FOCUS Interim Results: GT005 Gene Therapy Phase I/II Study for the Treatment of Geographic Atrophy
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FOCUS Interim Results: GT005 Gene Therapy Phase I/II Study for the Treatment of Geographic Atrophy Angiogenesis, Exudation, and Degeneration 2021 Nadia K. Waheed, MD, MPH Associate Professor, Tufts University School of Medicine Chief Medical Officer, Gyroscope Therapeutics F E B RUARY 12, 2021
Financial Disclosures
Office Holder
• Gyroscope Therapeutics
Consultant
• Apellis, Nidek, Boehringer Ingelheim
Grants/Research Support
• Carl Zeiss Meditec, Heidelberg, Nidek, Optovue, Regeneron, Topcon,
Shareholder
• Ocudyne
Angiogenesis, Exudation, and Degeneration 2021 2
CFI
Take Home Messages
CFH
• Complement over-activation has been implicated in AMD disease pathogenesis C3b
• Complement Factor I (CFI) is a natural down-regulator of the complement system
• GT005 is an investigational gene therapy designed to induce expression of CFI after
subretinal delivery
• GT005 has been well tolerated to date in the FOCUS Phase I/II trial in patients with GA
• Early data show majority of patients had increased vitreous CFI and downstream modulation
of complement biomarkers
• Randomized controlled Phase II trials evaluating safety and efficacy of GT005 are ongoing
Angiogenesis, Exudation, and Degeneration 2021 3
Strong Evidence of Role of Overactive Complement System in AMD
Pathology Genetics Clinical Data
Investigational complement inhibitors
have shown a 28-29% reduction in
GA progression (vs sham) in recent
Phase 2 studies*
Forest DL et al, 2015, Dis Model Mech, 8(5):421-427 Fritsche et al, 2016, Nature Genetics, 48 (2): 134-143 Lao DS et al, 2020, Ophthalmology, 127 (2): 186-195
• Biochemical analysis of drusen shows • Variants in multiple complement genes
presence of multiple components of (including CFI) shown to be associated
the complement pathway with increased risk of developing AMD
*Liao DS et al, 2020, Ophthalmology.127(2):186-195
Jaffe GJ et al, 2020, Ophthalmology.1:S0161-6420(20)30845-9
Angiogenesis, Exudation, and Degeneration 2021 4
CFI: A Natural Inhibitor of the Alternative Pathway
CFI – THE BODY’S
DOW N NATURAL REGULATOR
R E G UL AT I O N
C3b
• CFI’s function is to keep the
complement system in balance
• Given this critical role, we believe CFI is
well suited for gene therapy
CFI
• GT005 is designed to induce production
A MP L I F I C AT IO N of this natural regulator
TERMINAL
PATHWAY AND
CELL DEATH
CFD CFB
Angiogenesis, Exudation, and Degeneration 2021 5
GT005: Using Clinically Proven AAV2 Vector to Produce CFI
• Designed to enable cellular transduction and induce secretion of CFI
• Potential to allow for constitutive expression of CFI after single administration
• Potential to avoid saw tooth dynamics of repeated intravitreal injections of medications
• AAV2 clinically predicated with persistent durability at 3 years in other programs*
ITR = i nverse terminal repeat; CAG = CAG promotor; CMV = CMV promotor; CFI = complement factor I; WPRE = Woodchuck Hepatitis Vi rus (WHP) Posttranscriptional
Regulatory El ement which is a DNA sequence that, when transcribed creates a tertiary s tructure enhancing expression; bGHpA = poly A s ignal.
