A Single Dose Clinical Trial to Study the Safety of ART-I02 in Patients With Rheumatoid Arthritis

Brief Summary

Detailed Description

DMARDs such as methotrexate, sulfasalazine and leflunomide used alone or in combination, are considered to be standard treatment for RA and may be combined with other conventional DMARDs and/or corticosteroids and/or anti-inflammatory or centrally working analgetics (NSAIDS). During the last decade, treatment with biological (e.g. TNF-inhibitors), together with improved timing and dosing of conventional therapy, has significantly improved the outcome in a significant proportion of RA patients. The advent of biologicals and implementation of more intensive treatment protocols has significantly improved the outcome in a significant proportion of RA patients and prevented disabilities. However, drug-free remissions are still rare and hence most RA patients require continued immunosuppressive treatment which predisposes them to potentially serious infections. Also up to 50% of RA patients continue to suffer from symptomatic disease. Intra-articular glucocorticoids are often used in these patients, e.g. when single joints are inflamed. The duration of their effect is however variable. It regularly occurs in clinical practice that reasonable clinical remission in rheumatoid arthritis patients is achieved with current treatment options, but that one or more joints still display persistent signs of inflammation while the inflammation of other joints has been greatly reduced. This means that for the joint(s) still affected by active inflammation other therapies are required. There is a need for additional RA therapies with good tolerability and efficacy profiles that can be used in patients who suffer from a few inflamed joints despite previous treatment. Intra-articular gene therapy could provide a solution by providing local treatment for arthritis, with prolonged expression of a therapeutic protein at the site of inflammation after a single injection. ART-I02 is an investigational new drug, expressing human IFN-β from a recombinant (r) adeno-associated virus type 5 (rAAV5) β under the influence of a promoter, which is induced by an inflammatory stimulus. Due to the relapsing nature of RA, therapeutic expression should be maximal during flare-ups of the disease. This is achieved by employing the NF-kB responsive promotor to regulate expression of IFN-β. Under inflammatory conditions, the NF-kB responsive promoter will be activated in the synovium and will upregulate the expression of hIFN-β and turned down during remission. In this way, transgene expression can be controlled, following the intermittent course of disease. The selection of IFN-Beta as the therapeutic protein is based on the notion that IFN-β has anti-inflammatory, and bone and cartilage protective effects, which have been extensively demonstrated in non-clinical studies. This is a phase I open label, dose escalating study to investigate the safety of a single intra-articular ART-I02 injection in patients with RA and active arthritis of a wrist. In a two-phase staggered dose escalation design, dosing will start with a low dose (2.4x1012 vg/ wrist) and progress to the highest dose of 2.4x1013 vg/wrist. Three patients will be enrolled at each of the two dose levels. The interval between dosing of patients within dose escalation cohorts I and II is at least two weeks to allow for safety evaluation by the investigator. Following dosing of the last patient in cohort I and II, a dosing pause of two weeks is included to allow an assessment of the safety data by the Data Review Committee (DRC). Enrollment in the subsequent cohort will continue only after a thorough assessment of safety and tolerability data (medical history, vital signs, physical examination, laboratory parameters and adverse events) through day 14 post dose; for the first treated patient in each cohort safety data up to a minimum of six weeks, for the second patient up to a minimum of four weeks and for the third patient up to a minimum of two weeks are available at the time of the assessment of the safety data by the DRC. In cohort III nine patients will be administered the highest safety dose of ARTI02 as determined in the previous dose escalating cohorts (cohorts I and II) and following a thorough assessment of all available safety data including a minimum of 2 weeks data post ART-I02 administration from the 3rd patient of cohort II. The interval between dosing of patients within cohort III is at least one week. Cohort III is added to the study to substantiate the safety profile of the highest tolerated dose of ART-I02. The consideration to treat one joint in this clinical study is that it provides the opportunity to examine the administration of a single dose at the site where the promoter is activated and where the therapeutic protein IFN-β is required.

Primary Outcomes

Secondary Outcomes

• Change from baseline for clinical signs and symptoms of the target joint evaluated by the Composite Change Index (CCI)(Baseline, week 1, week 2 , week 4, week 8, week 12, week 16, week 20 and week 24 post administration of ART-I02)
• Change from baseline after single dose of ART-I02 on overall disease activity measured by DAS28, over 24 weeks.(Baseline, week 24 post administration of ART-I02)
• Change from baseline after single dose of ART-I02 on hand function measured by Grip strength measurement in the target and contralateral joint.(Baseline, week 1, week 2 , week 4, week 8, week 12, week 16, week 20 and week 24 post administration of ART-I02)
• Change from baseline after single dose of ART-I02 on synovitis, bone erosion and oedema in the injected joint evaluated by MRI 12 and 24 weeks after administration of ART-I02 using the OMERACT RA MRI scoring sys(Baseline, week 12, week 24 post administration of ART-I02)
• Change from baseline after single dose of ART-I02 on hand function measured by VAS pain in the target and contralateral joint.(Baseline, week 1, week 2 , week 4, week 8, week 12, week 16, week 20 and week 24 post administration of ART-I02)
• Change from baseline after single dose of ART-I02 on hand function measured by VAS function in the target and contralateral joint.(Baseline, week 1, week 2 , week 4, week 8, week 12, week 16, week 20 and week 24 post administration of ART-I02)
• Vector DNA in whole peripheral blood(Up to 24 weeks but maximally until such time that three consecutive samples have been tested negative)
• Vector DNA in urine(Up to 24 weeks but maximally until such time that three consecutive samples have been tested negative)
• Vector DNA in feces(Up to 24 weeks but maximally until such time that three consecutive samples have been tested negative)
• Vector DNA in saliva(Up to 24 weeks but maximally until such time that three consecutive samples have been tested negative)
• Induction of humoral immune responses against AAV by measuring antibodies against AAV(Baseline, week 4 and week 24 post administration)
• Induction of humoral immune responses against AAV by measuring neutralizing antibodies against AAV(Baseline, week 4 and week 24 post administration)
• Induction of cellular immune responses against hIFN-β by measuring T cell responses against hIFN-β(Baseline, week 4, 8, 12, 16 and week 24 post administration)
• Effect of a single intra-articular dose of ART-I02 on inflammation markers in synovium biopsies.(Week 24)
• Vector DNA in semen(Up to 24 weeks but maximally until such time that three consecutive samples have been tested negative)
• Induction of humoral immune responses against hIFN-β by measuring antibodies against IFN-β(Baseline, week 4 and week 24 post administration)
• Induction of humoral immune responses against hIFN-β by measuring neutralizing antibodies against hIFN-β(Baseline, week 4 and week 24 post administration)
• Induction of cellular immune responses against AAV5 by measuring T cell responses against AAV5(Baseline, week 4, 8, 12, 16 and week 24 post administration)