Hemophilia – the challenge for GeneTherapy

Hemophilia – the Challenge for GeneTherapy
Hemophilia
The Challenge for Gene Therapy
MEMBER OF THE STEERING COMMITTEE
FOR THE UNIQURE AMT-060 TRIAL:
> Dr. Wolfgang Miesbach
Hemophilia Center
Clinic of the Johann Wolfgang Goethe University
Frankfurt, Germany
2
Frankfurt Hemophilia Center
Background
> One of the largest hemophilia treatment centers
in Germany
> Treatment of patients with hemophilia, von
Willebrand disease and other defects since
1970’s
> Treatment of patients with thrombophilia or
patients with ITP or TTP
> Comprehensive care center (24 h care)
> Extensive experience with surgical procedures
in hemophilia patients
3
Hemophilia A and B
FEATURES
HEMOPHILIA A
HEMOPHILIA B
PREVALENCE
1 : 5,000 males
1: 30,000 males
COMMON CLINICAL SYMPTOMS
Haemarthroses, muscle haematoma
Haemarthroses, muscle haematoma
BLEEDING FREQUENCY/YEAR
12 – 30
12 – 30 (?)
FVIII/FIX HALF-LIFE (H)
12
18
CLONING FACTOR GENE
1984
1982
MOLECULAR MASS
PRIMARY STRUCTURE
265 kDa
2332 amino acids
68 kDa
265 amino acids
MOST FREQUENT GENE DEFECT
Intron 22 inversion
Missense mutation
INHIBITOR INCIDENCE (%)
25 – 30
3–5
4
Severe Hemophilia
Spontaneous Bleeds, Joint Damage, Compliance
MAIN MANIFESTATIONS
> Joint bleeds
> Chronic arthropathy
> Disability
SIGNIFICANT MEDICAL NEED
> Frequent infusions of FIX / FVIII
> Infusions are painful, require venous access
> Prophylaxis is available only in countries that
can afford it
> Compliance
> In-spite of current best standard of care patients
still have bleeds
5
Current Treatment Approach
COAGULATION FACTOR LEVELS
SEVERITY OF DISEASE
BLEEDING SYMPTOMS
FVIII/IX < 1 %
Severe
Spontaneous
FVIII/IX < 5 %
Moderate
Spontaneous and after trauma
FVIII/IX > 5 %
Mild
After trauma or surgery
CURRENT REPLACEMENT REGIMEN
RISK OF BLEEDING INCREASES AT < 1%
Collins, 2009
6
Non-adherence in Hemophilia
Zappa S et al. Haemophilia 2012 May; 18(3):e140–153
7
Frequency of Discontinuation & Restarting of Prophylaxis
In Adults with Severe Hemophilia
COUNTRY
PATIENTS DISCONTINUING
PROPHYLAXIS (%)
PATIENTS RESTARTING
PROPHYLAXIS (%)
USA
27/76 (36)
9/23 (39)
EUROPE
92/218 (42)
26/92 (28)
THE NETHERLANDS
18/58 (31)
0
DENMARK
10/22 (42)
n.a.
SWEDEN
3/42 (7)
n.a.
8
Decrease the Burden of Treatment
> Dosing interval
> Long-acting therapies
> Route of administration
> Subcutaneous, intravenous etc.
