You did it Canuck! And thank you. You put so much into this (not just this article but in general) for everyone and it is appreciated. 

I started to read it and will have to revisit it. Lots to take in! 

Enjoy your weekend. I am headed to the 60th FL State Convention for AA. (my other family)

Hiya Canuck,

The link wants a sign-in.

Is it possible to quote the article?

Thanks for digging through the data to bring us these helpful morsels.

Linux

Thanks for all your work for us, Canuck.

Syd

Thanks Canuck! Very promising news. Now if we can just see Big Pharm climb on-board and all of the regulatory agencies approve it. It's amazing how much it actually costs to provide these medications when money isn't the primary objective.

Sof/Vel - Current/Future pricing?

Novel HCV DAAs could be mass-produced under $90 per person

July 26, 2016

If international donors place larger orders, novel direct-acting antivirals to treat hepatitis C could be mass-produced for under $90 per person, according to data presented at AIDS 2016.

"A course of treatment to cure hepatitis C could be mass produced for under $90 per person, if we can follow the same methods of production used to treat 17 million people with HIV/AIDS using antiretrovirals," Andrew Hill, PhD, senior visiting research fellow in the pharmacology department at Liverpool University, told Infectious Disease News. "For this to happen, we need international donors or national health authorities to place large orders for treatment. We would need orders for at least 1 million courses of treatment to achieve the $90-unit price."

Andrew Hill

Novel DAAs can achieve sustained viral response rates above 90%, according to Hill and colleagues. However, the lowest price for a 12-week course of Sovaldi (sofosbuvir, Gilead Sciences) is $324 and "access" prices are available in countries only covering 50% of the worldwide epidemic, they said.

To measure how prices for novel DAAs are beginning to fall, the researchers extracted data from the first half of 2016 on the per-kilogram prices of exported active pharmaceutical ingredient (API) and exported volumes and determined per-pill API costs according to daily dosage. They estimated a cost of $0.04 per pill for formulation and excipients, $0.35 a month for packaging and a 50% profit margin.

They found that the total exports from India during this period were 10.2 tons of sofosbuvir, which is equivalent to 303,000 12-week treatment courses; 5,443 kg of Daklinza (daclatasvir Bristol-Myers Squibb), which is equivalent to 1,080,000 courses; and 240 kg of ledipasvir (Gilead Sciences), which is equivalent to 32,000 courses.

API prices decreased during this period. At the end of May 2016, the API price was $1,094/kg for sofosbuvir, $998/kg for daclatasvir, $2,441/kg for ledipasvir and between $8,900 and $11,700/kg for velpatasvir. Prices in the United States were 1,355 times higher than the target price for sofosbuvir, 4,500 times higher for daclatasvir, 984 times higher for Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) and between 346 and 413 times higher for Epclusa (sofosbuvir/velpatasvir, Gilead Sciences).

Overall, 12-week treatments of sofosbuvir can be manufactured for $62, sofosbuvir plus ledipasvir for $96, daclatasvir for $14 and sofosbuvir plus velpatasvir for between $181 and $216, all of which include a 50% profit margin.

"Currently, less than 1 million people are being treated for hepatitis C worldwide, according to our analysis of exported raw materials," Hill said. "By contrast there are an estimated 2 to 4 million new infections with hepatitis C each year. So unless we increase the numbers of people treated, the epidemic of hepatitis C will continue worldwide." - by Will Offit

Reference:

Gotham D, et al. Abstract A-792-0516-01639. Presented at: AIDS 2016 Annual Meeting; July 18-22, 2016; Durban, South Africa.

EPCLUSA and VOX

Gossipy stuff / Marketing type interview ...

