Janssen Announces SVR12 Rates with Twelve Weeks of Treatment with All-Oral, Once-Daily Regimen of Simeprevir Plus Sofosbuvir in Genotype 1 HCV Patients With and Without Cirrhosis

CORK, Ireland, April 23, 2015 /PRNewswire/ -- Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), today announced results for its hepatitis C treatment simeprevir at The International Liver Congress™ 2015 of the European Association for the Study of the Liver (EASL) in Vienna. Late-breaking results from the Phase 3 OPTIMIST-1 and OPTIMIST-2 trials highlight the clinical outcomes of simeprevir in an all-oral combination regimen in a wide range of patients with hepatitis C virus (HCV) infection.

"The new data for simeprevir presented at The International Liver Congress™ confirms its efficacy when combined with sofosbuvir in an all-oral, ribavirin-free regimen for HCV patients, including those who are treatment-naive and treatment-experienced, both with and without cirrhosis," said Gaston Picchio, hepatitis disease area leader, Janssen. "These data further demonstrate the role of simeprevir within the HCV treatment landscape, as it provides patients with an important therapeutic option."

The results from the OPTIMIST-1 and OPTIMIST-2 trials are the first Phase 3 data to be presented on simeprevir in combination with sofosbuvir (SMV/SOF) in patients with genotype 1 chronic HCV infection, both with and without cirrhosis. Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor developed by Gilead Sciences, Inc.

OPTIMIST-1¹

• OPTIMIST-1 is a Phase 3, randomized, open-label trial to investigate the efficacy and safety of the all-oral regimen of SMV/SOF among treatment-naive and treatment-experienced genotype 1 chronic HCV-infected patients without cirrhosis. The primary objective was to show superior sustained virologic response (SVR) at 12 weeks after treatment (SVR12) with 12 and eight weeks of treatment with SMV/SOF versus a historical control (patients previously treated with approved regimens containing a direct-acting antiviral, pegylated interferon and ribavirin).
• Ninety-seven (97) percent of patients treated with SMV/SOF for 12 weeks (n=150/155) achieved SVR12, which was superior to the SVR12 rate of 87 percent among the historical control.
  • SVR12 rates of 100 percent were seen among patients with IL28B CC genotype (n=43/43) and those with baseline NS5A and NS3 Q80K polymorphisms (n=9/9).
• Patients treated with eight weeks of SMV/SOF achieved an SVR12 rate of 83 percent (n=128/155), which was not superior to the SVR12 rate of 83 percent in the historical control.
  • High SVR12 rates were seen among patients with baseline HCV RNA <4 million IU/mL (96 percent; n=46/48), IL28B CC genotype (93 percent; n=38/41), patients with genotype 1b HCV infection (92 percent; n=36/39) and patients without baseline NS5A and Q80K polymorphisms (89 percent; n=78/88).
• The most frequently reported adverse events in the 12-week and eight-week treatment arms were headache (14 and 17 percent, respectively), fatigue (12 and 15 percent, respectively) and nausea (15 and 9 percent, respectively).

OPTIMIST-2²

• OPTIMIST-2 is a Phase 3, open-label, single-arm trial to investigate the efficacy and safety of SMV/SOF in treatment-naive and treatment-experienced genotype 1 chronic HCV-infected patients with cirrhosis. The primary objective was to show superior SVR12 with 12 weeks of treatment with SMV/SOF versus a historical control.
• Twelve (12) weeks of treatment with SMV/SOF resulted in SVR12 rates of 83 percent (n=86/103), which was superior to the SVR12 rate of 70 percent in the historical control.
• Higher SVR12 rates were seen in patients with baseline NS5A polymorphisms with or without NS3 Q80K polymorphisms (100 percent, n=13/13), patients with albumin ≥4 g/dL (94 percent; n=47/50) and treatment-naïve patients (88 percent; n=44/50).
• The most common adverse events were fatigue (20 percent), headache (20 percent) and nausea (11 percent).

"Chronic HCV infection is a leading cause of cirrhosis, and once it is developed, these patients can be very difficult to cure. The results of the OPTIMIST-2 study demonstrate the safety and efficacy of the all-oral regimen of simeprevir and sofosbuvir for genotype 1 chronic HCV patients with cirrhosis," said Eric Lawitz, M.D., Texas Liver Institute, principal investigator of the OPTIMIST-2 study.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is a major global public health concern. Approximately 170 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 Janssen's HCV Development Program
The goal of the Janssen hepatitis C virus (HCV) clinical development program is to provide physicians with multiple treatment options in order to offer patients the best possible chance at successful therapy.

Ongoing studies focus on the investigation of the NS3/4A protease inhibitor simeprevir in a number of different treatment combinations and HCV patient populations, including those who are difficult to cure.

Janssen's HCV pipeline also includes JNJ-56914845, an investigational NS5A replication complex inhibitor currently in Phase 2 studies, and following the acquisition of Alios BioPharma by Johnson & Johnson in November 2014, AL-335, a uridine-based nucleotide analog in Phase 1 development, and AL-516, a guanosine-based nucleotide analog NS5B polymerase inhibitor in pre-clinical development.

These compounds are being developed with the intent of targeting critical steps of the HCV replication cycle. 

About Simeprevir (OLYSIO^®)
Simeprevir is an NS3/4A protease inhibitor which has been developed by Janssen Sciences Ireland UC in collaboration with Medivir AB. 

In November 2013, simeprevir was initially approved by the U.S. Food and Drug Administration, and in May 2014, it was granted marketing authorization by the European Commission. Subsequent marketing authorizations have followed in several other countries around the world. Indications vary by market.

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.

About Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen R&D Ireland is part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit http://www.janssenrnd.com for more information.

INDICATIONS
OLYSIO^® is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen.

