Date: 2014-03-17
Type of
information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the Conference of the Asian Pacific Association for the Study of the Liver (APASL) in Brisbane, Australia
Company: Tibotec Pharmaceuticals-J&J (Ireland - USA) Medivir (Sweden)
Product: simeprevir (TMC435)
Action
mechanism:
- direct-acting antiviral agent/protease inhibitor/RNA polymerase (NS3A) inhibitor.
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir.
Disease: naïve adults with chronic genotype 1 hepatitis C virus (HCV)
Therapeutic
area: Infectious diseases
Country: 24 countries including USA and Europe
Trial
details:
- • On February 17, 2011, Tibotec Pharmaceuticals has announced that two global, registrational phase 3 trials are recruiting patients to examine TMC435, its investigational hepatitis C protease inhibitor, in treatment-naïve adults with chronic genotype 1 hepatitis C virus (HCV). A third global phase 3 trial is being conducted in genotype 1 HCV patients who have experienced a viral relapse after prior interferon-based treatment.
The first global, phase 3, double-blind, randomized study, known as TMC435-C208 or QUEST-1 (QD dosing of TMC435 of previoUsly untreated GEnotype 1 patienTs-1), will evaluate a single TMC435 once-daily oral tablet (150 mg) versus placebo in treatment-naïve HCV patients. Both groups will also receive peginterferon alfa-2a (Pegasys®) and ribavirin (Copegus®) as part of their treatment.
The second global, phase 3, double-blind, randomized study, known as TMC435-C216 or QUEST-2 (QD dosing of TMC435 of previoUsly untreated GEnotype 1 patienTs-2), also will evaluate a single TMC435 once-daily oral tablet (150 mg) versus placebo in treatment-naïve HCV patients. However, patients in this trial will either receive peginterferon alfa-2a (Pegasys®) and ribavirin (Copegus®) or peginterferon alfa-2b (PegIntron®) and ribavirin (Rebetol®) as part of their treatment.
A third global, phase 3, double-blind randomized study, known as TMC435-C3007 or PROMISE (PROtease inhibitor TMC435 In PatientS who have previously rElapsed on IFN/RBV), will evaluate a single TMC435 once-daily oral tablet (150 mg) verses placebo in HCV patients who experienced viral relapse after previous interferon-based therapy. Both groups will receive peginterferon alfa-2a (Pegasys®) and ribavirin (Copegus®). The complete treatment duration for all three trials will be 24 or 48 weeks, depending on patient response. In the PROMISE trial, 393 patients were randomized to receive one 150 mg capsule of simeprevir or placebo once daily plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin alone for either 12 or 36 weeks based on response-guided therapy criteria.
In parallel to these trials phase 3 studies for TMC435 have also recently been launched in Japan.
Latest
news:
- • On March 17, 2014, Medivir has announced that new phase III data for the once-daily protease inhibitor simeprevir have been presented at the Conference of the Asian Pacific Association for the Study of the Liver (APASL) in Brisbane, Australia.
• Pooled analysis of data from the phase III QUEST-1 and QUEST-2 studies confirmed efficacy in treatment-naïve genotype 1b HCV patients, with 85 percent (ITT analysis) of treatment-naïve patients achieving SVR12 when treated with simeprevir in combination with PegIFN/RBV, compared to 53 percent when treated with placebo in combination with PegIFN/RBV.
• In the PROMISE phase III trial of prior relapse patients, a subgroup analysis of genotype 1b patients demonstrated that 86 percent (ITT analysis) of these patients achieved SVR12 when treated with simeprevir in combination with PegIFN/RBV, compared to 43 percent when treated with placebo in combination with PegIFN/RBV.
In a pooled analysis of the QUEST-1 and QUEST-2 studies, 89 percent of treatment-naïve genotype 1b HCV patients treated with simeprevir in combination with pegylated interferon and ribavirin and met the criteria for response guided therapy (94 percent) achieved SVR12 compared to 53 percent of patients treated with placebo in combination with pegylated interferon and ribavirin (ITT-analysis 85 and 53 percent, respectively). In patients typically considered difficult to treat, 71 percent of patients with the IL28B TT genotype and 78 percent with METAVIR F3-F4 scores achieved SVR12 in the simeprevir arm. Two percent of patients in each treatment arm discontinued treatment with simeprevir or placebo early due to an adverse event.
An analysis of the PROMISE study found that 89 percent of prior-relapser genotype 1b HCV patients treated with simeprevir in combination with pegylated interferon and ribavirin and met the criteria for response guided therapy (95 percent) achieved SVR12 compared to 43 percent of patients treated with placebo in combination with pegylated interferon and ribavirin (ITT-analysis 86 and 43 percent, respectively). In patients typically considered difficult to treat, 68 percent of patients with the IL28B TT genotype and 84 percent with METAVIR F3-F4 scores achieved SVR12 in the simeprevir arm. No patients discontinued treatment with either simeprevir or placebo due to adverse events during the entire treatment phase in this analysis of PROMISE.
