Harvoni or Daclatasvir?

[elsharony]

What is the best for cirrhotic patients? Harvoni plus Ribavirn for 24 weeks or Daclatasvir plus Sofosbuvir and Ribavirin 24 weeks?  I am genotype 4 liver cirrhosis F4 relapsed on Sovaldi and Interferon and Ribavirin.

[patra_]

Deb:  I thought so, too!  The studies were not as specific as I would have expected on the Gt 1s and 4s and there was no info on the studies on the Gt3s.  I KNOW they have been studying them all year here in the States.

I did finally talk to someone on Drug research at FDA.  They referred me to a number at BMS.  It took me three or so transfers to get (forgot her name.  This lack of memory is driving me crazy!) anyway, a nurse in the research Division at BMS.

Got the usual Big Co party line - very nice about it but ALL I got, several times, was, "We have no information to give you at this time".

Don't know which was the key part of that sentence:  

1)       We have no information
2)        to give you.                       or
3).       at this time.

She used the whole sentence every time - really got the partyline down pat (pardon the pun).

BMS did make sure thet had my name, address and phone number in each of the Offices I spoke with.  If that was just courtsey in case we were cut off (they said - but then why the address?) or if they will follow up w/ info in the future I do not know!
Pat

[flyinlynn]

I did find just Sovaldi and Ribavirin for 24 weeks 100% 14 of 14 patients and Sovaldi Pegintron Ribavirin for 12 weeks 96 % SVR (treatment naive) 27 of 28 patients.

Also found this

http://www.hcplive.com/conferences/idweek/Combination-Treatment-with-Daclatasvir-Produces-Good-Results-in-Patients-with-Genotype-4-Hepatitis-C

Combination Treatment with Daclatasvir Produces Good Results in Patients with Genotype 4 Hepatitis C

In the study, 82 patients with genotype 4 HCV were treated with 60 mg once daily of the NS5A inhibitor daclatasvir in combination with peginterferon alfa 180 µg once weekly and weight-based ribavirin (1000-1200 mg/day) twice daily

OK this is the closest I have found. Note: Daklinza is Declatasvir

http://www.genengnews.com/gen-news-highlights/bms-daklinza-approved-in-europe-for-chronic-hepatitis-c/81250284/

GEN News HighlightsMore » Aug 27, 2014
BMS' Daklinza Approved in Europe for Chronic Hepatitis C
(Page 1 of 1)

The European Commission has approved the Bristol-Myers Squibb (BMS) drug candidate Daklinza® (daclatasvir) in combination with other treatments across genotypes 1, 2, 3, and 4 for chronic hepatitis C virus (HCV) in adults—the first pan-genotypic NS5A complex inhibitor approved for use in Europe.

BMS says Daklinza plus other drugs will enable a shorter 12- or 24-week treatment duration compared to 48 weeks for interferon- and ribavirin-based regimens. Four combinations of treatments and/or regimens are recommended by BMS, depending on the genotype being targeted:

■Daklinza plus sofosbuvir for 12 weeks against Genotype 1 or 4 without cirrhosis.
■Daklinza plus sofosbuvir for 24 weeks against Genotype 1 or 4 with compensated cirrhosis.
■Daklinza plus sofosbuvir and ribavirin against Genotype 3 with compensated cirrhosis and/or treatment experienced.
■Daklinza for 24 weeks plus 24 to 48 weeks of peginterferon alfa and ribavirin against Genotype 4
The Daklinza-sofosbuvir combination, according to BMS, provided cure rates of up to 100% in clinical trials, including patients with advanced liver disease, genotype 3 and those who have previously failed treatment with protease inhibitors.

And finally this from what I have found the combo you are asking about does not seem to have been tested at this time

From the European Medicines Agency

26 June 2014
EMA/419836/2014
Committee for Medicinal Products for Human Use (CHMP)
Assessment report
Daklinza
International non-proprietary name: daclatasvir

