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Post Info TOPIC: SOF/VEL and SOF/VEL/VOX


Guru

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RE: SOF/VEL and SOF/VEL/VOX
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News is starting starting to come out of the UK and Scotland about Vosevi finally becoming available over there (via recent chats with Mak who informed us he is lined up for it in October). Here is what has surfaced thus far.

 

Via an excerpt from a UK Hepatitis Trust newsletter today:

NEWS FROM SCOTLAND

We are delighted to hear that new treatment Vosevi (sofosbuvir-velpatasvir-voxilaprevir) treatment  was recently approved  byScottish Medicines Consortium for the following groups of people:

 

·         Those who have failed to achieve a sustained viral response (SVR) with a direct-acting anti-viral (DAA)

 

·         DAA-naïve, genotype 3 (GT3) HCV infection, with or without cirrhosis

 

Also,  Epclusa ihas been approved for:

 

·         Genotype 1 and 4 chronic HCV infection, including those with decompensated cirrhosis.

This is in addition to the earlier advice for those with Genotype 2, 3, 5 and 6 ...

 

Via Feb 21 industry news: 

https://www.thepharmaletter.com/article/nice-says-vosevi-ok-for-nhs-use

 

Via NICE:

https://www.nice.org.uk/guidance/ta507

 

 

 

 

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



Guru

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Just another (recent) 2018 review, on Epclusa's performance, specifically in regard to those with higher Fscores.

 

Excerpt from: Medscape

 

Sofosbuvir/Velpatasvir in Patients With Hepatitis C Virus Genotypes 1-6 and Compensated Cirrhosis or Advanced Fibrosis

Tarik Asselah; Stefan Bourgeois; Stephen Pianko; Stefan Zeuzem; Mark Sulkowski; Graham R. Foster; Lingling Han; John McNally; Anu Osinusi; Diana M. Brainard; G. Mani Subramanian; Edward J. Gane; Jordan J. Feld; Alessandra Mangia  

Liver International. 2018;38(3):443-450.

Abstract and Introduction

Abstract

... Background & Aims Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis.

Methods This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined.

 

Results Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naïve patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs.

Conclusions Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis...



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)

Tig


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Well, prehistoric, tar laden and maybe even feathered Dragons deserve the best anti virals, too! While Canada and BC are behind the times, I’m pleased that steps (even baby steps) are welcomed in the giant world of Dragon slaying. With the latest and greatest oral 2 & 3 drug DAA’s, it’s only a matter of time that there will be no other options available but these effective protocols. Everyone will hopefully soon have access to them. If we could get governments onboard with the equally effective generics, we could make a huge dent in this global menace. Iceland has taken this approach and may be one of the first to pioneer wide scale treatment for everyone. Fingers crossed!



__________________

Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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WELL! Finally! As usual, a day late and a dollar short. In the slow-mo world of Canada (and especially in BC, at the pre-historic dinosaur-land tar-sands-speed quagmire of our drug approval system here, Vosevi approval happened at lightening speed (comparatively speaking!).

How many were in dire need of Vosevi, waiting, back when BC first started "thinkin' on itwaaaay back in August of 2017? I fear some of the stats are likely grossly underestimated in the article below. That was a long cruel wait, for Vosevi to be made available to relapsers in BC, those in need of salvage therapy, to be waiting from August 2017 to now! Being "on the mark" in the US - Vosevi was being rolled out (for the benefit of many) starting from DAY ONE (August 2017). Ontario only started doling out Vosevi recently and BC only starts doling it out now, 7 months later, when they have exhausted their wheeling and dealing. The US started helping people wtih Vosevi at DAY ONE, in Canada, we were still (systematically) "talking" about it 7 months later!

I question the puny "numbers" the bean counters have come up with for this article to quote. The "numbers" may well be off by MUCH! How many GT3's alone are there in BC, how many HCV cases are there REALLY in BC, how many relapser people are there requiring HCV salvage re-treatment in BC. I doubt we count HCV "heads", accurately, we cannot even know how many people we have with undiagnosed HCV for heavens sake!

So many in dire need, so little time. Drugs available, but doled out "too little, too late" as we often see happen here in BC and in some of our other Provinces. Vosevi should NOT have been treated like they do other "orphan" drugs in Canada! Some relapsers have been waiting decades for the likes of Vosevi, and, how many treatment-naive would benefit from the likes of Vosevi!, and what will the ultimate outcome of theirs lives reveal, with being offered such a great drug triple as Vosevi, on such delayed basis. 

What drugs were relapsers forced to accept instead, in the interim, whilst waiting for BC to "get on it with Vosevi already!". Shameful the processes and delays that are caused to patients in need of superior, fast, effective action.

Back when this GT3a was treated with Vosevi (luckily, only by the skin of my teeth, by gaining an entry seat into a drug trial), had I not been fortunate enough to gain one of the few seats available for that trial - I would have faced extremely limited drug choices in BC at that time - without successfully pursuing and winning a trial seat, I would have been "told" to do sof/riba for 24 weeks, and only IF and AFTER I failed that, then and only then, would I then be considered for 24 weeks of sof/dacla! And, the kicker was that dac, then, had still not yet even waded it's way through to the end of the BC drug approval pipeline!. At F4, was I glad I won my seat in a Vosevi trial and got cured?, versus any idea of waiting for Vosevi (or dacla for that matter) to come available to me via the "system"?, yup - you bet I was! Another kicker, although Vosevi was and would still be today, an ideal/superior first treatment for me - I would still not be able to get it today (as a treatment-naive GT3a) - it is only being doled out for relapser salvage re-treatment. Man, talk about ideal health care choices - NOT! Something else that should be changed, (Vosevi for the masses when it is in the patients best interests) if we are truly serious about trying to eradicate HCV in a timely fashion, with the least amount of harm, as it (along with all the other good DAA's we now have in our arsenal) would benefit many and the most.

Ya,ya - small hurray, about erasing the restriction of having a certain Fscore in BC (a common sense thing the rest of US have all LONG ago understood) - a lot of unhealthy delay has occured to many due to that demand, that a patient had to hold a certain Fscore. About time! - long overdue for that to be "un-done".

Still, with so many needing treatment, not enough budgets, prioritizing people (line up's) based on things like "signs of disease severities" (and thus Fscores), Fscores then, as part of the assessments, cannot be excluded from considerations. 

Better late than never though - welcome Vosevi! - for the "few" lucky ones to whom the bean counters may dole it out to in BC.

 

http://www.cbc.ca/news/canada/british-columbia/hep-c-dix-announcement-2018-1.4574365



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)

Tig


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 Good Stuff!!  



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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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References belonging to the (prior) post (below) - had to post ref. here as I get message that the prior post was too long to submit in it's entirety! confuse So, here are the references that belong to the prior post below. 

References

1. Christensen S, Ingiliz P, Mauss S, et al. Do resistance associated substitutions (RAS) or ribavirin (RBV) use influence treatment success of sofosbuvir (SOF)/velpatasvir (VEL) in chronic hepatitis C genotype 3 (GT 3) infection? Results from the German hepatitis C cohort (GECCO). Program and abstracts of the 2017 Annual Meeting of the American Association for the Study of Liver Diseases; October 20-24, 2017; Washington DC. Abstract 63.

2. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373:2608-2617.

3. American Association for the Study of Liver Diseases/Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. September 2017. Available at: http://www.hcvguidelines.org. Accessed October 26, 2017.

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



Guru

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(Earlier) trial data (presented this year) re: Epclusa GT3 trials (from Germany) with or without riba - similar performance as we have seen in other GT3 Epclusa trials data released just before Epclusa was adopted for use in US.

 From Clinical Care Options - Conference coverage - Capsule Summary

GECCO: Sofosbuvir/Velpatasvir With or Without RBV Demonstrates High Efficacy in Genotype 3 HCV - Infected Patients, Including Cirrhotics in Real-World Setting

 Source: 2017 Annual Meeting of the American Association for the Study of Liver Diseases* (October 2017 - Washington)

 

Date posted: 10/26/2017

·         GECCO: prospective, multicenter German cohort study[1]

Summary of Key Conclusions

·         High sustained virologic response (SVR) rates at 12 weeks post treatment observed in genotype 3 HCV-infected patients receiving 12 weeks of sofosbuvir/velpatasvir with or without ribavirin (RBV) in "real-world" clinical cohort, including patients with cirrhosis

 

·         No evidence that RBV increased efficacy in cirrhotic patients

 

·         SVR in intent-to-treat (ITT) population: 95% in all patients

·         SVR in cirrhotic patients: 94% without RBV vs 87% with RBV

·         SVR in per protocol (PP) population: 99% in all patients

·         SVR in cirrhotic patients: 94% without RBV vs 100% with RBV

 

·         Baseline resistance associated substitution (RAS) had no impact on treatment efficacy

Background

·         Sofosbuvir/velpatasvir approved for treatment of genotype 1-6 HCV infection

·         FDA-approved regimen duration:

·         12 weeks of sofosbuvir/velpatasvir in treatment-naive and treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh A)

·         12 weeks of sofosbuvir/velpatasvir plus RBV in treatment-naive and treatment-experienced patients with decompensated cirrhosis (Child-Pugh B and C)

·         Phase III ASTRAL-3 compared 12 weeks of sofosbuvir/velpatasvir vs 24 weeks of sofosbuvir plus RBV in treatment-naive and treatment-experienced patients with genotype 3 HCV infection, including those with compensated cirrhosis[2]

·         SVR rates in sofosbuvir/velpatasvir arm across subpopulations:

·         91% in cirrhotic patients vs 97% in noncirrhotic patients

·         90% in pretreated patients vs 97% in treatment-naive patients

·         88% in patients with baseline NS5A RAS (A30K, L31M, and Y93H) vs 97% in patients with no baseline NS5A RAS; 84% in patients with baseline Y93H

·         American Association for the Study of Liver Diseases/Infectious Diseases Society of America HCV management guidelines recommend use of 12-week sofosbuvir/velpatasvir in genotype 3 HCV-infected populations[3]

·         Addition of RBV recommended in treatment-naive patients with compensated cirrhosis and Y93H mutation, and those with cirrhosis having previous NS5A or peginterferon/ribavirin treatment experience

·         Current study explored impact of baseline RASs, cirrhosis, RBV use on response to sofosbuvir/velpatasvir in genotype 3 HCV-infected patients receiving HCV therapy within clinical cohort setting

 

 Summary of Study Design

·         Patients participating in ongoing GECCO cohort enrolled from 9 sites in Germany

·         GECCO includes data from 2312 patients initiating direct-acting antiviral therapy since February 2014

·         576 patients in GECCO infected with genotype 3 HCV

·         Current analysis restricted to 232 genotype 3 HCV-infected patients treated with 12 weeks of sofosbuvir/velpatasvir with or without RBV since July 2016

Baseline Characteristics (graphs missing)

