Date: 2017-10-23
Type of
information: Presentation of results at a congress
phase: 2b
Announcement: presentation of results at the 2017 Liver Meeting™
Company: Janssen Research & Development, a J&J company (USA - NJ) Medivir (Sweden)
Product: JNJ-4178 (AL-335) simeprevir, odalasvir
Action
mechanism:
- direct-acting antiviral agent/protease inhibitor/RNA polymerase (NS5B) inhibitor/RNA polymerase (NS5A) inhibitor
- Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir.
- Odalasvir (also known as ACH-3102 - JNJ-4178) ) 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.
- Medivir announced on September 11th 2017 that Janssen Sciences Ireland UC had decided to discontinue the development of JNJ-4178. The discontinuation of development of JNJ-4178 does not affect the ongoing partnership with Janssen on Olysio® (simeprevir), or the existing licensing agreement with Janssen in which simeprevir is included. Medivir continues to be entitled to royalties on sales of single agent simeprevir globally.
Disease: chronic Hepatitis C Virus (HCV) genotype 1-6 infection, with and without cirrhosis
Therapeutic
area: Infectious diseases
Country: Belgium, Canada, France, Germany, Malaysia, The Netherlands, New Zealand, Poland, Singapore, Spain, Sweden, UK, Vietnam
Trial
details:
- This phase 2b multicenter study will include a screening period of maximum 6 weeks, a treatment period of 6 or 8 weeks and a 24-weeks post-treatment follow-up period. The total study duration for each subject will be 36 to 38 weeks. This study investigates a 3 direct-acting antiviral agent (DAA) combination of AL-335 (HCV NS5B inhibitor), odalasvir (ODV) (a second generation HCV NS5A inhibitor) and simeprevir (SMV) (HCV NS3A4 protease inhibitor) and a 2DAA combination of AL-335 and ODV. The results of this study will enable the selection of treatment regimen and duration to be further developed. (NCT02765490)
Latest
news:
- • On October 23, 2017, Medivir announced phase IIb data on JNJ-4178, the triple combination consisting of simeprevir, odalasvir and AL-335, following presentations at the 2017 Liver Meeting™ organized by the American Association for the Study Liver Diseases (AASLD) and held in Washington DC on 20-24 October.
- SVR12 data from OMEGA-1, a global open-label phase IIb study of the efficacy and safety of JNJ-4178 in non-cirrhotic patients with HCV genotypes 1, 2, 4, 5 and 6, were presented at the conference. The results showed that 98.9% (181/183) of patients treated with JNJ-4178 for 6 weeks achieved SVR12, while 97.8% (178/182) of patients treated with JNJ-4178 for 8 weeks achieved SVR12, with both arms meeting the prespecified endpoint of statistical non-inferiority compared to historic controls. The triple combination was generally well-tolerated in both arms of the study, with the most frequent adverse events being headache and fatigue.
- • 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.
| Dose |
HCV Genotype |
Dosing
Duration
(weeks) |
Number (%) with undetectable HCV RNA at SVR24* |
| AL-335
(mg QD) |
ODV
(mg) |
SMV
(mg QD) |
| 400 |
50 QD |
100 |
1 |
8 |
20/20 (100%) |
| 800 |
50 QOD |
75 |
1 |
8 |
20/20 (100%) |
| 800 |
50 QOD |
75 |
1 |
6 |
20/20 (100%) |
| 800 |
50 QOD |
-- |
1 |
8 |
21/25 (84%) |
| 800 |
50 QOD |
-- |
1 |
12 |
7/8 (88%) |
| 800 |
50 QOD |
75 |
3 |
8 |
0/5 (0%) |
| 800 |
50 QOD |
75 |
3 |
12 |
10/13 (77%)** |
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 December 28, 2016, Achillion Pharmaceuticals announced that it has received a $15 million milestone payment from Janssen Research & Development, related to enrollment in the OMEGA-1 Phase 2b global, clinical trial of JNJ-4178, a 3DAA combination of odalasvir, simeprevir, and AL-335 in patients with treatment-naive chronic hepatitis C virus infection (HCV) without cirrhosis. Initiated in November 2016, the objectives of OMEGA-1 are to investigate the efficacy, safety and pharmacokinetics of JNJ-4178 (AL-335 (800mg QD), odalasvir (25mg QD), and simeprevir (75mg QD)) in treatment-naive and treatment-experienced non-cirrhotic subjects with HCV genotype 1, 2, 4, 5, and 6 infection. A total of 300 patients are expected to be enrolled. Patients in the study will receive the triple combination for either six or eight weeks, and the primary efficacy endpoint will be the percentage of patients with a sustained virological response 12 weeks after the end of treatment (SVR12).
- • On November 28, 2016, Medivir announced that a phase IIb open-label study of the combination of simeprevir, odalasvir and AL-335, also known as JNJ-4178, has been initiated by Janssen Research & Development, in treatment-naive and treatment-experienced subjects with chronic hepatitis C virus infection without cirrhosis. This global, multi-center study includes clinical trial sites in North America, Europe and Asia and forms part of Janssen’s global development program for JNJ-4178. The objectives of the phase IIb study are to investigate the efficacy, safety and pharmacokinetics of JNJ-4178/ AL-335 (800mg QD), odalasvir (25mg QD), and simeprevir (75mg QD) in treatment-naive and treatment-experienced non-cirrhotic subjects with chronic hepatitis C virus genotype 1, 2, 4, 5, and 6 infection. Patients in the study will receive the triple combination for either six or eight weeks, and the primary efficacy endpoint will be the percentage of patients with a sustained virological response 12 weeks after the end of treatment (SVR12).
- An ongoing phase IIa study is assessing the same triple combination in patients with or without compensated cirrhosis.
- • On May 11, 2016, Medivir announced that Janssen Research & Development, has decided to initiate a phase IIb study to investigate the efficacy, safety and pharmacokinetics of different treatment regimens of AL-335, odalasvir, and simeprevir in treatment-naïve and treatment-experienced patients with chronic Hepatitis C Virus (HCV) genotype 1-6 infection, with and without cirrhosis. This global phase IIb study is a randomized, open-label, four-arm study of AL-335, a nucleotide-based HCV NS5B polymerase inhibitor, odalasvir, an HCV NS5A inhibitor and simeprevir, an HCV NS3/4A protease inhibitor. Approximately 400 patients will be randomized to one of four treatment arms and receive once daily treatment for a duration of six or eight weeks. Patients in two of the four arms will receive AL-335, odalasvir and simeprevir, while patients in the other two arms will receive only AL-335 and odalasvir. The primary endpoint of the study is the percentage of chronic HCV-infected subjects who achieve a sustained virologic response 12 weeks after the end of treatment (SVR12). The study is intended to start in June 2016 and the estimated date for completion is July 2017.
Is
general: Yes
