Gene and Cell Therapy Translation: from target to adopted product

Guidance document for PIsApril 2019

Translational Research Office (TRO)

Objective:

• Provide a workflow summarising key activities and considerations for development, evaluation and commercialisation of gene therapies, to facilitate their effective translation into the clinic. These include:

• Adeno-associated virus (AAV) therapies

• Lentiviral therapies

• Gene modified cell therapies

• Regenerative medicine therapies

Process Development

Work flow – overview

Regulatory advice

Unmet Clinical Need

Finance

Spin-Out

License-outSell-out

Regulatory Approvals

IDEA

GLP pre-clinicalStudies

Phase I/II Clinical Trials

Quality Control

Phase III-IV Clinical Trial

Marketing approval

Research gradeviral vector

Laboratory Evaluation

GMP grade viral vector

CTA submission

GMP Manufacturing

GMP formal release

Intellectual Property

Finance

Proof of concept in patients

Proof of concept in laboratory

Orphan Drug Designation

Patient and Public Involvement (PPI)

‘NHS ADOPTION’

• Development (project) team

• Therapeutic design and planning

• Laboratory evaluation

• Process development and manufacturing for GLP pre-clinical studies

• GMP manufacture process

• Clinical product

• Clinical evaluation (Phase I/II)

• Commercial adoption

Considerations

Development (project) team

• Successful translation of an idea into a NHS-adopted therapeutic is reliant upon the consideration & effective decision-making of a diverse group of individuals

• The input from experts throughout the product’s development path is essential and a ‘Development Team’ should be formalised early, including key members & responsibilities:

• The Team should meet regularly to ensure continuous review of progress, awareness & relevance to the clinical and competitor landscapes and to ensure decisive project advancement

Chair Project Management Documentation

Human factors Health Economics Patient & Public

Clinical Technical Manufacturing

Regulatory Business Development Adoption

Process Development

Therapeutic design and planning

Regulatory advice

Unmet Clinical Need

Finance

Spin-Out

License-outSell-out

Regulatory Approvals

IDEA

GLP pre-clinicalStudies

Phase I/II Clinical Trials

Quality Control

Phase III-IV Clinical Trial

Marketing approval

Research gradeviral vector

Laboratory Evaluation

GMP grade viral vector

CTA submission

GMP Manufacturing

GMP formal release

Intellectual Property

Finance

Proof of concept in patients

Proof of concept in laboratory

Orphan Drug Designation

PPI

‘NHS ADOPTION’

Therapeutic design and planning

IDEA:

• Target Product Profile (TPP) – captures the ‘benefit’ of the proposed therapeutic and key considerations in the strategic development of the product (incl. technical, scientific and medical information required to satisfy key stakeholders (regulators and funders))

TPP headings – Considered early to guide development

• Intended use- Indications, target patients, health economics

• Advanced Therapy Medicinal Product (ATMP) Description - Dosage, administration route, dosage forms

• Competitors

- Other therapeutics for the disease, comparison to the current gold standard

• Risk/side effect - Contraindications, adverse reactions, over dosage, anti-vector immunity

• Non-clinical testing- Toxicology, efficacy, vector stability/expression, regimen, duration, dose

• Clinical testing- Relevant safety & efficacy end points, storage, handling, administration

• Orphan drug designation, EU/FDA

Longer-term considerations for Adoption

• Intended use- ‘Unidentified’ opportunities for clinical benefit/use (e.g. arising from creative discussion with expanded audience)?

• Drug description- Modality, use in specific populations

• Contraindications - Destined for stand alone use or routine employment alongside/in combination (e.g. consider comorbidities)?

• Testing- Design in ‘Resilience’ (i.e. minimum service adaption to enable adoption and diffusion, regardless of context)Regulatory:

• PRIME (priority medicines)

• PiP – (paediatric investigation plan)

Therapeutic design and planning

UNMET CLINICAL NEED:

• As part of the TPP, comprehensively research and define the potential for benefit of the proposed therapeutic over current ‘standard of care’

• Finance – important consideration sufficient resources to cover costs for entire project including; research grade & GMP grade vector production, staffing etc.

