Production strategies for lentiviral vectors

Production strategies for lentiviral vectors 12th Annual bioProcessUK Conference, 25-26 Nov 2015 James Miskin, CTO, Oxford BioMedica (UK) Ltd Forwar...
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Production strategies for lentiviral vectors 12th Annual bioProcessUK Conference, 25-26 Nov 2015 James Miskin, CTO, Oxford BioMedica (UK) Ltd

Forward-looking statements Cohortpresentation does Dose not constituteAdministration (UPDRS) of offers 6 months 1 year (UPDRS) (the 2 years (UPDRS) This an offer to sell or 3amonths solicitation to (UPDRS) buy Ordinary Shares “Securities”). Although reasonable care has been taken to ensure that the facts stated in this presentation are Mean 27% Mean 30% Mean 29% Mean 20% 1, n=3 1x Original accurate and that the opinions expressed are fair and reasonable, the contents have not Max. up to 30% Max. up to 30% Max. up to of 50%this presentation Max. up to 44% been formally verified by Oxford BioMedica plc (the “Company”) or any other person. Accordingly, no Mean Meanaccuracy, 34% completeness Mean 29% or 2, n=3 2x Original representation or warranty, expressed or implied, is made as28% to the fairness, Max. up to 53% Max. up to 53% Max. up to 56% correctness of the information and opinions contained in this presentation, and no reliance should be placed on such the information in this26% presentation- is not complete and Mean 3, n=3information or2xopinions. Further, Enhanced - may be changed. Neither the Company nor any of its respective members, directors, officers or employees nor any other person accepts any liability whatsoever for any loss howsoever arising from any use of such information or opinions or otherwise arising in connection with this presentation. 2

This presentation may contain forward-looking statements that reflect the Company's current expectations regarding future events, its liquidity and results of operations and its future working capital requirements. Forward-looking statements involve risks and uncertainties. Actual events could differ materially from those projected herein and depend on a number of factors, including the success of the Company's development strategies, the successful and timely completion of clinical studies, securing satisfactory licensing agreements for products, the ability of the Company to obtain additional financing for its operations and the market conditions affecting the availability and terms of such financing.

2

Presentation overview •1, n=3Overview of gene and cell therapyMean 30% Mean 27% Mean 29% 1x Original •2, n=3Introduction to Oxford BioMedica Mean 28% Mean 34% Mean 29% 2x Original •3, n=3Manufacturing and QC Mean 26% 2x Enhanced • Manufacturing – next generation processes • Capacity expansion • What does it mean for the UK? • Summary Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 53%

Max. up to 53%

Max. up to 56%

2 years (UPDRS)

Mean 20% Max. up to 30%

-

3

What is cell & gene therapy ? •

Gene therapy

Cohort2

1, n=3

Dose

o

3, n=3

 



3 months (UPDRS)

The delivery of therapeutic DNA Mean into27% 1x Original Max. up to 30% patients’ cells: 

2, n=3

Administration

Mean 28% 2x Original Inserting a healthy copy of a gene into Max. up to 53% cells with a mutated gene which is causing Mean 26% 2x Enhanced disease Silencing or “knocking out” of a mutated gene whose expression is causing disease Introducing a new gene into the body to help fight a disease

OXB-102 for the1 year treatment of 6 months (UPDRS) (UPDRS) Parkinson’s disease Mean 30% Mean 29%

2 years (UPDRS)

Mean 20%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Mean 34%

Mean 29%

-

Max. up to 53%

Max. up to 56%

-

-

-

Stem cell diseases and Immunotherapy (e.g. CTL019)

Cell therapy o

The infusion or transplantation of whole cells into a patient for the treatment of a disease  

Autologous — cells come from you Allogeneic — the cells come from a matched related or unrelated donor

Potential for “one off” treatment giving longterm or permanent efficacy 4

Oxford BioMedica (OXB) - company overview •

Fully integrated discovery, clinical development and manufacturing cell & gene therapy medicines company



