Benitec Biopharma signs manufacturing deal for hepatitis C treatment

Benitec Biopharma signs manufacturing deal for hepatitis C treatment

Monday, May 25, 2015 by Proactive Investors

Benitec Biopharma (ASX:BLT) has entered into an agreement with Maryland-based Omnia Biologics to manufacture material for its current first-in-man clinical trial for its TT-034 hepatitis C treatment.

This ensures the company has enough clinical material to complete the current trial.

The company is also moving to establish its own scalable manufacturing process in collaboration with third parties to supply large markets it is targeting.

Hepatitis C Treatment

TT-034 is a ddRNAi-based therapeutic that is designed to treat and potentially cure hepatitis C with a single administration.

It targets the hepatitis C viral RNA at three separate, highly conserved sites, which minimises the ability of the virus to mutate and escape the therapy.

Once it reaches the liver cells, it enters the nucleus and produces three separate short hairpin RNAs continuously for the live of the cell.

This has the potential to guard against reinfection for months to years without the need to re-treat.

Proactive Investors Australia is the market leader in producing news, articles and research reports on ASX emerging companies with distribution in Australia, UK, North America and Hong Kong / China.

Hepatitis C - A Week In Review

A week in review

Here is a look back at this weeks headlines, including today's news with updates as the day progresses.

May 23
Alternative Medicine
3 things people get completely wrong about vitamin supplements
One myth I hear often is that natural substances can’t possibly be harmful. Clearly excess can be dangerous, but natural substances can also carry risks even in moderate doses. For example, kava, often used as a sleep aid or to reduce anxiety, has been linked to 
liver toxicity

Covered California Votes To Cap What Patients Pay For Pricey Drugs
Retired California school teacher Mikkel Lawrence sits with his cat, Max. Lawrence has hepatitis C and has struggled to afford the medicine he needs to treat it.



May 22
How hepatitis C treatment is a glimpse of health care’s future
What are the implications for Medicare?  Who will get the drug and who pays the bills?

HCV Video-Hot Topics
Old-Line Drugs: Hepatitis C
Will there still be a role for ribavirin and pegylated interferon-alfa?

Length of Treatment: Hepatitis C
Some treatments are eight weeks with one or two pills a day. Can it get shorter/easier?

When to Treat: Hepatitis C
Should all patients be treated as soon as possible or is it useful to wait in some /many/most cases?

Chris McGuigan: driving drug development
There has been debate about the cost of medicines to treat hepatitis C. Do you think they are priced excessively?
Sofosbuvir is certainly aggressively priced. Hepatitis C is difficult to treat and the natural outcome of the disease in many cases is a liver transplant, which is expensive in itself and impractical for all 180 million people worldwide with the disease. Previous therapy with pegylated interferon and ribavirin didn’t work in all the serotypes, side effects were a problem and compliance was rather low. Protease inhibitors weren’t a panacea, so people looked for polymerase inhibitors. Sofosbuvir was the first and it’s a good drug – well tolerated and curative in many cases. Gilead did pay US$11bn for Pharmasset to get this one drug and it’s fair to think they should be compensated for bringing such an innovative drug through.

Is it fairly priced? That’s beyond my pay grade, but hopefully Gilead will follow the lead of other pharmaceutical companies with HIV drugs in reducing prices in poorer countries. In any case it’s vital that pharmaceutical innovation is adequately rewarded.


Europe unaware of the hepatitis crisis, say patient organisations

Hep C med imports- Risky and potentially illegal

Full Text - PDF
Long-term treatment outcomes of patients infected with Hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a Sustained Virological Response

NHS England accused of interference over hepatitis C drug
Officials at NHS England have been accused of interfering in a process to decide whether a drug which can cure Hepatitis C should be made available to patients on the health service

Hepatitis C: Weighing the Price of a Cure
A new class of drugs has proven to be an exceptional clinical success, but it's their equally striking costs that are garnering more attention.

BEST OF EASL
Watch Expert Perspectives: Best of HCV from EASL 2015

CDC Hepatitis C section Under Fire - "Centers for Disease Control and Prevention: protecting the private good?"

