VEGF Trap – Eye
`CLEAR-IT 2 Final Primary
`Endpoint Results
`
`A Phase 2, Randomized, Controlled
`Dose- and Interval-Ranging Study of
`Intravitreal VEGF Trap-Eye in Patients
`with Neovascular Age-Related Macular
`Degeneration
`
`1
`
`Regeneron Exhibit 2028
`Page 01 of 20
`
`
`CLEAR-IT 2 Final Primary
`Endpoint Results
`
`A Phase 2, Randomized, Controlled
`Dose- and Interval-Ranging Study of
`Intravitreal VEGF Trap-Eye in Patients
`with Neovascular Age-Related Macular
`Degeneration
`
`1
`
`Regeneron Exhibit 2028
`Page 01 of 20
`
`
`
`Disclosures
`
`(cid:121) Commercial relationships
`– J. Heier, Regeneron financial support
`
`(cid:121) Trial registration
`– www.clinicaltrials.gov (NCT00320788)
`
`2
`
`Regeneron Exhibit 2028
`Page 02 of 20
`
`
`
`Angiogenesis Inhibition via VEGF Blockade
`Unmet Medical Needs Remain Despite Major
`Advances in Treatment of Wet AMD
`
`(cid:121) Ranibizumab (LUCENTIS®*) represents a major advance in wet
`AMD treatment
`– The approved regimen of ranibizumab in the U.S., 0.5 mg administered
`monthly, resulted in the following results at 1 year:1
`• Prevention of moderate vision loss in 95-96% of patients
`• A ≥15 letter (3-line) gain in 34- 40% of patients
`• Mean improvement in visual acuity of 7.2-11.3 letters (~6-10 at month 4)
`• Vision of ≥20/40 in 39-40% of patients
`• Vision of ≤20/200 in only 12-16% of patients
`(cid:121) A clinical need remains for an agent that can further improve vision
`• Further improvement in visual acuity
`• More patients with vision of ≥20/40
`• Fewer patients with vision of ≤20/200
`(cid:121) A clinical need remains for an agent that improves and maintains
`visual acuity with a dosing schedule requiring less than monthly
`injections
`
`* LUCENTIS® is a registered trademark of GENENTECH, Inc
`1 Rosenfeld, et al., N Engl. J Med., 2006 355(14):1419-31; Brown, et al., N Engl. J Med., 2006
`355(14):1432-44
`
`3
`
`Regeneron Exhibit 2028
`Page 03 of 20
`
`
`
`VEGF Trap-Eye*:
`A Unique VEGF Blocker
`(cid:121) Fusion protein of key domains from
`human VEGF receptors 1 and 2 with
`human IgG Fc
`
`VEGF Trap
`
`VEGFR2
`
`(cid:121) Contains all human amino acid
`sequences
`
`2 3
`
`2 3
`
`Fc
`
`Kd ~0.5 pM
`
`(cid:121) High affinity and binds VEGF more
`tightly than native receptors or
`monoclonal antibody
`
`(cid:121) Blocks all VEGF-A isoforms and
`Placental Growth Factor (PlGF)
`
`(cid:121) Penetrates all layers of the retina
`(MW ~110,000)
`
`Kinase
`
`Kinase
`
`Kd 10-30 pM
`Kd 100-300 pM
`*VEGF Trap–Eye is specially purified and formulated for intravitreal injection.
`IgG=immunoglobulin G; MW=molecular weight; VEGF=vascular endothelial growth factor; VEGFR=vascular
`endothelial growth factor receptor.
`
`4
`
`Structure of the VEGF Trap
`•
`
`______L-----------------1
`C
`•
`•
`\/
`
`1 2 3 4 5 6 7
`
`C C C C
`
`C C C C C C C
`
`1 2 3 4 5 6 7
`
`VEGFR1
`
`Regeneron Exhibit 2028
`Page 04 of 20
`
`
`
`CLEAR-IT 2 Study Objectives
`
`(cid:121) Primary objectives:
`– Assess the effect of intravitreal VEGF Trap-Eye on
`retinal thickness
`– Assess ocular and systemic safety and tolerability of
`repeated IVT doses of VEGF Trap-Eye in wet AMD
`(cid:121) Secondary objective:
`– Assess the effect of IVT VEGF Trap-Eye on best-
`corrected visual acuity in ETDRS letters
`
`5
`
`Regeneron Exhibit 2028
`Page 05 of 20
`
`
`
`Study Design
`
`Randomized, multi-center, double-
`masked trial
`N=159
`
`Screening procedures
`Reading Center Review
`
`Subjects randomized
`1:1:1:1:1
`
`.Q.Q..QP
`
`0.5mg q4 wks
`n=32
`
`2 mg q4 wks
`n=32
`
`0.5 mg q12 wks
`n=32
`
`2 mg q12 wks
`n=32
`
`4 mg q12 wks
`n=31
`
`Primary endpoint: Change in
`Primary endpoint: Change in
`Central Retinal/Lesion Thickness
`Central Retinal/Lesion Thickness
`(CRLT)
`(CRLT)
`
`Primary and secondary endpoints
`measured at week 12
`
`Secondary endpoint: BestSecondary endpoint: Best--
`
`Corrected ETDRS Visual Acuity
`Corrected ETDRS Visual Acuity
`(BCVA).