INTELLECTUAL PROPERTY:

• Engage with Business experts (i.e. UCLB) to ascertain if you have a novel invention, ensure freedom to operate and to protect foreground/arising intellectual property e.g. vector composition

• All researchers with potentially commercialisable research results should fill out a confidential Invention Disclosure Form (IDF) and submit it to their UCLB Business Manager:http://www.uclb.com/for-researchers/do-you-believe-you-have-a-novel-invention/

Therapeutic design and planning

PATIENT and PUBLIC INVOLVEMENT:

• Understanding the patient and clinician needs

– Does your TPP meet all of the essential requirements expressed by frontline clinical care providers, patient and public contributors (PPI)?

• Research is carried out ‘with’ or ‘by’ members of the public or potential patients etc.

– Advisory members of a project steering group

• Early PPI engagement will help raise awareness of the therapeutic during development, provide opportunities for PPI to shape the development programme, potentially facilitate patient recruitment for subsequent clinical evaluation and support financial investment.

• Consider patient groups and charities.

• Timely identification of future needs or opportunities for diversifying.

• Further information on PPI can be found via INVOLVE www.invo.org.uk/

AAV and Lentiviral - therapeutic design and planning

DESIGN of GENE THERAPY VECTOR – AAV and Lentiviral:

Considerations: Tropism, pre-existing immunity, immune response

• Synthesis of the transgene

– Functional protein established in vitro?

• Choice of capsid

– Expression/distribution, anti-vector immunity?

• Promotors

– Specific cell types to target?

– Level of expression of transgene?

• Desired titre of plasmids/vector?

– Feasibility of high titre research grade stocks for pre clinical evaluation

– Feasibility of GMP grade for clinical evaluation

• Who will synthesise? Cost?

– Location of production/import licences etc.

• Freedom to operate – potential IP (vector composition, use)?

• Lentiviral specific: suicide gene yes/no, choice of suicide gene, risk of suicide gene drug resistance?

AAV Lentivirus

Genetic material ssDNA ssRNA

Coat Naked Enveloped

Packaging capacity 4.7 kb 8 kb

Tropism/infection Serotype specific tropism Broad

Immunogenicity Low High

Host genome interaction Integrating/non-integrating Integrating

Transgene expression Potentially long lasting Long lasting

Viral vector characteristics - therapeutic design and planning

• AAV is the predominant viral vector used globally with the greatest potential for gene therapy, especially for monogenic loss-of-function diseases.

Gene modified cell therapies and Regenerative Medicine (RM) -therapeutic design and planning

Design of Delivery System – Autologous/Allogeneic

Considerations:• Route of administration/biodistribution/persistence

• Is a cell scaffold material of human origin or non-human required? (RM)

• Cell type

– Transduction efficiency

– Manipulated vs minimally manipulated (RM)

– Population doubling rate. Does the age of the patient affect the rate?

– Immunotolerance (MSCs, T-Cells, etc)

– Genetic stability/Tumourgenicity

• Vascularisation

− Is this a requirement for the cell population and its scaffold prior to orthotopic placement, if so how will this be achieved? (RM)

• Escape Mechanism

– Inclusion and choice of suicide gene

– Risk of suicide gene drug resistance

– Steroids

• Freedom to operate and potential IP (vector components, use, clinical data)

Process Development

Work flow – overview

Regulatory advice

Unmet Clinical Need

Finance

Spin-Out

License-outSell-out

Regulatory Approvals

IDEA

GLP pre-clinicalStudies

Phase I/II Clinical Trials

Quality Control

Phase III-IV Clinical Trial

Marketing approval

Research gradeviral vector

Laboratory Evaluation

GMP grade viral vector

CTA submission

GMP Manufacturing

GMP formal release

Intellectual Property

Finance

Proof of concept in patients

Proof of concept in laboratory

Orphan Drug Designation

‘NHS ADOPTION’

PPI

RESEARCH GRADE CELL AND GENE THERAPY VECTORS:

• Synthesise DNA – check sequence integrity

• Vector design – composition including; capsid choice, transgene & promoters for optimal expression

• Synthesis research grade viral vector – sufficient (titre/volume) for preclinical evaluation, QC/QA

• Expression stability of gene modification in host cell

• Transduction efficiency

Laboratory evaluation – therapy design

LABORATORY EVALUATION FOR CELL AND GENE THERAPY VECTORS :

• Does your research grade product match the TPP and meet all the essential requirements?

For cell therapy vectors:

– Effective tumour cell killing in vitro?