Helping doctors predict what's next for patients diagnosed with Hepatitis C

Cures for other viruses may follow Hep C
Working on the Hep C virus since 1987, Dr Lopez-Talavera believed at the time that researchers like himself would never be able to cure Hep C without interferon, and that one year of therapy would always be needed. “But as much as I knew, I didn’t know much. And I keep learning, learning more about the virus,” he said.

On what the shortest treatment duration was likely to be with these DAAs, he explained: “If you put just one Hep C virus, one single RNA, into the body of a patient it is going to go into the blood cells and to the liver where it uses the machinery inside the cell to replicate and produce new viruses, and all that takes around 80 days. So we thought that in order to be able to make sure you don’t have any virus in any of those steps…. you need at least 80 days of therapy....

Changing the face of hepatitis C management – the design and development of sofosbuvir

May 20
FDA Okays Hep-C Investigational Combo for Post-Transplant Patients
Based on favorable results from the ALLY-1 trial, the US Food and Drug Administration (FDA) has amended its breakthrough therapy designation for a hepatitis-C drug combo.

The change means that daclatasvir (Daklinza/ Bristol-Myers Squibb) and sofosbuvir (Sovaldi/Gilead ) may now be given to patients who have hepatitis C infections with either advanced cirrhosis or infections that have come back after patients received a liver transplant.

Hep C landscape shifts again as BMS combo nabs breakthrough tag

Dasabuvir in hepatitis C: Indication of added benefit in certain patients
All ten groups were reflected in the dossier compiled by the drug manufacturer, but the data were informative for only three of these groups. The benefit assessment was based on two randomized controlled approval studies (MALACHITE I and II), in which dasabuvir in combination with ombitasvir/paritaprevir/ritonavir and/or ribavirin was directly compared with triple therapy consisting of telaprevir, pegylated interferon and ribavirin.

HealthWell Foundation's New Fund Brings Financial Relief to Underinsured People Living with Hepatitis C

Series- Hot Topics In HCV
MedPage Today HCV HOT TOPICS - 10 Day Video Series
MedPage Today invited specialists from leading medical institutions to weigh in on the latest advancements in hepatitis C with one question each day for 10 days.

Achillion partners with J&J to develop hepatitis C drugs

High Cost of Hepatitis C Drug Prompts a Call to Void Its Patents

View all updates @ NATAP
EASL: The Impact of Ribavirin on Real World Adherence and Discontinuation Rates in HCV Patients Treated with Sofosbuvir + Simeprevir

May 19
New at Clinical Care Options
Audio - HCV Experienced Patients: Resistance testing, Cirrhosis and Genotype 3 Infection
Topics In This Webinar Include;
HCV therapy in the setting of renal impairment, resistance testing in DAA experienced patients, and the best approach to treat patients with cirrhosis or experienced patients who have genotype 3 infection.

DDW Daily News - Pricing remains main barrier to HCV eradication

Scientists identify crucial step in helping to prevent Hepatitis C virus replicating

May 18
SVR durability using new interferon-free DAAs in comparison to SVR with interferon-based regimens
In this month's issue of HCV Next, Michael S. Saag, MD., writes about SVR durability using new all-oral, interferon-free DAAs in comparison to SVR with interferon-based regimens, noting some experts suggest there may be a difference.

EASL- Delaying HCV therapy worsens treatment efficacy
VIENNA — Delaying treatment for hepatitis C virus infection until an increased fibrosis-4 score is reached negatively impacted the efficacy of the treatment among veterans, according to data presented at the 2015 International Liver Congress.

Hep C patient sues Blue Cross for blocking access to Harvoni
It had to happen: A patient denied the latest hepatitis C drugs has sued her insurance company. In this case, it's Anthem Blue Cross, and the California plaintiff says her plan blocked her from treatment because she's not sick enough to qualify under its rules.

