Janssen Submits Supplemental New Drug Application to U.S. FDA for OLYSIO™ (Simeprevir) for Once-Daily Use in Combination with Sofosbuvir for 12 Weeks for the Treatment of Adult Patients with Genotype 1 Chronic Hepatitis C

Filing Includes Data from Treatment-Naïve Patients with Advanced Fibrosis and Null Responders with All Stages of Liver Fibrosis

RARITAN, New Jersey – May 7, 2014 – Janssen Research & Development, LLC (Janssen) today announced it has submitted a Supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for simeprevir, an NS3/4A protease inhibitor marketed as OLYSIO™ in the United States, in combination with the nucleotide analog NS5B polymerase inhibitor sofosbuvir developed by Gilead Sciences, Inc. This regulatory submission is for the treatment of genotype 1 chronic hepatitis C (HCV) in adult treatment-naïve patients with advanced fibrosis and null responders with all stages of liver fibrosis.

OLYSIO™ is currently approved for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. OLYSIO™ efficacy has been established in combination with peginterferon alfa and ribavirin in HCV genotype 1-infected patients with compensated liver disease, including cirrhosis.

“Hepatitis C places a significant burden on the lives of those infected and if left untreated may cause significant damage to the liver, including cirrhosis and complications such as liver failure,” said Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development. “This filing brings us closer to potentially offering these patients a once-daily all-oral treatment combination that includes the direct-acting antiviral agents simeprevir and sofosbuvir.”

The regulatory submission for OLYSIO™ and sofosbuvir is supported by data from the Phase 2 COSMOS study which included treatment-naïve patients with advanced fibrosis (METAVIR F3 to F4 scores) and null-responder patients with all stages of liver fibrosis (METAVIR F0 to F4 scores).

In April 2014, Janssen announced initiation of the Phase 3 OPTIMIST trials examining the safety and efficacy of simeprevir and sofosbuvir without interferon or ribavirin for the treatment of chronic genotype 1 HCV infection.  In the first trial, known as OPTIMIST-1, the combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naive or treatment experienced.  In the second trial, known as OPTIMIST-2, the combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naive or treatment experienced.   For more information please visit www.clinicaltrials.gov.

About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver that affects approximately 3.2 million people in the United States and is a leading cause of chronic liver disease. Approximately 150 million people are infected with hepatitis C worldwide and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver, including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About OLYSIO™ (simeprevir)
OLYSIO™ is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S., and in March 2014 in Russia. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C and the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending Marketing Authorisation in the European Union for the use of simeprevir in combination with other medicinal products for the treatment of chronic HCV. This application is under review by the EMA.

Important Safety Information

What Is OLYSIO™?

• OLYSIO™ (simeprevir) is a prescription medicine used with other antiviral medicines, peginterferon alfa and ribavirin, to treat genotype 1 chronic (lasting a long time) hepatitis C in adults with stable liver problems.
• OLYSIO™ must not be taken alone. The efficacy of OLYSIO™ in combination with peginterferon and ribavirin is greatly decreased in patients who have genotype 1a Q80K. Please talk to your doctor about testing for genotype 1a Q80K and using a different therapy when genotype 1a Q80K is present.
• It is not known if OLYSIO™ is safe and effective in children under 18 years of age.

What is the most important information I should know and who should not take OLYSIO^™ (simeprevir)?

• OLYSIO^™, in combination with peginterferon alfa and ribavirin may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, or plans to become pregnant, do not take these medicines. You or your sexual partner should not become pregnant while taking OLYSIO^™ with peginterferon alfa and ribavirin and for 6 months after treatment is over.
  • Females and males must use two effective forms of birth control during treatment and for 6 months after treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy. Talk to your healthcare provider about forms of birth control that may be used during this time.
  • Females must have a pregnancy test before starting treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy, every month while being treated, and every month for 6 months after your treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy is over.
  • If you or your female sexual partner becomes pregnant while taking OLYSIO^™, peginterferon alfa, and ribavirin combination therapy or within 6 months after you stop taking these medicines, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes ribavirin while she is pregnant.
• OLYSIO^™ in combination with peginterferon alfa and ribavirin may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy.
  • Use sunscreen, and wear a hat, sunglasses, and protective clothing when you will be exposed to sunlight during treatment with OLYSIO^™.
  • Limit sunlight exposure during treatment with OLYSIO^™.
  • Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with OLYSIO^™.
  • Call your healthcare provider right away if you get any of the following symptoms:
    • burning, redness, swelling or blisters on your skin
    • mouth sores or ulcers
    • red or inflamed eyes, like "pink eye" (conjunctivitis)
• Do not take OLYSIO^™ alone. OLYSIO^™ should be used together with peginterferon alfa and ribavirin to treat chronic hepatitis C infection.

What should I tell my healthcare provider before taking OLYSIO^™?

• Before taking OLYSIO^™, tell your healthcare provider if you:
  • have liver problems other than hepatitis C virus infection
  • have taken the medicines telaprevir (Incivek^®) or boceprevir (Victrelis^®)
  • had a liver transplant
  • are receiving phototherapy
  • have any other medical condition
  • are of East Asian descent
  • are breastfeeding. It is not known if OLYSIO^™ passes into your breast milk. You and your healthcare provider should decide if you will take OLYSIO^™ or breastfeed. You should not do both.

• Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
• OLYSIO^™ and other medicines may affect each other. This can cause you to have too much or not enough OLYSIO™ or other medicines in your body, which may affect the way OLYSIO™ or your other medicines work, or may cause side effects. Do not start taking a new medicine without telling your healthcare provider or pharmacist.
• Especially tell your healthcare provider if you take any of the following medicines:
  amiodarone (Cordarone^®, Pacerone^®), amlodipine (Norvasc^®), atazanavir (Reyataz^®), atorvastatin (Lipitor^®, Caduet^®), carbamazepine (Carbatrol^®, Epitol^®, Equetro^®, Tegretol^®), cisapride (Propulsid^®, Propulsid Quicksolv^®), clarithromycin (Biaxin^®, Prevpac^®), cobicistat-containing medicine: (Stribild^®), cyclosporine (Gengraf^®, Neoral^®, Sandimmune^®), darunavir (Prezista^®), delavirdine mesylate (Rescriptor^®), dexamethasone (when administered by injection or when taken by mouth), digoxin (Lanoxin^®), diltiazem (Cardizem^®, Dilacor XR^®, Tiazac^®), disopyramide (Norpace^®), efavirenz (Sustiva^®, Atripla^®), erythromycin (E.E.S.^®, Eryc^®, Ery-Tab^®, Erythrocin^®, Erythrocin Stearate^®), etravirine (Intelence^®), felodipine (Plendil^®), flecainide (Tambocor^®), fluconazole (when taken by mouth or when administered by injection) (Diflucan^®), fosamprenavir (Lexiva^®), indinavir (Crixivan^®), itraconazole (when taken by mouth) (Sporanox^®, Onmel^®), ketoconazole (when taken by mouth) (Nizoral^®), lopinavir (Kaletra^®), lovastatin (Advicor^®, Altoprev^®, Mevacor^®), mexiletine (Mexitil^®), midazolam (when taken by mouth), milk thistle (Silybum marianum) or products containing milk thistle, nelfinavir (Viracept^®), nevirapine (Viramune^®, Viramune XR^®), nicardipine (Cardene^®), nifedipine (Adalat CC^®, Afeditab CR^®, Procardia^®), nisoldipine (Sular^®), oxcarbazepine (Trileptal^®), phenobarbital (Luminal^®), phenytoin (Dilantin^®, Phenytek^®), pitavastatin (Livalo^®), posaconazole (when taken by mouth) (Noxafil^®), pravastatin (Pravachol^®), propafenone (Rythmol SR^®), quinidine (Nuedexta^®, Duraquin^®, Quinaglute^®), rifabutin (Mycobutin^®), rifampin (Rifadin^®, Rifamate^®, Rifater^®), rifapentine (Priftin^®), ritonavir (Norvir^®), rosuvastatin (Crestor^®), saquinavir mesylate (Invirase^®), sildenafil (Revatio^®, Viagra^®), simvastatin (Zocor^®, Vytorin^®, Simcor^®), sirolimus (Rapamune^®), St. John’s wort (Hypericum perforatum) or products containing St. John’s wort, tacrolimus (Prograf^®), tadalafil (Adcirca^®, Cialis^®), telithromycin (Ketek^®), tipranavir (Aptivus^®), triazolam (when taken by mouth) (Halcion^®), verapamil (Calan^®, Covera-HS^®, Isoptin^®, Tarka^®), voriconazole (when taken by mouth or when administered by injection) (Vfend^®), warfarin (Coumadin^®)
• This is not a complete list of medicines that could interact with OLYSIO^™. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.
• Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

What are the most common side effects of OLYSIO^™?

