Therapeutic Goods Administration
`
`Table 20. Post-Randomization Ocular TEAEs Reported by >3 Subjects in Either Group, Study
`Eye [All Randomized Set)
`
`\‘ial
`
`PFS
`
`Total
`
`Preferred 'l'enn‘l
`{hi-=50}
`6:99)
`T=l45i)
`
`MedDRA. Version 13.0
`n (to)
`n {to}
`u ['42]
`No. of Subjects with Events. 116%)
`38 (76.0)
`58 (58.6]
`96 (64.4]
`
`8(8.1)
`9 (9.1]
`70.1)
`8 {3.1)
`7 (7.1)
`2 (2.0)
`4 (-1.0)
`6 (6.1]
`1 (1.0)
`3 (3.0)
`4 {4.0)
`4 (4.0)
`4 (4.0)
`
`16(10?)
`16(10.T]
`15(101]
`[-1 (9.4)
`9 (6.0)
`N717]
`7 (4.?)
`6 (4.0)
`6 (4.0)
`4L1?)
`4 [2 i)
`4 [17)
`
`Retinal haemonbmge
`Cataract
`VArcduced
`Conjuncfiral hemorrhage
`Vitreous floaters
`Blepharius
`Manda! degeneration
`Foreign body sensation in eyes
`Vitreous detachment
`Eye pain
`Eye promos
`Itqecuou sm- pain
`IOP increased
`
`81:16.0)
`H140]
`31116.0]
`6 (13.0]
`2 (4.0)
`5 {10.0)
`3 (6.0)
`0
`5 (10.0)
`I (2.0)
`
`4 (2.?)
`
`Study VGFT-UD-0706/13336 {HAVING}. ocular TEAEs in the study eye were reported in 26
`[59.1%] subjects with aflibercept 0.5 mg q4w, 20 [45.5%] subjects with 2 mg q4w, 23
`[54.8%] subjects with 2 mg qu. 19 [42.2%] subjects with 2 mg PRN and 21 [47.7%]
`Subjects with laser. The pattern ofTEAEs in the study was similar for all five treatment
`groups. Ocular procedure related TEAEs were reported in 16 [36.4%] subjects with
`aflibercept 0.5 mg qtiw, eleven [25.0%] subjects with 2 mg q4w, 17 [40.5%] subjects with
`2 mg q8w, 19 [42.2%] subjects with 2 mg PRN and 14 [31.1%] subjects with laser. Ocular
`TEAEs in the fellow eye were reported in 14- [31.8%] subjects with aflibercept 0.5 mg q4w,
`seven [15.9%] subjects with 2 mg q4w. 13 [31.0%] subjects with 2 mg q8w, 13 [28.9%]
`subjects with 2 mg PRN and eight [18.2%] subjEEts with laser. Conjunctival llaemor‘rbage,
`eye pain and ocular hyperaemia were more common in the treated eye than the fellow eye.
`Nou-ocular TEAEs were reported in 14 [31.8%] subjects with aflibercept 0.5 mg q4w. 32
`[72.7%] subjects with 2 mg q4w. 24 [54.5%] subjects with 2 mg q8w, 26 [61.9%] subjects
`with 2 mg PRN and 27 [60.0%] subjects with laser. The pattern ofnon-ocular TEAEs was
`similar for the five treatment groups. TEAEs ofinterest occurred to a greater extent in the
`aflibercept groups: 27 [15.4%] subjects overall compared with three [6.8%] subjects in
`the laser group [Table 21]. Two subjects in the aflibercept 2 mg q4w group had an
`increase in IOP of210 mmHg from baseline at Week 24.
`
`
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`Table 21. Treatment-Emergent Adverse Events of Interest [SAF].
`
`Preferred Teanil
`Total No. of Events. 11
`Total No. of Palients. n (“43]
`
`
`
`Laser
`(3:44)
`)1 %
`3
`3(6.8]
`
`3 [6.8)
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`0.5 q-l
`6:44)
`n (9/9)
`13
`11 {25.0)
`
`2 (4.5]
`2 (4.5]
`3 (6.8]
`1(23]
`0
`l (2.3]
`0
`l (2.3]
`l (2.3}
`0
`l (2.3]
`0
`
`Hypertension
`Blood pressure increased
`Anterior chamber cell
`[ritis
`Endophthalmitis
`Ceiebrorascular accident
`Hypertensive emergency
`Anterior chamber flare
`Ere-iris
`V’itritis
`Myocardial infarction
`Silent myocardial
`infarction
`0
`1 (2.3]
`0
`Epislaxis
`’ Events are presented in decreasing order of frequency in the All YEGF Trap-Eye column.
`
`2.0 q4
`5:44]
`11 ("xii
`
`1.0 q8
`(3:42)
`n 921:
`
`2.0 PR)"
`6:45]
`n {%
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`
`
`
`
`All \"EGF
`
`Trap—Eye
`6:175)
`n (‘30
`33
`3? (15.4]
`
`10 (5.?)
