse reactions [see
`Clinical Studies (14)].
`
`Metastatic Colorectal Cancer
`
`In Combination with bolus-IFL
`The safety of A vastin was evaluated in 392 patients who received at least one dose of A vastin in a double-blind,
`active-controlled study (A VF2107g), which compared Avastin (5 mg/kg every 2 weeks) with bolus-IFL to
`placebo with bolus-IFL in patients with mCRC [see Clinical Studies (14.1)}. Patients were randomized (1:1:1)
`to placebo with bolus-IFL, Avastin with bolus-IFL, or Avastin with fluorouracil and leucovorin. The
`demographics of the safety population were similar to the demographics of the efficacy population. All
`Grades 3-4 adverse reactions and selected Grades 1-2 adverse reactions (i.e., hypertension, proteinuria,
`thromboembolic events) were collected in the entire study population. Adverse reactions are presented in
`Table 2.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 2: Grades 3-4 Adverse Reactions Occurring at Higher Incidence ~2%) in Patients Receiving
`Avastin vs. Placebo in Study AVF2107g
`
`Adverse Reaction8
`
`Hematolol!V
`Leukopenia
`Neutropenia
`Gastrointestinal
`Diarrhea
`Abdominal pain
`Constipation
`Vascular
`Hypertension
`Deep vein thrombosis
`Intra-abdominal thrombosis
`Syncope
`General
`Asthenia
`Pain
`a NCI-CTC version 3
`
`A vastin with IFL
`(N=392)
`
`Placebo with IFL
`(N=396)
`
`37%
`21%
`
`34%
`8%
`4%
`
`12%
`9%
`3%
`3%
`
`10%
`8%
`
`31%
`14%
`
`25%
`5%
`2%
`
`2%
`5%
`1%
`1%
`
`7%
`5%
`
`In Combination with FOLFOX4
`The safety of A vastin was evaluated in 521 patients in an open-label, active-controlled study (E3200) in patients
`who were previously treated with irinotecan and fluorouracil for initial therapy for mCRC. Patients were
`randomized (1:1:1) to FOLFOX4, Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with
`FOLFOX4, or Avastin alone (10 mg/kg every 2 weeks). Avastin was continued until disease progression or
`unacceptable toxicity.
`
`The demographics of the safety population were similar to the demographics of the efficacy population.
`
`Selected Grades 3-5 non-hematologic and Grades 4-5 hematologic occurring at a higher incidence (;?:2%) in
`patients receiving Avastin with FOLFOX4 compared to FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea
`(18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (l 1 % vs. 4%), dehydration
`(10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1 %), other
`neurological (5% vs. 3%), ileus (4% vs. 1 %) and headache (3% vs. 0%). These data are likely to under-estimate
`the true adverse reaction rates due to the reporting mechanisms.
`
`First-Line Non Squamous Non-Small Cell Lung Cancer
`
`The safety of Avastin was evaluated as first-line treatment in 422 patients with unresectable NSCLC who
`received at least one dose of A vastin in an active-controlled, open-label, multicenter trial (E4599) [see Clinical
`Studies (14.3)). Chemotherapy nai"ve patients with locally advanced, metastatic or recurrent non-squamous
`NSCLC were randomized (1 :1) to receive six 21-day cycles of paclitaxel and carboplatin with or without
`Avastin (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients
`randomized to receive A vastin continued to receive A vastin alone until disease progression or until
`unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors
`only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more ofred blood), unstable angina, or receiving
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`therapeutic anticoagulation. The demographics of the safety population were similar to the demographics of the
`efficacy population.
`
`Only Grades 3-5 non-hematologic and Grades 4-5 hematologic adverse reactions were collected. Grades 3-5
`non-hematologic and Grades 4-5 hematologic adverse reactions occurring at a higher incidence (2:: 2%) in
`patients receiving A vastin with paclitaxel and carboplatin compared with patients receiving chemotherapy alone
`were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without
`neutropenia (7% vs. 3%), venous thromboembolism (5% vs. 3%), febrile neutropenia (5% vs. 2%),
`pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%),
`hyponatremia (4% vs. 1 %), headache (3% vs. 1 %) and proteinuria (3% vs. 0%).
