Corporate Presentation Winter 2021 - Freeline
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Corporate Presentation Winter 2021
Legal Disclaimer
2
Clinical-stage, fully integrated, next generation, systemic AAV
gene therapy company dedicated to transforming the lives of
patients suffering from systemic debilitating diseases
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 Factor IX expression levels in
FIX
the normal range
Fabry clinical program demonstrating evidence of sustained αGLA activity
αGLA
levels at 1-year post-treatment
Proprietary protein engineering, analytics and CMC platform that delivers novel,
high-quality gene therapy constructs at commercial scale * Certain adult Haem B patients
3
Leadership Team with deep CMC, research & development, and commercial expertise
in gene therapy and rare diseases
Haemophilia B data validates AAVS3 capsid and platform
Our rationally designed Potent liver High protein Lower dose levels &
AAVS3 capsid enables: transduction expression improved safety margin
200
190%
Factor IX (FIX) activity level (%)
Mean:
171% ***
150
143%
Freeline = One-stage assay,
central laboratory measurement
100 97% * 4.5e11 dose: mean value calculated
The normal range based on following FIX levels: patient 1,
44%% (week 26), patient 2 46% (week 26)
(50-150% FIX activity) ** 7.5e11 dose: value of patient 5 64%
(week 26). Patient 4 experienced loss of
expression due to transaminitis
*** 9.75e11 dose: mean value calculated
based on following FIX levels: patient 8
180% (week 26), patient 9 190% (week 26),
64%** patient 10 143% (week 26). Patient 7
experienced loss of expression due to
transaminitis
50
50% 1. Miesback et al; Blood 2018 131:1022-
~47% 46% 1031
Mean: 2. uniQure’s late-breaking ASH abstract; first
44% data from the Phase 3 HOPE-B Gene
Mean: 41% 45% * Therapy Trial. 54 patients week 26 data
Mean: 37% 3. Pfizer R&D Day Sep 2020 – 4 year follow-
Mean: 41% up data in 15 patients from Phase 1/2 trial.
31% Mean: 22% Note, now in Phase 3 development
=3 = 54 1% = 15 =2 =1 =3
~9%
4
2e13 vg/kg 2e13 vg/kg 5e11 vg/kg 4.5e11 vg/kg 7.5e11 vg/kg 9.75e11 vg/kg
Ph. 2b - AMT061 Ph. 3 - AMT061 Ph. 1/2 - SPK-9001
Phase 1/2 - FLT180a FIX Padua
FIX Padua1 FIX Padua2 FIX Padua3 Note - One-stage assay, central laboratory measurement.
Robust pipeline with retained global rights
Development
IND enabling Patient No. & WW
Programme Research1 studies2 Phase 1/2 Phase 3 US & EU53 Commercial rights4
Haemophilia B
FLT180a ~ 9,000
(RMAT designation)
1. In the research stage, we conduct in vitro
Fabry and in vivo preclinical studies to evaluate
different product candidates to select those
with the best tolerability and potency profiles
FLT190 ~ 9,000 2. In the IND enabling studies stage, we conduct
preclinical in vivo studies in disease-specific mouse
(Orphan designations) 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
Gaucher approximate diagnosed population for each indication.
~ 6,000 The seroprevalence of antibodies against the AAV capsid
FLT201 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;
Haemophilia A Waldek et al 2009; Deegan et al 2006.
~ 38,000 Gaucher Disease epidemiology: Nalysnyk
et al 2016; Weinreb et al 2008 & 2013; Charrow et al
FLT210 2000; National Gaucher Foundation; Orphanet; NIH
Technology Assessment Panel on Gaucher; Poorthuis
1999; Stirnemann et al 2012; Puopetova 2010; Mehta et
al 2006.
40,000
5
The Freeline mission: To be life changers Haemophilia B & A
Haemophilia gene therapy: Current state of the art
AAV gene therapy treatments
150
Normal FIX expression Normal coagulation
140 50 – 150%
Normal response to all
FIX activity level (%)
Aim: To achieve Factor IX (FIX) activity in
130 haemostatic challenges.
the normal range
No need for FIX replacement.