·         N = 232 genotype 3 HCV-infected patients included

·         n = 200 (86%) receiving sofosbuvir/velpatasvir

·         n = 32 (14%) receiving sofosbuvir/velpatasvir plus RBV

Description of Current Analysis

·         SVR rates evaluated in ITT and PP populations

·         12-week follow-up data available for 141 of 232 (61%) treated patients

·         Data pending in 84 of 232 (36%) patients

·         7 of 232 (3%) patients lost to follow-up

·         ITT analysis includes data from 148 of 232 patients

·         PP analysis includes data from 141 of 232 patients

Main Findings

·         High SVR rates observed in genotype 3 HCV-infected patients receiving 12 weeks of sofosbuvir/velpatasvir with or without RBV, including patients with cirrhosis

 

·         No evidence that RBV increased efficacy in cirrhotic patients

 

·         SVR in ITT population: 95% in all patient

 

·         SVR in cirrhotic patients: 94% without RBV vs 87% with RBV

 

·         SVR in PP population: 99% in all patients

 

·         SVR in cirrhotic patients: 94% without RBV vs 100% with RBV

 

SVR, n/N (%)

All Patients

Cirrhotic Patients

Sofosbuvir/Velpatasvir ± RBV

Sofosbuvir/Velpatasvir

Sofosbuvir/Velpatasvir + RBV

ITT analysis

140/148 (95)

16/17 (94)

13/15 (87)

PP analysis

140/141 (99)

16/17 (94)

13/13 (100)

·         Relapse occurred in 1 cirrhotic patient receiving sofosbuvir/velpatasvir without RBV

·         Previously treated with sofosbuvir plus RBV for 6 months with subsequent relapse

·         Primary RAS not detected at baseline

·         Y93H detected at relapse following sofosbuvir/velpatasvir

·         Baseline characteristics generally comparable in cirrhotic patients treated with vs without RBV, except INR

           Baseline RAS had no impact on treatment efficacy

·         SVR in ITT population: 94% no RAS vs 100% with RAS

·         SVR in PP population: 99% no RAS vs 100% with RAS

SVR, n/N (%)

All Patients Receiving Sofosbuvir/Velpatasvir ± RBV

No Baseline RAS

With Baseline RAS

ITT analysis

98/104 (94)

10/10 (100)

PP analysis

98/99 (99)

10/10 (100)

·         PP analysis included 109/141 patients with baseline RAS data available

·         All 10 of 109 (9%) patients with RAS achieved SVR

·         n = 5/10 with A30K including n = 1 pretreated, n = 3/5 received RBV (all 3 had cirrhosis)

·         n = 5/10 with Y93H including n = 1 pretreated, n = 1/5 received RBV (all 5 had cirrhosis)

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



Guru

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Re:  LT patients - This is an excerpt from AASLD recommendations dated September 21, 2017

Sofosbuvir/Velpatasvir

 To date, there have been no studies evaluating the safety and efficacy of the fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) in liver transplant recipients. For this reason, very limited recommendations on its use post liver transplantation can be made. However, with no treatment options for liver transplant recipients with genotype 2 or 3 infection who have decompensated cirrhosis, expert opinion led to the recommendation to use sofosbuvir/velpatasvir with weight-based ribavirin for these patients

_________________________________________________________________________________________________________________________

 

News Releases from Gilead - dated October 20, 2017 - poster #1069 is just one of 25 presentations Gilead was doing at "The Liver Meeting" - Washington

 

Epclusa in Liver Transplant Patients (Poster #1069)

In an open-label Phase 2 study evaluating once-daily Epclusa for 12 weeks among 79 liver transplant patients with genotype 1-4 chronic HCV infection, treatment with Epclusa resulted in an overall SVR12 rate of 96 percent, including patients with cirrhosis and prior treatment failure, and was well tolerated.

Patient Population

SVR12

     

Patient Population

SVR12

Genotype 1

95%
(35/37)

     

Genotype 1-4 without cirrhosis

97%
(70/72)

Genotype 2

100%
(3/3)

     

Genotype 1-4 with cirrhosis

86%
(6/7)

Genotype 3

97%
(34/35)

     

Genotype 1-4, treatment-naïve

94%
(30/32)

Genotype 4

100%
(4/4)

     

Genotype 1-4, treatment-experienced

99%
(46/47)

Baseline resistance mutations did not impact SVR rates. Two patients relapsed in this study - one treatment-naïve non-cirrhotic patient with HCV genotype 1a and one treatment-experienced non-cirrhotic patient with HCV genotype 3.

Common adverse effects (AEs) (>10 percent) were headache (24 percent), fatigue (20 percent) and cough (10 percent). Three patients (4 percent) experienced serious AEs; none was related to study drug. One patient discontinued treatment after one week due to hyperglycemia. There were no deaths, graft loss or episodes of acute liver transplant rejection.

Epclusa is approved for patients with genotype 1-6 without cirrhosis or with compensated cirrhosis, and in combination with RBV for patients with decompensated cirrhosis. The safety and efficacy of Epclusa in liver transplant recipients has not been established.

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



Guru

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Here's yet another review of new drugs now out on the market, namely Vosevi - this thread tries to confine itself to info mostly about Gileads "Epclusa (sof/vel) and "Vosevi" (sof/vel/vox), but so as to not break the below article up, the article is pasted here in it's entirety, and includes info about another regime - AbbVies "Mavyret" (glec/pib). 

 

EDITORIAL

Two Approvals Offer Even More Options for HCV TreatmentHCV Next, September/October - Ira M. Jacobson, MD

The approval of two new regimens for treating hepatitis C comes as a very welcome development in the field. It is great news for patients and providers because both regimens offer new options for therapy. 

For patient populations that we have been accustomed to treating with high levels of efficacy and tolerability, we now have new features like shorter duration of therapy. For those who previously failed direct- acting antiviral therapy who previously had no treatment, we now have an approved regimen.

Vosevi

Fortunately, only a small number of our patients - under 5% - falls into the category of having failed previous DAA therapy. Yet it has been a cherished goal in the field to be able to cure every single patient and leave no patient without a cure. Vosevi (sofosbuvir/velpatasvir/voxilaprevir; SOF/VEL/VOX, Gilead Sciences) should go a long way in helping us do that.

Vosevi is a combination of voxilaprevir, a potent and pangenotypic protease inhibitor that covers the most protease inhibitor resistant variants capable of emerging after exposure to first generation members of the protease inhibitor class, with the components of an already approved product, Epclusa (sofosbuvir/velpatasvir; SOF/VEL, Gilead Sciences), a combination of the pangenotype NS5A inhibitor, velpatasvir, and the familiar nucleotide polymerase inhibitor sofosbuvir. That dual combination has had the distinction being the first approved pangenotypic regimen and it's already in widespread use. Because of the incremental efficacy it offers in genotypes 2 and 3 compared with earlier regimens, including genotype 3 patients with cirrhosis, it represented a particular step forward for patients with genotypes 2 and 3 and has become the treatment of choice for these genotypes, as reflected in the AASLD Guidance (hcvguidelines.org) since its approval in 2016.

There have been a number of studies looking at various regimens for patients who fail first-generation DAAs. The regimens studied have sometimes consisted of a longer duration of treatment of the same regimen the patient received before or the same regimen for the same or longer duration combined with ribavirin. Less often, researchers have studied a combination of regimens made by different manufacturers combined in an individualized non-FDA approved manner. Some of these regimens such as Viekira Pak (ombitasvir/paritaprevir/ritonavir/dasabuvir, AbbVie) combined with Sovaldi (sofosbuvir, Gilead Sciences) have high levels of efficacy. Unfortunately, these combinations are quite expensive and are less accessible due to their unapproved status and lack of large pivotal trials that demonstrate their efficacy.

Vosevi was studied extensively in the POLARIS studies, of which there were four in total.

The two that have emerged as most relevant, because they evaluated the patient populations for which approval has been garnered, were POLARIS-1 and -4. In POLARIS-1, patients who previously failed an NS5A-containing DAA received Vosevi for 12 weeks. In POLARIS-4, the participants previously failed a DAA regimen that did not contain an NS5A inhibitor.

Of these two studies POLARIS-1 was more impactful because most patients who have been treated with DAA regimens so far have received an NS5A inhibitor. They have become foundational to the way we treat HCV in recent years. Only simeprevir/sofosbuvir, an early DAA combination used extensively in the early DAA era, falls into the POLARIS-4 category, but it is seldom used anymore.

POLARIS-1, demonstrated very high levels of efficacy for 12 weeks of SOF/VEL/VOX in patients with all genotypes who had been treated with an NS5A inhibitor previously. The comparator group was a placebo-recipient group which produced no SVRs.

The efficacy rate in the Vosevi group was 96% rate of SVR - 99% in those without cirrhosis and 93% in those with cirrhosis. There were six relapses in the cirrhosis group (n = 121) and no virologic failures in those without cirrhosis (n = 142).

A distinctive feature of this regimen that sets it apart from earlier regimens is that baseline resistance associated substitutions in the protease and NS5A domains did not affect efficacy. Moreover, the few patients who relapsed did not have treatment emergent resistant-associated substitutions. This leaves open the possibility, that deserves to be explored further, of whether repeated treatment with a longer duration of Vosevi with or without ribavirin might work in these failures.

In POLARIS 4, patients had failed DAAs that did not contain NS5A, so most of the patients had received sofosbuvir (85%) with or without a protease inhibitor. In POLARIS 4, the comparator group was 12 weeks of SOF/VEL.

Here there was a distinct advantage for 12 weeks of the triple regimen, with SVR rates of 97% vs 90% with SOF/VEL alone. It could be questioned why the results of SOF/VEL were distinctly under 95% in contrast to all other studies of POLARIS. This probably has something to do with the fact that whatever made patients fail a sofosbuvir-containing regimen previously, whether it's a bioavailability issue, an absorption issue or something else, this likely underlies a failure to succeed with sofosbuvir that was presumably again at play despite the addition of velpatasvir. The numerically higher SVR12 rates with SOF/VEL/VOX versus SOF/VEL in POLARIS-4 were limited to patients with genotypes 1a and 3.

With regard to safety, there is a slight increase in GI side effects with Vosevi, most of which were mild, consisting of nausea or diarrhea, and resulted in no treatment discontinuations.

The results of POLARIS-1 and -4 garnered FDA approval in July 2017, for 12 weeks of Vosevi in patients with genotypes 1 through 6, with or without compensated cirrhosis, who failed a regimen with an NS5A inhibitor, and for patients who had failed a sofosbuvir-containing regimen, without an NS5A, with genotypes 1a and 3. It should be underscored that Vosevi is only approved for compensated cirrhosis at this point; protease inhibitors are either not recommended or contraindicated in child's B or C patients across the board due to pharmacokinetic considerations.

In my practice, we have already recalled the few patients who failed DAA regimens with the intention to offer them this regimen.

