Post-Scripps Conference Download "New Treatments in Chronic Liver Disease"

I attended the Scripps Clinic 'New Treatments in Chronic Liver Disease' conference this past weekend in La Jolla, CA.  There were three sessions focusing just on HCV - 'Management of Chronic Hepatitis C in the DAA Era'; 'Controversy - Should We Treat IL28B CC Patients Without DAAs?' and the 'New Directions for HCV Therapy (2012 - 2014)'.  Adrian Di Bisceglie MD, Paul Pockros MD and Anna Lok, MD - all three superstars of Hepatology - did the honors. Below are some of the highlights (for me, anyway) in terms of the future of HCV treatment. Reductionism at its most subjective.

·        The future of Interferon & Ribavirin:

o   Interferon will likely be with us for at least the next 5 years, but may be regulated to patients that are tough to treat (i.e. cirrhotics, G1a)

o   Ribavirin will be a mainstay of therapy for the majority of patients.

o   A nuc may be able to replace RBV in a small subset of patients in combination therapy (PI +nuc + nonnuc, for example) The subset of patients were characterized as G2 & G3, non-cirrhotic, low BMI, non-smoking and/or post-transplant / dialysis patients and perhaps G1b with CC allele). 

o   The  economic ramifications of this strategy where examined. if a generic like RBV worked just as well as a nuc, then why use two or more DAAs where the cost of treatment will likely be much higher?

·        Ribavirin dose reduction with current therapy:

o   Docs doing CDCs every two weeks. When patient drops below 10 g/Dl, theydrop RBV down to 600.  If that doesn’t provide enough EPO is added.

o   Approval of EPO an issue – may take three weeks, what do we do then?

o   One doctor on the panel said “we don’t know how how we can go with RBV. Can we stop RBV for a couple of days until the patient normalizes? We don’t know.”

o   Another doctor on the panel replied that the current data on stopping RBV is “inadequate” (very vociferous on this).  Referenced the HCV Target registry Mike Fried was involved in to take a closer look at this issue.  Cautioned against this until the data is more clear.

·         New treatment notables: 

o   GS-7977 + RBV (no INF)  much less likely to cause anemia than current DAA therapy. Referenced a slide from the ELECTRON study that showed only an average of a 2 g drop in hemoglobin, no reduction in absolute neutrophil count. Also much less propensity for DDIs than current DAA therapy.

o   All agreed that the data they are most anxiously awaiting is the G1 treatment naïve data from the ELECTRON trial with GS-7997 + RBV (to be presented at EASL)

o   Doctor on the panel referenced ELECTRON demographics – G1a, no cirrhosis. “We need to see VERY high SVR rates in this INF-free trial in this population. I’m looking for 100% SVR”.

o   Resistance will always be a concern given the error-prone, highly replicative capacity of the virus. Less of a concern with the polymerase inhibitors because of the higher barrier to resistance.

o   Future much more certain for polymerase inhibitors and protease inhibitors than cyclophilin inhibitors at this point.

o   Less danger of drug-drug interactions with upcoming therapies – good news for post-transplant, dialysis and HIV/HCV co-infected patients.

·         Timeline predictions on evolution of HCV therapy:

o   Q4 2013/ Q1 2014 – Quad therapy vs new triple therapy options (PI + nuc/nonnuc + PEG/RBV)

o   Q4 2013/Q1 2014 IFN-free regimens for G2/3 and perhaps G1b (w/ CC allele)        and for those intolerant to IFN. (PI +nuc/nonnuc/NS5A w/+ RBV)…. Maybe w/out RBV for small segment of patients.

Encouraging Phase II Telaprevir HIV/HCV coinfection treatment data presented at CROI...

Posted on March 6 on Vertex Pharmaceuticals.com: Data presented at CROI from the Phase II Telaprevir trial looking at the safety and effectiveness of Telaprevir + P/R in the HIV/HCV co-infected patient (all on Atripla and Reyataz as their antiretroviral regimen).  While this is SVR12 data and not the 'true' SVR of 24 weeks past End of Treatment (EOT), this data looks encouraging with 74% (28/38) patients undetectable at SVR12.  Given the huge potential of drug-drug-interactions with Telaprevir and antiretroviral regimens, it looks as if the Atripla + Reyataz regimen in combination with TVR + P/R is the one to go with - VERY encouraging in that there have been no HIV breakthroughs while on TVR + P/R + Reyataz + Atripla. The coinfected patient is a critical patients - coinfected individuals have have markedly increased disease progression far and above that of the monoinfected patient.  Considering that Boceprevir cannot be used in the HIV/HCV coinfected patient, Vertex has this niche all to itself until the 2nd gen compounds prove themselves.  I'm sure these interim results come to the relief of many providers who treat this patient population. 

Data from Phase 2 Study of an INCIVEK® Combination Regimen Showed 74% of People Co-Infected with Hepatitis C and HIV Had Undetectable Hepatitis C Virus 12 Weeks After Treatment Ended (SVR12)

- INCIVEK was well tolerated with commonly used Atripla- and Reyataz-based HIV treatment regimens, and no patients experienced HIV breakthrough -

- Enrollment is ongoing in Phase 3 study evaluating 24- and 48-week treatment durations in people who are co-infected -

SEATTLE--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results from an ongoing Phase 2 study designed to evaluate the safety and tolerability of INCIVEK® (telaprevir) tablets in combination with pegylated-interferon and ribavirin in people who are co-infected with genotype 1 hepatitis C virus and human immunodeficiency virus (HIV). Data showed 74 percent (28/38) of patients who were treated with INCIVEK (in-SEE-veck) combination therapy had undetectable hepatitis C virus (HCV RNA) 12 weeks after the end of all study treatment (SVR12) compared to 45 percent (10/22) who were treated with pegylated-interferon and ribavirin alone. INCIVEK was well tolerated with commonly used Atripla®- and Reyataz®-based HIV treatment regimens. Changes in CD4 counts were similar between the treatment groups and no HIV viral load breakthroughs were observed in either treatment group during the study. The most common adverse events in the INCIVEK arms of the study were fatigue, pruritis (itching), headache, nausea and rash. No cases of severe rash were reported and there were no discontinuations due to rash. Interim results from this study are being presented at the Conference on Retroviruses and Opportunistic Infections (CROI), March 5 to 8, 2012 in Seattle.

"Hepatitis C generally progresses faster, leads to more long-term liver complications and has been harder to cure among people who also have HIV," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "These new INCIVEK data are important as we work toward our goal of helping cure more people with hepatitis C. We're actively enrolling co-infected patients in a Phase 3 study and expect that data from this study will be included in a submission for a supplemental approval of INCIVEK."

The Phase 2 study includes two parts: Part A is evaluating people who are not currently being treated with antiretroviral therapy (ART) for HIV infection and Part B is evaluating those who are taking an Atripla- or Reyataz-based regimen for HIV. This study enrolled patients who were new to hepatitis C treatment (treatment naïve). Patients who were randomized to receive INCIVEK were treated with 12 weeks of INCIVEK, pegylated-interferon and ribavirin, followed by 36 weeks of pegylated-interferon and ribavirin alone. Interim data also showed that 68 percent (26/38) of patients treated with INCIVEK combination therapy in this study had a rapid viral response (RVR, undetectable hepatitis C virus at week 4 of treatment) compared to none (0/22) of the patients who received pegylated-interferon and ribavirin alone.

