Clinical Trials

Date: 2017-04-22

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the European Association for the Study of the Liver (EASL) Special Conference

Company: Alios Biopharma, a J&J company (USA - NJ) Achillion Pharmaceuticals (USA - CT)

Product: JNJ-4178 (AL-335, odalasvir (ACH-3102) and simeprevir=

Action mechanism:

• direct-acting antiviral agent/protease inhibitor/RNA polymerase (NS5B) inhibitor
• Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir.
• Odalasvir (also known as ACH-3102) is a structurally distinct, second-generation NS5A inhibitor, which achieved 100% SVR12 in a Phase 2 study of genotype 1 HCV patients treated for 6-weeks with ACH-3102+sofosbuvir.
• AL-335 is a nucleotide-based HCV polymerase inhibitor.

Disease: chronic hepatitis C

Therapeutic area: Infectious diseases

Country: New Zealand

Trial details:

• This randomized, phase 2a, open-label study will assess the safety, pharmacokinetics and efficacy of the orally administered combination of AL-335, ACH-3102, and simeprevir in treatment-naïve subjects with chronic hepatitis C (CHC) infection. Patients will be randomized to one of three treatment arms and receive once daily treatment for a duration of four, six or eight weeks. The primary objective of the study is to establish the safety of the treatment regimen with secondary endpoints consisting of pharmacokinetics, the proportion of subjects achieving sustained viral response (SVR), and the effect on the viral resistance profile after treatment. The study is expected to enroll approximately 60 patients across the three treatment arms. (NCT02569710)

Latest news:

• • On April 24, 2017,  Medivir  communicated an update on the status of the development of JNJ-4178, the triple combination of simeprevir, odalasvir and AL-335, following The International Liver Congress™ 2017 of the European Association for the Study of the Liver (EASL).
• Data from an ongoing phase II study presented at The International Liver Congress™ 2017 demonstrate that this regimen has the potential to shorten treatment duration, offer high efficacy and is generally well tolerated in those whose disease is caused by HCV genotype 1. The three-drug regimen achieved 100% SVR12 for 6- and 8-week treatment duration in treatment-naïve, genotype 1, non-cirrhotic patients. The three-drug combination did not have sufficient efficacy in patients with HCV genotype 3 to justify further development in this patient population. All-oral combination regimens, containing odalasvir, AL-335 with or without simeprevir were generally safe and well tolerated.
• • On April 22, 2017, Achillion Pharmaceuticals announced the presentation of updated results from the ongoing phase 2 ‘604 Study' being conducted by Alios BioPharma. These results were presented as an oral presentation during the European Association for the Study of the Liver (EASL) 2017 International Liver Congress in Amsterdam. These results demonstrate that the triple combination of simeprevir, odalasvir and AL-335 has the ability to shorten treatment duration, offer high efficacy and be generally well tolerated in those whose disease is caused by hepatitis C virus (HCV) genotype 1 (GT1), one of the most prevalent causes of hepatitis C globally.
• Study results, presented by principal investigator Dr. Edward Gane, professor of medicine at the University of Auckland and chief hepatologist at Auckland City Hospital, included expanded safety and efficacy data and were made in a presentation entitled "Short duration treatment with AL-335 and odalasvir, with or without simeprevir, in treatment-naïve patients with hepatitis C virus (HCV) genotype 1 infection." It reports that 100% of patients receiving treatment for six or eight weeks with a triple combination of once-daily AL-335 800 mg and simeprevir 75 mg with odalasvir 50 mg every other day achieved a sustained viral response 24 weeks after the completion of treatment (SVR24).
• Summary of Phase 2 '604 Study' Design and Interim Results: The oral presentation features clinical trial data examining the safety, pharmacokinetics and efficacy of six and eight weeks of treatment with AL-335 and odalasvir with or without simeprevir to treat HCV in treatment naïve subjects across a range of HCV genotypes and stages of liver disease. Data from this study demonstrate that JNJ-4178, the three-drug combination of simeprevir, odalasvir and AL-335, was highly effective in treatment naïve patients with HCV genotype 1 infection without cirrhosis, achieving 100% SVR24 for treatment durations of both 6 and 8 weeks. The two-drug regimen of odalasvir and AL-335, a combination regimen not anticipated to move forward, achieved 84% SVR24 for treatment duration of 8 weeks in patients with HCV genotype 1 without cirrhosis. The three-drug regimen of simeprevir, odalasvir and AL-335 in HCV genotype 3 patients without cirrhosis achieved an SVR12 of 77% following 12 weeks of therapy, and is also not anticipated to move forward. Genomic sequencing results indicate that despite the presence of multiple NS5A mutations observed at baseline there was no apparent impact on SVR rates.
• The all-oral combination regimens containing odalasvir and AL-335, with or without simeprevir, were generally safe and well tolerated. Treatment results from the ‘604 Study' are summarized in the table below. Based on these data, JNJ-4178 is being further investigated for the treatment of HCV genotypes 1, 2, 4, 5, and 6.