Limitations of Use:

• OLYSIO^® monotherapy is not recommended.
• OLYSIO^® efficacy in combination with peginterferon alfa (Peg‑IFN‑alfa) and ribavirin (RBV) is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.
• OLYSIO^® is not recommended in patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C).
• OLYSIO^® is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO^® or other HCV protease inhibitors.

IMPORTANT SAFETY INFORMATION

Contraindications:

• There are no specific contraindications to OLYSIO^®. The contraindications to other antiviral drugs administered with OLYSIO^® for the treatment of CHC infection also apply to OLYSIO^® combination treatment.  Prescribers should consult the complete prescribing information for these drugs for a description of contraindications.

Warnings and Precautions:

• Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone:  Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO^®. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co-administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown. 
  
  Co-administration of amiodarone with OLYSIO^® in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co-administered OLYSIO and sofosbuvir: 
  
           o    Counsel patients about the risk of serious symptomatic bradycardia
  
           o    Cardiac monitoring in an in-patient setting for the first 48 hours of
                 co-administration is recommended, after which outpatient or self-monitoring
                 of the heart rate should occur on a daily basis through at least the first 2
                 weeks of treatment.
  
  Patients who are taking sofosbuvir in combination with OLYSIO^® who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.
  
  Due to amiodarone's long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO^® should also undergo similar cardiac monitoring as outlined above.
  
  Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.
  
   
• Hepatic Decompensation and Hepatic Failure:  Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO^® in combination with Peg‑IFN‑alfa and RBV or in combination with sofosbuvir.  Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure.  Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO^® and these events has not been established.
  
  OLYSIO^® is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).
  
  In clinical trials of OLYSIO^®, modest increases in bilirubin levels were observed without impacting hepatic function. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported.  Monitor liver chemistry tests before and as clinically indicated during OLYSIO^® combination therapy.  Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:
  • Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
  • Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.
    
     
• Risk of Serious Adverse Reactions Associated With Combination Treatment: OLYSIO^® should be used in combination with other antiviral drugs for the treatment of CHC infection. Therefore, consult the prescribing information for these drugs before starting therapy with OLYSIO^®.
  
   
• Photosensitivity: Photosensitivity reactions have been observed with OLYSIO^® combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with OLYSIO^® in combination with Peg‑IFN‑alfa and RBV. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.
  
  Use sun protective measures and limit sun exposure during treatment with OLYSIO^®. Avoid use of tanning devices during treatment with OLYSIO^®. Discontinuation of OLYSIO^® should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue OLYSIO^® in the setting of a photosensitivity reaction, expert consultation is advised.
  
   
• Rash: Rash has been observed with OLYSIO^® combination therapy. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of OLYSIO^® have been reported in subjects receiving OLYSIO^® in combination with Peg‑IFN‑alfa and RBV. Most of the rash events in OLYSIO^®‑treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, OLYSIO^® should be discontinued. Patients should be monitored until the rash has resolved.
  
   
• Sulfa Allergy: OLYSIO^® contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of OLYSIO^®.
  
   
• Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: Co‑administration of OLYSIO^® with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions.

Adverse Reactions

• Use with Peg-IFN-alfa and RBV: Adverse reactions (all grades, at least 3% higher frequency) for OLYSIO^® with Peg-IFN-alfa and RBV vs. Peg-IFN-alfa and RBV alone in the first 12 weeks were rash (including photosensitivity) (28% vs. 20%), pruritus (22% vs. 15%), nausea (22% vs. 18%), myalgia (16% vs. 13%), and dyspnea (12% vs. 8%).

• Use with sofosbuvir: The most common (> 10%) adverse reactions reported during 12 weeks treatment with OLYSIO^® in combination with sofosbuvir without RBV were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with OLYSIO^® in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported.

Use in Specific Populations

• Pregnancy Category C: Adequate and well-controlled trials with OLYSIO^® have not been conducted in pregnant women. OLYSIO^® should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method.

• Race: Patients of East Asian ancestry exhibit higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of OLYSIO^® should be carefully considered prior to use in patients of East Asian ancestry.

• Renal Impairment:  No dose adjustment of OLYSIO^® is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of OLYSIO^® have not been studied in HCV‑infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end‑stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.

• Hepatic Impairment: No dose adjustment of OLYSIO^® is required in patients with mild hepatic impairment (Child‑Pugh Class A). The safety and efficacy of OLYSIO^® have not been established in HCV‑infected patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). OLYSIO^® is not recommended for patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO^® combination therapy. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity.

• Other HCV Genotypes: The safety and efficacy of OLYSIO^® have not been established in patients infected with other HCV genotypes.

• Liver Transplantation: The safety and efficacy of OLYSIO^® have not been studied in liver transplant patients.

Not a complete list of Uses in Specific Populations.

Consult the PI for Peg-IFN-alfa and RBV or sofosbuvir before starting therapy with OLYSIO^®.  Safety information related to these drugs also applies to their use in OLYSIO^® combination treatment.

Please see full Prescribing Information and 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 R&D Ireland and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in new product development, including the uncertainty of clinical success and of obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. 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 28, 2014, including in Exhibit 99 thereto, and the company's 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.

References

¹ A Phase 3, randomised, open-label study to evaluate the efficacy and safety of 12 and 8 weeks of treatment with simeprevir plus sofosbuvir in treatment-naive and -experienced patients with chronic HCV genotype 1 infection without cirrhosis: The OPTIMIST-1 study. Presented at The International Liver Congress™ 2015.

² A Phase 3, open-label, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir plus sofosbuvir in treatment-naive or –experienced patients with chronic hepatitis c virus genotype 1 infection and cirrhosis: The OPTIMIST-2 study. Presented at The International Liver Congress™ 2015.

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