Cell and Gene Therapy
Global Regulatory Report
June 2023

Table of Contents• Section 1 – Overview of Report & Authors• Section 2 – Overview of Pipeline Products, Recent Approvals & Regulatory
Reviews• Section 3 – Regulatory Events, Key Global Legislative/Framework, Standards &the Latest Approved Products• Disclaimer• References, Methodology, Glossary of Key Terms

Overview of Report & Authors
Section 1

Overview of Report
Welcome to the first Cell and Gene Therapy Regulatory Report from ISCT and Citeline. This reportprovides a global overview of the cell and gene therapy regulatory landscape, including pipeline,
late-stage (Phase III and pre-registration), and approved products. It covers Cell, GeneticallyModified Cell, and Gene Therapies.
Over the last few years, the regulatory agencies have been updating legislations and frameworks to
keep up with the rapidly advancing cell and gene therapy space. As a result, ISCT and Citeline havecollaborated to highlight some of these changes and offer commentary on the updates and theireffects.
This report shows that year-over-year, cell therapies continue to make up the majority of all
approved products (71%). However, the pipeline for genetically modified cell therapies has grown to
include 1,150 therapies in development, compared to 839 non-genetically modified cell therapies
and 920 gene therapies.
Meanwhile, ISCT continues to track regulatory changes and events and provide comments on Key
Global Legislative/Framework Changes as well as international standards including WHO’s approach
towards the development of a global regulatory framework for cell and gene therapy products and
FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product.

About the authors• The International Society for Cell & Gene Therapy (ISCT) is a global society of clinicians, regulators,
researchers, technologists, and industry partners with a shared vision to translate cell and gene therapy into
safe and effective therapies to improve patients' lives worldwide.
• ISCT is the global leader focused on pre-clinical and translational aspects of developing cell and gene-based
therapeutics, thereby advancing scientific research into innovative treatments for patients. ISCT offers aunique collaborative environment that addresses three key areas of translation: Academia, Regulatory, andCommercialization. Through strong relationships with global regulatory agencies, academic institutions, andindustry partners, ISCT drives the advancement of research into a standard of care.
• Comprised of over 3,000 cell and gene therapy experts across five geographic regions and representationfrom over 60 countries, ISCT members are part of a global community of peers, thought leaders, andorganizations invested in cell and gene therapy translation. For more information about the organization,
visit ISCT.
• A special thanks to the ISCT Global Regulatory Task Force for their contribution. The ISCT GRTF works toaddress challenges and opportunities in established and evolving global regulatory environments• Citeline powers a full suite of complementary business intelligence offerings to meet the evolving needs oflife science professionals to accelerate the connection of treatments to patients and patients to treatments.
These patient-focused solutions and services deliver and analyze data used to drive clinical, commercial, andregulatory related-decisions and create real-world opportunities for growth.
• Our global teams of analysts, journalists and consultants keep their fingers on the pulse of thepharmaceutical, biomedical and medtech industries, covering it all with expert insights: key diseases, clinical
trials, drug R&D and approvals, market forecasts and more. For more information on one of the world’s mosttrusted life science partners, visit Citeline.

Global Overview of Pipeline Products, Recent
Approvals & Regulatory Reviews
Section 2

Global Overview of Pipeline Products
Cell, Genetically Modified Cell, and Gene Therapies

Global Pipeline Overview – by category• As of June 1, 2023, of the 2,909
pipelines (from preclinical topreregistration phase) therapies,
there are:
• 839 non-genetically modified celltherapies• 1,150 genetically modified celltherapies• 920 gene therapies

Source: Pharmaprojects | Citeline, June 2023

% of Global Pipeline Therapies

Gene therapies
32%

Non-geneticallymodified celltherapies
29%

Geneticallymodified celltherapies
39%

Global Pipeline Overview – by phase• As of June 1, 2023, the majority of therapies are in preclinical development• Non-genetically modified cell category has the most therapies under regulatory review with 44
therapies in Phase III or in pre-registration• Genetically modified cell category has the greatest absolute number of therapies in preclinicaldevelopment (804 therapies), while the gene category has the greatest proportion of preclinicaldevelopment (just over 80%)1Gene therapies

22

125

33

739

5
Genetically modified cell therapies

9

123

209

804

5
39

Non-genetically modified cell therapies

0%

Source: Pharmaprojects | Citeline, June 2023

173

10%

85

537

20%

30%

40%

50%

Pre-registration

Phase III

Phase II

Phase I60%
Preclinical

70%

80%

90%

100%

Approved Products
Cell, Genetically Modified Cell, and Gene Therapies

Overview of Approved Products – by category• As of June 1, 2023, 87 products
are approved globally• 62 non-genetically modified cell
products are approved• 11 genetically modified cell
products are approved• 14 gene products are approved% of Global Approved Products

16%
13%
71%

Non-genetically modified cell products
Genetically modified cell products
Gene products

Source: Pharmaprojects | Citeline, June 2023

Overview of Approved Products – by region*• As of June 1, 2023, there is a similar approval distribution pattern among North America,
Europe, and Asia
• Non-genetically modified cell products – the most approved product category in all regions besides
South America• Genetically modified cell products – the second most approved product category in North America andEurope. There is currently no approval in South America and Africa.
• Gene products – the least approved product category in North America and Europe and the second
most approved product category in Asia and Oceania. There is currently no approval in Africa.
40
30
20
10
0
North America
Approved gene products

EuropeAsia

Approved genetically modified cell products*Approvals by regions do not necessarily represent the approvals from one or more countries in the regions.
*Oceania includes Australia and New Zealand.

Source: Pharmaprojects | Citeline, June 2023

South America

AfricaOceania

Approved non-genetically modified cell products

Approved Non-Genetically Modified Cell Products(10-year period, June 2013 ̶ 2023)
Product name

Generic name

Disease(s)Locations approved

Originator company

autologous corneal epithelial cells

Year first
approved
2015

Holoclar

Limbal stem cell deficiency

EU, UK

Holostem Terapie Avanzate

TCD-51073

autologous myoblast cell therapy

2015

Heart failure

Japan

PrecigenStempeucel

allogeneic mesenchymal stem cells

2016

Ischemia, limb

India

Stempeutics

Apcedenautologous dendritic cells

2017

India

APAC Biotech

Alofisel
Kysleceldarvadstrocel
minimally manipulated autologous
pancreatic islets
Stemirac
autologous chondrocytes
autologous corneal epithelium cells
allogenic skin tissue cells

2018
2018

Cancer, colorectal; cancer, lung, nonsmall cell; cancer, ovarian; cancer,
prostate
Anal fistula, Crohn's disease
Pancreatitis

EU, Israel, Japan, UK
US

TakedaOrgenesis

2018
2019
2020
2021

Spinal cord injury
Arthritis, osteo
Limbal stem cell deficiency
Wound healing

Japan
South Korea
Japan
US

Nipro
Biosolution Co.
Teijin Pharma
Mallinckrodt

2021

Limbal stem cell deficiency

Japan

Teijin Pharma

2021

DiGeorge syndrome

US

Sumitomo Dainippon Pharma

2022

Limbal stem cell deficiency

Japan

Hirosaki Lifescience Innovation

Tab-celautologous cultured oral mucosal
epithelium
allogeneic processed thymus
tissue-agdc
autologous cultured oral mucosal
epithelium
tabelecleucel