Founded in 1996 with 230 employees



Core technology platform based on lentiviral vector gene delivery system



Strong IP portfolio with multiple partnerships for products, services and technologies



Immunotherapy based on 5T4 oncofoetal antigen targeted by antibodies/CAR-Ts and viral vectors





Extensive in-house manufacturing, analytics and process development capabilities – OXB Solutions

Broad portfolio of products

Windrush Court Corporate HQ & Laboratories 71,955 sq. ft (6,684 sq m)

Medawar Centre The Oxford Science Park 28, 000 sq. ft (2,610 sq. m)

Harrow House & Chancery Gate 19, 375 sq.ft (1,800 sq.m)

Yarnton (GMP4) 18,300 sq. ft (1,700 sq. m)

Reference: http://www.oxbsolutions.co.uk/

5

Broad portfolio of pipeline products Cohort2

Field

1, n=3 LentiVector® 2, n=3

Dose

Product

Administration

Indication

1x Original platform technology 2x

RetinoStat®

Original Wet AMD

3 months (UPDRS)

6 months (UPDRS)

Mean 27%

Mean 30%

Mean 29%

Max. up to 30%

Max. up to 50%

Max. up to 44%

Research/Pre-Clinical

Mean 28%

Phase I

1 year (UPDRS)

Phase I/II

Phase II

Phase I concluded Next phase being evaluated Mean (primaryMean end point met)

Max. up to 53%

34%

Max. up to 53%

29%

Next 2 years (UPDRS) inflection / Est. date Comment Mean 20% Max. up to 30%

- TBD

TBD

Max. up to 56%

OPHTHALMOLOGY

Proprietary

3, n=3

2x

EncorStat®

Corneal graft

Enhanced rejection

ProSavin® OXB-102

Parkinson’s disease

MoNuDin®

Motor neuron disease/ALS

TroVax®

Cancer (multiple)

CAR-T 5T4

Cancer (multiple)

26%

Pre-clinical Mean complete

-

Phase I/II prep’n

-

ProSavin ® Phase I/II concluded concluded OXB-102 Phase I/II preparation

FPI

-Phase I/II

2016

FPI OXB-102 Phase I/II

2016

End preclinical

2016

End Phase II

2015/16

End preclinical

2016

CNS

5T4 TECHNOLOGY Phase I, Phase I/II and Phase II investigator-led studies underway

Out-Licensed

ONCOLOGY

LentiVector® platform technology OPHTHALMOLOGY

SAR 422459

Stargardt disease

SAR 421869

Usher syndrome

Phase I/II ongoing

Phase I/II ongoing

Undisclosed development milestones and royalties

Launch TBD

6

OXB clinical experience with lentiviral vectors • OXB were the first to administer lentiviral vector directly to patients in vivo Mean 27% vector Mean 30% Mean 29% Mean 20% 1x •1, n=3 Four products share aOriginal common lentiviral platform Cohort2

2, n=3

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

• Parkinson's disease Original wet AMD Mean 28% Mean 34% Mean 29% 2x Max. up to 53% Max. up to 53% Max. up to 56% • Stargardt disease (SAR422459) and Usher syndrome type 1B (SAR421869) - Sanofi (ProSavin®),

(RetinoStat ®)

Mean 26% 2x Enhanced •3, n=3 Approval from both European (UK/France) and- USA regulators

-

• 3 INDs (US - RetinoStat ®, SAR422459, SAR421869) • 4 CTAs (UK - ProSavin®; France - ProSavin®, SAR422459, SAR421869)

• In vivo delivery (eye and brain) • Safe and well tolerated • 15 patients treated with ProSavin® • 41 patients treated with ocular products

• No IMP related SAE (follow-up; >7 years for ProSavin®, >4 years for RetinoStat®) • Ongoing safety profile is well tolerated • No transgene related immune responses observed

7

CTL019/Other CAR-T – Novartis contract Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

