corporate presentation fall 2020corporate presentation fall 2020. legal disclaimer 2. 3 fix αgla...
TRANSCRIPT
Corporate Presentation
Fall 2020
Legal Disclaimer
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FIX
αGLA
Proprietary capsid with significantly higher transduction efficiency in the liver
High protein levels at low doses allows us to target diseases perceived as beyond the reach of AAV GT
Potential for a functional cure for Haem B* with FIX expression levels in the normal range
Fabry clinical program demonstrating initial evidence of sustained αGLA activity levels
Leadership Team with deep CMC, development & commercial expertise in GT and rare diseases
Proprietary analytics and CMC capabilities that can deliver high quality at commercial scale
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6 * Certain adult Haem B patients
Clinical-stage, fully integrated, next generation, systemic AAV gene therapy company dedicated to transforming the lives of patients suffering from systemic debilitating diseases
Proprietary potent AAVS3 capsid and platform transduces more liver cells driving high protein expression
Transduction efficiences of AAV capsids in vitro in human hepatocyte:
• UnT Control: 1%
• AAVrh10: 5%
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0
10
20
30
AAV8 AAV5 AAVS3
Hu
man
hep
ato
cyte
tra
nsd
uct
ion
in v
itro
(% G
FP)
High protein expression
✓
✓
✓
4 to 12 times higher transduction obtained vs.
wildtype AAVs
(n=3)
Our rationally designed AAVS3capsid enables:
Potent liver transduction
Low dose levels and improved safety margin
Lead Haemophilia B program provides validation of approach at low dose levels
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FIX
act
ivit
y le
vel (
%)
50
100
150
AAV82T vg/kgFIX WT1
SPK-90010.5T vg/kgFIX Padua4
Mean: 22%
AMT0605T vg/kgFIX WT2
AMT06120T vg/kgFIX Padua3
Mean: 41%
Mean: 6%
FLT180a0.45T vg/kgFIX Padua
Steady state:38% *
FLT180a0.975T vg/kg
FIX Padua
Mean: 5%
200
Mean: 99% **
FLT180a1.5T vg/kgFIX Padua
Mean: 130%***
AAVS3 enables FIX activity levels in normal range
168%
92%
136%
73%
Normal Range
T= e12
* Stable FIX activity levels at 38% at 52 weeks, and following an additional 52 weeks, or two years after infusion, we have continued to observe a durable response of 38% mean FIX activity in this cohort
** Mean value calculated based on following FIX levels: patient 7 136% (d 21 +/-1), patient 8 82% (d 21 +/-1), patient 9 73% (d 21 +/-1), patient 10 105% (d 21 +/-1)
*** Mean value calculated based on following FIX levels: patient 3 92% (d 21 +/-1), patient 6 168% (d 21 +/-1)
1. Nathwani et al; N Engl J Med 2014; 371:1994-2004
2. Poster presented at The 13th Annual Congress of the European Association for Haemophilia and Allied Disorders, EAHAD 2020
3. Miesback et al; Blood 2018 131:1022-1031
4. George et al; N Engl J Med 2017; 377:2215-2227. and WFH 2018 presentation
= 2= 4= 2= 15= 3
Our platform has the potential to go beyond the reach of other AAV gene therapies
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Protein expression
Haemophilia A&B
LSDs
Inflammatory disorders and beyond
Unserved gene therapy need
Secreted proteins in the genome~1,700
~1,600 Secreted proteins within the packaging limit of AAV
Significantly expands potentially addressable patient population
Programme Research1IND enabling
studies2 Phase 1/2 Phase 3Patient No.US & EU53
Development & WW
Commercial rights4
Haemophilia B FLT180a(RMAT designation)
~ 9,000
Fabry FLT190(Orphan designations)
~ 9,000
GaucherFLT201
~ 6,000
Haemophilia A FLT210
~ 38,000
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Robust pipeline with retained global rights
40,000
1. In the research stage, we conduct in vitroand in vivo preclinical studies to evaluate different product candidates to select thosewith the best tolerability and potency profiles
2. In the IND enabling studies stage, we conduct preclinical in vivo studies in disease-specific mouse models and good laboratory practice, or GLP, toxicity studies in non-human primates and generate the CMC information and analytical data required for an investigational new drug, or IND, submission to the FDA for a clinical trial authorization, or CTA, submission to the EMA
3 These figures represent the total approximate diagnosed population for each indication. The seroprevalence of antibodies against the AAV capsid renders approximately 30-50% of patients ineligible for gene therapy
4. Owned and in-licensed intellectual property rights
Haemophilia epidemiology : World Federation of Hemophilia 2018.