GILD's plans for its HCV treatments: clear and concise

The company's EVP and CSO, Norbert Bischofberger, presented last week at a Goldman Sachs (NYSE:GS) conference. One of his comments about GILD's HCV plans was quite revealing. He said:

That is the end of the development [of HCV drugs for GILD]. I mean, there will always be some more studies that you do for a commercial product to look at different patient populations or elderly or pediatrics we're still doing that, but we actually stopped hepatitis C drug discovery about two years ago. We moved everybody in research from hepatitis C on to hepatitis B. And because we simply don't see what the additional needs there are. If you have one pill that's very safe you can treat somebody for eight or 12 weeks and you get cure rates of close to 100%, but that's a difficult thing to improve upon.

That's pretty clear, and beyond that, it looks to me as an almost direct challenge to J&J's (NYSE:JNJ) plans to enter this field (As a relevant aside, I think that JNJ should see if it buys GILD at some low price).

He also confirmed GILD's goal is to use its SOF/VEL combo (Epclusa will be the trade name) internationally for countries or regions where genotyping is not readily done, for cost and/or technical regions.

The questioner asked him to clarify the plans for GILD's three-drug HCV combo (sofosbuvir, velpatasvir and voxilaprevir = SOF/VEL plus a protease inhibitor), in this exchange:

 

Terence Flynn

Okay, fair enough. Separately you are conducting a Phase 3 program with a triple combo, maybe just remind us of the target profile here and then again where this drug will be positioned given what we just discussed.

Norbert W. Bischofberger

Yes, so what we're pursuing our Phase 3 studies with a triple combo in HCV is two populations, one for frontline therapy with eight weeks treatment duration in everybody without viral load cut off and the second I think that's the more important application, it is a universal salvage regimen. So you could use this drug if you have failed other direct acting antivirals you have acquired resistance mutations like in the NS5A or in the protease you could use this drug. And if of course if the Phase 3 would support that and you would then be able to achieve cure rates, high cure rates.

It appears from ClinicalTrials.gov that the Phase 3 studies could be completed by Q1 next year, thus if successful, the three-drug combo could reach the market in H1 2018.

GILD is pulling a Larry Bird on its competitors in HCV. It is saying that everybody else is playing for second; it's won the HCV battle and is moving on. Or to mix a sports metaphor, it's about to cross the finish line, and all the others are far in the jockey's metaphorical rear-view mirror.

Not about sof/vel, per say, but, IS about new daa's (in general) and GT3's. (I can't wait for the day when no GT has to do any riba regime!)  C.

Article - Researchers VS Nice - Daa's VS interferon/riba for GT3's (duh!)

Fibrosis in HCV genotype 3 progresses with age

June 27, 2016

Evidence of fibrosis was common in older patients with hepatitis C virus genotype 3 infection, indicating fibrosis progresses with age and this patient population should be treated as often and with the same medications as other severe HCV patient populations, according to data presented at the British Society of Gastroenterology Annual Meeting.

According to Keeley Fairbrass, of the Digestive Disease Centre, Bradford Teaching Hospitals NHS Foundation Trust, U.K., and colleagues, The National Institute for Health and Care Excellence (NICE) previously issued a guidance that recommended only patients with moderate to severe HCV be treated. More recently, NICE advised that patients with HCV genotype 3 be treated with pegylated interferon plus ribavirin, and not direct-acting antivirals.

The researchers sought to determine the rate of fibrosis in this patient population, due to the fact the current recommended treatment indicates a longer treatment duration with lower sustained virologic response and more adverse events.

They analyzed data from a single center database to measure demographics, age of liver biopsy, fibrosis stage and SVR in patients with HCV genotype 3. Between 1998 and 2015, 477 patients underwent biopsy.

"We aimed to plot the rate of progression of fibrosis in HCV [genotype 3] patients to ensure NICE guidance isn't disadvantageous to this group," the researchers wrote.

Among those with HCV genotype 1 (n = 112; 81 men, average age 40 years; 31 women, average age 42 years), 48% achieved SVR. In the HCV genotype 2 group (n = 16; 10 men, average age 39 years; 6 women, average age 43 years), 75% achieved SVR. For HCV genotype 3 (n = 337; 194 men, average age 39 years; 143 women, average age 40 years), 68% achieved SVR. In the HCV genotype 4 group (n = 12; 10 men, average age 38 years; 2 women, average age 45 years), 42% achieved SVR.

