nterim Analysis Results from a Phase 2 Study of Telaprevir with Peginterferon alfa-2A and Ribavirin in Treatment-naïve Subjects with Hepatitis C
I. M. Jacobson1; G. T. Everson2; S. C. Gordon3; R. Kauffman4; L. McNair4; A. Muir5; J. G. McHutchison5
1. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
2. Division of Gastroenterology and Hepatology, University of Colorado Health Science Center, Denver, CO, USA.
3. Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI, USA.
4. Vertex Pharmaceuticals, Cambridge, MA, USA.
5. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Background: The VX05-950-104 study (PROVE1) is a randomized, placebo-controlled Phase 2 study of telaprevir (TVR, VX-950), an HCV protease inhibitor, with Peg-IFN-2a and RBV, in naive subjects with genotype 1 hepatitis C. We report the results of a planned interim analysis.
Methods: Subjects were randomized into 4 groups; 3 groups received TVR 750 mg q8h, Peg-IFN-2a 180 μg/week, and RBV 1000-1200 mg/day for 12 weeks followed by 0 (n=20), 12 (n=80) or 36 (n=82) weeks of Peg-IFN-2a and RBV (TVR/PR groups). The control group (n=81) received up to 48 weeks of Peg-IFN-2a/RBV (PR). This analysis was performed when all treated subjects had completed 12 weeks of dosing. Follow-up information was also obtained for the subjects who completed the 12-week dosing arm. Plasma HCV RNA was isolated for viral sequencing at baseline and at each HCV RNA assessment in samples that contained greater than 1,000 IU/mL.
Results: The proportion of subjects with undetectable HCV RNA (LOD 10 IU/mL) at Week 4 was 79% (TVR/PR group), and 11% (control group) (p<0.001), and at Week 12 was 70% (TVR/PR group), and 39% (control group) (p 1-log above HCV RNA nadir) with previously described TVR resistant variants were observed in 12 of 175 (11 genotype 1a and 1 genotype 1b) subjects in the TVR/PR groups. In the group assigned to 12 weeks of treatment, 6 of 9 subjects with RVR and completing 12 weeks of treatment achieved SVR. The remaining 3 subjects relapsed with TVR resistant variants (genotype 1a: R155T/I). Discontinuations due to adverse events were more frequent in the TVR/PR group (11% vs. 3%). Rashes, gastrointestinal events and anemia were more common, and rashes more severe in the TVR/PR groups. An additional interim analysis will be conducted when all subjects have completed 36 weeks on-study, including 12-week post-treatment follow-up for the 24-week study arm subjects.
Conclusions: Compared with standard therapy, significantly more subjects receiving a TVR/PR regimen achieved undetectable HCV RNA at Weeks 4 and 12, and some subjects achieved an SVR after 12 weeks of TVR/PR. Other patients relapsed with TVR-resistant variants, suggesting that 12 weeks of TVR/PR may be adequate to eliminate wild-type virus. The post-treatment follow-up results in the 24-week group will evaluate whether the additional 12 weeks of PR is sufficient to eliminate the remaining TVR-resistant variants.
* for the PROVE1 study team
Final Results of Patients Treated with Peg-Interferon-Alfa-2a (Peg-IFN) and Ribavirin (RBV) Follow-on Therapy After 28-Day Treatment with the Hepatitis C Protease Inhibitor Telaprevir (VX-950), Peg-IFN and RBV
M. Rodriguez-Torres1; E. J. Lawitz2; J. G. McHutchison3
1. Fundacion de Investigacion de Diego, Santurce, PR, USA.
2. Alamo Medical Research, San Antonio, TX, USA.
3. Duke Clinical Research Institute & Division of Gastroenterology, Duke University, Durham, NC, USA.
Purpose: Telaprevir (TVR, VX-950) is an orally administered, highly selective peptidomimetic inhibitor of the Hepatitis C virus (HCV) NS3-4A protease. The VX05-950-102 study was designed to assess the safety of telaprevir when given in combination with Peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV) and to evaluate the antiviral response during 28 days of dosing. After completion of the 28-day study, all subjects received off-study therapy with Peg-IFN/RBV under the clinical care of their physicians. Here we report the outcome of treatment after this post-study therapy.
