Gene / Advanced therapies on the market

Gene/ Advanced Therapies on the market
EURORDIS Winter School 2018
Diego Ardigó, MD PhD
R&D Project Leader Chiesi Farmaceutici S.p.A.
Thearpeutic Scientific Committee Chair International Rare Disease Consortium (IRDiRC)

Content
 What is an ATMP
 Evolution of the pharmaceutical legislation
 What does it mean that ATMPs are pharma products
• Manufacturing and control
• Development
 Overview of approved ATMPs in Europe
 The Future of the field
| Advanced Therapies (ATMP) | EURORDIS Winter School | Diego Ardigó | Paris, 22 March 2018 |2

ATMPs: Advanced Therapy Medicinal Products
Cell-based
therapies
Tissue engineered
products
Gene therapies
• Anatomical and
functional replacement
of tissue
• Stable cell
transfection and
translation of a protein
• Effect of the protein
• Paracrine factors
production
• Cell-cell interaction
• Differentiation

| Advanced Therapies (ATMP) | EURORDIS Winter School | Diego Ardigó | Paris, 22 March 2018 |
Can cells be pharmaceutical products?
=
Donor
Stem cell
isolation
(Purification)
Preservation Administration
In-vitro
growth
(Genetical
modification)
Stem cell
isolation
Minimally
manipulated cells
Extensively
manipulated cells
4

As for all medicinal products, it must be demonstrated that a TEP is consistently
manufactured to a predefined quality and is safe and efficacious.
[from “Reflection paper on clinical aspects related to tissue engineered
products”; EMA/CAT, 19 March 2012]
Contain cells or tissues that have been modified so
they can be used to repair, regenerate or replace
tissue
A tissue engineered product may contain cells or
tissues of human or animal origin, or both.
It may also contain additional substances, such as
cellular products, bio-molecules, biomaterials,
chemical substances, scaffolds or matrices
[combined ATMP].
Tissue Engineered Products: what are they?

Gene therapy: definition
Long-term transfection of a
gene construct in host
(patient) cells to induce the
translation of a specific
protein.
Aim of a gene therapy product
• Replacing the function of a
defective gene
• Use the host cells as « protein
machinery»
Local or
systemic
administration
Infection
Integrated
gene
«Free» gene
Protein
synthesis
Gene
+
Vector
Target Cell

Types of gene therapy

Clinical risks of ATMPs
 Tissue traficking
 Immunogenic response (vs cells)
[affects both safety and efficacy]
 Unwanted tissue proliferation
 Tumor formation
Molecule
Systemic
compartment
Tissues
PD effect
Secondary PD
Unexpected
effects
Metabolism ExcretionAbsorption
Distribution
Cell
Systemic
compartment
Target tissue
Death
Differentiation
Proliferation
Biodistribution,
Migration
Cell
Virus
Systemic
compartment
Target tissue
Infection
Virus
Biodistribution,
Shedding
Protein
expression
Protein
PK-PD
DNA integration
 PD effects and dose-response paradigm
 Type B adverse reactions
 Drug-interactions
 Carcinogenicity
 Teratogenicity and reprotox issues
 Immunogenic response (vs virus or protein)
[affects both safety and efficacy]
 Tumorigenicity (by DNA disruption)
 Germline transmission
SmallMoleculeCellTherapyGeneTherapy

2001
Introducing
definitions of
ATMP
Dir 2001/83/EC
2003
Introducing
requirements of
ATMP
Dir 2003/33/EC
2008
Introducing CAT,
TEP
Reg 1394/2007
2009
the CAT starts
First ATMP approved in the EU
Introducing Risk based approach
Dir 2009/160/EC
2012
Glybera
First gene therapy
approved in the EU
2014
Holoclar
First stem cell therapy
approved in the EU
1997
A Proposed Approach to the
Regulation of Cellular and Tissue-
Based Products," (62 FR 9721)
1998
Guidance for
Industry: Guidance
for Human Somatic
Cell Therapy and
Gene Therapy
Evolution of the ATMP regulation

