TOPIC: Prof Ed Gane's remarks: implications for Twinvir

The remarks attributed to Prof Ed Gane on NZ radio recently that “there's a lot of concern about drugs coming out of Bangladesh at the moment” may cause some alarm and apprehension to, amongst others, those like me who are using Incepta's Twinvir – which comes from Bangladesh. Prof Gane's alleged remark about “concern about drugs coming out of Bangladesh” does not identify Twinvir by name, and is certainly not limited to Twinvir, but seems wide enough to include Twinvir.

How can anyone using Twinvir set their minds at rest that Prof Gane's remarks are groundless at least as far as Twinvir is concerned? At the moment I can think of only two ways. First, is there currently any reliable evidence that someone – anyone - has actually achieved SVR12 (or failing that SVR4) through the use of Twinvir? (Bearing in mind I am not sure if Twinvir has yet been on the market long enough for the period of 12 weeks treatment plus 12 weeks of post-treatment for a Twinvir-user to get to SVR12.)

Secondly, is there anyone of a scientific background who can confirm as scientifically correct the point attributed to Prof Ed Gane that a chemical may be confirmed as genuine Ledipasvir in a laboratory test but still not be effective as a medicine against the virus because it is not in the necessary “active, crystalline form”?

I tentatively suggest that anyone on this forum using Twinvir, or any other generic covered by Prof Gane's remark, could help each other by sharing information on their post-treatment results - whether that be SVR4 or SVR12, or relapse.

Hi Thurl

I finish my 12 week course of Sof/Led on Thursday and will post my 4 week post treatment results once I have them. Apprehensive but hopeful.

Cheers Lynne

Hello Thurl,

Twinvir was launched on 27th of August. I launched the product. Patients started using this medicine from September earliest. SVR 12 is measured 12 weeks after treatment cessation. So no, there hasn't been sufficient time to measure to SVR12 is any patients. But there are a number of patients who had been undetectable viral load during treatment. You are taking Twinvir. Have you measured your viral load during this time. What is your viral load status? I haven't read the comment of the New Zealand doctor. Can you share the link with me?

Asif, here is the link and also a link to another relevant post on here with some text

www.radionz.co.nz/national/programmes/ni...tis-c-buyers%27-club

(Prof Gane speaks near the end of the sound file at the bottom of the page)

Also some text here: fixhepc.com/forum/media-news/656-prof-ed...nine-to-noon-nz.html

Twinvir launched on the 27th August 2015, so there are patients past SVR4 but not SVR12. The first SVR12 results will appear in mid March.

My first patients started on it mid November. All were viral load zero within 4 weeks.

Prior to using it we tested Twinvir at the NATA accredited National Measurement Institute. If you search the certification documents for Sofosbuvir and Ledipasvir for the word Twinvir you will see that testing noted. You can find those certification reports here:

fixhepc.com/blog/item/16-testing-provisions-patient-safety.html

We did RVR testing on Twinvir during the period 20-28 November and observed excellent clinical effects with the worst 1 week viral load drop being 1,200,000 -> 636 (F3), the best being 2 million to undetected.

If you read the TGA submission here:

www.tga.gov.au/file/8444/download

You will find it stated that:

Ledipasvir is practically insoluble (<0.1 mg/mL) across the pH range of 3.0-7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL). The partition coefficient (log P) for ledipasvir is 3.8 and the pKa1 is 4.0 and pKa2 is 5.0.

This is why you must have stomach acidity to absorb it - without that it won't dissolve well. Once it is dissolved it's not in a crystalline form and will be absorbed. The normal volume of the stomach fluid is 20 to 100 mL and the pH is acidic (1.5 to 3.5) so I'm actually quite surprised it is not without food (to increase the acidity) but as you will read in the auspar document it still gets absorbed in the presence of food.

If you read Gilead's submission to the European Medicines Agency here:

www.ema.europa.eu/docs/en_GB/document_li...3850/WC500177996.pdf

On page 8 you will find Gilead stating:

Three crystalline forms are known and ledipasvir acetone solvate is the designated commercial form. The first step for finished product manufacture involves the dissolution of ledipasvir in ethanol followed by spray-drying and thus precise control of morphology and particle size is not considered important.

Ledipasvir acetone is what Twinvir uses.