`6 (3.4]
`3 (1.7]
`2 (1.1]
`2 (1.1)
`3 (1.1]
`l (0.6]
`l (0.6]
`l (0.6)
`l (0.6]
`l (0.5]
`l (0.6]
`
`l (0.6)
`
`Serious adverse events and deaths
`
`Study VGFT-OD-0502/14395 Port A, no serious adverse events [SAEs] occurred during the
`treatment phase but SAEs were reported for three subjects during the extended follow-up
`phase. One subject in the 1.0 mg cohort had atrial fibrillation, bradycardia. acute renal
`failure and pneumonia. One subject in the 2.0 mg cohort had cerebral infarction. angina
`pectoris, and esophageal dyskinesia and this patient subsequently withdrew from the
`study because of medical issues. One subject in the 4.0 mg cohort bad prostate cancer. A
`further two subjects had SAEs during the open—label extension: breast cancer and retinal
`detachment.
`
`Study VGFT-OD-0502/14395 Part C, there were no ocular SAEs. For the entire study, eight
`[28.6%] subjects reported systemic SAEs: squamous cell carcinoma ofthe skin in two
`patients; coion cancer, congestive cardiac failure in two patients. lobar pneumonia;
`fall/contusion/facial bones fracture; and hydronephrosis/urinary retention.
`
`Study VGFT-OD-0603, a total of 19 SAEs were reported in eight subjects. None of the SAEs
`appeared to be related to treatment.
`
`Study VGFT-OD-0603, one subject in the [VT-1 cohort died 47 days after the last dose of
`study drug due to cardiac arrest.
`
`Study VGFT—OD-0512, two subjects reported SAEs: one with coronary artery disease and
`one with streptococcal cellulitesx acute renal failure/ anemia} peripheral ischemia/
`osteomyelitis.
`
`Study VGFT—OD—0305, SAEs were reported in three subjects: one placebo, one given 0.3
`mg/kg and one given 3.0 mg/kg. The event in the 3.0 mgfltg subject was malignant
`hypertension, which was considered to be a dose-limiting toxicity. .4 second subject with
`proteinuria was also considered to have a dose limiting toxicity. Two subjects experienced
`serious ocular adverse events: both retina] haemorrhage.
`
`Study VGFT—OD—0306, one subject reported a SAEs: fallX left hip fracture.
`
`Study VGFT-OD-OSOB, SAEs were reported in eleven [34.4%] subjects in the 0.5 mg q4w
`group, five [15.6%] subjects in the 0.5 mg q12w group, ten [32.3%] subjects in the 2 mg
`
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`q4w group, seven [22.6%] subjects in the 2 mg q12w group and two [6.5%] subjects in the
`4 mg q12w group. One subject in the 0.5 mg q4w group developed suspected culture—
`negative endophthalmitis that was reported as an SAE of uveitis after receiving the fifth
`injection ofstudy treatment.
`
`Study VGFT-OD-OSOS, there were two deaths: one in the 2 mg q4w group [pancreatic
`carcinoma] and one in the 4 mg q12w group [pulmonary hypertension].
`
`Study VGFT-OD-0605/14393[WEN/1‘], SAEs were reported in 49 [16.1%] subjects in the
`aflibercept 2 mg q4w group, 58 [19.1%] subjects in the 0.5 mg q4w group, 58 [19.1%]
`subjects in the 2 mg q8w group and 71 [23.4%] subjects in the ranibizumab group. Ocular
`SAEs in the study eye were reported in seven [2.3%] subjects in the aflibercept 2 mg q4w
`group, six [2.0%] subjects in the 0.5 mg q4w group, three [1.0%] subjects in the 2 mg qu
`group and ten [3.3%] subjects in the ranibizumab group. Ocular 814135 in the fellow eye
`were reported in no subjects in the aflibercept 2 mg q4w group, three [1.0%] subjects in
`the 0.5 mg q4w group, two [0.7%] subjects in the 2 mg qu group and three [1.0%]
`subjects in the ranibizumab group. Non-ocular SAEs were reported in 49 [16.1%] subjects
`in the afliheFCept 2 mg q4w group, 58 [19.1%] subjects in the 0.5 mg q4w group, 58
`[19.1%] subjects in the 2 mg q8w group and 71 [23.4%] subjects in the ranibizumab
`group. The pattern ofnon-ocular SAEs was similar for the four study groups and as
`expected given the age range ofthe subjects.
`
`Study VGFT—OD-0605/14393 {VIEW 1], death was reported in one [0.3%] Subject in the
`aflibercept 2 mg q4w group, one [0.3%] subject in the 0.5 mg q4w group, seven [2.3%]
`subjects in the 2 mg q8w group and five [1.6%] subjects in the ranibizumab group.