Lives could be saved with hepatitis C treatment

Hepatitis C Recommendations for 2015 - DDW

NEWSLETTER


HCV Advocate Newsletter
May 15, 2015
Click Here

In This Issue:
EASL 2015: Snapshots
Alan Franciscus, Editor-in-Chief

This year’s conference had many outstanding presentations about hepatitis C drugs in development—too many to cover in one edition of the HCV Advocatenewsletter. As a result, we will be covering EASL in this edition as well in the next Mid-Monthly edition. I have tried to pick out a couple of most interesting studies from the presentations from AbbVie, BMS, Gilead, and Merck.
Planning for Disability
Jacques Chambers, CLU

Even though there are some wonderful, new medications on the market, some people with HCV will still need to consider going on disability at some time in the future. For most people, it is not always easy to know when the right time to leave is. Liver disease caused by HCV is often marked by a gradual progression toward disability. As well, the emotional issues involved around leaving work and "becoming disabled" further cloud the decision-making process. 
The Five: May Is Hepatitis Awareness Month
Alan Franciscus, Editor-in-Chief

May is Hepatitis Awareness month. In this month's column, I will provide a brief overview of the five hepatitis viruses—prevalence, how they are transmitted, and how to prevent transmission. Important Note: This is a very brief overview of viral hepatitis. For detailed information about viral hepatitis see our Viral Hepatitis: The Basics. 
Read more...

Blogs
Lucinda K. Porter, RN
Hepatitis C: Why We Aren’t Curing this Easy to Cure Disease
What if you had type 2 diabetes and your health insurance denied treatment because you weren’t sick enough. 

Lucinda K. Porter, RN
Author, Hepatitis C Advocate, Health Educator
Last Entry: Tell Your Hep Story (2015-05-22 05:58:39)
Here is a big way that anyone with hepatitis C can do to raise hepatitis awareness - tell your hep story.
click here to enter

Matt Starr
Hepatitis, Liver Disease Support Coach
Last Entry: Worry and Boredom in Hartland (2015-05-21 16:10:57)
I'm taking ribavirin and Harvoni, the newest, most successful treatment yet developed for the insidious hepatitis C virus, with a cure rate of over 90% for my genotype 1. The side effects from ribavirin are fatigue and anemia, which my body has resisted, but is slowly increasing.
click here to enter

Grace Campbell
A pseudonym for a person living with hepatitis C on Viekira Pak + Ribavirin
Last Entry: Hepatitis C: Uh oh. Buckle up - blood tests happening soon (2015-05-21 04:05:38)
It's Week 8 Blood Test time. You know what that means don't you. It's where I attempt to keep my anxiety under control by spending about $200 at the bookshop. That's my excuse for the purchases, anyway.
click here to enter

Greg Jefferys
My Hep C Travel Diary, Hepatitis C Advocate
Last Entry: 'The Medicine Is Out There But I Can't Afford It' (2015-05-20 10:50:27)
I am getting a lot of emails from folk with Hep C sharing their stories with me and their terrible frustration at not being able to access the medication that might cure them.
click here to enter

Kyle Jacobs
A pseudonym for a person living with hepatitis C on Harvoni
Last Entry: SVR 21 Weeks Post Treatment with Harvoni (2015-05-19 14:43:42)
Great news to report on my HCV viral load test! I still have a Sustained Virologic Response (SVR) for 21 weeks post treatment from Harvoni and according to my doctor, the incidence of late relapse is very low (less than 1%).
click here to enter

Rick Nash
Hepatitis C Advocate
Last Entry: I shall not die so easily. (2015-05-15 11:46:29)
I received the results from my 24 weeks of Harvoni.
click here to enter

Have a wonderful weekend!
Tina

Hep C med imports- Risky and potentially illegal

  • Posted by HCV New Drugs
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Hep C med imports
Hepatitis Australia is alerting people who are looking to purchase medicines from overseas for hepatitis C treatment, that due to poor quality checks, the practice is risky, as well as being potentially illegal. With new drugs now available in Australia (PD 12 May), Hepatitis Australia also says it should not be necessary to import from overseas, and it is important to have patients’ current status evaluated before starting new therapies.