`
`Recurrent Glioblastoma
`
`The safety of Avastin was evaluated in a multicenter, randomized, open-label study (EORTC 26101) in patients
`with recurrent GBM following radiotherapy and temozolomide of whom 278 patients received at least one dose
`of Avastin and are considered safety evaluable [see Clinical Studies (14.4)}. Patients were randomized (2:1) to
`receive Avastin (10 mg/kg every 2 weeks) with lomustine or lomustine alone until disease progression or
`unacceptable toxicity. The demographics of the safety population were similar to the demographics of the
`efficacy population. In the A vastin with lomustine arm, 22% of patients discontinued treatment due to adverse
`reactions compared with 10% of patients in the lomustine arm. In patients receiving A vastin with lomustine, the
`adverse reaction profile was similar to that observed in other approved indications.
`
`Metastatic Renal Cell Carcinoma
`
`The safety of Avastin was evaluated in 337 patients who received at least one dose of Avastin in a multicenter,
`double-blind study (BO 17705) in patients with mRCC. Patients who had undergone a nephrectomy were
`randomized (1:1) to receive either Avastin (10 mg/kg every 2 weeks) or placebo with interferon alfa [see
`Clinical Studies (14. 5 )} . Patients were treated until disease progression or unacceptable toxicity. The
`demographics of the safety population were similar to the demographics of the efficacy population.
`
`Grades 3-5 adverse reactions occurring at a higher incidence ( >2%) were fatigue (13% vs. 8%), asthenia (10%
`vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1 %; including hypertension and hypertensive crisis),
`and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric
`ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage,
`respiratory tract hemorrhage, and traumatic hematoma). Adverse reactions are presented in Table 3.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Adverse Reaction•
`
`Table 3: Grades 1-5 Adverse Reactions Occurring at Higher Incidence ~5%) of Patients Receiving
`:t
`A
`ti
`Pl b
`Alf . St d BO17705
`"th I t
`n er eron
`am U IV
`vas n vs. ace o w1
`A vastin with Interferon
`Placebo with Interferon
`Alfa
`Alfa
`(N=337)
`(N=304)
`
`Metabolism and nutrition
`Decreased annetite
`W eiclit loss
`General
`Fatiirue
`Vascular
`Hypertension
`Resniratorv. thoracic and mediastinal
`Epistaxis
`Dysphonia
`Nervous system
`Headache
`Gastrointestinal
`Diarrhea
`Renal and urinary
`Proteinuria
`Musculoskeletal and connective tissue
`Mvalgia
`Back pain
`a NCI-CTC vemon 3
`
`36%
`20%
`
`33%
`
`28%
`
`27%
`5%
`
`24%
`
`21%
`
`20%
`
`19%
`12%
`
`31%
`15%
`
`27%
`
`9%
`
`4%
`0%
`
`16%
`
`16%
`
`3%
`
`14%
`6%
`
`The following adverse reactions were reported at a 5-fold greater incidence in patients receiving Avastin with
`interferon-alfa compared to patients receiving placebo with interferon-alfa and not represented in Table 3:
`gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. O); blurred vision (8 vs. O); gingivitis (8 vs. 1);
`gastroesophageal reflux disease (8 vs. l); tinnitus (7 vs. l); tooth abscess (7 vs. O); mouth ulceration (6 vs. O);
`acne (5 vs. O); deafness (5 vs. O); gastritis (5 vs. O); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).
