46
15th Angiogenesis meeting 2018, Miami Roche virtual pipeline event Tuesday, 13 February 2018
15th Angiogenesis meeting 2018, Miami
Roche virtual pipeline event Tuesday, 13 February 2018
Agenda
Welcome
Karl Mahler, Head of Investor Relations
Roche in ophthalmology - overview
Jason S. Ehrlich, M.D. Ph.D., Global Head, Clinical Ophthalmology – Product Development
BOULEVARD: Phase 2 results of the bispecific VEGF/Ang2 antibody in diabetic macula edema
Sascha Fauser, M.D., Head pRED Ophthalmology
Q&A
Karl Mahler, Head of Investor Relations
2
Introduction
Karl Mahler
Head of Investor Relations
4
2018: Roche off to a good start
Record number of pipeline assets at pivotal stage in multiple disease areas
Hemlibra
polatuzumab vedotin
idasanutlin
ipatasertib
taselisib
VEGF-ANG2 biMAb
SMN2 splicer
V1a receptor ant. - autism
anti-myostatin adnectin
gantenerumab
crenezumab
Ocrevus
CapEndo
etrolizumab
2014 2016 2017 2015
Alecensa
Tecentriq
Hemlibra
idasanutlin
taselisib
lampalizumab
satralizumab (IL-6R MAb)
gantenerumab
crenezumab
Ocrevus
etrolizumab
Oncology Neuroscience Ophthalmology Immunology
Venclexta
Alecensa
Tecentriq
Hemlibra
idasanutlin
taselisib
lampalizumab
gantenerumab
Ocrevus
satralizumab
lebrikizumab
etrolizumab
Venclexta
Alecensa
Tecentriq
Cotellic
lampalizumab
gantenerumab
Ocrevus
satralizumab
lebrikizumab
etrolizumab
NM
Es
lin
e e
xte
nsio
ns
2
1
21
5
27
5
1
33
4
1
31
Diabetic macular edema (DME): High unmet medical need
Significant global burden due to vision loss
• Rate of T2D continues to grow; 40-45% will develop diabetic retinopathy (DR)1
• DME – is the most common diabetic eye disease and the leading cause of irreversible blindness in working age Americans1
Increased risk of DME with longer duration of
diabetes and increase HbA1c levels3
1 National Eye Institute. Facts About Diabetic Eye Disease. Available at: https://nei.nih.gov/health/diabetic/retinopathy.
2 NIH National Eye institute-https://nei.nih.gov/health/macular-edema/fact_sheet.
3 Varma et al. Prevalence of and Risk Factors for Diabetic Macular Edema in the United States:JAMA Ophthalmol. 2014 Nov; 132(11): 1334–1340.
Duration of Diabetes
Hb
A1
c
5
Mild NPDR Non-proliferative diabetic retinopathy
Moderate NPDR
Severe NPDR
PDR Proliferative Diabetic Retinopathy
DME
Occurrence
(~10% of DR will
develop DME1) Sta
ge
s o
f D
R
Roche in ophthalmology - overview
Jason S. Ehrlich, M.D., Ph.D.
Global Head, Clinical Ophthalmology - Product Development
Roche in ophthalmology
Taking on the leading causes of vision loss through pioneering therapies
Unmet Need
Innovative treatment
options are needed to
address the leading causes
of vision loss affecting 253
million people worldwide1
Breakthrough Science
We are pioneers striving for
transformative therapies
that leverage cutting edge
science for diseases with
high unmet medical need
Patient-Focused Innovation
Through our smart
innovations in molecular
engineering, biomarkers
and sustained drug delivery,
we strive to design the
right therapies for the
right patients
People and Partnerships
We hire the best people to
advance science and improve
people’s lives. We foster
extensive collaborative
partnerships with researchers,
clinicians and patient groups
7 1 WHO Fact Sheet, October 2017. Accessed 6 Feb 2018, http://www.who.int/mediacentre/factsheets/fs282/en/
Indication
Neovascular AMD
Diabetic Eye Disease
Retinal Vein Occlusion
Geographic Atrophy
Myopic CNV
Phase II Phase III In Submission Approved
anti-VEGF/ANG2
biMAb (RG7716)
anti-IL6R
(RG6168/SA237)
Lucentis 0.5 mg
PFS
Lucentis 0.5 mg
PFS
Lucentis 0.3 mg
(DME, DR)
Lucentis 0.5 mg
PFS
anti-VEGF/ANG2
biMAb (RG7716)
Giant Cell Arteritis
Multiple Sclerosis
Neuromyelitis Optica
Ocrevus
Actemra/RoActemra
Lucentis 0.3 mg
PFS (DME, DR)
ranibizumab Port
Delivery System
Phase I
NME
(RG6417)
Glaucoma NME
(RG7945)
Ophthalmology pipeline
8 Status as of February 1, 2018. Lucentis in collaboration with Forsight and Novartis
DME=diabetic macular edema; DR=diabetic retinopathy; PFS=prefilled syringe; biMAb=bispecific monoclonal antibody; NME=new molecular entity
Retinal vascular diseases remain leading causes of vision loss
9
2015 2025 2016 2026
DME AMD
2.8
5.3
5.7
4.2
53%
18%
16%
5% 8% nAMD, DME, RVO
Glaucoma
Dry Eye
Ocular inflammation/infections
Others
Market size: CHF 18.6bn
• Leading causes of vision loss in…
– working-age people in US, Europe: Diabetic eye disease (DME, PDR)
– elderly people in US, Europe: Neovascular AMD
2017 Ophthalmology market Neovascular AMD & DME market outlook