2022

EU, UK

Atara Biotherapeutics

Vyznova
Omisirge

corneal endothelial cell therapy
omidubicel

2023
2023

Post-transplant lymphoproliferative
disorderCorneal dystrophy
Stem cell engraftment

Japan
US

Aurion Biotech
Gamida Cell

Stemirac
CartiLife
Nepic
Stratagraft
OcuralRethymic
Sakracy

Source: Pharmaprojects | Citeline, June 2023

Approved Genetically-Modified Cell Products(10-year period, June 2013 ̶ 2023)
Product name

Generic name

Strimvelis

autologous CD34+ enriched cells

Year first
approved
2016

Kymriahtisagenlecleucel-t

2017

Yescarta

axicabtagene ciloleucel

2017

Zynteglo

betibeglogene autotemcel

2019

Tecartus

brexucabtagene autoleucel

2020

Libmeldy
Breyanzi

atidarsagene autotemcel
lisocabtagene maraleucel

2020
2021

Abecmaidecabtagene vicleucel

Skysona

Disease(s)Locations approved

Originator company

Adenosine deaminase deficiency

EU, UK

GSK

Cancer, leukemia, acute lymphocytic;
Cancer, lymphoma, B-cell, diffuse large;
Cancer, lymphoma, follicular
Cancer, lymphoma, B-cell, diffuse large;
Cancer, lymphoma, follicular
Thalassaemia

US, EU, UK, Japan, Australia,
Switzerland, Canada, South
Korea
Japan, China, Canada, EU, US,
UK, Australia
EU*, US

Novartis

EU, UK, US, Australia

Gilead Sciences

EU, UK
EU, UK, US, Japan, Canada,
Switzerland
US, EU, UK, Canada, Japan

GSK
Bristol-Myers Squibb

2021

Cancer, leukaemia, acute lymphocytic,
Cancer, lymphoma, mantle cell
Leukodystrophy, metachromatic
Cancer, lymphoma, B-cell, diffuse large;
Cancer, lymphoma, follicular
Cancer, myeloma

elivaldogene autotemcel

2021

Adrenoleukodystrophy

EU*, US

bluebird bio

Benodarelmacabtagene autoleucel

2021

China

JW Therapeutics

Carvykti

ciltacabtagene autoleucel

2022

Cancer, lymphoma, B-cell, diffuse large;
Cancer, lymphoma, follicular
Cancer, myeloma

US, EU, UK, Japan, Australia

Legend Biotech

Gilead Sciences
bluebird bio

bluebird bio*The first approval dates for these 2 products relates to their approval in the EU. However, bluebird bio had requested to withdraw them due to commercial
reasons.

Source: Pharmaprojects | Citeline, June 2023

Approved Gene Products(10-year period, June 2013 ̶ 2023)
Year first

Product name

Generic name

Imlygic

talimogene laherparepvec

2015

Luxturna

voretigene neparvovec

2017

approved

Disease(s)Locations approved

Originator company

Melanoma

US, EU, UK, Australia

Amgen

Leber’s congenital amaurosis; retinitis

US, EU, UK, Australia, Canada,pigmentosa

South Korea

Roche

US, EU, UK, Japan, Australia,
Zolgensma

onasemnogene abeparvovec

2019

Spinal muscular atrophy

Canada, Brazil, Israel, Taiwan,

Regenxbio

South Korea
Collategene

beperminogene perplasmid

2019

Ischaemia, limb

Japan

AnGes

Delytact

teserpaturev

2021

Brain cancer

Japan

Daiichi Sankyo

Upstazaeladocagene exuparvovec

2022

EU, UKPTC Therapeutics

Roctavianvaloctocogene roxaparvovec

2022

Haemophilia A

EU, UK

BioMarin

Hemgenixetranacogene dezaparvovec

2022

Haemophilia B

US, EU, UK

uniQureAdstiladrin

nadofaragene firadenovec

2022

Bladder cancer

US

Merck

Vyjuvek

beremagene geperpavec

2023

Epidermolysis bullosa

US

Krystal Biotech

Source: Pharmaprojects | Citeline, June 2023

Aromatic L-amino acid decarboxylase(AADC) deficiency

Products Under
Regulatory Review(Pre-registration and Phase III)
Cell, Genetically Modified Cell, and Gene Therapies

Non-Genetically Modified Cell Therapies Under Regulatory Review• 44 non-genetically modified cell therapies areunder regulatory review (pre-registration or Phase
III clinical trials)• 5 non-genetically modified cell therapies are in preregistration, accounting for 11% of late-stage nongenetically modified cell therapies• 39 non-genetically modified cell therapies are in
Phase III clinical trials, accounting for 89% of latestage non-genetically modified cell therapies% of non-genetically modified cell therapies in late-stage
development

Non-genetically modified cell therapies in pre-registration
Drug
Name

Generic
Drug Name

Cell Type

DiseaseCompany

Reviewer
AgencyACE-02

autologous
culturedepidermis
withmelanocytes

Skin cells

Piebaldism;
Vitiligo

TeijinPharmaMHLW(Japan)Sitoiganap

ERC-1671

Glioma-derived
cell lysates andirradiated cells

Brain cancer

Epitopoietic
Research

EMA (EUand UK)

Lantidra

donislecel

Pancreatic cells(Islet cells)

Diabetes, Type 1

CellTrans

FDA (US)

Astrostem

stem celltherapy,
autologous

Connective
tissue cells(Adipocytes)

Arthritis, osteo

K-StemCell

MFDS(SouthKorea)

SB-623vandefitemcel

Mesenchymal
stem cells (bonemarrow)

Traumatic brain
injurySanBioMHLW(Japan)11%89%

Pre-registration

Phase III

Source: Pharmaprojects | Citeline, June 2023

Genetically Modified Cell Therapies Under Regulatory Review• 14 genetically modified cell therapies are underregulatory review (pre-registration or Phase III
clinical trials)• 5 genetically modified cell therapies are in preregistration, accounting for 36% of late-stage
genetically-modified cell therapies• 9 genetically modified cell therapies are in Phase III
clinical trials, accounting for 64% of late-stage
genetically-modified cell therapies% of genetically modified cell therapies in late-stage
development

36%

Genetically modified cell therapies in pre-registration
Drug
Name

Generic Drug
Name

Cell Type

DiseaseCT-053

autologus
BCMA-CAR-T
cells

T cells

Cancer,myeloma

CARsgen
Therapeutic

NMPA(China)IB-1326

equecabtagene
autoleucel

T cells

Cancer,myelomaNanjing IASO
Biotherapeutics

NMPA(China)Exa-celexagamglogene
autotemcel

Hematopoietic
stem andprogenitor cells

Anemia, sickle
cell;
Thalassaemia

CRISPR
Therapeutics

FDA (US);EMA (EUand UK)

CNCT-19

inaticabtagene
autoleucel

T cells

Cancer,leukemia, acutelymphocytic

Juventas
Cell
Therapy

NMPA(China)Lovo-cellovotibeglogene
autotemcel

Hematopoietic
stem andprogenitor cells

Anemia, sickle
cell

bluebird bio

FDA (US)64%

Pre-registration

Phase III

Source: Pharmaprojects | Citeline, June 2023

Company

Reviewer
AgencyGene Therapies Under Regulatory Review• 23 gene therapies are under regulatory review(pre-registration or Phase III clinical trials)• 1 gene therapy is in pre-registration, accounting for
4% of late-stage gene therapies• 22 gene therapies are in Phase III clinical trials,
accounting for 96% of late-stage gene therapies% gene therapies in late-stage development
4%96%

Pre-registration

Phase III

Source: Pharmaprojects | Citeline, June 2023

Gene therapies in pre-registration
Drug
Name

Generic Drug
Name

Cell Type

DiseaseCompany

Reviewer
AgencySRP-9001

delandistrogene
moxeparvovec

Other/Unknown/
NA

Dystrophy,
Duchenne's
muscular

Sarepta
Therapeutics

FDA (US)Select Regulatory Review
Cell, Genetically Modified Cell, and Gene Therapies

Select Regulatory Review – Product Overview
VyjuvekFirst therapeutic approved by US FDA for Epidermolysis Bullosa

Vyjuvek(beremagene
geperpavec)

Company:

Krystal Biotech, Inc.

