Hep C Discussion Forum

Canuck · Guru

RE: SOF/VEL and SOF/VEL/VOX

Canuck · Guru

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.

Canuck · Guru

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.

Tig · Admin

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...

Canuck · Guru

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 E¹, Poordad F¹, Wells J¹, Hyland RH², Yang Y², Dvory-Sobol H², Stamm LM², Brainard DM², McHutchison JG², Landaverde C¹, Gutierrez 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.

Canuck · Guru

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

Canuck · Guru

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.

Tig · Admin

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

Canuck · Guru

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.

JimmyK · Guru

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

JimmyK

robertsamx · Guru

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

JimmyK · Guru

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!

Tig · Admin

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

Canuck · Guru

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.

Canuck · Guru

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. 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

Canuck · Guru

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

Canuck · Guru

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

Canuck · Guru

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)
POLARIS-1		1, 2, 3, 4, 5, 6	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)
POLARIS-4		1, 2, 3, 4	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)
POLARIS-2	DAA-naïve 18 percent (174/941) had cirrhosis	1, 2, 3, 4, 5, 6	SOF/VEL	12 Weeks	98% (432/440)
POLARIS-3	DAA-naïve All had cirrhosis	3	SOF/VEL/VOX	8 Weeks	96% (106/110)
POLARIS-3	DAA-naïve All had cirrhosis	3	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.

Canuck · Guru

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.

Malaysia, Singapore, Thailand, Vietnam: Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Participants With Chronic HCV

Spain: Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed Dose Combination (FDC) and Sofosbuvir/Velpatasvir FDC and Ribavirin in Participants With Chronic Genotype 3 HCV Infection and Cirrhosis

Sweden, Russia: Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Participants With Chronic Hepatitis C Virus Infection

New Zealand: Sofosbuvir/Velpatasvir Fixed-Dose Combination in HCV-Infected Adults Who Are Undergoing Liver Transplantation

Spain, Switzerland, UK: Sofosbuvir/Velpatasvir Fixed Dose Combination in Participants With Chronic Hepatitis C Virus Infection Who Have Received a Liver Transplant

Canuck · Guru

Tig found a good update:

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

Canuck · Guru

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. C.

Tig · Admin

Section title changed per your request! Let me know if it is listed according to your wishes.

Canuck · Guru

RE: GT 3's and SOF/VEL trials

Canuck · Guru

Geyawd! Another exhaustively complete one on sof/vel (I should say so! at 60 pages)! Near everything in one nutshell tho ...

http://www.gilead.ca/pdf/ca/Epclusa_pm_english.pdf

Hmmm - maybe this thread title should change, as it has morphed beyond just sof/vel trials for GT 3's, and is on to sof/vel and vox info applying to all GT's!

Sydhanrahan · Guru

Hi Pablo,

thanks for the succinct summary. This woman is just too smart for me. I try to start reading, concentrating really hard, screwing my mouth into what I hope is an intelligently following along expression, nodding wisely periodically but then.... I realise for the last five minutes my eyes have been dutifully scanning the words but my brain has been thinking about feeding the dog or my itchy armpit.

confuse

Syd

ps. Love you Canuck and appreciate all the info you find for us. Xxxx

Pablito · Senior Member

Great stuff Canuck. I think it's safe to say that if one can get prescribed sof/vel/vox, especially so for 12 weeks (instead of 8), you have the best chance of SVR compared to another other regime regardless of your genotype, prior treatment status and cirrhosis level.

Canuck · Guru

One of the earlier (phase 2) sof/vel/vox trials - comparing to sof/vel/vox to sof/vel/riba

When are they going to start using vox versus riba for a triple? We have relapaser's of other DAA's and folk with particularly well suited RAV's waiting!!

download this slide kit - HCV-Trials.com

www.hcv-trials.com/studies/TRILOGY-3/TRILOGY-3.pptx

SOF/VEL/GS-9857: 400/100/100 mg FDC qd. Lawitz E, EASL 2016, Abs. PS021, J Hepatol 2016;64:S146. Design.TRILOGY-3 Study: SOF/VEL/GS-9857 RBV...

Even though this earlier trial result is now "old", as we wait for further data updates on phase 3 results's - note the "sides" - (Vox triple compared to the riba triple) - we see "less"/different adverse side effects, none of riba's blood dyscrasia's. Aside from adverse effects, just based on effectiveness of the sof/vel/vox triple alone (gleaned from other reports) I believe that vox as an added NS3/4A for a sof/vel triple is superior over riba in multiple/different and important ways.