Worthy of mention are the POLARIS-2 and -3 studies in DAA-naive patients. POLARIS-2 compared 8 weeks of SOF/VEL/VOX 12 weeks of SOF/VEL in more than 900 patients with genotypes 1 through 6 except for genotype 3 patients with cirrhosis, and demonstrated SVR12 rates of 95% and 98%. The SVR12 rate in the triple therapy group failed to meet the protocol-specified noninferiority endpoint, a difference in efficacy driven almost entirely by lower SVR12 rates with triple therapy in the genotype 1a patients. Curiously, the Q80K protease polymorphism highly prevalent in genotype 1a, which historically reduced efficacy of the protease inhibitor simeprevir with pegylated interferon and ribavirin, was associated with lower SVR12 rates in the genotype 1a patients of POLARIS-2, even though the sensitivity of the Q80K-containing virus is not reduced in vitro to voxilaprevir as it was to simeprevir. The reason for the divergent results in the genotype 1a patients between the two treatment arms in POLARIS-2 remains unclear. In POLARIS-3, containing exclusively genotype 3 patients with cirrhosis, the trial design was identical and so were the SVR12 rates: 96% with 8 weeks of SOF/VEL/VOX and 12 weeks of SOF/VEL. Thus, SOF/VEL/VOX is an excellent genotype 3 regimen, but because it was equivalent to SOF/VEL in efficacy, rather than superior, it did not garner regulatory approval for this group of patients nor for the larger population of genotypes 1 through 6 DAA-naive patients.

Mavyret

Mavyret (glecaprevir/pibrentasvir, AbbVie) is a novel second generation regimen that includes two drugs: glecaprevir, a protease inhibitor, and pibrentasvir, an NS5A inhibitor. Both of these are true second-generation drugs individually, so this is a true second-generation regimen. This means they are pan-genotypic and they cover the resistance variants particular to the protease class and the NS5A class that confer loss of sensitivity in vitro or have characterized the viral populations of patients who have failed first generation regimens.

The Mavyret studies included a broad spectrum of patients - cirrhotics, non-cirrhotics, treatment-naive, interferon failures, DAA failures, HIV coinfection, renal failure, kidney and liver transplants. However, patients with decompensated cirrhosis were not included. This regimen, which has been abbreviated as G/P regimen, was studied without ribavirin.

One of the largest of these phase 3 trials was the ENDURANCE-1 study, which evaluated patients without cirrhosis receiving 8 weeks of therapy vs. 12 weeks of therapy. Patients could be either interferon-experienced or treatment-naive.

The SVR rates were 99.1% in more than 300 patients who received 8 weeks of therapy and 99.8% in the patients who received 12 weeks of therapy. These SVR rates reflect only one virologic failure in the 8-week group and none in the 12-week group.

Genotype 3 was studied in a separate study called ENDURANCE-3, which compared 8 or 12 weeks of G/P vs. 12 weeks daclatasvir plus sofosbuvir and showed statistically noninferior SVR rates of 95% for each of the two Mavyret regimens and 97% for daclatasvir plus sofosbuvir, though there were a few more relapsers in the Mavyret groups.

The ENDURANCE-2 and -4 studies evaluated 12 weeks of G/P in patients with genotype 2 and genotype 4 through 6, respectively with SVR rates of 99% in each study. In SURVEYOR-2, part 4, an 8-week regimen of G/P was studied in patients with genotypes 2, 4, 5 and 6 without cirrhosis with SVR 12 rates by modified intent-to-treat analysis of 98% to 100%. In EXPEDITION-1, the G/P regimen proved to be robust in patients with compensated cirrhosis, with an overall SVR rate of 99% in patients with genotypes 1, 2, 4 and 5. In patients with all genotypes and renal impairment, studied for 12 weeks with G/P there were no virologic failures in 104 patients. The regimen also proved to be robust in studies evaluating HIV/HCV coinfected patients, patients with renal impairment (with zero virologic failures out of 104 patients given G/P), and patient with renal or liver transplants.

In MAGELLAN-1, part 2, which evaluated Mavyret in patients with prior DAA failure, the regimen did very well except in patients who had been exposed to both a protease and an NS5A inhibitor, the latter finding attributable to the presence of dual class resistance substitutions. Most of the DAA-failure patients studied had genotype 1. Therefore this regimen is approved for the treatment of patients with genotype 1, who previously received a regimen containing an NS5A inhibitor or an NS3/4A protease inhibitor, but not both.

Overall, the results with G/P are very robust and established 8 weeks of G/P as a newly approved regimen, as of August 2017, for non-cirrhotic patients with all HCV genotypes. Although not the first approved 8-week regimen - that distinction belonging to Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) - G/P is approved for 8 weeks in interferon-experienced patients as well as treatment-naive patients across all genotypes and is independent of the patient's baseline viral load. Many clinicians value the concept of giving the shortest duration of therapy necessary without sacrificing SVR. Additionally, the regimen is approved for 12 weeks in cirrhosis and is highly efficacious.

We do have to be mindful of drug-drug interactions and clinicians would be well advised to review that list. There is no issue with proton-pump inhibitors.

Bottom Line

The availability of the first approved regimens in DAA failure patients, although affecting relatively few patients because of the high SVR rates with existing regimens, is a major advance toward the universal goal of "leaving no patient behind" without cure of their HCV. The data base from phase 3 trials for SOF/VEL/VOX is larger for DAA-failure patients than for G/P, and the approved DAA-failure is more expansive, with no genotype restrictions, a uniform duration of treatment of 12 weeks (vs. 16 weeks for G/P in prior NS5A treatment failures), and applicability to patients who have been exposed to both protease and NS5A inhibitors. Further data on G/P in DAA failures would be valuable and plans are in progress to obtain such data, and even for SOF/VEL/VOX we will have to explore approaches for 12-week failures, which among NS5A-experienced patients was confined to cirrhotics in the POLARIS-1 trial. Perhaps simply retreating for a longer time will suffice, given the lack of impact of baseline RASs on outcome with this regimen and the infrequency of treatment-emergent RASs in the few patients who fail.

With the G/P regimen we have a highly effective new option for 8-week treatment, in patients who are non-cirrhotic and DAA-naive. Clinicians will have to decide whether the capacity to shorten the duration of therapy is significant for them and their patients, but many clinicians have expressed the feeling that so long as there is no discernible impact on SVR, a shorter duration of treatment would be viewed favorably. Reduced costs, if facilitated by a shorter duration regimen, may also result in expanded access to therapy nationally and internationally. Whether in cirrhotics treated with 12 weeks of G/P, HIV/HCV coinfected patients or patients with renal or liver transplants, the efficacy of G/P appears to be excellent, and the regimen is very attractive for patients with renal impairment (sofosbuvir for patients with GFR <30 ml/min is still unapproved).

Finally, no discussion of the POLARIS studies would be complete without acknowledging the affirmation in these studies of the very high level of efficacy of SOF/VEL demonstrated in the previous ASTRAL studies, which led to its approval in 2016. This efficacy was reaffirmed abundantly in the studies of SOF/VEL/VOX, in which 12 weeks of SOF/VEL performed very well when compared to the triple regimen in DAA-naive patients.

All in all, we are living in a time when we can still marvel at our abilities to cure nearly every single patient with HCV who walks into our offices. These approvals and expansions further our ongoing goal of eradicating HCV.

Ira M. Jacobson, MD - HCV Next - Co-Chief Medical Editor



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Hm, not only in Canada you say! This is a welcome and "nice" announcement, BUT, we shall see. Just like many other good drugs in Canada that are announced as "being approved/available" to us (in theory), in practise ... how it "actually" gets doled out (once it gets down to each provincial and health authority bodies and their "rules and exceptions") is to be seen. Believe me, a lot of good drugs "truly" being available here have historically been lip-service in actuality. I hope Vosevi IS HEAVILY utilized here, across ALL provinces and jurisdictions without all the "read the fine print" arm-tying restrictions. C.

Health Canada approves Vosevi for retreatment of chronic HCV - August 17, 2017 - Helio

Health Canada approved Gilead's Vosevi for treating patients with chronic hepatitis C with genotypes 1 through 6 previously treated with an NS5A inhibitor-containing regimen, or with genotypes 1 through 4 previously treated with sofosbuvir-containing regimen without an NS5A inhibitor, according to a press release.

"The evolution of Gilead's portfolio of HCV single-tablet regimens has been driven by our commitment to address previously unmet needs and put the possibility of cure within reach for as many HCV patient populations as possible," Kennet Brysting, general manager of Gilead Canada, said in the release. "The approval of Vosevi in Canada completes our HCV portfolio and this will enable the company to commit to collaborative partnerships that will help drive progress towards the goal of eliminating HCV in Canada by 2030."

Phase 3 data from the POLARIS-1 study and the POLARIS-4 study supported the approval. Both studies evaluated the safety of efficacy of Vosevi (sofosbuvir/velpatasvir/voxilaprevir, Gilead Sciences) in patients with chronic HCV without cirrhosis or with compensated cirrhosis.

Reference: www.gilead.ca



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Angel,

Read this Vosevi one (especially for the GT1 info) and cure rates, etc. - it was down below, in this thread, if you have not already read it before. smile C. http://www.natap.org/2017/EASL/EASL_57.htm



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)

Tig


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The overall cure rates of Vosevi are 91% to 100% in patients who had been previously treated with sofosbuvir-containing therapies. Failure rates of Harvoni are approximately 5% average across the board. That's a fairly standard failure rate with all DAA's however. We're beginning to see upper 90 percentile success rates in many regimens, but that depends on genotype. Vosevi is a 12 week protocol for all patients.

This Merck trial is recruiting now.

ClinicalTrials.gov Identifier:
NCT02613403 w/wo Ribavirin 

Grazoprevir NS3/4A, Ruzasvir NS5A, and Uprifosbuvir NS5B  (16 weeks w/Ribavirin  and  24 weeks wo/Ribavirin)



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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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Hey angel,

That's nice that Gilead called you back! smile

Yup, thats the info that was already out there!

Epclusa and Vosevi have a proven track record of stellar results for GT1-6.

So, in other words, what we were saying prior and what you are saying now, is the same thing ... that Vosevi has worked, very well, for relapsers of many varied regimes, and for gentotypes 1 -6!

Right back to where we started! wink

If you search the "actual" Vosevi studies, you will find even more specific info re: cure rates, relating exactly to your parameters, GT1a/previous failure on ledi/ and re-treated with vosevi. If you are interested in doing more research. biggrin C.

BTW - I hope you are still not confused about who vosevi could possibly be for (any GT) ... re: other treatment-experienced relapsers, including ... "prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir or telaprevir)" ... 

 

 



-- Edited by Canuck on Friday 11th of August 2017 04:31:38 PM

__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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A very nice and knowlegable gentlemen actually called me back from Gilead today regarding Vosevi (pronounced Vah-so-vaaa) Sounds french actually... anyway regarding this statement:
vosevi is good for:
genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor
(In other words if you took sofobuvir with riba, or interferon ,this treatment is no good for you, if you took harvoni you are ok to treat with it)
 
He said in section 14 (of the insert info) it shows the success rate for treatment in the clinical trials for the 51% that had treated with harvoni and relapsed as 96% (this is not broken down by genotype)
 
I would probably be in the 4% that relapses... LOL.. that's how i am feeling....waiting for merck trial!!
 