• The most common side effects of OLYSIO^™ when used in combination with peginterferon alfa and ribavirin include skin rash, itching, nausea.
• Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
• These are not all of the possible side effects of OLYSIO^™. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please see full Prescribing Information, including Patient Information for more details.

###

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in new product development, including obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; general industry conditions including trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 29, 2013, including in Exhibit 99 thereto, and our subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.)

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Phone: (732) 524-6491

Source

A supplemental New Drug Application has been submitted to the U.S. FDA for Simeprevir in combination with Sofosbuvir

• The Supplemental New Drug Application for OLYSIO™ (simeprevir) for once-daily use in combination with sofosbuvir is for 12 Weeks treatment of adult patients with genotype 1 chronic hepatitis C.
• The filing includes data from treatment naïve patients with advanced liver fibrosis and prior null responders with all stages of liver fibrosis.

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that Janssen has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Association (FDA) for simeprevir, an NS3/4A protease inhibitor marketed as OLYSIO™ in the United States, in combination with the nucleotide analogue NS5B polymerase inhibitor sofosbuvir developed by Gilead Sciences, Inc.

“It is of great importance to continue to improve the treatments for hepatitis C. The supplemental filing of the data available on the combination of simeprevir and sofosbuvir is an important step towards making an efficacious once daily all-oral treatment available for these patients“, says Charlotte Edenius, EVP Development, Medivir.

OLYSIO™ is currently approved in the U.S. for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. OLYSIO™ efficacy has been established in combination with peginterferon alfa and ribavirin in HCV genotype 1-infected patients with compensated liver disease, including cirrhosis.

This regulatory submission is for the treatment of genotype 1 chronic hepatitis C (HCV) in adult treatment-naïve patients with advanced fibrosis and null responders with all stages of liver fibrosis.

The regulatory submission for OLYSIO™ and sofosbuvir is supported by data from the phase II COSMOS study which included treatment-naïve patients with advanced fibrosis (METAVIR F3 to F4 scores) and prior null-responder patients with all stages of liver fibrosis (METAVIR F0 to F4 scores).

Our partner, Janssen R&D Ireland Ltd initiated in April 2014 the phase III OPTIMIST (Optimal Treatment with a simeprevir and sofosbuvir Therapy) trials examining the safety and efficacy of simeprevir and sofosbuvir without interferon or ribavirin for the treatment of chronic genotype 1 HCV infection. In the first trial, known as OPTIMIST-1, the combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naive or treatment experienced. In the second trial, known as OPTIMIST-2, the combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naive or treatment experienced.

For more information please visit www.clinicaltrials.gov.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.50 CET on 7 May 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S. and in March 2014 in Russia. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C and the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending Marketing Authorisation in the European Union for the use of simeprevir in combination with other medicinal products for the treatment of chronic HCV. This application is under review by the EMA.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

Source

Retreatment of HCV with ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin

The New England Journal of Medicine

Original Article

Stefan Zeuzem, M.D., Ira M. Jacobson, M.D., Tolga Baykal, M.D., Rui T. Marinho, M.D., Ph.D., Fred Poordad, M.D., Marc Bourlière, M.D., Mark S. Sulkowski, M.D., Heiner Wedemeyer, M.D., Edward Tam, M.D., Paul Desmond, M.D., Donald M. Jensen, M.D., Adrian M. Di Bisceglie, M.D., Peter Varunok, M.D., Tarek Hassanein, M.D., Junyuan Xiong, M.S., Tami Pilot-Matias, Ph.D., Barbara DaSilva-Tillmann, M.D., Lois Larsen, Ph.D., Thomas Podsadecki, M.D., and Barry Bernstein, M.D.

April 10, 2014DOI: 10.1056/NEJMoa1401561

Patients with chronic hepatitis C virus (HCV) infection are at risk for progressive liver fibrosis, cirrhosis, portal hypertension, hepatocellular carcinoma, and decompensated liver disease. HCV infection can be cured with antiviral therapy, reducing the risk of illness and death associated with end-stage liver disease.1-3

For more than a decade, patients with HCV genotype 1 infection have been treated with peginterferon–ribavirin dual therapy, resulting in rates of sustained virologic response of approximately 40 to 50%.4-6 Response rates among previously untreated patients have been shown to increase to 68 to 75% with peginterferon–ribavirin plus a protease inhibitor (telaprevir or boceprevir, both introduced in 2011).7,8 However, rates of response to this triple therapy among patients previously treated with peginterferon–ribavirin dual therapy vary according to the prior treatment response, with rates of 69 to 88% among patients with a prior relapse (an undetectable level of HCV RNA during treatment but a detectable level after the end of treatment), 40 to 59% among patients with a partial response (a decrease in the HCV RNA level of ≥2 log₁₀ IU per milliliter at treatment week 12 but with a detectable level), and 29 to 33% among patients with a null response (a decrease in the HCV RNA level of <2 log₁₀ IU per milliliter at treatment week 12).9,10 Furthermore, peginterferon–ribavirin therapy is associated with clinically significant and frequent side effects, including influenza-like symptoms, neuropsychiatric disorders, and cytopenias. Side effects of telaprevir and boceprevir include rash and anemia.7-10

ABT-450 is an inhibitor of the HCV nonstructural 3/4A (NS3/4A) protease, which is administered with ritonavir (ABT-450/r). Ritonavir is a pharmacoenhancer that inhibits ABT-450 metabolism. Administration of ritonavir with ABT-450 increases peak and trough drug exposures, allowing for once-daily dosing.11 Ombitasvir (also known as ABT-267) is an HCV NS5A inhibitor; dasabuvir (also known as ABT-333) is a nonnucleoside HCV NS5B RNA polymerase inhibitor.12,13

A phase 2b study involving patients with HCV genotype 1 infection who had a null response to prior therapy with peginterferon–ribavirin showed that the rate of sustained virologic response to 12 weeks of treatment with ABT-450/r, ombitasvir, dasabuvir, and ribavirin was 93% 24 weeks after the end of treatment.14 We report the results of SAPPHIRE-II, an international, randomized, placebo-controlled, double-blind, phase 3 trial assessing the efficacy and safety of 12 weeks of the all-oral regimen of ABT-450/r–ombitasvir and dasabuvir with ribavirin in patients with HCV genotype 1 infection and no cirrhosis who had received previous treatment with peginterferon–ribavirin.

Methods

Patients

Patients 18 to 70 years of age were eligible for enrollment if they had chronic HCV genotype 1 infection and a plasma HCV RNA level of more than 10,000 IU per milliliter, without cirrhosis. Eligible patients had documentation of prior peginterferon–ribavirin dual therapy with a relapse (an undetectable level of HCV RNA at the end of treatment but a detectable level within 52 weeks after treatment), a partial response (a decrease in the HCV RNA level of ≥2 log₁₀ IU per milliliter at treatment week 12 but a detectable level at the end of treatment), or a null response (a decrease in the HCV RNA level of <2 log₁₀ IU per milliliter at week 12 or <1 log₁₀ IU per milliliter at week 4). (Details are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Patients were excluded if they did not have a response to prior triple therapy with peginterferon–ribavirin and a protease inhibitor. Additional exclusion criteria were a positive screening result for hepatitis B surface antigen or anti–human immunodeficiency virus (HIV) antibodies, a recent history of drug or alcohol abuse or a positive screening result for drugs or alcohol, and use of specified concomitant medications, including those contraindicated for use with ribavirin and ritonavir. Patients with an advanced stage of fibrosis (Metavir score >3, Ishak score >4, aspartate aminotransferase:platelet ratio index >2, and FibroTest score >0.72 or FibroScan result ≥9.6 kPa without a qualifying liver biopsy) were also excluded. (For details, see the Supplementary Appendix.)