120
Demanded by patients and
110 now potentially achievable
100
with Freeline approach
90
80
70 1. The frequency of joint
hemorrhages and procedures in
nonsevere hemophilia A vs B.
60 Soucie et al. 2018 blood
advances
2. uniQure’s late-breaking ASH
50 abstract; first data from the
Phase 3 HOPE-B Gene Therapy
Mild FIX expression Mean FIX: 37%; bleeds in 28% of Mild Haemophilia patients Trial. 54 patients week 26 data
3. Pfizer R&D Day Sep 2020 – 4 year
40 patients2 follow-up data in 15 patients
Phase 3 - AMT061 FIX Padua still experience joint bleeds1 from Phase 1/2 trial. Note, now
in Phase 3 development
30 Mean FIX: 22%; bleeds in 20% of 4. Nathwani et al; N Engl J Med
2014; 371:1994-2004
patients3
20 Phase 1/2 - SPK-9001 FIX Padua
7
10 Mean FIX: 5%4
Phase 1 - AGT4HB FIX WT
0
Moderate/Severe FIX expression Frequent spontaneous bleeds
Verbrinacogene setparvovec (FLT180a): Completed B-AMAZE
Phase 1/2 study
To establish a safe and effective dose of FLT180a that normalises factor IX activity levels between
Objectives 50 and 150%, and to optimise an immune management regimen to preserve expression
Key inclusion criteria
Adaptive dose escalation design:
• Severe or moderate Haemophilia B ≤ 2% Aim is to establish effective dose
• Adults ≥18 years
Key exclusion criteria
• Neutralising antibodies to AAVS3
• Liver disease Cohort 2
Sponsor: University College London
1.5e12 vg/kg Cohort 4 Funding: Freeline
Endpoints at 6 months Assessments: Safety; FIX activity level
9.75e11 vg/kg (one stage clotting assay); Exogenous
• Safety FIX concentrate usage; Bleeding
frequency
Cohort 3
• FIX activity level Enrolment criteria: Haemophilia B
7.5e11 vg/kg patients aged >=18 years with FIX
Cohort 1 activity levels 150 exposure
Target range for dose finding days to FIX and no history of inhibitors;
4.5e11 vg/kg Normal liver function; No evidence of
• 50 to 150% active Hepatitis B, C, or HIV infection
8
Immune • Prophylactic/reactive immunosuppression with
management Corticosteroids +/- Tacrolimus
strategy • Intensive monitoring
Patients receiving the 4.5e11 vg/kg dose show durable FIX
activity just below the normal range (~44%) for almost 3 years
Cohort 1 4.5e11 vg/kg No bleeds requiring FIX supplementation
200
FIX activity level (%)
150
The normal range
(50-150% FIX
100 activity)
50
0
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950
Days after Infusion
One-stage assay, central laboratory
measurement
Data as of 21st August 2020
9
The 1.5e12 dose demonstrates the potency of our AAVS3
capsid for future indications
Cohort 2 1.5e12 vg/kg No bleeds requiring FIX supplementation*
550
FIX activity level (%)
500
450
400
350
300
250
200
150
The normal range (50-150% FIX activity)
100
50
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
Days after Infusion
One-stage assay, central laboratory
measurement
Data as of 21st August 2020
*Patient 3 had transaminitis
10A dose between 7.5e11 & 9.75e11 vg/kg has the potential to
achieve FIX activity in the normal range
Cohort 3 7.5e11 vg/kg No bleeds requiring FIX supplementation in the patient that has FIX activity in the normal range*
300
FIX activity level (%)
250
200
150
The normal range
100 (50-150% FIX
activity)
50
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
Cohort 4 9.75e11 vg/kg No bleeds requiring FIX supplementation Days after Infusion
300 One-stage assay, central
laboratory measurement
FIX activity level (%)
250 Data as of 21st August 2020
ALT = alanine aminotransferase
200
Patient experienced loss of
expression due to transaminitis
150
*In cohort 3 (7.5e11 vg/kg) one patient
The normal range lost expression and resumed FIX