Further (on Lawitz's data):

HIGH EFFICACY OF SOFOSBUVIR/VELPATASVIR PLUS GS-9857 IN PREVIOUSLY TREATED PATIENTS WITH HCV GENOTYPES 1 THROUGH 6

Dr Eric Lawitz presented results from 3 phase 2 trials that evaluated the combination of sofosbuvir, velpatasvir, and GS-9857 (VOX) in patients with previously treated HCV.^1-8 Velpatasvir is an NS5A inhibitor, and GS-9857 is an NS3/4A inhibitor with a superior resistance profile compared with other NS3 protease inhibitors. All 3 DAAs have demonstrated efficacy against HCV genotypes 1 through 6. The single-center, open-label, phase 2 TRILOGY-3 trial enrolled patients with HCV genotype 1 infection previously treated for at least 6 weeks with a DAA.⁹The study design designated enrollment of approximately 50% of patients with compensated cirrhosis. Patients were stratified based on cirrhosis status and prior treatment with NS5A inhibitors. Twenty-four patients received a single daily tablet of sofosbuvir (400 mg)/velpatasvir (100 mg), plus daily GS-9857 (100 mg) for 12 weeks. In 25 patients, this regimen was administered with the addition of weight-based ribavirin. The primary endpoint was SVR12.

Patients had a mean age of 54 years (range, 18-75 years), and approximately two-thirds were male. Approximately 86% of patients had the IL28B non-CC genotype. As planned, half of patients had cirrhosis. The mean level of HCV RNA was 6.3 log10 IU/mL (range, 5.2-7.1 log10 IU/mL). Eighty-eight percent of patients had HCV genotype 1a infection. Previous treatment included an NS5A inhibitor in 41%. Among these patients, 6% had received only the NS5A inhibitor, 14% had also received an NS3 inhibitor, and 20% had received prior treatment with an NS5A inhibitor, an NS5B inhibitor, and an NS3 inhibitor. Among patients who had not received an NS5A inhibitor, prior treatments included an NS3 inhibitor (31%), an NS5B inhibitor (16%), and both (12%).

The overall SVR12 rate was 98%. One patient in the ribavirin-containing arm experienced virologic failure at follow-up week 4. The patient who relapsed was a 61-year-old black man with cirrhosis, who had previously received treatment with ledipasvir/sofosbuvir for 24 weeks. He relapsed after discontinuation of therapy. Baseline analysis for the TRILOGY-3 study showed that this patient had NS5A resistance-associated variants (RAVs), but no NS3 or NS5B RAVs. After relapsing during the follow-up period, the patient was found to have 1 additional NS5A RAV and 4 new NS3 RAVs. In the entire study population, 36 patients (75%) had baseline RAVs. Fifteen percent had NS5A RAVs only, 29% had NS3 RAVs only, and 31% had multiple-class RAVs. Among the 36 patients with any baseline RAVs, 35 (97%) achieved SVR12 (Figure 4). All 12 of the patients who lacked baseline RAVs achieved SVR12.

AEs were common but generally mild-to-moderate in severity. AEs of any grade were reported in 11 patients (46%) in the ribavirin-free arm and in 15 patients (60%) in the ribavirin-containing arm. In the ribavirin-containing arm, there was a single grade 3 AE, consisting of rash that resolved upon discontinuation of ribavirin. There were no permanent treatment discontinuations or deaths during the study. One serious AE of pneumonia occurred in the ribavirin-free arm; however, this patient completed the 12 weeks of DAA treatment and achieved SVR12. Grade 3/4 laboratory abnormalities were more common in patients who received ribavirin (24% vs 4%). Hemoglobin levels of less than 10 g/dL were observed in 6 patients (24%) in the ribavirin arm vs none in the ribavirin-free arm. The most common AEs of any grade in the ribavirin arm were fatigue (36%), anemia (16%), and diarrhea (13%). These AEs did not occur in the ribavirin-free arm.