Have a nice weekend!! connie/angelseven

 



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62 year old female      1a, f1-2, had virus 40 years   STARTED HARVONI for 8 weeks 11/19/14, relapsed one month after tx  ended in 1/15.  Fibrosis level was only .5 after fibroscan 12/15. Began treatment with Mavyret on January 20, 2018 for 16 weeks!  Ending May 12.



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The so-called (Aug 8th) roll-out (in USA ) for Vosevi IS highly anticipated/waited on, by some. This tidbit (excerpt) indicates that ... "within hours" the docs were scribbling scripts, in the EU, according to Gilead and the writer of this (larger) article.

 

... John Milligan, company president and chief executive officer, concluded the conference by reviewing the details of Vosevi's (sofosbuvir/velpatasvir/voxilaprevir) recent FDA approval. "We are aware that prescriptions of Vosevi were written within hours of its approval," Milligan said. Gilead anticipates approval in the EU for Vosevi in the third quarter of 2017. -  by Talitha Bennett



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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No test, and, No contest ... it's Vosevi all the waaay, hands down, or ... even with one hand tied behind your back!!!!!! heeheewheee biggrin



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Is there going to be a test? wink

Your Loving Big Brother

Jimmy



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Harvoni TX 2 12 weeks. UND weeks 4, 12 and now EOT + 4 Weeks. SVR-12 09/29/16. All Glory, Honor and Thanks be to God.

"I go to war with the brothers I trust."



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Finally! The full Vosevi package insert (all 35 pages).

Vosevi - Gilead Sciences, Inc.

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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HEY! biggrin Finally! 

I still can't find the "full prescribing information" for Vosevi as yet, only this thus far! Man, Gilead sure is tight-shipped, tight-lipped and they sure know how to keep gossip under wraps and make announcements a somewhat long and drawn out affair! 

BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Vosevi. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Contraindications

·         Vosevi is contraindicated with rifampin.

Warnings and Precautions

·         Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Vosevi due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

·         Risk of Reduced Therapeutic Effect Due to Concomitant Use of Vosevi with P-gp Inducers and/or Moderate to Potent Inducers of CYP2B6, CYP2C8 or CYP3A4: St. John's wort and carbamazepine are not recommended for use with Vosevi as they may significantly decrease sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations.

Adverse Reactions

·         The most common adverse reactions (>10%, all grades) with Vosevi were headache, fatigue, diarrhea, and nausea.

Drug Interactions

·         Coadministration of Vosevi is not recommended with phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifapentine, atazanavir, lopinavir, tipranavir/ritonavir, efavirenz, rosuvastatin, pitavastatin, and cyclosporine due to changes (decreased or increased) in concentrations of sofosbuvir, velpatasvir, voxilaprevir, and/or the other agent.

Consult the full Prescribing Information for Vosevi for more information on potentially significant drug interactions, including clinical comments

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Making the Dragon Extinct has a good ring to it.

wink



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Harvoni TX 2 12 weeks. UND weeks 4, 12 and now EOT + 4 Weeks. SVR-12 09/29/16. All Glory, Honor and Thanks be to God.

"I go to war with the brothers I trust."

Tig


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Outstanding news, RC! There's an FDA webpage with additional information. This is going to be a hard protocol to better based on several factors. The one thing alternative treatments offer though, is a lower price. Let's wait to see what price Gilead tacks on this gold mine...  The generic market will be inviting to those wanting something like this and are unable to get approval through their insurance carrier. The entire treatment picture is changing at light speed now. It's hard to believe how many different treatments are available now and in just a few years. Incredible stuff happening...

FDA Release: Vosevi Approved



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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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Vosevi....FDA approved today.!!!



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 M-61 (3 Treatments)( SOF-RIBA 2014)(SOF-RIBA-PEG 2016)(HCC 2016) (LIVER TRANSPLANT 8-2017)(VOSEVI-RIBA 2017) On my way to SVR.    SVR-12. 3-13-18



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Just more Vosevi gossip ...

Prediction of Gilead's "Vosevi" sales (over AbbVie's "Mavriet") 2017 to 2022- article from BMI Research, June 29, 2017

Antiviral drug companies are set to struggle with the improving cure rates associated with the current hepatitis C (HCV) drugs, which are reducing the patient pool and the possibility for new drug opportunities. A potential bright spot is the approval of pan-genotypic HCV therapies that offer a significant advantage over current therapies. Both Gilead Sciences and AbbVie have received a positive opinion from the EMA's CHMP and are looking for approval in the EU and US later in 2017.

The EMA's CHMP has adopted a positive opinion on Gilead's MAA for Vosevi, an investigational, once-daily, single-tablet regimen of sofosbuvir 400mg, velpatasvir 100mg, and voxilaprevir 100mg (SOF/VEL/VOX) for the treatment of chronic HCV(cHCV)-infected patients. The data included in the application support the use of SOF/VEL/VOX in patients with and without compensated cirrhosis, with all genotypes (GT1-6) of HCV infection regardless of prior therapy, including eight weeks of treatment for HCV direct-acting antiviral (DAA)-naive patients without cirrhosis, as well as 12 weeks of treatment for patients who have previously failed therapy with a DAA-containing regimen.

Gilead To Lead The Battle

Estimated Product Revenues (USDmn)

 

story-Europe-Antiinfectiv-2017-06-26-11-

 

 

 

 

 

Source: Bloomberg, BMI



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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More about sof/vel/vox (Vosevi) - (roll-out date Aug 8, 2017?) - just reiterating how well this regime is performing across all GT's, nearly irrespective of prior failures, presence of cirrhosis and RAV's.

Exerpt from - Digestive Disease Week (DDW) 2017 - William F. Balistreri, MD -July 03, 2017

Sofosbuvir/Velpatasvir/Voxilaprevir

 A pangenotypic combination of sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX) was designed to inhibit three distinct HCV targets: the NS5B polymerase, the NS5A protein, and NS3/4A protease, respectively.

Flamm and colleagues[3] presented cumulative data from 1056 patients with and without compensated cirrhosis who were infected with HCV genotype 1-6 and treated with the once-daily fixed-dose combination tablet of SOF/VEL/VOX in phase 3 studies.

Of the DAA-experienced patients, 59% had received an NS5A inhibitor-containing regimen, whereas 20% of the DAA-naive patients had prior treatment failure with pegylated interferon plus ribavirin.

The studies enrolled a diverse patient population that included a significant number of patients with historically negative predictors of response, including cirrhosis and prior exposure to DAA-containing regimens.

SOF/VEL/VOX was administered to DAA-experienced patients with HCV genotype 1-6 infection for 12 weeks, and DAA-naive patients received treatment for 8 weeks. Cirrhosis was observed in 38% of patients, and 70% had an HCV RNA level > 800,000 IU/mL.

The resultant SVR12 rate was 96% in NS5A inhibitor-experienced patients and 97% in DAA-experienced patients who had not previously received an NS5A inhibitor. Thus, this ribavirin-free regimen of SOF/VEL/VOX achieved high rates of SVR across subgroups.

 Predicting Treatment Outcomes

Reddy and colleagues[4] evaluated the effect of baseline resistance-associated substitutions (RASs) on treatment outcome and sought the emergence of RASs in patients who experienced virologic failure.

NS3, NS5A, and NS5B deep sequencing was performed at baseline for all patients and at the time of virologic failure. The investigators found that 79% of NS5A inhibitor-experienced patients had baseline NS3 and/or NS5A RASs. Of these patients, 75% had NS5A RASs - the most common RAS - at baseline.

SVR12 rates were similar in patients with and those without NS3 and/or NS5A RASs, and in those with and those without VOX- or VEL-specific RAS. Specifically, RASs at NS5A position Y93 were present in 25% of patients, of whom 95% achieved SVR12. All patients with more than two NS5A RASs achieved SVR12. In addition, 95% of patients with NS5B nucleoside inhibitor RASs achieved SVR12; two patients had S282T present at baseline, and both achieved SVR12. The overall prevalence of baseline NS3 and/or NS5A RASs was 47%, and all achieved SVR12. No NS3, NS5A, or NS5B RASs emerged in any patient who had relapse after treatment with SOF/VEL/VOX for 12 weeks.

Therefore, the investigators documented that baseline RASs had no impact on the virologic response in DAA-experienced patients in this cohort after treatment with SOF/VEL/VOX for 12 weeks, and that virologic relapse was not associated with the emergence of viral resistance.

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Ragdoll and Tig found and posted this, about Gilead's "Vosevi" (sof/vel/vox) .... yay! biggrin

http://www.businesswire.com/news/home/20170623005247/en/

Interestingly enough, on the exact same announcement dates, Europe ia also looking at AbbVie's "Mivaret" (glec/pib - no sof). 

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004430/smops/Positive/human_smop_001152.jsp&mid=WC0b01ac058001d127



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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More conversation about sof/vel/vox. (Excerpt from a larger commentary) - the second emerging therapy mentioned was glec/pib.

 

Digestive Disease Week (DDW) 2017

Nancy S. Reau, MD

June 13, 2017

 

Emerging Treatments

The fixed-dose combination (FDC) of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX; polymerase inhibitor/NS5A replication complex inhibitor/protease inhibitor) is one of two new second-generation pangenotypic therapies anticipated later this year.

POLARIS-1 evaluated this FDC in patients who previously did not respond to NS5A-containing direct-acting antiviral (DAA) therapy, and POLARIS-4 evaluated this FDC in patients who failed DAA therapy without NS5A exposure.

Reddy and colleagues[3] presented the integrated resistance analysis from these two studies. Deep sequencing was performed for all patients at baseline and at the time of virologic failure. Both NS3 or NS5A class resistance-associated substitutions (RAS), as well as VOX or VEL-specific RAS, were evaluated and reported using a 15% cutoff. RAS was noted in 83% of POLARIS-1 patients, of whom 29% had RAS to both NS3 and NS5A. SVR12 was 98% in those without RAS and 97% in those with RAS. Prevalence of RAS was lower in POLARIS-4, with 51% having no detectable RAS at a 15% cutoff, of which 99% achieved SVR12. There was 100% SVR12 in those with RAS in POLARIS-4. The authors concluded that baseline RAS had no impact on virologic response in this DAA-experienced study. Of note, there were no treatment-emergent RAS in those who relapsed after 12 weeks of SOF/VEL/VOX. Testing for RAS before re-treating a DAA failure is currently recommended; however, these data suggest that identifying the presence of resistance may not modify therapeutic decisions or efficacy.

