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TOPIC: Merk's new hep C drug (Grazoprevir/Elbasvir)

Merk's new hep C drug (Grazoprevir/Elbasvir) 6 years 4 days ago #1631

  • DorianLS
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I understand that Merk's application to the FDA for their own "Harvoni-like" 1 tablet formulation might be approved as early as the end of the year. I seem to recall having come across Chinese api's for these compounds. The reported cure rates which Merck has reported are extremely good - 95% to 100%. This looks to be an interesting development which might put further pressure on Galead's drug pricing for Harvoni. And for those pursuing Chinese api's these medications might warrant looking into. I'd be interested to hear if anyone here is knowledgeable about this.
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Merk's new hep C drug (Grazoprevir/Elbasvir) 6 years 3 days ago #1650

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Where did you come across chinese firms manufacturing these API's"?
Gen 1b 40yrs,tx naive, f3/f4.VL too high to quantify.
Started tx 12Oct.sof and riba India via greg.Dac from Mesochem.
4wk result virus not detected,all liver functions in normal ranges.
Only SE intermittent insomnia.Feel great and grateful otherwise
Last Edit: 6 years 3 days ago by miko3. Reason: Grammatical errors
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Merk's new hep C drug (Grazoprevir/Elbasvir) 6 years 3 days ago #1651

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Hi Miko, Gosh, I'm sorry - I seem to have made a mistake. I searched Alibaba and could not find anyone offering these products.
Apologies! Dorian
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Merk's new hep C drug (Grazoprevir/Elbasvir) 6 years 2 days ago #1670

  • DrJames
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See this for links to the latest about this combo: hepatitiscnewdrugresearch.com/grazoprevirelbasvir.html

It is only phase 2 stuff, so not at scale.

Grazoprevir (an NS3/4A protease inhibitor) and elbasvir (an NS5A inhibitor) and it is being used with Ribavirin.

It would be comparable to using Simeprevir (NS3/4A) and Ledipasvir/Daclatasvir (NS5A).

It is missing the secret sauce of Sofosbuvir's pan genotypic log 4.5 kill rate.

Merck show real decency with their $4.50 Gardasil vaccine price to the 3rd world compared to their $130 1st world price which of course looks nothing like Gilead's pricing structure. It would be great if they could get 95% + cure rates (preferably without Riba) but it's still an open question because the trials are still small.
YMMV
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5783

  • Jonathan
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James,

For your information I was in a 12 week trial with Grazoprevir/Elbasvir about eighteen months ago. Although I was undetected at EOT (and for 8 weeks during the trial period) I relapsed about two weeks later. I was informed the reason being that I had NS5A RAV's at baseline (L31M) and treatment emergent NS5A RAV's (Q30R) - although I did not have any NS3 RAV's at baseline or treatment emergent NS3 RAV's (that they could ascertain from population sequencing).

My specialist has suggested a 12 week course of sofosbuvir/simeprevir/ribavirin - what are your thoughts? Any alternative options that may have greater efficacy?

I am GT1a, F1-F2.
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5816

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Hi Jonathan,

Let's start by saying I don't have any practical experience treating DAA recurrence so this is only a combination of book knowledge and background knowledge. I would advise taking your specialist's advice, but here are some things to consider.

NS5A RAVs don't necessarily render NS5A inhibitors useless because resistance is invariably relative. Here is what it looks like on a petri dish:



The white disc contain antibiotic and the clear area around them gives a visual of how effective they are (or how resistant the bacteria are to being killed). The antibiotic concentration falls off with distance from the disc and where you see the bugs growing is where the antibiotic falls below the MIC (Minimum Inhibitory Concentration).

So if I was 1a I would have 12 weeks of Sofosbuvir+Daclatasvir+Simeprevir and I would be considering increasing the 12 towards 24 weeks on the basis is 8 weeks works for F0, 12 weeks for F1-3, and 24 weeks for F4 it is probably more like

F0 8 weeks
F1 12 weeks
F2 16 weeks
F3 20 weeks
F4 24 weeks

The trials divided people into cirrhotic and non cirrhotic and found the 12 vs 24. This was to make 2 statistical buckets rather than 4 buckets without enough n.