Methods: This study included 12 treatment-naïve, mostly Latino (10/12),patients infected with genotype 1. All subjects received TVR (750 mg q8h), Peg-IFN alfa-2a (180 µg weekly), and RBV (1000 or 1200 mg daily). At the completion of the 28 days, patients began off-study follow-on therapy with Peg-IFN alfa -2a/RBV.
Results: TVR/Peg-IFN/RBV was well tolerated in the 28-day study, with no serious adverse events. The adverse event profile was consistent with the profile commonly seen with Peg-IFN/RBV therapy. All subjects demonstrated a response to the study drug regimen, with 2 subjects reaching undetectable (< 10 IU/mL, Roche Taqman® Assay) levels of plasma HCV RNA within 8 days of the start of dosing, and all subjects had undetectable HCV RNA at the end of the 28-day study dosing period. At 12 weeks of follow-on therapy after completing the 28-day study dosing, 11 subjects had undetectable HCV RNA. All subjects continued on Peg-IFN/RBV therapy, and were followed for response in accordance with standard practice. Seven patients received a total of 48 weeks of treatment and achieved SVR. One patient received Peg-IFN/RBV for only 18 weeks (total treatment 22 weeks) before discontinuing, but also achieved SVR. Two patients had viral breakthroughs at 12 weeks and 24 weeks of treatment.Two patients were lost to follow up and were undetectable at last assessment. In total, 8/10 patients for whom results are available, achieved SVR. The side effect profile observed during the post-study dosing was consistent with the expected profile of Peg-IFN/RBV therapy.
Conclusions: The rapid and substantial initial antiviral effect of telaprevir was maintained by the majority of patients during post-study therapy with PegIFN/RBV. The observation that SVR was achieved in eight patients, including 1 who completed only 22 weeks of treatment, suggests that telaprevir-based regimens may allow increased SVR rates as compared to current therapies.
Evaluation of Viral Variants During a Phase 2 Study (PROVE2) of Telaprevir with Peginterferon alfa-2A and Ribavirin in Treatment-naïve HCV Genotype 1-Infected Patients
J. Pawlotsky5; T. Kieffer1; Y. Zhou1; E. Zhang1; M. Marcial1; R. Byrn1; T. Pfeiffer1; J. Miller1; A. Tigges1; D. Bartels1; A. Kwong1; P. Ferenci2; G. Dusheiko3; S. Zeuzem4
1. Infectious Diseases, Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA.
2. Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
3. Centre for Hepatology, Royal Free Hospital, London, United Kingdom.
4. Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany.
5. Department of Virology, Henri Mondor Hospital, University of Paris XII, Créteil, France.
Background: The VX05-950-104EU study (PROVE2) is a Phase 2 study of an HCV protease inhibitor, telaprevir (VX-950, TVR) 750 mg q8h, in combination with Peg-IFN-alfa-2a (P) 180 µg/week and ribavirin (R) 1000-1200 mg/day in treatment naive subjects with genotype 1 hepatitis C. Subjects were randomized into 4 groups that received: 1) TVR/P/R for 12 weeks, 2) TVR/P for 12 weeks, 3) TVR/P/R for 12 weeks followed by 12 weeks of P/R, and 4) P/R for 48 weeks (control group). Viral breakthrough (increase of > 1-log above HCV RNA nadir or increase to > 100 IU/mL in previously undetectable patients) was observed in some subjects during the first 12 weeks of therapy. Viral sequencing was used to evaluate the contribution of TVR resistance to antiviral response.
Methods: Plasma samples for viral sequencing were taken at baseline and at each HCV RNA assessment. The NS3-4A RNA region was amplified by nested RT-PCR and sequenced in samples with HCV RNA > 1,000 IU/mL. Prospectively defined criteria for identifying potential resistance mutations were applied using a Poisson distribution.