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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(From Helio - Journal Summary)

Investigational HCV regimen shows promise in two phase 3 trials

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May 31, 2017

 

An investigational fixed-dose combination regimen containing Sovaldi, velpatasvir and voxilaprevir for the treatment of hepatitis C virus resulted in high rates of sustained virologic response after 12 weeks of treatment among patients with or without compensated cirrhosis in whom previous therapy with direct-acting antiviral agents had failed, according to results of two international, phase 3 trials.

Marc Bourliére, MD, of Hospital Saint Joseph, France, and colleagues reported in The New England Journal of Medicine that the proportion of patients with hepatitis C virus (HCV) in whom therapy with direct-acting antiviral agents (DAAs) had failed is small; however, the number of these patients is substantial and will likely increase as more people are treated for HCV.

"This population of patients has been underrepresented in clinical trials and has limited retreatment options," they wrote.  

Therefore, the researchers conducted two phase 3 trials, POLARIS-1 and POLARIS-4, to assess the safety and efficacy of an investigational regimen containing the nucleotide polymerase inhibitor Sovaldi (sofosbuvir, Gilead Sciences), the NS5A inhibitor velpatasvir and the protease inhibitor voxilaprevir in patients with chronic HCV infection, including those with compensated cirrhosis, in whom previous therapy has failed.

In POLARIS-1, the researchers randomly assigned patients with HCV genotype 1 whose previous treatment included an NS5A inhibitor to receive a once-daily, single-tablet regimen containing 400 mg of sofosbuvir and 100 mg each of velpatasvir and voxilaprevir (n = 150) or placebo (n = 150) for 12 weeks. An additional 114 patients with other genotypes were enrolled in the sofosbuvir/velpatasvir/voxilaprevir arm.

In POLARIS-4, patients with HCV genotypes 1, 2 or 3 whose previous regimen did not include an NS5A inhibitor were assigned to receive either sofosbuvir/velpatasvir/voxilaprevir (n = 163) or Epclusa (sofosbuvir/velpatasvir, Gilead Sciences; n = 151) for 12 weeks. An additional 19 patients with HCV genotype 4 were enrolled in the sofosbuvir/velpatasvir arm.

All study participants in both trials were enrolled at more than 100 sites in the United States, Canada, New Zealand, Australia, France, Germany and the United Kingdom. Among patients who received an active treatment, 46% had compensated cirrhosis.

In POLARIS-1, the overall rate of sustained virologic response was 96% (95% CI, 93-98) among patients who received sofosbuvir/velpatasvir/voxilaprevir, which is significantly superior to a prespecified goal of 85% (P < .001), according to the researchers. Of 253 patients with a sustained virologic response, 249 returned for a 24-week visit post-treatment, and all still had a sustained virologic response. None of the patients in the placebo arm had a sustained virologic response.

In POLARIS-4, the overall rate of sustained virologic response was 98% (95% CI, 95-99) among those who received sofosbuvir/velpatasvir/voxilaprevir, which also was superior to the same prespecified goal as in POLARIS-1 (P < .001), and 90% (95% CI, 84-94) among those who received sofosbuvir/velpatasvir. Of 177 patients in the sofosbuvir/velpatasvir/voxilaprevir arm and 136 patients in the sofosbuvir/velpatasvir arm who had a sustained virologic response, 173 and 133 returned for the 24-week visit, and all had a sustained virologic response.

Across the study arms, the most common adverse events included headache, fatigue, diarrhea and nausea. The percentage of patients who discontinued active treatment due to adverse events was 1% or lower, the researchers reported.

"In conclusion, these results show that daily treatment with the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks is highly effective for patients infected with HCV of any genotype, with or without compensated cirrhosis, who did not have a sustained virologic response after treatment with DDA-based regimens, including NS5A inhibitors," they wrote.

Following these data, Gilead Sciences filed a New Drug Application with the FDA for sofosbuvir/velpatasvir/voxilaprevir. According to a press release, the regimen was previously granted breakthrough therapy designation by the FDA for the treatment of patients with chronic HCV genotype 1 in whom an NS5A inhibitor-containing regimen failed. If approved, it would be the first once-daily single tablet regimen available as a salvage therapy for patients with HVC genotypes 1 through 6 infection. - by Stephanie Viguers

 

Disclosure: Bourliére reports receiving grant support, consulting fees, lecture fees and fees for serving on an advisory board for AbbVie, Gilead Sciences and Merck Sharp & Dohme, as well as consulting fees, lecture fees and fees for serving on an advisory board for Janssen Pharmaceutical and Bristol-Myers Squibb, and meeting fees paid for by Genfit and Intercept Pharmaceuticals. Please see the full study for a list of all other authors. relevant financial disclosures.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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(From Helio - Journal Summary)

Sofosbuvir-velpatasvir safe, effective for patients with HIV/HCV coinfection

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May 4, 2017

 

Treatment with sofosbuvir and velpatasvir produced a safe, sustained virologic response in patients with HIV who were coinfected with hepatitis C virus, according to findings from a phase 3 study.

"As HIV - related morbidity and mortality has decreased, liver-related complications have become a leading cause of death in coinfected patients," Mark Sulkowski, MD, medical director of the Viral Hepatitis Center at Johns Hopkins University and an Infectious Disease News Editorial Board member, and colleagues wrote.

Researchers wrote that direct-acting antiviral agents offered safe and effective treatment for patients coinfected with HIV and HCV, and that current guidelines recommend coinfected patients receive the same treatment as patients with HCV monoinfection. 

"However, choosing an appropriate regimen can be complex ..." Sulkowski and colleagues wrote. "There remains an unmet clinical need for a simple well-tolerated, ribavirin-free, oral regimen with limited potential for interaction with HIV ART agents that is highly effective against all HCV genotypes."

The researchers conducted an open-label, single-arm study at 17 centers in the United States, with all patients receiving sofosbuvir-velpatasvir once daily for 12 weeks (n = 106). The main endpoint was sustained virologic response at the end of treatment. Sulkowski and colleagues assessed safety and efficacy in all patients who received at least one dose. 

Most patients were men (n = 91; 86%), and slightly less than half (45%) were black. About one-fifth (18%; n = 19) had cirrhosis. Overall, 101 patients achieved a sustained virologic response at 12 weeks (95%; 95% CI, 89-99). Patients who achieved sustained virologic response included 74 of 78 patients with genotype 1 (95%; 95% CI, 87-99), all 11 patients with genotype 2 (100%; 95% CI, 72-100), 11 out of 12 with genotype 3 (92%; 95% CI, 62-100) and all five with genotype 4 (100%; 95% CI, 48-100), Sulkowski and colleagues wrote. All patients with cirrhosis experienced sustained virologic response, the researchers reported. One withdrew consent, two were lost to follow-up and two patients relapsed.

Two patients experienced serious adverse events, and two discontinued treatment because of adverse events, the researchers wrote. Overall, the most common adverse events were fatigue (25%), headache (13%), arthalgia (8%) and upper respiratory tract infection (8%).

"In conclusion, sofosbuvir-velpatasvir for 12 weeks provides a simple, safe and highly effective treatment for patients coinfected with HCV and HIV," Sulkowski and colleagues wrote. "Its effectiveness in a broad range of patients across a wide range of ART regimens suggests that it could be used by the majority of patients with HIV/HCV coinfection including those with prior treatment experience, compensated cirrhosis and non-genotype 1 HCV infection." - by Andy Polhamus

Disclosure: Sulkowski reports advisory roles with Abbvie, Cocrystal, Gilead, Janssen, Merck and Trek, as well as research grants from Abbvie, BMS, Gilead, Janssen and Merck.

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Tig


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The one and done triplet! What's the hold up? Big Pharm and the regulators need to get this approved now. It's more about the size of the pie and how many slices are given to the least effective protocols. The final approval is held up by the lawyers, not the proof of effectiveness. Time to stop the legal dance and get down to curing Hep C.



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Just another re-review of how well sof/vel/vox is performing (period) and how well it is performing for the DAA experienced requiring salvage treatment in consideration of RAS/RAVs. Hurry up with rolling out the VOX already!

http://www.natap.org/2017/EASL/EASL_57.htm

 



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HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Another reference to a "potential" date for sof/vel/vox roll-out (I think)?

 

From "MRx Pipeline - April 2017", by Magellan Rx Management:

A view into upcoming speciality and traditional drugs

Hepatitis C Agents sofosbuvir/ velpatasvir/ voxilaprevir oral Gilead

PROPOSED INDICATIONS - Chronic hepatitis C virus (HCV) infection, genotypes (GT) 1-6

CLINICAL OVERVIEW - Sofosbuvir/ velpatasvir/ voxilaprevir (SOF/VEL/VOX) is an oral fixed-dose, single-tablet combination of an NS5B nucleotide polymerase inhibitor, an NS5A inhibitor, and an NS3/4A protease inhibitor. Two phase 3 clinical trials, POLARIS-1 and POLARIS-4, evaluated SOF/VEL/VOX in patients with HCV GT1-6 who have failed prior treatment with a direct-acting antiviral (DAA), including NS5Acontaining regimens (ledipasvir or daclatasvir). The studies reported an SVR12 rate > 96% in patients treated with 12 weeks of SOF/VEL/VOX compared to 90% in those treated with SOF/VEL (Epclusa®) and 0% in patients treated with placebo for the same duration. In 2 additional phase 3 studies, POLARIS-2 and POLARIS-3, DAA-naïve patients with GT1-6, including patients with cirrhosis, achieved SVR12 rate > 95% after 8 weeks of SOF/VEL/VOX treatment. SOF/VEL/VOX was well tolerated. The most common adverse events were headache, fatigue, diarrhea, and nausea. The studied dose was 1 tablet containing sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg, taken orally once daily.

PLACE IN THERAPY - Sofosbuvir/ velpatasvir (Epclusa; Gilead) is the only approved pangenotypic product on the US market for the treatment of chronic HCV. Products to treat patients who have failed previous therapy with DAAs continue to be an unmet medical need. SOF/VEL/VOX aims to become the first approved salvage therapy. It has been studied as a 12-week duration in this population. Moreover, SOF/VEL/VOX is seeking a shorter 8-week regimen in patients who are treatment-naïve. As a pangenotypic agent, SOF/ VEL/VOX will provide another single-tablet, once-daily option in the HCV armamentarium. Abbvie is also pursuing approval for its investigational fixed-dose combination pangenotypic DAA, glecaprevir/ pibrentavir, in treatment-naïve and treatment-experienced patients (including patients who have previously failed a DAA). It is dosed as 3 tablets once-daily. The role of genotype testing in practice remains to be elucidated with the increased availability of pangenotypic agents.

FDA APPROVAL TIMELINE - August 8, 2017 ü Breakthrough therapy (GT1 with failure of prior NS5A inhibitor therapy)

FINANCIAL FORECAST - (reported in millions) 2017 2018 2019 2020 2021 $ 29 $ 196 $ 321 $ 393 $ 400 The forecast is a projection of total US sales per year.

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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A new "PDUFA" date for VOX?