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003768/WC500172849.pdf


Genotype 4
There are no data on the use of sofosbuvir+daclatasvir in genotype 4. However, there are data on the use of daclatasvir in combination with peginterferon and ribavirin in genotype 4. These are indicative that the efficacy of daclatasvir against this genotype is not lower than against genotype 1a. The in vitro potency of daclatasvir against genotype 4 in the replicon system is similar to that in genotype 1b. Furthermore, while the genetic diversity of genotype 4 is recognised, substitutions at the positions recognised to impact daclatasvir potency tend to produce lower FCs in a genotype 4 background, compared to genotype 1 (particularly genotype 1a). In summary these data are indicative that daclatasvir is as effective in genotype 4 as in genotype 1; altogether genotype 4 may be comparable to genotype 1b in terms of daclatasvir response.
It has previously been recognised that sofosbuvir efficacy is roughly similar in genotypes 4 and 1. Furthermore, genotype 4 is not intrinsically more difficult to treat than is genotype 1. Therfore, as combination effects of direct acting antiviral drugs are not anticipated to be genotype-specific, the findings in AI444040 may be extrapolated to genotype 4. Such an extrapolation has previously been accepted by the CHMP in an analogous case. Safety is anticipated to be similar regardless of genotype. In the absence of precise efficacy estimates, the sofosbuvir+daclatasvir treatment durations recommended for genotype 1 are considered relevant also for genotype 4.
Furthermore, the applicant has requested that the use of daclatsvir with pegIFN/RBV, as used in the AI444042 study, be cited as a recommended regimen in section 4.2. of the SmPC. While the, relatively speaking, inferior safety profile of interferon-based regimens is recognised, the efficacy data from this study, along with the totality of the safety database for daclatasvir when used with pegIFN/RBV, is supportive of this proposal.

That is all I have hope that helps
Lynn

[elsharony]

Any information about the effeictifly of Daclatasvir plus Sofosbuvir and Ribavirin 24 weeks for genotype 4 cirrhotic patients? I will take that combination through a program called compassionate use of the drug even if it is not FDA approved. BMS will give me Daclatasvir  for free.

[elsharony]

Any information about the effeictifly of Daclatasvir plus Sofosbuvir and Ribavirin 24 weeks for genotype 4 cirrhotic patients? I will take that combination through a program called compassionate use of the drug even if it is not FDA approved. BMS will give me Daclatasvir  for free.

[Ekkiemom]

Am I just reading Patra's post wrong or does it sound like they got a little ahead of themselves in the studies?  It seems a bit worrisome to me that so much incomplete data was presented. Like I said maybe I'm reading incorrectly...
Deb

[Magnum]

Let me put it simply like this, which may help you make your decision. I underwent 5 failed treatment attempts. The last one with Interferon, Ribavirin and Victrelis nearly killed me. Nothing worked. I am on my 5th week of Harvoni. I cleared in three weeks. Before my transplant, my doctor told me that Harvoni was in clinical trials and that if I could wait long enough, I should do the treatment. No mention of Ribavirin. Mind you I was at near end stage with Cirrhosis. I rest my case...

Magnum

[dragonars]

I'm g2d have relasperd twice peg/rib sovald/rib. There's nothing left for me to try. 24 weeks sovald/rib is only thing left.

[patra_]

This information was reported on Gt1s and 4s.  The studies on Gt3 were not mentioned.

I aved copies and pasted this from the site can-do showed above, which deb mentioned earlier.  I have not quoted the first part of this as it talked about the value added and the groups studied.


     "For treatment-naive adults with chronic HCV genotype 1 infection without cirrhosis, and for treatment-experienced patients with HCV genotype 1, the G-BA specified both dual therapy and triple therapy as appropriate comparator therapy.
In four further subindications, daclatasvir was to be compared only with dual therapy: 1) in treatment-naive HCV patients with genotype 1 and cirrhosis, 2) in patients with HCV genotype 1 and additional HIV infection, 3) in patients with HCV genotype 3 infection with compensated cirrhosis and/or treatment-experienced, and 4) in patients with HCV genotype 4 infection.
However, the manufacturer only presented data for treatment-naive adults with chronic HCV genotype 1 infection without cirrhosis and for patients with HCV genotype 4 infection.
Incomplete study pool for HCV genotype 1
Since studies for the direct comparison were lacking, the manufacturer presented an indirect comparison for HCV genotype 1 patients without cirrhosis in its dossier. Using a "historical" comparison of individual arms of different studies, it aimed to derive conclusions on the superiority of daclatasvir versus the triple therapy. The manufacturer did not meet the requirements for the dossier, however: A search in trial registries was not conducted. In addition, the inclusion and exclusion criteria for the choice of studies were unsuitable. At least one relevant study was lacking in the study pool because of this.
The Bayesian Benchmarking Analysis (BBA) additionally cited was used to determine the minimum threshold a study would have to reach in order to show a statistically significant superiority of daclatasvir. The manufacturer did not meet the requirements for the dossier in this analysis either: The search was limited to a period of time up to 2012 and there was no search in trial registries. In addition, the analysis was restricted to the outcome "SVR" without addressing side effects of Treatment.
Genotype 4: unsuitable data due to lacking values
The manufacturer only evaluated one study of the two studies it presented for the direct comparison of daclatasvir in combination with dual therapy versus dual therapy alone in treatment-naive HCV genotype 4 patients. Due to treatment futility, there were treatment discontinuations in both study arms, and hence missing values in the outcome "SVR", the proportions of which differed greatly between the study arms. The imputation strategy for the values was unsuitable because its results were not robust and biased to the disadvantage of the appropriate comparator therapy.
The criteria for discontinuation in the appropriate comparator therapy did not comply with the Summary of Product Characteristics and were also not reasonable because they considerably shorten the treatment duration in a large proportion of patients thus causing a disadvantage for the comparator therapy with regard to the outcome "SVR". In summary, no suitable data were available for treatment-naive HCV genotype 4 patients either.
G-BA decides on the extent of added benefit
The dossier assessment is part of the overall procedure for early benefit assessments according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment."