"There is a great need for treatments that are well tolerated and offer co-infected patients a better chance at a cure for hepatitis C while maintaining suppression of their HIV," said Douglas Dieterich, M.D., Professor of Medicine in the Division of Liver Diseases, Mount Sinai School of Medicine, New York City. "It's very encouraging that nearly three out of four people had undetectable hepatitis C virus 12 weeks after stopping INCIVEK combination therapy and that their HIV medicines continued to work during treatment."

Interim Study Results

Sixty-two people 18 and older were enrolled in this Phase 2 study and 60 received at least one dose of study drug. This analysis was conducted 12 weeks after patients completed all treatment. The ART regimens evaluated in this study were selected based on current HIV treatment guidelines from the U.S. Department of Health and Human Services, International AIDS Society and drug-drug interaction studies of INCIVEK with commonly used ART medicines.

Interim Intent To Treat Analysis of Study #110

Part A (No ART)

Part B Atripla®-based regimen

Part B Reyataz®-based regimen

Total

INCIVEK- based Arm+

Control Arm++

INCIVEK- based Arm+

Control Arm++

INCIVEK- based Arm+

Control Arm++

INCIVEK- based Arm+

Control Arm++

RVR*

71% (5/7)

0% (0/6)

75% (12/16)

0% (0/8)

60% (9/15)

0% (0/8)

68% (26/38)

0% (0/22)

eRVR**

57% (4/7)

0% (0/6)

75% (12/16)

0% (0/8)

47% (7/15)

0% (0/8)

61% (23/38)

0% (0/22)

SVR12

71% (5/7)

33% (2/6)

69% (11/16)

50% (4/8)

80% (12/15)

50% (4/8)

74% (28/38)

45% (10/22)

Atripla-based regimen (efavirenz, tenofovir disoproxil fumarate and emtricitabine): INCIVEK was dosed at 1,125 mg, every 8 hours (q8h).

Reyataz-based regimen (ritonavir-boosted atazanavir, tenofovir disoproxil fumarate and emtricitabine or lamivudine): INCIVEK was dosed at 750 mg, every 8 hours (q8h).

*RVR: Rapid Viral Response; undetectable HCV RNA at week 4.

**eRVR: extended Rapid Viral Response; undetectable HCV RNA at weeks 4 and 12.

+12 weeks of INCIVEK, Pegasys® (PEG, pegylated-interferon alfa-2a) and Copegus® (RBV, ribavirin) followed by 36 weeks of only PEG and RBV.

++48 weeks of PEG and RBV only for hepatitis C treatment.

             
Atripla-based regimen (efavirenz, tenofovir disoproxil fumarate and emtricitabine): INCIVEK was dosed at 1,125 mg, every 8 hours (q8h).

Reyataz-based regimen (ritonavir-boosted atazanavir, tenofovir disoproxil fumarate and emtricitabine or lamivudine): INCIVEK was dosed at 750 mg, every 8 hours (q8h).

*RVR: Rapid Viral Response; undetectable HCV RNA at week 4.
**eRVR: extended Rapid Viral Response; undetectable HCV RNA at weeks 4 and 12.

+12 weeks of INCIVEK, Pegasys® (PEG, pegylated-interferon alfa-2a) and Copegus® (RBV, ribavirin) followed by 36 weeks of only PEG and RBV.
++48 weeks of PEG and RBV only for hepatitis C treatment.

The majority of adverse events in this study were mild or moderate. Adverse events that occurred more frequently in the INCIVEK arms compared to placebo (≥10 percent difference) were pruritis (itching), headache, nausea, rash, fever, and depression. Three patients, all in Arm B, discontinued all study treatment due to adverse events (one each due to gall stones, hemolytic anemia and nausea/vomiting).

About this Phase 2 Study

Vertex and its collaborator Janssen conducted extensive drug-drug interaction studies with INCIVEK and commonly used HIV medicines prior to initiating a development program in people co-infected with hepatitis C (HCV) and HIV. This Phase 2 study is a two-part (A and B), randomized, double-blind, placebo-controlled, parallel group, multi-center study in people chronically infected with both HCV and HIV who were new to HCV treatment. The primary endpoint of the study is to evaluate the safety and tolerability of INCIVEK combination therapy in people co-infected with HCV and HIV. A secondary endpoint is to evaluate rates of sustained viral response (SVR) 12 and 24 weeks after the end of treatment. The study is being conducted by Vertex in collaboration with Janssen.

Phase 3 Study Actively Enrolling

Enrollment is ongoing in a Phase 3 study evaluating 24- and 48-week response-guided regimens of INCIVEK combination therapy in people co-infected with HCV and HIV. Patients who are either new to treatment for HCV, or who had relapsed after at least one prior course of therapy with pegylated-interferon and ribavirin alone, will receive 24 or 48 weeks of INCIVEK combination treatment, based on their antiviral response. Patients who had not responded to a prior course of treatment (partial responders and nulls) will receive 48 weeks of INCIVEK combination treatment. A similar study is also being initiated by Janssen in its territories.

Data from In Vitro Evaluation of INCIVEK and HIV Protease Inhibitors

Also being presented at CROI this week are data from an in vitro evaluation of the anti-HIV activity of four HIV protease inhibitors (amprenavir, darunavir, lopinavir and atazanavir) in combination with INCIVEK. In the study, no antagonistic effects on the antiviral activity were observed when INCIVEK was used in combination with amprenavir, darunavir, and lopinavir, and slight antagonistic effects were observed on the antiviral activity of atazanavir.

About INCIVEK

INCIVEK ® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication. INCIVEK is the most prescribed direct-acting antiviral for the treatment of adults with genotype 1 chronic hepatitis C and has been used to treat more than 30,000 people in the United States.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for people with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic®.

INCIVEK® is a registered trademark of Vertex Pharmaceuticals Incorporated.

PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.

Reyataz® is a registered trademark of Bristol-Myers Squibb.

Atripla® is a registered trademark of Bristol-Myers Squibb and Gilead Sciences, LLC.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.2 However, approximately 60 percent of people do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9 Hepatitis C is four times more prevalent in the United States compared to HIV.9 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9

About Hepatitis C and HIV Co-Infection

There are 1 million people living with HIV in the United States, and an estimated 300,000 people living with HIV/AIDS in the United States are also infected with hepatitis C. 13 There have been dramatic improvements in the treatment of HIV and the prognosis for people living with HIV. However, liver disease progresses more rapidly in people co-infected with hepatitis C and HIV, with an increased rate of progression to cirrhosis, decompensated liver disease, hepatocellular carcinoma and death. 14, 15, 16, 17 The hepatitis C cure rate with a 48-week treatment of pegylated-interferon and ribavirin, the current standard of care for people with co-infection, is approximately 29 percent.18

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and Science magazine named Vertex number one on its 2011 list of Top Employers in the life sciences.

