HCV: second-generation protease inhibitors

Liver International

Special Issue: Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis

Volume 33, Issue Supplement s1, pages 80–84, February 2013

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New therapeutic strategies in HCV: second-generation protease inhibitors

Virginia C. Clark,
Joy A. Peter,
David R. Nelson*

Article first published online: 3 JAN 2013

DOI: 10.1111/liv.12061

Keywords:
Hepatitis C;
protease inhibitors;
ACH 2684;
MK 5172

Abstract
Telaprevir and boceprevir are the first direct-acting antiviral agents approved for use in HCV treatment and represent a significant advance in HCV therapy. However, these first-generation drugs also have significant limitations related to thrice-daily dosing, clinically challenging side-effect profiles, low barriers to resistance and a lack of pan-genotype activity. A second wave of protease inhibitors are in phase II and III trials and promise to provide a drug regimen with a better dosing schedule and improved tolerance. These second-wave protease inhibitors will probably be approved in combination with PEG-IFN and Ribavirin (RBV), as well as future all-oral regimens. The true second-generation protease inhibitors are in earlier stages of development and efficacy data are anxiously awaited as they may provide pan-genotypic antiviral activity and a high genetic barrier to resistance.

Abbreviations
AEs adverse effects
cEVR complete early virological response
PIs NS3-4A protease inhibitors
RVR rapid virological response
SVR sustained viral response

A large number of NS3-4A protease inhibitors (PIs) have reached clinical development, including two drugs, telaprevir and boceprevir, that have already been approved for use in combination with pegylated IFN-α (PEG-IFN) and ribavirin (RBV) in patients infected with genotype 1 hepatitis C virus. Telaprevir and boceprevir significantly improve virological outcomes in both treatment-naїve [1, 2] and -experienced genotype 1 patients [3, 4]. However, the clinical utility of these first-generation PIs is limited by a thrice-daily dosing schedule (with food), increased rates of adverse effects (AEs) (anaemia and rash), a low genetic barrier to resistance and extensive drug–drug interactions. These limitations highlight the opportunities for improvement in protease inhibitors. This review will discuss the newer protease inhibitors under late-stage development, which should be more potent, with higher barriers to viral resistance, and improved dosing regimens.

Second-wave protease inhibitors

 

Second-wave protease inhibitors offer several advantages over currently available drugs. Improved pharmacokinetics will allow a once-a-day dosing schedule and the side-effect profiles are more tolerable. However, these agents have similar genotype coverage and similar resistance profiles to telaprevir and boceprevir, and do not represent true second-generation PIs. The improved PIs have been referred to as second-wave PIs. They will probably replace first-generation PIs in combination with PEG-IFN/RBV to become the initial partners in the first generation of all-oral regimens. The following drugs are currently in phase II and III development (Table 1).

Table 1. HCV protease inhibitors
 

Telaprevir	Approved	First generation
Boceprevir	Approved	First generation
Simeprevir	Phase 3	Second wave
BI1335	Phase 3	Second wave
Asunaprevir	Phase 3 (all oral)	Second wave
Danoprevir/r	Phase 2	Second wave
Sovaprevir	Phase 2	Second wave
ABT450/r	Phase 2	Second wave
MK 5172	Phase 2	Second generation
ACH 2684	Phase 2	Second generation

Simeprevir (TMC435; Tibotec, Beerse, Belgium; Medivir Pharmaceuticals, Stockholm, Sweden; Janssen, Beerse, Belgium) is a once-a day-oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once-a-day dosing, and demonstrates potent antiviral activity and efficacy [5]. The final results of two phase IIb trials of TMC435 with PEG-IFN/RBV in naïve and treatment-experienced populations have been completed [6]. PILLAR study enrolled 368 treatment-naïve subjects with genotype 1 and compared two different doses (75mg vs 150 mg) and durations (12 weeks vs 24 weeks) of simeprevir therapy in combination with PEG-IFN/RBV for either 24 or 48 weeks. A sustained viral response (SVR) was achieved in 68–76% of patients with this triple therapy regimen and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy with very high SVR (93–96%). Adverse effects were similar to standard therapy, and the lowest rate of relapse was found in the study arm receiving 150 mg daily TMC435 in addition to PEG-IFN/RBV for 24 weeks (8%). In addition, SVR rates in the 150-mg dosing arms did not differ according to HCV subtype (1a vs 1b), but as expected, SVR was highest in the IL28B CC genotype.
 

ASPIRE was a randomized, double-blind, placebo-controlled phase IIb trial, which assessed the efficacy and safety of simeprevir in combination with PEG-IFN/RBV in 462 patients with genotype 1 HCV who had failed a previous PEG-IFN/RBV regimen. The ASPIRE study randomized patients to seven treatment arms, each of which was given simeprevir in combination with 48 weeks of PEG-IFN-2a/RBV. SVR rates were significantly higher in all simeprevir-containing treatment arms compared with PEG-IFN/RBV alone. The best results were obtained in the 150-mg dosing groups with a SVR of 85% vs 37% in prior relapsers, 75% vs 9% in partial responders and 51% vs 19% in prior non-responders. It is also important to note that higher 24-week SVR rates were observed with simeprevir-containing therapy in difficult-to-treat patient subgroups, including patients with cirrhosis and a previous non-response (31% SVR in non-response cirrhotics). As has been seen with most PI-based studies, breakthrough or relapse was associated with a resistant virus (42/43 people who experienced breakthrough and 34/36 who relapsed). Subjects with HCV genotype 1a were more likely to have the R155K mutation alone or with additional mutations, whereas people with HCV genotype 1b had the D168V mutation [7].
 

In both the naïve and treatment-experienced trials, TMC435 was generally well tolerated with no evidence of significant safety signals related to rash, anaemia or neutropaenia. However, transient elevations of direct and indirect bilirubin were seen in subjects who took a 150-mg dose of simeprevir. Elevations in bilirubin were not associated with an elevation of AST or ALT, returned to baseline with the cessation of therapy and are believed to be related to interference with bilirubin transporters.
 