US
EU5
Japan
USD bn
Wet AMD & DME: High growth disease areas
Source: Decision Resources (January 2018) Source: Evaluate Pharma (January 2018)
Note: Figures for 2017 involve forecast values for Q4 2017 as investor reports of all companies are not yet released
DME=diabetic macular edema; PDR=proliferative diabetic retinopathy; AMD=age-related macular degeneration
Vision can be recovered in neovascular AMD and DME
Anti-VEGF therapy can improve outcomes and has become SOC
10
DME phase III studies: Lucentis vs sham;
mean change from baseline in VA during 24-months2
1 Ophthalmology 2014; 121: 2247-2254; 2 RIDE/RISE: Ophthalmology 2011;118:1594-1602
AMD=age-related macular degeneration; DME=diabetic macular edema; VA=visual acuity
DME phase III studies: Aflibercept vs laser;
mean change from baseline in VA during 52-wks1
VISTA VIVID
*with censoring of values after additional treatment was given (LOCF)
*
Still, many patients remain visually impaired
Improved efficacy is a major unmet need in retinal vascular disease
11
Despite significant improvements, many people do not achieve a visual acuity score of 20/40 or better
1 RIDE/RISE: Ophthalmology 2011;118:1594-1602; DME=diabetic macular edema
Snellen (eye chart to measure visual acuity) equivalent of 20/40: a person needs to approach to a distance of 6 metres (20 ft) to read letters that a person with normal acuity
could read at 12m (40 feet). In an even more approximate manner, this person could be said to have "half" the normal acuity of 6/6 or 20/20.
RIDE and RISE phase III trials – DME1
0.3 mg ranibizumab
(n=125; 125)
Sham injection
(n=130; 127)
0.5 mg ranibizumab
(n=127; 125)
Snellen e
quiv
ale
nt
of
20/4
0
or
bett
er
(%)
Ranibizumab versus sham-injection: Change from baseline in percentage of patients with a Snellen
equivalent of 20/40 or better at 24 months
24 months 24 months
DME is underdiagnosed and undertreated today
12
5.4 mn DME prevalent cases (major markets) in 2015*
52% Diagnosed
~Only 50% of people diagnosed today4
39% Drug-
Treated
• Rate of type 2 diabetes continues to grow
• 40-45% of people with diabetes will develop diabetic retinopathy1,2
• DME is a type of DR that is a leading cause of vision loss for people
with diabetes3
Treatment received during the first year following diagnosis
0
2000
4000
6000
8000
10000
28 365 28 365 28 365 28 365 28 365
Observation anti-VEGF Laser Corticosteroid Combination
Nu
mb
er
of
Pa
tie
nts
Ranibizumab
Aflibercept
Bevacizumab
75% of all patients receive no
treatment in first 28 days
Days
Patien
t n
um
ber
J.R. Willis et al., AAO 2017
*Source: Decision Resources (January 2018) 1 National Eye Institute. Facts About Diabetic Eye Disease. Available at: https://nei.nih.gov/health/diabetic/retinopathy. 2 NIH National Eye institute-https://nei.nih.gov/health/macular-
edema/fact_sheet. 3 American Academy of Ophthalmology. What is Diabetic Retinopathy? Available at: http://www.geteyesmart.org/eyesmart/diseases/diabetic-retinopathy/index.cfm.
Accessed October 2, 2015. 4 Bressler NM, Varma R, Doan Q, et al. Prevalence of Visual Impairment from Diabetic Macular Edema and Relationship to Eye Care from the 2005 − 2008
National Health and Nutrition Examination Survey (NHANES)[abstract]. The Retina Society 45th Annual Scientific Meetings, Washington, DC; October 4−7, 2012 (accepted for
presentation).
DME is underdiagnosed and undertreated today
13
0
2000
4000
6000
8000
10000
28 365 28 365 28 365 28 365 28 365
Observation anti-VEGF Laser Corticosteroid Combination
Nu
mb
er
of
Pa
tie
nts
Ranibizumab
Aflibercept
Bevacizumab
Days
60% of all patients receive
no treatment in 1st year
Patien
t n
um
ber 5.4 mn DME prevalent cases (major markets) in 2015*
52% Diagnosed
~Only 50% of people diagnosed today4
39% Drug-
Treated
• Rate of type 2 diabetes continues to grow
• 40-45% of people with diabetes will develop diabetic retinopathy1,2
• DME is a type of DR that is a leading cause of vision loss for people
with diabetes3
Treatment received during the first year following diagnosis
J.R. Willis et al., AAO 2017
*Source: Decision Resources (January 2018) 1 National Eye Institute. Facts About Diabetic Eye Disease. Available at: https://nei.nih.gov/health/diabetic/retinopathy. 2 NIH National Eye institute-https://nei.nih.gov/health/macular-
edema/fact_sheet. 3 American Academy of Ophthalmology. What is Diabetic Retinopathy? Available at: http://www.geteyesmart.org/eyesmart/diseases/diabetic-retinopathy/index.cfm.