THE ABOVE SNIPPET IS THE FIRST PART OF AN ARTICLE SENT TO SUBSCRIBERS IN PHARMACY DAILY'S ISSUE FROM 22 MAY 15

CLICK HERE to download Pharmacy Daily from 22 May 15

Established in 2007, Pharmacy Daily is Australia's leading pharmacy industry publication, and is sent as a free subscription to people across the industry as a PDF newsletter every weekday

Watch Expert Perspectives: Best of HCV from EASL 2015

Expert Perspectives: Best of HCV from EASL 2015

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    A New Webcast with David Bernstein, MD, FACG and Mitchell Shiffman, MD, FACG on behalf of the American College of Gastroenterology
    Shiffman Headshot 2010
    Mitchell Shiffman, MD, FACG
    dberstein head
    David Bernstein, MD, FACG
    Dr. David Bernstein, North Shore Long Island Jewish Health System,  and Dr. Mitchell Shiffman, Liver Institute of Liver, Bon Secours Health System, were invited by the ACG to review noteworthy abstracts from the European Association for the Study of the Liver (EASL) meeting in Vienna.
    This Webcast features data from EASL on Hepatitis C selected by Dr. Bernstein and Dr. Shiffman and targeted for an audience of GI clinicians.This brief and informative presentation provides a review of data from EASL on current and future HCV therapies that are relevant to gastroenterologists in the United States. Dr. Bernstein and Dr. Shiffman review the latest clinical data, including patient reported outcome data on newer therapies. Access the Webcast.
    The Webcast was produced in collaboration with the International Coalition of Hepatology Education Providers (IC-HEP).

    CDC Hepatitis C section Under Fire - "Centers for Disease Control and Prevention: protecting the private good?"

    CDC Hepatitis C section Under Fire - "Centers for Disease Control and Prevention: protecting the private good?"
     
    BMJ 2015 (Published 15 May 2015)

    Download PDF @ NATAP
     
    Commentary:
    Executive Director: Jules Levin

    From Jules: lets be clear - who is really to blame - if the CDC itself, The White House, Congress would fund HCV adequately & appropriately then the CDC Foundation would not have to take any funds from industry. The CDC desperately wants to address the HCV epidemic & I do not see any evidence they are not acting appropriately; without CDC Foundation funding the CDC Hepatitis Section could do nothing because the CDC director & The White House & Congress give them next to nothing in funding for HCV. HCV is a public health epidemic & newly developed HCV drugs can cure HCV up to 100% with safe, tolerable, effective 12-week time-limited duration therapy, the 1st time in history that we can cure a virus with time-limted duration no less. SO, where is Tom Frieden, the CDC director, on this, why has HE not redirected funds from his budget to HCV? For years I have publicly stated the CDC has budget flexibility, they could move funds over to HCV but they refuse. Congress & The White House also refuse to fund HCV adequately, they provide a completely inadequate amount of $31 million to the CDC Viral Hepatitis section & recently The White House recommended an additional $31 mill which Congress is reviewing and this additional $31 mill White House recommendation is a joke - it should be just for starters $150 mill, that is what the CDC needs merely to launch a national screening project; because, it is estimated 75% of individuals with HCV are undiagnosed! so how can we cure anyone if they are undiagnosed.....

    Article
    Centers for Disease Control and Prevention: protecting the private good?
     
    BMJ 2015 (Published 15 May 2015)
     
    After revelations that the CDC is receiving some funding from industry, Jeanne Lenzer investigates how it might have affected the organisation's decisions The Centers for Disease Control and Prevention (CDC) includes the following disclaimer with its recommendations: "CDC, our planners, and our content experts wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products . . . CDC does not accept commercial support."