On the topic of crystalline forms most people don't know that Gilead tested crystalline Form-I Sofosbuvir but substituted Form-II in the commercial product. See page 12 here, and note that the AUC data in the commercial product is inferior to what was trailed.....

www.tga.gov.au/file/6066/download

We will be publishing generic SVR results at EASL if our abstract is accepted. The are no nasty surprises in it.

To have someone like Prof Gane speaking publicly about sourcing and using generics is an extremely strong endorsement of what Dr James is doing. Yes, there is the usual institutional caution - don't forget he is speaking as both individual specialist, but also as a representative of the NZ health service. So it is quite correct that he should voice some reservations about the authenticity of medications that have not been approved by MedSafe.

The only remark that I found difficult to accept was the notion that someone *might* achieve a SVR under generic versions of Sofosbuvir plus Ledipasvir but then in some way be more likely to rebound if they had taken a sub-standard version of Ledipasvir.

This seems to suggest that one can have UND (meaning undetectable because there absolutely no virus to detect), and UND meaning still some virus remaining (but an undetectable amount) which also has some "memory" that the Led taken was sub-standard. This seems to me to be arguing about what might happen with some tiny handful of hypothetically-still-existing virus particles which somehow might "know" what they are allowed to do next...

Last virus particle #1: Shoot, where has everyone gone?

Last virus particle #2: They just got zapped by a sub-standard version of of Ledipasvir. We're the only two left.

Last virus particle #1: It was sub-standard? Ok, let's start replicating again then.

Last virus particle #2. Urghhh.

Last virus particle #1. What was that?

Last virus particle #2. An antibody just ripped my head off. So long...

Last virus particle #1. Oh no, another antibody... Self-destruct in T-5 seconds...

If one gets down to UND during treatment, then surely the Sof+Led combo has done the job regardless of their crystal forms, and the usual SVR projections with the usual margins of error should apply?

Vororo, thanks so much for your comment, the chemistry is beyond my education. That scenario of generic Ledipasvir leading to relapses is a very scary one and I would love for it to be a fantasy/scare mongering. My specialist told me reaching UND would be a big test of the generic meds. Well I crossed that bridge at 4 weeks, now we have NZ's most prominent specialist suggesting it might unravel. What about the theory that taking Sofosbuvir alone might lead to UND, which he seems to suggest?

Thanks Lynne. It seems you are not much further ahead in treatment than I am. I will finish my 12-week course of Twinvir on Saturday. I will also post my results EOT. The best way to rebut Prof Gane is to show that that people using generics containing unlicensed Chinese-made ledipasvir (which seems to be the generic drug Prof Gane is most concerned about) can achieve SVR rates comparable to the equivalent branded medicines. People on the branded medicines, as well as people on generics (licensed and unlicensed), can relapse and no-one is expecting the generics to actually do better than the equivalent brand medicines. So stories of occasional relapse on generics do not call into question the efficacy of generics any more than occasional relapses on brands call into question the efficacy of the brands. What matters is to establish an overall picture of SVR rates for generics, particularly the unlicensed generics, which is comparable to the brand versions; that can only emerge if generic-users share their post-treatment results, whether as part of a formal study, as I understand Dr Freeman's to be, or not.

Asif – thanks for your post. My on-treatment results have been fine. Pre-treatment my VL was 1.8 million with ALT 176 and AST 106 . By week 4 of treatment my VL was undetected and my ALT and AST were both back in the normal range. At week 8 of treatment I remained VL undetected. However, according to Prof Gane little reassurance can be obtained from on-treatment results. What matters is the post-treatment results. This is because where ledipasvir is combined with sofosbuvir, which it usually is, Prof Gane says the sofosbuvir may be effective while the ledipasvir is not. In this situation, according to Prof Gane, the sofosbuvir alone can maintain viral-suppression as long as treatment is maintained but when treatment is finished if the ledipasvir component of the medicine was ineffective the virus will then spring back causing relapse.

Chapel - thank you for posting the link. I agree with you that Prof Gane's remarks seem to suggest that one way to respond to relapse - should it happen - is to go on permanent, lifelong sofosbuvir treatment, which alone should be enough to maintain viral suppression, if not cure - a bit like I understand that HIV patients take permanent, lifelong viral suppression medication. Is this correct? Could this be a way of dealing with relapse?