Finally, simeprevir may also provide opportunities for use in non-genotype 1 patients. A phase IIa proof-of-concept trial provided evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes except for genotype 3 [8]. Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, no antiviral activity was seen against genotype 3. Thus, simeprevir seems to offer significant improvement over boceprevir and telaprevir: once-a-day dosing, improved safety profile (lack of rash and anaemia) and expanded antiviral activity across more genotypes.

BI201335 (Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany) is another NS3/4A protease inhibitor with once-a-day dosing that has completed phase 2 testing. SILEN-C1 study reported the efficacy data from a randomized phase II trial with 429 genotype 1 treatment-naïve patients [9]. The treatment regimen included BI201335 in addition to PEG-IFN/RBV for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy. Response-guided therapy was evaluated and achievement of an eRVR (HCV-RNA negative at week 4 and week 12) resulted in randomization to stop therapy at week 24 or continue with PEG-IFN/RBV for a total of 48 weeks. The overall SVR rate was 83% for the 240-mg dose (lower for the 120-mg dose), and 92% of the patients with an eRVR achieved a SVR regardless of the subsequent duration of PEG-IFN/RBV. Adverse events (mostly gastrointestinal) resulted in drug discontinuation in 7.3% of subjects. SILEN-C2 study evaluated 288 partial or non-responders and evaluated the 240-mg dose, either once or twice daily in combination with PEG-IFN/RBV for 24 weeks [10]. The highest SVR was achieved in the once-a-day dosing groups: it was 50% in partial responders and 35% in non-responders. It should be noted that patients with cirrhosis were not included in this study. Both SILEN-C1 and C2 tested the efficacy of a 3-day lead-in with PEG-IFN/RBV. The expectation was that the lead-in would limit the development of resistance by providing better antiviral drug coverage when the PI was introduced. For unknown reasons, the lead-in arms in both trials showed a significant decrease in efficacy, and this strategy to limit resistance has been abandoned. SILEN-C3 evaluated treatment-naïve, genotype 1 patients and randomized them to either 12 or 24 weeks of once-a-day 120 mg BI 201335. Both groups received PEG-IFN/RBV for 24 weeks and patients who did not achieve an eRVR continued PEG-IFN/RBV until week 48. SVR rates were similar for both durations, 65% vs 73% overall and 82% vs 81% in those with eRVR respectively. Through all of the SILEN-C phase 2 trials, the adverse-event profile of BI 201335 appeared to be mild rash and photosensitivity along with some GI toxicity (nausea, diarrhoea and vomiting). As with a few other PIs under development, BI 201335 is associated with a transient rise in indirect or unconjugated bilirubin that is related to inhibition of the bilirubin transporter (inhibition of hepatic uptake of uridine diphosphate glucuronosyl transferase 1 family polypeptide A1, UGT1A1)[11]. The once-per-day dosing regimen that is moving forwards into phase 3 trials has fewer adverse events than the twice-per-day dosing regimen.

Danoprevir/r (RG7277; Roche, Basle, Switzerland; Intermune Pharmaceuticals, Brisband, CA) is a twice-a-day, ritonavir-boosted HCV protease inhibitor with good antiviral activity against genotypes 1, 4 and 6. Of note, the early hepatotoxicity signals of the drug were virtually eliminated by the addition of ritonovir boosting, which leads to strong inhibition of CYP3A and increased through concentrations of the PI. DAUPHINE is a large phase 2 trial in naïve patients that evaluated three different doses (50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, twice daily) and response-guided therapy in combination with PEG-IFN/RBV [12]. Twelve weeks after stopping therapy, antiviral negativity (SVR12) was 93% in the 200-mg dosing arm, 83% in the 100-mg arm and 67% in the 50-mg arm. At the 200-mg dose, the response was not influenced by either HCV subtype (1a vs 1b) or IL28B genotype (CC vs non-CC), suggesting that this regimen leads to potent viral suppression. Of note, genotype 4 patients had a 100% SVR 12 across all dosing arms. Danoprevir is also being evaluated in IFN-free regimens combined with the nucleoside inhibitor, Mercitabine (RG7128) [13].

 

Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor. Asunaprevir was initially studied at a dose of 600 mg twice per day, but was decreased to 200 mg twice per day because of increased liver enzymes. The combination of asunaprevir and daclatisvir was the first regimen to successfully cure HCV-infected patients without the use of IFN [14]. Despite potential approval in an IFN-free combination in genotype 1b patients and a potential quad regimen, asunaprevir is not likely to become the PI of choice for this second wave of PIs because of the twice-per-day administration and potential association with hepatotoxicity.
 

Sovaprevir (ACH-1625; Achillion Pharmaceuticals, New Haven, CT) is another NS3 protease inhibitor with very high potency, reporting a half-maximal inhibitory concentration of ~1 nm. A phase IIa study reported that ACH-1625, with PEG-IFN/RBV, resulted in a RVR in 75–81% of subjects compared with a RVR of 20% in patients receiving PEG-IFN/RBV alone [15]. A phase IIb study is under way at this time, but given the true second-generation PI also from Achillion (see below), it is less likely that this PI will be carried through to phase III trials.
 

ABT-450/r (Abbott, Abbott Park, IL; Enanta Pharmaceuticals, Watertown, MA) ABT-450 is being evaluated with ritonavir boosting to increase plasma concentrations and enable once-a-day dosing. A recent analysis included 35 treatment-naїve chronic hepatitis C patients randomly assigned to receive ABT-450/ritonavir or placebo [16]. Participants received ABT-450/ritonavir at doses of 50/100 mg, 100/100 mg or 200/100 mg once daily, or placebo, as monotherapy for 3 days, followed by 12 weeks of ABT-450/ritonavir or placebo at the same dose in combination with PEG-IFN/RBV. During the 3 days of monotherapy, the response was similar in all three ABT-450/ritonavir dose arms, with a mean maximum HCVRNA decrease of around 4 log IU/ml, compared with 0.36 log IU/ml in the placebo group. In an intent-to-treat analysis at 4 weeks, 88% of patients receiving ABT-450/ritonavir plus PEG-IFN/RBV had achieved a RVR (RVR; HCV RNA <25 IU/ml) compared with only 9% in the placebo arm. At 12 weeks, 92% receiving ABT-450/ritonavir vs 18% receiving placebo had achieved a complete early virological response (cEVR, again HCV RNA <25 IU/ml). HCV sub-genotype (1a or 1b), baseline HCV RNA and IL28B gene pattern were not associated with differences in virological response. ABT-450/r is also being studied in all-oral regimens and is more likely to receive approval in this IFN-free pathway.