`(BCVA).
`
`Re-assessment at week 16
`
`
`
`Patients were rePatients were re--dosed at week 12. PRN dosing scheduled allowed beginning week 16dosed at week 12. PRN dosing scheduled allowed beginning week 16..
`
`
`
`6
`
`Regeneron Exhibit 2028
`Page 06 of 20
`
`
`
`Baseline Characteristics
`
`
`
`(N=157*)(N=157*)
`
`
`Age (years)Age (years)
`
`Gender (%M:%F)Gender (%M:%F)
`
`Disease Duration (months)Disease Duration (months)
`
`Lesion Type: number (%)Lesion Type: number (%)
`
`ClassicClassic
`
`Predominantly ClassicPredominantly Classic
`
`Minimally ClassicMinimally Classic
`
`Occult LesionsOccult Lesions
`
`Disease StatusDisease Status
`
`Central Retinal/Lesion ThicknessCentral Retinal/Lesion Thickness
`
`Foveal ThicknessFoveal Thickness
`
`ETDRS BCVA (Letters)ETDRS BCVA (Letters)
`
`
`RangeRange
`
`53-9453-94
`
`
`
`0-670-67
`
`
`MeanMean
`
`78.278.2
`
`
`
`3.93.9
`
`
`
`38:6238:62
`
`
`30 (19.1)30 (19.1)
`
`30 (19.1)30 (19.1)
`
`37 (23.6)37 (23.6)
`
`60 (38.2)60 (38.2)
`
`
`456µm456µm
`
`327µm327µm
`
`5656
`
`
`186-1316µm186-1316µm
`
`116-1081µm116-1081µm
`
`27-8327-83
`
`*N=159 randomized; N=157 treated.
`
`7
`
`Regeneron Exhibit 2028
`Page 07 of 20
`
`
`
`Mean Change in Central Retinal Thickness:
`Significantly Improved vs Baseline at All Time Points
`
`0
`
`4
`
`Week
`
`8
`
`12
`
`16
`
`*P<0.0001.
`n=157
`
`-142*
`
`-138*
`
`-119*
`
`-111-
`
`All Values Combined
`
`-159*
`
`8
`
`Change in CR/LT Microns
`
`0
`-20
`-40
`-60
`-80
`-100
`-120
`-140
`-160
`-180
`Posterior Pole Scans, LOCF analysis
`
`Regeneron Exhibit 2028
`Page 08 of 20
`
`
`
`Mean Change in Visual Acuity:
`Significantly Improved vs Baseline at All Time Points
`
`5.6*
`
`5.8*
`
`5.7*
`
`6.6*
`
`-0-
`
`All Values Combined
`n=157
`*P<0.0001.