In patients with F0 to F2 fibrosis, SVR was 80%; in patients with F3 to F4 fibrosis, SVR was 70%; and in patients with F5 to F6, SVR was 65%.

"The point prevalence of fibrosis in HCV [genotype 3] at the time of liver biopsy ...[c]onfirms that fibrosis progresses with age, but not in an exponential way and also recognizes the well-described fall in SVR with increasing fibrosis," the researchers wrote.

The researchers concluded: "Our SVR data strongly suggests that we should provide all of our HCV [genotype 3] patients with the new potent DAAs to prevent progression of disease and subsequent consequences. We urge for a change in the current guidance." - by Melinda Stevens

References:

Fairbrass K, et al. Abstract #PTH-100. Presented at: British Society of Gastroenterology Annual Meeting; June 20-23, 2016; Liverpool, U.K.

Tig's links - more good data on sof/vel/vox.

Sov/Vel/Vox Triple

Gilead Triple

NS3/4A Protease Inhibitor GS-9857

Another author, re-write/compilation/look at old and new(er) stats on sof/vel/vox, but a dif. twist noted in the potential exploration in use of "RG-101". This RG-101 seemed to be a slow in coming/developing drug that was talked about quite some time ago on this site (between Mallani and Matt Chris mostly, I think?). I just found it kinda interesting that I have now seen the potential use of RG-101 being mentioned again, twice recently, once here: 

New Combination Therapy May Be Effective Against Chronic HCV Infection

By Will Boggs MD

June 14, 2016

NEW YORK (Reuters Health) - The new NS3/4A protease inhibitor GS-9857, in combination with sofosbuvir and velpatasvir (SOF/VEL), produces sustained viral response in most patients with hepatitis C virus (HCV) genotype 1 or 3 infections, according to a phase 2 trial from Gilead Sciences.

Various combinations of direct-acting antiviral agents (DAAs) provide sustained virologic responses in most patients infected with HCV, but there are ongoing efforts to optimize and shorten regimens.

Dr. Edward J. Gane from Auckland City Hospital in New Zealand and colleagues evaluated the efficacy and safety of short-duration regimens (four, six, or eight weeks) of SOF/VEL plus GS-9857 in a broad range of patients with genotype 1 (n=120) and 3 (n=41) HCV infections, including 63 treatment-naïve patients and 98 previously-treated patients.

Sustained viral response at 12 weeks (SVR12) was achieved by 27% of treatment-naïve patients with genotype 1 infection without cirrhosis after four weeks of treatment and by 93% after six, the team reports in Gastroenterology, online May 27.

SVR12 was 87% among treatment-naïve patients with cirrhosis after six weeks of treatment, while it was 67% among DAA-experienced patients with and without cirrhosis. In patients who had received other previous treatment and did or did not have cirrhosis, SVR12 with eight weeks of therapy ranged from 89% to 100%.

Among patients with genotype 3 infection, SVR12 was achieved by 83% of treatment-naïve patients with cirrhosis after six weeks of treatment and by 100% of previously treated patients with or without cirrhosis after eight weeks of treatment.

Of the 30 patients who did not achieve SVR12, 28 had virologic relapse after completing treatment, one withdrew consent four weeks after the treatment ended (at which time the patient had undetectable HCV RNA), and one never attained HCV RNA below 15 IU/mL on treatment.

Relapse rates were 73% among patients who received only four weeks of treatment, 19% among those who received six weeks of treatment, and 4% among those who received eight weeks of treatment.

SVR12 rates were also high among patients who had resistance-associated substitutions at baseline (84%-86%, depending on the threshold), and no treatment-emergent resistance-associated substitutions were detected in 26 of 28 patients who relapsed.

Common adverse events included headache, nausea, fatigue, and diarrhea, most of which were mild in severity. No patient discontinued treatment due to an adverse event.