Results: HCV RNA was undetectable (LOD 10 IU/mL) at Week 4 in 14% of subjects in the P/R group, 74% in the TVR/P/R groups (p<0.001), and 53% in the TVR/P group (p<0.001); and at Week 12 in 43% of subjects in the P/R group, 79% in the TVR/P/R groups (p<0.001), and 63% in the TVR/P group (p<0.015). During the first 12 weeks on treatment, 6 of 152 subjects (4%) in the TVR/P/R groups, 19 of 76 subjects in the TVR/P group (25%), and 1 of 77 subjects (1%) in the P/R group had viral breakthrough. The breakthroughs were associated with wild-type virus in the P/R group and previously identified TVR-resistant variants in the TVR groups (TVR/P/R: genotype 1a, n=4: mainly V36M and R155K; genotype 1b, n=2: mainly A156T; TVR/P: genotype 1a, n=12: mainly V36M and R155K; genotype 1b, n=7: mainly V36A, T54A, R155K, and A156S/T).
Conclusions: In this interim analysis, TVR/P/R produced a significantly greater antiviral response at Weeks 4 and 12 compared to TVR/P and P/R in treatment naïve subjects with genotype 1 HCV. In the TVR groups, viral breakthroughs were associated with the selection of known TVR-resistant variants. The breakthrough rate in the TVR/P group was higher than in the TVR/P/R groups, suggesting that suboptimal inhibition of viral replication provides a greater probability for selection of TVR-resistant variants. Some subjects with viral breakthrough on TVR had a subsequent decline in HCV RNA during treatment with P/R, indicating that emergence of TVR-resistance does not preclude response to P/R.
*on behalf of the PROVE2 Study Team
PROVE2: Phase II Study of VX950 (TELAPREVIR) in Combination with Peginterferon ALFA2A With or Without Ribavirin in Subjects With Chronic Hepatitis C, First Interim Analysis
S. Zeuzem9; C. Hezode1; P. Ferenci2; G. M. Dusheiko3; S. Pol4; T. Goeser5; J. Bronowicki6; S. Gharakhanian7; D. Devonish7; R. Kauffman7; J. Alam7; J. Pawlotsky8
1. AP-HP Hepatogastroenterology Srrvices, Henri Mondor Hospital, Creteil, France.
2. Internal Medicine III, Medical University, Vienna, Austria.
3. Center for Hepatology, Royal Free Hospital, London, United Kingdom.
4. AP-HP Liver Unit, Necker-Cochin Hospitals, Paris, France.
5. Gastroenterology & Hepatology, University of Cologne, Cologne, Germany.
6. CHU, Nancy University Hospital Center, Nancy, France.
7. Medicinal Development Group, Vertex Pharmaceuticals, Inc, Cambridge, MA, USA.
8. AP-HP Dept of Bacterology & Virology, Henri Mondor Hospital, Creteil, France.
9. Internal Medicine Clinic II, Saarland University Hospital, Homburg/Saar, Germany.
PROVE2, study VX05-950-104EU is a randomized, placebo-controlled phase II study of telaprevir (TVR), in combination with pegylated interferon alfa2a (Peg-IFN) and ribavirin (RBV), in treatment naïve subjects with genotype 1 chronic hepatitis C infection. Results of a planned interim, on-treatment, safety and efficacy analysis (IA) are reported.
A total of 332 subjects were randomized into four groups. Group A received standard of care Peg-IFN 180 mcg/weekly + RBV 1000-1200 mg, weight-based and TVR-placebo for 48 weeks. Group B TVR 750 mg q8h together with Peg-IFN+RBV for 12 weeks, followed by Peg-IFN and RBV for a further 12 weeks. Group C, TVR 750 q8h with Peg-IFN + RBV for 12 weeks. Group D, TVR + Peg-IFN for 12 wks. The Roche Taqman assay was used to quantify plasma HCV RNA (LOD 10 IU/mL). This first IA was performed when at least 90% of subjects completed the week 12 visit.