Dr Lawitz also presented results for treatment-experienced patients enrolled in 2 phase 2 trials that investigated treatment with sofosbuvir, velpatasvir, and GS-9857.¹⁰ Study GS-US-367-1168 included 197 patients with HCV genotype 1 infection; study GS-US-367-1169 included 128 patients with HCV genotype 2 to 6. Both trials included patients with or without cirrhosis, as well as patients who had received prior HCV treatment, including DAAs. Patients with HCV genotype 1 had received prior treatment with an NS5A inhibitor or at least 2 DAAs from different classes. Patients with genotypes 2 through 6 had received prior treatment with pegylated interferon plus ribavirin or any DAA. The 2 studies enrolled a total of 128 treatment-experienced patients, all of whom received 12 weeks of treatment with daily sofosbuvir (400 mg)/velpatasvir (100 mg) plus daily GS-9857 (100 mg).

The 128 patients had a mean age of 58 years (range, 37-77 years), 75% were male, and 82% were white. Approximately three-fourths of patients had the IL28B non-CC genotype, and 48% had cirrhosis. The mean HCV RNA level was 6.3 log10 IU/mL (range, 3.8-8.1 log10IU/mL). Patients had HCV genotypes 1 (49%), 2 (16%), 3 (27%), and 4 or 6 (7%). Prior DAA treatments included 1 DAA class in 28% and 2 or more DAA classes in 51%, and 27% of patients had received prior treatment with an NS5A inhibitor. Twenty-one percent of patients had received prior treatment with pegylated interferon plus ribavirin but no prior DAA treatment. Among the 66 patients (52%) with prior non-NS5A DAA treatment, 24% had received prior treatment with an NS5B inhibitor alone. Another 24% had received treatment with an NS5B inhibitor and an NS3 inhibitor. The remaining 4% of patients had received treatment with an NS3 inhibitor, an NS5B nucleotide polymerase inhibitor, and/or an NS5B nonnucleotide polymerase inhibitor. Among the 35 patients (27%) who had received prior treatment with an NS5A inhibitor, 11% had received prior treatment with an NS3 inhibitor and an NS5A inhibitor, with other combinations accounting for the remaining patients, including
1 patient who had failed all 4 classes
of DAAs.

At baseline, 77 patients (60%) had RAVs, and 76 of these patients (99%) achieved SVR12. The 1 patient who failed to achieve SVR12 was infected with HCV genotype 3 and relapsed at follow-up week 8. Among the 51 patients (40%) without baseline RAVs, 51 (100%) achieved SVR12. Among the 77 patients with baseline RAVs, 76 achieved SVR12 (99%; Figure 5). In the entire study group, SVR12 was reported in 100% of patients with HCV genotype 1, 2, 4, or 6 and in 97% of patients with HCV genotype 3. Subgroup analysis showed that the presence or absence of cirrhosis did not affect the likelihood of achieving SVR12. Similarly, prior treatment had no apparent impact on the likelihood of achieving SVR12. The single patient who experienced virologic failure had HCV genotype 3, was cirrhotic, had no prior NS5A exposure, and had been exposed to 1 class of DAA therapy prior to study enrollment.

Sixty-five percent of patients experienced an AE of any grade. Two patients (2%) experienced a grade 3 AE, and 2 patients (2%) experienced a serious AE. One patient (<1%) discontinued treatment due to an AE considered unrelated to study treatment, and 1 patient (<1%) died from a presumed sudden cardiac arrest 14 weeks after completing the study. Eleven patients (9%) had grade 3/4 laboratory abnormalities without clinical consequences. The most common AEs were headache (22%), diarrhea (19%), fatigue (20%), and nausea (14%).

-- Edited by Canuck on Saturday 17th of September 2016 05:38:24 PM

Canuck · Guru

Still not much data out there about that NS3/4A "VOX" yet (as far as it starting to be used along with sof/vel, versus just the folks getting it via trials), but, here is some more about it's "interactions":

B. DRUG INTERACTIONS

1. DDI with Voxilaprevir (GS-9857)

SOF/Velpatasvir/Voxilaprevir (VOX) is a three-drug fixed dose DAA combination being evaluated in Phase 3 trials. In vitro, VOX is a substrate for CYP3A4, CYP2C8, the OATP uptake transporters and the efflux transporters P-gp and BCRP. VOX is also an inhibitor of P-gp and BCRP in vitro. Dr. Kirby presented drug interaction studies with VOX (Abstracts #O_24 and #O_25). Tables below show results of VEL as a victim and perpetrator in interactions. Results indicate VOX is very sensitive to hepatic inhibition of OATP transporters, so coadministration of VOX with potent OATP inhibitors is not recommended.