Study Design and Conduct

The SAPPHIRE-II study was performed at 76 sites in Australia, North America, and Europe. Patients were randomly assigned in a 3:1 ratio to receive an active regimen or placebo (Figure S1 in the Supplementary Appendix). The randomization schedule was stratified according to the type of response to previous peginterferon–ribavirin treatment (relapse, partial response, or null response) and HCV genotype (1a or non-1a). During the double-blind period, patients assigned to the active regimen received 12 weeks of treatment with oral coformulated ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin administered twice daily according to body weight (1000 mg daily if the body weight was <75 kg and 1200 mg daily if the body weight was ≥75 kg). Patients assigned to placebo received matching placebo pills during this period. After the double-blind period, patients in the placebo group received the active regimen on an open-label basis for 12 weeks.

The study sponsor (AbbVie), investigators, and patients were unaware of the study-group assignments during the double-blind period. Laboratory results for levels of HCV RNA, hemoglobin, hematocrit, alanine aminotransferase, aspartate aminotransferase, and bilirubin (indirect and total) were not disclosed to these parties in order to prevent implicit unblinding. The study is ongoing, and all patients who received the active regimen will be followed for 48 weeks after the end of treatment.

All patients provided written informed consent. The study was conducted in accordance with International Conference on Harmonisation guidelines, other guidelines governing clinical-study conduct, applicable regulations, and ethical principles enumerated in the Declaration of Helsinki. An independent ethics committee or institutional review board at each participating site approved the study.

The study was designed jointly by the investigators and the sponsor. The investigators gathered the data. The sponsor conducted the data analyses. All the authors had full access to the data and signed confidentiality agreements with the sponsor regarding the data. The first draft of the manuscript was written by a sponsor-employed medical writer with input from all the authors. All the authors reviewed and provided feedback on all versions of the manuscript and made the final decision to submit it for publication. All the authors assume responsibility for the completeness and accuracy of the data and analyses presented and for the fidelity of the study to the protocol, available at NEJM.org.

Efficacy Assessments

HCV genotype and subtype were evaluated from plasma samples with the use of the Versant HCV Genotype Inno-LiPA Assay, version 2.0 (Siemens Healthcare Diagnostics). Plasma HCV RNA levels were measured by a central laboratory with the use of the COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, version 2.0 (Roche), with a lower limit of detection of 15 IU per milliliter and a lower limit of quantification of 25 IU per milliliter. Details of the collection of plasma samples, protocol-specified criteria for virologic failure, and resistance testing are provided in the Supplementary Appendix.

Safety Assessments

Adverse events were assessed at each study visit. The site investigator classified events as mild, moderate, or severe. Data on all adverse events were collected from the start of study-drug administration until 30 days after the last dose. Data on serious adverse events were collected throughout the entire study period. Adverse events and serious adverse events occurring during the double-blind period plus 30 days after the last dose of active study drugs are reported. Clinical laboratory testing occurred at visits during the double-blind treatment period and at post-treatment weeks 4 and 48.

Efficacy End Points

The primary efficacy end point was a sustained virologic response (i.e., an HCV RNA level of <25 IU per milliliter 12 weeks after the end of study treatment). Secondary efficacy end points were normalization of the alanine aminotransferase level, sustained virologic response at post-treatment week 12 according to HCV genotype (1a or 1b), virologic failure during treatment, and post-treatment relapse. Analyses were performed in the modified intention-to-treat population, defined as all randomly assigned patients who received at least one dose of the study drug during the double-blind treatment period.

Virologic failure during study treatment was defined as a confirmed HCV RNA level of 25 IU per milliliter or more after an HCV RNA level of less than 25 IU per milliliter during treatment, a confirmed increase in the HCV RNA level of more than 1 log₁₀ IU per milliliter above the nadir during treatment, or an HCV RNA level of 25 IU per milliliter or more at all assessments during treatment among patients who received at least 6 weeks of treatment. Virologic relapse was defined as a confirmed HCV RNA level of 25 IU per milliliter or more between the final visit during the double-blind treatment period and 12 weeks after the last dose of study drug among patients who completed treatment (duration of study-drug exposure, ≥77 days), had an HCV RNA level of less than 25 IU per milliliter at the final visit during the double-blind treatment period, and had data on HCV RNA levels available after the completion of treatment. Normalization of the alanine aminotransferase level was defined as a final value that did not exceed the upper limit of the normal range (as defined by the processing laboratory) during the double-blind period among patients with a baseline level above the upper limit of the normal range.

Statistical Analysis

The primary efficacy analyses assessed the noninferiority and superiority of the rate of sustained virologic response at post-treatment week 12 with ABT-450/r–ombitasvir, dasabuvir, and ribavirin, as compared with a calculated historical control rate of 65% (95% confidence interval [CI], 60 to 70). This control rate was based on response rates among patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon–ribavirin and who received retreatment with telaprevir and peginterferon–ribavirin.15,16 The control rate was weighted for the proportions of patients with a prior relapse, partial response, or null response that were expected in the current study (details in the Supplementary Appendix).

To establish that the rate of sustained virologic response with ABT-450/r–ombitasvir, dasabuvir, and ribavirin was noninferior to the historical rate, the lower boundary of the 95% confidence interval for the rate among patients receiving the active regimen during the double-blind period had to exceed the upper confidence boundary of the control rate minus 10.5 percentage points (60%). To establish that the rate of sustained virologic response with ABT-450/r–ombitasvir, dasabuvir, and ribavirin was superior to the historical rate, the lower boundary of the 95% confidence interval for the rate among patients receiving the active regimen during the double-blind period had to exceed the upper confidence boundary of the historical rate (70%). We calculated that a sample of 400 patients (300 recipients of the active regimen during the double-blind period) would provide more than 90% power to show noninferiority and superiority of the active regimen with a rate of sustained virologic response at post-treatment week 12 of 85%. A fixed-sequence testing procedure was used to maintain a type I error rate of 0.05 for the analyses of the primary and secondary efficacy end points. Details of the noninferiority and superiority analyses, sample-size determination, fixed-sequence testing procedure, and all secondary efficacy end points are provided in the Supplementary Appendix.

The primary analysis was performed after all patients receiving the active regimen during the double-blind period reached post-treatment week 12 and all patients receiving placebo reached week 12 of open-label treatment. Data regarding the primary analysis are reported.

SAS software, version 9.3, for the UNIX operating system (SAS Institute) was used for all analyses. All statistical tests and 95% confidence intervals were two-sided with a significance level of 0.05. For analysis of efficacy, normal approximation to binomial distribution was used to calculate 95% confidence intervals. For analyses of adverse events, abnormal laboratory values, and rates of normalization of the alanine aminotransferase level during the double-blind period, the active-regimen group and the placebo group were compared with the use of Fisher's exact test.

