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BOCEPREVIR & TELAPREVIR

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

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BOCEPREVIR & TELAPREVIR

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

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

  3. 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.

  4. 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

  5. Future • Direct Acting Antivirals (DAA)Boceprevir and telaprevir is first generation • 1. NS3/NS4A protease inhibitor2. NS5B RNA polymerase inhibitor3. 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

  6. 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

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