`
`0
`
`4
`
`8
`Week
`
`12
`
`16
`
`01234567
`
`Change in Visual Acuity (letters)
`
`LOCF analysis
`
`9
`
`Regeneron Exhibit 2028
`Page 09 of 20
`
`
`
`Mean Change in Retinal Thickness:
`Improved in All Dosing Arms; Monthly Dosing More
`Consistent in Effect
`
`
`
`00
`
`
`
`44
`
`
`WeekWeek
`
`88
`
`
`
`1212
`
`
`
`1616
`
`-107
`-135
`-160
`-183
`-210
`
`2q12
`0.5q12
`0.5q4
`2q4
`4q12
`
`
`
`0.5q40.5q4
`
`-M-
`
`
`
`2q42q4
`
`
`
`0.5q120.5q12
`
`.II
`
`IIIIIIIIII
`
`
`
`2q122q12
`
`-X-
`
`
`
`4q124q12
`
`
`
`00
`
`
`
`-50-50
`
`
`
`-100-100
`
`
`
`-150-150
`
`
`
`-200-200
`
`
`
`-250-250
`
`Change in CR/LT Microns
`
`Posterior Pole Scans, LOCF analysis. 0.5q4 and 0.5q12: n=32; 2q4, 2q12, and 4q12: n=31
`
`10
`
`Regeneron Exhibit 2028
`Page 10 of 20
`
`
`
`Maintenance of Visual Acuity:
`Maintained in All Dosing Arms
`
`
`100%100%
`
`90%90%
`
`80%80%
`
`70%70%
`
`60%60%
`
`50%50%
`
`40%40%
`
`30%30%
`
`20%20%
`
`10%10%
`
`0%0%
`
`Visual Acuity (Loss <3 Lines)
`Visual Acuity (Loss <3 Lines)
`
`Patients (%) Maintaining
`Patients (%) Maintaining
`
`
`
`44
`
`
`0.5q40.5q4
`■
`
`
`2q42q4
`■
`
`
`
`88
`
`
`WeekWeek
`
`0.5q120.5q12
`
`
`
`1212
`
`
`
`1616
`
`
`2q122q12
`■
`
`
`4q124q12
`■
`
`LOCF analysis. 0.5q4 and 0.5q12: n=32; 2q4, 2q12, and 4q12: n=31
`
`11
`
`Regeneron Exhibit 2028
`Page 11 of 20
`
`
`
`Mean Change in Visual Acuity:
`Improved in All Dosing Arms; Monthly Dosing
`Continued to Improve Vision out to Week 16
`
`10
`9.3
`
`2q4
`0.5q4
`
`5.6
`4.3
`3.9
`
`0.5q12
`2q12
`4q12
`
`0
`
`4
`
`Al
`
`0.5q4
`
`2q4
`
`8
`Week
`0.5q12
`
`12
`
`16
`
`.I
`
`IIIIIIIIIII
`
`I
`
`2q12
`
`-X-
`
`4q12
`
`12
`10
`
`02468
`
`Change in Visual Acuity (letters)
`
`LOCF analysis. 0.5q4 and 0.5q12: n=32; 2q4, 2q12, and 4q12: n=31
`
`12
`
`Regeneron Exhibit 2028
`Page 12 of 20
`
`
`
`Mean Change in Visual Acuity:
`Maintained at 8 Weeks With a Single Dose,
`and With Monthly Dosing
`
`10
`9.3
`
`2q4
`0.5q4
`
`5.6
`4.3
`3.9
`
`0.5q12
`2q12
`4q12
`
`,/
`
`"IIPM111110
`
`0
`
`I
`4
`
`-0-
`
`0.5q4
`
`-M-
`
`2q4
`
`- A -
`
`I
`8
`Week
`0.5q12
`
`I
`12
`
`16
`
`2q12
`
`-X-
`
`4q12
`
`12
`10
`
`02468
`
`Change in Visual Acuity (letters)
`
`LOCF analysis. 0.5q4 and 0.5q12: n=32; 2q4, 2q12, and 4q12: n=31
`
`13
`
`Regeneron Exhibit 2028
`Page 13 of 20
`
`
`
`Improvement of ≥3 Lines of Visual Acuity:
`Improved With All Doses
`
`8
`
`Week
`0.5q12
`
`4
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`Gain of 3 or More Lines
`
`Patients (%) With
`
`II .1 ii Ii Ii
`• •
`• •
`
`II
`
`16
`
`12
`
`0.5q4
`
`2q4
`
`2q12
`
`4q12
`
`LOCF analysis. 0.5q4 and 0.5q12: n=32; 2q4, 2q12, and 4q12: n=31
`
`14
`
`Regeneron Exhibit 2028
`Page 14 of 20
`
`
`
`Proportion of Patients With ≤20/200
`Vision Decreased With Monthly Dosing
`
`19%
`
`13%
`
`10%
`
`13%
`
`9%
`
`7%
`
`7%
`
`0%
`
`B Wk16
`2q4
`
`B Wk16
`0.5q12
`Dose Groups
`
`B Wk16
`2q12
`
`B Wk16
`4q12
`
`19%
`
`3%
`
`B Wk16
`0.5q4
`
`25%
`
`20%
`
`15%
`
`il=
`
`10%
`
`il=
`
`5%
`
`I=
`
`0%
`
`≤20/200 Vision
`Patients (%) With
`
`B=baseline.
