Role of Intra articuar TNF
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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
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Introduction
• Gene Tranfer through Vector• Recombinant Adeno Associated
Virus• Concept of Local TNF Antagonism• http://www.maxanim.com/genetics/c
DNA/cDNA.htm
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Viral Vectors
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Results
o Enrolmento Safety and Protocol amendmento Adverse effectso Clinical Efficacyo Local Gene Transfero Protein Expressiono Immune response to AAV2 capsid
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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
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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
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NEJM publishes investigation of the death
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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)
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Retroperitoneal hematoma
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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
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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
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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
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Phase 1: 12 weeks post 1st injection
Physical Examination
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Phase 2 : 12 weeks post 1st injection
Physical Examination
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Clinical Outcome after 1st injBoth Phases
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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)
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Phase 2 12 week patient reported
outcomes
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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
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Systemic outcomes12 weeks after 1st injection
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Clinical outcomes after 2nd inj
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Immune response to AAV2 Capsid
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Local gene transfer and expression
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Serious Adverse effects
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Adverse Events
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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
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Discussion
• Cons– Expensive– Single stranded DNA– Mild clinical efficacy– Local tissue invasion– Local reactions