Second-generation protease inhibitors

 

Two second-generation protease inhibitors, MK-5172 and ACH-2684, are in various stages of clinical development. These true second-generation PIs are expected to have broader genotype coverage and higher barriers to resistance, which represents a significant shift from the second-wave PIs.
 

MK-5172 (Merck & Co., Inc, Whitehouse Station, NJ) is a novel macrocyclic NS3/4a protease inhibitor under phase II clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major HCV genotypes, notably variants resistant to earlier protease inhibitors. R155 is the main overlapping position for resistance and different mutations at this amino acid site within NS3 protease confer resistance to nearly all protease inhibitors in development. However, MK-5172 exhibits potent antiviral activity against variants carrying mutations at position R155. Thus, based on its preclinical profile, MK-5172 is expected to be broadly active against multiple HCV genotypes, including genotype 3 as well as clinically important resistance variants making it highly suited for incorporation into newer all-oral regimens. MK-5172 was given in doses of 50–800 mg QD (monotherapy) to 48 men with HCV genotype 1 and 30 HCV genotype 3 patients for 7 days [17]. There were six arms (including a placebo arm). The maximum change in HCV levels was a decrease of −5.37 IU/ml in HCV genotype 1 and −4.41 IU/ml in genotype 3 patients. In the genotype 1 patients, 75% (30 of 40 pts) were below the level of HCVRNA quantification (25 IU/ml). The drug was generally well tolerated. In early-stage studies, MK-5172 in various doses has been shown to work across different genotypes [18] and can be dosed once a day, which makes it an attractive candidate for future clinical development.
 

ACH-2684 (Achillion Pharmaceuticals) is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and a safety profile at high drug exposures that strongly supports once-a-day dosing. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. It has preclinical activity against the six known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pm [19]. Achillion Pharmaceuticals, Inc reported proof-of-concept data from a Phase 1b clinical trial demonstrating that patients with HCV genotype 1 treated with ACH-2684 achieved a mean maximum 3.73 log¹⁰ reduction in HCV RNA after 3-day 400-mg monotherapy with once-a-day dosing. The compound also demonstrated good safety and tolerance both in healthy volunteers and in patients with HCV. This PI seems to represent an ideal partner for all-oral regimens that can help deliver pangenotypic activity with a high barrier to resistance.

Conclusion

 

The development of protease inhibitors represents a significant milestone in improving the efficacy of HCV treatment. However, the limitations of first-generation PIs have opened the door for continued drug development in this class. Several other direct-acting antivirals are under development [20]. Simeprevir, asunaprevir and BI are second-wave PIs in phase III trials, and will probably obtain approval with PEG-IFN/RBV in 2014. To be used in an all-oral regimen, second-wave PIs will need to be used in combination with other direct-acting antivirals to overcome the low genetic barrier to resistance. These combinations could include PIs and a nucleoside inhibitor with a high genetic barrier to resistance or PIs with a non-nucleoside inhibitor (or NS5A inhibitor) with a non-overlapping resistance profile. The future of protease inhibitors lies in the further development of second-generation drugs with a broad genotypic coverage and a high genetic barrier for resistance, which may be the ideal backbone for an all-oral HCV treatment regimen.

Disclosure

 

The authors have no disclosure.

References

 

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  Zeuzem S, Andreone P, Pol S., et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–28.
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  Bacon BR, Gordon SC, Lawitz E., et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207–17.
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  Manns M, Reesink H, Berg T, et al. Rapid viral response of once-daily TMC435 plus peginterferon/ribavirin in hepatitis C genotype-1 pstients: a randomized trial. Antivir Ther 2011; 16: 1021–33.
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  Fried M, Buti M, Dore GJ, et al. TMC435 in combination with peginterferon and ribavirin in treatment naïve HCV genotype 1 patients: final analysis of the PILLASR phase IIb study. 62nd Annual Meeting of the American Association for the Study of liver Diseases 2011; Novemeber 4-8; San Francisco, CA. Abstract LB-5.
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  Moreno C, Berg T, Tanwandee T, et al. Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study. J Hepatol 2012; 56: 1247–53.
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  Sulkowski MS, Asselah T, ferenci P, et al. Treatment with the 2nd generation HCV PI BI 201335 results in high and consistent SVR rates-results from SILEN-C1 in treatment naïve patients across different baseline factors. Hepatology 2011; 54(suppl): 473A.
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  Sulkowski MS, Bourliere M, Bronwicki JP, et al. Sustained viral response and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype 1 patients with non-response tp P/R. 46th Annual Meeting of the European Association for the Study of the Liver;2011March 30-April 3;Berlin, Germany; Abstract 66/330.
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  Everson G, Cooper C, Shiffman ML, et al. Rapid and sustained achievement of undetectable HCV RNA during treatment with ritonavir-boosted danoprevir/PEG-IFNa-2A/RBV in HCV genotype 1 or 4 patients: Dauphine week 36 interim analysis. 47th Annual Meeting of the European Association for the Study of Liver Disease; 2012 April 18–22; Barcelona, Spain. Abstract 1177.
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  Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomized, double-blind, placebo-controlled, dose escalation trial. Lancet 2010; 376: 1467–75.
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  Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 216–24.
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  Poordad F, Lalezari J, Lawitz E, et al. Continued high virologic response rates with ACH-1625 daily dosing plus PEGIFN-alpha 2a in a 28-day and 12-week phase 2a trial. 47th Annual Meeting of the European Association for the Study of Liver Disease; 2012 April 18-22; Barcelona, Spain. Abstract 1151.
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  Lawitz E, Gaultier I, Poordad F, et al. ABT-450/Ritonavir (ABT-450/r) Combined with Pegylated Interferon Alpha-2a and Ribavirin After 3-Day Monotherapy in Genotype 1 HCV-Infected Treatment-naive Subjects: 12-Week Interim Efficacy and Safety Results. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 252.
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  Petry A, Brainard D, Van Dyck K, et al. Safety and antiviral efficacy of MK-5172, a novel HCV NS3/4a protease inhibitor with potent activity against known resistance mutants in genotype 1 and 3 HCV infected patients. 61st Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA 2010.
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  Summa V, Ludmerer SW, McCauley JA. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012; 56: 4161–7.
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AASLD-Achillion Programs: Sovaprevir, ACH-3102 and ACH-2684