Results

Patients

A total of 562 patients were screened, 395 underwent randomization, and 394 received at least one dose of study drug (Figure S2 in the Supplementary Appendix). Patients were screened from November 2012 through May 2013. The final date for data collection regarding the analysis of the rate of sustained virologic response at post-treatment week 12 among patients receiving the active regimen during the double-blind period was December 3, 2013. Baseline demographic and clinical characteristics of the study patients are shown in Table 1

Efficacy

Among 297 patients receiving the active regimen during the double-blind period, 98.7% had an HCV RNA level of less than 25 IU per milliliter at treatment week 4 (95% CI, 97.3 to 100); 99.0% had an HCV RNA level of less than 25 IU per milliliter at treatment week 12 (95% CI, 97.9 to 100). A total of 286 patients in the active-regimen group had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% CI, 94.2 to 98.4) (Figure 1); this was noninferior and superior to the historical control rate with telaprevir and peginterferon–ribavirin. A total of 166 of 173 patients with HCV genotype 1a infection had a sustained virologic response, for a rate of 96.0% (95% CI, 93.0 to 98.9); 119 of 123 patients with HCV genotype 1b had a sustained virologic response, for a rate of 96.7% (95% CI, 93.6 to 99.9). The HCV genotype (1a or 1b) could not be determined for 1 patient, who had a sustained virologic response.

The rates of sustained virologic response were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients) (Table 2) Rates of sustained virologic response were high across subgroups defined by race, age, fibrosis score, and IL28B genotype (Figure 2). No patient had virologic failure during treatment; all patients completing treatment (≥77 days of study-drug exposure) had an HCV RNA level of less than 25 IU per milliliter at the end of treatment.

Seven of 293 patients who completed therapy (2.4%) had a post-treatment viral relapse (Table 2). All patients with a relapse reported high adherence to study drugs. At the time of relapse, 4 of the 5 patients with HCV genotype 1a infection and 1 of the 2 patients with HCV genotype 1b infection had at least one amino acid variant known to confer resistance to one of the three direct-acting antiviral agents included in the regimen. The most frequently detected variants in the 4 patients with HCV genotype 1a infection who had variants at the time of relapse were D168V in NS3 (2 patients), M28V (3 patients) and Q30R (2 patients) in NS5A, and S556G in NS5B (2 patients). The patient with HCV genotype 1b infection who had resistance-associated variants present at the time of relapse had Y56H and D168A in NS3, Y93H in NS5A, and C316N and S556G in NS5B. The rate of normalization of the alanine aminotransferase level was significantly higher in the active-regimen group than in the placebo group (96.9% [217 of 224 patients] vs. 12.8% [10 of 78 patients], P<0.001).

Safety

During the double-blind treatment period, 91.2% of patients in the active-regimen group and 82.5% of patients in the placebo group had an adverse event (Table 3). In both groups, the two most common adverse events were headache (in 36.4% of patients in the active-regimen group and in 35.1% of those in the placebo group, P=0.90) and fatigue (33.3% and 22.7%, respectively; P=0.06). Among adverse events occurring in more than 10% of patients in either group, only pruritus had a higher frequency in the active-regimen group than in the placebo group (13.8% vs. 5.2%, P=0.03). Among adverse events occurring in less than 10% of patients in both groups, those with a higher frequency in the active-regimen group were anemia (P=0.01), a decrease in the hemoglobin level (P=0.04), and vomiting (P=0.006), and those with a higher frequency in the placebo group were constipation (P=0.02), erythema (P=0.05), neck pain (P=0.05), and neutropenia (P=0.01)

There were no moderate or severe adverse events that occurred more frequently with the active regimen than with placebo (P>0.10 for all comparisons). Six patients in the active-regimen group (2.0%) and one patient in the placebo group (1.0%) had at least one serious adverse event (Table S5 in the Supplementary Appendix). Three patients in the active-regimen group (1.0%) and no patients in the placebo group discontinued the study drug owing to adverse events. Discontinuation was due to elevated aminotransferase levels (grade 3), diarrhea, and acute renal failure in one patient each. The case of acute renal failure was a serious adverse event; the site investigator deemed this event to be unrelated to direct-acting antiviral treatment (details in Table S5 in the Supplementary Appendix).

Abnormalities in laboratory values of grade 3 or 4 that occurred during the double-blind period are shown in Table 3. The most common abnormality of grade 3 or 4 in patients in the active-regimen group was an elevated total bilirubin level, occurring in seven patients (2.4%) (maximum total bilirubin level, 173 μmol per liter [10.1 mg per deciliter]); in six of the patients, these elevations were classified as grade 3. None of these patients had concomitant grade 3 or 4 elevations in the alanine aminotransferase or aspartate aminotransferase level. Elevations in the total bilirubin level were predominantly due to indirect bilirubin and resolved in all patients by post-treatment week 4. Four patients with hyperbilirubinemia of grade 3 or 4 had jaundice or ocular icterus. No patient discontinued treatment owing to hyperbilirubinemia.

During the double-blind period, elevations in the alanine aminotransferase level of grade 3 or 4 occurred in 1.7% of patients in the active-regimen group and in 3.1% of patients in the placebo group. Elevations in the aspartate aminotransferase level of grade 3 or 4 occurred in 1.0% of patients in each group.

During the double-blind period, abnormalities in the hemoglobin value of grade 1 (below the lower limit of the normal range to 10.0 g per deciliter) and grade 2 (8 to <10.0 g per deciliter) occurred in 52.0% and 4.7% of patients in the active-regimen group, respectively. One patient in the active-regimen group (0.3%) had a hemoglobin value of grade 3 (6.5 to <8.0 g per deciliter). No patient had a hemoglobin value of grade 4 (<6.5 g per deciliter) (Table S6 in the Supplementary Appendix). No patient discontinued the study drug owing to anemia. In 6.4% of patients in the active-regimen group, the ribavirin dose was modified owing to adverse events. No patient received erythropoietin or a transfusion. There were no deaths from any cause in the active-regimen group or the placebo group.

Discussion

In this large, multicenter, phase 3 trial involving patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon–ribavirin, 96.3% of patients who received retreatment with ABT-450/r–ombitasvir and dasabuvir with ribavirin had a sustained virologic response at post-treatment week 12. According to a modified intention-to-treat analysis, the rate of sustained virologic response with this combination regimen was noninferior and superior to the historical control rate with telaprevir plus peginterferon–ribavirin in a similar patient population. This rate of sustained virologic response also exceeds reported response rates of 59 to 80% in retreatment studies involving patients with HCV genotype 1 infection who received boceprevir or simeprevir with peginterferon–ribavirin.9,18

The results of our study confirm previous data suggesting that this 12-week regimen combining antiviral drugs with multiple mechanisms of action is effective regardless of the prior response to peginterferon–ribavirin.14 The rates of sustained virologic response in this study were high even among patients with a null response to prior treatment, who made up nearly half the study population; such patients have been the least likely to have a response to retreatment regimens comprising peginterferon–ribavirin plus a protease inhibitor.10,18 In patients with a prior null response, 12 weeks of telaprevir with 48 weeks of peginterferon–ribavirin resulted in rates of sustained virologic response of 29 to 33%, whereas the use of simeprevir with peginterferon–ribavirin for similar durations resulted in rates of 38 to 53%.10,18 In contrast, in this study the 12-week regimen resulted in a 95.2% rate of sustained virologic response among patients with a prior null response.

Data from trials of peginterferon-containing and peginterferon-free regimens have suggested that the HCV genotype (1a or 1b) affects the efficacy of some regimens.19-21 However, in this trial, high rates of sustained virologic response were observed among patients with HCV genotype 1a and among those with HCV genotype 1b (96.0% and 96.7%, respectively), with few true virologic failures.

The double-blind design of this trial allowed a comparison of adverse events in patients receiving the active regimen with events in those receiving placebo. One percent of patients discontinued active therapy owing to an adverse event. Pruritus was the only adverse event occurring in more than 10% of patients in either study group that was significantly more frequent with the active regimen than with placebo. Although there were three adverse events occurring in less than 10% of patients in each group that were significantly more frequent with the active regimen (anemia, a decrease in the hemoglobin level, and vomiting), four adverse events occurring in less than 10% of patients in each group were significantly more frequent with placebo (constipation, erythema, neck pain, and neutropenia).

