TITLE: Safety and Pharmacodynamics of Oral TLR-7 agonist GS-9620 in patients with Chronic Hepatitis B
AUTHORS (FIRST NAME, LAST NAME): Edward J. Gane1, Eric Sicard2, Stuart C. Gordon3, Daniel Gruener4, Stuart K. Roberts5, Suzanne Kim6, Wendy Cheng7, Carla S. Coffin8, Richard Fedorak9, Paul Y. Kwo10, Barbara A. Leggett11, Daryl Lau12, Young-Suk Lim13, Stefan Pflanz14, Benedetta Massetto14, Mani Subramanian14, John G. McHutchison14, Bradley Freilich15, Kumar Visvanathan16
INSTITUTIONS (ALL): 1. Auckland Clinical Studies, Auckland, New Zealand.
2. Algorithme Pharma, Inc, Montreal, QC, Canada.
3. Henry Ford Health Systems, Detroit, MI, United States.
4. CRI Worldwide, LLC, Philadelphia, PA, United States.
5. Alfred Hospital, Melbourne, VIC, Australia.
6. West Coast Clinical Trials, LLC, Costa Mesa, CA, United States.
7. Royal Perth Hospital, Perth, WA, Australia.
8. Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine , University of Calgary, Calgary, AB, Canada.
9. University of Alberta , Alberta, AB, Canada.
10. Indiana University , Indianapolis, IN, United States.
11. Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia.
12. Beth Israel Deaconess Medical Center, Boston, MA, United States.
13. Asan Medical Center, Seoul, Korea, Republic of.
14. Gilead Sciences, Inc, Foster City, CA, United States.
15. Kansas City Research Institute, Kansas City, MO, United States.
16. Southern Health, Monash University and St.Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia.
ABSTRACT BODY: Background and Aims: GS-9620 is an orally available specific agonist of TLR-7, a highly conserved innate immune receptor. GS-9620 has demonstrated a rapid and sustained reduction in viral load and surface antigen levels in animal models of viral hepatitis (woodchuck [Stephan Menne et al, J Hepatol 2011; 54: S441] and chimpanzees [Robert E. Lanford et al, Gastroenterology 2013; 144(7):1508-1517]). In healthy volunteers and in patients with chronic hepatitis C, low doses (0.3 mg-4 mg) of GS-9620 demonstrated ISG15 and CCL8 mRNA induction without systemic IFNα related adverse events. We assessed the safety, tolerability and pharmacodynamics (PD) of GS-9620 in patients with chronic hepatitis B (CHB).
Methods: A dose escalation (0.3 mg, 1 mg, 2 mg, 4 mg) placebo controlled study of a single dose or 2 doses one week apart, one in treatment naïve CHB patients and one in virologically suppressed CHB patients, is ongoing. Serum levels of IFNα and IP10 are being assessed by Cyraplex assay, and whole blood mRNA expression of ISG15 and CCL8 genes are being determined by qRT-PCR.
Results: Patients demographics are summarized in the table. GS-9620 was well tolerated in both single (SAD) and multiple (MAD) dose cohorts, in both CHB patient populations. None of the patients experienced treatment related grade 2-4 AEs or hematologic reductions. In both CHB patient populations, induced expression of interferon stimulated gene ISG15 and CCL8 was observed in the majority of patients in all dose cohorts (table). Peak mean induction was observed by Day 3 (48 hours) with return to baseline values by Day 8. No increase in serum IFNα was observed. No clinically significant changes in HBsAg levels or HBV DNA were observed.
Conclusions: Oral administration of GS-9620 stimulates a pre-systemic immune response without clinical significant systemic adverse events associated with IFNα in chronic hepatitis B patients.
They will slowly drive the dosing to the tolerated maximum, and then the treatment time will be very important. But this is an immunotherapy, since it is a toll like receptor 7 agonist. Everything is quite open at this time.
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