*Ma gui re AM et a l, 2019, Ophthalmology; 126:1273-1285
Angiogenesis, Exudation, and Degeneration 2021 6
FOCUS Phase I/II Open-Label Study to Evaluate GT005 Safety and Tolerability
• Completed dose escalation and currently enrolling dose-expansion cohort
• 22 patients dosed as of December 2020; data collection ongoing
• Measuring transgene expression and pharmacodynamic markers by vitreous sampling
• Interim data available from patients in Cohorts 1, 2, 3 and initial patients dosed in Cohort 4
Dose escalation Dose expansion OrbitTM Subretinal Delivery System OrbitTM Subretinal Delivery System
(Transvitreal) (Transvitreal) Integration Expansion
First patient dosed January 2019
First patient dosed March 2020 First patient dosed October 2020 Planned
Dosing complete
Enrolling Cohort 5 complete
Cohort 3 Cohort 4 Cohort 6 Cohort 7
Dose 3 Doses 1, 2, 3 Dose 3 Dose TBD
n=4 n = up to 20 n=3 n= up to 20
Cohort 2
Cohort 5
Dose 2
n=4 Dose 2
n=3
Cohort 1
Dose 1
n=3
Safety Evaluation
(after 3 participants complete 5 w eeks follow -up)
Angiogenesis, Exudation, and Degeneration 2021 7
3 Dose Levels of GT005 Were Well Tolerated in Initial Cohorts
Ocular Treatment-Emergent Adverse Events (TEAEs) in Cohorts 1-4
Cohort 1 (n=3) Cohort 2 (n=4) Cohort 3 (n=4) Cohort 4 (n=8)
Dose: (2E10 vg) Dose: (5E10 vg) Dose: (2E11 vg) Dose: (5E10-2E11 vg)
TEAEs (n=4) TEAEs (n=7) TEAEs (n=6) TEAEs (n=4)
• Cataract • Age-related macular degeneration* • Cataract • Cataract
• Cataract (fellow eye) • Blepharitis (both eyes) • Choroidal neovascularisation • Hallucination
• Dry eye • Cataract • Eye contusion (fellow eye) • Intraocular pressure increased
• Eye Oedema • Conjunctivitis viral (both eyes) • Iridocyclitis • Visual acuity reduced
• Dry age-related macular • Retinal haemorrhage
degeneration (fellow eye) † • Vitreous floaters
• Glaucoma (fellow eye)
• Glaucoma
• No dose-related trends in frequency/type • 1 possible GT005-related adverse event
of AEs - Choroidal neovascularization treated with anti-VEGF (moderate severity)
• No GT005-related SAEs • 12 surgery-related adverse events
• No safety signal on laboratory - 9 mild (1 corneal abrasion post op causing vision decrease)
parameters - 3 moderate (2 cataracts; 1 sub-RPE injection)
• Other ocular AEs in study eye of note
- 2 study eye AEs reported with increased IOP
- 1 with history of glaucoma, Tmax 27, resolved with drops
- 1 with IOP elevation at wk1 visit. Tmax 29, resolved at 5 weeks
*Miscoded (Sub-RPE injection)
†BCVA drop in fellow eye secondary to GA progression Data as of December 2020
Angiogenesis, Exudation, and Degeneration 2021 8
Interim Data Shows No Signs of GT005-Related Inflammation
Interim FOCUS Immunogenicity Data
• GT005 associated with clinically benign • AAV2 antibodies (n=12)
immunogenicity • Pre-existing antibodies to AAV2 vector in 9 patients
• No increases in AAV2 antibody titers post-treatment
• No antibody-mediated immunogenicity to the • T-cell immunogenicity (n=11)
CFI transgene • Pre-existing T-cell immunogenicity to AAV2 vector in 2 patients
• Increases in T-cell response post-treatment that were transient in
• No association of immune responses with nature and at a low magnitude
adverse events • Anti-CFI antibodies (n=8)
• No anti-CFI antibodies seen in patients tested to date
Data as of December 2020
Angiogenesis, Exudation, and Degeneration 2021 9
Secondary Endpoints Data
Visual Acuity Preserved at 48 Weeks Post Treatment
Mean (95% CI) BCVA Mean (95% CI) BCVA change from Baseline
80 10
70
5
60
0
(ETDRS letters)
BCVA change
50
(ETDRS letters)
BCVA
40 -5
30
-10
20
-15
10
0 -20
0 4 8 12 16 20 24 28 32 36 40 44 48 0 4 8 12 16 20 24 28 32 36 40 44 48
n=22 n=10 n=8 n=22 n=10 n=8
Study Week Study Week
Study Eye Fellow Eye Study Eye Fellow Eye
Data as of December 2020
Angiogenesis, Exudation, and Degeneration 2021 10Transgene Expression: Consistent and Durable Increase in Vitreous CFI levels
• 9/10 patients had elevated CFI levels post-GT005 administration; average increase of 146% from baseline
• 1st patient treated continues to have sustained CFI increase at 84 weeks
• Increases in vitreal CFI seen in both RV and non-RV patients
2500
1200 Low dose (2E10 vg)
Increase in CFI from baseline
2000 Medium dose (5E10 vg)
Increase in CFI from
1200 High dose (2E11 vg)
baseline (ng/mL)
Open symbol = RV GA
800 Closed symbol = Broad GA
800
(ng/mL)
400
400
0
0 -400
2e10 vg 5e10 vg 2e11 vg
(n=2) (n=2) (n=6) 0 10 20 30 40 50 60 70 80 90
Dose Study week
Maximum CFI level (at any timepoint) above baseline; DataData
as ofcut:
December 2020
05OCT2020
Bars=mean SEM; only data from 12 weeks included
Data as
Data cut:
of 05OCT2020;
December 2020
Angiogenesis, Exudation, and Degeneration 2021 11Previously Published Data Implies
Significant Impact on Amplification Loop
Proc Natl Acad Sci U S A. 2011 May 24;108(21):8761-6.