Accessed October 2, 2015. 4 Bressler NM, Varma R, Doan Q, et al. Prevalence of Visual Impairment from Diabetic Macular Edema and Relationship to Eye Care from the 2005 − 2008
National Health and Nutrition Examination Survey (NHANES)[abstract]. The Retina Society 45th Annual Scientific Meetings, Washington, DC; October 4−7, 2012 (accepted for
presentation).
Real world outcomes in nAMD, DME limited by treatment burden
Potentially addressed by extending durability of anti-VEGF, targeting additional MOAs, or both
14
• Patients received a mean of 5.0 and 2.2 injections in the first and second year,
respectively.
• There were substantial differences in visual outcomes and injection frequency
between countries. More frequent visits and injections were associated with
greater improvements in visual acuity
• Almost 50% of patients receiving anti-VEGF treatment within 28 days of initial
diagnosis received ≤3 injections in the first year of treatment.
Anti-VEGF injections* in 1st year of treatment in patients provided
anti-VEGF within 28 days of initial DME diagnosis2 Mean change in visual acuity from baseline over time for patients with AMD1
-4
-2
0
2
4
6
8
0 90 180 270 360 450 540 630 720Mean
VA
dif
fere
nce
fro
m b
aselin
e b
y c
ou
ntr
y (
LO
CF
)a
Days
Germany (n=420)
France (n=398)
United Kingdom (n=410)
MORE VISITS
& INJECTIONS
FEWER
Italy (n=365)
The Netherlands (n=350)
Total (n=2227)
19.3%
16.4%
14.1%
10.2% 9.6%
7.7% 7.3%
5.4% 4.0%
5.9%
0%
5%
10%
15%
20%
1 2 3 4 5 6 7 8 9 10+
Pa
tie
nts
(%
)
Number of Anti-VEGF Injections
1 F.G. Holz et al., Br J Ophthalmol 2015; 2 J.R. Willis et al., AAO 2017
AMD=age-related macular degeneration; DME=diabetic macular edema; MOA=mechanism of action; VA=visual acuity
Approaches to potentially achieve better outcomes
1. Sustained delivery of intravitreal therapies for months at a time
LADDER: Phase 2 multicenter, randomized, interventional, active treatment-controlled study (NCT02510794)
Solid-state reservoir implant
slowly elutes ranibizumab
Implanted in OR
by vitreoretinal surgeon
Refillable in the office using
proprietary needle assembly
Primary endpoint: Time to first refill
Study fully enrolled, data expected 2H2018
R Wet AMD population
(N = 220)
RPDS Implant RBZ formulation 1
N=60
RPDS Implant RBZ formulation 2
N=60
RPDS Implant RBZ formulation 3
N=60
ITV SOC RBZ 0.5 mg/mL Monthly
N=40
15 ForSIGHT VISION4 acquired by Roche, January 2017
AMD=age-related macular degeneration; RPDS=ranibizumab port delivery system; RBZ=ranibizumab; ITV=intravitreal; SOC=standard of care
Approaches to potentially achieve better outcomes
2. Address vascular homeostasis by targeting Ang-2 along with VEGF
Fc region
Human vitreous levels
• First bispecific antibody in ophthalmology
binding to VEGF and Angiopoetin-2 (Ang2)
• Optimized Fc for faster systemic clearance
(FcRn), no effector function (FcγR)
Anti-VEGF/Ang2 biMAb
anti-VEGF anti-Ang2
Dual Ang-2/VEGF inhibition in DME may improve both efficacy and durability
• Ang2 and VEGF are key drivers of angiogenesis
• Angiopoietin/Tie2 axis modulates endothelial
cell stabilization2
16
• Levels of Ang-2 elevated in retinal vascular diseases1
1 EMBO Mol Med 2016;8:1265; 2 Am J Pathol 2002;160:1663
DME=diabetic macular edema; biMAb=bispecific monoclonal antibody
17
nAMD, Treatment naïve
N=75 NCT03038880
Ranibizumab 0.5 mg q4w
RG7716 short interval duration
RG7716 long interval duration
Primary outcome: Mean change from
Baseline in BCVA letter score at week 40
R
nAMD, Treatment naïve
N=273 NCT02484690
Ranibizumab 0.5 mg Q4 weeks (9 months)
9 month primary efficacy readout
RG7716 D1 Q4 weeks (9 months)
RG7716 D2 Q4 weeks (9 months)
RG7716 D2 Q4 X 4 mo
RBZ Q4 X 3 mo
RG7716 D2 Q8 x 5 months
VA2 D2 Q4 x 6 months
Dose response
H2H
Q8 weekly durability
Sub group analysis
incomplete responders
Primary outcome: Mean change from
baseline in BCVA letter score at week 36
R AVENUE
STAIRWAY
Diabetic macular edema
N=150 anti-VEGF naïve, 60 anti-
VEGF previously-treated NCT02699450
Ranibizumab 0.3 mg
RG7716 1.5 mg
RG7716 6 mg
Primary outcome: Mean change from
baseline in BCVA letter score at week 24
R BOULEVARD Observational period up to
week 36
Every fourth week up to week 20,
for a total of 6 administrations
VA2 RG7716 phase 2 program in both DME and nAMD
Data at Angiogenesis 2018
Data expected in 2018
Data expected in 2018
AMD=age-related macular degeneration; DME=diabetic macular edema; BCVA=best corrected visual acuity
BOULEVARD: Phase 2 results of the bispecific VEGF/Ang2 antibody in
diabetic macula edema
Sascha Fauser, M.D.,
Head pRED Ophthalmology
19
RG7716
Anti-VEGF/Anti–Angiopoietin-2 Bispecific Antibody RG7716 in Diabetic Macular Edema
Results From the Phase 2 BOULEVARD Clinical Trial