    Continue reading @ NATAP

    Changing the face of hepatitis C management – the design and development of sofosbuvir

    Changing the face of hepatitis C management – the design and development of sofosbuvir

    Authors Noell BC, Besur SV, deLemos AS
    Published Date April 2015 Volume 2015:9 Pages 2367—2374
    DOI http://dx.doi.org/10.2147/DDDT.S65255
    Received 3 January 2015, Accepted 12 March 2015, Published 24 April 2015
    Approved for publication by Professor Shu-Feng Zhou
    Bennett C Noell,* Siddesh V Besur,* Andrew S deLemos


    Department of Medicine, Center for Liver Diseases and Transplantation, Carolinas Medical Center, Charlotte, NC, USA

    *These authors contributed equally to this work

    Abstract: The availability of direct-acting antiviral (DAA) therapy has launched a new era in the management of chronic hepatitis C. Sofosbuvir, a uridine nucleotide analog that inhibits the hepatitis C RNA-dependent RNA polymerase, is the backbone of chronic hepatitis C therapy. Acting at the catalytic site of the polymerase, sofosbuvir is highly potent in suppressing viral replication and has a high genetic barrier to resistance. Sofosbuvir is effective across all hepatitis C genotypes, and is a mainstay of interferon-free combination therapy. In Phase II and III studies, genotype 1 patients who took sofosbuvir in combination with another DAA such as the NS3-4A protease inhibitor, simeprevir, or the NS5A replication complex inhibitors, ledipasvir or daclatasvir, achieved a sustained virologic response rate of over 90%. Harvoni®, a combination tablet of sofosbuvir and ledipasvir, dosed once daily is recommended for 24 weeks for treatment-experienced genotype 1 patients with cirrhosis, but 12 weeks of therapy is sufficient for all other populations. While genotype 2 (12 weeks or 16 weeks) and treatment-naïve genotype 3 patients (24 weeks) have excellent response rates with sofosbuvir and ribavirin, treatment-experienced cirrhotic genotype 3 patients may need the addition of another DAA such as daclatasvir. Sofosbuvir is efficacious in special populations such as HIV–hepatitis C virus-coinfected patients and liver transplant recipients and has already made a profound impact in these groups. Since it is renally eliminated, patients with advanced kidney disease or on dialysis must await dosing recommendations. Sofosbuvir-based regimens appear to be well tolerated with headache and fatigue being the most common side effects. The opportunity to cure patients with hepatitis C with sofosbuvir combination therapy is likely to change the future for our patients, particularly if the emphasis shifts to identifying those patients unaware that they are infected and providing affordable access to treatment.

    Keywords: NS5B polymerase inhibitor, ledipasvir, chronic hepatitis C, sustained virologic response

    Introduction
    Chronic hepatitis C (CHC) infection is a worldwide health concern affecting approximately 185 million people, about 3.5–4.4 million of whom reside in the US.1,2 Eighty percent of patients infected with hepatitis C develop a chronic infection, which will progress to cirrhosis in 20% of patients. End-stage liver disease due to CHC is currently the leading indication for liver transplantation in the US. Approximately 350,000 people across the world died from complications related to hepatitis C cirrhosis in 2010, and in the US, one million hepatitis C virus (HCV)-infected patients will have cirrhosis by 2020.3

    The tremendous human cost from sequelae of CHC infection is now beginning to be framed in a new light due to the availability of highly effective all-oral therapies to cure hepatitis C infection. Patients no longer require treatment with pegylated interferon (Peg-IFN), which caused innumerable side effects resulting in poor adherence to therapy. Moreover, the patients most in need of treatment, namely cirrhotics and post-liver transplant patients, had dismal sustained virologic response (SVR) rates with Peg-IFN and ribavirin (RBV). With all-oral direct-acting antiviral (DAA) therapy, these patients now have actual life-saving therapies available with outstanding SVR rates. At the moment, it is not an exaggeration to say that sofosbuvir serves as the fulcrum, providing the foundation on which the change in caring for CHC patients is possible.