"These results suggest that 8 weeks is the threshold of treatment duration with combination DAAs for the easier-to-treat patient population, not 4 or 6 weeks as suggested by recent viral kinetic models," the researchers note. "Future attempts to shorten duration of DAA regimens to less than 8 weeks will probably require the addition of a host-targeting agent such as RG-101, an miR-122 antagonist, which has been shown to do so in the interim results of an ongoing phase 2 study."

"SOF/VEL/GS-9857 is now coformulated as a single tablet which is being evaluated in the larger Phase III program, which includes different patient populations, including DAA-experienced patients," they add. "This group of DAA-experienced patients is growing and currently represents an unmet medical need."

Dr. Assy Nimer from Ziv Medical Center in Haifa, Israel, who has studied various aspects of HCV infection and its treatment, told Reuters Health by email, "The most interesting or surprising results is the low rate of SVR at week 4 in naïve HCV genotype 1 patients without cirrhosis, indicating that the combination of three potent DAA is not effective for 4 weeks but is highly effective for 8 weeks of treatment."

"The best treatment duration of the new DAA combination would be between 8 and 12 weeks," he concluded, adding that "this type of new medications will likely be effective in minimizing resistance-associated variants (RAV), which persist for years."

Gilead Sciences supported the trial, employed several authors, and had various relationships with the rest, including Dr. Gane.

Dr. Gane did not respond to a request for comments.

SOURCE: http://bit.ly/1UaduVG

Gastroenterology 2016.

So, still no "new" news on GS-9857!!

I stumbled across gs-9857's "new" name today, by accident, looking for any new sov/vel/gs-9857 trials, where I saw gs-9857 fondly (and officially) referred to as "VOX".

Tig did find a molecular pic of "VOX" today (good'un for avatar use)!

But after a search (you knew I would) I really could find no good revealing new data about this mysterious NS3/4A protease inhibitor "VOX" (formerly gs-9857)

I did find the reference as to when it's name (VOXILAPREVIR) was first registered - Nov. 2, 2014 (bor-ing), and the last date the name might have been changed - Jan. 10, 2016 (yawn), AND that it has a close (Latin) "international" name of VOXILAPREVIRUM", but that is NOT really the kind of data I wished for.

The closest thing I could find to "new" news was from a May 23rd conference (about Gilead company performance) where the EVP of Gilead R&D spoke of all their drugs, and of sof/vel/vox, and made mention of the newness of the name voxilaprevir (to him!) - apparently he had only been getting his mouth used to using the name for about 2 weeks! The EVP also made mention of the "pan-ness" of sof/vel (pan enough for all GT's), and proudly made mention (yet again) of the fast-tracking consideration sof/vel has received, with a decision date on same supposedly pending Jun 28.

Of the recent sof/vel/vox trials, even the "primary" result due date, is not going to be until Dec of 2016!!

So, for now, all one can do (when they ponder just what kind of NS3/4A protease inhibitor IS this that I am ingesting anyway), is to re-read the Gilead trial handout that specifies possible sides. Or, try to compare VOX to one of the many other and older types of NS3/4A protease inhibitors!!

Vox being described as an "aco-molar" inhibitor, doesn't tell me much, nor does it's "appearance" to perform better, as a good pan PI, provide me much comfort! "Sounds" good (in theory) the suspected lessening of RAV probs., but I can't wait until they actually publish something new, and something from these recent trials, on vox!! (and on vel too!) Sigh,  C.

Another one, continuing the data dialog that has already been surfacing about treating GT3's (and all GT's) with velpa.

This one is was mostly in regard to GT1 numbers, but some generalities apply to 3's and other GT's.

Generated from highlights out of the "in progress" Barcelona Liver Meeting. C.

Triple therapy shows efficacy in treatment-experienced patients

BARCELONA A new three-pronged approach to hepatitis C virus effectively treated prior non-responders with genotype 1, according to a presenter at the International Liver Congress.

