Legal status Investigational | CAS Number 1174920-78-5 | |
RG7795 (ANA773 previously) is an experimental oral prodrug of 5-amino-3-(3′-deoxy-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidin-2,7-dione developed by Anadys Pharmaceuticals which forms an active metabolite that is an agonist for TLR7. It causes an induction of endogenous type 1 interferons. It is designed to treat hepatitis B with indications for bladder cancer. Early clinical trials found it to be well tolerated and to have potent antiviral activity irrespective of viral genotype, viral load, gender or previous response to IFN based therapies.
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Development
Phase I trials ended in 2009 and showed RG7795 to have potent antiviral activity at a well tolerated dose. As such, Anadys's CEO described it as "a potential replacement for injectable interferon." In late 2011, Anadys was acquired by Roche, which is currently engaged in Phase II clinical trials of this drug for HBV infection.
Potential uses
TLR7 agonists have previously been shown effective at treating viral infection. Imiquimod is a topical TLR7 and TLR8 agonist used to treat malignant and benign skin conditions. Resiquimod is a similar agent, primarily designed to be used topically but was studied in clinical trials as an oral agent for treating hepatitis C. Treatment was discontinued because adverse events were recorded consistent with systemic cytokine induction. A similar problem was recorded with ANA975 and it is possible they both have the same problem: activating TLR7 and TLR8. Both receptors are activated by guanosine and uridine rich ssRNA however they target different cells and induce different cytokine profiles. TLR7 agonists target Plasmacytoid dendritic cell and induce INF-α and chemoattractants whilst targets Myeloid Drendritic Cells and Monocytes inducing pro-inflammatory cytokines TNFA IL-12, IL-1 and IL-6. RG7795 intends to be a pure TLR7 agonist, thereby reducing the risk of systemic cytokine induction. Isatoribine is a TLR7 agonist IV drug licensed for the treatment of hepatitis however has interferon associated side effects including haematological effects. RG7795 reports no hematological side effects, its developers believe that as a well tolerated oral drug it can be the mainstay of interferon based therapy for Hepatitis.
Mechanism of action
RG7795 beaks down to its active metabolite which is a selective agonist for TLR7. This receptor is found in the endosomes of pDCs and require endosomal maturation for signalling to take place, as well as in heart, liver and spleen cells. TLR7 associates with the ‘Toll Interleukin-1 Receptor (TIR) Domain’ containing protein MyD88. This recruits ‘Il-1 Receptor Associated Kinase’ (IRAK) and ‘Tumour necrosis factor Receptor Associated Factors’ (TRAFs). TRAF6 activates NF-κB transcription factor ‘Mitogen Activated Protein Kinases’ (MAPK) and ‘c-jun NH2 Terminal Kinases' (Jnk) which activates the transcription factor ‘Activating Transcription Factor 2’ (ATF2). TRAF3 activates ‘TANK Binding Kinase 1’ (TBK1) which activates ‘Interferon Regulatory Factor 3’ (IRF3). IRF3 and ATF2 will upregulate the synthesis of type 1 Interferons. and. When interferons bind to their target cell they initiate signalling through the JAK-STAT pathway which results in the expression of ‘Interferon Stimulated Genes’ (ISGs) which create an antiviral state. These include 2’,5’-Oligoadenylate Synthase (OAS) and Ribonuclease-L (RNASEL) which breaks ssRNA strands which can inhibit viral replication and p56 which binds to ‘Eukaryotic Initiation Factor 3’ (EIF3) inhibiting replication as it blocks the ‘Internal Ribosome Entry Site’ (IRES) where its mRNA translation is initiated., RG7795 activates NK cells and eosinophils through TLR7 and produces the chemokine CXCL11 which will localise T-cells to area they are released from.
Side effects
The phase 1 trial recorded side effects characteristic of interferon therapy: headaches, nausea, fatigue, myalgia and pyrexia were fairly common and appeared dose related. No haematological abnormalities were found. Maximum Plasma concentration was achieved one hour post dose and declined rapidly. No accumulation was observed with multiple dosing. This is based on a small study however and further research will be needed.