`
`Study 311523 (VIEWZJ, treatment emergent SAEs were reported in 49 [15.9%] subjects in
`the aflibercept 2 mg q4w group, 41 [13.8%] subjects in the 0.5 mg q4w group, 48 [15.6%]
`subjects in the 2 mg qu group and 35 [12.0%] subjects in the ranibizumab group. Ocular
`treatment emergent 524135 in the study eye occurred in six [1.9%] subjects in the
`aflibercept 2 mg q4w group, five [1.7%] subjects in the 0.5 mg q4w group, nine [2.9%]
`subjects in the 2 mg q8w group and nine [3.1%] subjects in the ranibizumab group. Ocular
`treatment emergent SAEs in the fellow eye occurred in nine [2.9%] subjects in the
`aflibercept 2 mg q4w group, two [07%] subjects in the 0.5 mg q4w group, three [10%]
`subjects in the 2 mg q8w group and three [1.0%] subjects in the ranibizumab group. Non—
`ocular treatment emergent SAEs occurred in 36 [11.7%] subjects in the aflibercept 2 mg
`L14w group, 37 [125%] subjects in the 0.5 mg L14w group, 38 [12.4%] subjects in the 2 mg
`q8w group and 26 [89%] subjects in the ranibizumab group [Table 22].
`
`
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`Table 22. N on-ocular treatment-emergent SAEs occurring in at least 2 subjects in any
`treatment group [safety analysis set]
`
`System organ class
`MedDRA preferred term
`
`VEGF Trap-Eye
`Ranibizumab
`Combined
`0.504
`208
`204
`0.504
`(N =- 201)
`[N I 300}
`[N I 297}
`{N I: 307}
`[N a 913}
`n "I.
`it
`fit.)
`n “/n)
`it (1t.
`:1 {‘it.
`
`Any non-ocular serious TEAE
`26 [ 3 9]
`36 [11.7)
`3? (12.5}
`38 (12.4}
`111 [12.2)
`Cardiac disorders
`5 [ 1.7}
`8 t 2.6}
`7 l 2.4}
`11 t 3.0}
`26{ 2.0}
`Myocardial infarction
`2t 0.?)
`0t 0.0}
`St 1.0}
`3 ( 1.0}
`St 0.?)
`Acute coronary syndrome
`0( 0.0}
`2 t 0.6)
`2 t 0.7}
`1 ( 0.3}
`St 0.5}
`Atrial fibrillation
`2 ( 0.7}
`1 t 0.3)
`0{ 0.0}
`3 ( 1.0)
`4{ 0.4}
`Neoplasms benign.
`malignant and unspecified
`[incl cysts and polyps}
`Breast cancer
`Basal cell carcinoma
`Gastrointestinal disorders
`Injury. poisoning and
`procedural complications
`Upper limb fiacture
`Fall
`Nervous system disorders
`Cerebrouascular accident
`Transient ischaemic attack
`infections and inhstations
`Pneumonia
`Respiratory. thoracic and
`mediastinal disorders
`General disorders and
`administration site
`conditions
`Vascular disorders
`Husculcslreletal and
`connective tissue disorders
`Skin and subcutaneous
`tissue disorders
`Hepatohiliary disorders
`Renal and urinary disorders
`Investigations
`Surgical and medical
`procedures
`Metabolism and nutrition
`0.0
`0
`0.0
`0
`0.0
`0
`0.0
`0
`0-7
`2
`disorders
`Note: System organ classes (8005} as well as pretence terms mtmn eacn SOC are sorted in descending order
`by frequency in the VEGF TraoEye competed group.
`
`511
`s}
`iron
`cram
`6(20}
`
`St 2.0}
`0( 0.0)
`0( 0.0}
`3{ 1.0}
`2[ 0.7)
`0( 0.0}
`Bi} 2.0}
`2{ 0.?)
`
`17th
`4too
`2(03
`16:13}
`
`141' 1.5}
`2t 0.2)
`1( 0.1}
`1:” 1.4}
`at 0.3]
`2( 0.2)
`121 1.3}
`4( 0.4}
`
`9133}
`311m
`2ron
`6123}
`
`7[ 2.4}
`2( 0.7}
`1( 0.3)
`2[ 0.?)
`01 0.0}
`0{ 0.0)
`0[ 0.0}
`0( 0.0}
`
`3:13}
`0t0m
`atom
`4113}
`
`1( 0.3}
`0( 0.0)
`0t 0.0)
`Bi 2.6}
`1( 0.3}
`2( 0.6)
`At 1.3}
`2( 0,6)
`
`{1
`a)
`(on
`(om
`{on}
`
`3
`
`110
`
`2[ 0.7}
`01: 0.0)
`2( 0.?)
`2[ 0.?)