European Regulation for Advanced Therapies
Celis P. First EMA Workshop
on ATMP - 3 April 2009,
modified
CAT “Reflection paper on
classification of ATMPs”
EMA/CAT/600280/2010

Regulatory landscape for cell and gene therapy in US
CBER: Center for Biologics Evaluation and Research

Manufacturing steps of a CBMP or ex-vivo GT
Cell isolation
• Starting material: donated cellular material from donor(s)
• Donation, procurement, testing and traceability procedures
• Risk of disease transmission, prions
In-vitro
expansion
• Raw materials (xenogenic? prions?)
• Banking system and stability
• No/ limited downstream processing
(Transfection)
• Seeding cell line is a starting material (full characterization)
Formulation
• Definition of DS and DP
• Formulation/ devices
• Shipment conditions
• Shelf-life / stability / in-use stability
12

Small
molecules
Biologics
[by extraction]
Biologics
[by fermentation]
In-vivo
GT
CBMP
Ex-vivo GT
TEP
Molecular dimensions
Complexity
Active
substance
Viable cells after
manipulation with
or without other
starting materials
CBMP: Cell-Based Medicinal Product; GT: Gene Therapy; TEP: Tissue-Engineered Product
Complete
product
characterizatio
n
Partial product
characterization
(primary structure and post-
transcriptional modifications)
Limited product
characterization
(identity, purity,
potency)
The complexity of advanced therapeutics
13

Could you tell the difference?
?

How to manufacture ATMPs
Ingredients
Cleaning and
cutting
Pre-processing
Cooking
Sauce/
graving/ sides
Presentation
Equipment,
temperature,
lenght
Recipe
Chef
training
Reliable butcher
Color, smell, etc.
Temperature
Touch
Color
Sight
Color
Smell

Control of manufacturing process
GoodManufacturingPractices CRITICAL
PROCESS
PARAMETERS
Ingredients
Cleaning and
cutting
Pre-processing
Cooking
Sauce/
graving/ sides
Presentation
Equipment,
temperature,
lenght
Recipe
Chef
training
Reliable butcher
Color, smell, etc.
Temperature
Touch
Color
Sight
Color
Smell
STARTING/
RAW MATERIAL
IN-PROCESS
CONTROLS
RELEASE
TESTS
CRITICAL QUALITY
ATTRIBUTES
16

Recognised Paradigm for biotechnological products
Product
Process
(and its control)

Biotech product paradigm:
the product equals the manufacturing process
German
filtered lager
Irish stout
• Roughly the same basic
starting ingredients
(barley malt, hop, yeast,
water)
• Roughly “similar”
manufacturing process
=
Completely different
characteristics
Belgian
lambic
witbier
British ale
The oldest and most diversified biotechnology product
18

Where this complexity comes from?
Small
molecules
for mass
market
Orphan
indications
Frequent Rare
Advanced
therapies
Small
molecule
Recombinant
biologic
Advanced
therapy Advanced
therapy for
rare
disease

Small
molecules
for mass
market
Orphan
indications
Frequent Rare
Significant impact on clinical development:
• Proof-of-concept
• Dose-finding
• Proper phase III planning/ derisking
• Understanding and management of clinical risks
20

Small
molecules
for mass
market
Advanced
therapies
Small
molecule
Recombinant
biologic
Advanced
therapy
Significant impact on product
quality:
• Process control
• Robustness/ reproducibility
• Safety risks
Significant impact on pre-clinical
development:
• Proof-of-concept
• PK and tox
21