It sounds like scare tactics to me. They haven't tested the meds and are commenting on the possibility of them not being up to snuff. If they haven't tested the meds it doesn't seem to be very scientific on their part. You'd figure a knowledgable expert would do some clinical research before speaking about possible problems. Twinvir has been tested here and passed. Lesovir-C is made by Beximco and they are a drug company with FDA approval. Hmmmm. I guess we will all have to wait and see.

I once asked Rachel at Mesochem if she sold simeprevir and if so, what was the price. Her response: "We sell simeprevir, but not simeprevir sodium". Turns out plain old simeprevir can't be absorbed by the body. It has to be processed further into "simeprevir sodium".
I think the Mesochem ledipasvir is perfect. So is the dac. Some people have far different reactions to meds than others. I took generics for four weeks, then switched to Harvoni-no difference. The generics nailed the virus in four weeks-just like many if you are seeing or about to see. I can't be used as a reference because I finished up with Harvoni. Not because of worries about generic quality, but because I had fought my ass off for two years to get them
Why would a company like Mesochem go to the trouble of making something so complicated and not make it right?
I think Gane is a "company man" giving us the "company line". They can't attack our system, so they attack the medicine. In a very few months, they will lose that opportunity when all the SVR 12 tests start rolling in. This is Gilead's Battle of the Bulge- their primary weapons are fear and disinformation.
Its a long way from Arkansas to NZ, but fear-mongering seems to work wherever its practiced.
M

Hi Chapel,

I don't remember what prof Gane said about Sofosbuvir alone and rebound after SVR. I don't have time to listen again to the broadcast. But here is an earlier post from Dr James on log kill and treatment failure mechanisms:

fixhepc.com/forum/resistance/164-resista...lure-mechanisms.html

The key is to zap the virus as quickly as possible with a high log kill in the first weeks. Then even if "UND" might mean a few undetectable stragglers remain, a few more weeks of treatment would guarantee that they also eventually get whacked. I imagine that if someone gets UND on Sof alone, then there would only be a risk of rebound if the UND appeared right at the end of the treatment. So this is why a dual DAA combo is always recommended, and why triple or even quad-combos (3-week treatment) is the way of the future:

fixhepc.com/forum/media-news/512-raymond...g-generics.html#6378

If 3-weeks of quad-DAA really is enough, it seems to me that this must mean reaching UND in just a few days!

So if you or Lynn are at UND after 4 weeks on dual-DAAs, it seems a pretty safe bet that you can now relax and enjoy the show...

The Stats may be slightly behind on Generics everything I have read/seen about these drugs suggests if you
reach Undetected by week/2/4/6/8/10/12 you have a 98% chance of being SVR at 12 weeks post treatment.

Look at the results thus far, most if not all of those on Twinvir are UD by week 12 at the latest, if Sob was
the only ingredient working we would see about 30% not reaching UD at all throughout the 12 weeks.

So, the suggestion that Sob alone is keeping the virus UD during treatment leading to failure post treatment
is not within any research I have read at all.

Thurl, my understanding of those who fail treatment is you re-treat them I have never heard of anyone yet having to do
life long suppression treatment I guess for the small % who fail its an option.

Prof Gane's fields of expertise are hepatology and virology not API molecular chemistry and manufacturing. He will be receiving advice about those aspects as do all experts about related but non core areas. As he is an intelligent man with some knowledge that advice will need to be plausible for him to heed it and issue a warning. But plausible does not equal correct and may be applicable in some instances but not others.

The comment about needing sophisticated facilities to manufacture Ledipasvir sounds about right. However, mentioning that in the same interview as expressing concerns about some Chinese manufactured drugs does not mean that Mesochem is incapable of producing quality Ledipasvir.

I understand little about chemistry and chemical makeup. There surely must be a way to take a sample of Mesochem ledipasvir and determine, beyond any doubt, its exact properties. I understand it has been analyzed many, many times, but Gane obviously is sowing doubt about the results.
REDEMPTION is testing its efficacy.
M

As Doctor James said by nature Doctors are conservative for our good do you think Dr James would write a script for something he didn't have confidence in or the Compounding Pharmacies which are registered Australian Businesses would distribute meds they are unsure about They are all tested look at the massive HCV viral destruction going on here these meds are the real deal Professor Gane and rightly so is just exercising caution but also appears encouraged by FixHep C result. my take anyway.