`1( 0.3}
`0( 0.0}
`0[ 2.1}
`0( 0.0)
`
`1 [ 0.3}
`
`4t 1.3}
`
`1 [ 0.3}
`
`2[ 0.7}
`
`7{ 0.0}
`
`3[ 1.0}
`2[ 0.7}
`
`4( 1.3}
`2t 0.6}
`
`1[ 0.3}
`2[ 0.7}
`
`1[ 0.3}
`2[ 0.7}
`
`B[ 0.7}
`St 0.7}
`
`2[ 0.7}
`
`31' 1.0}
`
`0[ 0.0}
`
`2{ 0.7}
`
`51 0.5}
`
`2( 0.7}
`0( 0.0}
`0( 0.0}
`0( 0.0}
`
`1t 0.3}
`2[ 0.6}
`it 0.3}
`2t 0.6}
`
`21 0.7}
`1 [ 0.3}
`0[ 0.0}
`0[ 0.0}
`
`1{ 0.3}
`01 0.0}
`21 0.7}
`0[ 0.0}
`
`4[ 0.4}
`3[ 0.3}
`3{ 0-3}
`2[ 0.2}
`
`2[ 0.7}
`
`0[ 0.0}
`
`H 0.3}
`
`'l[ 0.3}
`
`2[ 0.2}
`
`Study 311523 (Vii-3W2}, there were nine deaths in total: three [1.0%] subjects in the
`aflibercept 2 mg q4w group, two [0.7%] subjects in the 0.5 mg q4w group. two [0.7%]
`subjects in the 2 mg q8w group and two [0.7%] subjects in the ranibizumab group.
`
`StudyVGFT-OD-0702/14262, SAEs were reported in 64 [40.8%] subjects. Ocular SAES were
`reported in eight [5.1%] subjects. Non—ocular SAEs were reported in 59 [37.6%] subjects.
`Procedure related SAEs were reported in two (1.3%) subjects.
`
`StudyVGFT-OD-0702/14262, eight [5.1%] subjects died but none ofthe deaths appeared to
`be reiated to study treatment.
`
`Study VGFT-OD-0706/1‘3336 {DA VINCU, SAEs were reported in seven [15.9%] subjects in
`the ailibercept 0.5 mg q4w group, nine [20.9%] subjects in the 2 mg q4w group, eight
`[19.0%] subjects in the 2 mg q8w group, three [6.7%] subjects in the 2 mg PRN group and
`six [13.6%] subjects in the laser group. There were more infections reported as SAEs in
`the aflibercept groups: nine [5.1%] subjects compared with none in the laser group.
`Ocular 811135 in the study eye were reported in one [2.3%] subject with aflibercept 0.5 mg
`
`
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`q4w, one [2.3%] subject with 2 mg q4w. one [2.4%] subject with 2 mg q8w. one [2.2%]
`subject with 2 mg PRN and three [6.8%] subjects with laser. Ocular SAEs in the fellow eye
`were reported in one [2.4%] subject with 2 mg q8w. Non-ocular SAEs were reported in six
`[13.6%] subjects with aflibercept 0.5 mg q4w, eight [18.2%] subjects with 2 mg q4w, six
`[14.3%] subjects with 2 mg q8w. two [4.4%] subjects with 2 mg PRN and three [6.8%]
`subjects with laser.
`
`Study VGFT—OD-0706/I3336 {DAVINCI}, death was reported in one [2.3%] patient with
`aflibercept 0.5 mg q4w [multi-organ failure], one [2.3%] patient with 2 mg q4w [sudden
`unexplained]. and one [2.4%] patient with 2 mg q8w [convulsions].
`
`There were no SAEs reported in Study VGFT-OD-0502/14395 Putt B, Study VGFT-OD-0307,
`Study PD Y6655 or Study PD Y6656.
`
`There were no deaths reported in Study VGFT—OD—0502/14395 PartA, Part8 and Part C; or
`in Study VGFT-OD-OSIZ, Study VGFT—OD-0305, Study LEFT-030306, Study VGFT—OD-0307,
`Study PDY6655 and Study PDY6656.
`
`Laboratory findings
`
`Study VGFT—OD—0502/14395 Part A, there was one clinically significant abnormality in a
`laboratory test: elevated creatinine kinase to 923 0/1..
`
`Studies VGFT—OD—0502/14395 Putt 8 and Port C, there were no clinically significant
`laboratory abnormalities.
`
`Study VGFT—OD-0603, one subject was reported with a urinary tract infection [UT]] and
`one with hypokalaemia. Both abnormalities resolved.
`
`Study VGFT—OD—OSIZ, laboratory test abnormalities were consistent with the subjects’
`history ofdiabetes.
`
`Study VGFT—OD—0305, proteinuria was reported in 5 patients: 2 in the 1.0 mgfltg group and
`3 in the 3.0 mgfltg group. Haematuria was reported in one subject in the VEGF Trap 1.0
`mg/kg group
`
`Study DEFT-000306, proteinuria was reported in six [85.7%] subjects.
`
`Study VGFT—OD-0307, one subject had proteinuria related to treatment
`
`Study PDY6655, one subject had elevated alanine aminotransferase [ALT] [155.8 [0/1.] and
`one had elevated aspartate aminotransferase [AST] [981U/L].