Inhibitors of CYP3A4, CYP2C8, and P-gp are likely okay with VOX. As with all HCV treatments, interactions with HMG-CoA reductase inhibitors (statins) must be considered with a potential need to change statins or use a reduced dose of the statin. It is likely based on these data that VOX will have problematic interactions with efavirenz and HIV protease inhibitors.

http://regist2.virology-education.com/2016/17HIVHEPPK/40_Kirby.pdf

voxPerp

Canuck · Guru

2 WEEK PCR's

A study, and then a doc's comment at bottom, reflecting on any importance attached to a 2 week PCRs data in older regime(s) study: (Another feather in the cap alluded to for the new world of sof/vel!)

Clinical value of on-treatment HCV RNA levels during different approved sofosbuvir-based antiviral regimens.

Maasoumy B., et al.
J Hepatology 2016 ; April 13 (Epub ahead of print)

Background & Aims : EASL guidelines recommend HCV-RNA measurements at specific time-points during sofosbuvir(SOF)-therapy. However, it remains unclear, how these results should be interpreted. We aimed to analyse whether on-treatment HCV-RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays.

Methods : Samples were collected from 298 patients(HCV-genotypes; GT1-5) at weeks(w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two University clinics and tested for HCV-RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin(RBV) 12/24w (n=99), pegylated-interferon-alfa(Peg-IFN)/SOF/RBV 12w (n=51), SOF/simeprevir(SMV)±RBV 12w (n=69) or SOF/daclatasvir±RBV 12/24w (n=79).

Results : HCV-RNA levels during the first 4 weeks of SOF/RBV-therapy were significantly lower in GT3-patients who achieved SVR compared with those who relapsed. All GT3-patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with >45IU/ml(p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR:100% vs. 29%;p=0.0002). In contrast, HCV-RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens. Residual HCV-RNA was frequently detected by ART at later stages of therapy. However, SVR-rates remained high in these patients. At the end of SOF/SMV±RBV6 therapy HCV-RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR.

Conclusions : HCV-RNA levels assessed at week 2 of SOF/RBV-therapy can predict relapse in GT3-patients. Detectable HCV-RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension.

Expert's Commentary

The practical impact of this paper is not marginal. For years we have been using on- treatment viral kinetics to individualize IFN-based treatment duration for our chronic HCV infected patients. Now, with the use of Direct Antiviral Agents the meaning of this predictor can be considered insignificant. The only exception seems to be presented in this study identifying, in patients with genotype 3 infection a week 2 HCV RNA >45 IU/ml by Cobas Ampli Prep/CobaseTaqMan or >60 IU/ml by Abbott Real Time, as predictive of relapse. This result appears of immediate utility, although with the arrival of new and more potent combinations for treatment of genotype 3 patients, such as the combination of velpatasvir and sofosbuvir, the week 2 prediction can be expected to be less relevant. Interestingly, the study clarifies also the issue of a residual viremia at the end of treatment. Until now no systematic evaluation of this observed phenomenon was available. Detectable HCV RNA below the quantification threshold, at the end of the established treatment duration can be observed in up to 20% of patients receiving oral antivirals. According to the study results, we should not consider a residual viremia as predictive of relapse. As shown in this study, in 92% of subjects this residual HCV RNA was not followed by a relapse and should not generate attempts to extend treatment duration.

Alessandra Mangia, San Giovanni Rotondo, Italy

Canuck · Guru

Yawn. Ho-hum. Here's some already stale "stock" talk ... still no new riveting new news on VOX! Mildly interesting tho - SOF/VEL patent to 2032, as is the "guess" that VOX and VEL really were created "in-house", and that sof/vel is a good buy for countries 'cause they will save a bundle, because of no GT'ing required? And, just when is this triplet VOX "salvage" thing ever going to be rolled-out?

For hepatitis C

1. Sofosbuvir/velpatasvir (SOF/VEL)

This has a patent expiry of 2032 for both the US and EU.

I look at this as a breakthrough, first-in-class product that may be receiving insufficient attention from analysts. It has a PDUFA date of June 28. The cure rates even for genotypes that are notoriously difficult to treat, such as genotype 3, are impressive (95%).

In addition to being first-in-class, perhaps time will also show it to be best in class.