Achillion Provides Update on Clinical HCV Development Programs

Drug-Drug Interaction Study of Sovaprevir and ACH-3102 Completed -

- ACH-2684, Second-Generation Protease-Inhibitor, Achieves Comparable Activity in Cirrhotic Versus Non-Cirrhotic Patients -

- Posters Discussing Sovaprevir, ACH-3102 and ACH-2684 to be Presented at AASLD 2012 -

NEW HAVEN, Conn., Nov. 12, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today provided an update on the sovaprevir and ACH-3102 clinical development programs and announced new Phase 1b clinical trial results on ACH-2684.

Sovaprevir and ACH-3102 Development Update
Achillion announced today the completion of a drug-drug interaction (DDI) study evaluating the combination of sovaprevir and ACH-3102. The study, conducted in 24 healthy volunteers, concluded that there was no interaction between the two investigational compounds and that both sovaprevir and ACH-3102 were safe and well-tolerated by study participants with no significant adverse events reported.

"With the completion of this DDI study, we now plan to submit to the FDA a Phase 2 protocol that will evaluate an all-oral, interferon-free regimen containing sovaprevir and ACH-3102 for 12 weeks and, pending discussions with the regulatory agency, we intend to initiate this combination study with the goal of reporting rapid virologic response, or RVR, in the first half of 2013," stated Michael D. Kishbauch, President and Chief Executive Officer of Achillion.

Milind Deshpande, Ph.D., President of Research and Development and Chief Scientific Officer of Achillion commented, "We also continue to enroll and treat patients in our ongoing Phase 2 trial evaluating ACH-3102 and ribavirin for the treatment of genotype 1b CC HCV patients and, based upon emerging clinical trial results, we plan to initiate discussions with regulatory agencies to expand the enrollment to include additional genotype 1b patients and look forward to providing an update on this study later in the fourth quarter detailing RVR and safety results."

ACH-2684: Phase 1b study in Chronic HCV GT1 Cirrhotic Patients
Achillion also reported today additional proof-of-concept data from its Phase 1b clinical trial of ACH-2684, a second-generation protease inhibitor, which demonstrated that chronic genotype 1 HCV treatment-naive patients with cirrhosis treated with 400 mg

ACH-2684 once daily for three days achieved a mean maximum 3.67 log10 reduction in HCV RNA (range 3.10-4.40 log10) as compared to 0.22 log10 reduction for placebo. The antiviral activity achieved in this treatment-naive patient population was similar to the 3.68 log10 reduction in HCV RNA in non-cirrhotic genotype 1 HCV treatment-naive patients receiving the same dose of ACH-2684. The full dosing cohort (n=8; 6 active, 2 placebo) included one subject that received active drug who, based upon baseline viral population sequencing, was demonstrated to have nearly 100% substitution at position R155K. Presence of approximately 100% R155K mutation at baseline in subjects who have not been exposed to a protease inhibitor regimen is highly unusual and likely indicative of prior treatment that was not revealed at study enrollment. Further analysis is on-going and this patient's antiviral activity is excluded from the reductions above.

Safety data demonstrated that ACH-2684 was well tolerated in this patient population with no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, and were transient in nature.

"With the unique pharmacokinetic profile of ACH-2684, which we believe does not require active uptake of the compound into the liver, we are very pleased to have achieved the same robust antiviral activity in patients with compensated cirrhosis," commented Dr. Deshpande. "We believe these results support the continued development of this second-generation protease inhibitor and will look to fully leverage its activity in special populations of HCV patients."
Posters Presentations by Achillion at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD):

-- Poster 1171: Viral Kinetics Modeling to aid in Dose Selection Decisions
for Phase-2/3 Clinical Trials, A. Agarwal, et al. Session: Clinical HCV
2. Date: Tuesday, November 13, 2012.

-- Poster 1886: In vitro Studies Demonstrate a High Probability of Curing
Genotype-1 Hepatitis C with Combination of a Novel NS3 Protease
Inhibitor ACH-2684 and a Novel NS5A inhibitor ACH-3102, Y. Zhao, et al.
Session: HCV Therapy: Pre-clinical and Early Clinical Development. Date:
Tuesday, November 13, 2012.

About ACH-3102
ACH-3102, Achillion's second generation, pan-genotypic NS5A inhibitor, is a pico-molar potent compound that has been improved from first-generation NS5A inhibitors to maintain excellent potency against both wild type HCV as well as potency against resistant mutants that have been identified in clinical studies. In vitro, ACH-3102 has demonstrated potent activity against all HCV genotypes and shown additive to synergistic activity when combined with NS3 protease inhibitors, NS5B polymerase inhibitors, and ribavirin. ACH-3102 was shown to be safe and well tolerated in Phase 1 studies with potent antiviral activity achieved after a single dose. ACH-3102 is currently being evaluated in a Phase 2 trial in combination with ribavirin for 12 weeks as a treatment for chronic HCV genotype 1b.

About Sovaprevir
Sovaprevir is a Phase 2 pan-genotypic HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. Sovaprevir is an open chain, non-covalent, reversible inhibitor of NS3 protease. In clinical and preclinical studies, sovaprevir demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With low single-digit nanomolar potency specific to HCV, sovaprevir is equipotent against HCV genotypes 1a and 1b at IC50 of approximately 1nM. Sovaprevir achieved sustained viral response rates of approximately 80% in combination with pegylated-interferon and ribavirin for the treatment of HCV genotype 1, and will be evaluated in all-oral, interferon-free regimens, Fast Track status was granted to sovaprevir in 2012 for the treatment of chronic HCV.