• QD: every day; QOD: every other day; RNA: ribonucleic acid; SVR: sustained virologic response. *All results SVR24, with the exception of genotype 3 which is SVR12 **One patient did not attend SVR12 follow-up.
• Janssen has initiated a multi-center, randomized, open-label Phase 2b study of JNJ-4178, the triple combination of once-daily odalasvir 25mg, AL-335 800mg, and simeprevir 75mg for treatment durations of six and eight weeks. Designated OMEGA-1, this trial has now completed enrollment of more than 365 treatment-naïve and treatment-experienced, non-cirrhotic patients chronically infected with HCV genotype 1,2,4,5 and 6. Results from this trial are anticipated during the second half of 2017. In addition, the ‘604 Study' is ongoing and will assess the triple combination JNJ-4178 in patients with compensated cirrhosis. In addition to the OMEGA-1 and ‘604 Study,' a number of supplemental clinical trials are being conducted by Janssen including those assessing special populations, certain drug-drug interactions, the bioavailability of a fixed dose combination, and providing for long-term follow-up of patients, all supporting the global development of JNJ-4178.
• • On September 23, 2016, Achillion Pharmaceuticals, announced that updated interim results were presented in an ePoster describing a phase 2 study being conducted by Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies (Janssen) at the European Association for the Study of the Liver (EASL) Special Conference in Paris, France. These results, updated to include expanded safety and efficacy data, were presented in the ePoster entitled "Short duration treatment with AL-335 and odalasvir (ODV), with or without simeprevir (SMV), in treatment-naïve patients with hepatitis C virus (HCV) genotype (GT) 1 infection." It reports that 100 percent of patients receiving treatment for as short as six weeks with a triple combination of once-daily (QD) AL-335 800mg and simeprevir (SMV) 75mg with 50mg every other day (QOD) of ODV achieved a sustained viral response 12 weeks after the completion of treatment (SVR12).
• Summary of Phase 2 Study Design and Interim Results: This study was designed to determine the safety, pharmacokinetics, and efficacy of different dosing regimens containing ODV and AL-335, with or without SMV, in treatment-naïve patients with GT1 HCV infection for treatment durations of eight or six weeks. Of the GT1 non-cirrhotic patients that received the triple combination of ODV, AL-335, and simeprevir 100 percent remained HCV RNA undetectable at SVR12 and all patients in cohort 1 achieved SVR24 (i.e., cohorts 1, 3, and 4; N=60, 20/cohort). Cohort 1 evaluated the triple combination of ODV (50mg QD), AL-335 (400mg QD) and simeprevir (100mg QD) for eight weeks, while cohorts 3 & 4 assessed ODV (50 mg QOD), AL-335 (800 mg QD), and SMV (75 mg QD) for eight and six weeks, respectively. In cohort 2, which assessed the dual combination of ODV (50mg QOD) and AL-335 (800mg QD) for eight weeks, 90 percent of subjects achieved SVR12 (N=20).
• In all of these cohorts, the dosing regimens were generally well-tolerated. The majority of adverse events (AEs) were mild and the most commonly reported events were headache, fatigue, and upper respiratory tract infection. As previously reported in the abstract, there was one serious adverse event (SAE) in cohort 1 that resulted in premature discontinuation of all study drugs. This consisted of a Mobitz Type 1 2nd degree atrioventricular block and was deemed probably related to ODV and possibly related to AL-335 and simeprevir. The event was not associated with clinical or echocardiographic abnormalities, did not require any therapeutic intervention, resolved following treatment discontinuation, and the patient went on to achieve SVR24. No clinically significant laboratory, echocardiography, or ECG abnormalities (except the SAE) were reported.
• Ongoing Phase 2 Triple Combination Development Program: The interim results from this phase 2 study confirmed the treatment duration and dose for each component of the triple combination (i.e., once-daily ODV 25mg, AL-335 800mg, and SMV 75mg for treatment durations of six and eight weeks). The development program will include a multi-center, randomized, open-label study that will enroll treatment-naïve and treatment-experienced non-cirrhotic patients chronically infected with hepatitis C virus genotypes 1, 2, 4, 5, and 6. In addition, the ongoing phase 2a study is assessing the triple combination in patients with or without compensated cirrhosis, and with HCV genotype 3 infection.