100 prophylaxis
(50-150% FIX activity)
50
11
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
Days after InfusionIn the Phase 1/2 study FLT180 was well tolerated with
a favourable safety profile
Key safety results
No infusion reactions and no discontinuations of infusion
No other allergic reactions to date
Most common drug related SAE was transient transaminitis. Manifests as an elevation in ALT +/- a
decrease in expression and is not a safety signal
A single patient in the highest dose cohort developed an AV fistula thrombosis in the context of
supraphysiological FIX levels
12Potential to provide a functional cure by normalising
FIX activity
Key learnings from the B-AMAZE Phase 1/2 Study
Demonstrated that the dose with potential to achieve FIX activity in the normal range is expected
to be between 7.5e11 and 9.75e11 vg/kg
Stable and durable response up to almost 3 years post treatment to date
No bleeds requiring supplemental FIX*
Favourable safety profile
*This excludes one patient in cohort 3
(7.5e11 vg/kg) who lost expression and
Short course of prophylactic tacrolimus combined with prophylactic prednisone and close resumed FIX prophylaxis
monitoring expected to preserve expression and eliminate the need for FIX supplementation 13Successful EOP2 meeting with FDA supports initiation of
pivotal Phase 2b/3 study with a path to accelerated approval
• The Phase 2b portion of the pivotal study is designed to read out data to confirm the dose, then seamlessly initiate
the Phase 3 under the same protocol
• Aim to file for accelerated approval using the surrogate endpoint of FIX activity levels combined with demonstration
of a positive correlation between 26-week FIX activity levels and 52-week Annualised Bleeding Rate
S D Phase 1/2 S D Long term safety study
Patients 1 to 10 2024
FIX activity at 6 months
EOP2 File BLA
meeting S D E Phase 2b/3
Accelerated
Fully enrolled Approval
Complete S = Safety
D = Durability
Enrolling E = Efficacy
Run in study 6 months baseline 14The Freeline mission: To be life changers Haemophilia A
FLT210 is the only Factor VIII construct that fits within
the carrying capacity of an AAV capsid
Vector size comparison Key attributes of FLT210
5.2
Smallest disclosed liver specific
5.1 promoter in development
5 Shortened FVIII gene to reduce
expression cassette size Note: Haem A candidate nomination
reached. Toxicology, CMC and disease
4.9 animal model confirmation work ongoing
Sources of construct sizes:
Allows expression cassette to fit 1. As presented at ASGCT (2016) and WFH
kb
(2020)
4.8 within the natural capacity of AAV 2. As documented in patent (int. patent
number: WO 2016/025764 A2)
Standard 4.7 capsid 3. McIntosh J, Lenting PJ, Rosales C, et al.
Therapeutic levels of FVIII following a single
4.7 kbp AAV peripheral vein administration of rAAV
vector encoding a novel human factor VIII
capacity variant. Blood. 2013;121(17):3335-3344.
4. Bunting S, Zhang L, Xie L, et al. Gene
Therapy with BMN 270 Results in
4.6 Therapeutic Levels of FVIII in Mice and
Primates and Normalization of Bleeding in
Hemophilic Mice. Mol Ther. 2018;26(2):496-
509.
4.5 Potential to deliver more
SB-525 1 SPK-8011/SPK-8016 2 BMN270 4 FLT210
predictable, less variable
/ 3
expression and to improve 16
durabilityThe Freeline mission: Fabry & Gaucher To be life changers disease
FLT190 demonstrates increased GLA expression and reduction in
pathologic substrate in key tissues in Fabry mouse model
Kidney GLA activity levels Heart GLA activity levels
300 400
300
200
GLA in Kidney
(nmol/hr/mg)
(nmol/hr/mg)
GLA in Heart
200
100
100
WORLD symposia 2019: Jey Jeyakumar et al.