GILD's main speaker at the Merrill Lynch conference, EVP Paul Carter, volunteered that this is going to be a very important product for developing countries, most notably China. His comments indicated that GILD is hard at work getting SOF/VEL to the Chinese market ASAP.

The benefit of SOF/VEL is that once HCV is found to be chronically infecting a patient who will benefit from cure, nearly everyone can just take one pill a day for 12 weeks with a high chance of cure. This is going to be transformative for parts of the world with limited scientific and/or financial resources, as patients can be treated with no genotyping needed.

Also, within the developed world, certain important genotypes (mainly types 2 and 3) will be treated with SOF/VEL rather than (usually) Sovaldi and accompanying drug(s). Whether this replacement of Sovaldi by SOF/VEL will have much economic benefit to GILD is unclear.

However, maybe a marketing benefit could be bundling SOF/VEL with anything ranging from access, or preferred access as appropriate, to Harvoni and/or SOF/VEL for genotypes 1 and 4. It's these genotypes where the real competition with AbbVie's and Merck's (NYSE:MRK) products occurs. In return, a lower price on SOF/VEL could be offered.

In any case, the key with this combo is that it opens up vast numbers of patients globally to treatment with a GILD product.

Velpatasvir, the "VEL" in the combo's current name, was developed in-house at GILD to my knowledge.

2. SOF/VEL plus voxilaprevir (formerly GS-9857, voxilaprevir is a pan-genotypic protease inhibitor)

Mr. Carter went into the rationale for developing this product. He noted that protease inhibitors are prone to have additional side effects. He offered up the standard GILD points that safety and efficacy, not duration of treatment, is what the regulators care about, and more or less the only things they care about. So, GILD is thinking of this triplet as salvage therapy, for difficult cases, etc., but with potentially shorter treatment courses.

For those keeping score, I do not recall GILD acquiring GS-9857, but I could be wrong. For now I'm thinking of it as yet another anti-viral that has been discovered internally.

Tig · Admin

Good question! That was as clear as mud.... smile

Canuck · Guru

Oh, for the love of plain English!!

VOX and P450 inhibitors/inducers

http://www.natap.org/2016/Pharm/Pharm_54.htm

Sheesh, grapefruit or NO grapefruit, 'fer pet's sake! C.

Canuck · Guru

GT 3's and SOF/VEL trials - and, SOF/VEL/VOX, and Epclusa roll-out (for all GT's 1-6, and "relapse rescue").

Tig · Admin

RE: GT 3's and SOF/VEL trials

wendyo · Guru

Sure SF...

I can't find the exact article but here is something very similar:

http://www.drugchannels.net/2016/08/seven-takeaways-from-new-2017-cvs.html

Shadowfax · Guru

Great post Canuck!

It's good to see that Epclusa is getting on the momentum program and $60,000 at least is going in the right direction.

Lisa

I am glad to see the drug companies being challenged and especially when some tax payer money helped fund them. I wonder how many other countries will not recognize Gilead's patent on their drugs. I realized they need to recoup their R&D money but selling 100 x more drugs at lower costs will still get them there and wipe of the disease.

Wendy,

Is that list available? Could you possibly post a link to it?

Have a great weekend everyone.

SF

wendyo · Guru

On a similar note, in our local news today there was an article on which drugs CVS and Express Scripts will not cover in 2017 and many of the HCV treatments were on there but it did list what they are replaced with and they listed many of the new protocols, which I was glad to see.

Loopy Lisa · Guru

I was reading yesterday that Hilary Clinton has challenged drug companies over their prices, naming specifically Gilead and their Hep C drugs. Tax payers money help fund their research and they repay us with huge prices on top. These huge profits are stopping a universal cure for a disease that is now effectively is easy to treat and cure. I am pretty happy to hear this is now being targeted. I know there are many countries still not able to access these simple life saving drugs and we are effectively and there is no justification. Lets hope something is done about it now...

Canuck · Guru

More about Epclusa (in Canada) for GT 1-6 - hmph, riba reccomendations! - what going to happen to that VOX they trialed?

Here is how Epclusa is meant to be used for different types of HCV-associated liver disease:

people who have chronic HCV infection without cirrhosis (severe scarring of the liver) or who have compensated (symptom-free) cirrhosis - one tablet taken once daily with or without food for 12 consecutive weeks
people who have chronic HCV infection and symptoms (decompensated) of cirrhosis - one tablet taken once daily with or without food for 12 consecutive weeks. The antiviral drug ribavirin must also be taken. Ribavirin is taken twice daily with food, also for 12 consecutive weeks.