The most common laboratory abnormality in the active-regimen group was a transient elevation in the total bilirubin level, occurring in 2.4% of patients. These elevations are consistent with the known role of ABT-450 as an inhibitor of the OATP1B1 transporter.22,23 Hemoglobin values of 8.0 to less than 10.0 g per deciliter (grade 2), 6.5 to less than 8.0 g per deciliter (grade 3), and less than 6.5 g per deciliter (grade 4) occurred in 4.7%, 0.3%, and 0% of patients in the active-regimen group, respectively. No patient discontinued the study treatment owing to anemia.

Patients who did not have a response to triple therapy with an approved protease inhibitor and peginterferon–ribavirin were excluded from this study. Thus, the results cannot be extrapolated to that population. Although this study did not include previously untreated patients, Feld et al. now report in the Journal that treatment with the same regimen of new antiviral agents and ribavirin in such patients was associated with a high rate of sustained virologic response at post-treatment week 12.24

In conclusion, an all-oral combination regimen of ABT-450/r, ombitasvir, and dasabuvir with ribavirin resulted in rates of sustained virologic response at post-treatment week 12 of more than 95%, regardless of HCV genotype (1a or 1b) and with low rates of treatment discontinuation, in previously treated patients with HCV genotype 1 infection and no cirrhosis, including those with a prior null response. The similarity of safety and efficacy data in the previous phase 2 trial and this phase 3 trial supports further exploration of this all-oral regimen in other difficult-to-cure populations, such as patients with HCV and HIV coinfection and liver-transplant recipients.

---

Supported by AbbVie.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on April 10, 2014, at NEJM.org.

We thank the trial participants, investigators, and coordinators who made this study possible; George Liossis, Jun Sun, Kevin Howieson, Christine Collins, Gretja Schnell, Jill Beyer, Michelle Irvin, Preethi Krishnan, Thomas Reisch, and Rakesh Tripathi of AbbVie for their contributions; and Christine Ratajczak (AbbVie) for medical-writing services.

Source Information

From Johann Wolfgang Goethe University, Frankfurt am Main (S.Z.), and Medizinische Hochschule Hannover, Hannover (H.W.) — both in Germany; Weill Cornell Medical College, New York (I.M.J.), and Premier Medical Group of the Hudson Valley, Poughkeepsie (P.V.) — both in New York; AbbVie, North Chicago (T.B., J.X., T.P.-M., B.D.-T., L.L., T.P., B.B.), and Center for Liver Diseases, University of Chicago Medical Center, Chicago (D.M.J.) — both in Illinois; Centro Hospitalar de Lisboa Norte and Medical School of Lisbon, Lisbon, Portugal (R.T.M.); Texas Liver Institute, University of Texas Health Science Center, San Antonio (F.P.); Hôpital Saint Joseph, Marseille, France (M.B.); Johns Hopkins University, Baltimore (M.S.S.); Liver and Intestinal Research Centre, Vancouver, BC, Canada (E.T.); St. Vincent's Hospital (Melbourne), Fitzroy, Australia (P.D.); Saint Louis University, St. Louis (A.M.D.); and Southern California Liver Centers and Southern California Research Center, Coronado (T.H.).

Address reprint requests to Dr. Zeuzem at Johann Wolfgang Goethe University Hospital, Theodor Stern Kai 7, 60590 Frankfurt, Germany, or at zeuzem@em.uni-frankfurt.de.

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Efficacy and Safety of Danoprevir/Ritonavir plus Peginterferon Alfa-2a/Ribavirin in HCV Genotype 1 Prior Null Responders

Antimicrob Agents Chemother. 2013 Dec 2. [Epub ahead of print]

Gane EJ, Rouzier R, Wiercinska-Drapalo A, Larrey DG, Morcos PN, Brennan BJ, Le Pogam S, Nájera I, Petric R, Tran JQ, Kulkarni R, Zhang Y, Smith P,Yetzer ES, Shulman NS.

Auckland Clinical Studies, Auckland, New Zealand.

Abstract

Background & Aims: Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a/ribavirin in treatment-naive HCV genotype (G)1-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a/ribavirin in G1 prior peginterferon/ribavirin null responders.Methods: Null responders (<2-log₁₀ reduction in HCV RNA at week 12) were given open-label DNVr 100/100 mg q12h + peginterferon alfa-2a/ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log₁₀ decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a/ribavirin; those without an EVR discontinued all study drugs.Results: Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) with G1a. 96% of patients had an IL28B non-CC genotype. An SVR24 was achieved in 67% of patients, with a higher rate in G1b-infected (88%) vs. G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No Grade 3/4 ALT elevations were observed.Conclusions: DNVr plus peginterferon alfa-2a/ribavirin demonstrated high SVR24 rates in HCV G1b prior null responders and was well tolerated.

PMID: 24295986 [PubMed - as supplied by publisher]

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New GT-1b Data from ABT-450 Containing Regimen Being Presented at The Liver Meeting

SVR12 Rates of 95% in HCV Treatment Naïve Patients and 90% in Prior Null Responders Reported in PEARL-I Study

WATERTOWN, Mass.--(BUSINESS WIRE)--Nov. 3, 2013-- Enanta Pharmaceuticals, Inc., (NASDAQ: ENTA) a research and development-focused biotechnology company dedicated to creating small molecule drugs in the infectious disease field, today announced that additional data from AbbVie’s M13-393 study, referred to as PEARL-I, will be presented in an oral presentation at 5:15 p.m. ET today at The Liver Meeting, the 64^th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C.

In PEARL-I, SVR12 rates of 95% (40/42) in hepatitis C (HCV) GT-1b treatment-naïve patients and 90% (36/40) among prior null responders will be presented in this intent-to-treat analysis. Two patients in the treatment-naive arm did not achieve SVR12 due to loss to follow up. In the null responder arm, one patient experienced breakthrough and three patients relapsed.

PEARL-I is a phase-2b, interferon-free, 320 patient study being conducted by AbbVie to evaluate the once-daily, two-DAA regimen consisting of ABT-450/r (protease inhibitor plus ritonavir) + ABT-267 (AbbVie’s NS5A inhibitor) in HCV treatment-naïve patients and treatment-experience patients. GT-1b treatment arms are ribavirin-free and also include cirrhotic patients while GT-4 arms explore treatment with and without ribavirin.

“We are very encouraged by the strong SVR12 rates from this simplified 2-DAA, once-daily regimen that includes our lead HCV protease inhibitor, ABT-450,” commented Jay R. Luly, Ph.D., President and Chief Executive Officer. “We look forward to data from Phase 3 studies of three-DAA regimens containing ABT-450 being reported in the coming months.”

Protease Inhibitor Collaboration with AbbVie (formerly the research-based pharmaceutical business of Abbott Laboratories)

In December 2006, Enanta and Abbott announced a worldwide agreement to collaborate on the discovery, development and commercialization of HCV NS3 and NS3/4A protease inhibitors and HCV protease inhibitor-containing drug combinations. ABT-450 is a protease inhibitor identified as a lead compound through the collaboration. Under the agreement, AbbVie is responsible for all development and commercialization activities for ABT-450. Enanta received $57 million in connection with signing the collaboration agreement, has received $55 million in subsequent clinical milestone payments, and is eligible to receive an additional $195 million in payments for regulatory milestones, as well as double-digit royalties worldwide on any revenue allocable to the collaboration’s protease inhibitors. Also, for any additional collaborative HCV protease inhibitor product candidate developed under the agreement, Enanta holds an option to modify the U.S. portion of it rights to receive milestone payments and worldwide royalties. With this option, Enanta can fund 40 percent of U.S. development costs and U.S. commercialization efforts (sales and promotion costs) for the additional protease inhibitor in exchange for 40 percent of any U.S. profits ultimately achieved after regulatory approval instead of receiving payments for U.S. commercial regulatory approval milestones and royalties on U.S. sales of that protease inhibitor.