Pravin U. Dugel, MD1
Jayashree Sahni, MBBS, FRCOphth, MD2; Shamil Sadikhov, MSc2; Meike Pauly-Evers, PhD2; Piotr Szczesny, MD, PhD2; Robert Weikert, MSc2
on behalf of the BOULEVARD Study Investigators
1 Retina Consultants of Arizona, Phoenix, AZ, USC Eye Institute, Keck School of Medicine, University of
Southern California, Los Angeles, CA 2 Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
Presented at Angiogenesis, Exudation, and Degeneration 2018, February 10, 2018
20
Disclosures
• Relevant financial disclosures
– Dr. Dugel is a consultant for Genentech/Roche and Novartis
– Dr. Dugel sits on the Aerpio board of directors
• Study disclosures
– This study includes research conducted on human subjects
– Institutional Review Board approval was obtained prior to study initiation
– Funding was provided by F. Hoffmann-La Roche Ltd. for the study and third-party writing assistance, which was provided by Betsy C. Taylor, PhD, CMPP, of Envision Pharma Group
21
Take-Home Points
• RG7716 is the first bispecific antibody designed for intravitreal use that simultaneously binds and neutralizes both Ang-2 and VEGF-A
• RG7716 demonstrated statistically significant BCVA gains over ranibizumab at week 24 in anti-VEGF treatment-naïve patients with DME
• Secondary functional and anatomical endpoints (OCT, DRSS) support BCVA primary outcome
• RG7716 was well tolerated and showed no new or unexpected safety signals
RG7716 met its primary endpoint in the BOULEVARD phase 2 DME trial
BOULEVARD clinical trial (NCT02699450).
Ang-2, angiopoietin-2; BCVA, best-corrected visual acuity; DME, diabetic macular edema; DRSS, Diabetic Retinopathy Severity Score; OCT, optical coherence tomography; VEGF-A, vascular endothelial growth factor A.
22
Significant Unmet Need Remains for Patients With DME
There is a need for therapies that improve efficacy and/or reduce treatment burden
Anti–VEGF-A monotherapies have hit a ceiling for efficacy
• In RCT, only ~ 30%–45% of anti–VEGF-treated patients with DME gained ≥ 15 letters*,3-8
• Real-world data show that patients are not receiving the optimal number of injections, highlighting the need
for therapies that can reduce treatment burden3-12
• DR/DME is a multifactorial disease involving multiple pathways beyond VEGF13,14
• Current anti-VEGF treatments only target 1 pathway, primarily addressing vessel leakage and proliferation15
• Targeting additional pathways beyond VEGF could improve BCVA outcomes and decrease treatment burden
* Results for years 1 and 2 of treatment.
1. Guariguata L et al. Diabetes Res Clin Pract. 2014;103(2):137-149. 2. Bourne RR et al. Lancet Glob Health. 2013;1(6):e339-349. 3. Massin P et al. Diabetes Care. 2010;33(11):2399-2405. 4. Korobelnik JF et al. Ophthalmology. 2014;121(11):2247-2254.
5. DRCR.net. N Engl Med. 2015;372(13):1193-1203. 6. Nguyen QD et al. Ophthalmology. 2012;119(4):789-801. 7. Brown DM et al. Opthalmology. 2015;122(10):2044-2052. 8. DRCR.net. Ophthalmology. 2016;123(6):1351-1359. 9. Granstrom T et al.
Diabetes Res Clin Pract. 2016;121:157-165. 10. Wecker T et al. Br J Ophthalmol. 2017;101(3):353-359. 11. Willis JR et al. Presented at AAO 2017. 12. Ciulla TA et al. Presented at ARVO 2017. 13. Cohen SR et al. Dev Ophthalmol. 2016;55:137-146.
14. Romero-Aroca P et al. J Diabetes Res. 2016;2016:2156273. 15. Boyer DS et al. Ther Adv Endocrinol Metab. 2013;4(6):151-169.
BCVA, best-corrected visual acuity; DME, diabetic macular edema; DR, diabetic retinopathy; RCT, randomized clinical trial; VEGF, vascular endothelial growth factor.
DME is an increasing global burden
• Global rate of diabetes is growing and is expected to increase to affect 592 million by 20351
• DR, including associated DME, is a leading cause of vision loss in working-age adults2
23
Ang-2 Signaling Implicated in the Pathology of DR and DME
Evidence supports rationale for Ang-2 inhibition
Ocular Characteristics of
DR and DME
Associated With
Ang-2 Signaling
Elevated vitreous levels of Ang-21-4
Retinal microvascular inflammation5,6
Blood-retinal-barrier breakdown5
• Pericyte dropout2,5
• Endothelial cell destabilization5
• Retinal vessel leukostasis5,6
Capillary sprouting and remodeling9
Vascular destabilization
Microaneurysms
Fluid leakage
Ischemia
1. Regula JT et al. EMBO Mol Med. 2016;8(11):1265-1288. 2. Saharinen P et al. Nat Rev Drug Discov. 2017;16(9):635-661. 3. Patel JI et al. Br J Ophthalmol. 2005;89(4):480-483. 4. Tuuminen R et al. Acta Ophthalmol. 2015;93(6):e515-e516. 5. Klaassen I
et al. Prog Retin Eye Res. 2013;34:19-48. 6. Cohen SR et al. Dev Ophthalmol. 2016;55:137-146. 7. Scholz A et al. Ann N Y Acad Sci. 2015;1347:45-51. 8. Huang H et al. Nat Rev Cancer. 2010;10(8):575-585. 9. Campochiaro PA. Prog Retin Eye Res.