Development of a drug (small molecule)
• Proof-of-Concept
• PK/ ADME
• Genotoxicity
• Safety
pharmacology
• Acute/ short-term
toxicology
Pre-clinical
package
to support FIH
Two species tox
Phase I Phase II Phase III
Two pivotal trials• Safety & PK in
healthy
volunteers
• Food effect
• DDI and special populations safety/ PK
• Cardiac safety
• Bioequivalence (new formulation)
• Safety & PK in
patients
• PoC
• Dose
selection
• Long-term toxicology
• Carcinogenicity
• Reproductive toxicology
Information
package
• Animal ADME
• Safety and short-
term tox
• NOAEL (MABEL)
Pre-clinical package
to support MA
Post-approval
• PASS / (PAES)
• Registries
• Additional PV
• Phase IV studies
• Pediatric studies
Information package
• Proof-of-efficacy
• Dose-response
• Phase III dose
• Phase III sample size
Information
package
• Pivotal efficacy
• HTA data
• «Large»safety
database
• Data in special
populations and
sub-groups
MA
• Consolidated
• Based on risk
management
and gate
reviews
• Almost linear
progressive
increase in
costs
• Long-term
predictability

Approved ATMPs in EU
Breaking news:
EMA positive opinion Dec 2017
Alofisel® (darvadstrocel)
First allogeneic cell therapy

Drug name Composition Indication
Marketing
authorization
Current
approval status
Chondrocelect ® Autologous chondrocytes
Repair of single symptomatic cartilage defects of the femoral
condyle of the knee
2009
Withdrawn
(Jul 2016)
Glybera ® Alipogene tiparvovec Lipoprotein lipase deficiency 2012
Withdrawn
(Oct 2017)
MACI ® Matrix-applied autologous
chondrocytes
Repair of symptomatic, full-thickness cartilage defects of the
knee
2013
Suspended
(Dec 2014)
Provenge ® Sipuleucel-T
Asymptomatic or minimally symptomatic metastatic castrate
resistant prostate cancer adults in whom chemotherapy is not
yet clinically indicated
2013
Withdrawn
(May 2015)
Holoclar ® Autologous human corneal
epithelial cells
Moderate to severe limbal stem cell deficiency 2015 Authorized
Imlygic ® Talimogene laherparepvec
Regionally or distantly metastatic unresectable melanoma
(Stage IIIB, IIIC and IVM1a)
2015 Authorized
Spherox ® Spheroids, i.e. spherical
aggregates of chondrocytes
Symptomatic articular cartilage defects in femoral condyle and
patella, where size of the affected area is no larger than 10 cm²
2017 Authorized
Strimvelis ® Autologous CD34+ cells
transduced to express ADA
Adenosine deaminase deficiency 2016 Authorized
Zalmoxis ® Allogeneic T cells
genetically modified
add-on treatment in adults who have received a haematopoietic
stem cell transplant from a partially matched donor
2016 Authorized

Approved Cell/Gene Therapy Products in USA
Drug name Composition TherapeuticModality Indication MA Current approval status
Provenge® Sipuleucel-T
Autologous peripheral blood
mononuclear cells activated
with PAP-GM-CSF
Asymptomatic or minimally symptomatic metastatic
castrate resistant (hormone refractory) prostate cancer
2010 Withdrawn
Imlygic®
Talimogene
laherparepvec
Genetically modifiedoncolytic
viral therapy
Regionally or distantly metastatic unresectable
melanoma (Stage IIIB, IIIC and IVM1a)
2015 Authorized
MACI®
Matrix-applied
autologous
chondrocytes
Autologous cultured
chondrocytes on a porcine
collagen membrane
Repair of symptomatic, full-thickness cartilage defects
of the knee
2016 Authorized
Kymriah® Tisagenlecleucel
Anti-CD19 chimeric antigen
receptor (CAR) T-cell
therapy
Refractory B-cell precursor acute lymphoblastic
leukemia (ALL) (patients up to 25 years of age)
2017 Authorized
Luxturna® Voretigene
neparvovec-rzyl
Adeno-associated virus
vector-based gene therapy
Confirmed biallelic RPE65 mutation-associated retinal
dystrophy
2017 Authorized
Yescarta® Axicabtagene
ciloleucel
CD19-directed genetically
modified autologous T cell
immunotherapy
Relapsed or refractory large B-cell lymphoma after two
or more lines of systemic therapy
2017
Authorized
Does not include: minimally manipulated products for non-homologous use