The median age was 45 years (18-65), median weight 70.9 kg (45-115), 58.7% were male, 94.1% Caucasian, 7.5 % had stage F3 fibrosis, 34.1% were infected with genotype 1a, and 54.1% with 1b. The median baseline HCV RNA was 6.4 Log10IU/ml (3.3-7.7). Overall, discontinuation occurred in 6.4% of Group A, 17.1% of Groups B+C and 10.5% of Group D subjects prior to week 12. Discontinuations for AEs, occurred in 2.6% of Group A, 12.5% of Groups B+C and 7.9% of Group D subjects. Pruritis, rash, asthenia, nausea, and anemia were the most common AEs associated with TVR; anemia and nausea were less frequent in Group D. The table summarizes ITT viral responses.
TVR (Telaprevir, VX950)+Peg-IFN+RBV produces a significantly greater, on-treatment, anti-viral response at weeks 4 and 12 compared to Peg-IFN+RBV in naïve subjects with genotype 1 HCV. Dosing without RBV reduced the on-treatment anti-viral response; further follow-up will evaluate effects on SVR and relapse rates. Consistent with prior studies, the adverse event profile showed that skin events, nausea and anemia are the most important AE’s associated with TVR. Further results will confirm the optimal treatment duration and dosage regimen for Phase 3.
HCV RNA Un-detectable Group A (%)
Groups B+C (%)
Group D (%)
Week 4 14.3 74.3* 52.6*
Week 12 42.9 78.9* 63.2+
*p<0.001 compared to Group A; +p=0.015 compared to group A
thanks so much for posting these data.
I have too much brain fog to trust my conclusions, but I did conclude from two abstracts, that the percentage of people that reach undetectable by week 4 is the same percentage that reaches SVR.
Did you conclude that as well or am I suffering too much from brain fatigue to process all the data?
Thanks for posting - Eric
Busy posting and haven't read anything yet, but I will get around to it. That said, what you say doesn't surprise me as RVR has seemingly been ruling the SVR roost for some time now.
thanks for all the posts. Lots of reading here.
I know, haven't read most of them myself yet :)
hey jim can you give us your take on this in laymans terms? i'm not to good at understanding these studies. as usual thanks for the great info
Final Results of Patients Receiving Peg-Interferon-Alfa-2a (Peg-IFN) and Ribavirin (RBV) After a 14-Day Study of the Hepatitis C Protease Inhibitor Telaprevir (VX-950), With Peg-IFN
C. J. Weegink1; N. Forestier2, 3; P. L. Jansen1; S. Zeuzem2, 3; H. W. Reesink1
1. Academic Medical Center, Amsterdam, Netherlands.
2. J.W.Goethe University Hospital, Frankfurt a.M., Germany.
3. Saarland University Hospital, Homburg/Saar, Germany.
Purpose: Telaprevir (TVR, VX-950) is a highly-selective peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3●4A protease that is designed to block HCV replication. This 14-day study was designed to explore the viral kinetics and safety during dosing with TVR in combination with peginterferon-alfa-2a (Peg-IFN). Here we report the final results of patient status after stopping follow-on standard therapy with Peg-IFN and ribavirin (RBV).
Methods: The VX04-950-103 clinical study randomized twenty treatment-naïve patients with chronic genotype 1 hepatitis C infection to three dosing arms. Eight patients received TVR (750 mg as tablets q8h) with Peg-IFN on Days 1 and 8, and eight patients received TVR alone. Four patients received Peg-IFN alone on Days 1 and 8. At the completion of the 14-day study, off-study therapy with Peg-IFN and RBV was offered to all patients. Nineteen of 20 patients began therapy within 5 days of completing the 14-day dosing period. The patient who refused post-study Peg-IFN/RBV was in the TVR-alone group.
