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BiotechTracker: ISIS 104838 Moves Towards Phase III 
September 19, 2003 Isis’s (NASDAQ: ISIS) ISIS 104838 has generated biological activity, preliminary clinical marker, and preliminary clinical profiles that have increased the construct’s probability of advancing to phase III clinical trials for the management of rheumatoid arthritis (RA). Interim results from randomized, placebo-controlled, phase IIa investigation show that administration of ISIS 104838 300 mg is associated with reduced synovial (joint-lining) TNFa mRNA levels and stabilized blood TNFa levels. Final results and additional data analyses will be presented at the 67th Annual Meeting of the American College of Rheumatology (ACR), October 23-28 in Orlando. 

ISIS 104838 is an antisense inhibitor that blocks production of TNFa, a cytokine (small hormone-like protein that transmits signals between cells) important in immune responses and inflammation. Several marketed products, such as Amgen’s (NASDAQ: AMGN) Enbrel and Johnson & Johnson’s (NYSE: JNJ) Remicade, target TNFa. 

The phase IIa study was designed to assess ISIS 104838’s ability to reach synovial tissue and reduce TNFa levels in both blood and synovia. The trial also began to evaluate the construct’s pharmacological effects as they relate to TNFa inhibition. Study subjects were randomized to receive ISIS 104838 100 mg, ISIS 104838 300 mg, or placebo. They received six doses of subcutaneous or intravenous study drug over one month. 15 evaluable patients have generated data as of the abstract publication. ISIS 104838: 

synovial tissue concentrations increased linearly with dose 
subcutaneous versus intravenous administration did not significantly differ in terms of achieving dose / tissue concentration response 
dose-response (and a significant difference versus placebo) was observed for decreased TNFa mRNA expression in synovial tissue 
administration was associated with a mean plasma TNFa level stabilization for high dose recipients, whereas mean plasma TNFa levels increased for placebo recipients 
generated reassuring preliminary clinical marker profiles in terms of mean swollen joint decreases
42% decrease at the end of the treatment period (day 29) for high dose recipients versus 21% for placebo recipients 
33% decrease at the end of the follow up period (day 85) for high dose recipients versus 8% for placebo recipients 
generated reassuring preliminary clinical marker profiles, especially for preservation of therapeutic effect, in terms of mean tender joint decreases
27% decrease at the end of the treatment period for high dose recipients versus 26% for placebo recipients 
22% decrease at the end of follow up period for high dose recipients versus 3% for placebo recipients
generated reassuring, though statistically equivocal, preliminary clinical profiles in terms of American College of Rheumatology 20% (ACR 20) improvement-based response criteria (achievement of ACR 20)
4 of 5 (80%) high dose recipients by the end of the treatment period compared to 4 of 6 placebo recipients 
small sample, no follow up, non-primary endpoint suggests need for additional phase II clarification prior to phase III initiation 
was well tolerated.
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