2015;49:67-81. 10. Flecht M et al. J Clin Invest. 2012;122(6):1991-2005.
Ang-2, angiopoietin-2; DME, diabetic macular edema; DR, diabetic retinopathy.
2,5,7,8
2,7,8
9,10
2,5
24
RG7716: the First Bispecific Antibody Designed for Intravitreal Use
Engineered for efficacy, duration within the eye, and fast systemic clearance
Regula JT et al. EMBO Mol Med. 2016;8(11):1265-1288.
Ang-2, angiopoietin-2; Fab, fragment antigen binding; Fc, fragment crystallizable; FcRn, neonatal Fc receptor; VEGF-A, vascular endothelial growth factor A.
Anti–VEGF-A Fab
• Proven efficacy through
VEGF-A inhibition
Anti–Ang-2 Fab
• Enhanced activity
through Ang-2 inhibition
Optimized Fc
• Faster systemic clearance (FcRn)
• No effector function (FcγR)
1 molecule – 2 targets
25
Time, s
RG7716 Simultaneously Binds Both Ang-2 and VEGF-A
Dual inhibition independent of binding order
Ang-2 VEGF-A Ang-2 VEGF-A
RG7716
Regula JT et al. EMBO Mol Med. 2016;8(11):1265-1288.
Ang-2, angiopoietin-2; RU, response units; VEGF-A, vascular endothelial growth factor A.
0 100 200 300 400 500
40
35
25
20
15
10
5
0
30
45
1st VEGF-A
binding
2nd Ang-2
binding
1st Ang-2
binding
2nd VEGF-A
binding
Re
sp
on
se
, R
U
26
The BOULEVARD Study: RG7716 in DME
27
Study Design
Randomized, active comparator-controlled, double-masked, phase 2 clinical trial
229 patients with
center-involving DME*
Study
Treatment
0 4 8 12 16 20 24
Time, Weeks
R
* Safety data set consists of 224 patients; 2 patients removed due to GCP non-compliance at a single site; 3 patients were randomized but did not receive treatment. † Patients randomized 1:1:1 into the 3 treatment arms; 2 patients removed from analysis due to GCP non-compliance at a single site. ‡ Patients randomized 1:1 into 0.3 mg ranibizumab and 6.0 mg RG7717 treatment arms. § Ranibizumab treatment given and patient exited study if both CST increased by ≥ 50 μm from week 24 and BCVA decreased by ≥ 5 ETDRS letters from week 24 due to DME.
BOULEVARD clinical trial (NCT02699450).
BCVA, best-corrected visual acuity; CST, central subfield thickness; DME, diabetic macular edema; GCP, Good Clinical Practice; R, randomized; VEGF-A, vascular endothelial growth factor A.
• 168 anti-VEGF treatment-
naïve patients†
• 61 previously anti–VEGF-
treated patients‡
6.0 mg RG7716
1.5 mg RG7716
0.3 mg ranibizumab
Primary endpoint
0.3 mg ranibizumab
if required§
Off-Treatment
Observation
28 32 36
28
Key Inclusion and Exclusion Criteria
* CST as measured by Spectralis (Heidelberg) at screening; ≥ 315 μm for Cirrus and Topcon and ≥ 295 μm for Optovue. BOULEVARD clinical trial (NCT02699450).
BCVA, best-corrected visual acuity; CST, central subfield thickness; DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; PDR, proliferative diabetic retinopathy;
PRP, panretinal photocoagulation; VEGF, vascular endothelial growth factor.
Key inclusion criteria
• Age ≥ 18 years
• Center-involving DME
• CST ≥ 325 μm*
• BCVA 73–24 ETDRS letters
(20/40–20/320 Snellen equivalent)
Key exclusion criteria
All patients
• Any signs of high-risk PDR
• Any prior PRP
• Any macular laser photocoagulation within
3 months prior to study start
Previously anti–VEGF-treated patients only
• Anti-VEGF treatment within 3 months prior
to study start
29
Key Study Objectives
• Primary objective
– Efficacy of RG7716 compared with ranibizumab in anti-VEGF treatment-naïve patients at week 24
• Mean BCVA change from baseline using a linear model adjusting for baseline BCVA and randomization stratification factors*
• Key secondary and exploratory objectives
– Ocular and systemic safety
– Anatomical outcomes
– DR severity outcomes
– Duration of effect
– Outcomes in previously anti–VEGF-treated patients
– Systemic and ocular pharmacokinetics
– Analysis of plasma, aqueous humor, and vitreous biomarkers
* Linear model adjusted for baseline BCVA, previous macular laser treatment status at randomization, and BCVA category (≥ 64 letters vs ≤ 63 letters) at baseline.
BOULEVARD clinical trial (NCT02699450).
BCVA, best-corrected visual acuity; DR, diabetic retinopathy; VEGF, vascular endothelial growth factor.
30
Study Results: Week 24 Data for Anti-VEGF Treatment-Naïve Patients
31
Baseline Demographics
Well balanced across treatment arms
Observed data; anti-VEGF treatment-naïve patients only. BOULEVARD clinical trial (NCT02699450).