Fabry Disease epidemiology: Metchler et al 2012; Spada et al 2016; Fabry Register; Fabry Outcome Survey; Waldek et al 2009; Deegan et al 2006.
Gaucher Disease epidemiology: Nalysnyk et al 2016; Weinreb et al 2008 & 2013; Charrow et al 2000; National Gaucher Foundation; Orphanet; NIH Technology Assessment Panel on Gaucher; Poorthuis 1999; Stirnemann et al 2012; Puopetova 2010; Mehta et al 2006.
Haemophilia B & AThe Freeline mission: To be life changers
Adaptive B-AMAZE trial in Haemophilia B designed to establish a dose that demonstrates normal range of FIX activity
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Adaptive dose escalation design:Aim is to establish effective dose (50 – 150% FIX)
Objective: To assess the safety and efficacy of systemic administration of FLT180a in adult patients with severe
Haemophilia B
4.5e11 vg/kg
1.5e12 vg/kg
7.5e11 vg/kg
9.75e11 vg/kg
Results to date have informed our optimised immune management strategy with the potential to prevent loss of
factor IX expression during the critical period of 4 to 16 weeks
= Bookends of normal range
*Immune management includes initiation of Prednisolone and Tacrolimus at week 3 with rapid taper of steroids until discontinuation at month 3; continue tacrolimus until discontinuation up to month 5. Immune management treatment includes patient monitoring for 9 months, followed by annual monitoring of FIX activity levels.
Assessments: Safety; FIX activity level (one stage clotting assay); Exogenous FIX concentrate usage; Bleeding frequency
Enrolment criteria: Haemophilia B patients aged >=18 years with FIX activity levels <2%; Lack of neutralising antibodies to AAVS3; >50 exposure days to FIX and no history of inhibitors; Normal liver function; No evidence of active Hepatitis B, C, or HIV infection
Oral treatment with Prednisolone and Tacrolimus at day 21 (post dosing) and continuing through month 3 for Prednisolone and up to month 5 for Tacrolimus*
Established dose response with multiple cohorts achieving normalisation of FIX activity
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250
FIX
act
ivit
y le
vel (
%)
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
FLT180a7.5e11 vg/kg
FIX Padua
Week 52: 60%*
FLT180a9.75e11 vg/kg
FIX Padua
200
Normal Range
Mean week 3: 99%**
FLT180a1.5e12 vg/kg
FIX Padua
Mean week 3: 130%***
AAVS3 enables FIX activity levels in normal range
168%
92%
160
136%
73%
* Based on 1 data point, patient 5 at week 52. Patient 4 on 7.5e11 had ALTs
** Mean value calculated based on following FIX levels: patient 7 136% (d 21 +/-1), patient 8 82% (d 21 +/-1), patient 9 73% (d 21 +/-1), patient 10 105% (d 21 +/-1)
*** Mean value calculated based on following FIX levels: patient 3 92% (d 21 +/-1), patient 6 168% (d 21 +/-1)
= 2= 4= 1
Durable FIX activity achieved beyond 2 years
110
10
20
30
40
50
60
70
80
90
100
0 56 112 168 224 280 336 392 448 504 560 616 672 728 784
FIX
act
ivit
y le
vel (
%)
Years
Pt 1 FIX (Local)
Pt 2 FIX (Local)
Steady state indicator
Data as of 15th June 2020
Normal rangeImmune management Durability
4.5e11 vg/kg - with short duration prophylactic steroid
NormalRange
✓
Patient 1
Patient 2
1 2
Durable FIX activity levels in the normal range
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Immune management includes initiation of Prednisolone and Tacrolimus at week 3 with rapid taper of steroids until discontinuation at month 3; continue tacrolimus until discontinuation up to month 5. Immune management treatment includes patient monitoring for 9 months, followed by annual monitoring of FIX activity levels.