`
`Persistent, Recurrent, or Metastatic Cervical Cancer
`
`The safety of Avastin was evaluated in 218 patients who received at least one dose of Avastin in a multicenter
`study (GOG-0240) in patients with persistent, recurrent, or metastatic cervical cancer[see Clinical Studies
`(14. 6)). Patients were randomized (1: 1: 1: 1) to receive paclitaxel and cisplatin with or without Avastin (15
`mg/kg every 3 weeks), or paclitaxel and topotecan with or without Avastin (15 mg/kg every 3 weeks). The
`demographics of the safety population were similar to the demographics of the efficacy population.
`
`Grades 34 adverse reactions occurring at a higher incidence(~ 2%) in 218 patients receiving Avastin with
`chemotherapy compared to 222 patients receiving chemotherapy alone were abdominal pain (12% vs. 10%),
`hypertension (11 % vs. 0.5%), thrombosis (8% vs. 3%), diarrhea (6% vs. 3%), anal fistula (4% vs. 0%),
`proctalgia (3% vs. 0%), urinary tract infection (8% vs. 6%), cellulitis (3% vs. 0.5%), fatigue (14% vs. 10%),
`hypokalemia (7% vs. 4%), hyponatremia (4% vs. 1 %), dehydration (4% vs. 0.5%), neutropenia (8% vs. 4%),
`lymphopenia (6% vs. 3%), back pain (6% vs. 3%), and pelvic pain (6% vs. 1 %). Adverse reactions are
`presented in Table 4.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 4: Grades 1-4 Adverse Reactions Occurring at Higher Incidence~ 5%) in Patients Receiving
`A vastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240
`
`A vastin with
`Chemotherapy
`(N=218)
`
`Chemotherapy
`(N=222)
`
`80%
`15%
`
`34%
`26%
`24%
`21%
`19%
`16%
`
`29%
`10%
`
`22%
`10%
`
`22%
`8%
`
`17%
`
`17%
`
`16%
`10%
`
`15%
`6%
`6%
`
`14%
`
`12%
`12%
`
`75%
`22%
`
`26%
`19%
`15%
`7%
`10%
`11%
`
`6%
`3%
`
`14%
`5%
`
`13%
`1%
`
`10%
`
`1%
`
`10%
`3%
`
`10%
`1%
`0%
`
`8%
`
`6%
`5%
`
`Adverse Reactions
`
`General
`Fatigue
`Peripheral edema
`Metabolism and nutrition
`Decreased appetite
`Hyperglycemia
`Hypomagnesemia
`Weight loss
`Hyponatremia
`Hypoalbuminemia
`Vascular
`Hypertension
`Thrombosis
`Infections
`Urinary tract infection
`Infection
`Nervous system
`Headache
`Dysarthria
`Psychiatric
`Anxiety
`Respiratory, thoracic and mediastinal
`Epistaxis
`Renal and urinary
`Increased blood creatinine
`Proteinuria
`Gastrointestinal
`Stomatitis
`Proctalgia
`Anal fistula
`Reproductive system and breast
`Pelvic pain
`Hematology
`Neutropenia
`Lymphopenia
`a NCI-CTC vemon 3
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
`
`Stage Ill or IV Following Initial Surgical Resection
`The safety of A vastin was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo
`controlled, three arm study, which evaluated the addition of A vastin to carboplatin and paclitaxel for the
`treatment of patients with stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer
`following initial surgical resection [see Clinical Studies (14. 7)}. Patients were randomized (1: 1: 1) to carboplatin
`and paclitaxel without Avastin (CPP), carboplatin and paclitaxel with Avastin for up to six cycles (CPB 15), or
`carboplatin and paclitaxel with A vastin for six cycles followed by A vastin as a single agent for up to 16
`additional doses (CPB15+). Avastin was given at 15 mg/kg every three weeks. On this trial, 1215 patients
`received at least one dose of A vastin. The demographics of the safety population were similar to the
`demographics of the efficacy population.