Vertex's press releases are available at www.vrtx.com.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including Dr. Kauffman's statements in the second paragraph of this press release and statements regarding ongoing and planned Phase 3 studies of INCIVEK combination therapy in people co-infected with HCV and HIV. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the outcomes from future clinical trials of INCIVEK combination therapy in co-infected patients may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

(VRTX-GEN)

References:

1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed February 22, 2012.

2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

9 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed February 22, 2012.

10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed February 22, 2012. This report was commissioned by Vertex Pharmaceuticals, Inc.

11 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

12 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

13 HIV Advocate. HIV/HCV Coinfection. Available at: http://www.hcvadvocate.org/hepatitis/factsheets_pdf/HIV_HCV20coinfecton_10.pdf. Accessed February 28, 2012.

14 Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study. CID 2004;38:128-33.

15 Martinez-Sierra C, Arizcorreta A, Diaz F, Roldan R, Martin-Herrera M, Perez- Guzman E, et al. Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. CID 2003;36:491-8.

16 Matthews GV, Dore GJ. HIV and hepatitis C coinfection. JGH. 2008; 23: 1000-1008.

17 Bruno R, Sacchi P, Puoti M, Soriano V, Filice G. HCV chronic hepatitis in patients with HIV: clinical management issues Am J Gastroenterol 2001; 97:1598—1606.

18 Levin, J. Pegasys/RBV in APRICOT Study- Adherence Improves SVR 300% in genotype 1. Available at: http://www.natap.org/2005/ICAAC/icaac_31.htm Accessed February 28, 2012.



Vertex Pharmaceuticals Incorporated

Media:

Dawn Kalmar
Erin Emlock
Zach Barber
617-444-6992
mediainfo@vrtx.com

or

Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755

Source: Vertex Pharmaceuticals Incorporated

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HCAB Position Statement: Hepatitis C Drug Development and Drug-Drug Interaction Studies...

This HCAB (Hepatitis C Community Advisory Board) position statement was published on 2/28/12 regarding Hepatitis C drug development and drug-drug interaction (DDI) studies. In short, the HCAB would like drug developers to be more proactive in doing DDI studies before the drugs come to market. They admonish Merck specifically for not doing DDI studies with commonly available antiretrovirals and their HCV antiviral drug, boceprevir. Further, they applaud the efforts of Vertex and J&J for doing full due diligence in DDI studies prior to the launch of Telaprevir. 

HCAB Position Statement: Hepatitis C Drug Development and Drug-Drug Interaction Studies

February 17, 2012 -- The Hepatitis C Community Advisory Board (HCAB) recognizes the value of more effective and less toxic treatment for hepatitis C virus (HCV). We believe that sponsors can conduct key drug-drug interaction (DDI) studies with direct-acting antivirals (DAAs) and other candidates in development and medications commonly used by people with hepatitis C and those coinfected with HIV/HCV prior to their approval, without delaying development of these important therapies.

DAAs may share metabolic pathways with drugs that are commonly used by populations with a high prevalence of hepatitis C, such as hormonal contraceptives, methadone, buprenorphine, lipid-lowering agents, immunosuppressive drugs, herbal remedies, and commonly prescribed psychiatric medications.

In recognition of the suboptimal efficacy and tolerability of [pegylated interferon] and ribavirin, rapid trajectory of liver disease progression, and increasing mortality from HCV-related complications among HIV/HCV coinfected patients, regulators in the US and the EU encourage sponsors to conduct trials in HIV/HCV coinfected patients prior to approval for HCV monoinfection. Sponsors have already opened, or plan to launch these trials.

The recent discovery of drug-drug interactions between boceprevir and boosted HIV protease inhibitors underscores the importance of DDI studies with DAAs. Although we commend the sponsor, Merck, for opening one of the first coinfection trials with a DAA, we were outraged that Merck chose not to conduct DDIs with commonly used antiretroviral agents prior to launching the trial, and prior to gaining approval for boceprevir. Vertex and Tibotec were able to bring telaprevir [Incivek] to market with a much fuller portfolio of DDI data, although both drugs were developed within the same timeframe.

HCAB asks FDA [the US Food and Drug Administration], EMA [European Medicines Agency] and pharmaceutical companies to work together to minimize potential harm to hepatitis C monoinfected and HIV/HCV coinfected patients from uncharacterized drug-drug interactions. Furthermore, we call upon sponsors to perform DDI studies (as indicated by metabolic profile of their drug or drugs) with DHHS [US Department of Health and Human Services], EACS [European AIDS Clinical Society] and WHO [World Health Organization]-recommended antiretroviral agents for first-line, and treatment-experienced HIV/HCV coinfected people prior to approval, and strongly encourage studies of hormonal contraceptives, methadone, buprenorphine, lipid-lowering agents, immunosuppressive drugs, herbal remedies, and commonly prescribed psychiatric medications.

2/28/12

Source

Hepatitis C Community Advisory Board. HCAB Position Statement: Hepatitis C Drug Development and Drug-Drug Interaction Studies. February 16, 2012.

G&E News: Patients’ Expectations About New HCV Direct-Acting Antivirals Often Unrealistic...

Lovingly pinched on 2/21/12 from Gastroenterology & Endoscopy News. Ms. Frangou interviews three well-regarded giants of Hepatology, Andrew Muir, Raymond Chung and Gary Davis about the disconnects that often occur between patient expectations with triple therapy and reality. An excellent article about the realities of treatment, definitely worth the read. It would be great to see more attention paid to the mid-level practitioners who are really doing the majority of heavy lifting in this disease state. Getting their perspective on treating patients would be hugely valuable, as they are the ones that often manage the patients day-to-day, manage the patients support systems and often have the frustrating role of pushing through the prior authorizations to get these drugs for patients in the first place. They are definitely the heroes on the front lines fighting this disease.  

Hepatology in Focus

ISSUE: FEBRUARY 2012 | VOLUME: 63

Patients’ Expectations About New HCV Direct-Acting Antivirals Often Unrealistic

Careful Patient Selection, Education Is Key for Success

by Christina Frangou

San Francisco—Soon after the FDA approved two direct-acting antiviral agents (DAAs) last spring for treating infection with hepatitis C virus (HCV), a 57-year-old black man came to see gastroenterologist Andrew Muir, MD.

The man had been diagnosed with hepatitis C in 2001. A liver biopsy one year later revealed he had stage II fibrosis. At the time, the patient declined treatment, saying the duration was too long and offered too few benefits.

But recently, he came back to Dr. Muir wanting to try a new protease inhibitor. Based on his reading, the man believed he could avoid interferon (IFN) and ribavirin (RBV), take a protease inhibitor as monotherapy for 24 weeks and expect a 75% chance of achieving a sustained virologic response (SVR).

Unfortunately, the patient’s expectations were unrealistic on all counts. The new protease inhibitor can only be given in conjunction with IFN and RBV, and the treatment duration varies. For blacks, therapy usually lasts a full 48 weeks, and in clinical trials, only 30% of black patients achieved an SVR with 28 weeks of therapy. Moreover, among black patients in the Phase III trials, SVR rates fell short of the 75% that the patient expected, and in treatment-naive blacks, only 62% receiving telaprevir and 53% on boceprevir achieved an SVR.