Limbal Stem Cell Deficiency (LSCD) due to
chemical or physical ocular burns
Limbus
CorneaCongiuntiva
Holoclone
(committed stem cell of
the corneal epithelium)
Injury Wound Conjunctivalization

Manufacturing process

Packaging

Logistic challenge
 Customer service (Chiesi)
 Patient’s inclusion in Holosight registry
 Manufacturing capacity/ scheduling (Holostem)
 Segregated manufacturing for infective patients
 Variable manufacturing time based on cell growth
 Surgical room and team planning
 Impossibility to stop batch manufacturing after ICB
thawing
 36 hours of shelf-life
.
• Limited number of treatment centers
• Accurate logistic validation of sites
Key logistic elements

The evolution of ATMPs
CELL
THERAPY
TISSUE
ENGINEERED
PRODUCTS
GENE
THERAPY
CAR-T
Modified CD34
AAV (muscle)
ZFN
TALEN
CRISPR
AAV (liver)
AAV (brain)
In-vivo lenti
Scaffolds
3D matrix
Multiple cell types
Hollow organs
reconstruction
Genetically-modified
Non-homologous use
Allogeneic cells?
iPSCs
Nanotecnologies
RNAi
RNA-therapies
Skin
Cartilage
Cornea
In-vivo
gene
editing
AAV re-administration/
platform
Biosimilars
Digital
Diagnostics
Large scale
Manufacturing 4.0
Delivery systems

The evolution of ATMPs
Ultra-rare
(PoC)
Rare
Common
IMPACT
• Economy of scale for development
• Development of standards
• “Platform” approach
• Increased characterization
• Change in manufacturing approach
& ↓ COG
• Significant issue with budget impact
• Prevalent cases “cured”
• Competition and second-line ATMP
therapy

BACK UP SLIDES

Advanced therapy products approved in Europe

ChondroCelect®
COMPOSITION: Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins
THERAPEUTIC MODALITY: cell therapy
INDICATION: Repair of single symptomatic cartilage defects of the femoral condyle of the knee
MANUFACTURER: Tigenix Biopharmaceutical
Relevant clinical studies:
Main Study: TIG/ACT/01/2000, phase III, multicentric,
randomized, controlled trial
AIM: compare ChondroCelect to the procedure of microfracture in
the repair of sympthomatic single cartilagineous lesions of the
femoral condyles on the knee.
Primary efficacy endpoints:
• superiority in structural repair at 12 months compared to the
control group
• KOOS (Knee Injury and Osteoarthritis Outcome Score) of
ChondroCelect vs Microfracture group
Source: EMA website
WITHDRAWN in 2015 for
commercial reasons.

Glybera®
COMPOSITION: viral vector containing human lipoprotein lipase (LPL) gene variant LPLS447X
THERAPEUTIC MODALITY: gene therapy
INDICATION: familial lipoprotein lipase deficiency (LPLD) adult patients suffering from severe or multiple pancreatitis attacks despite
dietary fat restrictions. LPLD is a rare autosomal recessive lipid disorder caused by a mutation in the gene which codes lipoprotein
lipase (LPL)
MANUFACTURER: UniQure biopharma
Source: EMA website
Trial number Strudy description Relevant results
CT-AMT-010-01
(start date: 2005)
AAV1-LPLS447X was administered to 8 LPLD patients in a
12-week, open label dose escalating study
• No drug-related serious adverse events occurred and no dose-limiting toxicity was
observed.
• In half of the subjects a T-cell response to the vector was seen.
• Compared to pre-administration, a transient and variable reduction in median triglyceride
levels was recorded for all patients.
CT-AMT-011-01
(start date: 2007)
Open label, dose escalating study to assess the safety profile
and reduction of fasting plasma triglyceride (TG) levels after
12 weeks post Glybera administration in 14 LPLD patients.
All patients were controlled on low fat diets in the 12-week
main study period.
• T-cell responses were seen in roughly half of the patients without clinical sequelae.
• From the triglyceride data the 1 x 1012 gc/kg dose appears the most optimal.
CT-AMT-011-02
(start 2009)
Open-label study
Fixed dose of 1x1012 gc/ kg body weight administered by a
single series of intramuscular injections. 5 eligible subjects
were included in the study with all subjects receiving
alipogene tiparvovec.
• One patient was diagnosed with pulmonary embolism 7 weeks after therapy.
• A transient reduction of triglycerides for up to 12 weeks in some individual patients has
been observed. After this time, triglyceride levels reverted back to baseline.
• A demonstrable improvement of postprandial CM metabolism was shown in 5/5 patients
up to week 14 and in 3/3 patients who were followed up to 52 weeks.
CT-AMT-011-03 Combined retrospective and prospective study of subjects
who had taken part in studies CT-AMT-10-01, CT-AMT-11-
01, CT-AMT-11-02.
• In a follow-up period of up to 3 years after treatment, there was a decreasing trend in the
incidence and severity of pancreatitis in the 12 patients who had multiple attacks during
their life time.
WITHDRAWN because
uniQure biopharma did not
apply for a renewal of the
marketing authorisation.