HbA1c, glycated hemoglobin.
Characteristic
0.3 mg Ranibizumab
n = 59
1.5 mg RG7716
n = 54
6.0 mg RG7716
n = 53
All Patients
N = 166
Mean age, years (SD) 61.6 (9.5) 61.4 (7.7) 60.5 (9.1) 61.2 (8.8)
Male, n (%) 37 (62.7%) 19 (35.2%) 33 (62.3%) 89 (53.6%)
Race, n (%)
American Indian or Alaska native
Asian
Black or African American
White
Unknown
0 (0%)
0 (0%)
9 (15.3%)
49 (83.1%)
1 (1.7%)
0 (0%)
0 (0%)
11 (20.4%)
42 (77.8%)
1 (1.9%)
2 (3.8%)
1 (1.9%)
10 (18.9%)
39 (73.6%)
1 (1.9%)
2 (1.2%)
1 (0.6%)
30 (18.1%)
130 (78.3%)
3 (1.8%)
Ethnicity, n (%)
Hispanic or Latino
11 (18.6%)
8 (14.8%)
9 (17.0%)
28 (16.9%)
Mean duration of diabetes at
randomization, years (SD) 14.0 (10.5) 15.6 (10.0) 14.5 (9.3) 14.7 (10.0)
Mean HbA1c, % (SD) 7.8% (1.6) 8.2% (1.6) 7.7% (1.8) 7.9% (1.7)
32
Baseline Ocular Characteristics
Generally well balanced across treatment arms
Observed data; anti-VEGF treatment-naïve patients only. BOULEVARD clinical trial (NCT02699450).
BCVA, best-corrected visual acuity; CST, central subfield thickness; DR, diabetic retinopathy; ETDRS, Early Treatment Diabetic Retinopathy Study; NPDR, non-proliferative DR; PDR, proliferative DR; PRP, panretinal photocoagulation.
Characteristic
0.3 mg Ranibizumab
n = 58
1.5 mg RG7716
n = 54
6.0 mg RG7716
n = 51
All Patients
N = 163
Vision
Mean BCVA, ETDRS letters (SD) 61.2 (9.9) 60.9 (11.1) 60.0 (11.0) 60.8 (10.6)
20/40 or better vision, n (%) 13 (22.4%) 15 (27.8%) 11 (21.6%) 39 (23.9%)
Worse than 20/40 vision, n (%) 45 (77.6%) 39 (72.2%) 40 (78.4%) 124 (76.1%)
Anatomic
Mean CST, μm (SD) 490.9 (139.0) 535.4 (163.1) 496.5 (135.0) 507.4 (146.7)
Diabetic retinopathy status, n (%)
DR questionable
Mild NPDR
Moderate NPDR
Moderately severe NPDR
Severe NPDR
Prior PRP
Moderate PDR
Missing/cannot grade
n = 59
0 (0.0%)
5 (8.5%)
14 (23.7%)
23 (39.0%)
15 (25.4%)
1 (1.7%)
0 (0.0%)
1 (1.7%)
n = 54
1 (1.9%)
5 (9.3%)
8 (14.8%)
21 (38.9%)
16 (29.6%)
1 (1.9%)
0 (0.0%)
2 (3.7%)
n = 53
0 (0.0%)
5 (9.4%)
10 (18.9%)
25 (47.2%)
9 (17.0%)
1 (1.9%)
1 (1.9%)
2 (3.8%)
N = 166
1 (0.6%)
15 (9.0%)
32 (19.3%)
69 (41.6%)
40 (24.1%)
3 (1.8%)
1 (0.6%)
5 (3.0%)
33
Mean BCVA Gains From Baseline (Observed Values)
RG7716 treatment provided dose-dependent improvements in vision
0
2
4
6
8
10
12
14
16
18
0 4 8 12 16 20 24
Mean
BC
VA
Ch
an
ge F
rom
Baselin
e,
ET
DR
S L
ett
ers
Time, Weeks
Observed data; anti-VEGF treatment-naïve patients only. Error bars represent 80% CI.
BOULEVARD clinical trial (NCT02699450). BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study.
0.3 mg ranibizumab (n = 59) 1.5 mg RG7716 (n = 54) 6.0 mg RG7716 (n = 53)
+ 14.8
+ 12.3
+ 10.1
34
0
2
4
6
8
10
12
14
16
18
0 4 8 12 16 20 24
Adjusted Mean BCVA Gains From Baseline
RG7716 met its prespecified primary endpoint of efficacy
+ 13.9
+ 11.7
+ 10.3
Observed data; anti-VEGF treatment-naïve patients only. Error bars represent 80% CI.
* Linear model adjusted for baseline BCVA, previous macular laser treatment status at randomization, and BCVA category (≥ 64 letters vs ≤ 63 letters) at baseline. † Protocol prespecified significance level,
P < 0.2. BOULEVARD clinical trial (NCT02699450). BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study.
P = 0.03†
80% CI 1.53, 5.61
+ 3.6
Linear model adjusted for baseline BCVA and randomization stratification factors*
Ad
jus
ted
Mean
BC
VA
Ch
an
ge
Fro
m B
aselin
e,
ET
DR
S L
ett
ers
0.3 mg ranibizumab (n = 59) 1.5 mg RG7716 (n = 54) 6.0 mg RG7716 (n = 53)
Time, Weeks
35
Mean CST Change From Baseline (Observed Values)
CST reduction directionally supports BCVA primary outcome
Observed data; treatment-naïve patients only. Error bars represent 80% CI.