Data as of 15th June 2020
9.75e11 vg/kg cohort - patient 7: Immune management had not been optimised and therefore patient was not on prophylactic optimised steroid and tacrolimus programme.
9.75e11 vg/kg - with prophylactic steroid and tacrolimus
Immune management Durability ✓✓✓
No bleeds requiring supplemental FIX to date ✓
0
50
100
150
200
250
300
350
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250
Days after Infusion
Pt 8 FIX (Local)
Pt 9 FIX (Local)
Pt 10 FIX (Local)
FIX
act
ivit
y le
vel (
%)
Patient 8
Patient 9
Patient 10
NormalRange
Normal range
FLT180a has demonstrated a favourable safety profile
Most common SAE was transaminitis. SAEs recorded (excluding transaminitis): Patient six: Pulmonary Sepsis & AV fistula thrombosis; Patient four: appendicitis; Patient nine: Blood creatinine increased; Patient ten: abdominal pain upper
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Most common drug related SAE was transient transaminitis. Manifests as a decrease in expression and is not a safety signal
No evidence of neutralising antibody formation against FIX
No infusion reactions observed to date
✓
✓
✓
Safety
H1 2021H2 2020 H1 2022 H1 2023
Planning to file BLA in 2023
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PHASE 1/2
Fully enrolled
Enrolling
EOP2 meeting
Patients 1 to 10FIX activity at 6 months
H2 2023
Long term safety study
File BLA Accelerated
ApprovalEDS
DSDS
EDS = Safety = Durability = Efficacy
Run in study 6 months baseline
PHASE 2b/3
Haemophilia AThe Freeline mission: To be life changers
Platform able to package shortened FVIII gene within the wild type AAV capacity
Note: Haem A candidate nomination reached. Toxicology, CMC and disease animal model confirmation work ongoing
Sources of construct sizes:
1. As presented at ASGCT (2016) and WFH (2020)
2. As documented in patent (int. patent number: WO 2016/025764 A2)
3. McIntosh J, Lenting PJ, Rosales C, et al. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood. 2013;121(17):3335-3344.
4. Bunting S, Zhang L, Xie L, et al. Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice. Mol Ther. 2018;26(2):496-509.
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4.5
4.6
4.7
4.8
4.9
5
5.1
5.2
SB-525 SPK-8011/SPK-8016
BMN270 FLT210
kb
Vector size comparison
Standard 4.7 kbp
AAVcapacity
Delivery of more functional intact transgenes and
predictable, less variable expression
Key attributes of FLT210:
Smallest known liver specific promoter
Shortened FVIII gene to reduce expression cassette size
Allows expression cassette to fit within the natural capacity of AAV capsid
✓
✓
✓
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Fabry & Gaucher disease
The Freeline mission: To be life changers
Fabry mouse model demonstrates increased GLA expression and reduction in pathologic substrate
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WORLD symposia 2019: Jey Jeyakumar et al. Liver-directed gene therapy corrects Fabry disease in mice
FLT190 vector genome pseudo-typed with AAV8 in GLA KO mice; Dose: 2e12 vg/kg. Error bars: mean ± SD
Time point: 16-week disease development prior to treatment; analysis 14 weeks post-treatment. Gb3/Lyso-Gb3 data (n=4, 2 males and 2 females)
Kidney GLA activity levels Heart GLA activity levels
Electron microscopy x5000
0
100
200
300
wt Untreated Treated
GLA
in
Kid
ney
(nm
ol/
hr/
mg)
0
100
200
300
400
wt Untreated Treated
GLA
in
Hea
rt(n
mo
l/h
r/m
g)Electron microscopy x5000
Adaptive Phase I/II dose finding study in previously treated and naive patients with Fabry disease
190.75e12 vg/kg
1.5e12 vg/kg
4.5e12 vg/kg
Dose finding plan:For patients with prior ERT therapy