Educate To Encourage Adherence

Unrealistic expectations are common among patients with HCV infection who, after years of waiting for better therapies, are eager to try treatment with the new DAAs, said Dr. Muir. The DAAs on the market today are complex, with varied stoppage rules, monitoring points and some serious adverse events and drug–drug interactions.

“This is a real problem for clinicians. There’s tremendous excitement about these new therapies, but oftentimes, patients’ expectations are not in line with what these drugs can deliver,” said Dr. Muir, clinical director of hepatology at Duke University Medical Center, Durham, N.C.

In a presentation at The Liver Meeting 2011, Dr. Muir stressed that clinicians need to take time to carefully prepare patients for DAA therapy. Physicians must have clear, detailed discussions with their patients before and throughout treatment to optimize the benefits of DAA therapy, he said.

“The major challenges are preparing patients for the rigors of therapy, checking in frequently to make decisions about the duration of treatment and managing any issues as the patient goes along,” said Dr. Muir.

When patients come into the office considering treatment with DAAs, the first step is to clarify their expectations, said Dr. Muir. Patients need to learn the reality about DAAs if they want treatment to succeed.

Dr. Muir outlines for patients the complex prescribing rules, the contraindications, the lifestyle changes and duration of treatment with DAAs. The lifestyle changes can be significant, he cautions patients. Both telaprevir and boceprevir must be taken three times a day, or once every eight hours, and always with a meal. Dr. Muir then asks if the patient still wants treatment when these things are taken into account.

“That’s no small feat. Patients must adhere to that regimen because lapses in the concentration of telaprevir and boceprevir have historically been the risk period for breakthrough variants on therapy,” said Raymond Chung, MD, chief of hepatology and vice-chief of gastroenterology at Massachusetts General Hospital, Boston. Many of Dr. Chung’s patients limit or reschedule their work hours while on DAA therapy to help with adherence.

The key to getting patients through DAA treatment successfully is to select patients carefully and prepare them assiduously, said Gary L. Davis, MD, director of general and transplant hepatology at Baylor University Medical Center, Dallas. “This means that any issues that might impact compliance, tolerance and drug access should be dealt with before treatment starts. Educating the patient is essential. Patients and their support person need to clearly understand the importance of dosing compliance, lab monitoring and treatment stopping rules/end points.”

The treatment care team then needs to remain in close contact with the patient throughout treatment to reinforce adherence and offer feedback on their process, he added. At Dr. Chung’s office at Massachusetts General Hospital, one nurse practitioner has been assigned full-time to managing patients on DAAs. She works with them on everything from managing possible reactions like rash and anemia to helping them set up a daily schedule for taking the medications.

“We have 50 to 100 patients in varying stages of DAA treatment,” said Dr. Chung. “Every one of these patients is coming in for frequent visits—weekly in the beginning—and they are very much in need of monitoring, not just for adverse events like rash but also for fatigue and their ability to carry out work.”

Begin With a Thorough History

Before patients start the new therapies, gastroenterologists and hepatologists should consider getting a liver biopsy to help guide treatment, said Dr. Muir. Physicians also should confirm a patient’s history of treatment for HCV. If patients were previously on antiviral therapies, physicians need to find out as much as they can about that experience.

“You must ask whether we can improve upon previous treatment,” said Dr. Muir. “Were there adverse events with treatments? Were there dose reductions? If so, were they appropriate? How was patient adherence to medications? Did they use alcohol?”

Based on that information, physicians should outline the likelihood of each individual patient achieving an SVR, he said. The key predictors of SVR are whether patients are treatment-naive or treatment-experienced, whether they have cirrhosis and their race. Another important issue for patients is treatment duration. Duration will vary depending on each patient’s characteristics. “It’s important to speak with every patient about their likelihood of a shorter duration of treatment,” said Dr. Muir.

The American Association for the Study of Liver Diseases recommends 48 weeks of treatment for all patients with cirrhosis, as fewer patients with cirrhosis were included in the clinical trials that led to approval of the new drugs. Among those included, virologic response levels were lower than for patients without cirrhosis. For treatment-naive patients, 46% of non-black and 29% of black patients in the boceprevir SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial achieved undetectable levels of HCV by 28 weeks, making them eligible for the shortened course of treatment (Poordad F et al. N Engl J Med 2011;364:1195-1206). In the telaprevir trial, 58% of patients had an early rapid virologic response (Jacobson IM et al. N Engl J Med 2011;364:2405-2416).

Patients’ interleukin-28B (IL28B) genotype also affects the expected duration of treatment. For both boceprevir and telaprevir, patients with the IL28B CC genotype are most likely to attain an early virologic response, more likely to receive a shortened course of therapy and more likely to have an SVR, according to studies presented at last year’s annual meeting of the European Association for the Study of the Liver.

Follow Through: Monitor for Response, Resistance, Reactions, Interactions

When the new HCV drugs were first approved, physicians’ offices reported some trouble getting approval from third-party payers for the full course of treatment, said Dr. Chung. His office had to provide documentation of successful early virologic response to get the go-ahead from payers to approve continuation of treatment with a protease inhibitor.

“You can imagine that if any gaps occur in the virologic tests or their reporting, this could lead to interruption of protease inhibitor therapy. It’s been a real challenge,” he said.

Experts recommend following patients very carefully over the course of treatment, monitoring any virologic breakthroughs or adverse reactions to the medications, particularly rash and anemia. Dr. Chung sees patients after the first, second and fourth week of therapy, and every four weeks thereafter if patients are having an uneventful course. Treatment monitoring is essential to prevent unwarranted continuation of treatment in patients when a breakthrough has occurred, he said.

“That would signal the emergence of resistant variants. Upon discovery, it would be paramount to discontinue the entire regimen to prevent selection of additional resistance mutations,” he said.

Equally important is the need to monitor patients closely for adverse reactions and drug–drug interactions. As IFN and RBV remain the backbone of this HCV regimen, the same contraindications exist as with standard dual therapy: decompensated cirrhosis, renal insufficiency, advanced cardiac/pulmonary disease, active depression, severe mental illness, anemia/neutropenia/thrombocytopenia and noncompliance.

Additionally, there are important drug–drug interactions with boceprevir and telaprevir. Both DAAs inhibit the CYP3A4/5 enzyme. Drugs metabolized by CYP3A4/5 may have increased effect in the presence of boceprevir or telaprevir. The DAAs themselves are metabolized by this cytochrome. As a result, other drugs that induce or inhibit CYP3A4/5 could affect HCV levels.

“Planning is key to deal with drug–drug interactions,” said Dr. Muir. It’s very important to do a risk–benefit analysis of treatment with boceprevir and telaprevir, taking into account patients’ comorbidities, he added.

It is important to review all drugs that the patient is taking, including over-the-counter and herbal medications. Check with the patient’s primary care provider, cardiologist and psychiatrist about medication use, Dr. Muir said. “It’s a good time to revisit the need for all medications. Ask if the antidepressant can be changed, the blood pressure medicines. Can the patient hold their statin for 12 weeks?” he said.

