Clinical Trials

Date: 2015-12-04

Type of information: Presentation of results at a congress

phase: preclinical

Announcement: presentation of results at HEP DART 2015

Company: Arrowhead Research Corporation (USA - CA)

Product: ARC-520

Action mechanism: RNAi

Disease: hepatitis B

Therapeutic area: Infectious diseases

Country:

Trial details:

Latest news:

• • On December 7, 2016, Arrowhead Research Corporation presented data at HEP DART 2015 showing that in chronically HBV-infected chimpanzees treated with ARC-520 in combination with nucleoside analogs, 7 of 9 (78%) exhibited signs of immune reactivation, which is likely a necessary step for achieving a functional cure of chronic HBV. One chimpanzee also exhibited an on-treatment therapeutic ALT flare and sustained virologic improvements 31 weeks off all treatment. ARC-520 is currently being studied in multiple Phase 2b global clinical trials. Christine Wooddell , Ph.D., director of liver targeting for Arrowhead, presented poster titled, "Sustained reduction of HBV DNA, RNA and proteins, and HBeAg seroconversion in a chronically HBV-infected chimpanzee treated with nucleoside analog/ARC-520 combination therapy." In this presentation, Dr. Wooddell and co-authors show that 7 of 9 chimps, HBeAg positive and negative, exhibited indications of an immune response during ARC-520 treatment, as evidenced by elevations in T-cell responsive serum cytokines. Chimp Manetta exhibited deep decreases in HBV DNA, RNA and viral proteins during ARC-520/NUC treatment. The sustained induction of CXCL9 in Manetta was associated with a therapeutic ALT flare (218 U/L) followed by HBeAg seroconversion. Sustained virologic improvements were still observed 31 weeks after all treatment was removed. At this final time point, serum HBV DNA was 5 log10 lower, HBsAg was 1.7 log10 lower, and liver HBV RNA was 99% lower than pre-study. HBV suppresses the immune system to allow chronic HBV infection. Interferon gamma (IFN-?) is a key antiviral cytokine critical to innate and adaptive immune responses. IFN-? produced by natural killer cells and natural killer T cells induces the chemokines CXCL9 and CXCL10 to mediate a T-cell response. An elevation of CXCL9 in the chimps studied is a promising sign of immune system reactivation. 8 out of 9 chimps exhibited episodes of serum cytokine CXCL9 elevation. For 7 chimps these occurred during ARC-520 treatment and in one chimp (Tattoo) these coincided with seroclearance of HBeAg that began prior to study. To reduce viral replication prior to treatment with ARC-520, chimps were treated for 8-24 weeks with entecavir or in one case (chimp Michele) with entecavir and tenofovir. Following the NUC lead-in period, animals were administered ARC-520 intravenously at 4-week intervals (q4w). Dose levels were 2, 3, or 4 mg/kg ARC-520, along with maintenance doses of entecavir or entecavir and tenofovir. All 9 chimpanzees responded to ARC-520 with HBsAg reductions of 0.5 - 2.7 log10 at nadir, the greater reductions being in HBeAg positive chimps. HBsAg levels in all chimps continued to decrease with repeat dosing. Chimps were monitored for up to 31 weeks off all treatment.

Is general: Yes