Summary of important safety information

Before starting a new medication, always speak to your doctor, nurse and pharmacist about its potential interactions with other drugs (such as prescribed and over-the-counter medicines, supplements and herbs). These healthcare providers can tell you how to take Epclusa safely.

Here is some limited safety information:

The drug amiodarone is used to treat abnormal heart rhythm. Gilead does not recommend that people who are taking amiodarone also take Epclusa, as this can result in reduced heart rhythm (slower rate of heart beats; bradycardia). This can be dangerous. If patients taking amiodarone have no alternative to using Epclusa, Gilead recommends that doctors order cardiac monitoring in people who take these medicines together.
Epclusa contains velpatasvir. The HIV drug efavirenz (Sustiva, Stocrin and in Atripla) reduces the amount of velpatasvir in the blood. Therefore, efavirenz users should not take Epclusa.
The herb St. John's wort (or its active ingredients hypericin and hyperforin) should not be used with Epclusa, as it can lower levels of both sofosbuvir and velpatasvir.

Access to Epclusa - (only in Canada you say??) as usual ... every Province will be different!

After Health Canada licenses a drug, physicians can prescribe it but patients must pay for it themselves unless they have a private insurance plan that covers it. It may take weeks or months for such coverage to take effect after licensure. In the months ahead, Gilead Sciences and provincial and territorial formularies will be negotiating the price of Epclusa ...

... in Canada, provincial and territorial ministries of health heavily subsidize the cost of anti-HCV medications. Each ministry has a listing of drugs for which it is prepared to pay. These listings are called formularies. Formularies can also place restrictions on who can access the drugs they are covering.

... In the months ahead, Gilead Sciences and provincial and territorial formularies will be negotiating the price of Epclusa. Your pharmacist, nurse or doctor can tell you when Epclusa is listed on your region's formulary.

The wholesale cost of Epclusa in Canada is about $60,000 for a 12-week course of therapy. Pharmacies in Canada can anticipate being able to order Epclusa from wholesalers by mid-August 2016.

The pharmaceutical company has stated: "To assist eligible HCV patients in Canada with access to Epclusa, Gilead Canada has added Epclusa to the Gilead Momentum Support Program, which provides information to patients and healthcare providers to help ensure patient access to medication." Patients who may be interested in the use of Epclusa should first speak to their healthcare provider. For more information regarding the Momentum Support Program in Canada, call 1.855.447.7977.

Only in BC you say? Check it out - "approved" does not mean "available", to all people, in every Province. Apparently I could, between Aug 24 and Sep 21 lobby BC Pharmacare to say, "Yes, please - make Epclusa available via Pharmacare in BC" - that doesn't mean that Epclusa would then be available to me or anyone anytime soon! Even today, I (as a "former" GT 3a, I love saying that BTW - "former"!)) I would still not be able to get even Daklinza easily! I have watched Daklinza stalled in BC Pharmacare since at least July of 2015! Good grief, GT3's still wait (along with all the other 1 thru 6 GT's that Epclusa could be helping today)! Hm, let's hope they work out the MONEY part of our liver problem, sometime soon!

http://www.hepctip.ca/wp-content/uploads/2016/08/August.png

-- Edited by Canuck on Thursday 18th of August 2016 05:47:18 AM

Linuxter · Guru

Not to worry Tig,

Yesterday you were only as "Old as Dirt" ...

it's today that you're actually "Older Than Dirt" ... so you got at least a whole day's reprieve there.

Dave

Cheddy · Moderator

Happy birthday season Tig. There's still time for cake, though the bon fire and the ice cream may have messy results.

Just wanted to say, I'm glad you were born. biggrin Really am.

RAGDOLL · Senior Member

Hey Tig, Happy Birthday, welcome to the 60 + Club. Hope you had a great day. Chris

wendyo · Guru

Happy Birthday Tig

Convention was in my area so just gone for the day/night

Tig · Admin

"OLDER THAN DIRT"? Boo Hoo, Hoo.... I'm silently weeping in my bonfire of candles on my non existent cake, lol! I didn't even get a darn cake! I asked for a DQ ice cream cake and the blasted place was out! How dare they! Do they not realize the importance of this day? I hope you will be kind enough to find one and send it. Overnight FedEx and dry ice should do the trick, ha, ha!