`
`LOCF analysis. 0.5q4 and 0.5q12: n=32; 2q4, 2q12, and 4q12: n=31
`
`15
`
`Regeneron Exhibit 2028
`Page 15 of 20
`
`
`
`Proportion of Patients With ≥20/40
`Vision Increased in All Dosing Arms
`
`55%
`
`23%
`
`31%
`
`22%
`
`36%
`
`32%
`
`16%
`
`10%
`
`B Wk16
`2q4
`
`B Wk16
`0.5q12
`Dose Groups
`
`B Wk16
`2q12
`
`B Wk16
`4q12
`
`44%
`
`16%
`
`B Wk16
`0.5q4
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`il=
`
`il=
`
`il=
`
`Patients (%) With
`
`≥20/40 Vision
`
`B=baseline. LOCF analysis. 0.5q4 and 0.5q12: n=32; 2q4, 2q12, and 4q12: n=31
`
`16
`
`Regeneron Exhibit 2028
`Page 16 of 20
`
`
`
`Safety:
`Generally Well-Tolerated
`
`(cid:121) No ocular Serious Adverse Events (SAE) reported in
`study eyes
`(cid:121) No reports of clinically significant intraocular
`inflammation
`(cid:121) No incidence of endophthalmitis
`(cid:121) No drug-related systemic SAEs
`(cid:121) Non drug-related systemic SAEs:
`– 1 incident of angina pectoris (2q4 group)
`– 1 incident of congestive heart failure (0.5q4 group)
`– 1 incident of coronary artery disease (2q4 group)
`
`17
`
`Regeneron Exhibit 2028
`Page 17 of 20
`
`
`
`Safety:
`Treatment-Emergent Ocular Adverse Events
`Reported in > 5 Patients
`Study Eye, All Groups Combined
`
`
`
`Adverse EventAdverse Event
`
`
`Conjunctival HemorrhageConjunctival Hemorrhage
`
`Increased IOP (transient post injection)Increased IOP (transient post injection)
`
`Retinal HemorrhageRetinal Hemorrhage
`
`Eye PainEye Pain
`
`Vitreous DetachmentVitreous Detachment
`
`Detachment of Retinal Pigment Detachment of Retinal Pigment
`
`EpitheliumEpithelium
`
`Visual DisturbanceVisual Disturbance
`
`Visual Acuity Reduced (patient reported)Visual Acuity Reduced (patient reported)
`
`Retinal Pigment EpitheliopathyRetinal Pigment Epitheliopathy
`
`Retinal OedemaRetinal Oedema
`
`
`NumberNumber
`
`(N=157)(N=157)
`
`3838
`
`2121
`
`1313
`
`1111
`
`1111
`
`
`
`99
`
`
`99
`
`77
`
`66
`
`66
`
`
`Percent Percent
`
`(%)(%)
`
`24.224.2
`
`13.413.4
`
`8.38.3
`
`7.07.0
`
`7.07.0
`
`
`
`5.75.7
`
`
`5.75.7
`
`4.54.5
`
`3.83.8
`
`3.83.8
`
`18
`
`Regeneron Exhibit 2028
`Page 18 of 20
`
`
`
`Conclusions
`
`(cid:121) VEGF Trap-Eye significantly reduced retinal thickness from baseline, the
`primary study endpoint (p<0.0001)
`(cid:121) VEGF Trap also significantly improved visual acuity from baseline (p<0.0001)
`(cid:121) VEGF Trap-Eye 0.5 mg and 2 mg dosed every 4 weeks demonstrated the most
`improvement in retinal thickness and visual acuity at the 12-week primary
`endpoint and continued to show improvement at 16 weeks
`– 160-183 micron decrease in retinal thickness
`– 9.3-10.0 letter improvement in visual acuity
`– Reduction in number of patients with <20/200 vision to 0-3%
`– Increase in number of patients with >20/40 vision to 44-55%
`(cid:121) While quarterly dosing significantly improved retinal thickness and visual acuity
`versus baseline at all times, the effect was not as robust as with monthly dosing
`– A single dose maintained its effect on visual acuity out to 8 weeks
`(cid:121) Safety profile was predictable with no drug-related systemic side effects and no
`significant ocular inflammation
`
`19
`
`Regeneron Exhibit 2028
`Page 19 of 20
`
`
`
`VIEW 1 Phase 3 Study Design
`Currently Enrolling Patients
`
`Multi-center, active-
`1
`controlled, masked trial
`
`Screening procedures
`(N=1200 patients)
`4,
`
`Subjects randomized
`1:1:1:1
`
`VEGF
`Trap-Eye
`
`0.5 mg q4 wks
`
`2.0 mg q4 wks
`
`2.0 mg q8 wks*
`
`41.
`
`0.5 mg q4 wks
`
`Ranibizumab
`
`1
`
`Primary and secondary endpoints
`measured at week 52
`
`*After a 3-month monthly loading dose period.
`
`20
`
`Regeneron Exhibit 2028
`Page 20 of 20
`
`
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