The roll-out date for the sof/vel/vox triplet seems to keep changing - one of the last roll-out dates we heard (thru the grapevine) was maybe June 2017. Now, is it August 2017?

Drugs get "PDUFA" dates. PDUFA stands for "Prescription Drug User Fee Act". Involves annual fees paid by a drug manufacturer for a drug to be on the market.

I found an article that refers to Gileads PDUFA date being August 2017 - does that mean that the VOX triplet roll-out will now not be until August?

(Excerpt from Biopharma) - one of those "speculative" reviews on company performances, such as Gilead.

... Epclusa (sofosbuvir/velpatasvir), launched in 2016, has already made sales of $1 billion, and a new combination regimen is on the horizon, but this may not make all the running, according to analysts at Maxim Group: "We expect to see 2017 as another tough year for the HCV franchise, even with the potential approval and launch of the new HCV regimen (sofosbuvir/velpatasvir/voxilaprevir) in 3Q17 - PDUFA date on August 8." ...

(Another tidbit) - from another source of "stock market type gossip" - they have Gilead seeing only an additional 7% scoop of people who need this "universal rescue" sof/vel/vox triple regime. Mostly, GT3's and relapsers of any GT.

This stellar sof/vel/vox triplet performs so well, as far as all GT's, relapsed GT's, despite RAV's, even cirrhotics, it is a shame that it has not been in use already, instead people are still being forced to have no choice but to keep relying on the less well tolerated riba when they are in need of the safe haven of a triplet.

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Tig


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My negative nelly feelers are tingling whenever I hear of these delays. Why are we continuing to see this? Time to do some detective work! Gilead must know why this 3rd Crown Jewel has yet to be marketed outside the trials. Waiting for the right price, or a clear approval? If something better comes along before then, they stand to lose a lot of marketshare. Wiley like a fox...



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Tig

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Just yet another (small) study showing the effectiveness of the sof/vel/vox triplet for any GT ("pan" as previously shown, and then further shown in this data about GT1's who previously failed other treatment). Importantly, as in other sof/vel studies, they demonstrate the effectiveness of a sof/vel/vox triple, and, that riba (even if added to the sof/vel/vox triple) offered no benefit.

I wish they would hurry up and make vox readily market-available so that people can have sof/vel/vox as a triple. We need a choice/alternate from a sof/vel/riba only triplet. Currently there is no choice but to do sof/vel/riba when a triple is needed (as it is only riba that is available and being used as the third drug). I think sof/vel/vox is a better tolerated (and very successful) triplet "rescue" regime for relapsers, than a riba-based triplet, and/or for anyone, when there is any justifiable reason/need for epclusa to be expanded into a triplet therapy.

 

 Hepatology. 2017 Feb 21. doi: 10.1002/hep.29130. [Epub ahead of print]

 

Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in DAA-experienced patients with genotype 1 HCV.

Lawitz E1Poordad F1Wells J1Hyland RH2Yang Y2Dvory-Sobol H2Stamm LM2Brainard DM2McHutchison JG2Landaverde C1Gutierrez J1.

 

Abstract

The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1-infected patients who fail direct-acting antiviral (DAA)-based regimens remains unknown. In this phase 2, open-label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virologic response on a DAA-based regimen were randomized to receive treatment with a fixed-dose combination tablet of sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin for 12 weeks. Patients were stratified by their cirrhosis and prior NS5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with sustained virologic response at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [95% CI], 86% to 100%) receiving sofosbuvir-velpatasvir-voxilaprevir alone, and 24 of 25 patients (96%; 95% CI, 80% to 100%) receiving the same treatment with ribavirin. None of the patients discontinued sofosbuvir-velpatasvir-voxilaprevir therapy due to an adverse event (AE). The most commonly reported AEs with sofosbuvir-velpatasvir-voxilaprevir alone were diarrhea and bronchitis; and with sofosbuvir-velpatasvir-voxilaprevir plus ribavirin were fatigue, anemia, gastroenteritis, and nausea.

CONCLUSION:

A fixed-dose combination of sofosbuvir-velpatasvir-voxilaprevir was well-tolerated and effective at achieving virologic response in patients with HCV genotype 1 infection and prior DAA treatment experience.

 

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Some reflections out of the Netherlands:

Epclusa Most Effective for HCV Genotype 3 vs. Other DAAs -  Berden FAC, et al. Clin Gastroenterol Hepatol. 2016;doi:10.1016/j.cgh.2016.10.034. - HCV Next, January 2017

Researchers in the Netherlands found that Sovaldi plus velpatasvir, known as Epclusa in the United States, was the most effective regimen for the treatment of hepatitis C genotype 3 infection compared with other direct-acting antiviral regimens, according to published findings.

"The findings of our network meta-analysis can be used to prioritize DAA regimens for HCV genotype 3 patients in guidelines and clinical practice," Joost P.H. Drenth, MD, PhD, professor of gastroenterology and hepatology, Radboud University Medical Center, the Netherlands, and colleagues wrote.

The researchers performed a systematic search of PubMed, Embase and Web of Science databases through March 2016 to identify clinical studies where patients with HCV genotype 3 were treated with DAAs. Twenty-seven studies were included (n = 3,415 patients) and then used in a Bayesian network meta-analysis using a random effects model to indirectly compare regimens among patients with and without cirrhosis.

"Key agents used in HCV genotype 3 patients are [Sovaldi (sofosbuvir, Gilead Sciences)], combined with ribavirin, [Daklinza (daclatasvir, Bristol-Myers Squibb)] or velpatasvir (Gilead Sciences)]," the researchers wrote. "The comparative efficacy of individual combinations is largely unknown, mainly because of the paucity of head-to-head trials, while that information is necessary to steer guideline developmental and clinical decision making."

Among patients without cirrhosis who underwent 12 weeks of treatment, more achieved SVR when they received Epclusa (sofosbuvir/velpatasvir, Gilead Sciences) with ribavirin (99%); sofosbuvir/velpatasvir without ribavirin (97%); sofosbuvir plus daclatasvir with ribavirin (96%); and sofosbuvir with peginterferon plus ribavirin (95%).

Among patients with cirrhosis, more achieved SVR when they received sofosbuvir/velpatasvir (96%) or sofosbuvir/daclatasvir plus ribavirin (94%) for 24 weeks, and sofosbuvir/velpatasvir plus ribavirin for 12 weeks (94%).

"The key finding is that sofosbuvir/velpatasvir regimens achieve the highest efficacy in HCV genotype 3. ...The advantage of sofosbuvir/velpatasvir over other regimens is that ribavirin can be omitted in noncirrhotics and that it shortens duration of treatment in cirrhotics," the researchers wrote.

The researchers note that ribavirin did add a value to the DAA regimen, despite cirrhosis; however, the actual effect it has on SVR depends on the efficacy of the regimen overall.

"The increase in SVR due to ribavirin is highest with regimens that have a lower intrinsic efficacy," they wrote.

The researchers concluded: "An indirect comparison of DAA-based treatments, using Bayesian network meta-analysis, found regimens containing sofosbuvir and velpatasvir to be the best option for patients with HCV genotype 3 infection," adding that choice of treatment varies due to several factors, including adverse events, availability and price of DAAs, among others. - by Melinda Stevens



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Another tidbit about sof/vel vox (and glec/pib) from a well known hep doc (USA) communicating with other docs in the hep business (post-Boston meeting), how drug developments affect their practice. Bodes well in favour of sof/vel/vox. I wish we would hear of sof//vel/vox coming quicker to use in more countries than just the US,  used for more GT's, and not just for relapsers. Normally I've tried to keep this thread narrowed to Epclusa and vox news, but in this case, I've just left the glec/pib info in, the article in it's entirety, not edited, just so as to do this docs writing justice.

How Data From the 2016 Boston Hepatology Meeting Will Influence Future HCV Patient Management - 1/31/2017 

I am really enjoying treating patients with HCV infection in this era of highly effective direct-acting antivirals (DAAs). Think about it: Our patients present with life-threatening, chronic infections, and we cure more than 95% of them with few adverse events. Other than insurance challenges, what's not to love?

Despite the relatively easy road to cure with modern therapy in most of my HCV-infected patients, I can think of 2 recent patients who presented challenges: a patient with relapse and resistance associated substitutions (RASs) after treatment with a DAA and a patient with genotype 3 HCV infection and severely reduced renal function.

Will these patients have the opportunity to achieve HCV cure with simple, safe, and effective DAA therapy? After the 2016 hepatology meeting in Boston, the answer is yes!

Relapse and Resistance 
The first patient was a 59-year-old black man with genotype 1a HCV infection and stage 3 fibrosis. We treated him with 12 weeks of ledipasvir/sofosbuvir, and it was going very well until he had posttreatment relapse. He was one of the 5% of patients who do not achieve HCV cure. Testing for RASs revealed NS3 Q80K and NS5A Y93H.

For this patient, the POLARIS-1 study offers a guiding light. In this study, the 3-drug, fixed-dose combination of sofosbuvir (SOF), velpatasvir (VEL), and the pangenotypic HCV NS3 protease inhibitor voxilaprevir (VOX) taken once daily for 12 weeks led to HCV cure in 96% of 263 persons who, like my patient, had failed to respond to NS5A-containing DAA regimens.

In fact, in the POLARIS-4 study, in DAA-experienced patients who had not received an NS5A inhibitor, 12 weeks of this 3-drug combination that includes VOX was also more effective than the current 2-drug combination of SOF/VEL without VOX (SVR12: 97% vs 90%, respectively).

Furthermore, RASs had no effect on SVR12 for SOF/VEL/VOX in either of these studies.

In the United States, the expectation is that this triple regimen will be available in mid-2017 for the treatment of persons infected with genotypes 1-6 HCV in whom DAA treatment failed to achieve HCV cure. Based on these results, I will recommend that my patient wait for this agent to become available.

Genotype 3 and Chronic Kidney Disease (CKD) 
My second patient was a 44-year-old woman, born in Pakistan, with genotype 3 HCV infection and stage 4 HCV-related CKD (with an estimated glomerular filtration rate [eGFR] of approximately 25 mL/min). Her hepatitis C needed to be cured, but the recommended regimen for treatment of persons with genotype 3 infection and renal disease is peginterferon and weight-based ribavirin - not an ideal regimen. The other option is the off-label use of SOF/VEL, which is not recommended in the setting of CKD with eGFR < 30 mL/min owing to the accumulation of GS-331007, the inactive metabolite of SOF.

For this patient, the EXPEDITION-4 study appears to offer a peginterferon- and ribavirin-free path to HCV cure. In this study, the 2-drug combination of the NS3 protease inhibitor glecaprevir (GLE) and next-generation NS5A inhibitor pibrentasvir (PIB), taken as 3 tablets once daily, led to HCV cure in 98% of 104 patients with stage 4/5 CKD, most of whom were on dialysis (82%). This is a pangenotypic HCV regimen that is expected to be the treatment of choice for persons with CKD and HCV genotype 2/3 infection in mid-2017, which may finally banish peginterferon as a recommended therapy for hepatitis C.