• On May 21, 2013, Medivir has reported that its partner Janssen R&D Ireland has announced primary efficacy and safety results from the global phase III PROMISE study. Results demonstrated that use of the investigational protease inhibitor simeprevir (TMC435) led to sustained virologic response 12 weeks after the end of treatment (SVR12) in 79 percent of treatment-experienced genotype 1 chronic hepatitis C adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir was administered once daily with pegylated interferon and ribavirin.
In the study, 37 percent of patients receiving pegylated interferon and ribavirin (placebo) alone achieved SVR12. In the simeprevir arm, on-treatment failure rates were 3 percent and relapse rates were 19 percent, compared to 27 percent and 48 percent in the placebo arm. All patients had previously relapsed following pegylated interferon-based therapy.
Patients enrolled in PROMISE were stratified by hepatitis C virus (HCV) genotype 1 subtype and IL28B genotype. SVR12 rates among patients treated with simeprevir according to IL28B genotype were 89 percent for the CC allele, 78 percent for the CT allele, and 65 percent for the TT allele, compared to 53 percent for the CC allele, 34 percent for the CT allele and 19 percent for the TT allele in the placebo arm.
Among patients with METAVIR scores F0 to F2, 82 percent of patients treated with simeprevir and 41 percent with placebo achieved SVR12. Among patients with METAVIR scores F3 and F4, 73 percent and 74 percent of patients treated with simeprevir and 20 percent and 26 percent treated with placebo achieved SVR12, respectively. The METAVIR score is used to quantify the degree of inflammation and fibrosis of the liver and patients are scored on a five-point scale.
The most common adverse events seen in patients receiving simeprevir in PROMISE were fatigue (32 percent versus 42 percent for placebo), headache (32 percent versus 36 percent for placebo) and influenza-like illness (30 percent versus 20 percent for placebo). In the simeprevir arm, rash (19 percent versus 14 percent for placebo), itching (24 percent versus 17 percent for placebo), neutropenia (15 percent versus 17 percent for placebo), anemia (11 percent versus 6 percent for placebo), increased bilirubin (6 percent versus 2 percent for placebo), and photosensitivity conditions (4 percent versus none for placebo) were also observed. One patient in the simeprevir arm and no patients in the placebo arm discontinued treatment due to an adverse event.
The data were presented as a late breaker oral presentation at Digestive Disease Week 2013 in Orlando, Florida based on abstract number 869b, “Simeprevir (TMC435) With Peginterferon/Ribavirin for Treatment of Chronic HCV Genotype 1 Infection in Patients Who Relapsed After Previous Interferon-Based Therapy: Results From PROMISE, a Phase III Trial.
• On April 23, 2013, Medivir has announced that data will be presented on simeprevir (TMC435) for the treatment of genotype 1 hepatitis C patients at The International Liver Congress 2013 of the European Association for the Study of the Liver (EASL) in Amsterdam, The Netherlands. These primary efficacy and safety results from two global phase III studies demonstrate that use of the investigational protease inhibitor simeprevir led to sustained virologic response 12 weeks after the end of treatment (SVR12) in 80 and 81 percent, respectively, of treatment-naïve genotype 1 chronic hepatitis C adult patients with compensated liver disease, when administered once daily with pegylated interferon and ribavirin. In both studies, 50 percent of patients receiving pegylated interferon and ribavirin alone achieved SVR12.
In QUEST-1 and QUEST-2, patients were randomized to receive simeprevir or placebo for 12 weeks plus pegylated interferon and ribavirin for 24 or 36 weeks. In findings related to a secondary endpoint, 85 (QUEST-1) and 91 percent (QUEST-2) of patients receiving simeprevir were able to shorten therapy with pegylated interferon and ribavirin to 24 weeks due to meeting response-guided therapy (RGT) criteria. Of those patients meeting RGT criteria to stop treatment at 24 weeks, 91 percent (QUEST-1) and 86 percent of patients (QUEST-2) achieved SVR12.
Patients enrolled in QUEST-1 and QUEST-2 were stratified by HCV genotype 1 subtype and IL28B genotype. In QUEST-1, among patients treated with simeprevir, SVR12 rates according to IL28B genotype were 94 percent (CC), 76 percent (CT), and 65 percent (TT). In QUEST-2, in the simeprevir arm, SVR12 rates according to IL28B genotype were 96 percent (CC), 80 percent (CT), and 58 percent (TT). Among patients with METAVIR scores F3 and F4, 70 percent of patients treated with simeprevir in QUEST-1 and 66 percent of patients treated with simeprevir in QUEST-2 achieved SVR12. Among patients with METAVIR scores F0 to F2, 83 percent of patients treated with simeprevir in QUEST-1 and 85 percent of patients treated with simeprevir in QUEST-2 achieved SVR12. The METAVIR score is used to quantify the degree of inflammation and fibrosis of the liver and patients are scored on a four-point scale.