`
`Grades 3-4 adverse reactions occurring at a higher incidence (~2%) in either of the Avastin arms versus the
`control arm were fatigue (CPB15+ -9%, CPB15 - 6%, CPP - 6%), hypertension (CPB15+ - 10%, CPB15 - 6%,
`CPP- 2%), thrombocytopenia (CPB15+ - 21%, CPB15 - 20%, CPP - 15%) and leukopenia (CPB15+ - 51 %,
`CPB15 - 53%, CPP - 50%). Adverse reactions are presented in Table 5.
`
`Table 5: Grades 1-5 Adverse Reactions Occurring at Higher Incidence(~ 5%) in Patients Receiving
`Avastin with Chemotherapy vs. Chemotherapy Alone in GOG-0218
`
`Adverse Reactions
`
`A vastin with
`carboplatin and
`paclitaxel followed
`
`by A vastin alone .
`
`(N=608)
`
`A vastin with
`carboplatin and
`paclitaxer·
`(N= 607)
`
`Carboplatin and
`paclitaxel"**
`(N= 602)
`
`General
`Fatigue
`Gastrointestinal
`Nausea
`Diarrhea
`Stomatitis
`Musculoskeletal and connective tissue
`Arthralgia
`Pain in extremity
`Muscular weakness
`Nervous system
`Headache
`Dysarthria
`Vascular
`Hypertension
`Respiratory, thoracic and mediastioal
`Epistaxis
`Dyspnea
`Nasal mucosal disorder
`a NCl-CTC version 3, * CPB15+, •• CPB15, ***CPP
`
`80%
`
`58%
`38%
`25%
`
`41%
`25%
`15%
`
`34%
`12%
`
`32%
`
`31%
`26%
`10%
`
`72%
`
`53%
`40%
`19%
`
`33%
`19%
`13%
`
`26%
`10%
`
`24%
`
`30%
`28%
`7%
`
`73%
`
`51%
`34%
`14%
`
`35%
`17%
`9%
`
`21%
`2%
`
`14%
`
`9%
`20%
`4%
`
`Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
`The safety of A vastin was evaluated in 179 patients who received at least one dose of A vastin in a multicenter,
`open-label study (MO22224) in which patients were randomized (1: 1) to Avastin with chemotherapy or
`chemotherapy alone in patients with platinum resistant, recurrent epithelial ovarian, fallopian tube, or primary
`peritoneal cancer that recurred within < 6 months from the most recent platinum based therapy [see Clinical
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Studies (14.8)). Patients were randomized to receive Avastin 10 mg/kg every 2 weeks or 15 mg/kg every 3
`weeks. Patients had received no more than 2 prior chemotherapy regimens. The trial excluded patients with
`evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical
`symptoms of bowel obstruction. Patients were treated until disease progression or unacceptable toxicity. Forty
`percent of patients on the chemotherapy alone arm received A vastin alone upon progression. The demographics
`of the safety population were similar to the demographics of the efficacy population.
`
`Grades 3-4 adverse reactions occurring at a higher incidence ( ~ 2%) in 179 patients receiving Avastin with
`chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension ( 6. 7% vs. 1.1 % ) and
`palmar-plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%).
`Adverse reactions are presented in Table 6.
`
`Table 6: Grades 2-4 Adverse Reactions Occurring at Higher Incidence (~ 5%) in Patients Receiving
`A vastin with Chemotherapy vs. Chemotherapy Alone in Study M022224
`
`Adverse Reaction"
`
`Hematolo!!v
`Neutrooenia
`Vascular
`Hypertension
`Nervous system
`Peripheral sensory neuropathy
`General
`Mucosal inflammation
`Renal and urinary
`Proteinuria
`Skin and subcutaneous tissue
`Palmar-plantar erythrodysaesthesia
`Infections
`Infection
`Respiratory. thoracic and mediastinal
`Epistaxis
`a NCI-CTC vemon 3
`
`A vastin with
`Chemotherapy
`(N=l79)
`
`Chemotherapy
`(N=l81)
`
`31%
`
`19%
`
`18%
`
`13%
`
`12%
`
`11%
`
`11%
`
`5%
`
`25%
`
`6%
`
`7%
`
`6%
`
`0.6%
`
`5%
`
`4%
`
`0%
`
`Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
`
`StudyAVF4095g
`The safety of Avastin was evaluated in 247 patients who received at least one dose of Avastin in a double-blind
`study (AVF4095g) in patients with platinum sensitive recurrent epithelial ovarian, fallopian tube or primary
`peritoneal cancer [see Clinical Studies (14. 9]. Patients were randomized (1: 1) to receive Avastin (15 mg/kg) or
`placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by A vastin or placebo
`alone until disease progression or unacceptable toxicity. The demographics of the safety population were
`similar to the demographics of the efficacy population.