1.5e13 vg/kg
FLT190 demonstrated durable increases in plasma GLA in Patient 1 at lowest dose
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0.0
0.4
0.8
1.2
1.6
0 7 14 21 28 35 42 49 56 63 70 77 84
Pla
sma
GLA
nm
ol/
hr/
ml
Days post infusion
Data as of 15th June 2020
* Normal range for GLA in plasma is 5-9 nmol/ hr/ ml
Below 1 nmol/hr/ml is diagnostic for Fabry disease
Baseline - Patient 1
Steady state – Patient 1
5.0
9.0
Patient 1 results
Normal Range*
Increase patient 1
GaucherThe Freeline mission: To be life changers
0
1
2
3
4
Naïve FLT200 FLT201
Pla
sma
GC
ase
leve
l (m
U/m
l)
Plasma
Low doses of longer acting FLT201 result in high uptake in tissues commonly affected by Gaucher Disease
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FLT200 and FLT201 have been pseudo-typed with AAV8 for evaluation in mouse
• Better substrate clearance vs. standard of care (velaglucerase alfa) in Gaucher mice
• Novel GCase variant, FLT201 has a greater than 20-fold longer half-life than wild-type protein
Conclusion
LungBone marrowSpleen
Anti-GCase – DAB, Haematoxylin counterstain, AAV8
Time post infusion (min)
GC
ase
leve
l (n
mo
l/h
/ml)
0 2040 60 2000 4000 6000 8000 100000
5
10
15
20
VPRIV (60 U/kg)
FLT200 (2x1012 vg/kg)
P< 0.0001
CMC, Manufacturing & Supply
The Freeline mission: To be life changers
Platform built on deep AAV expertise enables supply of pipeline of products with the goal of maximising safety and efficacy
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What we have
✓ Product safety built into manufacturing design from the start
✓ High product potency enabling lower dose
✓ Increased predictability and longevity
✓ Enhanced production yield and low cost of goods
✓ Agile supply allowing fast response to changing business needs
Proprietary analytics and characterisation
algorithms
Why it’s important
Proprietary mammalian production system
Proprietary promoters and construct designs
Capacity secured for product candidates
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Multiple supply chains running same commercial-scale production platform
Long term clinical/ commercial facility planned
Clinical SupplyCommercial
SupplyToxicology
Haemophilia B
Fabry
Pipeline
Commenced
GMP manufacture(iCELLis® 500)
Cambridge, MA, USHaem B
Fabry
Stevenage, UK
Gaucher, Haem A, future pipeline
Seneffe, BE
MilestonesThe Freeline mission: To be life changers
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Haem B - Completed enrollment anddosing for Phase 1/2 study✓
Haem B - Initiated baseline screening study✓
Fabry - Complete dose escalation inPart 1 of Phase 1/2 study
Platform - Secured Brammer capacity for potential Haem B product candidate commercialisation
✓
Haem B - Initiate pivotal study
Haem B - Present durability data up to 3 years
Fabry - Resume dosing Gaucher - Initiate Phase 1/2 study
Platform - Further develop plans for Freeline manufacturing facility
Haem A - Complete preclinical proof of concept study
Haem B - Present longer durability data from Phase 1/2 study
Fabry - Submit IND
Multiple near-term value-creating milestones expected
20212020
✓
ConclusionThe Freeline mission: To be life changers
Clinical-stage, fully integrated, next generation, systemic AAV gene therapy company dedicated to transforming the lives of patients suffering from systemic debilitating diseases
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Potent capsid & high protein levels
Durable efficacy in the normal range
Broad proprietary pipeline
Committed to functional cures
Quality driven by CMC & Analytics
Leadership with deep expertise
Thank you