– Effective cell therapy eradication via suicide gene activation in vitro?

• Does the DNA produce functional protein – assessed in transient transfection assays?

• ‘In-house’ development and target validation

• Consider which Proof-of-Concept (PoC) animal models are appropriate for target and modality

Laboratory evaluation

• In most cases, the Joint Research Office (JRO) or Comprehensive Clinical Trials Unit (CCTU) will support and oversee investigator-initiated, clinical evaluation of therapeutic development programmes at UCL:– http://www.ucl.ac.uk/jro/academic-clinical-trials/sponsorship-clinical-trials

• Early engagement with the JRO is essential to facilitate timely:- Foreword planning for evaluations to satisfy the regulatory authorities (e.g. MHRA, EMA, FDA)

Laboratory evaluation - JRO engagement

Process Development

Work flow – overview

Regulatory advice

Unmet Clinical Need

Finance

Spin-Out

License-outSell-out

Regulatory Approvals

IDEA

GLP pre-clinicalStudies

Phase I/II Clinical Trials

Quality Control

Phase III-IV Clinical Trial

Marketing approval

Research gradeviral vector

Laboratory Evaluation

GMP grade viral vector

CTA submission

GMP Manufacturing

GMP formal release

Intellectual Property

Finance

Proof of concept in patients

Proof of concept in laboratory

Orphan Drug Designation

‘NHS ADOPTION’

PPI

Pre-clinical studies and regulatory submissions

Outsourced Work:

Outsourced work – exceptional costs?

UCL procurement rules for work over £50k (animal work exempt)

- GMP manufacture

- Suppliers/components

- Fee for service or collaborator?

- Stability studies

- GLP animal work – which/how many species? – seek MHRA guidance

- Which Contract Research Organisation (CRO)? – TRO expertise

- Toxicology +/-Biodistribution studies

Contracting:

- CRO manufacturer will usually operate under a Master Services Agreement (MSA) and Schedule of Work (SoW)

which defines terms, scope, objectives, timelines and deliverables of the work package

- If a collaborator rather than a fee for service supplier, there will also be a collaboration agreement

- May themselves sub-contract tasks or testing

Pre-clinical studies and regulatory submissions – Contractual considerations

• If employing a contract research organisation (CRO), UCL Research Services will lead on contracts for pre-clinical work and UCL JRO or CTU will lead on contracts for clinical-trial related work

• If progressing via a UCL spin-out then external legal support will be required for outsourced contracts

• All documentation relating to manufacturer, suppliers needs to be included for a CTA i.e. IMPD/IB, HRA – MHRA class gene therapies as ATMPs (Directive 2001/83/EC, ATMP regulation 1394/2007 applies)

• Committee for Advanced Therapies (CAT) oversee all marketing authorisations

• Engage early to reduce risk– ensure due diligence with all CROs completed. Slots for CRO: check details – delays etc

• Contract agreements for preclinical GLP Toxicology & GMP CROs, CTUs – secure SoWs - all agreements in conjunction with UCL Research Services, TRO and UCLB

• GMP batches ready – supply chain secured – stability and potency ongoing for duration of studies

Process Development

Work flow – overview

Regulatory advice

Unmet Clinical Need

Finance

Spin-Out

License-outSell-out

Regulatory Approvals

IDEA

GLP pre-clinicalStudies

Phase I/II Clinical Trials

Quality Control

Phase III-IV Clinical Trial

Marketing approval

Research gradeviral vector

Laboratory Evaluation

GMP grade viral vector

CTA submission

GMP Manufacturing

GMP formal release

Intellectual Property

Finance

Proof of concept in patients

Proof of concept in laboratory

Orphan Drug Designation

‘NHS ADOPTION’

PPI

REGULATORY and ETHICAL COMPLIANCE:

• Assign responsibility for generating regulatory documentation and submissions

• The JRO, Clinical Trials Unit and TRO support developers in:- Seeking local, national and international approvals (Ethics, HRA, MHRA, R&D)

• Regulatory approvals from MHRA, HRA (NHS led studies), R&D approvals locally in place. TMF ready CTUs and SIVs arranged. Clinical sites “recruitment ready”

- IMPD/IB/clinical trial protocol development and finalisation- Database development, testing and release

- Engaging with Regulators in advance to identify and address potential hurdles to translation- Ensuring rigorous compliance of UCL researchers and contractors to required international standards