For my patient, the question remains: What should I recommend for her genotype 3 HCV infection and CKD? For now, my plan is to hold off on HCV treatment until GLE/PIB is approved. This will also give her time to consider kidney transplantation options down the road.

Furthermore, in persons without cirrhosis, the ENDURANCE-1 study showed glecaprevir/pibrentasvir (GLE/PIB) to be highly effective (SVR12: 99%) when used for only 8 weeks in patients with HCV genotype 1.

My expectation is that, following the approvals of SOF/VEL/VOX and GLE/PIB, ribavirin will be used for only a handful of patients. Ribavirin has been a gritty solider in the fight against hepatitis C, but like interferon, I will not miss prescribing this drug.

Future Challenges 
The 2016 hepatology meeting in Boston offered future solutions to some of my most vexing patient challenges - solutions that promise to bring more joy to my clinic. Easy Street, right? Well, the meeting did leave us with some new challenges.

An observational, postmarketing study found that HBV reactivation sometimes occurs during HCV DAA treatment, and a prospective study in cirrhotic patients reminds us that the risk of hepatocellular carcinoma is ongoing, even following cure.

For these issues, the meeting provided more data but little consensus, so their clinical management will remain complex for now.

I am interested to hear how new data from Boston are affecting your management of hepatitis C. Feel free to join in the conversation below.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)

Tig


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The addition of a pan NS3/4A PI in the drug regimen of a patient previously treated with a NS5A should be a welcome addition to treatment. They utilized Incivek and Victrelis back in my day to try and accomplish the same goal. Unfortunately, the side effects and rates of SVR were far lower. Very often it came down to a resistant variant being the culprit responsible for breakthrough or relapse in those that did.

I'm convinced that a comprehensive baseline examination of pre tx RAV/RAS should be accomplished for everyone. Some claim pan genotypic drugs remove that cconsideration, but I've seen RAV's cause one headache after another. With the advent of all these new drugs, I believe (until such time they are sure) they need to do an initial screen on everyone, not just a few hundred or thousand in these trials. It's getting much better and the continued research should resolve this. Lets hope it's soon.

#NoHep



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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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Just another reiteration about sof/vel/vox.

 

(Part of a larger Editorial/Commentary on various HCV topics from the Nov 2016 Boston Liver Meeting) - this excerpt only having to do with the sof/vel/vox topic.

 

William F. Balistreri, MD - January 24, 2017

 

Sofosbuvir/Velpatasvir/Voxilaprevir

SOF and velpatasvir (VEL), pan-genotypic inhibitors of the HCV NS5B and NS5A proteins, respectively, are coformulated (400 mg/100 mg) for once-daily administration with 100 mg of voxilaprevir (VOX; formerly GS-9857), a pan-genotypic NS3/4A protease inhibitor. Collectively, this regimen is referred to as SOF/VEL/VOX.

Evidence presented at the meeting suggests that this single-tablet regimen has the potential to be safe, well tolerated, and effective for patients who previously failed a DAA regimen containing NS5A inhibitor. These patients currently have limited retreatment options.

DAA-Naive HCV Genotypes 1 to 6

Foster and colleagues[5] hypothesized that the SOF/VEL/VOX fixed-dose combination, which targets three distinct viral proteins, would allow the treatment duration to be shortened to 8 weeks without affecting response rates. They compared 12 weeks of SOF/VEL with 8 weeks of SOF/VEL/VOX in patients with genotype 3 HCV infection and cirrhosis. The SVR12 rate was high with both regimens (96%). Treatment was generally well tolerated; rates of serious and grade 3/4 adverse events were low in both groups.

Jacobson and colleagues[6] compared treatments in patients infected with HCV genotypes 1 to 4 and compensated cirrhosis who had not received previous treatment with an HCV DAA. The 941 subjects - 18% of whom had cirrhosis and 23% of whom had failed previous interferon-based therapy - were randomly assigned to receive open-label SOF/VEL/VOX for 8 weeks or SOF/VEL for 12 weeks. HCV RNA levels declined rapidly; the SVR12 rate was 95% with the three-drug combination and 98% with the two-drug combination. No patient experienced on-treatment virologic breakthrough. One month after treatment, relapse rates were higher in the SOF/VEL/VOX group than in the SOF/VEL group (3.0% vs 0.5%).

DAA-Experienced HCV Genotypes 1 to 6

Zeuzem and colleagues[7] evaluated 12 weeks of treatment with the SOF/VEL/VOX fixed-dose combination and SOF/VEL as salvage regimens in DAA-experienced patients who had not previously received an NS5A inhibitor. Of the 333 patients infected with HCV genotypes 1 to 6, the most common previous treatment regimens were SOF plus RBV with or without peginterferon and SOF plus simeprevir. After 12 weeks of treatment, the SVR12 rate was higher with SOF/VEL/VOX than with SOF/VEL (97% vs 90%). Treatment was well tolerated, and no serious adverse events were attributed to the study medications.

Salvage Regimen in NS5A Inhibitor-Experienced Genotypes 1 to 6 Infection

For patients who have failed a treatment regimen containing an NS5A inhibitor, there is concern about long-lasting NS5A resistance-associated substitutions.

Bourlière and colleagues[8] found that after 12 weeks of treatment with daily SOF/VEL/VOX, the average SVR12 rate was 96% in patients with chronic HCV infection previously treated with an NS5A inhibitor. This combination was effective in patients with and without cirrhosis for all HCV genotypes. Baseline resistance-associated substitutions had no effect on SVR12.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Rc how are things going? Been thinking and praying for you. wink

 

JimmyK



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Harvoni TX 2 12 weeks. UND weeks 4, 12 and now EOT + 4 Weeks. SVR-12 09/29/16. All Glory, Honor and Thanks be to God.

"I go to war with the brothers I trust."



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I'm looking forward to this new triple combo. Some day it will be the first line defence. But I could use a salvage right about now!!  RC



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 M-61 (3 Treatments)( SOF-RIBA 2014)(SOF-RIBA-PEG 2016)(HCC 2016) (LIVER TRANSPLANT 8-2017)(VOSEVI-RIBA 2017) On my way to SVR.    SVR-12. 3-13-18



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Tig56 wrote:

Salvage? Why not tout this as a first line treatment instead of a secondary approach? This is so effective, using it in this manner, seems like a delay. Maybe the horse will get there, but putting the cart before it, makes the horse have to work harder and longer... Yes?

JMHO  


 Simply put, Gilead would love to sell a 12 week course of DAA's followed by the course sent in to salvage the failure. That is a lot of cash.

Also it is designed to be the answer to the competitors failures.

 

Cha Ching!



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Harvoni TX 2 12 weeks. UND weeks 4, 12 and now EOT + 4 Weeks. SVR-12 09/29/16. All Glory, Honor and Thanks be to God.

"I go to war with the brothers I trust."

Tig


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Salvage? Why not tout this as a first line treatment instead of a secondary approach? This is so effective, using it in this manner, seems like a delay. Maybe the horse will get there, but putting the cart before it, makes the horse have to work harder and longer... Yes?

JMHO  



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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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Healio/Hepatitis C - FDA NEWS

Gilead submits NDA for investigational treatment of HCV - December 8, 2016

Gilead Sciences today filed a New Drug Application with the FDA for an investigational fixed-dose hepatitis C virus treatment.

The NDA is for a once-daily single tablet regimen containing 400 mg of sofosbuvir (Sovaldi, Gilead) and 100 mg each of velpatasvir and voxilaprevir (sof/vel/vox).

It would be the first once-daily single tablet regimen available as a salvage therapy for patients with HVC genotypes 1 through 6 infection who have failed prior treatment with direct-acting antiviral regimens including NS5A inhibitors, Gilead announced in a news release.

The data submitted in the NDA are from the phase 3 POLARIS-1 and POLARIS-4 studies and support the use of the regimen for 12 weeks in such patients without cirrhosis or with compensated cirrhosis, the company said.

"The remaining clinical need to treat HCV patients is a safe and effective cure for patients who have failed previous therapy with DAA regimens, including those with NS5A inhibitors," Norbert Bischofberger, PhD, executive vice president of research and development and chief scientific officer at Gilead, said in the release. "Sof/vel/vox has the potential to fill that need by offering single tablet dosing and high cure rates across all HCV genotypes for patients with and without cirrhosis, who have failed prior treatment with other highly effective regimens."

The sof/vel/vox fixed-dose combination was previously granted breakthrough therapy designation by the FDA for the treatment of patients with chronic HCV genotype 1 who previously failed an NS5A inhibitor-containing regimen.

 

Disclosures: Bischofberger works for Gilead.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Info from the recent Boston Meeting is starting to come out - this is "some" of the data about my 8 week trial. There will be more data forthcoming on this trial (and other trials), as well as many other topics covered in the Boston Meeting.

I could not find a way to copy and paste my trial results here, so here is the link, unfortunately I think you have to be registered and "log" into this site to read the thing - if so, I'll keep working on another way to get it showing.  smile C.

 

Polaris 3 -  GT3 Trial Results - SOF/VEL/VOX 8 weeks versus SOF/VEL 12 weeks

POLARIS-3: 8-Week SOF/VEL/Voxilaprevir Regimen Achieves High SVR12 Rate in Cirrhotic Patients With Genotype 3 HCV Infection

Source: Clinical Impact of New Hepatology Data From Boston 2016*

 

(Here is another, dif.  link, to a similar write up on the trial results - maybe it will show easier, in the interim):    http://www.natap.org/2016/AASLD/AASLD_34.htm



-- Edited by Canuck on Sunday 20th of November 2016 04:50:43 AM

__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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This link is about a new "typed" GT7, found in a Gilead trial. Not many GT7's ever seen thus far (I read somewhere).

Gilead was enrolling GT 1-6's into their trial. One gentleman they chose WAS typed GT2, so, he was entered into their trial designed for GT's 1-6. Turns out ... he is a GT7!! They had to plunk him mid-stream to be over in the "other" category, until it could be sussed that he was indeed not a GT2, but rather, a special 7! (fooled-ya!, I sure appear to be a 2, don't I, hee hee)  So, in the end, it's nice to know - (like a little surprize bonus) to find out (accidental-like) that sof/vel happens to work good on GT7's too!! Really pan!

http://www.natap.org/2016/HCV/hep2863.pdf



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Just another "graphic" portrayal of the stats on sof/vel/vox - easy to see at a glance how well cirrhotic GT3's did on only 8 weeks of sof/vel/vox. 

 

·         A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir for 8 Weeks Compared to Sofosbuvir/Velpatasvir for 12 Weeks in DAA-Naïve Genotype 1-6 HCV-Infected Patients: The POLARIS-2 Study, by Ira M. Jacobson, et al. (LB-12)

 

Summary: This study compared treatment with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks with treatment with sofosbuvir/velpatasvir (brandname Epclusa) for 12 weeks in patients with genotype 1-6 hepatitis C, who had or didn't have liver cirrhosis, and who hadn't previously been treated with a direct-acting antiviral agent (DAA). The most common side effect were headache, fatigue, diarrhea and nausea while taking SOF/VEL, and diarrhea and nausea while taking SOF/VEL/VOX.