About ACH-2684
ACH-2684 is a next-generation HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex.

ACH-2684 is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and safety profile at high drug exposures. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. ACH-2684 has shown pico-molar potency against NS3 protease that is specific to HCV. It has preclinical activity against the 6 known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pico-molar. The drug candidate was discovered internally and is being advanced by Achillion.

About HCV
The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including nearly 4 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat.

Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease.

Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to:
the expected potency, safety, tolerability, effectiveness and other characteristics of sovaprevir, ACH-3102 and ACH-2684; and Achillion's plans and timing for advancing its clinical trials, including the combination trial of sovaprevir and ACH-3102, the ongoing trial of
ACH-3102 and ribavirin, and future studies of ACH-2684. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: replicate in later clinical trials positive results found in earlier stage clinical trials of sovaprevir, ACH-2684 and ACH-3102; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2011 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

CONTACT: Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 752-5510
gschulman@achillion.com
Media:
Christin Culotta Miller
Ogilvy PR
Tel. (212) 880-5264
christin.miller@ogilvy.com
Investors:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
mfenton@achillion.com
Investors:
Lee Stern
The Trout Group, LLC
Tel. (646) 378-2922
lstern@troutgroup.com

ACH-2684 -Proof-of-Concept Data 3.73 log10 Reduction in Geno 1 HCV RNA After Three Days

Achillion Announces Additional Proof-of-Concept Data With ACH-2684 for the Treatment of Hepatitis C
Achieves Up to 3.73 log10 Reduction in Genotype 1 HCV RNA After Three Days of Treatment With Once-Daily 400 mg ACH-2684 in Phase 1b Study

NEW HAVEN, Conn., May 21, 2012 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. /quotes/zigman/100395/quotes/nls/achn ACHN 0.00% today reported proof-of-concept data from a Phase 1b clinical trial demonstrating that patients with chronic hepatitis C (HCV) genotype 1 (GT 1) treated with ACH-2684, a second-generation protease inhibitor, achieved a mean maximum 3.73 log10 reduction in HCV RNA after three-day 400 mg monotherapy with once-daily (QD) dosing. The compound also demonstrated good safety and tolerability both in healthy volunteers and in patients with HCV.

"We believe ACH-2684, with its potent antiviral activity achieved without boosting and once-daily dosing, is one of the most intriguing protease inhibitors in clinical development for the treatment of HCV," commented Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "As we continue to focus our efforts on advancing our internally developed all-oral, interferon-free HCV regimen consisting of ACH-1625, our next generation protease inhibitor, in combination with ACH-3102, a second generation pan-genotypic NS5A inhibitor, we believe that the profile of ACH-2684 provides a significant strategic and therapeutic option for potential combinations with either ACH-3102 or other direct-acting antiviral agents."

ACH-2684 Phase 1 Clinical Trial

Achillion is evaluating ACH-2684 in a Phase 1 randomized, double-blind, placebo-controlled clinical trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity in healthy subjects and HCV-infected patients. The trial consists of three segments: Phase 1a assessment of single ascending oral doses (SAD) in healthy volunteers, Phase 1a 14-day multiple ascending doses segment (MAD) in healthy volunteers, and Phase 1b evaluation of three days of oral repeat doses in subjects with GT 1 or 3 HCV. The MAD segment of this trial will be initiated during the second quarter and full trial results are expected to be presented at a medical meeting in the fourth quarter of 2012.

During the oral repeat doses segment in subjects infected with GT 1 HCV, a total of 30 patients were enrolled including 6 patients receiving placebo and 24 patients treated with three doses of 100 mg once daily (n=8), 400 mg once daily (n=8), or 400 mg twice daily (n=8) of ACH-2684. No serious adverse events (SAE) were reported and there were no patient discontinuations during treatment. The mean maximum GT 1 HCV RNA decline during therapy for the 100 mg QD, 400 mg QD, and 400 mg BID groups were 3.36 log10, 3.73 log10, and 4.16 log10, respectively, compared to a 0.68 log10 decline for patients receiving placebo. There were no viral breakthroughs observed during ACH-2684 monotherapy. Additional assessments of GT 3 activity are currently under development.

Safety data from the SAD and HCV-infected segments of the trial demonstrated ACH-2684 was well tolerated at all doses evaluated up to and including the maximum total daily dose of 1400 mg. There were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, and were transient in nature. Dosing in the 14-day MAD segment is being initiated during the second quarter with longer term safety data expected to be available in the third quarter of 2012.

About ACH-2684

ACH-2684 is a next-generation HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-2684 is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and safety profile at high drug exposures. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. ACH-2684 has shown pico-molar potency against NS3 protease that is specific to HCV. It has preclinical activity against the 6 known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pico-molar. The drug candidate was discovered internally and is being advanced by Achillion.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including more than 5 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat. Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to: the potency, safety, tolerability, effectiveness and other characteristics of Achillion's ACH-2684, ACH-1625 and ACH-3102; Achillion's expectations regarding timing for the commencement, completion and reporting of results of clinical trials of drug candidates including ACH-2684, ACH-1625 and ACH-3102; and Achillion's ability to advance a potentially best-in-class all-oral, interferon-free combination of ACH-1625 and ACH-3102 and ACH-2684 in combination with ACH-3102 or other direct acting antiviral agents. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: replicate in later clinical trials positive results found in earlier stage nonclinical studies and clinical trials of ACH-2684, ACH-1625 and ACH-3102; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2011 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

This news release was distributed by GlobeNewswire, www.globenewswire.com

SOURCE: Achillion Pharmaceuticals, Inc.

AASLD-Achillion Presents Updated Data on Multiple Compounds

Updates;
AASLD Nov 2011

Achillion to Present Updated Clinical and Preclinical Data on Multiple Compounds at AASLD 2011

NEW HAVEN, Conn., Oct. 3, 2011 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals,Inc. (Nasdaq:ACHN), a leader in the discovery and develop ment of small molecule drugs to combat the most challenging infectious diseases, today announced that four abstracts on HCV compounds discovered and developed by Achillion were accepted for presentation at the 62^nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD) to be held November 4-8, 2011 in San Francisco, CA.