Women taking oral contraceptives should be advised to try other methods of contraception, such as an intrauterine device or barrier methods. Additionally, pregnant women should not take either drug, as both are considered pregnancy category X, meaning the risks “clearly outweigh potential benefits,” according to the FDA.

Anemia and rashes are the two most common adverse events associated with the new therapies. Experts suggest physicians be proactive about managing both.

Before a patient starts therapy, do a pretreatment evaluation for anemia and consider the impact on comorbidities, such as cardiac and pulmonary disorders. Weigh the benefits of reducing the dose versus increasing or starting erythropoietin.

For rashes, patients should be proactive by moisturizing twice a day, limiting sun exposure and wearing loose-fitting clothing. Dr. Chung recommends including a dermatologist on the treatment team.

Keep an Eye on the ‘Holy Grail of Therapy’

One other important element that needs to be taken into account when considering patients for DAA therapy is whether patients should wait for something else to be approved, said Dr. Chung. Recent results from Phase II studies of second-generation DAAs suggest that some combination of these could be approved in the next three years (see “New Polymerase Inhibitor Could Become Cornerstone of Interferon-free HCV Treatment Regimen,” by Christina Frangou. Gastroenterology & Endoscopy News 2012;63[2]:16 and “Second Study of New Hep C Drug Is Promising for Difficult-to-Treat HCV Genotype 1 Patients,” by Christina Frangou. Gastroenterology & Endoscopy News 2012;63[2]:17-19). These therapies omit IFN from the treatment regimen and can generally be taken orally once a day, with or without food.

“That’s something critical to consider. With all the complexities of therapy—the issues of tolerability, adherence, drug–drug interactions, quality of life—there’s another equally important set of events going on, and that’s the emerging data on all-oral, interferon-free treatments,” said Dr. Chung. “It’s clear that the promise of interferon-sparing therapy is very real. For all of us, that would be the holy grail of therapy.”

Dr. Chung currently recommends that all patients with HCV infection who have advanced-stage disease, regardless of whether they are treatment-naive or experienced, should be considered for boceprevir or telaprevir, provided the benefits outweigh the risks. Patients who can reasonably defer treatment because of early-stage disease or who cannot tolerate IFN may be able to wait for investigational therapies to be approved. These patients also may be eligible for investigational studies, which are ongoing.

Dr. Muir disclosed that he is on advisory committees or review panels for Merck & Co., and Vertex Pharmaceuticals; is a consultant for Inhibitex, Merck & Co., and Vertex Pharmaceuticals; and receives grant/research support from Abbott Laboratories, Anadys, Bristol-Myers Squibb, Gilead, Medtronic, Merck & Co., Pfizer, Roche, Santaris, Scynexis and Vertex Pharmaceuticals. Dr. Chung receives grant/research support from Gilead, Merck & Co., Pfizer and Romark. Dr. Davis is a consultant for Vertex Pharmaceuticals and receives grant/research support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Novartis, Pharmasset, Tibotec and Vertex Pharmaceuticals.

Merck posts 'Dear Doctor' letter regarding use of Victrelis with boosted HIV protease inhibitors...

Thank you NATAP.org. DHCP letter that came out today (Feb 6th, 2012) regarding drug-drug interactions with Boceprevir and ritonovir-boosted PIs. In short. "Merck does not recommend the coadministration of VICTRELIS and ritonavir-boosted HIV protease inhibitors." 



S. Sethu K. Reddy, MD Merck & Co., Inc.


Vice President PO Box 250

US Medical Affairs West Point, PA 19486-0250


February 6, 2012

IMPORTANT DRUG WARNING

SUBJECT: Results of Pharmacokinetic Study in Healthy Volunteers Given VICTRELIS™

(boceprevir) and Ritonavir-Boosted HIV Protease Inhibitors May Indicate Clinically Significant Drug

Interactions for Patients Coinfected with Chronic Hepatitis C and HIV


Dear Health Care Professional,

The purpose of this communication is to inform you of recent pharmacokinetic study results evaluating drug

interactions between VICTRELIS, an oral chronic hepatitis C virus (HCV) NS3/4A protease inhibitor, and

ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors in healthy volunteers (n=39).

VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in

combination with peginterferon alfa and ribavirin (PR), in adult patients (18 years and older) with

compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous

interferon and ribavirin therapy. In the pharmacokinetic study, concomitant administration of VICTRELIS

with Norvir® (ritonavir) in combination with Reyataz® (atazanavir) or Prezista® (darunavir), or with Kaletra®

(lopinavir/ritonavir) resulted in reduced exposures of the HIV medicines and VICTRELIS. Specifically,

VICTRELIS reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir, and darunavir

by 49%, 43%, and 59%, respectively. Mean reductions of 34% to 44% and 25% to 36% were observed in

AUC and Cmax of atazanavir, lopinavir, and darunavir. Coadministration of ritonavir-boosted atazanavir with

VICTRELIS did not alter the exposure of VICTRELIS, but coadministration of VICTRELIS with

lopinavir/ritonavir or ritonavir-boosted darunavir decreased the exposure of VICTRELIS by 45% and 32%,

respectively.

These drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by

potentially reducing the effectiveness of these medicines when coadministered. VICTRELIS is not indicated

for use in patients who are infected with both HIV-1 and chronic HCV. The safety and efficacy of

VICTRELIS™ (boceprevir) has not been established in this coinfected population. Merck does not

recommend the coadministration of VICTRELIS and ritonavir-boosted HIV protease inhibitors.

Health care providers who might have initiated VICTRELIS in combination with PR in HIV-HCV coinfected

patients on fully suppressive antiretroviral therapy containing a ritonavir-boosted protease inhibitor should

discuss these findings with those patients, and closely monitor those patients for HCV treatment response

and for potential HCV and HIV virologic rebound.

Patients should be advised to contact their health care provider before stopping any of their

medications.

Merck is sharing these pharmacokinetic data with regulatory authorities in the countries where VICTRELIS

is approved. Merck will be submitting requests to regulators to update the product labeling with these data.

These data have been submitted for scientific presentation at an upcoming medical forum.

For more information, please consult the enclosed Prescribing Information for VICTRELIS. The Prescribing

Information can also be found at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.

Should you have any questions, require further information on product safety, or wish to report an adverse

event with VICTRELIS, please contact Merck at 1-877-888-4231. Alternatively, an adverse event can be

reported directly to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Sincerely,

S. Sethu K. Reddy, MD

Enclosure: Prescribing Information for VICTRELIS

- 3 -

Indications and Usage for VICTRELISTM (boceprevir)

VICTRELIS was approved by the US Food and Drug Administration (FDA) on May 13, 2011 for the

treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon

alfa and ribavirin (PR), in adult patients (18 years and older) with compensated liver disease, including

cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV

infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with PR.

• VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment

regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.

• VICTRELIS in combination with PR has not been studied in patients documented to be historical null

responders (<2-log10 HCV-RNA decline by Treatment Week 12) during prior therapy with PR. The clinical

studies included subjects who were poorly interferon responsive. Subjects with <0.5-log10 HCV-RNA

decline in viral load at Treatment Week 4 with PR alone are predicted to have a null response (<2-log10

viral load decline at Treatment Week 12) to PR therapy.

• Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a

lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of

resistance-associated substitutions upon treatment failure, compared to patients with a greater response

to PR.

Selected Safety Information for VICTRELIS

All contraindications to PR also apply since VICTRELIS must be administered with PR.

Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR is

contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in

female patients and female partners of male patients. Patients must have a negative pregnancy test prior to

therapy; have monthly pregnancy tests; and use 2 or more forms of effective contraception, including

intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has

concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS

and concomitant ribavirin.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for

clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening

events. VICTRELIS is also contraindicated in coadministration with potent CYP3A4/5 inducers, where

significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy.

Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital,

phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s

Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca®

(tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally

administered midazolam.

- 4 -

Anemia and/or Neutropenia – The addition of VICTRELIS™ (boceprevir) to PR is associated with an

additional decrease in hemoglobin concentrations compared with PR alone and/or may result in worsening

of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa

and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not

be administered in the absence of PR.

Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to

initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at Treatment

Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (>35%) in clinical trials in adult patients receiving the

combination of VICTRELIS with PR were: fatigue, anemia, nausea, headache, and dysgeusia. Of these

commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates ≥5%

above the rates for PR alone in either clinical study. The incidence of these adverse reactions in previously

untreated subjects that were treated with combination therapy with VICTRELIS compared with PR alone

were: fatigue (58% vs 59%), anemia (50% vs 30%), nausea (46% vs 42%), and dysgeusia (35% vs 16%),

respectively. The incidence of these adverse reactions in previous treatment failure patients that were

treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55% vs 50%),

anemia (45% vs 20%), nausea (43% vs 38%), and dysgeusia (44% vs 11%), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for

drug-drug interactions must be considered prior to and during therapy.

Merck reports increased Victrelis sales in Q4 2011...

Posted on 2/2/12 on Zacks.com - Merck reveals Q4 financials, beating EPS speculations. For us HCV drug development wonks, we find Victrelis on an upward trajectory, with sales increasing to $87 million, up from $31 million and $21 million reported in the 3rd and 2ndquarters of 2011. They boast of a huge formulary win, that of the Veterans Health Administration, the nation's largest provider of Hepatitis C care.

Merck Beats on EPS, Guides In-Line
By: Zacks Equity Research
February 02, 2012 |Comments: 0

Merck & Co. (MRK) reported fourth quarter 2011 earnings per share (excluding special items) of 97 cents, a couple of cents above the Zacks Consensus Estimate and 10.2% above the year-ago earnings.

Revenues for the quarter increased 1.7% to $12.3 billion, just shy of the Zacks Consensus Estimate of $12.5 billion. Including one-time items, Merck swung to a profit of 49 cents per share from the year-ago loss of 17 cents.

The company reported full-year earnings of $3.77 per share, a penny above Zacks Consensus Estimate and 10.2% above the year-ago earnings. Earnings exceeded the top end of the company’s guidance range of $3.72 - $3.76 per share. Full-year revenues increased 4.5% to $48 billion, slightly below the Zacks Consensus Estimate of $48.2 billion. Including one-time items, Merck earned $2.02 per share, well above the year-ago earnings of 28 cents.

The Quarter in Details

Merck’s Pharmaceutical segment posted sales of $10.8 billion, up 3%. Products like Januvia, Janumet, Singulair, Isentress and Gardasil contributed to sales. However, the strong performance of these products was partially offset by lower sales of Vytorin. Remicade sales also declined during the quarter.

Singulair, indicated for the chronic treatment of asthma and relief of symptoms of allergic rhinitis, recorded $1.5 billion in sales, up 8% from the year-ago period. However, Singulair sales will experience a severe decline following its US patent expiry in August 2012.

Meanwhile, with Merck transferring exclusive marketing rights for Remicade and Simponi to Johnson & Johnson (JNJ), Remicade and Simponi combined sales fell 24%. We expect Merck to focus on improving penetration rates and drive growth in Europe, Russia and Turkey.

Isentress, the company’s product for HIV infection, recorded an increase of 24% to $387 million during the reported quarter.

The diabetes franchise, consisting of Januvia and Janumet, continued to perform well, and witnessed growth across all regions. Combined sales increased 40% to $1.3 billion. While Januvia sales increased 42% to $960 million, Janumet sales increased 34% to $386 million. Merck is working on increasing sales of its diabetes franchise by gaining approval for additional indications. The diabetes franchise should benefit from the recent approval of Juvisync, which is a combination of Januvia and Zocor.

Gardasil, Merck’s cervical cancer vaccine, recorded sales of $274 million, up 24% year over year. Sales were driven by increased vaccination of males aged 9-26 years. Zostavax sales came in at $78 million with performance being driven by an improvement in the supply situation. Merck reported that it has filled all backorders and the supply situation has returned to normal in the US.

Meanwhile, Merck’s ProQuad, MMR II and Varivax vaccines recorded combined sales of $276 million, down 3%. Vytorin sales fell 16% to $475 million during the quarter.

Merck provided an update on its recently approved hepatitis C treatment, Victrelis (boceprevir). Sales increased to $87 million, up from $31 million and $21 million reported in the third and second quarters of 2011, respectively. We were encouraged to see the sequential improvement in Victrelis sales.

According to the company, Victrelis was added to the VA formulary, which is the largest single provider of services to hepatitis C patients in the US. This represents a significant commercial opportunity for Victrelis.

Merck has an agreement with Roche (RHHBY) for the global marketing of Victrelis as part of a triple combination therapy. Victrelis is available in the US and 19 other countries.

Emerging markets accounted for 17% of pharmaceutical sales in the fourth quarter of 2011 with China continuing to put in a strong performance.

Merck’s animal health segment posted sales of $868 million, up 6%. Increased sales of companion animal, swine and poultry products helped drive growth.

Consumer Care sales fell 5% to $361 million in the fourth quarter of 2011, mainly due to lower sales of Claritin and Coppertone.

Total costs declined 1.4% to $8.6 billion. Marketing and administrative expenses increased 5.9% to $3.6 billion in the fourth quarter of 2011 due to the impact of product launches, US health care reform fees and corporate charges. R&D spend declined 4.8% to $2.1 billion in the fourth quarter of 2011, mainly due to efficiency savings.

In-Line Guidance for 2012

With the release of fourth quarter results, Merck provided its outlook for 2012. The company expects adjusted earnings in the range of $3.75 - $3.85 per share. Guidance was in line with expectations -- the Zacks Consensus Estimate currently stands towards the higher end of the guidance range at $3.83 per share.

Revenues are expected to remain flat or close to 2011 levels. The company said that revenues would be negatively impacted by 2-3% at current exchange rates.

Merck expects R&D spend to remain at similar levels as in 2011. The company spent $7.7 billion on R&D in 2011. The company’s late-stage pipeline is advancing with five regulatory filings expected in 2012 and 2013. These include Bridion (a neuromuscular reversal agent), V503 (an investigational vaccine to help protect against certain HPV associated cancers), odanacatib (once-weekly oral treatment of osteoporosis), Tredaptive (atherosclerosis) and suvorexant (insomnia).