Current phase:

US FDA Approval

Indication:

Epidermolysis Bullosa

Target:Collagen

Formulation/dosing:

Viral gene therapy; topical gel of non-integrating, replication-incompetent HSV-1 expressing thehuman collagen VII protein

Designations:

Fast Track, Orphan, PRIME, Rare Disease, RMAT

Upcoming regulatory events:

CHMP Opinion from 9/1/23–3/31/24

Pivotal Study

GEM-3 (Update: 2/17/23)

Supporting clinical studies

Gem-1/2 (Completion date: 12/2019)

Patient
inclusion≥ 6 months old and older at the time of Informed Consent with
Dystrophic Epidermolysis Bullosa confirmed by genetic testing,including COL7A1, and 2 cutaneous wounds matching the criteria

Patient inclusion

2 years of age and older with Dystrophic Epidermolysis
Bullosa and at least one wound matching the criteria

Study design

Interventional, Randomized, Parallel Assignment, Quadruple Blind

Study design

Interventional, Randomized, Parallel Assignment

Primary focus

Safety and efficacy

Primary focus

Treatment

The pivotal GEM-3 trial met its primary endpoint of complete woundhealing at six months and its secondary endpoint of complete woundhealing at three months.

Study status

Complete

Trial efficacy
data
Trial safety
data

B-VEC was well tolerated, with no drug-related serious adverse eventsor discontinuations due to treatment.

Study results

Repeat topical applications of B-VEC were associatedwith durable wound closure, full-length cutaneous type
VII collagen (COL7) expression, and anchoring fibril
assembly with minimal reported adverse events

Source: Pharmaprojects | Citeline, June 2023

Select Regulatory Review – Large Impact Events

Vyjuvek – Regulatory Insights
Summary of regulatory outcomes

Regulatory
overview▪ On May 19, 2023, the US FDA approved Vyjuvek for the treatment of wounds in patients 6months of age and older with dystrophic epidermolysis bullosa (DEB) with mutation(s) in thecollagen type VII alpha 1 chain (COL7A1) gene

Expected event

CHMP Opinion

Expected event date

9/1/2023 – 3/31/2024

MAA filing date

12/14/22

Designations

Fast Track, Orphan, PRIME, Rare Disease, RMAT

Previous regulatory
decision

FDA regulatory approval (US)▪ Krystal Biotech filed the marketing authorization application (MAA) for beremagene geperpavec(B-VEC) with the European Medicines Agency (EMA) and is currently working closely with the
EMA through the MAA validation process

Additional notes Regulatory Decision

Comments▪ Submission for CHMP Opinion▪ Based on an internal analysis of the centralized European approval procedure, it is estimated the European marketing
authorization for this drug for this indication will be granted in approximately 11-17 months. As the approval decision isnormally issued 67 days from adoption of a positive Committee for Medicinal Products for Human Use (CHMP) opinion,
it is estimated the CHMP opinion to occur between September 2023 and March 2024.

▪ US FDA Approval▪ The safety and effectiveness of Vyjuvek was established primarily in a Phase III, randomized, double-blinded, placebocontrolled study (GEM-3) involving a total of 31 subjects with DEB, including 30 subjects with RDEB and one subject with
DDEB.
▪ In addition, in a different Phase III clinical study, two young patients with RDEB (6 and 7 months of age, respectively)
received topical Vyjuvek weekly without any new safety findings.

Source: Pharmaprojects | Citeline, June 2023

Select Regulatory Review – Product Overview
Exa-celPotential to be first gene-edited therapy approved
Company:

Vertex Pharmaceuticals Incorporated & CRISPR Therapeutics

Current phase:

BLA

Indication:

Sickle Cell Anemia

Target:BCL11A|CRISPR/CRISPR-Cas9

Formulation/dosing:Non-viral gene therapy; single-dose infusion CTX001 (autologous CD34+ hHSPCs modified withCRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene)

Designations:

Fast Track, Orphan, PRIME, Rare Disease, RMAT

Upcoming regulatory events:

Approval Decision (UK) from 7/1/23–9/30/23 CHMP
Results from 9/1/23–3/31/24

Pivotal Study

CLIMB-SCD-121 (Update: 12/10/22)

Supporting clinical studies

CLIMB-151 (Update: 1/25/23)

Patient inclusion

12 to 35 years of age with severe SCD and a history of ≥2 VOCs per year in theprevious 2 years

Patient inclusion

Study design

Interventional, Single Group Assignment, Open Label

2 to 11 years of age with severe SCD and ahistory of ≥2 VOCs per year in the previous
2 years

Primary focus

Safety and efficacy

Trial efficacy
data

Data from 31 patients showed a single dose of Exa-cel leads to early increasesin HbF and total HB that are durable up to nearly 3 years. All patients were freeof VOCs.

Study design

Interventional, Single Group Assignment,
Open LabelPrimary focus

Safety and efficacy

Study status

Actively recruiting

Exa-cel(exagamglogene
autotemcel)

Trial safety data

Safety profile is consistent with that of busulfan myeloablation and autologous
HSCT. No patients with SCD had Exa-cel related SAEs.

Source: Pharmaprojects | Citeline, June 2023

Select Regulatory Review – Large Impact Events

Exa-cel - Regulatory Insights
Summary of regulatory outcomes

Regulatory
overview▪ Vertex announced that the Exa-cel filing for approval (UK) and MAA submissions werecompleted in the fourth quarter of 2022 in EU and UK for SCD

Expected event

Approval Decision (UK)

Expected event date

7/1/23–9/30/23

MHRA filing date

01/24/23

Designations

Fast Track, Orphan, PRIME, Rare Disease, RMAT

Previous regulatory
decision

PDUFA for BLA - First Review (US)▪ April 3, 2023, Vertex Pharmaceuticals announced the completion of the rolling Biologics
License Applications (BLAs) to the US Food and Drug Administration (FDA) for theinvestigational treatment exagamglogene autotemcel (exa-cel) for sickle cell disease (SCD)▪ June 8, 2023, US Food and Drug Administration (FDA) accepted the Biologics License
Applications (BLAs) for the investigational treatment exagamglogene autotemcel (exa-cel) for
severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT).