As increasing numbers of patients get treated, the number of patients that, cumulatively, will fail will increase over time despite rates of 95% or higher,Eric Lawitz, MD, of Texas Liver Institute, University of Texas Health Science Centre, San Antonio, said in a press conference. In our quest to get universal success for all patients, we need regimens that can take the next step to allow patients who have failed these really good regimens we have today and allow them to be successful. This is a small study but is groundwork for an evolving field.

Lawitz showed data from a small study with two fixed-dose treatment groups: Sovaldi (sofosbuvir)/velpatasvir/GS-9857 (Gilead Sciences; n = 24) and sofosbuvir/velpatasvir/GS-9857 plus ribavirin (n = 25).

Factors that may predict failure were evenly stratified across the two groups, Lawitz said, referring to age, BMI, ethnicity, genotype and previous treatment with direct-acting antivirals. Forty percent, he said, had previous NS5A experience.

Overall, the study showed an SVR rate of 98% with just one relapse in the ribavirin group and mostly mild to moderate adverse events.

The addition of ribavirin to three antivirals did not have any additional benefit, he said. The baseline resistance associated variants that would emerge as a result of treatment failure with antivirals did not reduce the rate of success. Having three antivirals with different mechanisms of action allow you to achieve 98% success rate irrespective of failure with other classes of antivirals. by Katrina Altersitz

Reference:

Lawitz, E. PS021. Presented at: International Liver Congress. April 13-17, 2016; Barcelona.

Hi SF,

I cut and pasted the actual article now, below the link.  C.

BTW - this article info is nothing earth shatteringly new - it's just a "recently written" article on the same info already "out there" - the data is still based on small numbers of subjects, and limited numbers of trials, especially pertaining to G3's - it is just presented and highlighted differently in this particular article.

ARTICLE ABOUT SOF/VEL - in general, a synopsis of trials done, that included most GT's - of particular interest to me of course was one sentence, in regard to 1's and 3's:

 ... "The presence of pretreatment NS5A resistance-associated variants did not appear to affect SVR12 rates in most patients with genotype 1 or 3 HCV infection." ....

In regard to velpa (without riba), and velpa in general, this reiterates of some of it's "thought" valuable attributes, which may prove very meaningful, especially for the harder to treat G's, re-treatment of G's (or treatment of any G's packing DAA 5A RAV's).  C.

http://www.medscape.com/viewarticle/854507 (below, if link doesn't open)

Title - "HCV:  Simpler 12-Week HCV Treatment on Horizon"

Data from two phase 2 clinical trials reveal that 400 mg sofosbuvir plus 100 mg velatasvir is a well-tolerated and highly effective treatment for patients infected with hepatitis C virus (HCV) genotypes 1 to 6. One study tested 12 weeks of therapy in treatment-experienced patients, whereas the other tested the same regimen in treatment-naive patients.

The two studies were published online November 10 in theAnnals of Internal Medicine. Both studies had a randomized, open-label design.

Previously Treated Genotypes 1 or 3 Respond

In one of the studies, Stephen Pianko, MD, PhD, from Monash Health in Clayton, Australia, and colleagues tested the combination in patients with HCV genotypes 1 or 3 who had failed a prior therapy. Patients with genotype 3 were excluded if they had failed a prior experimental or approved direct-acting antiviral HCV treatment, but similar restrictions were not made for patients with genotype 1 infection.

The researchers randomly assigned patients to treatment with sofosbuvir (400 mg) and either 25 or 100 mg velpatasvir, with or without ribavirin. Overall, the combination of sofosbuvir and velpatasvir appeared safe and effective in these pretreated patients.

Although the study was not powered for comparisons among treatment groups, the researchers did note that the sustained virologic response rates at 12 weeks (SVR12) in patients infected with HCV genotype 3 were numerically higher among those treated with 100 mg velpatasvir than in those treated with 25 mg velpatasvir.