Clinical Trial Results:

 

SVR4 %

Total

GT1

GT2

GT3

GT4

GT5

GT6

Other

SOF/VEL/VOK 8 Weeks

96 (482/ 501)

95 (221/ 233)

97 (61/ 63)

100 (92/ 92)

94 (17/ 18)

94

100 (30/ 30)

100 (2/2)

SOF/VEL 12 Weeks

98 (432/ 440)

99 (229/ 232)

100 (53/ 53)

97 (86/ 89)

96 (55/ 57)

 

100 (9/9)

 

 

 (hm, 2 question mark symbols seem to appearing within GT5 and Other (bottom row). They are not supposed to showing up as question marks, in the original text, those 2 ques. marks are supposed to be showing up as "2 dashes" only!)

 



-- Edited by Canuck on Monday 7th of November 2016 06:05:22 AM

__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Hey Tig!

You just finished posting the same thing, from dif source - great minds think alike eh! 

So, this one will be (mostly) just a duplication of which you already found. But it such a good topic tho, worthy knowing about the up and coming. And it IS the "latest" tidbit showing up on these drugs. biggrin

New Triple Combo Cures Most DAA-Experienced and Hard-to-Treat Hepatitis C Patients Without Ribavirin 

 Monday, 24 October 2016    Written by HIVandHepatitis.com

An investigational 3-drug coformulation from Gilead Sciences produced sustained virological response (SVR) in 95% to 98% of hard-to-treat hepatitis C patients in the Phase 3 POLARIS trials, including people who were previously treated with direct-acting antivirals and those with hepatitis C virus (HCV) genotype 3 and compensated cirrhosis, according to a recent company announcement. Gilead plans to request Food and Drug Administration approval of the new combination by the end of the year.

The advent of direct-acting antiviral agents (DAAs) that can be used in interferon-free regimens has revolutionized treatment for chronic hepatitis C. While the new drugs are far more effective and better tolerated than interferon-based therapy, there is still room for better options for some difficult-to-treat individuals including those who did not respond to prior DAA therapy and may have drug-resistant virus.

Some current standard-of-care DAA regimens require a longer duration or addition of ribavirin for hard-to-treat patients, which adds to the side effects, cost, and inconvenience of treatment.

The new single-tablet regimen combines drugs from 3 different classes -- the previously approved HCV polymerase inhibitor sofosbuvir and NS5A inhibitor velpatasvir, plus the investigational protease inhibitor voxilaprevir (formerly GS-9857). All agents are pangenotypic, meaning they are active against all HCV genotypes and can potentially be used on a global basis without the need for genotypic testing.

The Phase 3 POLARIS trials tested the triple combination taken for 8 or 12 weeks without ribavirin in more than 1000 patients.

In POLARIS-1, 96% of NS5A-experienced patients with HCV genotypes 1-6 were cured with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir, compared with none of the placebo recipients. POLARIS-4 showed that the triple combination for 12 weeks worked better than a dual combination of sofosbuvir/velpatasvir for DAA-experienced patients who had not used NS5A inhibitors (SVR12 97% vs 90%).

POLARIS-3 demonstrated that 8 weeks of sofosbuvir/velpatasvir/voxilaprevir worked as well as 12 weeks of sofosbuvir/velpatasvir for patients with hard-to-treat genotype 3 and liver cirrhosis. However POLARIS-2, with a more diverse group of mostly non-cirrhotic DAA-naive patients with genotypes 1-6, did not reach the threshold for non-inferiority.

Below is an edited excerpt from a Gilead press release describing the studies and their findings in more detail.

 

Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velapatasvir and Voxilaprevir in Treatment-Naive and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients

- If Approved, SOF/VEL/VOX Would Be the First Once-Daily Single-Tablet Regimen Available for Salvage for Patients Who Have Failed Prior HCV Therapy with Oral Direct-Acting Antiviral Agent Regimens 

- U.S. NDA Planned for Q4 2016

Foster City, Calif. -- October 20, 2016 -- Gilead Sciences, Inc.(NASDAQ: GILD) today announced topline results from four international Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4) evaluating an investigational, once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection.

In the POLARIS-1 and POLARIS-4 studies, 445 patients with genotype 1-6 HCV infection who were previously treated with direct-acting antiviral agents (DAAs) received 12 weeks of SOF/VEL/VOX. The POLARIS-1 study enrolled patients who failed prior treatment with an NS5A inhibitor. The POLARIS-4 study enrolled patients who failed prior treatment with a DAA that was not an NS5A inhibitor, most with either an NS5B inhibitor alone (73 percent) or an NS5B inhibitor and an NS3/4A protease inhibitor (25 percent).

In the POLARIS-2 and POLARIS-3 studies, 611 patients who were not previously treated with a DAA received 8 weeks of SOF/VEL/VOX. The POLARIS-2 study enrolled patients with genotype 1-6 HCV infection with or without compensated cirrhosis. The POLARIS-3 study enrolled patients with genotype 3 HCV infection, all of whom had compensated cirrhosis.

The primary endpoint for all studies was SVR12. The intent-to-treat SVR12 rates observed in the POLARIS studies are summarized in the following table. Complete results from all four studies will be presented at The Liver Meeting 2016 in Boston.

Study

 

Population

 

Genotype

 

Treatment

 

Duration

 

SVR12 Rates

POLARIS-1

 

NS5A inhibitor-experienced

 

41 percent (172/415) had cirrhosis

 

1, 2, 3, 4, 5, 6

 

SOF/VEL/VOX

 

12 Weeks

 

96%

(253/263)

 

 

 

Placebo

 

12 Weeks

 

0%

(0/152)

POLARIS-4

 

DAA-experienced (No NS5A inhibitor)

 

46 percent (153/333) had cirrhosis

 

 

1, 2, 3, 4

 

SOF/VEL/VOX

 

12 Weeks

 

97%

(177/182)

 

 

 

SOF/VEL

 

12 Weeks

 

90%

(136/151)

POLARIS-2

 

DAA-naïve

 

18 percent (174/941) had cirrhosis

 

1, 2, 3, 4, 5, 6

 

SOF/VEL/VOX

 

8 Weeks

 

95%

(476/501)

 

 

 

SOF/VEL

 

12 Weeks

 

98%

(432/440)

POLARIS-3

 

DAA-naïve

 

All had cirrhosis

 

3

 

SOF/VEL/VOX

 

8 Weeks

 

96%

(106/110)

 

 

 

SOF/VEL

 

12 Weeks

 

96%

(105/109)

Patients treated with SOF/VEL/VOX for 12 or eight weeks had similar overall incidence of adverse events compared to placebo-treated or SOF/VEL-treated patients. The most common adverse events among patients who received SOF/VEL/VOX were headache, fatigue, diarrhea, and nausea. Among the 1,056 patients who received SOF/VEL/VOX in the four studies, one patient (less than one percent) receiving SOF/VEL/VOX for 12 weeks discontinued due to an adverse event.

"Despite recent advances that have provided high cure rates and simplified treatment for most HCV patients, those who have failed previous treatment with direct acting antivirals continue to represent an unmet medical need. The POLARIS study results demonstrate that combining three potent antivirals with different mechanisms of action and high barriers to resistance can provide high cure rates for patients who have failed other highly effective oral DAA regimens," said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. "Based on these Phase 3 results, we plan to submit regulatory applications for SOF/VEL/VOX for the treatment of chronic HCV in the United States in the fourth quarter of 2016 and shortly thereafter in Europe."

About the POLARIS Studies

The POLARIS-1 study was a double-blind, placebo-controlled study in 415 genotype 1-6 NS5A inhibitor-experienced patients. The most common prior NS5A inhibitors were ledipasvir (55 percent) and daclatasvir (23 percent).

The open-label POLARIS-4 study evaluated the use of SOF/VEL/VOX or SOF/VEL for 12 weeks in 333 genotype 1-4 HCV-infected patients with prior DAA experience that did not include an NS5A inhibitor. Most patients (85 percent) had prior DAA experience with sofosbuvir.

The open-label POLARIS-2 study evaluated the use of SOF/VEL/VOX for eight weeks or SOF/VEL for 12 weeks in 941 genotype 1-6 DAA-naive HCV-infected patients, including 18 percent with cirrhosis and 23 percent who had previously failed treatment with an interferon-based regimen.

The open-label POLARIS-3 study randomized patients with genotype 3 HCV infection and cirrhosis to receive SOF/VEL/VOX daily for eight weeks or SOF/VEL for 12 weeks. Of the 219 patients treated, 31 percent had previously failed treatment with an interferon-based regimen.

The POLARIS-1, POLARIS-3, and POLARIS-4 studies met their respective pre-specified primary endpoints for the patients receiving SOF/VEL/VOX. The POLARIS-2 study did not meet its primary endpoint; with a pre-specified 5 percent margin, the SVR12 rate for patients receiving treatment with SOF/VEL/VOX for eight weeks was not statistically non-inferior to the SVR12 rate for patients receiving SOF/VEL for 12 weeks.

About SOF/VEL/VOX

The SOF/VEL/VOX fixed-dose combination is an investigational product and its safety and efficacy have not been established. It has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration for the treatment of chronic genotype 1 HCV patients who have previously failed an NS5A inhibitor-containing regimen.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The companys mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

For more information on Gilead Sciences, please visit the companys website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

 

10/24/16  Source Gilead Sciences. Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velpatasvir and Voxilaprevir in Treatment-Naive and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients. Press release. October 20, 2016.

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Nice, that in North America, especially across the U.S.A. we see the blossoming - people finally getting Epclusa by prescription! Even in "slow poke" Canada, we have now seen a start, at least one lucky soul on site, who got her Epclusa by Canadian script! But, for others in other countries, the newer DAA treatments (never mind SOF/VEL) still remains far away, their best hope at receiving any "choice" or any "better" drug choice may come down to being lucky enough to find a trial! Here are the only SOF/VEL trials I've found around the world lately, for which Gilead may be "recruiting". (Just in case somebody, somewhere is looking for a SOF/VEL trial). Funny, there seem to be no further SOF/VEL/VOX trials tho. Just one trial which includes a Riba component. I will be looking forward to hearing more about VOX making it's debut, over Riba, as a triplet therapy with SOF/VEL.
 
 
 
 
 
 


__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



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Tig found a good update:

Can't wait to hear the upcoming Boston results/report ... Gilead's Sov/Vel/Vox Update 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)



Guru

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Posts: 2403
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Tanks, computer guy. I don't rightly know what the best title would be for this long convoluted thread, thought that would be "some" closer!, and thanks for changing it, but PLEASE - feel free to re-title it again, if so inclined. Please! Appreciate it muchly. biggrin C.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 62 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)

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