INFLAMMATORY ARTHRITIS

tgAAC94 Development Status
Anti-TNF-α therapies are now widely used in the treatment of inflammatory arthritis.  However, there are a number of patients being treated with systemic anti-TNF-α therapies who do not fully respond and still have residual disease in one or several affected joints.  Currently we are conducting clinical trials with tgAAC94 in this patient population, in order to asses the clinical benefit that tgAAC94 may provide to patients who are on concurrent systemic anti-TNF protein therapies, but continue to suffer from inflammatory arthritis in certain joints.  We believe that local administration of a TNF- α antagonist has significant clinical and commercial potential in the treatment of inflammatory arthritis.

Strong Efficacy Data in Animal Models of RA Support Development of tgAAC94
Targeted Genetics has conducted multiple preclinical studies to assess the safety and potential efficacy of tgAAC94.  In a rat model of arthritis, direct injection of AAV vectors containing the TNFR:Fc (rat) gene into an arthritic joint improved a number of disease parameters, including:

• Reduction in severity of arthritis
• Reduction of circulating levels of TNF-a
• Suppression of cartilage and bone damage
• Reduction in the level of other proinflammatory cytokines within the treated joint
• Suppression of inflammation in treated joint, as well as in other non-injected joints of same animal
• No drug-related safety concerns were noted in either normal animals or animals with arthritic joints at all time points evaluated following a single or multiple injection of AAV-ratTNFR:Fc into the joint.  

Phase I Clinical Trials Demonstrate Safety of tgAAC94
In 2005, Targeted Genetics reported preliminary results from its Phase I clinical trial of tgAAC94 in subjects with inflammatory arthritis.  The primary objective of this study was to evaluate the safety of intra-articular injection of tgAAC94 in subjects not on concomitant systemic TNF-α antagonist therapy.  This Phase I trial has been completed.  Eleven of the fifteen subjects enrolled in the trial were randomized to receive either one of two escalating dose levels of tgAAC94, while the other four received a placebo.  The trial contained a placebo arm primarily to assess whether any adverse events were attributable to an intra-articular injection itself, as opposed to an intra-articular injection of tgAAC94.  The conclusions from analysis of results through 24 weeks after injection are:

• tgAAC94 was well-tolerated at doses up to 1x1011 DRP per mL of joint volume 
• No drug-related serious adverse events reported to date  
• Although the study was not powered to show efficacy, subjects treated with a single dose of tgAAC94, showed continued improvement in signs and symptoms in treated subjects (n=11)
• Dose-response correlation suggested by a greater reduction in mean scores at the higher dose
• Some improvement noted in mean tenderness and swelling scores in subjects receiving placebo 

Ongoing Clinical Development of tgAAC94
In October 2005, Targeted Genetics initiated a follow-on Phase I clinical trial in subjects with inflammatory arthritis, which was subsequently modified in March 2006 and re-designated from Phase I to Phase I/II.  The trial design was amended in order to enhance the understanding of the safety and therapeutic index of tgAAC94.  This double-blinded, placebo-controlled study was increased to enroll up to 120 subjects and to evaluate tgAAC94 at three dose levels in subjects with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis, and expanded to include those who may be receiving concomitant treatments of anti-TNF-α therapy, but continue to experience inflammation in one or more joints. 

In the first segment of this double-blind, placebo-controlled study, subjects will receive a single intra-articular injection of tgAAC94 or placebo in the affected joint and be monitored until swelling in the target joint reaches pre-determined criteria for re-injection.  At that time, those who were injected with tgAAC94 as well as those subjects initially injected with placebo will receive an injection of tgAAC94 in the affected joint as part of the open-label segment of the study.  The primary endpoint of the study is to establish the safety of higher doses and of repeat administration of tgAAC94 into the joints of subjects with and without concomitant TNF-α inhibitor therapy.  Secondary endpoints include evaluation of:

• Pain and Swelling
• Duration of response
• Overall disease activity following intra-articular administration of tgAAC94 into affected joints
• Both patient and functional assessment of target joint
• Joint inflammation and damage as assessed by Magnetic Resonance Imaging (MRI).