Neutral on Merck

We currently have a Neutral recommendation on Merck, which carries a Zacks #3 Rank (short-term Hold rating). Merck is entering a challenging period with its biggest product, Singulair, slated to lose US exclusivity in August. Singulair sales came in at $5.5 billion in 2011, accounting for 13.3% of Pharmaceutical sales.

We believe Merck will continue resorting to cost-cutting initiatives to drive the bottom-line. Meanwhile, some of the company’s recent launches should start contributing significantly to the top line in the forthcoming quarters.

Seeking Alpha.com's Chris Katje on Gilead potential for antiviral dominance...

A bullish outlook for Gilead from Seeking Alpha author Chris Katje. His view is that Gilead will have market dominance in both HIV and HCV. He sees that Gilead will have full control of the Pharmasset HCV portfolio through the buyout, thus negating any worry about royalty payments. I'd also add the potential for co-formulation between Pharmasset's portfolio and Gilead's current HCV portfolio, which has always been Gilead's hallmark. An interesting read and it seems the rest of the market seems to agree with Katje, as Gilead stock has received several outlook upgrades from analysts. It just took some time for the initial sticker shock to wear off.

Acquisition of Pharmasset

Gilead Sciences (GILD) announced its intent to acquire Pharmasset (VRUS) for a whopping $11 billion on Monday morning. The deal has led many analysts and investors to question if Gilead overpaid for the deal. I think the deal is a great long-term play for the company and actually could present a buying opportunity of shares, which were down sharply after the announcement. Shares were up around five percent the following day after the announcement. Gilead will now be a large player in the HIV and Hepatitis markets.

Pharmasset has no drugs on the market, which is the biggest reason why people question the valuation. Drug candidate PSI-7977 appears to show enough promise that other companies were nibbling at acquiring the company. Gilead is confident in its acquisition and is funding the deal through cash and $6 billion in debt it is taking on. Hepatitis C is being targeted by this drug and it could actually save many Americans from the life threatening liver damage that is usually caused by the disease and leads to many liver transplants. The drug is expected to be filed with the Food and Drug Administration in 2014. Pharmasset owned the worldwide rights to the drug so Gilead will take full control and will not have to worry about licensing or royalty payments. Gilead now will be the leader in the race to find an all oral drug for the treatment of Hepatitis C.

Why the Acquisition and Hefty Premium

Gilead presented a slide show on its website shortly after the announcement to acquire Pharmasset. Gilead reconfirmed its goal of creating the best Hepatitis C drug, which would be determined by some of the following:

Taken Once Daily
Manageable Side Effects
Higher Cure Rates Than Current Drugs on the Market
Increased Treatments With a New Drug

Gilead has recognized that a combination of two or more drugs may be needed to create this super Hepatitis C drug. This is where I believe that Gilead’s acquisition will ultimately pay off. Gilead has combined several of its own drugs with products of other companies to create better acting and more effective drugs for patients.

Competition in Hepatitis C Market

Several other Hepatitis C drugs have popped up on the market recently. Victrelis is a drug owned by Merck (MRK), acquired through its acquisition of Schering Plough. The drug has so far been a disappointment as it only brought in $31 million of revenue in the third quarter reported on October 31, for Merck. Incivek, a drug owned by Vertex Pharmaceuticals (VRTX), on the other hand posted sales of $419 million in the past quarter. Analysts have already been lowering price targets of VRTX because of the likely competition from PS-7977 pending approval. Vertex will enjoy a couple of years of dominating market share before the competing drug enters the market. Annual sales could hit $2 to $3 billion for Vertex. Merck on the other hand is playing second fiddle and is likely to never see blockbuster status with its Hepatitis C drug.

Gilead’s Biggest Acquisitions

Gilead has a long history of acquiring other drug companies as many large drug companies do. Highlights include:

1999 Nexstar Pharmaceuticals - Gained two drugs through the acquisition. One, Ambisome, is still a marketed drug by Gilead. Deal seemed to be made more for the company’s intent on expanding in Europe.

2003 Triangle Pharmaceuticals - Emtriva, now a part of two Gilead drugs, was gained through this $464 million acquisition. Atripla and Truvada both use the component emtricitabine, a former Triangle product.

2006 Corrus Pharma - Has a current drug in Gilead’s pipeline aimed at treating Cystic Fibrosis.

2006 Myogen - Myogen was the most expensive acquisition previous to Pharmasset coming in at $2.5 billion. This has also been one of the most important and successful acquisitions made by Gilead as it brought three drugs, two marketed, and one currently sold by Gilead to the company.

2009 CV Therapeutics - Billion dollar purchase helped strengthen and diversify Gilead’s pool of drugs as it gained two drugs aimed at cardiovascular diseases.

Several other million dollar deals were made by Gilead over the last eight years. Gilead has made many of its acquisitions to strengthen its own technology and combine existing drugs with new ones.

Gilead’s Products

Gilead remains the market leader in drugs that treat the HIV virus. Its marketed products in the HIV market are:

Atripla is marketed with Bristol Myers Squibb (BMY) after its approval in 2006. The drug treats HIV and will lose patent expiration in 2021.

Complera is one of Gilead’s newest drugs on the market. It was approved by the FDA in August of 2011, and is co-marketed with Johnson and Johnson (JNJ).

Emtriva was approved in 2003 and will expire in 2021.

Truvada treats HIV and is one of Gilead’s top selling drugs. It was approved in 2004 and will lose its patent protection in 2021.

Viread treats Hepatitis B and HIV viruses. The drug was the first successfully launched HIV drug in 2001 by Gilead. The drug, which is a huge seller for Gilead, will lose patent protection in 2017.

Gilead has drugs in several other fields that compete with numerous other large drug companies. The other drugs currently on the market are:

Ambisome treats infections like fungal, meningitis, and Cryptococcus. The drug was approved in 1997 and will lose patent protection in 2016. The marketing partner on the drug is Astellas Pharma.

Cayston is Gilead’s cystic fibrosis drug that was approved in 2010. The drug has exclusive patent protection until 2021. Gilead markets the drug on its own and maintains all revenue from the drug.

Hepsera treats Hepatitis B and is owned and marketed by Gilead. The drug was approved in 2002 and its patent expires in 2014.

Letairis has since 2007 treated Pulmonary Hypertension. The drug is co-marketed with GlasxoSmithKline (GSK) and loses patent protection in 2015.

Lexiscan is a cardiovascular drug marketed with Astellas Pharma and it will lose patent protection in 2019.

Macugen is an age-related macular degeneration drug first approved in 2004, which is shared with Pfizer (PFE) and will lose patent protection in 2017.

Ranexa treats chest pain and will lose patent protection in 2019. The drug is co-marketed with Swiss drug company Roche.

Tamiflu treats the influenza virus as an oral capsule. The drug, which loses its patent protection in 2016, is licensed to Roche.

Vistide treats Cytomegalovirus and also certain eye problems involving the retina. The drug was founded in 1996 and has since lost its patent protection.