MACI®
COMPOSITION: viable autologous chondrocytes expanded ex vivo expressing chondrocyte-specific marker
genes, seeded onto a CE marked porcine derived Type I/III collagen membrane
THERAPEUTIC MODALITY: cell-based implantation matrix
INDICATION: symptomatic single or multiple full-thickness cartilage defects of the knee, with or without bone involvement, in adults
MANUFACTURER: Genzyme Europe
SUSPENDED in 2014
by the CHMP in
accordance with
Article 118 of Directive
2001/83/EC.
Main Study: MACI00206, prospective, randomized, open-label,
parallel-group, multicentre study
AIM: to demonstrate the superiority of matrix-induced
autologous chondrocyte implantation (MACI implant) versus
arthroscopic microfracture for the treatment of symptomatic
articular cartilage defects of the femoral condyle including the
trochlea.
Primary efficacy endpoints: Among co-primary endpoints:
change from baseline to Week 104 for the patient’s KOOS, pain
and function (Sports and Recreational Activities [SRA]) scores
Source: EMA website

Provenge®
COMPOSITION: autologous active cellular immunotherapy, which consists of autologous peripheral blood mononuclear cells
(PBMCs), including antigen presenting cells (APCs), activated with PAP-GM-CSF
THERAPEUTIC MODALITY: cell therapy for infusion
INDICATION: asymptomatic or minimally symptomatic metastatic (non- visceral) castrate resistant prostate cancer in male adults
in whom chemotherapy is not yet clinically indicated
MANUFACTURER: Dendreon
Main Study: D9902B (IMPACT)
randomised, multicentre, placebo-
controlled, parallel group phase 3 trial
AIM: assess the efficacy of sipuleucel-
T in prolonging survival of subjects with
symptomatic or minimally symptomatic,
metastatic, androgen independent
prostatic adenocarcinoma
Primary efficacy endpoints: Overall
Survival
Source: P T. 2011 Apr; 36(4): 197–202.
WITHDRAWN in 2015 for
commercial reasons.

