BOCEPREVIR & TELAPREVIR CHRIS SU http://www.youtube.com/watch?v=R4ld4WRUxq0

FDA APPROVED May 2011 (Vertex, 375mg oral) (Merck, 200mg oral)

Mechanism of action HCV Virus enters -> + RNA (9.6 kb) read by host ribosomes and translated -> polyprotein precursor (3000 aa) -> cleaved by a combination of host and viral proteases (triangles = host, black arrow = auto-protease, white arrow = NS3-4A serine protease)* NS4A works as an activating cofactor to NS3. Telaprevir competes with substrate and targets substrate binding site of the NS3-4A complex. Boceprevir binds to NS3 active site. * Lin, Hepatitis C Viruses: Genomes and Molecular Biology.

Therapy Given as a triple therapy with PEG-IFN (Pegasys, injection) and ribavirin (oral). Virologic response increased from 63% to 75%* Duration of tx 12 months to 6 months* Downsides: -Only applicable to Type 1 -Low barrier to resistance (hence triple therapy) Boceprevir: orally 800 mg 3 times daily with food** Telaprevir: orally 750 mg 3 times daily with food** Side effects: anemia, rash (telaprevir)** *Jacobson, NEJM, 2011:364 **FDA data

Future Direct Acting Antivirals (DAA) Boceprevir and telaprevir is first generation 1. NS3/NS4A protease inhibitor 2. NS5B RNA polymerase inhibitor 3. NS5A replication complex inhibitor Four Phase 3 drugs (as of March 2012) in the pipeline, two in the first category, one in each of the others (“second generation” DAA) In the future – “quad therapy” (2 DAA + riba + inf) e.g. NS3/4A + NS5A

INF-FREE Treatment Several studies (Phase 2) suggest that 2 DAA (with or without RBV, but no INF) might be sufficient -INFORM: NS3/4A and NS5B - 87.5% of tx-naïve achieved viral suppression in 2 weeks -SOUND-C2: NS3/4A and NS5B and RBV – 76% at week 12 Also other studies for Type 2 and 3 HCV By 2014 combination DAA therapy should be mainstream (with goal to remove INF)* Ultimate goal: eradication or cure of HCV via all-oral therapy* *Medscape, The Next Generation of DAAs