Fibrosis is a spectrum from none to lots so if we need lots of treatment time for high fibrosis we "probably" would be better to use a bit more than 12 weeks for F2 and F3. Can't prove it. Can't show you evidence, but makes logical sense to me.

It's not directly applicable to you but the recent trial n=468 for F3/F4 GT3 patients failed to show any benefit for 24 weeks Sof+Dac+Riba versus Sof+Dac alone. fixhepc.com/media/kunena/attachments/391/CCO.pdf
YMMV
Last Edit: 5 years 9 months ago by DrJames.
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5878

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"NS5A RAVs don't necessarily render NS5A inhibitors useless because resistance is invariably relative."

Hi Doc,

I can't see how an NS5A inhibitor is going to kill off an NS5A RAV. I am not sure if it is valid to compare the mechanism of antibiotics with the mechanism of the DAA's.
I have no medical training, but my simple understanding is that each class of DAA inhibitor is like a gate which closes off one path the virus can use if it mutates. If you have 3 DAA's of different classes which close off all 3 gates then the virus is basically f*****. But if you have NS5A RAVS and use a combo of 3 DAA's then the NS5A gate is rendered ineffective for them. There's still a good chance that the other 2 gates will stop the virus including the RAVs, but not as good a chance as if all 3 gates were closed. The virus is highly mutagenic and will escape if it possibly can.

There is not a lot of data on retreatment with an NS5A inhibitor. Here is one study on retreatment with Harvoni:
www.natap.org/2015/EASL/EASL_26.htm

I think it is just too early to really know until real world data starts to come in. Maybe by that time there will also be more new drugs and trials specifically to find out what will overcome NS3 and NS5A resistance.
dt
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5888

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From theAASLD guidelines:
www.hcvguidelines.org/full-report/retrea...r-therapy-has-failed

"Recommended regimen for patients in whom previous treatment with any HCV nonstructural protein 5A (NS5A) inhibitors has failed (including daclatasvir plus sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir plus dasabuvir).
For patients with minimal liver disease, deferral of treatment is recommended, pending availability of data.

For patients with cirrhosis or other patients who require retreatment urgently, testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended. The specific drugs used in the retreatment regimen should be tailored to the results of this testing as described below. Treatment duration of 24 weeks is recommended and, unless contraindicated, weight-based RBV should be added."
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5895

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I can't see how an NS5A inhibitor is going to kill off an NS5A RAV

I just gave you a visual. 1/2 the white dot antibiotics would be rated "resistant" but there is still effect (at higher concentrations).

Resistance is relative, not absolute as in a binary yes/no.

First read: fixhepc.com/forum/experts-corner/164-res...lure-mechanisms.html

Then consider that an AK47 round will penetrate most body amour unless it hits the chest plate. Then assume you empty the whole magazine into that chest plate.....

Trust me, bullet resistant is correct. Bullet proof is not.

RESISTANCE IS RELATIVE
YMMV
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5896

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Jonathan asked:
"My specialist has suggested a 12 week course of sofosbuvir/simeprevir/ribavirin - what are your thoughts? Any alternative options that may have greater efficacy?

His specialist is in line with the AASLD recommendations for his case if he is cirrhotic:
"For patients who have NS5A inhibitor RAVs detected and who do not have NS3 inhibitor RAVs detected, treatment with simeprevir, sofosbuvir, and RBV for 24 weeks is recommended.