Holoclar®
COMPOSITION: ex-vivo expanded autologous human
corneal epithelial cells containing stem cells
THERAPEUTIC MODALITY: tissue engineered product
INDICATION: moderate to severe limbal stem cell deficiency
(LSCD), unilateral or bilateral, due to physical or chemical
ocular burns.
A minimum of 1 - 2 mm2 of undamaged limbus is required
for biopsy
MANUFACTURER: Chiesi Farmaceutici S.p.a.
Trial number Strudy description Relevant results
HLSTM01 Pivotal study including 106 patients from 2 centres in Italy
with the diagnosis limbal stem cell deficiency (LSCD) who
underwent at least one Holoclar transplantation during the
time period from 1998 to 2007, with data provided for 113
transplantation events. Study HLSTM01 aimed at
evaluating efficacy and safety of Holoclar treatment
Primary endpoint: Success of transplantation
• Treatment success, starting from year 1 post-transplantation, reached a plateau of 75% until year 5.
• After year 5, only 5 patients had long term follow-up, of which 4 were reported as continued treatment
success.
• Several patients underwent subsequent keratoplasty within the time period of 2 or 3 years after Holoclar
transplantation.
HLSTM02 Supportive study including 29 LSCD patients from 7 Italian
centres with 29 transplantation events.
HLSTM02 evaluated the safety of the product, with
supporting evidence for efficacy
• Success according to the subjective, overall clinical judgment of the investigator, was reported in 19 out
of 29 patients (65.5%) and failure in 6 patients (20.7%). Information was missing in 4 cases (13.8%).
• Analysis of patients with LSCD due to ocular burns only confirmed the results in the overall population.
Source: www.insights.bio
Source: EMA website

Imlygic®
COMPOSITION: attenuated herpes simplex virus type-1 (HSV-1) derived by functional deletion of 2 genes (ICP34.5 and ICP47) and
insertion of coding sequence for human granulocyte macrophage colony-stimulating factor (GM-CSF)
THERAPEUTIC MODALITY: gene therapy
INDICATION: unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a) with no bone, brain, lung or
other visceral disease
MANUFACTURER: Amgen Europe
Main Study: Study 005/05, phase III,
multinational, open-label, and
randomised clinical study
AIM: efficacy and safety of treatment
with Imlygic compared to
subcutaneously-administered GM-CSF
in patients with unresectable stage IIIB,
IIIC and IV melanoma
Primary efficacy endpoint:
durable response rate (DRR)
Source: EMA website

Strimvelis®
COMPOSITION: Autologous CD34+ cells transduced to express adenosine deaminase (ADA)
THERAPEUTIC MODALITY: ex-vivo stem cell gene therapy
INDICATION: severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID)
DISEASE: Adenosine deaminase deficiency (ADA) is an inherited condition that affects the immune system and typically leads to
severe combined immunodeficiency (SCID). It is caused by a mutation in the gene that encodes ADA protein
MANUFACTURER: GlaxoSmithKline Trading Services Limited
Main results:
primary endpoint: both, the pivotal trial population as well as the integrated population show superior survival as well as intervention free survival
compared to SCT and long term PEG-ADA administration.
Source: Aiuti at el., NEJM, 2009;360(5):447-58.

Zalmoxis®
COMPOSITION: allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low
affinity nerve growth factor receptor (ΔLNGFR) and the herpes simplex I virus thymidine kinase (HSV-TK Mut2)
THERAPEUTIC MODALITY: genetically modified cell-based therapy
INDICATION: adjunctive treatment in haploidentical haematopoietic stem cell transplantation (HSCT) of adult patients with high-
risk haematological malignancies
MANUFACTURER: MolMed S.p.a.
Main Study: TK007, multicenter, international,
open-label, non-randomized phase I-II study
AIM: evaluate the safety and activity of MM-
TK cells in patients with haematological
malignancies who underwent allogeneic HSCT
from haploidentical donor
Primary efficacy endpoints: proportion of
patients who achieved immune reconstitution
(IR) (absolute CD3+ cell count of 100/μL or
more for two consecutive observations
Main results:
patients treated
with MM-TK
have a lower
NRM as
compared to the
patients that
were not
treated.
Source: EMA website

Spherox®
COMPOSITION: spheroids of human autologous matrix-associated chondrocytes
THERAPEUTIC MODALITY: cell-based therapy
INDICATION: Symptomatic articular cartilage defects in femoral condyle and patella, where size of the affected area is no larger
than 10 cm²
MANUFACTURER: CO.DON AG
Source: EMA website
Main results:
Mean improvement
(±SE) from baseline to
36 months in overall
KOOS was greater in
the CCI group than the
MF group (21.25 ± 3.60
vs 15.83 ± 3.48,
respectively)

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