    DAA therapy refers to pharmacological targets that specifically inhibit hepatitis C viral proteins. Identification of the four structural and six nonstructural proteins of HCV was possible only after the HCV RNA genome was sequenced (Figure 1). An intense effort by industry to develop attractive drug targets ensued but was initially complicated by the nature of the virus itself. The RNA polymerase NS5B does not have proofreading capability, and therefore, sequence diversity in the HCV genome exists at all times, even within individual patients. As a result, the first-generation DAAs, the NS3-4A protease inhibitors, telaprevir and boceprevir, were ineffective as monotherapy due to naturally occurring drug resistance mutations and required coadministration with Peg-IFN and RBV. Another example, simeprevir, a once-daily NS3-4A inhibitor, approved only a year ago in combination with Peg-IFN and RBV, is not recommended for genotype 1a patients who harbor the baseline Q80K resistance mutation. Sofosbuvir circumvents this problem by targeting the catalytic site of the NS5B viral polymerase, thereby profoundly diminishing viral replication directly.4 Furthermore, resistance mutations in the active site would be predicted to confer a lack of viral fitness (see Resistance section). These two factors, in combination with sequence conservation in the NS5B active site across all six hepatitis C genotypes, are responsible for the exceptional efficacy data of sofosbuvir.

    Mechanism of action
    NS5B is one of six nonstructural proteins encoded on the HCV genome. It is an RNA-dependent RNA polymerase responsible for replicating the HCV RNA genome which is a vital step in the HCV life cycle. The RNA-dependent RNA polymerase exhibits a classic fingers, palm, and thumb structure where interactions between the finger and thumb subdomains create the catalytic site that ensures synthesis of positive- and negative-strand HCV RNA.5 There are currently two types of NS5B inhibitors, nucleos(t)ide inhibitors and non-nucleoside inhibitors. Nucleoside inhibitors bind to the catalytic site of the RNA polymerase causing chain termination. Non-nucleoside inhibitors bind to a less conserved site resulting in a conformational change that distorts the positioning of residues binding RNA, thus inhibiting polymerization. Sofosbuvir belongs to the class of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribose nucleoside inhibitors (Figure 2).

    A variety of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribose nucleosides have been shown to be potent inhibitors of HCV NS5B polymerase in clinical studies.68 Ultimately, second-generation compounds of these agents were selected due to improved potency and enhanced pharmacokinetics with hopes of enabling once-daily dosing.9 Unfortunately, many of the second-generation preliminary agents were not phosphorylated effectively in vivo due to being poor substrates to cellular kinases. In order to circumvent this rate-limiting step, a phosphoramidate prodrug strategy was used to synthesize compounds with improved bioavailability and transport into hepatocytes, thus enhancing intracellular concentrations of the active nucleoside. Sofosbuvir is a phosphoramidate prodrug that is metabolized in the liver to β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine-5′-monophosphate.8 The conversion of the monophosphate form to the active triphosphate involves four enzymatic steps and one nonenzymatic chemical step.10 The first step involves hydrolysis of the carboxyl ester moiety by serine protease, cathepsin A (CatA), and serine esterase, carboxylesterase 1 (CES1). The second step involves a nonenzymatic rapid chemical activation resulting in an alanyl phosphate intermediate. The third step of metabolism involves deamination by the cellular enzyme histidine triad nucleotide-binding protein 1 (Hint1), and the final two steps leading to the active triphosphate form are phosphorylation events catalyzed by cellular kinases UMP-CMP kinase and nucleoside diphosphate kinase (NDPK). Once converted to the triphosphate form, the uridine nucleotide acts as a defunct substrate for the NS5B polymerase causing chain termination, therefore ceasing RNA replication.

    The active site moiety of NS5B is found in all HCV genotypes, which accounts for sofosbuvir’s pangenotypic activity. A study utilizing a molecular modeling approach used several quantitative structure–activity relationship (QSAR) properties to evaluate the performance of sofosbuvir on genotypes 1a, 2b, 3b, and 4a. Genotypes 1a and 3b were found to have the best QSAR values compared to genotypes 2b and 4a, suggesting that sofosbuvir would have better activity against HCV genotypes 1a and 3b.4 Lam et al demonstrated that sofosbuvir inhibited enzymatic activity of NS5B polymerase in genotypes 1–4 with similar 50% inhibitory concentrations between all the groups.11