• • On September 9, 2016, Achillion Pharmaceuticals announced that new interim results from a phase 2a study being conducted by Alios BioPharma, part of the Janssen Pharmaceutical Companies (Janssen), were published as part of the abstracts released for the upcoming European Association for the Study of the Liver (EASL) Special Conference, September 23 - 24, 2016, in Paris, France.
• Data included in the abstract were as of the time of submission in July 2016. Updated results, including sustained viral response 12 weeks after completion of therapy (SVR12) for all cohorts, are scheduled to be presented on Friday, September 23, 2016, in an ePoster entitled "Short duration treatment with AL-335 and odalasvir (ODV), with or without simeprevir (SMV), in treatment naïve patients with hepatitis C virus (HCV) genotype (GT) 1 infection." Interim results from cohorts 1-4, summarized in the table below, showed that the triple combination regimen was highly effective and well tolerated in non-cirrhotic patients with GT1 HCV.
• Of the 20 patients treated in cohort 1, who received the triple combination of odalasvir (50mg QD), AL-335 (400mg QD) and simeprevir (100mg QD) for eight weeks (triplet, 8 weeks), 100 percent remained HCV RNA undetectable 24 weeks after completing therapy (SVR24). Additional patients were subsequently enrolled into two further cohorts (3 & 4), where they received adjusted doses of the same triplet combination for either eight or six weeks. In cohort 3 all were HCV RNA negative and remained HCV RNA undetectable 4 weeks after completing therapy (SVR4) and in cohort 4 all were HCV RNA negative (N=18) or below the limit of quantitation (N=2) at end of treatment. Of the 20 patients treated in cohort 2, who received the dual combination of odalasvir (50mg QOD) and AL-335 (800mg QD) for eight weeks (doublet, 8 weeks), 90 percent remained HCV RNA undetectable twelve weeks after completing therapy (SVR12).
• All-oral combination regimens, containing odalasvir, AL-335 with or without simeprevir were generally safe and well tolerated. The majority of adverse events (AEs) were mild, most commonly headache, fatigue, and upper respiratory tract infection. In cohort 1, there was a single serious adverse event (Mobitz Type 1 2nd degree atrioventricular block), which was attributed to treatment. This ECG abnormality was not associated with clinical or echocardiographic abnormalities, and resolved following treatment discontinuation. No clinically significant laboratory abnormalities were observed.
• • On August 11, 2016, Achillion Pharmaceuticals announced that interim results from an ongoing phase 2a clinical trial, being conducted by Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), to evaluate all-oral combination regimens, containing odalasvir, AL-335 and simeprevir, were accepted for presentation at the EASL — American Association for the Study of Liver Diseases (AASLD) Special Conference: New Perspectives in Hepatitis C Virus Infection — The Roadmap for Cure, being hosted in Paris, France on September 23 — 24, 2016.The eposter, entitled "Short duration treatment with AL-335 and odalasvir (ODV), with or without simeprevir (SMV), in treatment naïve patients with hepatitis C virus (HCV) genotype (GT) 1 infection," will be presented on Friday, September 23, 2016. This phase 2a study aims to establish the safety, pharmacokinetics and efficacy of doublet and triplet regimens, consisting of odalasvir and AL-335 with or without simeprevir, in treatment naïve patients with genotype 1 HCV infection for treatment durations of eight weeks or less.
• • On October 16, 2015, Achillion Pharmaceuticals announced that Alios Biopharma Inc., part of the Janssen Pharmaceutical Companies (Janssen) has initiated treatment in a phase 2a clinical trial to evaluate the safety, pharmacokinetics and efficacy of AL-335, odalasvir (also known as ACH-3102), and simeprevir in treatment-naïve patients with genotype 1 chronic hepatitis C virus (HCV) infection. As previously announced on May 19, 2015, Achillion has granted Janssen an exclusive, worldwide license to develop and, upon regulatory approval, commercialize HCV products and regimens containing one or more of Achillion's HCV assets which include odalasvir (ACH-3102), ACH-3422, and sovaprevir.

 

Is general: Yes