Additional notes Regulatory Decision

Comments▪ Submission for CHMP Opinion (EU)▪

Based on an internal analysis of the centralized European approval procedure, it is estimated the European marketing
authorization for this drug for this indication will be granted in approximately 11 17 months. As the approval decision isnormally issued 67 days from adoption of a positive Committee for Medicinal Products for Human Use (CHMP) opinion,
we then estimate the CHMP opinion to occur between September 2023 and March 2024.

▪ Submission for Approval Decision (EU)▪

The MHRA offers a 150-day assessment timeline for marketing authorization applications (MAAs) for new active
substances and biosimilar products or existing active substances in the UK. Under this process, the MHRA will evaluate
the application for marketing authorization and reach its opinion on approvability within 150 days of submission of avalid application. The assessment procedure also includes a stopped-clock period of up to 60 days for the applicant toaddress any questions from the MHRA. As such, a decision is expected between July 2023 and September 2023.

▪ BLA Submission (US)▪

The FDA has granted Priority Review for SCD and Standard Review for TDT and assigned Prescription Drug User Fee Act(PDUFA) target action dates of December 8, 2023, and March 30, 2024, respectively.

Source: Pharmaprojects | Citeline, June 2023

Select Regulatory Review – Product Overview
SRP-9001
Potential to be the first gene therapy U.S. FDA approved for Duchenne Muscular Dystrophy

SRP-9001(delandistrogene
moxeparvovec)

Company:

Sarepta Therapeutics, Inc.

Current phase:

BLA

Indication:

Duchenne Muscular Dystrophy (DMD)

Target:Microdystrophin

Formulation/dosing:

Viral gene therapy; single intravenous infusion of SRP-9001

Designations:

Fast Track, Orphan, Rare Disease

Upcoming regulatory events:

PDUFA/Approval Decision (U.S.) from 5/23–6/23

Pivotal StudyENDEAVOR (Update: 7/6/22)

Patient
inclusion

4 to 7 years of age, ambulatory male at birth with DMD confirmed bydocumented clinical findings and prior genetic testing. Participant will have had astable dose equivalent of oral corticosteroids for at least 12 weeks and rAAVrh74
antibody titers are not elevated as per protocol requirements

Study design

Interventional, Single Group Assignment, Open LabelPrimary focus

Safety and efficacy

Trial efficacy
data

Across multiple new analyses, SRP-9001 treated patients showed statisticallysignificant and clinically meaningful benefit versus propensity-matched external
controls.

Trial safety
data

The safety and tolerability profile of SRP-9001 is similar to past reports. The mostcommon treatment-related adverse event was vomiting.

Source: Pharmaprojects | Citeline, June 2023

Supporting clinical studies

EMBARK (Update: 12/22)

Patient inclusion

4 to 7 years of age, ambulatory with DMD
confirmed by documented clinical findings
and prior genetic testing; participant will
have had a stable dose equivalent of oralcorticosteroids for at least 12 weeks andrAAVrh74 antibody titers are not elevatedas per protocol requirements

Study design

Interventional, Randomized, Parallel
Assignment, Quadruple Blind

Primary focus

Safety and efficacy

Study status

Enrolled

Select Regulatory Review – Large Impact Events

SRP-9001 – Regulatory Insights
Summary of regulatory outcomes

Regulatory
overview
Expected event

PDUFA for BLA – First Review (US)Expected event date

5/29/23

NDA/BLA filing date

9/29/22

Designations

Fast Track, Orphan, Rare Disease

Previous regulatory
decision

Priority Review (US)▪ On May 24, 2023, Sarepta Therapeutics announced that the FDA has informed Sarepta that it
requires modest additional time to complete the review of the company's BLA for SRP-9001 for thetreatment of ambulant individuals with Duchenne muscular dystrophy (DMD) who have a confirmed
mutation of the DMD gene, including final label negotiations and post-marketing commitment
discussions, and that it anticipates that the review will be complete by June 22, 2023.
▪ On May 12, 2023, the U.S. Food and Drug Administration (FDA) Cellular, Tissue and Gene Therapies
Advisory Committee (CTGTAC) voted 8 to 6 in support of accelerated approval of SRP-9001(delandistrogene moxeparvovec) for the treatment of ambulatory patients with Duchenne muscular
dystrophy with a confirmed mutation in the DMD gene,

Additional notes Regulatory Decision

Comments▪ MAA Submission (EU)▪

Roche plans to file for approval of RG6356 for the treatment of DMD in 2024.

▪ J-NDA Filing (Japan)▪

Chugai plans to file for approval of SRP-9001 for the treatment of DMD in Japan in 2024.

▪ Cellular, Tissue, and Gene Therapies Advisory
Committee Meeting (US FDA)▪

On May 12, 2023, the committee met in an open session to discuss the Biologics License Application (BLA) 125781
from Sarepta Therapeutics, Inc. for delandistrogene moxeparvovec with the requested indication for the treatment of
ambulatory patients with Duchenne Muscular Dystrophy (DMD) with a confirmed mutation in the DMD gene. The
meeting was open for the public.
Despite the FDA’s highly negative tone in the briefing document, the advisory committee narrowly voted in favor ofaccelerated approval for Sarepta’s gene therapy, SRP-9001. Panelists appreciated the risk/benefit profile for SRP-9001,
as well as the importance of time in an indication such as this. However, a key concern among panelists was theinability to complete the pivotal Phase III EMBARK trial before approval, which would mean an approval based on
insufficient evidence of efficacy. Sarepta managed to convince many that accelerated approval would not cause thetrial to lose its integrity, and also noted that very few patients would be treated commercially with SRP-9001 before
the completion of EMBARK. Data from the trial are expected by the end of 2023.

▪

Source: Pharmaprojects | Citeline, June 2023

Select Regulatory Review – Product Overview
Lumevoq
Potential to be the first gene therapy U.S. FDA approved for Leber's Hereditary Optic Neuropathy

Lumevoq(GS-010)Company:

GenSight Biologics S.A.

Current phase:

Phase III

Indication:

Leber's Hereditary Optic Neuropathy (LHON)

Target:Mitochondrial Electron Transport Chain|NADPH: Quinone Oxidoreductase-1 (NQO1)

Formulation/dosing:

Viral gene therapy; single dose of GS010 (recombinant adeno-associated viral vector serotype 2(rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4))

Designations:Orphan, Rare Disease, SPA

Upcoming regulatory events:

Product launch (EU) from 9/1/2023 – 12/31/2023
Supporting clinical studies

REVEAL (Completion date: 6/20)

Patient inclusion

18+ years of age with onset of vision loss based on medically documented
history or subject testimony, in both eyes for 181 and ≤365 days in durationand documented results of genotyping showing the presence of the G11778A
mutation in the ND4 gene and the absence of the other primary LHONassociated mutations (ND1 or ND6) in the subject's mitochondrial DNA

Patient inclusion

18+ years of age with LHON based on a
genetic test confirming the presence of theG11778A mutation in the mitochondrial ND4
and visual acuity ≤ 1/10 of the less functionaleye

Study design

Interventional, Randomized, Parallel Assignment, Quadruple Blind

Study design

Interventional, Safety Study, Single Group
Assignment, Open LabelPrimary focus

Safety and efficacy

Primary focus

SafetyTrial safety andefficacy data

The results show sustained efficacy and favorable safety for bilateral
intravitreal injection of the gene therapy with a statistically significant visualacuity improvement from baseline in both treated eyes, showing an
additional benefit of a bilateral injection compared to a unilateral injection.