Gilead’s Pipeline

Gilead has twenty drugs listed on its site in current phases of trial. The drugs target HIV, Hepatitis C, numerous Cardiovascular diseases, Diabetes, Leukemia, Non-Hodgkin’s Lymphoma, and other diseases. Like many other large drug companies, Gilead has kept a strong pipeline targeting some of the biggest diseases affecting the world today. Three drugs targeting HIV are in Phase III trials currently. The Pharmasset acquisition will improve the company’s pipeline as it focuses on becoming a large player in the Hepatitis C market. Gilead will likely test several of its own Hepatitis drugs with Pharmasset products to create dual drugs much like it has with its HIV drugs.

The most important drug for Gilead in my opinion is known as the Quad. The drug combines Gilead’s own products and will help cut part of its revenue share with other marketing partners. The drug has held up well in trials. The drug will be brought in front of the FDA in 2012 and could be a substantial revenue earner for Gilead. The Quad drug is cutting down on symptoms from Gilead’s Atripla including dizziness, insomnia and depression. There are two trials testing Gilead drugs together in the Quad trials. Atripla had sales of $2.9 billion over the last year. However a portion of that revenue is given to Bristol Myers Squibb for its contribution to the drug. The approval of the quad pill could provide a nice bump to the share price in 2012.

Gilead’s Current Sales

Gilead is the leader in the HIV drug market and has shown its dominance. From the slide show presentation after the Pharmasset announcement it listed trailing twelve month revenue at $7.4 billion. The total market for HIV drugs is currently $13 billion so Gilead controls 50% of this blockbuster medical category. In the last fiscal year Gilead had earnings per share of $3.32 based on earnings of $2.9 billion.

Analysts call for earnings of $4.37 for the next fiscal year. With a closing share price of $39.28 on Friday, the price-to-earnings ratio is less than nine. According to Yahoo Finance, over 91% of the shares are currently held by institutions and mutual funds. More than 900 funds hold shares of Gilead as it represents one of the best plays on the healthcare and drugs industry.

Analyst Upgrades

Several days after the acquisition of Pharmasset was announced, analysts have upgraded shares. Citigroup and Bank of America both upgraded the shares after revaluating. Bank of America said that the company’s Hepatitis C program could some day be worth $15 to $30 billion. Gilead currently has a market capitalization of just under $30 billion so this deal could clearly define the company for the future.

My Share Valuation

I think the buyout of Pharmasset is a great purchase for Gilead. Gilead has made great use of drugs acquired through pipelines of companies it has bought out. Gilead absolutely owns the HIV drug market and the deal should help insure it gets a large portion of the Hepatitis C drug market in the future as well. For the coming year shares should trade closer to 12 times earnings, which would represent a share price of $52.44. The approval of the Quad drug as well as earnings announcements could power shares past $60. I think long term the company could double its market capitalization to $60 billion with its marketed HIV drugs and several Hepatitis C drugs on the market. I think shares would be a great purchase for an IRA as a bet on the company for the future.

Disclosure: I have no positions in any stocks mentioned, but may initiate a long position in GILD over the next 72 hours.

Hep C Protease Inhibitors May Not Be Cost-Effective For Some First-Time Treatment Takers

From http://www.hepmag.com, a synopsis of an AASLD study authored byZiad Gellad, MD, MPH, of Duke University Medical Center that argues triple therapy may not be the most cost-effective stragtegy for genotype 1 patients with the IL-28B CC genotype. As we know, patients with the CC genotype are more likely to respond to peg-interferon and ribavirin alone, at a significant cost savings compared to starting these patients on a HCV protease inhibitor. According to Gellad, " for first-time treatment takers with the IL-28B CC genotype, adding Incivek “is unlikely to be cost-effective under current cost and efficacy conditions”

Hepatitis C virus (HCV) protease inhibitors are not cost-effective for first-time treatment takers with HCV genotype 1 and the IL-28B CC genotype, according to analysis conducted by Ziad Gellad, MD, MPH, of Duke University Medical Center in Durham, North Carolina, and his colleagues. They reported their findings on Monday, November 7, at the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco. According to the study authors, people with the IL-28B CC genotype are more likely to be cured with pegylated interferon and ribavirin alone than people with the IL-28B CT or TT genotypes, for whom the addition of either Incivek (telaprevir) or Victrelis (boceprevir) may be more cost effective.

A 24- to 48-week course of pegylated interferon and ribavirin ranges from $18,000 to $30,000. As Gellad noted, “adding Incivek (telaprevir) or Victrelis (boceprevir)”—both recently approved HCV protease inhibitors—“more than doubles the cost of therapy, to a range of $48,000 to $85,000.”

An advantage of Incivek and Victrelis is that they can improve the effectiveness of treatment when added to a combination of pegylated interferon and ribavirin. This is particularly true for people with the IL-28B CT or TT genotype, which is believed to reduce the effectiveness of pegylated interferon, which remains a backbone of hepatitis C treatment. Conversely, those with the IL-28B CC genotype are much more likely to respond effectively to pegylated interferon-ribavirin therapy. Thus, it remains unclear if adding either Incivek or Victrelis to pegylated interferon/ribavirin—provided that the patient has an IL-28B CC genotype and is starting therapy for the first time—translates into added effectiveness worth the additional cost of either drug.

The authors created a model that allowed them to analyze three HCV treatment strategies. The first strategy involved 48 weeks of treatment with pegylated interferon plus ribavirin. The second strategy involved 24 weeks of pegylated interferon and ribavirin according to response-guided therapy (RGT) rules, which take into consideration viral load measurements at weeks four and 12 of treatment. The third strategy involved 12 weeks of Incivek in combination with either 24 or 38 weeks of pegylated interferon plus ribavirin.

According to the analysis by Gellad’s team, the cure rates among first-time treatment takers with the CC genotype were similar, yet the costs of each regimen varied considerable. Among those who qualified for 24 weeks of RGT with pegylated interferon and ribavirin alone, the cure rate was expected to be roughly 71 percent at a cost of $46,785. The cost increased to $54,931 when interferon/ribavirin was used for a total of 48 weeks, with an expected cure rate of 66 percent. If retreatment was necessary in either circumstance, roughly 87 percent to 91 percent would be cured.

Starting hepatitis C treatment with an Incivek-inclusive regimen was expected to cure 89 percent of HCV-positive individuals with the CC IL-28B genotype—at a cost of $68,788. According to estimates of lifetime treatment costs and quality-adjusted life-years (QALYs) measurements, however, the gain did not differ significantly compared with the other two strategies.

Adding Incivek to pegylated interferon and ribavirin was cost-effective for first-time treatment takers in certain circumstances, Gellad and his colleagues noted, such as when it enhanced the early response to hepatitis C treatment (known as extended rapid virologic response, or eRVR). An eRVR—when hepatitis C viral load is undetectable at treatment week 4 and remains that way at week 12—is a strong predictor of being cured. Incivek was considered cost-effective when it boosted the eRVR rate to 89 percent. For people who did not have an eRVR, Incivek was cost effective if it could increase cure rates to over 80 percent. In addition, the authors considered Incivek to be cost-effective for retreating people who relapsed or did not respond to dual therapy.

In summary, for first-time treatment takers with the IL-28B CC genotype, adding Incivek “is unlikely to be cost-effective under current cost and efficacy conditions,” said Gellad, who concluded by recommending research to compare effectiveness of treatment with and without an HCV protease inhibitor in this group.