About Enanta

Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs in the infectious disease field. Enanta is discovering and developing novel inhibitors designed for use against the hepatitis C virus (HCV). These inhibitors include members of the direct acting antiviral (DAA) inhibitor classes – protease (partnered with AbbVie), NS5A (partnered with Novartis) and nucleotide polymerase – as well as a host-targeted antiviral (HTA) inhibitor class targeted against cyclophilin. Additionally, Enanta has created a new class of antibiotics, called Bicyclolides, for the treatment of multi-drug resistant bacteria, with a focus on developing an intravenous and oral treatment for hospital and community MRSA (methicillin-resistant Staphylococcus aureus) infections.

Forward Looking Statements Disclaimer

This press release contains forward-looking statements, including with respect to clinical data, plans for announcing additional data, and the planned clinical development of ABT-450. Statements that are not historical facts are based on our management’s current expectations, estimates, forecasts and projections about our business and the industry in which we operate and our management’s beliefs and assumptions. The statements contained in this release are not guarantees of future performance and involve certain risks, uncertainties and assumptions, which are difficult to predict. Therefore, actual outcomes and results may differ materially from what is expressed in such forward-looking statements. Important factors that may affect actual results include final results of ongoing clinical trials, the development and marketing efforts of AbbVie (our collaborator on ABT-450), regulatory actions affecting clinical development of ABT-450 and clinical development of competitive product candidates. Enanta cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this release, and Enanta undertakes no obligation to update or revise these statements, except as may be required by law.

Source: Enanta Pharmaceuticals, Inc.

Investor Contact
Enanta Pharmaceuticals, Inc.
Carol Miceli, 617-607-0710
cmiceli@enanta.com
or
Media Contact
MacDougall Biomedical Communications
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kwatson@macbiocom.com

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Santaris Pharma A/S Completes Enrollment in Phase 2 Clinical Trial of Miravirsen

Santaris Pharma A/S Completes Enrollment in Phase 2 Clinical Trial of Miravirsen In Null Responders to Pegylated Interferon and Ribavirin for the Treatment of the Hepatitis C Virus

-- Enrollment also begins in study investigating miravirsen in combination with telaprevir and ribavirin in null responders to pegylated interferon and ribavirin --

Hørsholm, Denmark/San Diego, California, August 27, 2013 — Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced the completion of enrollment of its Phase 2 miravirsen 12-week monotherapy study of miravirsen, a host-targeted, pan-HCV genotype antiviral agent, in subjects who were "null responders" to pegylated interferon alpha and ribavirin (peg-IFNα/RBV). The company also announced the enrollment of the first patient into another Phase 2 study of miravirsen in combination with telaprevir and ribavirin, also in null responders to peg-IFNα/RBV.

"The current standard of treatment for HCV is a combination of a direct acting-antiviral agent protease inhibitor with pegylated-interferon plus ribavirin. However, there remains a pressing need for therapeutic regimens that can attain high sustained virologic responses without peg-IFNα/RBV, which is poorly tolerated, and without drug-drug interactions. Miravirsen’s unique mode-of-action has shown potential in providing antiviral activity in patients who have failed previous treatment regimens for the hepatitis C virus," said Maribel Rodriguez-Torres, M.D., president of Fundacion de Investigacion and the study’s Principal Investigator. "We are excited to have completed enrollment and look forward to following the enrolled patients and reporting the data from this study. So far, the emerging viral load data suggest that miravirsen might be a unique treatment option, in combination with other antivirals, for the treatment of this type of difficult to treat patients."

The Phase 2, open-label study assesses the safety, antiviral activity and pharmacokinetics of miravirsen monotherapy over a total of 12 weeks of treatment. Patients enrolled in the study were chronically infected with HCV genotype 1 and had previously failed treatment with peg-IFNα/RBV therapy. Miravirsen was given as a total of five doses over five weeks, followed by a further four doses once every other week over seven weeks.

Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the levels of HCV RNA are profoundly reduced.

Santaris Pharma A/S has also enrolled its first patient into another Phase 2 clinical trial that will assess the safety, tolerability and antiviral activity of miravirsen given for 12 weeks in combination with telaprevir (TVR) and ribavirin (RBV) in patients with HCV infection who are non-responders to peg-IFNα/RBV.

"We are pleased to report on the progress in the miravirsen clinical program," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "We hope that data from these two 12-week studies in the hard to treat patients will confirm the earlier promising efficacy and safety data from the four-week monotherapy study in treatment naïve patients that was recently published in the New England Journal of Medicine. We continue to believe that miravirsen given in combination with direct acting-antiviral agent(s) has the potential to cure chronic HCV infection in hard-to-treat patients."

The first series of non-clinical and clinical studies demonstrated the following key attributes for miravirsen:

• Miravirsen has a novel mechanism of action, inhibits a well conserved hepatic host target thus has an high barrier to resistance with predicted activity against all HCV genotypes, is not metabolized by cytochrome P450 enzymes therefore drug interactions are unlikely
• In in vitro studies, miravirsen was active against all six HCV genotypes, additive activity to direct acting antiviral agents (DAAs), active against DAA resistant virus and a showed a high barrier to resistance
• In clinical trials with four weeks of monotherapy, miravirsen was well tolerated, showed dose dependent antiviral activity that can be maintained weeks after the end of therapy
• In two separate drug-drug interaction clinical trials, miravirsen showed no interactions with peg-IFNα/RBV or with telaprevir

About Hepatitis C

Hepatitis C infection is a viral disease caused by the hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates that approximately 3 percent of the world’s population have been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver canceri. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per yearii. In Europe, there are about 4 million carriersi. The current standard of care treatment for genotype 1 is a protease inhibitor given with pegylated-interferon α and ribavirin. This triple combination is effective in about 70-80% of those treatedii. Even though in Europe and the United States genotype 1 is the most prevalent, there are 50-70 million people worldwide that are infected with a non-genotype 1 virus. In these patients, the combination of pegylated-interferon α and ribavirin remains the currently approved standard of care treatmentiii. Patients that are not effectively treated have an increased risk for the progression of liver disease. 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^iv.

About microRNAs

MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.

About Locked Nucleic Acid (LNA) Drug Platform

The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company’s proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA is also sometimes referred to as BNA (Bicyclic or Bridged Nucleic Acid). LNA-based drugs are a promising new class of therapeutics that enable scientists to develop drugs that work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.

About Santaris Pharma A/S

Santaris Pharma A/S is a privately held, clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the company’s proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The company’s research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies address a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The company has strategic partnerships with RaNA Therapeutics, Bristol-Myers Squibb, miRagen Therapeutics, Shire, Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the company holds exclusive worldwide rights to manufacture and sell products that comprise LNA as active ingredient for studies performed with a view to obtaining marketing approval. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit www.santaris.com for more information.

Santaris Pharma A/S® is a registered trademark of Santaris Pharma A/S. Santaris^TM, Santaris Pharma^TM, Cureon^TM and LNA-antimiR™ are trademarks of Santaris Pharma A/S.

Media Contacts: Liz Narrillos Roux, Edelman (liz.narrillosroux@edelman.com) - Office: (323)202-1074

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Boceprevir benefits null, partial responders to prior HCV therapy with peginterferon/ribavirin

Provided by Healio

June 4, 2013

ORLANDO, Fla. — Therapy with boceprevir in addition to pegylated interferon and ribavirin led to high sustained virologic response rates in patients with hepatitis C who failed previous interferon-based treatment in a study presented at Digestive Disease Week.

In the single-arm, open-label, multicenter roll-over PROVIDE study, researchers randomly assigned 168 patients with chronic HCV genotype 1 to 800 mg boceprevir three times daily, in addition to a standard dose of peginterferon alfa-2a and weight-based ribavirin (PR), for up to 44 weeks. All participants had been in control arms of prior phase 2 and 3 boceprevir studies and had experienced relapse or null or partial response to PR (51% partial responders, 31% null responders and 17% relapse responders, with 1% not classifiable).

Patients enrolled more than 2 weeks after their previous therapy also received a 4-week lead-in with PR alone (n=156). Four patients discontinued treatment during this period, leaving 164 boceprevir recipients for analysis.