`
`Study PDY6656, one subject in the 4 mngg group had an elevation ofAST to 101 IUXL on
`Day 43 that had normalised by the end of study. One subject in the placebo group and one
`subject in the 2 rag/kg group had decreases in neutrophi} count that had normalised by
`the end ofstudy.
`
`Study VGFT—OD-OSOB, there were few clinically significant laboratory tests abnormalities
`and these did not appear to be dose or frequency related. The majority ofplasnia samples
`assayed for free aflibercept concentrations were below the lower limit of quantification
`[LLOQ].
`
`Study VGFT—OD-0605/14393 {VIEW 1), the pattern of abnormal test results was similar for
`all three treatment groups and compatible with the age range ofthe study subjects. Shift in
`urine protein creatinine ratio from normal at baseline to high at Week 52 was reported for
`30 [16.9%] subjects in the aflibercept 2 mg q4w group, 34 [21.1%] subjects in the 0.5 mg
`q4w group. 26 [15.3%] subjects in the 2 mg qu group and 35 [19.7%] subjects in the
`ranibizumab group.
`
`Study 311523 (WEI/1’2), the pattern of significant abnormalities in laboratory tests was
`similar for all four treatment groups.
`
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`StudyVGFT-OD-0702/14Z62, there were no clinically significant laboratory test
`abnormalities
`
`Study VGFT—OD-0706/i3335 {DA ViNCl}, abnormalities in laboratory tests were uncommon
`and did not indicate any association with study treatment. Six [3.4%] subjects in the
`aflibercept groups developed proteinuria compared with none in the laser group.
`
`Safety in special populations
`
`Older persons were well represented in the study population. There were no data
`provided from the paediatric population or during pregnancy.
`
`Immunological events
`
`Study VGFT—UD-0502/14395 Port A, one subject developed anti -aflibercept antibodies
`[concentration <1.2 mg/L].
`
`Study VGFT-OD-0605/14-393 {WEN/1}, a positive anti-drug antibody assay was reported in
`13 [4.3%] subjects in the aflibercept 2 mg q4w group. eleven [3.6%] subjects in the 0.5 mg
`qtlw group. six subjects in the 2 mg qu group and 15 (4.9%} subjects in the ranibiaumab
`group. One subject in the aflibercept 2 mg qd-w group exhibited neutralising activity. The
`presence of anti-drug antibody did not appear to influence efficacy {Table 23].
`
`Table 23. Supportive Analysis of the Proportion of Subjects with Maintained Vision at Week
`52 by Anti-VEGF Trap Antibodies Status, LOCF {Per Protocol Set]
`
`Sub Group
`
`POSITIVE
`
`NEGATIVE
`
`Treatment
`Group
`VTE ZQJ (N =13)
`110.504 EN: 15}
`
`VTE 0.504{N=ll_l
`RD.5Q4T_N=1’5J
`
`VTElQflm=|fl
`R059: (N =15)
`
`\‘TE 2:}: {N = 272)
`R osqq m = 253)
`
`VTEOfIQ—‘l (N=259)
`R 0.504 (N = 253]
`
`VTE EQB (N = 259)
`R 0.5Q4 (N = 353)
`
`Subjects who _ ainra n
`Vision M it's-9k 51
`1:
`(’13)
`11{8-1.6%)
`14(93.3%)
`
`[0(90.9%J
`”(93.3%)
`
`6(10'0'Vo)
`14(9132'4.)
`
`1601 95.6%)
`239 c: 94.3%)
`
`249(96.i5’a)
`239i: 94.5%)
`
`345 i 95.0%)
`339 (_ 9-1 5%)
`
`Difference [1]
`‘9.
`t 95.1 °vb CJJ
`8.? {44.1 32.1)
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`
`Study 311523 {VIEW 2}. systemic reactions related to immunogenicity were reported in
`two [0.6%] subjects in the aflibercept 2 mg q4w group, four (1.3%} subjects in the 0.5 mg
`qliw group. five [1.6%] subjects in the 2 mg q8w group and seven [2.4%] subjects in the
`ranibizumab group. There were no anaphylactic reactions reported in the aflibercept
`groups whereas one anaphylactic reaction was reported in the in the ranibizumab gorup.
`Anti-drug antibodies were detected in 16 [5.4%] subjects in the aflibercept 2 mg q4w
`group, 15 [4.9%] subjects in the 0.5 mg q4w gorup, three [1.0%] subjects in the 2 mg qu
`group and eight [27%) subjects in the ranibizumab group. No subject was detected with
`neutralising anti-drug antibodies. Antibody status did not appear to influence efficacy
`[Table 24-].
`
`
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`AusPAR Eylea Afiibercepl Beyer Australia Ltd Phil-20100380?
`3-5 Final 30 July 2012
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`Page 62 of 93
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`Therapeutic Goods Administration
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`-ii DH}? 2.!!!
`
`Table 24. Proportion of subjects with maintained vision at Week 52 by AB positivefnegative,
`LOCF {Full analysis set]
` Subjects wrfli maintained
`AB developmi flag I:
`Tmnneni group
`mini: 1: week 520".)