1, n=3

1x

Original

Mean 27%

Mean 30%

Mean 29%

Mean 20%

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

2, n=3 Overview

2x

3, 2x licence • n=3 Non-exclusive

Original Enhanced to OXB’s IP

OXB provides a key link in the CTL019 Mean 34% Mean 29% Max. up to 53% supply Max.chain up to 53% Max. up to 56% Mean 28% Mean 26% •

• Initial 3 year manufacturing contract for clinical supply for Novartis CTL019 programme – potential to extend • Process development collaboration • Financial terms include: • $14m up front, including an equity investment and IP licence • Undisclosed royalties on CTL019 and other CAR-T products • Up to $76m over 3 year manufacturing and process development

Novartis licensed CAR-T technology -from University of Pennsylvania • Novartis to develop the CTL019 product (and other CAR-T products) • Complex supply chain:

• OXB produces GMP lentiviral vector encoding CAR targeting CD19 • White blood cells isolated from patients • Vector used to transduce expanded T-cells

• The modified T-cells are infused back into the patient` • Once inside the patient, the T-cells multiply, ‘hunt’ cancer cells and destroy them

8

OXB Partnership; role in CTL019 therapy 03 Dose

Administration

1. vector for Original 1, n=3Lentiviral 1x permanent modification of 2, n=3 2x Original patient T-cells

OXB

Cohort2

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Mean 27%

Mean 30%

Mean 29%

Mean 20%

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Mean 28%

Mean 34%

Mean 29%

-

Max. up to 53%

Max. up to 53%

Max. up to 56%

Mean 26%

3, n=3Patient-specific 2x Enhanced 2. apheresis to collect T-cells

01 -

-

-

04

Novartis

3. T-cell genetic modification with lentiviral vector performed under controlled conditions in vitro

3 months (UPDRS)

02

05

4. Modified T-cells are expanded ex vivo

5. Modified cells are then reinfused into the patient

9

Manufacturing capabilities •

Primary OXB focus to-date has been related to in vivo gene therapy - requires Mean 27% Mean 30% Mean 29% Mean 20% 1, n=3 1x Original high concentration factor cf. ex vivo (2000-fold) Cohort2

2, n=3





• • •

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Significant interest Original and growing expertise vivo applications Mean 28% in ex Mean 34% Mean 29% 2x Max. up to 53%

Max. up to 53%

Max. up to 56%

Mean 26%

-

-

-

2x

Enhanced

-

Considerable in-house effort to develop a GMP-compliant robust process Early clinical stages can be supported by CMOs OXB heavily involved in technical support and troubleshooting

Process development must be supported by extensive analytical programme • •



Administration

OXB developed & optimised current process prior to tech transfer

3, n=3



Dose

Series of custom assays developed and validated at OXB (conducted at OXB to GMP since 2006) Supplemented with a range of generic / compendial methods

Control of manufacturing is vital to support product development and commercialisation • •

Control of supply chain Dual supply strategy

CONFIDENTIAL

10

o

GMP manufacturing – drug substance Cohort2

Dose

1, n=3

1x

2, n=3

Administration

Working cell bank Original

2x

3, n=3 Benzonase® endonuclease Treatment, Pool

Vial

Original Day Enhanced

2x Clarified Vector

1

Normal Flow Filtration

Cell expansion 6 months (UPDRS)

3 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Mean 29% 10-Layer Max. up to 44% Cell Factory

Mean 20% -

T225 Mean 27% Max.Flask up to 30%

Mean 30% 2-Layer Max. up to 50% Cell Factory

Mean 28%

Mean 34%

Mean 29%

Max. up to 53%

Max. up to 53%

Max. up to 56%

-

-

Mean 26% (2x) Crude Vector Harvest

Medium exchange

Max. up to 30%

Day 11

Transient transfection P

Induce vector production

Day 14

Day 14

Ultra/ Chromatography diafiltration

Day 15

Final Formulation

Day 13

Day 13

Drug substance

Hold ≤ -70 ̊C

Day 15

Day 15

CTL019

P Gag-Pol P

Rev

P

Env

Day 12

11

o

GMP manufacturing – drug product Cohort2

Dose

Administration

1, n=3

1x

Original

2, n=3

Labelling/ packaging2x

3, n=3

2x

Vial fill Original Enhanced

3 months (UPDRS)