    Pharmacokinetics/drug–drug interactions
    Sofosbuvir reaches peak plasma concentrations within 0.5–2 hours following oral administration and is approximately 60% bound to human plasma proteins. Administration with a standardized high-fat meal did not substantially affect its peak or area under the curve (AUC); therefore, it can be administered with or without food. Sofosbuvir undergoes extensive metabolism by the liver as described above to form the active nucleoside triphosphate, GS-461203. Dephosphorylation of GS-461203 results in the formation of the inactive metabolite GS-331007. Following a single 400 mg dose, the terminal half-life was 0.4 hours for sofosbuvir and 27 hours for the GS-331007 metabolite. Approximately 78% of the inactive metabolite is renally eliminated with the rest eliminated through the feces or as unchanged drug.

    Population pharmacokinetic analyses in HCV-infected subjects indicated that race, sex, or age (19–75 years) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.12 Pharmacokinetics of sofosbuvir in pediatric patients has not been established. The AUC of the inactive metabolite, GS-331007, was increased 55%, 88%, and 451% in a pharmacokinetic study of HCV-negative subjects with mild, moderate, and severe renal impairment, respectively. Grade 4 laboratory abnormalities were limited to those with severe renal impairment.13 Dose adjustment for patients with mild-to-moderate renal impairment is currently not necessary. The safety and efficacy of sofosbuvir are currently being studied in patients with severe renal impairment including end-stage renal disease patients requiring dialysis. Currently, use in these patients is not recommended. The AUC of sofosbuvir increased by 126% and 143% in patients with hepatic impairment with Child-Pugh classes B and C, respectively. There was no difference in tolerability or effect in these patients, and the presence of cirrhosis had no clinically relevant effect on exposure.14 Dosage adjustment is not necessary for patients with mild, moderate, or severe hepatic impairment.

    Sofosbuvir is a substrate of P-glycoprotein (P-gp); therefore, inhibitors or inducers of P-gp may alter serum concentrations of sofosbuvir. For example, the potent intestinal P-gp inducers (rifampin and St John’s wort) should be avoided, since they can decrease the sofosbuvir plasma concentration and reduce its efficacy. Coadministration with anticonvulsants is also not recommended. There was no effect on pharmacokinetic parameters when cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, or rilpivirine was coadministered with sofosbuvir. Sofosbuvir is not affected by cytochrome P450 metabolism, thus reducing the number of potential drug–drug interactions.15,16

    Resistance
    In vitro studies using HCV replicons to characterize resistance found S282T to be the only mutation across various genotypes and subtypes resistant to sofosbuvir. The S282T mutation conferred a 9.5-fold increase in the 50% effective concentration (EC50) of sofosbuvir against HCV replicons.17 Sofosbuvir remained susceptible to HCV replicons with resistant mutations to RBV, protease inhibitors, and NS5A inhibitors.17,18 Svarovskaia et al performed an extensive resistance analysis of 1,645 patients from Phase II and III sofosbuvir clinical trials using both deep sequencing and phenotypic analysis.19 There was no S282T mutation or polymorphisms present at baseline that were associated with failure to achieve SVR. Out of the 282 patients who did not achieve SVR, no resistant variants were detected during treatment in patients receiving dual and triple therapy; however, one patient receiving sofosbuvir monotherapy in the ELECTRON trial developed the S282T mutation.20 The S282T variant was present in greater than 99% of the viral population at 4 weeks posttreatment. This decreased to 27% at 8 weeks posttreatment and ultimately became undetectable at weeks 12 and 24 posttreatment. Analysis of all NS5B sequences identified L159F and V321A as sofosbuvir-treatment emergent substitutions. However, neither variant was associated with resistance to sofosbuvir in the replicon system.19 Sofosbuvir has a high genetic barrier to resistance. This may be due to the limited replicative fitness of the S282T strain of HCV compared to the wild type as Svarovskaia et al found, or could be due to sofosbuvir’s ability to rapidly reduce viral replication, thereby limiting the time resistant strains have to develop.19 The high barrier to resistance in addition to lack of cross-resistance between sofosbuvir and other classes of HCV inhibitors makes it an ideal candidate for combination therapy.