`
`Grades 3-4 adverse reactions occurring at a higher incidence (2:: 2%) in patients receiving Avastin with
`chemotherapy compared to placebo with chemotherapy were: thrombocytopenia (40% vs. 34%), nausea (4% vs.
`1.3%), fatigue (6% vs. 4%), headache (4% vs. 0.9%), proteinuria (10% vs. 0.4%), dyspnea (4% vs. 1.7%),
`epistaxis (5% vs. 0.4%), and hypertension (17% vs. 0.9%). Adverse reactions are presented in Table 7.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 7: Grades 1-5 Adverse Reactions Occurring at a Higher Incidence~ 5%) in Patients Receiving
`A vastin with Chemotherapy vs. Placebo with Chemotherapy in Study A VF4095g
`
`Adverse Reaction•
`
`General
`Fati!rue
`Mucosa! inflammation
`Gastrointestinal
`Nausea
`Diarrhea
`Stomatitis
`Hemorrhoids
`Gingival bleeding
`Hematolo2:v
`Thrombocytopenia
`Respiratory, thoracic and mediastinal
`Epistaxis
`Dvspnea
`Cough
`Orooharvngeal oain
`Dysphonia
`Rhinorrhea
`Sinus congestion
`Nervous svstem
`Headache
`Dizziness
`Vascular
`Hypertension
`Musculoskeletal and connective tissue
`Arthralgia
`Back pain
`Psvchiatric
`Insomnia
`Renal and urinary
`Proteinuria
`Iniurv and procedural
`Contusion
`Infections
`Sinusitis
`a NCI-CTC vemon 3
`
`A vastin with Car bop la tin
`and Gemcitabioe
`(N=247)
`
`Placebo with Carboplatin
`and Gemcitabioe
`(N=233)
`
`82%
`15%
`
`72%
`38%
`15%
`8%
`7%
`
`58%
`
`55%
`30%
`26%
`16%
`13%
`10%
`8%
`
`49%
`23%
`
`42%
`
`28%
`21%
`
`21%
`
`20%
`
`17%
`
`15%
`
`75%
`10%
`
`66%
`29%
`7%
`3%
`0%
`
`51%
`
`14%
`24%
`18%
`10%
`3%
`4%
`2%
`
`30%
`17%
`
`9%
`
`19%
`13%
`
`15%
`
`3%
`
`9%
`
`9%
`
`Study GOG-0213
`The safety of Avastin was evaluated in an open-label, controlled study (GOG-0213) in 325 patients with
`platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not
`received more than one previous regimen of chemotherapy [see Clinical Studies (I 4. 9) J. Patients were
`randomized (1:1) to receive carboplatin and paclitaxel for 6 to 8 cycles or Avastin (15 mg/kg every 3 weeks)
`with carboplatin and paclitaxel for 6 to 8 cycles followed by A vastin as a single agent until disease progression
`or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the
`efficacy population.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0017
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Grades 3-4 adverse reactions occurring at a higher incidence(~ 2%) in patients receiving Avastin with
`chemotherapy compared to chemotherapy alone were: hypertension (11 % vs. 0.6%), fatigue (8% vs. 3%),
`febrile neutropenia (6% vs. 3%), proteinuria (8% vs. 0%), abdominal pain (6% vs. 0.9%), hyponatremia (4% vs.