Classical Pathway Lectin Pathway Alternative Pathway
Ba Ba
• Published data indicate that protective variants*
Ba
C3 in C3, CFB and CFH decrease complement
Ba activity by 48% when compared to common risk
Amplification Loop
Ba variants [PNAS (2011) 108(21):8761-6]
CFI CFH C3b
CFB CFD
• Ba is a direct readout of the amplification loop**
CFH+CFI
C5 • Inhibition of the amplification loop by CFI (GT005)
iC3b
C3c leads to a 41% drop in vitreal Ba levels, indicating
+ C3d CR1+CFI
significant inhibition of the amplification loop
MAC
Degradation
Cell lysis and death
* C3 R102G, CFH V62I, CFB R102G
** It is unclear whether the relationship between Ba levels and lytic activity is linear
Angiogenesis, Exudation, and Degeneration 2021 12Significant Decreases in Ba and C3 Breakdown Product Vitreous Levels After GT005 Administration Average Decrease of 41% in Ba and 42% in C3 Breakdown Product Vitreous Levels Data as of December 2020 The assay used for Ba and C3 breakdown products measurements are standard and validated Statistical analysis: Wilcoxon matched pairs test (post-treatment compared to baseline); Data shown as Mean ± SD Angiogenesis, Exudation, and Degeneration 2021 13
Significant Correlation Between Increases in Local CFI Levels and
Decreases in Ba with GT005
Notes:
Data as of December 2020
Statistical analysis: Spearman correlation; Data used: latest available data point up to week 56 for individual patients
Angiogenesis, Exudation, and Degeneration 2021 14Phase II Studies Evaluate Two Patient Populations
Primary Endpoint: GA Progression at 48 Weeks
• 75 GA patients with CFI rare variants • 180 GA patients (broad GA population)
• Arm 1: Low dose • Arm 1: Medium dose
• Arm 2: High dose • Arm 2: High dose
• Arm 3: Untreated control • Arm 3: Untreated control
High dose GT005
Long-term study
Randomization
Screening
ORACLE
Low/medium dose GT005
Untreated control
All participants enrolling in HORIZON and EXPLORE genotyped; participants in HORIZON being stratified by AMD genotype subgroup
Angiogenesis, Exudation, and Degeneration 2021 15CFI
Take Home Messages
CFH
• Complement over-activation has been implicated in AMD disease pathogenesis C3b
• Complement Factor I (CFI) is a natural down-regulator of the complement system
• GT005 is an investigational gene therapy designed to induce expression of CFI after
subretinal delivery
• GT005 has been well tolerated to date in the FOCUS Phase I/II trial in patients with GA
• Early data show majority of patients had increased vitreous CFI and downstream modulation
of complement biomarkers
• Randomized controlled Phase II trials evaluating safety and efficacy of GT005 are ongoing
Angiogenesis, Exudation, and Degeneration 2021 16Acknowledgements
Principal Investigators
• Clare Bailey, MD, FRCP, FRCOphth
• Jeff Heier, MD
• Tsveta Ivanova, DM, PhD, MRCOphth
• Arshad Khanani, MD, MA
• Robert MacLaren, MB ChB, Dphil, FRCOphth, FRCS, FACS, FMedSci VR
• Jared Neilsen, MD, MS, MBA
• Sobha Sivaprasad, MBBS, MS, DM, FRCS, FRCOphth, FRCSEd
• Paulo Stanga, MD
• David Steel, MBBS, MD, FRCOphth
Study Teams
Participants
Angiogenesis, Exudation, and Degeneration 2021 17You can also read
