Study of Intra-articular Delivery of tgAAC94 in Inflammatory Arthritis Subjects
Condition: Arthritis, Rheumatoid; Arthritis, Psoriatic; Ankylosing Spondylitis
MeSH terms: Spondylitis; Arthritis; Spondylitis, Ankylosing; Arthritis, Rheumatoid; Arthritis, Psoriatic
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The 13G01 clinical trial is a Phase I/II dose escalation study designed to be conducted in
      adults with inflammatory arthritis who have persistent moderate or severe swelling in one or
      more joints, without a disease severe enough to warrant a change in regimen for the next
      three months.

      The study will permit subjects who are concurrently on anti-tumor necrosis factor (TNF)-alpha
      antagonists. For subjects on disease modifying antirheumatic drugs (DMARDs), a stable regimen
      for inflammatory arthritis for the previous three months, with no changes in doses in the
      four weeks prior to screening will be required.

      The primary objectives are:

        1. to evaluate the safety of intra-articular administration of tgAAC94 in subjects
           currently taking TNF-alpha antagonists, and

        2. to evaluate the safety of repeat intra-articular administration of tgAAC94 (gene therapy
           vector).
    

Detailed description: 
      tgAAC94 is a recombinant adeno-associated virus serotype 2 (AAV2) vector genetically
      engineered to contain the cDNA for a human tumor necrosis factor receptor
      (TNFR)-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene. The DNA sequence of TNFR:Fc in tgAAC94
      codes for a protein sequence identical to etanercept (Enbrel®). TNF-alpha has been strongly
      implicated as a major participant in the inflammatory cascade that leads to joint damage and
      destruction in diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and
      ankylosing spondylitis (AS).

      Intra-articular delivery of the TNFR:Fc gene (tgAAC94) should result in expression of the
      secreted protein in the joint space and provide local high concentrations of soluble TNFR:Fc
      for an extended period of time without requiring frequent administration. Thus, this proposed
      therapy would be useful in those inflammatory arthritis patients who have a persistently
      problematic joint despite the use of systemic TNF-alpha blockade or who have a limited number
      of arthritic joints.

      Extensive preclinical studies using rAAV2 containing several different transgenes in a
      variety of animal models have shown efficient and persistent gene transfer and expression
      with minimal toxicity. The parent virus (wild-type AAV2) is a naturally occurring,
      non-replicating virus that depends on a helper virus, such as adenovirus, for replication.
      The recombinant AAV2 vector is unable to replicate in target host cells because it lacks the
      AAV genes, whose protein products are also required in trans, for replication and packaging
      of progeny virus. Extensive epidemiological studies have found AAV2 to be non-pathogenic.

      Although there is no cure for arthritis, treatment has been revolutionized by the advent of
      anti-TNF-alpha therapies. These include etanercept (Enbrel®), infliximab (Remicade®) and
      adalimumab (Humira®), which consist of soluble TNF receptors, chimeric human-mouse
      anti-TNF-alpha monoclonal antibodies and fully human anti-TNF-alpha monoclonal antibodies,
      respectively. Clinical studies have shown these products to improve the signs and symptoms,
      inhibit the structural damage, and impact functional outcomes in patients with these
      inflammatory arthritides.
    

Intervention name(s): tgAAC94 gene therapy vector; tgAAC94 gene therapy vector; tgAAC94 placebo; tgAAC94 gene therapy vector; tgAAC94 gene therapy vector; tgAAC94 gene therapy vector; tgAAC94 gene therapy vector
Intervention type(s): Genetic; Genetic; Genetic; Genetic; Genetic; Genetic; Genetic
Intervention description(s): Single Dose 1x10^11 DRP/mL; Second dose of 1x10^11 DRP/mL tgAAC94 administered once target joint reaches predetermined criteria for re-injection (on or after Week 12) at the same concentration as initial dose.; placebo; Single Dose 1x10^12 DRP/mL tgAAC94; Second dose of 1x10^12 DRP/mL tgAAC94 administered once target joint reaches predetermined criteria for re-injection (on or after Week 12) at the same concentration as initial dose.; Single Dose 1x10^13 DRP/mL tgAAC94; Second dose of 1x10^13 DRP/mL tgAAC94 administered once target joint reaches predetermined criteria for re-injection (on or after Week 12) at the same concentration as initial dose.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: tgAAC94; Rheumatoid arthritis; Inflammatory arthritis; Arthritis; Gene therapy; AAV