`Dtfierence [11(95 '-'. c: 'i
`.\‘
`VTEJQKIFHSJ
`370194. 7in
`vii OER-3.193760}
`RflfiQ-lflhlfifli
`2059-1 64}
`VTEU were
`36-16031}
`-l}| 66H 29.2.95}
`R0 SM=2SOi
`26584 6-!)
`V1'EJQ8(N=302)
`383(95 36)
`R0 5046-230}
`3658-! 6-1]
`W'EJQJGV'flSi
`13136.67}
`RDJQMN=EI
`8000.00]
`VTEOEQKN-lfi)
`14033 .55}
`R0 W=8)
`8000.01in
`\mQ‘ifN-S}
`3000.00}
`R05Q‘3CN=SJ 8000.001
`
`
`'3'
`
`13 Sit-3.81.5054;
`
`fiéii-S 96.19 39)
`
`Anti aflibercept antibodies were not detected in Study VGFT—flD-0502/14395 Part 3, Study
`VGFT-OD-OSIZ. Study VGFT—OD-OS'OS. Study VGFT-OD-0306, Study DEFT-000307. Study
`PD mass, Study PD Y6656, Study veteran-0508, StudyVGFT—OD-0702/14262 or Study VGFT—
`00-070 6/1 333 6.
`
`Safety related to drug-drug interactions and other interactions
`
`No data with regard to drug-drug interactions were included in the submission.
`
`Discontinuation due to adverse events
`
`Study VGFT—OD-OSGZ/I 4395 Port A, [as discussed above] one subject in the 2.0 mg cohort
`had cerebral infarction, angina pectoris and esophageal dyskinesia and subsequently
`withdrew from the study because ofmedical issues.
`
`Study VGFT~OD-0502/14395 PortC, one subject withdrew because ofa low platelet count
`that had been present from baseline.
`
`Study VOW—000305, three subjects discontinued due to AEs [DAB]: two in the 3.0 lug/kg
`group [hypertension and malignant hypertension] and one in the 1 mg/kg group
`[headaclie/ hypertension/ proteinuria].
`
`Study VGFT—OD-GBOS, one subject withdrew because ot'a TEAE: hypertension.
`
`Study VGFT-OD-0307, two subjects in the placebo group withdrew due to TEAEs.
`
`Study PDY6655, two subjects discontinued due to AEs following subcutaneous
`administration: delayed allergic dermatitis at the injection site; and multiple trauma
`caused by car accident.
`
`Study VGFT—OD—OSOB, DAB occurred for seven subjects overall: one [3.1%] in the 0.5 mg
`q‘i-w group. three [9.4%] in the 0.5 mg q12w group, none in the 2 mg q4w group, 2 [6.5%]
`in the 2. mg q12w group and one [3.2%] in the 4 mg qi 2w group. Two of the DAEs were
`considered to be treatment related: retinal haemorrhage and retinal oedema.
`
`Study VGFT-OD-0605/14393 {WEN/1), AEs leading to the discontinuation of study
`treatment was reported in three [1.0%] subjects in the aflibercept 2 mg q4w group, five
`[1.6%] subjects in the 0.5 mg q4w group, three [1.0%] subjects in the 2 mg qu group and
`five [1.6%] subjects in the ranibizumab group.
`
`Study 311523 {WEN/2) TEAE leading to discontinuation ofstudy treatment was reported
`in twelve [3.9%] subjects in the aflibercept 2 mg q4w group, 14 [4.7%] subjects in the 0.5
`mg q4w group, ten [3.3%] subjects in the 2 mg q8w group and {our [1.4%] subjects in the
`ranibizumab group.
`
`
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`StudyVGFT~OD-0702/14262, three [2%] subjects permanently discontinued study
`treatment: macular degeneration; reduced visual acuity; and metastatic non—small cell
`lung cancer.
`
`Study VGFT—OD-0706/13336 {DAVINCI}, DAE was reported in one [2.3%] subject with
`afiibercept 0.5 mg q4w [uveitis].
`
`There were no withdrawals due to TEAEs in Study VGFT—OD-0502/14395 Part B, Study
`VGFT-OD-0603, Study VGFT—OD-OSIZ or Study PDY6656.
`
`Additional safety data
`
`Study VGFT—OD-0910/14832 is an open label. iong term safety and tolerability study
`follow-on to Study VGFT-DD-0605. The study includes subjects with neovascular AMD that
`have completed Study VGFT-OD-0605. The study is ongoing and a report was not provided
`with the current submission. Limited data were provided in the sponsor's Summary of
`Clinical Safety. The study treatment is aflibercept 2 mg PRN. but at ieast every 12 weeks,
`by intravitreal injection with an injection volume of 50 uL. The study is of 18 months
`duration. A total of 178 subjects had been recruited. Three SAEs were reported in the
`sponsor’s Summary of Clinical Safety: device dislocation; renal cancer and urinary tract
`infection.