As many of you know, I have a huge interest in this drug w/hepc 3s and its outcome approval.  

I pray that those of us who are 3s will not need an additional tx, but there are all those out there who have failed, or who have not entered tx yet.

I guess that makes me read the info very very carefully, looking for the positives for us.

Not meaning to disrespect anyone - just write me off as a fanatic on this issue.

[can-do-man]

http://medicalxpress.com/news/2014-12-daclatasvir-hepatitis-added-benefit-proven.html

Haven't really read through it but from glancing at it. It doesn't sound like good news. But like I said haven't really with through it.

[fretboard]

Good news.  Cirrhotic patients only need Harvoni for 24 weeks, no Ribavirin required.  Check out the links.  


http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf

http://hepatitiscnewdrugs.blogspot.com/2014/11/aasld-gilead-announces-harvoni-study.html

[patra_]

Oh, in that same street insider (I think), was the info that AbbVie should get approval Dedision today or next Friday.  

I have never visited that site before so am not sure about either of those reports

[patra_]

AWM:  I think you are talking about the joint trials between Gilead & B-MS, which Gilead terminated in Dec 2013.  B-MS have done some studies in 2014.

I finally got a callback from FDA (while I was in the middle of Wal-Mart, Christmas shopping)!  His 1st question concerned a FIO (Freedom of Information form.  When I finally got him to understand what Info I was seeking, just had a Decision been made, and if, so what, he, naturally, gave me another phone number.  Monday will find me faint, but pursuing....

[AWorriedMom]

You are right. Some heppers were treated with Daclatisvir and Sovaldi. But it was in a trial. I believe there was a 100% success rate but Gilead refused to let the studies continue. They had Ledisprevir in the wings and that is the drug they wanted to use with Sovaldi....ergo we have Harvoni.

[patra_]

From the street insider 11-26-14:

    Bristol-Myers Squibb (BMY) Receives Complete Response Letter from FDA for Daclatasvir NDA

Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for daclatasvir, an NS5A complex inhibitor, in combination with other agents for the treatment of hepatitis C (HCV).

The initial daclatasvir NDA submitted to the FDA focused on its use in combination with asunaprevir, an NS3/4A protease inhibitor. Given the withdrawal of asunaprevir by Bristol-Myers Squibb in October, the FDA is requesting additional data for daclatasvir in combination with other antiviral agents for the treatment of HCV. Bristol-Myers Squibb is in discussions with the FDA about the scope of these data.

“Despite the recent advances in the treatment of hepatitis C there remain significant areas of unmet high need in this disease area,” said Francis Cuss, Executive Vice President and Chief Scientific Officer, R&D, Bristol-Myers Squibb. “Our commitment remains to make daclatasvir-based regimens available to help these difficult-to-treat patients achieve cure, and we will continue to collaborate with the FDA to bring daclatasvir to patients in the U.S. as quickly as possible.”

