SB 9200 an oral selective immunomodulator is safe and efficacious in treatment-naive, non-cirrhotic HBV patients: Results from Cohort 1 of the ACHIEVE trial

Abstract

SB 9200 is a novel oral selective immunomodulator which targets the host pattern recognition receptors Retinoic Acid Inducible Gene (RIG-I) and Nucleotide Oligomerization Domain protein 2 (NOD2) to activate innate and adaptive immunity. SB 9200 at 400mg daily for 7 days in HCV genotype 1 patients reduced HCV RNA by > 0.9log10 in 30% of patients and was considered equivalent to PEG-IFN. SB 9200 is currently being evaluated in the ACHIEVE trial, a double-blind, placebo-controlled phase 2 study in HBV treatment-naïve patients to identify the optimal dose of SB 9200 as both monotherapy and in combination with tenofovir 300mg daily. PATIENTS: 20 treatment-naïve non-cirrhotic HBV patients were randomized 4:1 to SB 9200 25mg daily or placebo for 12 weeks. Primary end points were safety and antiviral response defined by reduction in HBV DNA at week 12. There were M 12: F 8, mean age 40.5 years with 18 Asians and 2 Caucasians. 11 were HBeAg-positive and 9 HBeAg-negative, genotype A 2, B 9, C 7 and D 2. Baseline viral burden was higher in HBeAg+ (mean HBV DNA 7.1 log10; mean quantitative HBsAg 4.38 log10) compared to the HBeAg- patients (mean HBV DNA 5.5 log10; mean quantitative HBsAg 3.18 log10). RESULTS: There were no clinical, hematological or biochemical SAEs and no interferon-like side effects. 11 patients had treatment-emergent AEs and there was no difference in the number or type of AEs between SB 9200 or placebo patients with the most common (20%) being non-specific GI complaints of constipation, abdominal pain, nausea and diarrhea. All AEs were graded mild to moderate. Three patients had ALT flares > 200 IU. Two placebo patients had viral flares including an HBeAg-neg reversion to HBeAg-pos; the other flare was immune-related at week 4 in a patient on SB 9200 who had an associated 2.32 log10 reduction in HBV DNA and a 1.01 log10 reduction in HBsAg. All 3 patients were dose-reduced to every other day. At week 12, mean change in HBV DNA was -0.58 log 10 in SB 9200 compared to +0.37 log10 in placebo patients (p = 0.014). HBV DNA reduction was greater in SB 9200- treated HBeAg-neg patients (mean -0.86 log10) compared to HBeAg-pos patients (mean -0.37 log10). Overall 5 of 16 patients (31%) had a maximal >0.5log10 reduction in HBsAg (range 0.52 – 1.01 log10). CONCLUSION: Low-dose SB 9200 (25mg daily) demonstrated safety and anti-viral activity in treatment-naïve patients consistent with activation of innate immunity and potential suppression of cccDNA. The greater response in HBeAg-neg patients versus HBeAg-pos patients is possibly related to the effect of viral burden at such a low dose of SB 9200.