`0.9%), headache (3% vs. 0.9%), and pain in extremity (3% vs. 0%).
`Adverse reactions are presented in Table 8.
`
`Table 8: Grades 1-5 Adverse Reactions Occurring at Higher Incidence~ 5%) in Patients Receiving
`Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213
`
`Adverse Reactions
`
`Musculoskeletal and connective tissue
`Arthral!!ia
`Mvalgia
`Pain in extremity
`Back pain
`Muscular weakness
`Neck pain
`Vascular
`Hypertension
`Gastrointestinal
`Diarrhea
`Abdominal pain
`Vomiting
`Stomatitis
`Nervous svstem
`Headache
`Dysarthria
`Dizziness
`Metabolism and nutrition
`Decreased appetite
`Hyperglycemia
`Hvooma!!nesemia
`Hyponatremia
`W ei!!ht loss
`Hypocalcemia
`Hvpoalbuminemia
`Hyperkalemia
`Resoiratorv. thoracic and mediastinal
`Epistaxis
`Dyspnea
`Comm
`Rhinitis allergic
`Nasal mucosal disorder
`Skin and subcutaneous tissue
`Exfoliative rash
`Nail disorder
`Dry skin
`Renal and urinarv
`Proteinuria
`Increased blood creatinine
`Hepatic
`
`A vastin with
`Carboplatin and Paclitaxel
`(N=325)
`
`Carboplatin and Paclitaxel
`(N=332)
`
`45%
`29%
`25%
`17%
`13%
`9%
`
`42%
`
`39%
`33%
`33%
`33%
`
`38%
`14%
`13%
`
`35%
`31%
`27%
`17%
`15%
`12%
`11%
`9%
`
`33%
`30%
`30%
`17%
`14%
`
`23%
`10%
`7%
`
`17%
`13%
`
`30%
`18%
`14%
`10%
`8%
`0%
`
`3%
`
`32%
`28%
`25%
`16%
`
`20%
`2%
`8%
`
`25%
`24%
`17%
`6%
`4%
`5%
`6%
`3%
`
`2%
`25%
`17%
`4%
`3%
`
`16%
`2%
`2%
`
`1%
`5%
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0018
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Adverse Reactiona
`
`Increased aspartate aminotransferase
`General
`Chest pain
`Infections
`Sinusitis
`a NCI-CIC vemon 3
`
`Hepatocellular Carcinoma (HCC)
`
`A vastin with
`Carboplatin and Paclitaxel
`(N=325)
`15%
`
`Carboplatin and Paclitaxel
`(N=332)
`9%
`
`8%
`
`7%
`
`2%
`
`2%
`
`The safety of Avastin in combination with atezolizumab was evaluated in 1Mbrave150, a multicenter,
`international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable
`hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.1 OJ}.
`Patients received 1,200 mg of atezolizumab intravenously followed by 15 mg/kg A vastin (n=329) every 3
`weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable
`toxicity. The median duration of exposure to Avastin was 6.9 months (range: 0-16 months) and to atezolizumab
`was 7.4 months (range: 0-16 months).
`
`Fatal adverse reactions occurred in 4.6% of patients in the A vastin and atezolizumab arm. The most common
`adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and
`infections (1.2%).
`
`Serious adverse reactions occurred in 38% of patients in the Avastin and atezolizumab arm. The most frequent
`serious adverse reactions (~ 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1 %).
`
`Adverse reactions leading to discontinuation of A vastin occurred in 15% of patients in the A vastin and
`atezolizumab arm. The most common adverse reactions leading to A vastin discontinuation were hemorrhages
`(4.9%), including bleeding varicose vein, hemorrhage and gastrointestinal, subarachnoid, and pulmonary
`hemorrha