Results: At week 12 of therapy, all 8 patients in the TVR/Peg-IFN group and 5 of 7 patients in the TVR alone group had undetectable HCV RNA. At week 24, all 15 patients who received TVR had undetectable HCV RNA(<10 IU/mL). Ten patients (6/8 TVR/Peg-IFN and 4/7 TVR alone) chose to stop Peg-IFN/RBV treatment at week 24 and 5 patients chose to continue Peg-IFN/RBV for a total of 48 weeks. All groups were followed for the subsequent 24 weeks. In patients who had received TVR-based therapy for 14 days before starting off-study Peg-IFN/RBV therapy, 7/10 patients treated for a total of 24 weeks and 2/5 patients treated for a total of 48 weeks achieved a sustained viral response (SVR) One patient, treated for 48 weeks, was lost to follow-up. From the group who received Peg-IFN alone before 48 weeks of Peg-IFN/RBV therapy, 1/4 patients achieved SVR. The side effect profile observed during the post-study dosing was consistent with the expected profile of Peg-IFN/RBV therapy. Sequence analysis of the 5 patients who relapsed after TVR-based therapy is in progress.
Conclusions: SVR was achieved in 9 of 15 patients treated for 14 days with TVR or TVR/Peg IFN followed by Peg-IFN/RBV therapy for a total of 24 or 48 weeks. These results suggest that TVR-based regimens may increase SVR rates compared to current therapies. Large Phase 2 clinical studies of TVR-based regimens are now ongoing to evaluate this hypothesis and the possibility of shortening the duration of therapy.
Have only glanced at them so far but will read more later, but honestly haven't been following the trials as closely as I used to. You might also want to look for some more professional commenatry on sites like this: http://www.hivandhepatitis.com/
If they don't already, I'm sure they will soon have an AASLD 2007 section.
Some crisp charts would have been nice, but maybe they're reserving that for the full presentations. So meanwhile, I'll probably sit down with pencil and paper and chart out the different scenarios unless someone (hopefully) beats me to the punch.
Thanks for posting the info Jim....I didn't realize that a side of TVR is anemia, perhaps that is why they had some no riba study people, but that appears to have not worked out to well..Pro
to my knowledge Vertex so far has not done studies with cirrhosis patients. This kind of examination is just on the way: http://tinyurl.com/2jf9bp
Maybe I'm missing something but did you read the "EXCLUSION criteria" section. It included: Tested positive for HIV, Hepatitis C, Hepatitis B
In Prove 1 cirrhotics were excluded. I'm almost certain they were excluded in Prove 2 as well. Travelmom's daughter is in Prove 3 and has cirrhosis, but I think she was given a special exception because of her age. Not sure but I think pretty much all VX testing to date has more or less excluded cirrhotics, so I doubt there's any real data available to demonstrate how well TV+SOC works in those with cirrhosis. But child24, I'm sure Telaprevir would help those with cirrhosis, there's no reason why it's powerful antiviral effectiveness wouldn't help them get cured too (as long as ribavirin is included, of course).
Thank you for posting the results. Would you please post a link as well? I tought we would not hear from VRTX until Nov 2nd.
The trial Drofi posted is not for those with Hep C, or so it appears. And yes, cirrhosis can be reversed like fibrosis, according to more recent thinking. Of course no guarantees.
Don't think you can direct link. If you want to see these abstracts (and more) from the source, go to the AASLD web site and register:
Then go to "abstacts", then "abstract viewer".
Good luck, not a very intuitive site but you should find what you want with a little patience.
Amanda was in Group C - no Riba. I know this, because Jodi (Travelmom) talked to me about it since I was also in the a Group C - no Riba group. I don't feel like I'm speaking out of line here, since I believe she's said to us on the boards here, before about Amanda not having the Ribavirin.
I hope that answers your question....
Thanks so much for posting this. I can't wait for you to translate it into English. I don't really understand it, but it seems very positive? Also , it seems that all of the patients were genotype 1, whereas in other trials other, more easily treated genotypes were included; comparing this to them is apples and oranges, right. S.
Thanks for posting as it was greatly appreciated... btw, I'm Stage 4 (cirrosis) and in Prove 3 study at week 19 and so far so good.
That's wonderul and hopefully some encouragment for Nick that they appear to be accepting stage 4's.