Aseptic Meanprocessing 27%

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Mean 30%

Mean 29% Max. Pooled up to 44% Drug substance Mean 29%

Mean 20%

Max. up to 30%

Max. up to 50%

Ultrafiltration Mean 28%

Sterile filtration Mean 34%

Max. up to 53%

Max. up to 53%

Max. up to 56%

Mean 26%

-

-

Max. up to 30%

-

Day 1

Finished drug product

QC Testing QA Batch Review

QP Release

Shipment

Clinical centres

Day 1

1. Control over volumetric concentration factor 2. Final volume determined by number of Ultra-diafiltered Drug Substance (UDFDS) lots and test data 12

Established (current) vector manufacturing process • Well-established OXB process Mean 27% Mean 30% Mean 29% 1, n=3 1x Original • Excellent stability profile: Mean 28% Mean 34% Mean 29% 2, n=3 2x Original (Typical shelf life of platform 3, n=3products 2x at ≤-70°CEnhanced is 30-48m)Mean 26% • Evidence for robust process (5 products, multiple batches; average ~30% yield) • Good safety profile in patients • Exclusively SUS (limited requirements for cleaning validation) • Extensive use of closed systems (scope for more) • Established robust supply chain • Supply agreements for single-source raw materials • GMP compliant process – suitable for global products Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 53%

Max. up to 53%

Max. up to 56%

2 years (UPDRS)

Mean 20% Max. up to 30%

-

13

Quality Control – for in vivo use Cohort2

1, n=3 2, n=3 3, n=3

Drug Substance Drug Product Dose Administration 3 months (UPDRS) 6 months (UPDRS) 1 year (UPDRS) 2 years (UPDRS) • Bioburden • Residual Sodium Butyrate* Mean 27% Mean 30% Mean 29% Mean 20% 1x Original Max. up to 30% • Max. up to 50% Max. up to 44% Max. up to 30% • Endotoxin (LAL) Residual Benzonase* • Mycoplasma – cult and non-cult Mean 28%• pH Mean 34% Mean 29% 2x Original Max. up to 53% Max. up to 56% • Adventitious agents (in vivo, in vitro)Max. up to 53% • Sterility • RCL 2x(end of production cells) (LAL) Mean 26%• Endotoxin Enhanced • Strength (Transducing Units, TU/mL) • Total protein content • RNA copy number (copies per mL) • SV40 Large T DNA (293T cells only) • Particle to infectivity ratio (RNA copies / • Total Residual DNA (Picogreen) strength) • DNA characterisation (HEK293T, plasmids) • Residual BSA • Appearance • RCL • Strength (Transducing Units, TU/mL) • Potency (product specific assay e.g. HPLC, angiogenesis assay) • Identity – PCR • PERT (RT units) • Particle to infectivity ratio (RNA copies / strength) • Specific Activity (strength/total protein) 14

QC - validation, qualification & assay performance • Qualification & Validation Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

•1, n=3 Assays qualified or validated to support development of 20% Mean 27% Mean Phase 30% I/II Mean 29% Mean 1x Original(as applicable) Max. up to 30% Max. up to 50% Max. up to 44% Max. up to 30% therapeutic vectors, and in preparation for Phase III 28% Mean 34% Mean 29% 2, n=3 • 2x Established assaysOriginal are qualifiedMean Max. up to 53% Max. up to 53% Max. up to 56% • New/custom in-house assays areMean validated 26% 3, n=3 2x Enhanced • Qualitative tests • Specificity, accuracy, precision/repeatability, intermediate precision • Quantitative tests • Specificity, accuracy, linearity, precision/repeatability, intermediate precision, limit of detection, limit of quantitation, range

