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Safety, Tolerability, and Clinical Outcomes after
Intraarticular Injection of a Recombinant
Adeno-associated Vector Containing a TNF Antagonist Gene: Results of a
Phase 1/2 Study
The Journal of Rheumatology 2010; 37:4; Mease etal
Introduction
• Gene Tranfer through Vector• Recombinant Adeno Associated
Virus• Concept of Local TNF Antagonism• http://www.maxanim.com/genetics/c
DNA/cDNA.htm
Viral Vectors
Adeno Associated Virus Vector
• Small virus which infects humans and some other primate species
• AAV is not currently known to cause disease and consequently the virus causes a very mild immune response
• AAV can infect both dividing and non-dividing cells and may incorporate its genome into that of the host cell
• These features make AAV a very attractive candidate for creating viral vectors for gene therapy
Adv Biochem Eng Biotechnol. 2005;99:119-45
Past: Phase 1 Study
• Safety and tolerability of rAAV2-TNFR:Fc at doses up to 1 × 1011 DRP/ml
• 15 patients with inflammatory arthritis not receiving systemic TNF antagonist
Current study: Phase 1&2 study
• Repeat injections of higher doses in subjects being treated with or without systemic TNF antagonism
• 1 × 1011 DRP/ml, 1 × 1012 DRP/ml, 1 × 1013 DRP/ml
• Assess safety and tolerability• Clinical efficacy• 21 rheumatology practices in US
Materials and Methods
• Entry criteria >18yrs Diagnosis of RA, PsA & AS Persistent peripheral arthritis at least 1
joint Moderate (grade 2)/Severe (grade 3) Failure or inadequate response to 1
DMARD or biologic Have to continue same regimen through
the trial
Study Design
• Two phases • Phase 1 dose escalation enrolment• Phase 2 expansion simultaneous enrolment• Two injections administered to each patient • First injection , Double Blind, Placebo
controlled • Randomized in 3:1 • Second injection • open label , same dose, on or after 12-30
weeks of first injection
Study population
• 6 cohorts of 20 patients• Divided equally Phase 1 and 2• Phase 1: 3 cohorts for escalating
doses• Phase 2: 3 cohorts for simultaneous,
3 concentrations
Study Agent and Volume
• rAAV2-TNFR:FC• Recombinant adeno associated virus,
genotype 2• Genetically engineered complementary
DNA of fusion gene of etanercept• Extracellular domain TNF receptor
combined with Fc portion of immunoglobulin IgG1
• Knee 5ml, ankle 2ml, elbow 1.5,wrist 1ml, MCP 0.5ml
• Placebo: isotonic buffered solution
Study Procedure
• First injection: Evaluation prior to injection and post injection at or until second injections on 0.5 , 1 , 4 , 8, 12 , 18, 24 , 30 weeks
• Second injection: same as for first• Criteria of second injection: degree
of swelling similar or worse then at baseline on or after 12 weeks until 30 week
Study Procedure
o Gene Transfer or Biodistributiono Monitoring of Fusion genome or DNA in
blood, synovial fluid and local and systemic tissue
o Monitoring of TNF fusion protein in serum, synovial fluid
o Monitoring of TNF antagonism or TNF binding activity
o Immune response to AAV2 capsido Clinical outcome, local and systemic effects
Gene and Protein analysis
• Gene Transfer : PCR for fusion DNA Subjects with 1 × 1012 DRP/ml, 1 × 1013 DRP/ml Blood: Pre and post 1 , 4 , 8 , 12 weeks Synovial: Pre and post 4, 12 weeks , also
unscheduled
Protein Expression : quantitative radioimmunoassay Standardized drug curves for patients on
etanercept, adalimumab and infliximab Pt not on antiTNF, lower limit of detection
was 0.012ug/ml
Immune response
• Humoral immune response: neutralizing antibody titer (NT) against AAV2 prior & 4 , 12 , 24 , 30 week
• Cellular immune response: ELISASPOT assay detects IFN-g release and number of T cells stimulated by synthetic AAV2 peptide
Clinical Outcome
Local Joint assessment• Tenderness and swelling ; Grade 0-3• Parameters for clinically relevant