Sustained virologic response (SVR) at 24 weeks occurred in 41% of null responders, 67% of partial responders and 96% of relapsers in final analysis, for an overall SVR rate of 65%. Relapse occurred in 13% of null responders, 15% of partial responders and no relapsers (11% average rate). Most patients who experienced SVR were men, not of black race, and had viral loads of 800,000 IU/mL or lower upon initiation. SVR rates were similar among those with HCV genotype 1a and 1b, and poorer among patients with platelet counts less than 200,000.

Commonly reported adverse events included anemia (49% of cases), dysgeusia (35%) and neutropenia (23%), and the safety profile was similar to previous studies. Eight percent of the cohort discontinued treatment because of adverse events.

“Overall, the data of this final analysis led to the conclusion that boceprevir combined with peginterferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders; and, most importantly, null responders,” researcher John M. Vierling, MD, professor of medicine and surgery, director of Baylor Liver Health and chief of hepatology at Baylor College of Medicine in Houston, said.

Disclosure: The researchers report numerous financial disclosures.

For more information:

Vierling JM. 869c: Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures After Retreatment With Boceprevir (BOC) and PR: Final Results of the PROVIDE Study. Presented at: Digestive Disease Week 2013; May 18-21, Orlando, Fla

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Eric J. Lawitz, MD, reviews COSMOS trial with HCV genotype 1 patients

Provided by Healio

May 22, 2013

ORLANDO, Fla. — Eric J. Lawitz, MD, of the Texas Liver Institute at the University of Texas, San Antonio, discusses his late-breaking poster “SVR Results of a Once Daily Regimen of Simeprevir (Tmc435) Plus Sofosbuvir (Gs-7977) With or Without Ribavirin (RBV) in HCV GT 1 Null Responders” at Digestive Disease Week 2013....

He reports encouraging results for SVR among patients who underwent a 12-week regimen of simeprevir and sofosbuvir and were previously null responders to peginterferon and ribavirin.

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Gilead Provides Update on Hepatitis C Development Programs

-- Sustained Virologic Response Achieved with Oral Regimen of Sofosbuvir, GS-5885 and Ribavirin in 9/9 Null Responder Genotype 1 Hepatitis C Patients --

-- Second Phase 3 Study Evaluating Fixed-dose Combination of Sofosbuvir and GS-5885 to Begin Later this Month --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Jan. 7, 2013-- Gilead Sciences (Nasdaq:GILD) today announced several updates regarding its late-stage pipeline candidates for the treatment of chronic hepatitis C virus (HCV) infection. The company released new results from an arm of the ongoing Phase 2 ELECTRON study examining the nucleotide sofosbuvir and the NS5A inhibitor GS-5885, and provided a progress report on a range of Phase 2 and 3 clinical trials evaluating a once-daily fixed-dose combination tablet of these medicines. These updates will be highlighted today as part of Gilead’s corporate presentation at the 31st Annual J.P. Morgan Healthcare Conference taking place in San Francisco.

“Since the acquisition of Pharmasset only a year ago, we have fully enrolled four Phase 3 studies of sofosbuvir and during the first quarter of this year we will have initiated two Phase 3 studies of the sofosbuvir and GS-5885 fixed-dose combination,” said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. “We are on track to submit the initial regulatory filing for sofosbuvir by mid-2013 and to file for approval of the fixed-dose combination of sofosbuvir and GS-5885 in 2014.”

Update on Phase 2 ELECTRON Study

Gilead today announced full data from one cohort of the ongoing Phase 2 ELECTRON study examining a 12-week course of all-oral therapy with sofosbuvir, GS-5885 and ribavirin (RBV) among genotype 1 HCV patients who had previously failed to respond to an interferon (IFN)-containing regimen, or “null responders.”

Preliminary data, presented in November at the annual meeting of the American Association for the Study of Liver Diseases (AASLD), demonstrated that three of nine patients (3/9) remained HCV RNA undetectable four weeks after completing therapy (SVR4). Today’s announcement confirms that all nine patients (9/9) in this cohort achieved SVR4. These patients will continue to be observed to determine sustained virologic response rates at weeks 12 and 24 of follow-up (SVR12 and SVR24).

Results from eight other arms of the ELECTRON study, evaluating sofosbuvir alone and with RBV and/or pegylated IFN, were published earlier this month in the New England Journal of Medicine (N Engl J Med 368;34-44).

Advancing a Fixed-Dose Combination Tablet for HCV

Gilead is currently evaluating a once-daily fixed-dose combination tablet containing sofosbuvir and GS-5885 in several Phase 2 and 3 trials. The studies evaluate sofosbuvir/GS-5885 with and without RBV among a range of genotype 1 HCV patient populations.

• ION-1: This Phase 3 trial was initiated in October 2012 and is evaluating sofosbuvir/GS-5885 with and without RBV for 12 or 24 weeks among treatment-naïve genotype 1 patients. Pending a review of results from the two 12-week arms (n=50/arm) of an initial enrollment of 200 patients, ION-1 will continue to recruit patients and assess sofosbuvir/GS-5885 in a total of 800 individuals.
• ION-2: Gilead today announced that a second Phase 3 study for sofosbuvir/GS-5885, ION-2, is expected to begin screening patients in January 2013. This study will evaluate the fixed-dose combination, with RBV for 12 weeks and with and without RBV for 24 weeks of therapy among 400 treatment-experienced genotype 1 HCV patients. Participants in this study will have failed past therapy with regimens containing IFN or IFN plus a protease inhibitor.
• LONESTAR: Gilead also announced that enrollment is now underway for a new Phase 2 study of sofosbuvir/GS-5885 for 12 weeks and of sofosbuvir/GS-5885 with and without RBV for 8 weeks among genotype 1 treatment-naïve patients. Two additional arms in this trial will evaluate sofosbuvir/GS-5885 with and without RBV for 12 weeks among treatment-experienced genotype 1 patients who had previously received a protease inhibitor-containing regimen. This study, which will enroll 100 patients, is the first trial to evaluate the combination of sofosbuvir and
  GS-5885 for only eight weeks of treatment.

Sofosbuvir, GS-5885 and the fixed-dose combination tablet are investigational products and their safety and efficacy have not yet been established.

Four ongoing Phase 3 studies will support Gilead’s initial regulatory filing in mid-2013 for an all-oral therapy with sofosbuvir plus RBV among genotype 2/3 treatment-naïve, treatment-experienced and interferon-intolerant patients, and for sofosbuvir in combination with RBV and peg-IFN among treatment-naïve patients with HCV genotypes 1, 4, 5 and 6. Topline results from the first Phase 3 study, POSITRON, were announced in November 2012, and results from the remaining three studies (FISSION, FUSION and NEUTRINO) are anticipated in Q1 2013. Results from ION-1, ION-2 and LONESTAR are intended to support a regulatory filing for the fixed-dose combination of sofosbuvir/GS-5885 by mid-2014.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

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 the possibility that the proportion of patients who maintain a sustained virologic response 12 and 24 weeks post-treatment in the null responder arm of the ELECTRON study will not be as favorable as the sustained virologic response rates reported in this press release, and the possibility of unfavorable results from additional arms of ELECTRON and other clinical trials involving sofosbuvir and sofosbuvir and GS-5885 with and without RBV. As a result, sofosbuvir and GS-5885 as single agents or as a fixed-dose combination may never be successfully commercialized. In addition, Gilead may make a strategic decision to discontinue development of the compounds or the fixed-dose combination regimen if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. Further, Gilead may be unable to file for regulatory approval of sofosbuvir and the fixed-dose combination of sofosbuvir/GS-5885 in the currently anticipated timelines or at all. If marketing approval is granted for any of these products, there may be significant limitations on their use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2012, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences

Gilead Sciences
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

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Abbott's Investigational Interferon-Free Hepatitis C Treatment Regimen Achieved SVR12 (Observed Data) Rates in 99 Percent of Treatment-Naïve and 93 Percent in Prior Null Responders for Genotype 1 Patients in Phase 2b Study

October 15, 2012

Abbott Park, Illinois (NYSE: ABT) — Abbott today announced initial results from "Aviator," a phase 2b study of its interferon-free, investigational regimen for the treatment of hepatitis C (HCV). Initial results show sustained virological response at 12 weeks post treatment (SVR12) in 99 percent of treatment-naïve (n=77) and 93 percent of null responders (n=41) for genotype 1 (GT1) HCV patients taking a combination of ABT-450/r, ABT-267, ABT-333 and ribavirin for 12 weeks, based on an observed data analysis.