Ongoing Daclatasvir Clinical Development

Bristol-Myers Squibb is dedicated to the ongoing clinical development program for daclatasvir, a potent, pan-genotypic NS5A complex inhibitor (in vitro), which is currently being investigated globally in multiple treatment regimens for HCV patients with high unmet need. The company continues to progress its daclatasvir clinical trial program focused on difficult-to-treat patients, including pre- and post-liver transplant (ALLY-1), HCV patients co-infected with HIV (ALLY-2) and patients with genotype 3 (ALLY-3). The Phase 3 UNITY studies investigating Bristol-Myers Squibb’s investigational all-oral fixed-dose-combination DCV-TRIO regimen (daclatasvir/asunaprevir/beclabuvir) are also ongoing and include study populations of non-cirrhotic naïve, cirrhotic naïve and previously treated patients.  "

Not quite the same as being denied - sounds like they are seeking more information.

  

[Ekkiemom]

I thought that some HEPPERS were already Txg with this med so I was confused on how they would then treat them. Is this one of the old school meds that if you treat with it you cannot treat with others? Not too familiar with it
Deb

[AWorriedMom]

As Ekkimom says Daclatasvir has not been app-roved by the FDA. You will not be able to get it.

A very small study showed Harvoni to work on people who failed sovaldi. There were 14 people in the study. However, if I were you, I would go for the Abbvie drugs. they were tested on over 300 patients with Stage 4, most of whom were non-responders previously. I am a previous null responder to every treatment I tried. I am a 1a with long standing cirrhosis and have had HCV since 1965. The Abbvie drugs (24 week arm) cleared me in just a few short weeks. They are likely to be approved some time today or if not today, next Friday.

Good luck.

[patra_]

I read that article and it looks, to me like a 'value added' benefit study from Europe.

I KNOW that the daclatasvir trials sent in for approval by FDA was for studies on Gt 3, was done on daclatasvir w/Sovald, and already approved med.

I called the FDA day befor yesterday to see if I could get, first, an update on the decision or on-going consideration of the Dac only (not the combo that BMS has already withdrawn) and, second, more specific information on the study or studies that are being considered in the Dac.

So far, no response, but I wait, with hope.  

Back to what I said at the beginning, Gt 1 , I would recommend Harvoni.  Gt 3 I would recommend the Daklinza (daclatisvir).  Others Gts, I have nit read enough to recommend.

Pat

[hepcandme]

Well, there's this:

http://hepatitiscnewdrugs.blogspot.com/2014/12/daclatasvir-for-hepatitis-c-added.html

that doesn't have a lot of good things to say about the way Declatasvir presented its data

but I am really interested in how this all plays out in terms of which drugs provide benefits for patients with different scenarios - Genotype, cirrhosis, etc.

[Ekkiemom]

The article is on the Hepatitis Central website  "Dacalatasvir denied by FDA".
Below article is link to rest of article
D

[Ekkiemom]

I just read something today that said Daclatasvir has just been denied by the FDA now. I'm sorry I can't remember where I saw the info. Pls correct me if I'm wrong.
Good Health
Deb

[patra_]

Good, if you have to be cirrhotic, this is easier to deal with!

You may have already checked in to a liver friendly diet,but if not, that can help your liver because first, it is not as hard for the liver to process, and, second, it has properties that can help the liver help itself as you go through tx (treatment).

Fresh fruits, and berries, and veggies, especially green, leafy ones, 'good' fats like those found in yogurt (plain, not the jazzes up with sugars ones), cream cheese, cottage cheese, nuts, avacados, (Iam sure I am missing something here), white meats if you eat meat - chicken, turkey, fish, eggs, hard cheese (proteins) as well as legumes.  Drink LOTS of water - 1 oz per pound of body weight up to 1/2 your body weight daily.

Hope this helps and isn't throwing too much info at you all at once.

Pat

[elsharony]

I am a compensated cirrhosis

[patra_]

Opps!  I have what my Husband calls 'Happy Fingers' - touched the wrong thing.

Anyway, as I was saying, I have not read much at all on what Gts AbbVis has been using in their trials.  I do know that we have some posters who are involved.

Here's hoping one of them has some definitive info on that product - which is coming on the market very soon.

Hang in there and, I am sure, more info will beforthcoming.

Pat

P.S.  Are you compensated or decompensated cirrhosis?

[patra_]

That is a very good question.  Also, throw the new AbbVie combo pill into the mixture, just to get the whole picture.

If you were Gt 1a or b I would say Harvoni.

If yyou were Gt 3, I would say Daclatasvir w/Sol.

I know that Bristol-Myers, Squibb has done studies on hard to treat including cirrhotics - all genotypes, with good results.  

I understand that Gilead is doing some studies on cirrhotics,  but do not know what result and if the are only working w/Gt 1, as in former trials.