Moreover, the SVR12 rates in the 100-mg treatment group compared favorably with those previously reported for other regimens, according to the authors. In contrast, patients with genotype 1 HCV infection appeared to have similar rates of SVR12, regardless of velpatasvir dose or the presence of absence of ribavirin.

The presence of pretreatment NS5A resistance-associated variants did not appear to affect SVR12 rates in most patients with genotype 1 or 3 HCV infection.

Treatment-Naive Patients With Genotypes 1 to 6 Respond

In a separate study, Gregory T. Everson, MD, from the University of Colorado, Denver, in Aurora, and colleagues enrolled previously untreated, noncirrhotic patients and demonstrated high rates of SVR12 across genotypes 1 to 6. In the case of patients infected with HCV genotypes 1 or 2, SVR rates were lower at 8 weeks of treatment when compared with 12 weeks of treatment.

The investigators documented low rates of serious adverse events and had only one patient discontinue as a result of serious adverse events.

"This is, to our knowledge, the first demonstration of a [direct-acting antiviral] combination with pangenotypic activity against HCV genotypes 1 to 6. The SVR rates in this study for treatment-naive noncirrhotic patients were similar to those observed with standard-of-care regimens," write Dr Everson and colleagues.

"It is important to have a simple regimen that works against all genotypes," said Naim Alkhouri, MD, a hepatologist at the Cleveland Clinic in Ohio in an interview with Medscape Medical News. He was not affiliated with the current study but has consulted for Gilead on other projects.

He said the results represent an advance for patients because such a treatment regimen would preclude the need for HCV genotyping before the initiation of treatment. Moreover, such treatments would represent a simple, all-oral, effective, and well-tolerated regimen.

Both trials were funded by Gilead Sciences. Dr Pianko reports receiving personal fees or other support from the following companies: Gilead Sciences, Roche Diagnostics, AbbVie, Bristol-Myers Squibb, and Merck. Several coauthors report one or more type of financial or nonfinancial support from one or more of the following companies: Gilead Sciences, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, Merck, Boehringer Ingelheim, Conatus, Galectin, Intercept, Lumena, ViiV, UpToDate, and ViralEd. One coauthor is an employee and stockholder of Gilead Sciences. Dr Everson reports grants and personal fees from Gilead Sciences, AbbVie, Merck, Bristol-Myers Squibb, and Janssen Pharmaceutica, and several patents for liver function diagnostics with exclusive licensing to HepQuant and royalty payments to the University of Colorado and himself. Several coauthors report personal fees, grants, or other support or relationships with one or more of the following companies: Gilead Sciences, Bristol-Myers Squibb, ViiV Healthcare, Vertex Pharmaceuticals, Pfizer, Merck, AbbVie, Janssen Pharmaceutica, Tacere Therapeutics, Salix Pharmaceuticals, Tobira Therapeutics, Intercept Pharmaceuticals, Galectin Therapeutics, Hologic, Genentech, Hoffmann-La Roche, MassBiologics, Enanta Pharmaceuticals, and Idenix Pharmaceuticals. Two coauthors report they are employees of and shareholders in Gilead Sciences. Dr Alkhouri is on the advisory board for Gilead Sciences.

Ann Intern Med. Published online November 10, 2015. Pianko full text, Everson abstract

Hi Canuck,

You should do well. It's about time Gilead followed AbbVie and adopted the shotgun approach.

Unlike V-Pak, all of the Gilead drugs are top class, and having a nucleoside NS-5B inhibitor puts this combo way ahead of AbbVie.

GS-9857 appears to be a potent NS-3 blocker with a higher resistance profile compared with the previous antiproteases.

The duration of treatment is the unknown for this combo. The Phase 2 Trials showed 6 weeks was not enough. I hope 8 weeks does the job for you. There was a suggestion that the Trials should include 10 and 12 week arms.

Interesting that the IL28B gene has resurfaced. It was thought this was only important for Interferon regimes. To find the CC's do better with the new DAA's raises a lot of questions.

Keep us posted. This may be the ideal combo for Geno3. Cheers.