Full results from the study will be presented at the Latebreaker Session of The Liver Meeting, the Annual Meeting of the American Association for the Study of Liver Disease (AASLD) in Boston, November 9-13. Abstracts are available at www.aasld.org.

The observed data analysis used in this abstract does not include six patients who had not yet reached post-treatment week 12 or had missing values (data points) at the time of the abstract submission. All virologic failures and safety discontinuations were included in the analysis.

"There is a significant unmet medical need for genotype 1, the most common form of HCV in the U.S. and Europe," said Kris Kowdley, M.D., director of the Liver Center of Excellence in the Digestive Disease Institute at Virginia Mason Medical Center, and Clinical Professor of Medicine at the University of Washington in Seattle. "Results from this phase 2b study suggest that sustained virological response can be achieved without interferon in a high proportion of genotype-1 patients, including patients who have not responded to previous treatment. This is exciting news as we continue to study treatment options for patients."

"Based on the promising results we've seen, Abbott has selected a triple direct acting antiviral regimen, with and without ribavirin for phase 3 development," said Scott Brun, M.D., divisional vice president, Infectious Disease Development, Abbott. "The ability to show sustained virological response in these patient populations, without the use of interferon, is extremely encouraging."

Study M11-652 (Aviator)

• Kris Kowdley, et al.; Monday, November 12 (3:00-3:15 p.m. ET)
  "A 12-Week Interferon-free Treatment Regimen with ABT-450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-Naïve Patients and 93% in Prior Null Responders with HCV Genotype1 Infection"

The objective of this phase 2b study was to assess the safety, and efficacy of ABT-450/r (dosed 100/100 to 200/100mg QD), ABT-267 (25mg QD), ABT-333 (400mg BID) and ribavirin in non-cirrhotic treatment-naïve patients and prior peg-interferon/ribavirin null responders for 8, 12 or 24 weeks.

Enrollment was open to GT1-infected patients regardless of IL28B host genotype and ribavirin dosing was weight-based.

The 12-week regimen of three direct acting antivirals plus ribavirin had the highest SVR12 rates among the 8 and 12 week arms. Results from the 12 week treatment groups containing three direct acting antivirals plus ribavirin are summarized in the chart below.

 

	Treatment-naïve (N=79)	Null responders(N=45)
BL HCV RNA (log10 IU/mL)	6.5±0.6	6.6±0.5
BL IL28B non-CC genotype	72%	96%
SVR4	78/79 (99%)	42/45 (93%)
OD SVR12	76/77 (99%)	38/41 (93%)
PTW12 data missing*	2	4
Breakthrough	0	3
Relapse	1	0
OD SVR12 (GT1a)	52/53 (98%)	24/27 (89%)
OD SVR12 (GT1b)	24/24 (100%)	14/14 (100%)
OD SVR12 (IL28B non-CC)	54/55 (98%)	36/39 (92%)

*	Did not follow up (2 treatment-naïve patients and 1 null responder) or have not yet reached PTW12 (3 null responders)

Additional data presented in the abstract represent all 8- and 12-week arms (n=448) of this 14-arm study (571 patients enrolled: 438 treatment-naïve and 133 prior null responders). SVR₁₂ rates for other 8- and 12-week regimens ranged from 89-92 percent. Complete SVR₁₂ data for 8- and 12-week arms will be presented at the Liver Meeting.

Four of 448 patients (one percent) in the 8- and 12-week arms discontinued due to adverse events. Of five serious AEs (1 percent), 1 (arthralgia or joint pain) was possibly study drug-related. In the trial, the most common adverse events were fatigue (28 and 27 percent) and headache (28 and 31 percent) for treatment naïve and null responders respectively.

Abbott Data at AASLD

In addition to Aviator, there are four poster presentations on Abbott's investigational medicines for the treatment of HCV:

• Tami Pilot-Matias et al.; Sunday, November 11 (8:00 a.m.-5:30 p.m. ET)
  "Characterization of Resistant Variants in NS3 and NS5B Detected in Subjects Treated with ABT-450/r, Ribavirin, and Either ABT-072 or ABT-333 in the Pilot and Co-Pilot Studies Who Experienced Virologic Breakthrough or Relapse"
• Preethi Krishnan et al.; Tuesday, November 13 (8:00 a.m.-12:00 p.m. ET)
  "Antiviral Activity and Resistance Profiles for ABT-267, a Novel HCV NS5A Inhibitor, In Vitro and During 3-Day Monotherapy in HCV Genotype-1 (GT1)-Infected Treatment-Naïve Subjects"
• Lane Kirbach et al.; Tuesday, November 13 (8:00 a.m.-12:00 p.m. ET)
  "Evaluation of Patient Preferences for Treatment Outcomes in Hepatitis C Virus (HCV)"
• Amit Khatri et al.; Sunday, November 11 (8:00 a.m.-5:30 p.m. ET)
  "Pharmacokinetics and Safety of Co-administered ABT-450 plus Ritonavir (ABT-450/r), ABT-267 and ABT-333 as a Single Dose in Subjects with Normal Hepatic Function and in Subjects with Mild, Moderate and Severe Hepatic Impairment"

About the Hepatitis C Virus

Hepatitis C is a liver disease affecting as many as 170 million people worldwide. The virus is primarily spread through direct contact with the blood of an infected person. HCV increases a person's risk of developing chronic liver disease, cirrhosis, liver cancer and death; and liver disease associated with HCV infection is growing rapidly.

About Abbott's HCV Development Programs

Abbott's HCV portfolio includes investigational medicines with three different mechanisms of action, including protease (ABT-450/r), polymerase (ABT-333) and NS5A (ABT-267) inhibitors, currently being studied in clinical trials. ABT-450 is being developed with low dose ritonavir which enhances the pharmacokinetic properties of ABT-450. The use of ritonavir 100 mg with ABT-450 for the treatment of HCV is investigational. ABT-450 was discovered during the course of a collaboration between Abbott and Enanta Pharmaceuticals for HCV protease inhibitors and regimens that include protease inhibitors.

ABT-450 is being developed by Abbott for use in combination with Abbott's other investigational medicines for the treatment of HCV. Abbott is well-positioned to explore combinations and co-formulations of these medicines.

Ritonavir Use in Treatment of HIV

Ritonavir is in a class of medicines called the HIV protease inhibitors. Ritonavir is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. Ritonavir is for adults and for children greater than 1 month in age and older.

Ritonavir does not cure HIV infection or AIDS and does not reduce the risk of passing HIV to others. People taking ritonavir may still get opportunistic infections or other conditions that happen with HIV infection. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.

Ritonavir Safety in Treatment of HIV

Patients should not take ritonavir with certain medicines, as these can cause serious or life-threatening problems such as irregular heartbeat, breathing difficulties, or excessive sleepiness. Patients should not take ritonavir if they have had a serious allergic reaction to any of its ingredients. Some patients taking ritonavir may develop liver and pancreas problems, which can cause death.

Patients may develop large increases in triglycerides and cholesterol, diabetes, high blood sugar, changes in body fat, increased bleeding in people with hemophilia, allergic reactions, and/or changes in heart rhythm. Patients may develop signs and symptoms of infections that they already have after starting anti-HIV medicines.

For more information, please see the Important Safety Information and full Prescribing Information for ritonavir.

About Abbott

Abbott (NYSE: ABT) is a global, broad-based health care company devoted to the discovery, development, manufacturing and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs approximately 91,000 people and markets its products in more than 130 countries.

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