So, even given that resistance is relative, what do you know that allows you to say with any degree of confidence that an NS5A in the combo would have greater efficacy than ribavirin against NS5A RAVS?

dt
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5902

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Here's a recent write up:
"Management of patients with hepatitis C virus resistance‚Äďassociated variants to NS5A inhibitors: Where are we now?"
onlinelibrary.wiley.com/doi/10.1002/cld.507/full

" We do know that almost all patients who fail to achieve SVR will have resistant variants, and if treatment involved NS5A agents, these patients will have long-lived RAVs, most likely for years. The screening of all patients who previously failed a regimen containing an NS5A inhibitor is recommended when considering retreatment with a regimen containing an NS5A inhibitor. It is not a matter of if a RAV will be found, because that is almost a given. The specific RAV and the number of RAVs are critical in determining if the patient can be retreated with an NS5A again. The likelihood of SVR can range from 30% to 100% if retreated with a regimen containing an NS5A, depending on these specifics. To further complicate the issue, not all NS5A agents have the same liability to the same RAVs, making it even more critical to know what variants are present."

dt
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5904

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Hi folks,

Here is my (non-medical) understanding of RAVs.

Imagine a world in which Big Pharma executives were paid an annual bonus in which all their crisp $100 dollar bills were glued together? Probably they would figure out a way to make a super-sized tailor-made pocket that would be just right for their juicy bonus.

But what if we could change the juicy bonus by just a bit, without telling anyone in advance?
:)

Each different NS5A inhibitor is a small molecule with a slightly different shape, but each is capable of blocking a key active site or "pocket" on the NS5A protein. Usually a RAV (resistance associated variant) has some kind of mutation in the amino acid composition of the protein near the active site. For example Q30R means the usual "Q" has mutated to "R" which causes the shape of the active site to change and the inhibitor to fit the pocket less well (or not at all). As far as the virus is concerned, the trick is to make such a change without also knocking out its original biological function (whatever that is for NS5A). The nasty thing about Hep-C is it mutates rapidly, and this is how it escapes our immune systems. But most mutations are away from any active pockets, because otherwise the mutated form just wouldn't work any more. So the trick for the virus to survive a drug molecule is to find a mutation on the drug's target site that does not also render the protein useless.

From Jonathan's story, it seems that the Q30R mutation allows the virus to survive elbasvir (NS5A inhibitor), and taking that with grazoprevir (a NS3/4A inhibitor) alone is not enough to kill the virus.

Sofosbuvir blocks a "pocket" on NS5B, and that protein seems to be more essential to the virus (or its harder for the virus to make an escape mutant in the NS5B pocket that survives).

But the point I really want to make is that a virus protein might escape one drug, but it can still be clobbered by another one which fits the pocket in a slightly different way - with or without the mutation. So in Jonathan's case, a different NS5A inhibitor from elbasvir could still work on his NS5A RAV.

As there are lots of new antivirals coming on-line, this means lots more possible combination treatments. But it then becomes a question of doing many clinical tries to see which actually work.

If you follow that kind of argument through, the best Hep-C treatment would use a triple combination - whack NS5A, NS5B, and one of the others like NS3A or NS4A all at the same time. There's no way a virus can simultaneously mutate all three proteins in the space of a few weeks! Result? No more virus despite the RAVs. It then just comes down to a question of cost ... How many DAAs can we afford to throw into the deadly mix for a cost-effective treatment?

Big Pharma is often accused as producing lots of "me too" drugs, just to make more money. But for anti-virals, as long as the new molecule fits the pocket in a slightly different way, this could end up being a real advantage as far as alternative treatments are concerned.

And of course, each new alternative *should* bring down the cost. But as we all know, the Mutant-Executives who work in Big Pharma have figured out how to escape the rules of the market and still keep their fat bonus pockets full.

Still, the more DAAs, the better...
;)
Diagnosed Jan 2015: GT3, A0+F0/F1. Fatigue + Brain-Fog.
Started Sof+Dac from fixHepC 10-Nov-2015. NO sides.
Pre-Tx: AST 82, ALT 133, Viral Load 1 900 000.
Week4: AST 47, ALT 58. VL < 15 (unquantifiable).
Week12 (EOT): AST 30, ALT 26, VL UND
Week16 (EOT+4): AST 32, ALT 28, GGT 24, VL UND
Week28 (EOT+16): AST 26, ALT 22, GGT 24, VL UND
Ever grateful to Dr James.

Relapsed somewhere after all that... Bummer!