During the congress, a poster presentation detailing Phase 2 segment 1 clinical trial results for ACH-1625, a once-daily protease inhibitor, will report updated 28-day safety and efficacy results for ACH-1625 administered in combination with pegylated-interferon and ribavirin for the treatment of treatment naïve genotype 1 HCV. Preclinical data on ACH-2684, a once-daily pan-genotypic protease inhibitor, as well as novel preclinical data for Achillion's second generation NS5A inhibitor compounds, will be reported during poster presentations at AASLD.

The Achillion data presentations at AASLD are as follows:

Date/Time	Presentation Title
November 5 2:00 — 7:30 p.m.	Pharmacokinetic Modeling of ACH-2684, a Hepatoselective Phase I Pan-Genotypic HCV NS3 Protease Inhibitor: Predictions and Correlation with Human Pharmacokinetics
November 5 2:00 — 7:30 p.m.	Novel Hepatitis C Virus NS5A Inhibitors with Improved Potency against Genotype -1a Replicons and Replicons Carrying Mutations Associated with Viral Resistance to 1st Generation NS5A Inhibitors
November 5 2:00 — 7:30 p.m.	Combinatory Effect of Direct Anti-HCV Agents on Antiviral Efficacy and Viral Resistance in Genotype-1a and -1b Replicons as well as Replicons Carrying NS3 Protease or NS5A Protein from Patient Isolates
November 7 8:00 a.m. — 5:30 p.m.	High Rapid Virologic Response(RVR) with ACH-1625 Daily Dosing plus PegIFN-alpha 2a/RBV in a 28-day Phase 2a Trial

"As we look toward the upcoming AASLD meeting in November, we continue to work toward our goal of delivering on a number of significant milestones for Achillion. Our focus remains on reporting top-line Phase 2 12-week EVR results for ACH-1625 in combination with pegylated-interferon and ribavirin for the treatment of genotype 1 treatment-naïve HCV, and realizing proof-of-concept Phase 1 results for both ACH-2684 against HCV genotypes 1 and 3, and ACH-2928 against genotypes 1a and 1b, all near the end of this year," commented Michael D. Kishbauch, President and Chief Executive Officer of Achillion.

Abstracts can be accessed at the AASLD website at http://www.aasld.org.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of Achillion's NS5A inhibitors, which may not be duplicated in clinical studies, and Achillion's expectations regarding results, timing and duration of clinical trials and reporting of results from clinical trials of ACH-1625, ACH-2684 and Achillion's NS5A inhibitors, including ACH-2928. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are Achillion's ability to complete the development of its drug candidates under the timelines it anticipates in current and future clinical trials; to obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; to establish commercial manufacturing arrangements and to identify, enter into and maintain collaboration agreements with appropriate third-parties; and to raise the capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

CONTACT: Company Contact:

      Glenn Schulman

      Achillion Pharmaceuticals, Inc.

      Tel. (203) 752-5510

      gschulman@achillion.com

   

      Investors:

      Mary Kay Fenton

      Achillion Pharmaceuticals, Inc.

      Tel. (203) 624-7000

      mfenton@achillion.com

   

      Media:

      Christin Culotta Miller

      Ogilvy PR

      Tel. (646) 229-5178

      christin.miller@ogilvypr.com

Hepatitis C News; Achillion Phase 1 Trial of ACH-2684 and More

In The News ; May 25, 2011 8:55 AM EDT

Achillion Announces Initiation of Phase 1 Trial of ACH-2684 for the Treatment of Hepatitis C

Human Trial Will Evaluate Safety of Pan-Genotypic Protease Inhibitor in Both Healthy Subjects and Genotype 1 or 3 HCV-Infected Patients

NEW HAVEN, First-in-Conn., May 25, 2011 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq: ACHN), a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today announced that the Company has begun dosing in a Phase 1 clinical trial of ACH-2684, a novel pan-genotypic protease inhibitor being developed for the treatment of chronic hepatitis C virus (HCV) infection.

The Phase 1 clinical study is a randomized, double-blind, placebo-controlled trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity of ACH-2684. The trial consists of three segments including assessment of single ascending oral doses in healthy volunteers, a 14 day multiple ascending doses segment in healthy volunteers, and evaluation of 3 days of oral ascending repeat doses in subjects with either genotype 1 or genotype 3 hepatitis C infection. The trial will take place in the United States and is designed to enroll up to 78 healthy volunteers and up to 40 HCV-infected patients.

"This first-in-human clinical trial will be instrumental in establishing the safety profile of ACH-2684 in humans," stated Elizabeth A. Olek, D.O., Vice President and Chief Medical Officer of Achillion. "It will also provide Achillion with important preliminary efficacy data against HCV genotypes 1 and 3, and help us to select doses for subsequent clinical development."

"We are very excited to take ACH-2684 into the clinic and advance what we hope will be a unique pan-genotypic, once-daily protease inhibitor," said Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "Furthermore, we expect to shortly launch the 12-week segment of the Phase 2 trial of our lead ACH-1625 protease inhibitor, as well as a Phase 1 trial of our ACH-2928 NS5A inhibitor. We believe we remain poised to deliver a trio of important HCV clinical milestones near the end of this year, namely, 12-week EVR results on ACH-1625 and human proof-of-concept data on both ACH-2684 and ACH-2928. These are all important components in our ultimate strategy of becoming a leader in the development of HCV combination therapies involving our protease and NS5A inhibitors."

About ACH-2684

ACH-2684 is a pan-genotypic HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-2684 is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and safety profile at high drug exposures. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. ACH-2684 has shown pico-molar potency against NS3 protease that is specific to HCV. It is active against the 6 known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 picomolar. The drug candidate was discovered internally and is being advanced by Achillion.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-2684, which may not be duplicated in clinical studies and Achillion's expectations regarding timing and duration of clinical trials and reporting of results from clinical trials of ACH-1625, ACH-2684 and ACH-2928. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010.

All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.