response based on VAS >30% global improvement in target
joint >30% improvement in function Proportion of patients with 2 point
decrease in pain
Patient Based Outcomes
• Patient Based evaluation in phase 2: • VAS 10cm: Global symptoms,
function, satisfaction with response to study drug
• Functional Assessment of target joint
• Disability of arm, shoulder and hand scale• Modification of RA outcome score
Clinical Outcome
• Systemic Efficacy Measures– Tender and swollen joint counts– Patient VAS pain score– Physician global VAS– Patient global VAS– ESR, CRP– HAQ, BASDAi, ACR 20, DAS scores
Results
o Enrolmento Safety and Protocol amendmento Adverse effectso Clinical Efficacyo Local Gene Transfero Protein Expressiono Immune response to AAV2 capsid
Enrolment and Disposition
• 147 screened, 127 subjects selected and randomized
• 61 in Phase 1 dose escalation: 3 cohorts
• 62 in phase 2 expansion: 3 cohorts• Randomized equally and 1:3 ration for
study drug versus placebo• July 2007, 74/127 had received
second injection
Safety and Protocol amendment
- Hold on study • A case of disseminated histoplasmosis after
18 weeks of open label second injection • Dose of 5 × 1012 DRP/ml ( NOT 1 × 1012
DRP/ml) in 36 years female with RA on concomitant adalimumab therapy
NEJM publishes investigation of the death
Liver-biopsy -areas of necrosis, with mild inflammatory infiltrate; histoplasma organisms (arrows) can be seen (Panel B, Gomori methenamine silver stain)
A specimen of the right kidney has random foci of necrosis containing histoplasma organisms (arrows) (Panel C, Gomori methenamine silver stain)
Retroperitoneal hematoma
Delay in the study
• Study resumed after protocol amended for rescreening prior to second injection for safety monitoring (details on clear)
• SAE was thought to be unrelated to study
• 21/37 received 2nd injection after 2-7month delay
• 12 withdrew consent
Adverse effects• More in Study group but same for 1st and
2nd injection• 20% higher local site reaction occurring
with in 2 weeks of injection correlated with increased dose
• Local reactions were unrelated to systemic TNF use but linked to higher NT titers
• 3 given systemic steroids• 6 -Serious Infections: (3,2,1 in each dose
group respectively)• 3/6 were on systemic anti TNF therapy
Clinical EfficacyPhase 1 versus Phase 2 @ 12
weeks Clinically relevant decrease in swelling
noticed only in phase 1 study group arm• Phase 1 had 13%-27% compared to none
in placebo• Phase 2 had 12-19% in treatment group
and 19% in placebo
Clinically relevant decrease in tenderness• No difference in either arm of both phases
Phase 1: 12 weeks post 1st injection
Physical Examination
Phase 2 : 12 weeks post 1st injection
Physical Examination
Clinical Outcome after 1st injBoth Phases
Phase 2 patient reported outcomes
12 week of 1st injection• Pertaining to Target Joint• >30% improvement in target joint
global VAS : 42% versus 19% (p=0.14)• >30% improvement in target joint
function VAS : 32% versus 19% (p=0.36)
• 2 point decrease in joint pain : 12% versus 6% (p=0.67)
Phase 2 12 week patient reported
outcomes
Systemic outcomes12 weeks after 1st injection
• Modest improvement in systemic measures of inflammatory arthritis in both phases
• All treatment group irrespective of the dose and systemic anti TNF therapy had modest improvement in their
Systemic outcomes12 weeks after 1st injection
Clinical outcomes after 2nd inj
Immune response to AAV2 Capsid
Local gene transfer and expression
Serious Adverse effects
Adverse Events
Discussion
• Pros– New concept of treatment– Large number of patients– Attempt to address efficacy– Alternative to systemic therapy– No proven systemic TNF antagonism– Less although immunogenic
Discussion
• Cons– Expensive– Single stranded DNA– Mild clinical efficacy– Local tissue invasion– Local reactions