BOULEVARD clinical trial (NCT02699450). BCVA, best-corrected visual acuity; CST, central subfield thickness.
– 177.9 μm
– 200.3 μm
– 237.5 μm
0.3 mg ranibizumab (n = 59) 1.5 mg RG7716 (n = 54) 6.0 mg RG7716 (n = 53)
-300
-250
-200
-150
-100
-50
0
0 4 8 12 16 20 24
Time, Weeks
Mean
CS
T C
han
ge
Fro
m B
aselin
e,
μm
36
-300
-250
-200
-150
-100
-50
0
0 4 8 12 16 20 24
Adjusted Mean CST Change From Baseline
CST reduction directionally supports BCVA primary outcome in a dose-dependent manner
Observed data; anti-VEGF treatment-naïve patients only. Error bars represent 80% CI.
* Linear model adjusted for baseline CST, previous macular laser treatment status at randomization, and BCVA category (≥ 64 letters vs ≤ 63 letters) at baseline; protocol prespecified significance level,
P < 0.2. BOULEVARD clinical trial (NCT02699450). BCVA, best-corrected visual acuity; CST, central subfield thickness.
Linear model adjusted for baseline CST and randomization stratification factors*
– 204.7 μm
– 217.1 μm
– 225.8 μm
Ad
jus
ted
Mean
CS
T C
han
ge
Fro
m B
aselin
e,
μm
0.3 mg ranibizumab (n = 59) 1.5 mg RG7716 (n = 54) 6.0 mg RG7716 (n = 53)
Time, Weeks
37
RG7716 Resulted in Improved Proportions of 2- and 3-Line Gainers
Supporting BCVA primary outcome in a dose-dependent manner
* ≥ 10 ETDRS letters from baseline. † ≥ 15 ETDRS letters from baseline.
Observed data, week 24; anti-VEGF treatment-naïve patients only. BOULEVARD clinical trial (NCT02699450).
BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study.
57.1 61.2
70.5
0
20
40
60
80
Pati
en
ts,
%
≥ 2-Line Gainers*
at Week 24
32.7 36.7
43.2
0
20
40
60
80
Pati
en
ts,
%
≥ 3-Line Gainers†
at Week 24
0.3 mg ranibizumab (n = 49) 1.5 mg RG7716 (n = 49) 6.0 mg RG7716 (n = 44)
38
RG7716 Resulted in Improved DR Severity Scores
≥ 2-step DRSS improvement data support BCVA primary outcome in a dose-dependent manner
Observed data, week 24; anti-VEGF treatment-naïve patients only. BOULEVARD clinical trial (NCT02699450).
BCVA, best corrected visual acuity; DR, diabetic retinopathy; DRSS, Diabetic Retinopathy Severity Score.
12.2
27.7
38.6
0
20
40
60
80P
erc
en
t o
f P
ati
en
ts
≥ 2-Step DR Improvement at Week 24
0.3 mg ranibizumab (n = 49) 1.5 mg RG7716 (n = 47) 6.0 mg RG7716 (n = 44)
39
Safety: All Patients
40
Safety – All Patients (Anti-VEGF Treatment-Naïve and Previously Treated)
No new safety signals or unexpected findings
Selected Adverse Events, Study Eye or Systemic, n (%)
0.3 mg Ranibizumab n = 89
1.5 mg RG7716 n = 55
6.0 mg RG7716 n = 80
All Patients N = 224
Intraocular inflammation 0 0 0 0
Endophthalmitis 0 0 0 0
Retinal detachment 0 0 0 0
Vitreous hemorrhage 3 (3.4%) 0 1 (1.3%) 4 (1.8%)
Hypertension 7 (7.9%) 5 (9.1%) 6 (7.5%) 18 (8.0%)
Non-fatal myocardial infarction 1 (1.1%) 0 0 1 (0.4%)
Non-fatal stroke 0 0 0 0
Vascular death 1 (1.1%) 0 1 (1.3%) 2 (0.9%)
All deaths attributed to cardiac, cerebral, hemorrhagic,
embolic, other vascular, or unknown causes 1 (1.1%) 0 2 (2.5%) 3 (1.3%)
Any other death 1 (1.1%)a 1 (1.8%)b 0 2 (0.9%)
IOP, mmHg
Baseline; week 24 (pre-dose); (change from baseline) 15.1; 15.4 (0.1) 16.0; 16.6 (0.6) 15.3; 15.3 (-0.1) NA
a Kidney failure. b Gangrene.
Observed data; safety population includes both anti-VEGF treatment-naïve and previously anti–VEGF-treated patients.
BOULEVARD clinical trial (NCT02699450). IOP, intraocular pressure; NA, not applicable.
41
Safety – All Patients (Anti-VEGF Treatment-Naïve and Previously Treated)
• Ocular and systemic safety profile of RG7716 was consistent with the safety
profile observed in patients with DME treated with intravitreal anti-VEGF drugs,
with no new safety signals observed
• No adverse events of intraocular inflammation or endophthalmitis
• No increase in mean intraocular pressure
• No increase in mean blood pressure
No new safety signals or unexpected findings
Observed data; safety population includes both anti-VEGF treatment-naïve and previously anti–VEGF-treated patients. BOULEVARD clinical trial (NCT02699450).