CONTACT: Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 752-5510
gschulman@achillion.com

Investors:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
mfenton@achillion.com

Media:
Christin Culotta Miller
Ogilvy PR
Tel. (646) 229-5178
christin.miller@ogilvypr.com

Source: Achillion Pharmaceuticals, Inc.

Telaprevir/Incivek

With the approval of Incivek™ (telaprevir) for the treatment of those with Hepatitis C, genotype 1, and the potential to cut treatment time to just 24 weeks, many questions arise. Here we have summarized some of these questions.

Incivek™ (Telaprevir) - Your Questions Answered

by Editors at Hepatitis-Central.com

With the approval of a new treatment option for those with Hepatitis C genotype 1 there is bound to be questions. Based on the information provided by Vertex, developer of Incivek™, we have provided summaries for many of the questions that are being asked. Learning more about this new combination therapy and discussing this information with your healthcare provider are essential.

Simply click on any of the links below for more details:

• What is Incivek™ (telaprevir)?
• What is the dosage for Incivek™ (telaprevir)?
• Does the dosage and administration of Incivek™ (telaprevir) differ for various people?
• When is Incivek™ contraindicated?
• What types of adverse reactions were reported when taking Incivek™?
• Are there any other warnings one should know regarding Incivek™ combination therapy?
• At what point would one know the Incivek™ combination therapy is not working?
• Can those co-infected with HIV and Hepatitis C begin Incivek™ combination therapy?
• When can I get a prescription for Incivek™ (telaprevir)?
• How can I get assistance paying for Incivek™ (telaprevir)? Is Incivek™ covered by insurance?

Posted by Editors at May 23, 2011 5:43 PM

Requirements for using and reposting articles


Patient Assistance Program
INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Programs


 Vertex CEO unfazed by competition, future rivals

(Reuters) - As Vertex Pharmaceuticals (VRTX.O) launches its first commercial product this week, Chief Executive Matthew Emmens appears unfazed by competing against industry behemoths or by the wave of potential rival drugs in development.

Emmens took over for company founder and scientist-at-heart Joshua Boger two years ago because of his extensive commercial experience as CEO of Shire (SHP.L) and many years working for Merck & Co. (MRK.N) With the U.S. approval of Vertex's highly anticipated hepatitis C drug Incivek, Emmens' time in the spotlight has arrived.

"One of the things we really wanted to do is think simple, think focused and think you're launching a company too," Emmens told Reuters on Tuesday, a day after the drug that was Boger's baby for well over a decade won FDA approval.

Incivek, which is expected to be a multibillion-dollar seller, will compete head-to-head with Merck's equally new Victrelis. Both drugs in studies have shown an ability to significantly increase the likelihood of a cure compared with current standard drugs, and can substantially reduce the current 48-week treatment regimen for many patients.

"These are cures. It's an amazingly good thing," Emmens said of the promise of his company's new drug.
While the drugs were not tested against each other, Incivek demonstrated a higher cure rate, a higher percentage of patients who will qualify for shorter treatment, and is simpler to use. Victrelis may prove to be less expensive and does not cause the bothersome rash seen with Incivek.
Merck bolstered its considerable marketing muscle last week by announcing a surprise Victrelis co-promotion deal with Roche (ROG.VX), meaning the Vertex sales force will be up against two of the biggest and most experienced in the business.

"It was a little bit of a surprise because they're arch competitors," Emmens said, referring to the fact that Merck and Roche sell rival interferon products for hepatitis that must be used in combination with the new drugs.

"To me it doesn't change the drugs," Emmens said. "We've got a real strong label; we are simple (to use) and almost 8 out of 10 people who walk in the door as first time patients are going to get cured."
HIGH DOCTOR, PATIENT AWARENESS
Emmens, noting the irony of competing against Merck where he and Boger met and worked for many years, acknowledged that doctors will likely have far greater exposure to Victrelis sales representatives because of the Merck-Roche tie-up.

"It doesn't threaten me," he said.
"It's a relatively small number of prescribers. I don't think we need to shout too loudly," Emmens said.
"Physician awareness is high for both drugs. Awareness is well in the 90 percent range and the awareness of the basic features of both drugs is higher than any drug area I've ever been in," added Emmens.
There have also been estimates of as many as 100,000 people waiting in the wings for the new drugs to arrive.

"I think the patients waiting for treatment and aware of this drug are significant, probably unlike any market I've ever seen," Emmens said.
"I think there will be a flood in the office of patients, at least that's what physicians are telling us. We know we already have prescriptions, yesterday," he said, adding that Incivek will be in pharmacies Wednesday night or Thursday.

Emmens defended the high wholesale price set for Incivek of $49,200 for a 12-week course of treatment, saying it was justified by the cure rate and ability to prevent much more costly treatments, such as liver transplants.

"We've done extensive work to feel out the sensitivity of pricing with payers. I think that we can convince them that it's worth it," Emmens said.
"If your drug is perceived to be a premium drug, which ours is, I think we priced it appropriately," he said, adding that extensive Vertex programs will limit the out-of-pocket cost to patients.
Vertex is planning campaigns to raise hepatitis C awareness and promote greater screening for a disease that most people are unaware they have until serious liver problems develop. But Emmens is reluctant to directly promote the Incivek brand.

"I'll never say never, but I'll just tell you that I don't see it," he said. "I think pummeling the world with advertising in many ways works against what may be best for the physician and patient."
With dozens of hepatitis C drugs in development, analysts have cautioned that the days of Vertex and Merck owning the market could be limited.

Emmens was unfazed, noting that it was easy to become exuberant over early results of small studies and that most experimental drugs fail. In addition, the comparative bar for new treatments has been substantially raised.

"The new standard you have to compare yourself to is tough," Emmens said. "It's us."
While his sales force is well-prepared and raring to get started, Emmens attributes some his gray hair to the two dozen drug launches he has been through in previous roles, including one in which a truck filled with a new medicine skidded off the road in a snowstorm.