Trial safety data

Well tolerated with a good safety profile
during 5 years of follow-up and may offer
meaningful lasting improvements in vision forthis LHON population

Pivotal Study

REFLECT, RESCUE, REVERSE (Update: 3/23)

Source: Pharmaprojects | Citeline, June 2023

Select Regulatory Review – Large Impact Events

Lumevoq – Regulatory Insights
Summary of regulatory outcomes

Regulatory
overview
Expected event

Product launch (EU)Expected event date

9/1/23–12/31/23

MAA filing date

09/15/20

Designations

Orphan, Rare Disease, SPA

Previous regulatory
decision

MAA Withdrawal▪ On April 20, 2023, GenSight Biologics announced that the Committee for Advanced Therapies(CAT) of the Committee Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMA) assessed the data presented during the oral explanation on LUMEVOQ European
regulatory dossier. Following interactions with the CAT indicating that the data provided thus far
would not be sufficient to support a positive opinion of the marketing authorization of
LUMEVOQ by EMA, GenSight decided to withdraw its application ahead of a final opinion by theCAT.
▪ GenSight submitted the MAA for LUMEVOQ to the EMA in September 2022 based on thebenefit-risk balance established by results from a Phase-I/IIa study (CLIN-01), two pivotal PhaseIII efficacy studies (CLIN-03A: RESCUE, and CLIN-03B: REVERSE and the long-term follow up studyof RESCUE and REVERSE (CLIN 06 – readout at Year 3 post-injection).

Additional notes Regulatory Decision

Comments▪ MAA Withdrawal▪

▪
▪ FDA response to a Type-C meeting (US)

Source: Pharmaprojects | Citeline, June 2023▪

The decision to withdraw the MAA enables the Company to discuss the best possible path forward for LUMEVOQ
with the EMA in the coming weeks, aiming at submitting a new application addressing remaining objections as soon
as possible, in Europe and other countries. The company is exploring options including generating new clinical data,
which may induce material delays and additional costs.
GenSight confirms that the manufacturing validation campaign is on track with its partner in the United-States, as
planned, with a product released for human use by the end of 2023.
The FDA provided feedback in January 2022 recommending that the company conduct an additional placebocontrolled trial to bolster the demonstration of LUMEVOQ efficacy in view of the unexpected bilateral effect observedin unilaterally treated patients in the Phase III RESCUE, REVERSE and REFLECT trials. This feedback from the FDA is in
response to a Type-C meeting with the company held in December 2021.

Upcoming Regulatory Events, Highlights of Key
Global Legislative/Framework Changes, Recent
or Upcoming Standards & Highlights of theLatest Approved Products
Section 3Upcoming Regulatory Events

Upcoming Regulatory Events
START DATEEND DATE

EVENT DESCRIPTIONTYPE OF EVENTNAME OF AGENCY

March 17, 2023

June 20, 2023

Guidance document: Pharmacogenomic Data Submissions

Public consultation

CBER-FDA

April 3, 2023

July 3, 2023

Guidance document: Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial
Intelligence/Machine Learning (AI/ML)-Enabled Device Software Functions

Public consultation

CBER-FDA

April 5, 2023

July 5, 2023

Guidance document: Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory
Decision-Making

Public consultation

CBER-FDA

April 21, 2023

Sept. 30, 2023

Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorization

Public consultation

CAT-EMAMay 17, 2023

July 17, 2023

Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for PediatricExclusivity Under the Best Pharmaceuticals for Children Act Guidance for Industry

Public consultation

CBER-FDA

17 May 2023

17 July 2023

Guidance for Industry: Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children
Act: Scientific Considerations

Public consultation

CBER-FDA

May 19, 2023

Vary*

E6(R2) Guideline “Good Clinical Practice” (GCP)

Public consultation

ICH

May 24, 2023

July 24, 2023

Guidance for Industry: Generally Accepted Scientific Knowledge in Applications for Drug and Biological Products: Nonclinical Information

Public consultation

CBER-FDA

May 30, 2023

Aug. 1, 2023

Guidance document: Decentralized Clinical Trials for Drugs, Biological Products, and Devices

Public consultation

CBER-FDA

June 14, 2023

June 16, 2023

Committee for Advanced Therapies (CAT) Meeting

Meeting

CAT-EMA

June 26, 2023

June 27, 2023

Multi-stakeholder workshop on Real- w orld Data (RWD) quality and Real-World Evidence (RWE) use

Workshop

EMA

12 July 2023

14 July 2023

Committee for Advanced Therapies (CAT) Meeting

Meeting

CAT-EMA

Sept.1, 2023

Sept. 1, 2023

Advisory Committee on Biologicals (ACB) Meeting #20

Meeting

TGA

TBD

TBD

Guidance for Industry and Staff: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies

Public consultation

CBER-FDA

TBD

TBD

Draft Guidance for Industry: Considerations for the Use of Human- and Animal- derived Materials and Components in the Manufacture of
Cell and Gene Therapy and Tissue-Engineered Medical Products

Public consultation

CBER-FDA

TBD

TBD

Draft Guidance for Industry: Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medical Products

Public consultation

CBER-FDA

TBD

TBD

Draft Guidance for Industry: Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and TissueBased Products (HCT/Ps)

Public consultation

CBER-FDA

TBD

TBD

Draft Guidance for Industry: Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products

Public consultation

CBER-FDA*The public consultation deadline varies depending on the regulatory agency partners, click here to find out more.

Highlights of Key Global Legislative/Framework Changes

ICH – E6(R3) Draft Guideline: Good Clinical Practice[1,2]About the guideline• This is a revision of the E6(R2)Guideline “Good Clinical Practice”(GCP), it is because, since thedevelopment of E6(R2), clinical trials
have continued to evolve with new
designs and technologicalinnovations.
• The proposed revision to ICH E6
would likely primarily benefit
innovators who typically conductclinical trials, such as those in thepharmaceutical and biotech sectors.

Scope and application• Addressing the application of GCP
principles to the increasingly diverse
trial types and data sources being
employed to support regulatory andhealthcare-related decision-making on
drugs and provide flexibility wheneverappropriate to facilitate the use oftechnological innovations in clinical
trials.

European Health Union – Commission Proposal to Reform EU
Pharmaceutical Legislation[3]About the proposal

6 key elements of the proposal• The Commission is proposing to revise theEU's pharmaceutical legislation ― thelargest reform in over 20 years• The revision will make medicines moreavailable, accessible, and affordable. It will
support innovation and boost thecompetitiveness and attractiveness of the EU
pharmaceutical industry, while promoting
higher environmental standards.
• The revision includes proposals for a new
directive and a new regulation, which revise
and replace the existing pharmaceuticallegislation, including the legislation on
medicines for children and for rare diseases.

• Better access to innovative and affordable
medicines for patients and national healthsystems• Promoting innovation and competitivenessthrough an efficient and simplified regulatory
framework• Effective incentives for innovation• Addressing shortages of medicines andensuring security of supply• Stronger protection of the environment• Tackling antimicrobial resistance (AMR)

FDA – Distributed Manufacturing and Point-of-Care Manufacturingof Drugs | Discussion Paper[4]About the paper• This discussion paper presents areas
associated with Distributed
Manufacturing (DM) and Point-ofCare (POC) manufacturing that FDA
has identified for consideration as
FDA evaluates our existing risk-based
regulatory framework as it applies tothese technologies.