`
`Study VGFT-OD-0819/14232 {COPERN1CUS} is a randomised double masked sham
`controlled study the efficacy and safety ofatlibercept in central retinal venous occlusion
`[CRVO]. The study is ongoing. The study includes subjects at least 18 years of age with
`centre involved macular edema secondary to CRVO with mean central retinal thickness
`2250 pm on OCT. The study treatments were: afiibercept 2 mg q4-w by intravitreal
`injection in comparison with sham injections q4w. Efficacy data were not reported. SAEs
`reported to date were included in the sponsor's Summary of Clinical Safety. A total of 189
`subjects had been recruited. There were 58 SAEs reported in 29 [15.4%] subjects. The
`most commonly reported SAEs were: vitreous haemorrhage in four [2.1%] subjects,
`glaucoma in two [1.1%] subjects. iris neovascularisation in two [1.1%] subjects,
`pneumonia in two (1.1%] subjects and retinal haemorrhage in two [1.1%] subjects.
`
`Study 14130 {GALILEO} is a randomised double masked sham controlled study the efficacy
`and safety ofafiibercept in CRVO. The study is ongoing. The study includes adults 2 18
`years, with centre—invoived macular edema secondary to CRVO for no longer than 9
`months with mean central subfield thickness 2 250 pm on optical coherence tomography
`[OCT] and with ETDRS BCVA of 20/40 to 20/320 (73 to 24 letters] in the study eye. The
`study treatments were: afiibercept 2 mg q4w by intravitreal injection which was
`compared with sham injections q4w. Efficacy data were not reported. SAEs reported to
`date were included in the sponsor's Summary of Clinical Safety. A total of 177 subjects had
`been recruited. A total of 17 SAEs were reported in 13 [7.6%] subjects. No SAE was
`reported in more than one subject.
`
`Post marketing experience
`
`No postmarketing data were included with the current submission.
`
`Evaluator’s overall conclusions on clinical safety
`
`Intravitreal aflibercept is associated with an increased rate of conjunctiva] haemorrhage,
`eye pain and reduction in visual acuity. These adverse events appear primarily to be due
`to the procedure ofintravitreal injection rather than the local effects ofafiibercept. There
`was an increase in IOP ofaround 3.2 iang immediately post treatment that did not
`increase with subsequent treatments. Ocular adverse events did not appear to be
`influenced by dose or dosing regimen. However. ocular AEs were more common with the
`
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`Therapeutic Goods Administration
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`vial presentation than with the pre—filled syringe. A similar rate of ocular AEs was
`observed with ranibizumab.
`
`Intravenous [high dose] aflibercept is associated with headache, hypertension, proteinuria
`and dysphonia. Hypertension was a dose limiting adverse event at a dose level of 3mg/kg.
`
`The rates of SAE and death did not indicate any safety issues with aflibercept. The
`conditions leading to non-ocular SAE and death were as expected for the age group and
`general health of the population of subjects included in the studies. Ocular SAEs appeared
`to be related to the procedure ofintravitreal injection and not to afiibercept.
`
`The rates of clinical laboratory test abnormalities with intravitreal aflibercept were low
`and were consistent with the age and general health ofthe study population. Proteinuria
`appears to be associated with intravenous high dose aflibercept.
`
`Less than 5% ofthe treatment population developed anti-aflibercept antibodies. The
`development ofanti—aflibercept antibodies was not associated with loss of efficacy,
`immunological AEs or increased risk ofAE.
`There was a low rate of withdrawal from the clinical studies due to AE. This indicates that
`
`intravitreal aflibercept is well tolerated.
`
`List of questions
`
`During 2010, the TGA began to change the way applications were evaluated. As part of this
`change. after an initial evaluation, a List of Questions to the sponsor is generated.
`
`Efficacy
`
`It is not clear from the clinical studies how the sponsor determined the final dosing
`recommendations in the product information document. The proposed dosing regimen [2
`mg intravitreal injection each month for the first three injections followed by
`administration every second month] would provide the sponsor with a marketing
`advantage, that is, a perception that less frequent closing is required. Hence, it is important
`that the dosing regimen is supported by data. Can the sponsor provide a justification for
`the dosing regimen proposed in the Product Information document?
`
`The sponsor provided a response to this question [see Response to the Clinical Evaluation
`Report].
`
`Clinical summary and conclusions
`
`Clinical aspects
`
`Eylea [aflibercept] is intended for intravitreal administration and systemic exposure is
`important from a safety perspective but not from an efficacy perspective. The systemic
`exposure following intravitreal injection was minimal in comparison with studies of
`intravenous aflibercept. This would be expected given the differences in total close: up to 4
`mg intravitreal compared with up to 4 mg/kg intravenous.