• Consideration of the precedent for trial design/adaptive design approaches

• Consider the inclusion of PPI as part of trial design and development. Support can also be sought from local PPI leads within the JRO.

https://www.hra.nhs.uk/planning-and-improving-research/research-planning/public-involvement/

https://www.ucl.ac.uk/joint-research-office/about

Early phase clinical studies and clinical evaluation – Considerations

Clinical evaluation

PHASE II CLINICAL TRIAL:

• Phase II clinical trials objective is to assess safety and efficacy of therapeutic in extended target patient population

• Participant follow-up (10 years)

• Protocol based upon anticipated real world dosing regimen

• Trials must be compliant with GCP

PHASE I/II CLINICAL TRIAL:

• Drug developers are required to conduct first in human clinical trials to establish the safety of a new therapeutic

• Phase I/II clinical trials can also encompass a secondary objective of assessing efficacy, if administered to a patients’ population and can be compared to standard of care practice

• Single/dose escalation study to establish efficacy and expression

• Trial must be compliant with Good Clinical Practice (GCP).

Process Development

Work flow – overview

Regulatory advice

Unmet Clinical Need

Finance

Spin-Out

License-outSell-out

Regulatory Approvals

IDEA

GLP pre-clinicalStudies

Phase I/II Clinical Trials

Quality Control

Phase III-IV Clinical Trial

Marketing approval

Research gradeviral vector

Laboratory Evaluation

GMP grade viral vector

CTA submission

GMP Manufacturing

GMP formal release

Intellectual Property

Finance

Proof of concept in patients

Proof of concept in laboratory

Orphan Drug Designation

‘NHS ADOPTION’

PPI

Commercial adoption

GOING TO MARKET:

• Having completed the primary clinical safety and efficacy evaluation, regulatory authorities require manufacturers to:

- Undertake further Phase III and IV clinical trials in the wider population- Establish potency assay- Lock-down commercial manufacturing process- Validate all in-process and release assays- Regulatory body (MHRA/EMA/FDA) approval- NICE approval

• In practice, the resources required for such an undertaking are often beyond UCL and the therapeutics would be expected to be commercially adopted:

- SELL-OUT: Therapeutic sold in entirety for one-off deal to a company/manufacturer

- LICENCED-OUT: UCL retains the therapeutic but grants license to company for marketing

- SPIN-OUT: UCLB investment establishes a separate commercial entity to market the therapeutic

Commercial adoption- NHS uptake: Key tips to facilitate adoption

DESIGN FOR MARKET:

• Continuously undertake internal and external stakeholder review of the therapeutic:

- The Development (Project) Team should meet regularly (at least every 1-2 months)

- Ensure the identification and measurement of tangible data that will support adoption (e.g. outcomes meaningful to ward managers, hospital laboratory managers)

• Be mindful of the key ‘facets’ to be developed for successful adoption:

FISCAL OPPORTUNITY - Clearly defined and attractive market potential

SYSTEM OPERATIONS - Awareness and solutions to operational challenges of delivering the healthcare

COMMUNICATION - Effective publicity of the therapeutic throughout its lifetime

HUMAN FACTORS - Minimized use-related hazards, risks and inconvenience wherever practically possible

PROOF - Provision of ‘work as done’ evidence (i.e. in both clinical and laboratory scenarios)

IPR - Secure intellectual property rights (IPR) as early as possible, then drive for market adoption as soon as possible

Commercial adoption – UCL support towards NHS uptake

UCL has implemented and is growing strategic platform partnerships to facilitate the accelerated development, commercialisation and adoption of therapeutics into the NHS

UCL’s Translational Research Office (TRO) builds on an increasingly vibrant translational culture across the wider university community by providing integrated support for translational research and industrial partnerships: www.ucl.ac.uk/translational-research

Key contacts for support

UCL Businesswww.uclb.com/for-researchers/

Translational Research Officewww.ucl.ac.uk/translational-research/

Joint Research Officewww.indigo-sandbox.ucl.ac.uk/jro/contact-us

Cell, Gene and Regenerative MedicinesTherapeutic Innovation Networkwww.ucl.ac.uk/slms/ovph/TINs

Research Serviceswww.ucl.ac.uk/finance/research/rs-contacts.php UCL Partners

https://uclpartners.com/contact-us/