Scope and application• The discussion paper considers
relevant background, including
terminology, to the FDA’s regulation of
DM and POC, identifies challenges
presented by DM and POC, and poses
key questions to facilitate publiccomment.
• The discussion paper does notconstitute guidance; instead, its
purpose is to gather feedback fromthe public to inform future policy
development.

FDA – draft guidance on Considerations for the Design and Conduct ofExternally Controlled Trials for Drug and Biological Products[5]About the guidance

Scope and application• This guidance provides
recommendations to sponsors
and investigators considering
the use of externally controlled
clinical trials to provide evidenceof the safety and effectivenessof a drug and biological product.

• This guidance focuses on the useof patient-level data from otherclinical trials or from real-world
data (RWD) sources, such as
registries as well as electronic
health records (EHRs) andmedical claims.

Health Canada – Draft guidance on advanced therapeutic products
framework[6]About the guidance

Scope and application• The guidance document
provides an overview of how
Health Canada designates andregulates advanced therapeutic
products (ATPs) under sections
21.9 to 21.96 of the Food andDrugs Act.

• This guidance applies to:• All ATPs that are or may be set out
in Schedule G of the act• The following activities related to
ATPs:• manufacture, prepare, preserve,
package, label, test, store, import,
advertise, sell

MHRA – UK to introduce first-of-its-kind framework to make it easier tomanufacture innovative medicines at the point of care[7]About the framework• The framework is specifically designed
to create and regulate a step change
in the range of manufacturing options
to enable the supply and increase theavailability of innovative new
medicinal products to patients.
• This new manufacturing and supply
system in the UK healthcare system
will benefit patients that currently
have no or few treatment options byimproving the availability ofinnovative medicines.

Scope and application• The aim is to support increased
manufacture of point-of-care
products whilst ensuring theseproducts attain the same assuranceof safety, quality and efficacy
currently in place for moreconventional medicinal products.

TGA – Update to the Manufacturing Principles for Medicines, APIs &Sunscreens[8]About the guidance• TGA adopted the PIC/S Guide to Good
Manufacturing Practice for Medicinal
Products (PE009-15) that was issued
on May 1, 2021, as the
Manufacturing Principles for
medicines, active pharmaceuticalingredients and sunscreens.
• This adoption of the PIC/S Guide
commenced on July 1, 2022, fromwhich point, GMP inspectors will use
the new Guide to GMP during
inspections.

Summary of change(s)• The changes in version 15 relate toAnnex 2 - Biological Medicines, which
has been split into two sub-annexes:• Annex 2A “Manufacture of advanced
therapy medicinal products for humanuse”; and• Annex 2B “Manufacture of biological
medicinal substances and products forhuman use.”

New Zealand Ministry of Health – Therapeutic Products Bill

About the bill[9]ISCT general comments• The bill will replace the Medicines Act 1981 that iscurrently the main legislation for enabling access tosafe medicines and medical devices. The bill would
repeal most provisions of the Medicines Act, except
those relating to pharmacy ownership, and revoke theregulations made under the act. It would also revoke
the Dietary Supplements Regulations.

• Although there is a good coverage of amendments tonational legislation within the bill, a separate
document explaining the implications for thoserequired to adhere to other pieces of legislation or
regulations would be useful and since this bill has notcovered topics regarding unproven stem celltherapies, provisions about it should be included.

• Changes that the bill proposes include:• requiring therapeutic products to receive amarket authorization before they could be
imported into, exported from, or supplied in
New Zealand• providing for the regulation of a range ofcontrolled activities• establishing a Therapeutics Products Regulator• In addition, it is important to provide explanation on
the scheme and how it is similar to, and differs from,other regulatory schemes internationally, and how it
articulates with other national legislation (e.g., Human
Tissue Act 2008) and the types of amendments madeto other national legislation to accommodate it.

WHO – Approach Towards the Development of a Global Regulatory
Framework for Cell and Gene Therapy Products

About the white paper[10]

ISCT general comments• Publication of this early draft is to provide
information about the proposed documentWHO approach towards the development ofa global regulatory framework for cell andgene therapy products, to a broad audienceand to ensure the transparency of theconsultation process.

• WHO to establish a platform to whom eachstate (independently from the level ofexperience of its own regulatory body) may
refer to. Use of certain established networks,
such as those already working in Asia or
Africa, will likely have limited effect upon the
direction of global harmonization.
• WHO to consider a centralized organizationthat functions as reference body andestablishes the basic guidelines for
manufacturing, control, shipping, indication,
application, and surveillance of ATMPs, forexample, as ICH has done to foster alignment
on multiple topics including analytics, etc.
The number of countries aligning to ICH
standards continues to grow.

Recent or Upcoming Standards

FACT-JACIE International Standards for HCT Product Collection, Processing
and Administration – 9th edition

About the standards• These standards represent the basic
fundamentals of cellular therapy thatcan be applied to any cell source ortherapeutic application and areintended to be used throughout
product development and clinical
trials.

Publication timeline• The new edition of this standard will
be published in early 2025.

FACT Standards for Immune Effector Cells – The Second Edition

About the standards• These standards promote quality
practice in immune effector celltherapies and apply to a wide range of
immune effector cells used tomodulate an immune response fortherapeutic intent, whether
genetically modified or not. This
includes, but is not limited to,dendritic cells, natural killer cells, T
cells, B cells, genetically engineered
chimeric antigen receptor T cells(CAR-T cells), and therapeutic
vaccines.

Publication timeline• The final standards will be publishedin November 2023 and will become
effective in February 2024.

Highlights of the Latest Approved Products

First Gene Therapy to Treat Adults with Hemophilia B – Hemgenix®[11-18]

About the productApproval history• Hemgenix® is an adeno-associated viral(AAV5) vector-based gene therapy that
encodes factor IX. Patients withhemophilia B have mutations (changes)
in a gene which the body needs to makethe clotting protein Factor IX, resulting ineither a partial or complete lack of its
activity.

• August 2022 – was granted orphan
designation by the TGA• Nov. 22, 2022 – received FDA BLA
approval• Feb. 20, 2023 – received EU
Conditional Marketing Approval• March 27, 2023 – received conditional
marketing authorization from UK MHRA
• April 5, 2023 – was granted an
OGTR licenseFirst therapy to Treat Transplant Patients with
Post-transplant Lymphoproliferative Disease – Ebvallo™[19-22]

About the product• The first therapy to treat transplantpatients with post-transplant
lymphoproliferative disease• A medicine used to treat adults andchildren from 2 years of age who,
after receiving an organ- or a bonemarrow-transplantation, develop a
blood cancer called Epstein-Barr virus
positive post-transplant
lymphoproliferative disease (EBV+PTLD)

Approval history• Dec. 16, 2022 – the Committee for
Medicinal Products for Human Use(CHMP) adopted a positive opinion,
recommending the granting of amarketing authorization under
exceptional circumstances

First Topical Gene Therapy for Treatment of Wounds in Patients with
Dystrophic Epidermolysis Bullosa – Vyjuvek™[23]

About the productApproval history• Vyjuvek™, a herpes-simplex virus type 1(HSV-1) vector-based gene therapy, forthe treatment of wounds in patients 6months of age and older with dystrophic
epidermolysis bullosa (DEB) with
mutation(s) in the collagen type VII alpha1 chain (COL7A1) gene.
• Vyjuvek™ is a genetically modified(engineered in a laboratory) herpessimplex virus used to deliver normal
copies of the COL7A1 gene to thewounds.