Respect and deference is always foremost in my thoughts, especially when it is followed up with a nice DQ Toffee ice cream cake! YUM, YUM, YUM..... biggrin

Canuck · Guru

Wendy,

Back so soon! Glad it was good.

Are you trying to be nice to TIG because it is his birthday (that's the rumour anyway) and because he is wise, benevolent and older than dirt?

I figured out that that is why you complimented him with that "TYG = Thank you God". hee hee

Tig, I will have you know I am your senoir and as an elder I expect some respect and deference man. wink hee hee - wheee!

Tig · Admin

Thanks Canuck! LOTS of good information and will be a great resource. That will be a "multi cup" of coffee reading assignment! We are all grateful for your persistence smile

wendyo · Guru

Dave you will be pleased to know I did not eat any doughnuts and drank more water than coffee lol.

Had a great time with my other family. Worked registration, saw lots of old friends and heard 2 great speakers. Canuck, one was from Canada! Saw 2 of my counselors from when I was in treatment 25 years ago. (they all had bets I would never make it) I am beyond blessed to have this community as well as that one in my life. TYG = Thank you God!

Canuck · Guru

Wendy, I've been to 3 different kinds of AA meetings, I did not go exactly for the usual reasons some people might go, but I wanted to go and did, and was warmly welcomed. It was a really good learning thing for me, and an eye opener, a very good positive encounter. I quickly was awed at the depths of us, in all our glory of strengths, sober honesty and humbling weaknesses. I never so quickly bonded, related, cried and laughed with a group of people faster with these 3 different groups who were as diverse as any group can be. I gained immediate respect for people who were struggling and winning. I benefited for it and learned a lot. I was so impressed by this group of people, much like how I am impressed by this group of people. C.

Canuck · Guru

Hey,

That link about VOX that I was trying to make work before, NOW, it does work, but, after you click on the link "Journal of Viral Hepatitis" to get to the journal, then you have to scroll down and click on the first "article" listed there (to open it and read it) ...

Journal of Viral Hepatitis

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1-4 Infection

A Randomized, Double-blind, Dose-ranging Phase 1 Study

M. Rodriguez-Torres; S. Glass; J. Hill; B. Freilich; D. Hassman; A. M. Di Bisceglie; J. G. Taylor; B. J. Kirby; H. Dvory-Sobol; J. C. Yang; D. An; L. M. Stamm; D. M. Brainard; S. Kim; D. Krefetz; W. Smith; T. Marbury; E. Lawitz

Disclosures

J Viral Hepat. 2016;23(8):614-622.

Linuxter · Guru

Have a safe trip and do enjoy the convention Wendy

I'm picturing 748000 gallons of coffee and at least that many donuts on a HUGE table toward the back and a Serenity Prayer that can be heard as far away as Cleveland, OH smile

Dave

Hep C Discussion Forum

**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

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

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

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

- U.S. NDA Planned for Q4 2016

download this slide kit - HCV-Trials.com

HIGH EFFICACY OF SOFOSBUVIR/VELPATASVIR PLUS GS-9857 IN PREVIOUSLY TREATED PATIENTS WITH HCV GENOTYPES 1 THROUGH 6

Sofosbuvir / Velpatasvir (American Brand Name Epclusa)

Sofosbuvir / Velpatasvir in Canada

Clinical Trial Results for Sofosbuvir / Velpatasvir

Summary of important safety information

Access to Epclusa - (only in Canada you say??) as usual ... every Province will be different!

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1-4 Infection

A Randomized, Double-blind, Dose-ranging Phase 1 Study

Legal Disclaimer:

Hep C Discussion Forum

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

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

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

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

- U.S. NDA Planned for Q4 2016

download this slide kit - HCV-Trials.com

HIGH EFFICACY OF SOFOSBUVIR/VELPATASVIR PLUS GS-9857 IN PREVIOUSLY TREATED PATIENTS WITH HCV GENOTYPES 1 THROUGH 6

Sofosbuvir / Velpatasvir (American Brand Name Epclusa)

Sofosbuvir / Velpatasvir in Canada

Clinical Trial Results for Sofosbuvir / Velpatasvir

Summary of important safety information

Access to Epclusa - (only in Canada you say??) as usual ... every Province will be different!

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1-4 Infection

A Randomized, Double-blind, Dose-ranging Phase 1 Study

Legal Disclaimer:

**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