DME, diabetic macular edema; VEGF, vascular endothelial growth factor.
42
Outlook
• Efficacy in previously anti–VEGF-treated patients
• Additional anatomical outcomes
• Duration of effect
Presentation of additional data and analyses at future meetings
BOULEVARD clinical trial (NCT02699450).
VEGF, vascular endothelial growth factor.
43
BOULEVARD phase 2 study in DME*
• X
• X
• X
• RG7716 demonstrated robust visual acuity gains in patients with DME at 6 months, with a mean of + 13.9 letters gained from baseline
• RG7716 demonstrated statistically significant BCVA gains over ranibizumab at 6 months (mean gain of + 3.6 letters over ranibizumab, P = 0.03)
• ≥ 2- and ≥ 3-line gainers, CST reduction, and DRSS improvement data support BCVA primary outcome
• Both primary and secondary outcomes showed a dose-dependent response
• RG7716 was well tolerated and showed no new or unexpected safety signals
Conclusions
RG7716 met its primary endpoint in the BOULEVARD phase 2 DME trial
RG7716
• The first bispecific antibody specifically designed for intravitreal use that simultaneously binds and neutralizes both Ang-2 and VEGF-A
* Results for anti-VEGF treatment-naïve patients.
44
Thank You to the More Than 70 Participating Study Sites
45
Thank You to All Involved in the BOULEVARD Trial
• The authors would like to thank all those involved in the BOULEVARD trial, in particular all of the patients and their families, and all of the investigators
• Principal investigators (all US):
Adrean S, Retina Consultants of Orange County; Alfaro V, Charleston Neuroscience Inst; Antoszyk A, Char Eye Ear & Throat Assoc; Awh C, Tennessee Retina PC.; Baker C, Paducah Retinal Center; Barbazetto I, Vitreous-Retina-Macula; Brooks-Jr H, Southern Vitreoretinal Assoc; Brown D, Retina Consultants of Houston; Busquets M, Associates in Ophthalmology; Callanan D, Texas Retina Associates; Calzada J, Charles Retina Institution; Campochiaro P, Wilmer Eye Institute; Castellarin A, California Retina Consultants; Chan C, Southern CA Desert Retina Cons; Chittum M, Retina Consultants of Southern; Clark L, Palmetto Retina Center; Danzig C, Rand Eye; Das A, University of New Mexico; Dreyer R, Retina Northwest; Dugel P, Retinal Research Institute, LLC; Eichenbaum D, Retina Vitreous Assoc of FL; Eifrig C, Retina Associates of Orange County; Elman M, Elman Retina Group; Ghuman T, National Ophthalmic Research Institute; Goldberg R, Bay Area Retina Associates; Googe J, Southeastern Retina Associates; Gordon A, Associated Retina Consultants; Gupta S, Retina Specialty Institute; Hampton R, Retina Vit Surgeons/Central NY; Hershberger V, Florida Eye Associates; Higgins P, Retina Center of New Jersey; Hunter, III A, Oregon Retina, LLP; Jain A, Ophthalmic Clinical Trials San Diego; Javid C, Retina Associates Southwest PC; Jhaveri C, Retina Research Center; Keyser B, New Jersey Retina Research Foundation; Khanani A, Sierra Eye Associates; Khurana R, Northern California Retina Vitreous Associates; Kiss S, Weill Cornell Eye Associates, New York-Presbyterian Hospital/Weill Cornell Medical Center; Kwun R, Retina Associates of Utah; Ladd B, Eye Surgeons of Richmond Inc. Virginia Eye Institute; Lee P, Retina Consultants of Western New York; Leys M, West Virginia University Eye Institute; Lim J, Univ of Illinois at Chicago; London N, Retina Consultants, San Diego; MacCumber M, Illinois Retina Associates SC; Marcus D, Southeast Retina Center; Maturi R, Midwest Eye Institute; McCabe F, Vitreo-Retinal Associates; Miller D, Cincinnati Eye Institute; Nielsen J, Wolfe Eye Clinic; Ober M, Retina Consultants of Michigan; Ohr M, OSU Eye Physicians & Surgeons; Parke D. Wilken, Vitreoretinal Surgery; Patel S, W Texas Retina Consultants PA; Payne J, Palmetto Retina Center; Peace J, United Med Res Inst; Pearlman J, Retinal Consultants Med Group; Prensky J, Pennsylvania Retinal Spec.; Rathod R, Orange County Retina Med Group; Schadlu R, Arizona Retina and Vitreous Consultants; Schwartz S, Jules Stein Eye Institute/ UCLA; Sheth V, University Retina and Macula Associates, PC; Shirkey B, Retina Associates of Kentucky; Singer M, Med Center Ophthalmology Assoc; Singerman L, Retina Assoc of Cleveland Inc; Singh R, Cleveland Clinic Foundation, Cole Eye Institute; Stern J, Capital Region Retina; Stoller G, Ophthalmic Consultants of LI; Stoltz R, Georgia Retina PC; Stone C, West Carolina Retinal Assoc PA; Torti R, Retina Specialists; Wirthlin R, Spokane Eye Clinical Research; Wong R, Austin Retina Associates; Wykoff C, Retina Consultants of Houston; Yates P, Univ of Virginia Ophthalmology; Zilis J, Colorado Retina Associates, PC.