The most common adverse events seen in patients receiving simeprevir in QUEST-1 were fatigue (42 percent versus 41 percent for placebo), itch (26 percent versus 16 percent for placebo), and headache (33 percent versus 39 percent for placebo). The most common adverse events seen in patients receiving simeprevir in QUEST-2 were fatigue (37 percent versus 42 percent for placebo), itch (25 percent versus 25 percent for placebo), headache (39 percent versus 37 percent for placebo), fever (31 percent versus 40 percent for placebo), and influenza-like illness (26 percent versus 26 percent for placebo). In QUEST-1, in both the simeprevir and placebo arms, 3 percent of patients discontinued treatment due to an adverse event. In QUEST-2, 2 percent of patients in the simeprevir arm and 1 percent of patients in the placebo arm discontinued treatment due to an adverse event.
• On December 20, 2012, Medivir has announced top-line results from three pivotal phase III trials examining the one pill, once-daily, investigational protease inhibitor, simeprevir (TMC435), administered with pegylated interferon and ribavirin. Results from the QUEST-1 and QUEST-2 trials found that 80% and 81% of treatment-naive patients with chronic genotype 1 hepatitis C infection who were treated with simeprevir achieved sustained virologic response 12 weeks after the planned end of treatment (SVR12). Results from the PROMISE trial found that 79% of prior relapsed patients treated with simeprevir achieved SVR12. All three studies utilized response-guided treatment (RGT) criteria and 85%, 91% and 93 % of the patients, respectively, were eligible to stop all treatments after 24 weeks.
The overall safety, tolerability and efficacy results from these studies were consistent with those previously obtained in phase II studies. Final analysis of the phase III trials is ongoing and the full data set from these studies will be submitted for presentation at future scientific conferences.
In the global QUEST-1 and QUEST-2 trials, 394 and 391 respectively, treatment-naïve patients with genotype 1 hepatitis C were randomized to receive either 150 mg of once-daily simeprevir for 12 weeks plus pegylated interferon and ribavirin for 24 or 48 weeks based upon response guided treatment criteria (simeprevir group) or pegylated interferon and ribavirin alone for 48 weeks (control group).
In the PROMISE study, 393 patients, who had previous relapse after completing HCV treatment with pegylated interferon and ribavirin, were randomized to receive either 150 mg of once-daily simeprevir for 12 weeks plus pegylated interferon and ribavirin for 24 or 48 weeks based on response guided treatment criteria (simeprevir group) or pegylated interferon and ribavirin alone for 48 weeks (control group).
- Summary Table
| Sustained Virologic Response (SVR12 Rates in Simeprevir (TMC435) Dose Groups (150 mg q.d.) vs PR PlaceboIntention-To-Treat (ITT) Population |
|
Treatment Naive Patients |
Treatment Experienced - Prior Relapser Patients |
| % (N) |
QUEST-1 TMC435 150 mg QD 12wks PR24/48 wks |
QUEST-2 TMC435 150 mg QD 12wks PR24/48 wks |
PROMISE TMC435 150 mg QD 12wks PR24/48 wks |
| SVR12 |
80 (264) |
81 (257) |
79 (260) |
| SVR12 Placebo PR48wks |
50 (130) |
50 (134) |
37 (133) |
| Percentage of Patients in Simeprevir Treatment Arms Meeting RGT Criteria Who Could Stop All Treatment at Week 24 |
|
QUEST-1 |
QUEST-2 |
PROMISE |
| % |
85 |
91 |
93 |
| Percentage of Patients Who Displayed Advanced Liver Disease Upon Study Entry |
| METAVIR Score F3-F4 (%) |
30 |
22 |
31 |
- q.d.: once daily; PR: pegIFNalpha and ribavirin;
SVR12: patients with undetectable HCV RNA (<25 IU/mL Undetectable) 12 weeks after planned EoT.
All simeprevir (TMC435) groups: p<0.001 vs placebo.
Prior Relapser: undetectable HCV RNA at EoT and detectable within 12/24 weeks of follow-up
RGT: Response Guided Treatment: HCV RNA < 25 IU/mL (detectable or undetectable) at Week 4 and undetectable HCV RNA (< 25 IU/mL undetectable) at Week 12 (all other patients continued Peg-IFN/RBV up to W48)
In all three phase III studies, AEs leading to permanent discontinuation were lower in the simeprevir treated subjects compared to the placebo control (pegylated interferon and ribavirin).
• On August 31, 2011, Medivir announced that TMC435, developed by Tibotec Pharmaceuticals, has successfully completed enrollment of three ongoing global phase 3 trials and further reports that all patients are now on TMC435 or active control treatment. The trials are QUEST 1 and QUEST 2, in treatment naive patients, and PROMISE in the treatment experienced relapser patient population. In all three trials, the duration of total treatment is response guided and patients in the TMC435 arms are eligible to stop all treatment at week 24 if predefined response-guided criteria are met.
Global Phase 3 Program in brief:
· TMC435-C208 or QUEST-1 includes approximately 375 treatment-naïve patients
· TMC435-C216 or QUEST-2 includes approximately 375 treatment-naïve patients
· TMC435-C3007 or PROMISE includes approximately 375 who have relapsed after prior interferon-based treatment
Is
general: Yes