> Immunogenicity
> Inhibitor development
> Safety profile
> Portability, devices, cost
> Optimize individual treatment
9
Hemophilia
Ideal Target for Gene Therapy
> Molecular level well understood
> Patients and treaters can be readily identified in specialist centers
> Animal model exists
> Single gene carried by various vectors
> Correction of deficiency > 2% offers prospects of reducing bleeding tendency
> Factor level in blood can be monitored easily
10
REPLACEMENT
THERAPY
Factor IX
Hemophilia Gene Versus Replacement Therapy
5%
Factor IX
GENE THERAPY
No spontaneous intermittent bleedings
5%
11
AAV8/FIX
Single Intervention Reduces Need for Prophylactic Treatment(1)
SUSTAINED, DOSE DEPENDENT EFFECT OVER > 4 YEARS AFTER A SINGLE INTERVENTION:
> 4/6 high dose patients did not require further FIX treatment; 4/7 on prophylaxis could stop prophylaxis
% Expression
of normal
12
11
10
9
8
7
6
5
4
3
2
1
Low-dose
Mid-dose
High-dose
Presented in New England Journal of Medicine 12/2011
Disease
Severity
Oral Presentation
Mild
Moderate
Patient 1
2
3
4
5
6
7
(1)
8
9
Patient 10
Severe
Third party trial conducted by St. Jude’s Children Research Hospital and UC London
12
AAV8/FIX Long-term Follow-up
KEY POINTS:
> 92% reduction of factor IX concentrate units used
> Median annual bleeding episodes dropped from 15.5 to 1.5 (90%)
Nathwani AC NEJM 2014; 371:1994
13
Inhibitor Formation in Hemophilia B
> Inhibitors occur in 2-5% of patients with severe Hemophilia B on prophylactic therapy
> Hepatic adeno‐associated viral (AAV) gene transfer in non-clinical studies may induce FIX‐specific immune tolerance
(Cao et al, 2007; Dobrzynski et al, 2006; Mingozzi et al, 2003)
> Clinical trials with liver directed AAV gene therapy support that FIX specific immune tolerance can be achieved
> Whether pre-existing inhibitor can be reversed with AAV gene therapy remains to be determined
14
Clinical Trial with AAV5-FIX
15
Target Product Profile
AAV5-FIX for the Treatment of Hemophilia B
TARGET INDICATION:
> Prevention of bleeding episodes (and to reduce the need for Factor IX replacement therapy) in patients with
hemophilia B, plasma FIX activity <2% and with a history of frequent bleeding episodes requiring treatment with
exogenous FIX or continuous FIX prophylaxis
TARGET EXPRESSION LEVEL: <5%
> Supported by non-clinical data:
> NHP data support starting dose expression level close to 5%
> Linear dose-response in NHP supports doubling potential of circulating FIX
TARGET CLINICAL BENEFIT: 90% REDUCTION IN CONSUMPTION AND BLEEDING RATE
> Supported by long-term follow-up data from Nathwani published in 2014
16
Target Product Profile
AAV5-FIX for the Treatment of Hemophilia B
TARGET SAFETY PROFILE
> Absence of organ toxicity and no need for immune suppression rescue treatment
> Supported by AAV5 safety data obtained at similar dose levels in AIP patients
> Immune tolerance of endogenous expressed FIX protein without inhibitor response against FIX
> Supported by non-clinical and clinical data suggesting immune tolerance can be achieved with gene therapy
> Favorable long-term safety profile
> Supported by long-term follow-up with UCL FIX gene cassette by Nathwani
> Risk of carcinogenicity negligible
> Established for AAV with Glybera
17
Objectives
18
AAV5/FIX Phase I/II Dose Escalation Study
Protocol Based on Cross Referencing
POPULATION
AAV8 mammalian
AAV5 insect cell
> 10 patients (severe bleeding phenotype)
> Severe (< 1% FIX) on prophylactic therapy
> Moderate (≤ 2% FIX) on-demand therapy
High
Dose (gc/kg)
(2.0 × 1013)
uniQure
uniQure
Mid
(2.0 ×
1012)
ST Jude
CROSS REFERENCING
ST Jude
Low
(2.0 × 1011)
ST Jude
>St. Jude FIX safety
data
>Porphyria AAV5
safety data
OBJECTIVES
> Assess safety/tolerability
> Define FIX expression level
KEY EFFICACY ASSESSMENTS
> Factor IX activity
> FIX product consumption
> Annual bleeding rate
> Health related quality of life
TIMELINES
> Study begin Q1/15
> Study results Q4/15, interim Q2 / Q3
19
Other Relevant Design Details
Intra-cohort Staggering
20
Inter-cohort Staggering Allows for Fast Trial Execution
21
Development Timelines Hemophilia B
PRELIMINARY RESULTS
Phase 1/2
INITIATE
Phase 3
MID 2015
2016/17
1Q2015
MID 2016
START DOSING
Phase 1/2
CLINICAL TRIAL REPORT
Phase 1/2
22
Future Competitive Environment
Product Pipeline
Preclinical
Other
Phase 1
FIX-CTP; OPKO Health
rFIX
ALN-AT3SC; Alnylam
Phase 2
CB 2679d, Catalyst, ISU Abxis
IXinity; Emergent
N9-GP; Novo Nordisk
Concizumab; Novo Nordisk
Phase 3
Pre-reg
CSL 654; CSL
BAX 817; Baxter
BAX 335; Baxter
LR769; rEVO, LFB
AMT 060; uniQure
Bypassing agents
Gene therapy
AAV8-hFIX19; Spark
PF-05280602, Catalyst, Pfizer
AAV10FIX; Dimension
CSL 689 CSL
FIX gene editing; Shire
23
Global Perspectives of Gene Therapy
Level of Prophylactic Treatment Varies with Country Economy and Health Care System
% HAEMOPHILIA INDIVIDUALS ON PROPHYLAXIS < 18 YEARS
100
% HAEMOPHILIA INDIVIDUALS ON PROPHYLAXIS > 18 YEARS
Germany >95%
Germany 50%
US 40%
US 15%
Countries
Countries
Source: WFH presentation by Mark Brooker, Prague, October 2012
24
Summary of uniQure’s Hemophilia B program
All Elements in Place to Advance Rapidly into Pivotal
> Full freedom to operate
> 2 year AAV5 safety data from Porphyria trial
> 4.5 year FIX cassette safety and efficacy data from St Jude trial
GENE CASSETTE
> Industrial grade/scale manufacturing
FIX Cassette excl.