"It's always better to have a drug launch in warm weather," he quipped.
(Reporting by Bill Berkrot and Lewis Krauskopf, editing by Matthew Lewis)


VIDEO

Hepatitis C Educational Program
Produced by Liver Specialists of Texas, this is Part 1 of a series of hepatitis C educational classes for patients preparing to start hepatitis C therapy, using Interferon and Ribavirin, as well as the new protease inhibitor, boceprevir, available as Victrelis. The series will review bacground information about the function of the liver, diseases that are common to the liver, the natural history of heppatitis C, as well as treatment options. Management of the side effects of hepatitis C therapy will be stressed in the couse.

Also See The Texas Liver Youtube Channel for more videos





HIV/HCV

Twice-weekly pegylated interferon-α-2a and ribavirin results in superior viral kinetics in HIV/hepatitis C virus co-infected patients compared to standard therapy -
"Our study suggests that twice-weekly peg-IFN-α-2a for 4 weeks followed by weekly dosing and ribavirin has a superior early virologic response compared with the standard therapy of weekly peg-IFN-α-2a and ribavirin among HIV/HCV co-infected genotype 1 individuals, particularly among African-Americans."

Untreated HIV Increases Inflammation in Women
Rifapentine plus isoniazid administered once-weekly for 3 months to treat latent tuberculosis worked better than daily isoniazid for 9 months, with fewer premature treatment discontinuations, researchers reported at the recent American Thoracic Society meeting.

Healthy You

High Calcium Intake No Better for Bone Health
Women with a low dietary intake of calcium are at increased risk of fractures and osteoporosis, Swedish researchers reported, but above a threshold, there's little additional benefit.

Pharmaceuticals

The Problem With Labeling: Too Many Side Effects
In response to regulatory demands and mounting litigation, drugmakers have puffed up their product labeling to the point where the verbiage occupies numerous pages and contains a laundry list of possible side effects. Yet all these warnings have a down side, because they may undermine patient adherence and overwhelm docs as they try to find suitable treatments, according to a new study.


 Vertex Plans Focus On Marketing Against Two Pharma Giants

--Vertex to use small, focused

sales force for new hepatitis C drug against similar treatment from Merck and Roche

--"We designed a sales force around our medicine," CEO says.

--Vertex also supporting campaign for increased hepatitis C screening.

By Thomas Gryta

Of DOW JONES NEWSWIRES

NEW YORK -(Dow Jones)- Vertex Pharmaceuticals Inc. (VRTX) is using a focused strategy in selling its newly approved hepatitis C drug Incivek against two of the world's largest pharmaceutical companies.

While the Cambridge, Mass., drug maker is launching its first drug--the first prescriptions arrived just hours after Monday's approval from the Food and Drug Administration--it is facing a formidable opponent. Merck & Co. (MRK) got approval for its own hepatitis C pill Victrelis earlier this month and has signed a promotional agreement with Roche Holding AG (RHHBY). Both drugs work in similar ways, improving cure rates.

Vertex said it is using a small, experienced sales force to get its message to doctors about the viral liver disease, mixed with support for a coming awareness program to help identify new patients.

"It is a very focused market, and we have highly specialized sales force," Vertex Chief Executive Matthew Emmens said in an interview Monday. "You only need a 100 or so representatives to cover the doctors."

Emmens projected that the ideal sales force would visit the top half of prescribing physicians eight to 10 times a year, but frequency isn't as important with Incivek, he said, because physicians have generally been following its development.

In general, Wall Street has been predicting that Vertex will lead the market because of its effectiveness, simpler dosing and broader range of data.

A Merck spokeswoman said the availability of new drugs for hepatitis C is " great news" and that the company looks forward to being part of the "exciting new era" with Victrelis.

Although it is a smaller company, many of Vertex's leaders previously have worked in large pharmaceutical companies and are using that experience to their advantage, according to Emmens.

Vertex started building its marketing organization two years ago and its sales force about a year ago, getting 10 applications for every hire.

"We designed a sales force around our medicine from scratch," Emmens said, contrasting that strategy with large companies that push new drugs on an already active sales force.

Aside from a traditional sales effort and the initial demand for the drug, Emmens expects that new patients will continue to be identified through increased awareness and testing.

Hepatitis C can lead to liver failure, liver cancer and the need for a transplant, but patients can carry the disease for decades before it is detected and severe damage has already been done.

Vertex cited estimates of 700,000 to 1 million U.S. diagnosed patients, with 3 million to 4 million total patients infected with the blood borne virus.

To raise awareness among those undiagnosed patients, Vertex is supporting plans for a grass-roots effort that will involve local governments and community organizations to encourage people to be tested for the hepatitis C virus.

Along with other companies, including Roche, Merck and Johnson & Johnson (JNJ) , Vertex has donated to an organization that is helping the Centers for Disease Control to evaluate changing the screening methods for the disease.

The disease typically is spread through injectible drug use and blood transfusions before 1992, when screening for the virus in the blood supply began.

Currently, testing is typically done in so-called high-risk individuals, but the CDC is evaluating using a one-time age-based test for all people. The CDC estimates that 75% of hepatitis C patients were born from 1945 to 1965 and Emmens expects the new recommendations to come in early 2012.

Although Emmens declined to talk about his own sales expectations for Incivek, he contended that Wall Street's expectations for new hepatitis drugs to quickly challenge Incivek and Victrelis may be overly optimistic.

Emmens said new treatments would likely have to prove themselves against the latest generation of drugs, effectively raising the barrier for new entrants.

"The best anyone can do is three years from now. We'll see if they make it," he said.

-By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com

--Katherine Hobson contributed to this article. (END) Dow Jones Newswires 05-24-111802ET Copyright (c) 2011 Dow Jones & Company, Inc.


FDA Oversight Of J&J Is ‘Deeply Troubling’

The ‘phantom recall’ scandal last year in which Johnson & Johnson hired contractors to yank over-the-counter meds such as Motrin from store shelves rather than conduct a proper recall prompted congressional hearings and contributed to a consent decree, among many other things. And during one hearing, the FDA agreed to review procedures that allowed the health care giant to, essentially, circumvent agency oversight (back stories here, here and here). Now, though, Darrell Issa, who chairs the House Committee on Oversight and Government Reform, which held those hearings, has written FDA commish Margaret Hamburg to say the agency has failed to take “promised and necessary corrective actions at its San Juan office.”