• Assay control • • • •

Assay positive & negative controls Qualified standards Internal assay performance standards Trending of assay performance

15

Key QC quality procedures at OXB • Training Mean 27% Mean 30% Mean 29% Original •1, n=3Deviation,1x CAPA & change control systems •2, n=3Assay validation/qualification Mean 28% Mean 34% Mean 29% 2x Original • Qualification of assay controls Mean 26% 3, n=3 2x Enhanced • Traceability of assay reagents • Assay performance monitoring • Equipment maintenance program • IQ/OQ/PQ on key pieces of equipment • Use of validated Excel spread sheets for complex calculations Cohort2

Dose



• • •

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 53%

Max. up to 53%

Max. up to 56%

2 years (UPDRS)

Mean 20% Max. up to 30%

-

Provide robust data with data integrity guaranteed and audit trail to capture changes

QC checking and QA verification of clinical batch data COAs & COTs Out-of-Specification (OOS), Out-of-Trend (OOT) & Out-of-Expectation procedures (SOPs)

16

Manufacturing strategy to satisfy current / future demand • Considerations for current and future processes: Cohort2

• • 2, n=3 • 3, n=3 • • • 1, n=3

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Process complexity (multiple Mean vessels 27% vs single) Mean 30% Mean 29% Mean 20% 1x Original Manual handling requirements vs single use closed systems (risk, COGs) Mean 28% Mean 34% Mean 29% 2x Original Reliance on raw material supply (e.g. FBS vs serum-free) Mean 26% number 2x per clean Enhanced Output room suite (COGs), of independent suites Need to support OXB and partner projects and programmes Strategy dependent on indication & phase of development Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 53%

Max. up to 53%

Max. up to 56%

Max. up to 30%

Overall strategy: Existing process - ongoing supply, characterisation & validation Unabated progression of clinical trial(s)

Parallel development of future process(es) 17

Scale up & manufacturing challenges Application of systems thinking to develop the next generation processes Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

1, n=3

1x

Original

Mean 27%

Mean 30%

Mean 29%

Mean 20%

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Mean 28%

Mean 34% Mean 29% Stable, high producer Max. up to 53% Max. up to 56% packaging/producer cell lines

-

-

-

2, n=3

2x

Original

Cells

Max. up to 53%

3, n=3

2x

Development of rapid analytics for in-process and release testing

Automated, high through-put cell line generationMean 26% Enhanced

Analytics

LentiVector®

-

Vector

Vector design & optimisation

Platform

Process

Media

Single-use fixed-bed bioreactor

High through-put media & feed development

Purification development programme Serum-free suspension culture in single-use bioreactor 18

Cell Line Generation – Manual vs. Automated Cell Screening System (ACSS) Clones to Screening Result: Manual Situation Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1, n=3

1x

Original

Mean 27%

Mean 30%12

Max. up to 30%

2, n=3

2x

Original

Mean 28% Max. up to 53%

3, n=3

2x

Enhanced

Mean 26%

Max. up to 50%

1 year (UPDRS)

Mean 29% weeks Max. up to 44%

100-200 clones Mean 34% screened Mean 29% Max. up to 53%

2 years (UPDRS)

Mean 20% Max. up to 30%

-

Max. up to 56%

Clones to Screening Result: Automated Concept -

-

-

8 weeks ‘Bottleneck’ in terms of number of clones that can be selected, screened and evaluated

Up to 3000 clones screened

19

Boosting upstream productivity Transgene repression in vector production [TRiP] cell system Dose Administration is normally 3 months (UPDRS) 6 months (UPDRS) • During manufacture, transgene expressed Mean 27% 30% 1, •n=3 Can reduce 1x vector yieldOriginal activity, and impact productMean Max. up to 30% Max. up to 50% purity and yield Mean 28% Mean 34% 2, n=3 2x Original • Ideally transgene expression should be toMax. up to 53% Max.repressed up to 53% allow consistent vector production and purification, Mean 26% 3, n=3 2x Enhanced irrespective of transgene identity. • Transgene Repression in vector Production [TRiP] cell system has been developed for the manufacture of lentiviral vectors. • TRiP may increase production cell output and improve vector particle purity. Cohort2