`
`Following intravitreal injection of2 mg aflibercept the exposure to free aflibercept,
`expressed as AUCW, was median [range] 0.0221 [0 to 0.474] mgoday/L, and exposure to
`aflibercept:VEGF complex expressed as median AUCW, was (range) 4.67 [2.12 to 6.71]
`mgoday/L [Study VGFT-OD-0702.PK]. Following 4 mg intravitreal injection, for
`aflibercept: VEGF complex T11m was 12 weeks and the mean C"m was [SE] 0.236 [0.0302]
`mg/mL [Study VGFT-OD-0603]. Following 4 mg intravitreal injection, the mean
`
`
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`Therapeutic Goods Administration
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`concentrations ofaflibercept were 0.0502 and 0.0272 mgXL on Days 3 and 8, respectively
`[Study VGFT—OD—0512).
`
`Following intravenous administration. Cum for free aflibercept was 50 mg/L for a 3.0
`mg/kg dose, around 16 mg/L for a 1.0 mg dose and 5 mg/L for a 0.3 mg/kg dose. The Cm,1x
`for total aflinercept was 50 mg/L for the 3.0 mg/kg close, around 15 mg/‘L for the 1.0 mg
`dose and 5 mg/L for the 0.3 mg/kg dose [Study VGFT—OD—0305].
`
`Following 20 mg/kg afiibercept by intravenous or subcutaneous administration, the mean
`[CV%) AUC and Cm; for free afiibercept were 177 [33) pg.day/mL and 44.4 [36) ug/mL,
`respectively, for intravenous whereas the AUC and Cmax were 84.9 [30) ugday/mL and
`7.76 [39) ug/mL for subcutaneous administration. For bound aflibercept, the mean [CV96]
`AUC and C"lax were 57.7 [19] tigday/mL and 1.84 [2 2) ugme, respectively, for
`intravenous administration and 47.3 [27) ugday/mL and 1.60 [27) ug/mL, respectively,
`for subcutaneous administration [Study PDY6655].
`
`Following intravenous administration, the mean [CV96] Cum for free aflibei‘cept was 18.2
`[18) ug/mL for a 1 mg/kg dose, 39.7 [27) ug/mL for a 2 mg/kg dose and 78.6 [15) ug/mL
`for a 4 mg/kg dose. The mean [CW/o] AUC was 64.8 [20) ugday/mL for a 1 mg/kg dose,
`180 [20) for a 2 mgg’kg dose and 4-19 [21) for a 4 mg/kg dose [Study PDY6656]. Bound
`aflibercept concentrations were not close proportional but C"lax and AUC for total
`afiibercept were close proportional.
`
`Aflibercept at high doses administered intravenously significantly increases blood
`pressure. However, the level ofsystemic exposure from intravitreal administration would
`not be sufficient to cause similar effects on blood pressure.
`
`Intravenous or subcutaneous 2 mngg aflibercept increased SBP by a mean ofup to 6.5
`mmHg and DBP of up to 7.22 mmHg with a maximal effect at Day 16 post administration
`[Study PDY6655]. SBP was increased by 10.27 [5.77 to 14.78) mmHg and DBP by 10.67
`[7.68 to 13.66) mmHg by 4 mgfkg aflibercept administered intravenously [Study
`PDY6656). The increase in biood pressure persisted for up to 44 days at the 4 mgfltg dose
`level. Plasma renin activity and aldosterone concentrations were decreased.
`
`Benefit risk assessment
`
`Benefits
`
`The primary efficacy measures used in the drug development program were ciinically
`important and had been adequately validated. The efficacy outcome measures were
`refined during Phase I development. BCVA became the tool used to determine the primary
`efficacy outcome measures in the pivotal studies. The secondary efficacy measures [CRT
`and macular volume] assessed pathology and disease severity. Fluorescein angiography
`was not useful to demonstrate differences between treatments.
`
`In the initial dose finding studies, the greatest effect was in the 2 mg to 4 mg dose grouping
`[Study VGFT—OD—0502/14395 Part A]. Effect increased with increasing close up to 4 mg.
`Peak effect appeared to be at Day 29 [Study VGFT-OD-0502714395 Part C]. Different
`formulations, volumes and concentrations of aflihercept were evaluated in Study VGFT-
`OD—0603/14396 [CLEAR—1T 1b), which enabled a 50 pl. volume to be used in further
`studies.
`
`There were some Phase I data ofaflibercept administered intravenously. Study VGFT-OD-
`0305 indicated that a dose of3 mgfkg afiibercept by intravenous injection was effective
`but that a dose of 1 mg/kg was not. Study VGFT—OD—0306 indicated that intravenous
`treatment with aflibercept would not be as effective long-term as intravitrea].
`
`The Phase II study [Study VOW—000508714394 [CLEAR-IT AMD—ZD did not clearly
`indicate the most appropriate dosing regimen. in the Phase II study the greatest reduction
`
`
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`in CRT at Week 12 was with a 2 mg q4w dosing regimen but at all other time points over
`52 weeks the greatest reduction in CRT was with 4 mg q 12w. The greatest improvement in
`BCVA through to Week 52 was with 2 mg q4w. However. the greatest improvement in
`vision