0 0 Liver-directed gene therapy corrects Fabry
disease in mice
wt Untreated Treated wt Untreated Treated
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)
Electron microscopy x5000 Electron microscopy x5000 18FLT190 produced a 3-fold increase in plasma GLA,
sustained over one year post treatment
Dose finding plan
For patients with prior 1
Enzyme Replacement
Therapy or Pharmacological 0.75e12 vg/kg 1.5e12 vg/kg 4.5e12 vg/kg 1.3e13 vg/kg
Chaperone Therapy
9.0
Normal Range*
5.0
Plasma GLA nmol/hr/ml
1.6
1.2
Steady state – Patient 1
Data as of 15th June 2020
Increase
0.8 patient 1 * Normal range for GLA in plasma is 5-
9 nmol/ hr/ ml
Below 1 nmol/hr/ml is diagnostic for
Fabry disease
0.4
Baseline - Patient 1
19
0.0
0 7 14 21 28 35 42 49 56 63 70 77 84
Days post infusionThe Freeline mission: To be life changers Gaucher
Low doses of FLT201 in Gaucher mice result in higher expression
and increased uptake in tissues affected by Gaucher disease
• Novel GCase variant FLT201 is more stable in plasma than wild-type protein
• This leads to a greater than 20 fold increase in potency vs. wild-type protein and better substrate clearance in key
tissues Gaucher mice
Velaglucerase
ERT (60 U/kg)alfa FLT201
AAV-GBA
300 (60 U/kg)
GCase activity in blood (mmol/h/ml)
Spleen Bone marrow Lung
200
Velaglucerase
alfa
FLT201 dose: 2x1012 vg/kg
100
30
20
FLT201 dose: 2x1011 vg/kg
10 Velaglucerase alfa is an Enzyme
Replacement Therapy for Gaucher disease
0 Anti-GCase – DAB, Haematoxylin counterstain, AAV8
0 204060 2000 4000 6000 8000 10000 21
Time post injection (min)CMC, The Freeline mission: Manufacturing To be life changers & Supply
Platform built on deep AAV expertise enables supply of pipeline
of products with the goal of maximising safety and efficacy
What we have Why it’s important
Proprietary promoters and ✓ Product safety built into manufacturing
construct designs
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
23
Proprietary mammalian Proprietary analytics
production system and characterisation
algorithmsCapacity secured for product candidates
Commercial
Toxicology Clinical Supply
Supply
Haem B,
Cambridge, MA, US Gaucher
GMP
manufacture
(iCELLis® 500) Fabry,
Seneffe, BE Gaucher
Gaucher, Haem A,
Stevenage, UK future pipeline
Haemophilia B
Fabry
Multiple supply chains running same commercial-scale production platform Gaucher
Pipeline
Long term clinical/ commercial facility planned Commenced
24The Freeline mission: Milestones and To be life changers Conclusion
Multiple near-term value-creating milestones expected
2020 2021
Haem B - Completed 10 patient Phase 1/2 study Haem B - Initiate pivotal study
and held EOP2 meetings with FDA and MHRA
Haem B - Initiated baseline screening study for Haem B - Present durability data up to 4 years
Phase 2b/3
Haem B - Presented longer durability data Haem A - Complete preclinical proof of concept
from Phase 1/2 study
Fabry - Complete dose escalation in Part 1 of
Gaucher – Filed CTA
Phase 1/2 study
Platform - Secured capacity for potential Haem B Gaucher - Initiate Phase 1/2 study
product candidate commercialisation
Funding - Raised $300 mm in Series C and Platform - Further develop plans for Freeline 26
NASDAQ IPO manufacturing facilityClinical-stage, fully integrated, next generation, systemic AAV
gene therapy company dedicated to transforming the lives of
patients suffering from systemic debilitating diseases
Potent capsid & Durable efficacy in Broad proprietary
high protein levels the normal range pipeline
Committed to Quality driven by Leadership with 27
functional cures CMC & Analytics deep expertiseThank you
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