1 year (UPDRS)

2 years (UPDRS)

Mean 29%

Mean 20%

Max. up to 44%

Max. up to 30%

Mean 29%

-

Max. up to 56%

-

-

Potent repression of GFP transgene in cells transfected with TRiP system components

20

Source: Published PCT number WO 2015/092440

Manufacturing strategy considerations Targets for future process development • Suitable cell bank(s) Mean 27% 1, n=3 1x Original • Transient / stable production Mean 28% 2x suspension Original •2, n=3Serum-free platform preferred •3, n=3Scalability is important Mean 26% 2x Enhanced • Reduced COGs (per patient dose) Cohort2

Dose

Administration

3 months (UPDRS)

Max. up to 30%

Max. up to 53%

o o o o



Acceptable and appropriate product quality •

• • •

Increased scale Increased yield Process simplification, reduced interventions Minimise process risk and operator error Vector functionality, process impurities etc.

For ongoing clinical programmes – comparability with existing process Closed systems Automation

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Mean 30%

Mean 29%

Mean 20%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Mean 34%

Mean 29%

-

Max. up to 53%

Max. up to 56%

-

-

-

Drive to increase operating efficiency • Greater utilisation of production capacity

 Reduction of cycle time increases equipment and facility utilisation (i.e. more capacity available)  Minimise storage space and variability using validated process equipment

• Reduce the possibility of processing errors

 Minimize manual handling  Reduce opportunities for product contamination  Training of operators

21

Scale up & manufacturing challenges Process evolution of the LentiVector® platform Planar 2 technologies Cohort Serum-containing

1, n=3

Scale-out based on 2, n=3 surface area

Dose

1x

Packed-bed systems

Suspension Administration platform 3 months (UPDRS)

Serum containing/ serumSerum-free Original free

single-use 1 year (UPDRS) bioreactor

Mean 30%

Max. up to 30%

Max. up to 50%

Max. up to 44%

Scale-up

Mean 34%

Mean 29%

Suspension platform

Max. up to 53%

Process simplification, Process simplification, on-line monitoring, on-line monitoring, Mean Enhanced reduced manipulations, reduced manipulations, lower risk profile lower risk profile

26%

50L single-use Max. up to 53% bioreactor

-

Mean 29%

2 years (UPDRS)

Mean 27%

based on fixed Easy to scale-up further Mean 28% 2x Scale-up Original bed compaction density

More laborious, time consuming, limited 3, n=3 2x monitoring of mono-layer, multiple manipulations, higher risk profile

200L 6 months (UPDRS)

Max. up to 56%

Mean 20% Max. up to 30%

-

-

5L bioreactor

Scale-up Packed-bed systems 66-500m2 single-use Packed-bed bioreactor

HEK293T monolayer

Transient, packaging & producer cell line development

0.53-4m2 single-use packed–bed bioreactor

Scale-out

Current adherent with serum process T-225 Flasks 225cm2

20µm

Nunc™ Cell Factory™ Systems CF-10 tray systems, HYPERStack™ Vessels HS-12/HS-36, 6,000/18,000cm2

Nunc™ Automatic Cell Factory™ System CF-40 tray systems 25,280cm²

2D Planar technologies

22

Boosting upstream productivity o

Serum free suspension culture 200L single-use bioreactor

Key features Cohort2



Dose

Administration

3 months (UPDRS)

Proven scalable platform up to 2000L in single Mean 27% 1, n=3 1x Original use bioreactor format Max. up to 30% • Suspension adapted HEK293T cell lines 28% 2x Original •2, n=3 Transient, packaging or producer cell lines Mean Max. up to 53% • Serum and animal component - free Mean 26% 3, n=3 2x Enhanced