Jan 2018: VL 63 000 (still GT3).
Last Edit: 5 years 10 months ago by Vororo.
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5910

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"But the point I really want to make is that a virus protein might escape one drug, but it can still be clobbered by another one which fits the pocket in a slightly different way - with or without the mutation. So in Jonathan's case, a different NS5A inhibitor from elbasvir could still work on his NS5A RAV.

As there are lots of new antivirals coming on-line, this means lots more possible combination treatments. But it then becomes a question of doing many clinical tries to see which actually work."

I totally agree Vororo. But WHICH NS5As will work for the types of NAVs that Jonathan has, that is the significant question that clinical trials have not yet answered. In the meantime, what is he to do? Just try any NS5A that's not elbasvir and hope for the best? And if that is not the one that works then does he end up with even more kinds of NS5A RAVS to deal with next go round? What if there are many kinds of RAVS present and no one NS5A inhibitor will kill them all? Do you take more than one NS5A? What about the dosage required? That's a lot of unanswered questions.

dt
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5915

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Hi dt,

Yes, lots of unanswered questions. Also, its difficult to separate the marketing from the medicine. It seems to me that making a treatment guideline about whether or not someone is "treatment-naive" (for NS5A or anything else) only makes sense if there is only one treatment for each target protein. And this is not the case now. But the report you cite says there is just not enough data to really know.

As Dr James said before, Jonathan's treatment did not involve the usual sofosbuvir. So unless he wants to be a guinea-pig again, probably his next treatment should be sofosbuvir+X, where X is not grazoprevir or elbasvir.

Unless, elbasvir is some kind of "me-too" version of ledipasvir or daclatasvir, I'd guess its probably OK to try the usual Sof+Dac or Sof+Led combo. The received medical advice is Sof+Led for GT-1: fixhepc.com/getting-treated/genotype-spe...-hepc-treaments.html.

Just looking at the pictures, they all look like quite different but vaguely similar molecules. But these pictures are only 2D chemical representations, and not how they might look in a 3D.

en.wikipedia.org/wiki/Elbasvir
en.wikipedia.org/wiki/Daclatasvir
en.wikipedia.org/wiki/Ledipasvir

Sorry, Jonathan. I'm not trying to plan your future here!
:)

Heck, I'm not a Dr, so I stop now...
Diagnosed Jan 2015: GT3, A0+F0/F1. Fatigue + Brain-Fog.
Started Sof+Dac from fixHepC 10-Nov-2015. NO sides.
Pre-Tx: AST 82, ALT 133, Viral Load 1 900 000.
Week4: AST 47, ALT 58. VL < 15 (unquantifiable).
Week12 (EOT): AST 30, ALT 26, VL UND
Week16 (EOT+4): AST 32, ALT 28, GGT 24, VL UND
Week28 (EOT+16): AST 26, ALT 22, GGT 24, VL UND
Ever grateful to Dr James.

Relapsed somewhere after all that... Bummer!

Jan 2018: VL 63 000 (still GT3).
Last Edit: 5 years 10 months ago by Vororo.
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Merk's new hep C drug (Grazoprevir/Elbasvir) 5 years 10 months ago #5921

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The official received medical advice for GT1 folks who have already treated with an NS5A is not sof+led or sof+dac. It is what the AASLD and Jonathan's consultant recommended, ie. simeprevir, sofosbuvir, and RBV for 24 weeks.

I do agree that sof should form the backbone of Jonathan's next tx, because it has a high barrier to resistance unparallelled by any other drug on the market, and it wasn't used last time. I see no reason why sim should not also be used because no NS3 RAVs were found. The question I have is about whether the 3rd DAA should be an NS5A or ribavirin and which one will achieve higher efficacy? The answer, so far as I can make out, is that it depends. The use of an NS5A to treat NS5A RAVS requires analysis ot the RAVS present and targeted therapy with specific choice of NS5A to be used. One size does not fit all, as yet.

I want to add that I think this subject is really an important one for anybody currently treating with an NS5A, ie. most people. Fine if that tx leads to SVR first time round. If it does not then we, and that includes me, are going to have a steep learning curve to deal with our own NS5A RAVS.

dt
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