1. BOCEPREVIR & TELAPREVIR
CHRIS SU

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 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

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 % 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