5L bioreactor Shake flask

ambr™ bioreactor

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Mean 30%

Mean 29%

Mean 20%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Mean 29%

-

50L single-use Mean 34% Max. up to 53% bioreactor -

Max. up to 56%

-

-

Key benefits • • • • • • •

Serum-free Operated in batch/fed-batch or perfusion mode Fewer operators required Can be operated as a closed system Better on-line monitoring and process control Increased process robustness Lower risk profile 23

Manufacturing production capabilities & capacity o



GMP1 Grade C/D (ISO 7/8) – 4,198 sq. ft (390 sq. m) clean room suite o o



GMP2 Grade C/D (ISO7/8) - 2,691 sq.ft (250 sq. m) clean room suite o o o



Suspension platform up to 5 x 50/200L Duo SUB Planar 2D technologies e.g. CF-10 Areas for cell expansion, media make-up, buffer preparation and downstream processing Operational readiness H1 2017

Filling suite with a Grade B/C (ISO 6/7) – 3,552 sq.ft (330 sq. m) o o



Suspension platform 2 x 50/200L Duo SUB Planar 2D technologies e.g. CF-10 Operational readiness Q1 2016

GMP3 Grade C/D (ISO7/8) - 7,696 sq.ft (715 sq. m) clean room suite o o o o



Planar 2D technologies e.g. CF-10, areas for cell expansion and downstream processing Operational

Aseptic processing and semi-continuous vial filling Operational readiness H1 2017

GMP4 Grade C/D (ISO7/8) - 6,028 sq. ft (560 sq. m) new off-site API Facility o o o o

Suspension platform up to 2 x 50/200L Duo SUB Planar 2D technologies e.g. CF-10 Areas for cell expansion, media make-up, buffer preparation and downstream processing Operational 24

GMP4 – Yarnton Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

1, n=3

1x

Original

Mean 27%

Mean 30%

Mean 29%

Mean 20%

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Mean 28%

Mean 34%

Mean 29%

-

Max. up to 53%

Max. up to 53%

Max. up to 56%

Mean 26%

-

-

2, n=3 3, n=3

2x 2x

Original Enhanced

Empty warehouse (Q1 2015)

Mezzanine floor constructed (Q2 2015)

-

USP

DSP 25

OXB – infrastructure and capacity • OXB - investing in capacity, quality, CoG improvements, in readiness for Mean 27% 30% 29% Mean 20% 1, n=3 1x Original commercial production of lentiviral vectorMean products –Mean in-house OXB and partners2x Mean 28% Mean 34% Mean 29% 2, n=3 Original Cohort2

3, n=3

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Max. up to 53%

Max. up to 53%

Max. up to 56%

Mean 26%

-

-



Clean rooms



Equipment



Analytical, development labs



Resources (FTEs)

2x

Enhanced

-

• Strategy to provide multiple independent production suites

• Future-proof facility design •

Suitable for current process or future process(es)

26

Summary • CMC plays a critical role in product commercialisation Cohort2

Dose

Administration

3 months (UPDRS)

6 months (UPDRS)

1 year (UPDRS)

2 years (UPDRS)

1, n=3

1x

Original

Mean 27%

Mean 30%

Mean 29%

Mean 20%

Max. up to 30%

Max. up to 50%

Max. up to 44%

Max. up to 30%

Max. up to 53%

Max. up to 53%

Max. up to 56%

Mean 26%

-

-

• Achieve the right balance between process advancement and product Mean 28% Mean 34% Mean 29% 2, n=3requirements 2x Original 3, n=3



2x Enhanced Suitable quality attributes



Appropriate scale and capacity, with acceptable cost of goods



Dual supply

-

• Support for process characterisation and validation • In the near future - multiple promising lentiviral vector based cell and gene therapies approaching commercialisation •

Robust proof of concept, compelling clinical data



OXB – multi-fold increased productivity in next gen process: Phase III/commercial process can be used at Phase I/II, helping to get these important, lifesaving treatments to patients 27

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