• May 19, 2023 – received FDA BLA
approvalCell Therapy for Patients with Blood Cancers to Reduce Risk of Infection
Following Stem Cell Transplantation – Omisirge®[24]

About the productApproval history• Omisirge® (omidubicel-onlv), a
substantially modified allogeneic (donor)
cord blood-based cell therapy to quicken
the recovery of neutrophils (a subset ofwhite blood cells) in the body and reduce
the risk of infection.
• The product is intended for use in adults
and pediatric patients 12 years and older
with blood cancers planned for umbilicalcord blood transplantation following a
myeloablative conditioning regimen(treatment such as radiation or
chemotherapy).

• April 17, 2023 – received FDA
BLA approval

Cell Therapy for Patients with Relapsed or Refractory Multiple Myeloma –Carvykti®[25-30]

About the productApproval History• Ciltacabtagene autoleucel is a B-cellmaturation antigen (BCMA)-directed
genetically modified autologous chimericantigen receptor (CAR) T-cell therapy.
• Each dose is customized using a patient’s
own T-cells, which are collected andgenetically modified, and infused backinto the patient.

• Feb. 28, 2022 – received FDA BLA
approval• May 25, 2022 – received EMA
conditional marketing authorization• Designated as an orphan drug by UK
MHRA until Jan. 4, 2033
• Sept. 27, 2022 – received PMDA
approval• 22 February 2023 – received FDA
supplement approval• 6 June 2023 – received TGA approval

Disclaimer

Disclaimer
Although the information provided in this report has been produced from sources believed to bereliable, no warranty, express or implied, is made by the publishers regarding the accuracy,
adequacy, completeness, legality, reliability or usefulness for any particular purpose.
The publishers provide this information on an “as is” basis and disclaim any and all warranties,
express and implied, including, but not limited to, any warranties of accuracy, reliability, title,
merchantability, fitness for a particular purpose, freedom from contamination by computer viruses(if provided digitally) and non-infringement of proprietary rights.
In no circumstances will the publishers be liable for any trading, investment, commercial or otherdecisions based on or made in reliance on the report. Changes may periodically be made to theinformation included in the report and these changes may or may not be incorporated in any newversion of the report. Data can also quickly become out of date.
In no event shall the publishers be liable for any special, indirect, or consequential damages or any
damages whatsoever, whether direct, indirect, consequential, incidental, or special, or any claim for
attorney’s fees arising out of or in connection with the information provided in the report.

*The publishers: ISCT and CitelineReferences, Methodology, Glossary of Key Terms

References
1.

ICH, Public Consultations, https://www.ich.org/page/public-consultations, accessed 12 June 2023.

2.

ICH, Draft Guideline – Good Clinical Practice (GCP) E6(R3),https://database.ich.org/sites/default/files/ICH_E6%28R3%29_DraftGuideline_2023_0519.pdf, accessed 12 June 2023.

3.

European Commission, Press release - European Health Union: Commission proposes pharmaceuticals reform for more accessible,
affordable and innovative medicines, https://ec.europa.eu/commission/presscorner/detail/en/IP_23_1843, published 26 April 2023,
accessed 4 May 2023.

4.

US FDA, Distributed Manufacturing and Point-of-Care Manufacturing of Drugs | Discussion Paper, https://www.fda.gov/aboutfda/reports-budgets-cder/distributed-manufacturing-and-point-care-manufacturing-drugs-discussion-paper, published 18 October
2022, accessed 05 April 2023.

5.

US FDA, Draft guidance: Considerations for the design and conduct of externally controlled trials for drug and biological products,
https://www.fda.gov/media/164960/download, published February 2023, accessed 29 March 2023.

6.

Government of Canada, Draft guidance on advanced therapeutic products framework: Overview, https://www.canada.ca/en/healthcanada/programs/consultation-draft-guidance-advanced-therapeutic-products-framework/overview.html, published 28 December
2022, accessed 29 March 2023.

16.

PharmaTimes Online, CSL’s Hemgenix receives MHRA
authorisation, https://www.pharmatimes.com/news/csls_hemgenix_receives_mhra_authorisation_1490181 published 27 March
2023, accessed 29 March 2023

17.

ISCT, Australia and New Zealand Legal and Regulatory Affairs - Watchdog Update April 2023,
https://www.isctglobal.org/telegrafthub/blogs/lauren-reville/2023/04/12/watchdog-update-australia-and-new-zealand-legal-an,
accessed 17 May 2023

18.

Dealings not involving intentional release (DNIR), https://www.ogtr.gov.au/sites/default/files/2023-05/may_dnir_list_2023.pdf,
updated 22 May 2023, accessed 30 May 2023

19.

EMA, First therapy to treat transplant patients with post-transplant lymphoproliferative disease,https://www.ema.europa.eu/en/news/first-therapy-treat-transplant-patients-post-transplant-lymphoproliferative-disease ,published 14 October 2022, accessed 29 March 2023

20.

EMA, Ebvallo, https://www.ema.europa.eu/en/medicines/human/EPAR/ebvallo, approved 16 December 2022, accessed 29 March
2023.

21.

EMA, Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 10-13 October 2022,
https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-10-13-october2022#:~:text=The%20committee%20adopted%20a%20positive,positive%20post%2Dtransplant%20lymphoproliferative%20disease,published 14 October 2022, accessed 1 May 2023.

22.

ISCT, North America Legal and Regulatory Affairs – Watchdog Update February 2023,
https://www.isctglobal.org/telegrafthub/blogs/lauren-reville/2023/02/07/north-america-legal-and-regulatory-affairs-watchdo,
accessed 17 May 2023

23.

FDA News Release, FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis
Bullosa, https://www.fda.gov/news-events/press-announcements/fda-approves-first-topical-gene-therapy-treatment-woundspatients-dystrophic-epidermolysis-bullosa, published 19 May 2023, accessed 30 May 2023.

10. World Health Organization, WHO approach towards the development of a global regulatory framework for cell and gene therapy
products, https://cdn.who.int/media/docs/default-source/biologicals/bs2424_cgtp-document-for-2nd-publicconsultation.pdf?sfvrsn=11a0c885_1, accessed 05 April 2023

24.

FDA News Release, FDA Approves Cell Therapy for Patients with Blood Cancers to Reduce Risk of Infection Following Stem Cell
Transplantation, https://www.fda.gov/news-events/press-announcements/fda-approves-cell-therapy-patients-blood-cancersreduce-risk-infection-following-stem-cell, published 17 April 2023, accessed 30 May 2023.

11. EMA, Hemgenix, https://www.ema.europa.eu/en/medicines/human/EPAR/hemgenix, updated 13 April 2023, accessed 4 May 2023

25.

