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Brief Marketplace Overview

1Q, 2011

It is estimated that 3 – 5 million individuals in the U.S., and 170 – 200 million globally are infected with Hepatitis C six genotypes and 15 subtype variants.  The current standard of care for Hepatitis C, consisting of PEG-IFN + ribavirin, is effective after 24 – 48 weeks, yielding a sustained viral response (SVR) 45% of the time in GT1 (overall the majority of infections), 75% in GT2, and 65% in GT3.  Primary treatment goals are directed toward the prevention of chronic Hepatitis C, cirrhosis, and hepatocellular carcinoma.  However, side effects occur in 60 – 80% of patients (flu-like symptoms, fever, rash, anorexia, thyroid dysfunction, anemia, and mood disorders), necessitating a dose reduction, with treatment withdrawal in 5 – 10%.  The pool of non-responder GT1 patients is growing who have no current alternatives for further treatment until telaprevir and boceprevir become available.  An inherited polymorphism found on chromosome 19 at rs12979860, close to the IL28B gene, is strongly associated with SVR, as are additional SNPs (single nucleotide polymorphisms) in the IL28B region. For those who exhibit resistance to the protease inhibitors, a recent trial with 87 patients with GT1 infection, INFORM-1, patients received up to 13 days of either oral combination therapy with RG7128, a polymerase inhibitor, and RG7227/danoprevir, an NS3/4A protease inhibitor or with matched placebos.  Results revealed a median reduction in HCV RNA in 88% of those who received 1000 mg BID of RG7128 and 900 mg BID of danoprevir, although in another trial by InterMune, the 900 mg dose of danoprevir was halted due to a 6% incidence of ALT elevation.





Merck and Vertex Pharmaceuticals, each with protease inhibitor compounds active at the translation and polyprotein processing step as illustrated above, are racing to regulatory approval for their Hepatitis C compounds, with the prospect of renewed optimism for those unresponsive to Standard of Care (SOC) treatment.  Clinical trials for boceprevir reveal a 66% response rate in GT1 treatment naïve patients after 48 weeks of treatment with anemia and dysgeusia as common side effects, significantly inferior to telaprevir’s 75% response rate after 12 weeks of telaprevir + 24 weeks of standard treatment.  Although telaprevir has exhibited higher efficacy rates and fewer side effects in clinical trials, interest in both compounds is anticipated to be high.  Numerous hepatologists have designated a portion of their patient population for the anticipated launch of each compound, so marketplace entry is projected to alter the competitive landscape significantly.


As is typical of Merck, they have been less than forthcoming publicly regarding their filing and PDUFA date, however, industry rumor abounds.  Market entry within 1 month of one another should not provide a significant edge on that basis alone.  Merck is expected to assemble an aggressive launch campaign, highlighting boceprevir’s strengths. 





Roche is working with various partners on innovative compounds to follow Pegasus.  Schering-Plough (Merck Schering as of 2009) and Roche have been primary competitors for years in the Hepatitis C field, now looking toward formidable competitive new entrant threats. 







Tactics and strategies at EASL will be carefully calculated by the marketed competitors, along with Merck and the other forthcoming marketplace entrants.  The pipeline includes TMC435 an oral once daily protease inhibitor from Medivir/Tibotec/JNJ which has entered Phase III as of February, 2011 in the U.S. and Eastern Europe.  TMC435 inhibits NS3/4A proteins from genotypes 1 – 6, binding non-covalently with fast association and slow dissociation from the protease.  The Phase III trial will recruit 375 patients with genotype 1 who have relapsed after prior interferon therapy.  TMC 435 regimens will be of 24 or 48 weeks duration, in combination with peginterferon alfa-2a (Pegasys) and ribavirin.  A treatment naïve trial will begin later this year.






Numerous additional competitors remain in Phase II predominantly with protease or polymerase inhibitor (active at the RNA replication step illustrated above) MOAs, (after many have fallen out due to toxicity or lack of efficacy), including Pfizer, BI, Intercell/Novartis, BMS, Anadys, Globeimmune, iTherX, Idenix, Gilead, Achillion, Transgene, Triopep/Inovio, Arrow/AZ, Abbott/Enanta, Pharmasset.  Numerous compounds are presently in Phase I and preclinical presently.


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