license from St. Jude
VECTOR
MANUFACTURING
AAV5
excl. license
from NIH
Safe,
robust,
scalable,
proprietary
25
Summary
Gene Therapy for Hemophilia
> AAV based liver directed gene therapy can secure long term expression of FIX at therapeutically relevant levels
(NEJM 2011)
> > 90% Reduction in bleeding risk and consumption can be achieved (NEJM 2014)
> Hemophilia patients are increasingly aware of the potential life changing benefits of gene therapy
26
Harald Petry, Ph.D.
Hemophilia A
> Hemophilia A is a genetic, recessive disorder caused by production of dysfunctional or insufficient amount
of factor VIII (FVIII) protein, a key protein involved in the blood coagulation cascade
> Patients suffer from spontaneous bleeding in the large joints and soft tissue and are at risk for intracranial
hemorrhage. Recurrent episodes of joint bleeding can lead to crippling arthropathy, particularly in severely
affected patients
> The majority of hemophilia cases are inherited X-linked recessive trait and therefore most frequently affects
males. However cases due to spontaneous mutations also arise (up to 30%)
> Hemophilia comprises the majority of hemophilia patients (80%), with incidence of ~1:10,000 to 1:50,000
males affecting 400,000 people worldwide
28
Packaging of FVIII Gene and Cellular Processing
How Packaging of a Too-large FVIII Gene was Expected to Work
5.7 kb
pAAV-HLP-coFVIII-N6
HLP-coFVIII-N6
sPA
HLP
A1
A2
B / N6
A3
C1
C2
OVERSIZED rAAV
Annealing of plus
and minus genomes
Transcription of the transgene
 protein expression
Reassembly of the
intact gene cassette
during concatemer
formation
29
Packaging of FVIII Gene and Cellular Processing
How packaging of a Too-large FVIII Gene Actually Worked
µg AAV DNA
+
PACKAGED DNA
5’
_
3’
5’
3’
5
4
3
rAAV vector ˃ 5 kb
EXPECTED CONCATAMERIC
STRUCTURES
dsDNA-concatamers
AAV2/5-FVIII
4e13
AAV5-FVIII
1,2e14
pVD
S/X
concatemers
concatemers
HH
HT
M
full length mRNA
Active protein
30
Achievements in 2014, Plans for 2015
On the Way to Phase I
> A partially deleted B-domain FVIII variant has been shown to increase secretion of FVIII as compared to
wild type or to FVIII with complete B-domain deletion
> A rAAV5-based FVIII including this partial deletion has been generated in house and Proof of Concept has
been demonstrated (i.e. production of active FVIII protein in vitro and in vivo)
> Plans for 2015
> Screening of five proprietary FVIII constructs ongoing, first mouse results expected in December 2014
> NHP studies with ‘own’ FVIII: pilot experiment planned to start in January in parallel generation of an antibody to
discriminate between human and monkey FVIII
> Generation of smaller expression cassettes to increase quality of the product.
HEMOPHILIA A
31
04
Gene Therapy for Acquired
Diseases: Congestive Heart
Failure
Patrick Most, M.D.
32