12. Pharmaceutical Technology, CSL receives EC CMA approval for haemophilia B gene therapy, CSL receives EC CMA approval forhaemophilia B gene therapy (pharmaceutical-technology.com), published 21
February 2023, accessed 20 March 2023

FDA D.I.S.C.O. Burst Edition: FDA approval of CARVYKTI, https://www.fda.gov/drugs/resources-information-approved-drugs/fdadisco-burst-edition-fda-approval-carvykti-ciltacabtagene-autoleucel-treatment-adult-patients, accessed 9 June 2023.

26.

EMA, Carvykti, https://www.ema.europa.eu/en/medicines/human/EPAR/carvykti, accessed 9 June 2023.

27.

UK MHRA, Orphan Register, https://www.gov.uk/government/publications/orphan-registered-medicinal-products/orphanregister#carvykti, updated 9 June 2023, accessed 9 June 2023.

28.

Businesswire, CARVYKTI Receives Approval from MHLW Japan,
https://www.businesswire.com/news/home/20220926005847/en/CARVYKTI%E2%84%A2-ciltacabtagene-autoleucel-ReceivesApproval-from-Japan%E2%80%99s-Ministry-of-Health-Labour-and-Welfare-MHLW-for-the-Treatment-of-Patients-with-Relapsedor-Refractory-Multiple-Myeloma, accessed 9 June 2023

29.

FDA Supplement Approval – CARVYKTI, https://www.fda.gov/media/165633/download, accessed 9 June 2023.

30.

TGA, ARTG ID 410143, Carvykti, https://www.tga.gov.au/resources/artg/410143, accessed 9 June 2023.

7.

Press Release, UK to introduce first-of-its-kind framework to make it easier to manufacture innovative medicines at the point ofcare, https://www.gov.uk/government/news/uk-to-introduce-first-of-its-kind-framework-to-make-it-easier-to-manufactureinnovative-medicines-at-the-point-of-care, published 25 January 2023, accessed 05 April 2023.

8.

Australia TGA, Update to the Manufacturing Principles for medicines, APIs & sunscreens,
https://www.tga.gov.au/news/notices/update-manufacturing-principles-medicines-apis-sunscreens-0, published 25 August 2022,
accessed 30 March 2023.

9.

New Zealand Parliament, Therapeutic Products Bill, https://www.parliament.nz/en/pb/sc/make-asubmission/document/53SCHE_SCF_BILL_130084/therapeutic-products-bill, published 7 February 2023, accessed 29 March 2023

13. CISION PR Newswire, First Gene Therapy for Hemophilia B, CSL's HEMGENIX®, Approved by the European Commission,
https://www.prnewswire.com/news-releases/first-gene-therapy-for-hemophilia-b-csls-hemgenix-approved-by-the-europeancommission-301751222.html, published 20 February 2023, accessed 20 March 2023
14. HEMGENIX, https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix, content current as of 4 January 2023, accessed 22
March 2023
15. TGA, Notice for etranacogene dezaparvovec (CSL Behring Australia Pty Ltd), https://www.tga.gov.au/resources/designationsdeterminations/notice-etranacogene-dezaparvovec-csl-behring-australia-pty-ltd, date of review outcome 30 August 2022, accessed
22 March 2023

Methodology: Sources and Scope of Therapies• Sources for all data come from Citeline (formerly Pharma Intelligence)• Pipeline and trial data
• Data derived from Pharmaprojects and Trialtrove• Therapeutic classes included in report categorizations:• Gene therapies:• Genetically modified cell therapies:• Cell therapies:• Event data
• Data derived from Biomedtracker

Glossary of Key Terms*
Therapy Type Definitions
Gene therapy is the use of genetic material to treat or prevent disease. For the purpose of this report, the following terms shall mean the following:

Gene therapy

Therapies containing an active ingredient synthesized following vector-mediated introduction of a genetic
sequence into target cells in- or ex-vivo. Used to replace defective or missing genes (as in cystic fibrosis) as
well as to introduce broadly acting genetic sequences for the treatment of multifactorial diseases (e.g., cancer).
Direct administration of oligonucleotides without using vectors is covered separately in the antisense therapy
class; RNA interference class; or oligonucleotide, non-antisense, non-RNAi class. Platform technologies forgene delivery are covered separately in the gene delivery vector class.

56 terms/ Q1 2023*The key
and definitions used in this report are referring to the method the data is pulled, organized, and presented.

Glossary of Key Terms*
Therapy Type Definitions, cont.
Genetically modified cell therapy includes the following:

Cellular therapy, chimeric antigen receptor

Cellular therapy consisting of T cells that have been modified to express a chimeric antigen receptor (CAR) –this is a cell surface receptor that gives the T cells the ability to target a specific protein and fight the targeted
cells

Cellular therapy, other

Cellular therapies that do not fall under "Cellular therapy, stem cell," "Cellular therapy, CAR," "Cellular therapy,
TIL," or "Cellular therapy, TCR" categories or the specific cellular therapy is unspecified

Cellular therapy, stem cell

Regenerative therapy which promotes the repair response of injured tissue using stem cells (cells from which
all other specialized cells would originate)

Cellular therapy, T cell receptor

Cellular therapies whereby natural T cells collected for the patient are engineered to express artificial receptors(usually through viral transfections) that would target specific intracellular antigens (as peptides bound toproteins encoded by the major histocompatibility complex, MHC)

Cellular therapy, tumour infiltrating lymphocyte

Adoptive cellular transfer of tumour resident T cells from tumor material, their expansion ex vivo and transfer
back into the same patient after a lymphodepleting preparative regimen

Lytic virus

Therapies with a replication-competent virus, that lyse pathogenic cells directly. These are normally geneticallymodified to render them harmless to normal tissues. Examples include oncolytic viruses which specificallyattack cancer cells

and definitions used in this report is referring to the method the data is pulled, organized, and presented.
57 terms/ Q1 2023*The keyGlossary of Key Terms*
Therapy Type Definitions, cont.
Cell therapy includes the following therapeutic classes:

Cellular therapy, stem cell

Regenerative therapy that promotes the repair response of injured tissue using stem cells (cells from which allother specialized cells would originate).

Cellular therapy, tumor infiltrating lymphocyte

Adoptive cellular transfer of tumor resident T cells from tumor material, their expansion ex vivo, and transfer
back into the same patient after a lymphodepleting preparative regimen.

Cellular therapy, other

Cellular therapies that do not fall under the categories of cellular therapy, stem cell; cellular therapy, CAR;
cellular therapy, TIL; cellular therapy, TCR; or the specific cellular therapy are unspecified.

58 terms/ Q1 2023*The key
and definitions used in this report is referring to the method the data is pulled, organized, and presented.

Glossary of Key Terms*
Development status definitions
Pipeline

Drugs that are in active development

PreclinicalNot yet tested in humans

Phase I

Early trials, usually in volunteers, safety, PK, PD

Phase IIFirst efficacy trials in small numbers of patients

Phase III

Large-scale trials for registrational data

Pre-registration

Filing for approval made to regulatory authorities

Approved

Approval from relevant regulatory authorities forhuman use

Unspecified indications
Cancer, unspecified

Indications for which the specific tumor type is not
specifiedCancer, hematological,
unspecified

Indications for which the specific hematologicalcancer is not specified

Cancer, solid,
unspecified

Indications for which the specific solid tumor is not
specified

59 terms/ Q1 2023*The key
and definitions used in this report is referring to the method the data is pulled, organized, and presented.