    Sofosbuvir/ledipasvir
    One combination recently approved by the US Food and Drug Administration (FDA) is sofosbuvir plus the NS5A replication complex inhibitor ledipasvir (Figure 3). Pharmacokinetic properties of combined ledipasvir, sofosbuvir, and circulating metabolite GS-331007 were studied in healthy adult subjects and subjects with CHC. While sofosbuvir and GS-331007 AUC and maximum concentration (Cmax) were similar in healthy subjects and those with CHC, ledipasvir AUC and Cmax were 24% lower and 32% lower, respectively, in HCV-infected subjects. Ledipasvir undergoes a slow oxidative metabolism through an unknown mechanism and is eliminated as an unchanged drug through biliary excretion. There was no detectable metabolism of ledipasvir by Cytochrome P450 enzymes. Ledipasvir solubility decreases as pH increases; thus, medications that increase gastric pH may result in a decreased concentration of ledipasvir. Omeprazole at doses of 20 mg once daily given 2 hours prior to ledipasvir resulted in lower AUC and Cmax. Only small decreases in ledipasvir AUC and Cmax were observed when given simultaneously with ledipasvir/sofosbuvir combination; therefore, proton-pump inhibitors at doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.21 Amino acid substitutions Y93H and Q30E have conferred high levels of reduced susceptibility to ledipasvir in cell culture for genotypes 1a and 1b. Ledipasvir is fully active against the sofosbuvir resistance-associated substitution S282T in NS5B, and ledipasvir resistance-associated substitutions in NS5A are fully susceptible to sofosbuvir.

    Comparative effectiveness of sofosbuvir and current use in clinical practice
    Genotype 1
    Sofosbuvir (Sovaldi®) originally gained FDA approval on December 6, 2013, in combination with Peg-IFN and RBV for genotypes 1 and 4, and in combination with RBV for genotypes 2 and 3. This label was based upon five Phase III clinical trials in a total of 1,724 HCV-mono-infected subjects with genotypes 1–6 CHC (see package insert). NEUTRINO was a single-arm, open-label multicenter trial in treatment-naïve patients (n=327) with genotypes 1 and 4–6.22 Patients received 12 weeks of sofosbuvir (400 mg daily) with weight-based RBV (1,000 mg in patients <75 kg, 1,200 mg if >75 kg daily) plus weekly Peg-IFN alpha (180 μg). The majority of patients were Caucasian (79%), genotype 1 (89%), and non-cirrhotic (83%). The SVR rate at 12 weeks (SVR12) following treatment was 92% (genotype 1a) vs 82% (genotype 1b). The SVR12 in patients with cirrhosis was 80%, and 71% in patients with multiple predictors of poor response to Peg-IFN (genotype 1, advanced fibrosis [F3/F4], IL28B non-C/C, and baseline viral load >800,000 IU/ mL) (Table 1).

    Shortly after the approval of Sovaldi® with Peg-IFN and RBV for genotype 1 CHC patients, Phase III clinical trials with the fixed-dose combination of sofosbuvir (400 mg) with the NS5A inhibitor, ledipasvir (90 mg), were completed. The anticipation for this combination was pronounced, particularly for genotype 1 CHC patients with cirrhosis, who were in need of a safe and effective all-oral DAA combination. A total of 1,518 subjects with genotype 1 CHC received sofosbuvir/ledipasvir (Harvoni®) in the ION trials. ION-323 enrolled treatment-naïve patients with early-stage or no fibrosis (Metavir F0–F2) to either 8 weeks or 12 weeks of Harvoni®. The SVR12 in the 8-week treatment group with or without RBV was 94%, and 96% in the 12-week treatment group. ION-124 compared 12 weeks vs 24 weeks in treatment-naïve patients with and without cirrhosis. The SVR12 in the 12-week arm was 99% (176/177) in patients without cirrhosis and 94% (32/34) in patients with cirrhosis, with again no difference with the addition of RBV. Lastly, ION-225 investigated the response rate of 12 weeks vs 24 weeks of Harvoni® in treatment-experienced patients with or without cirrhosis and included patients who had failed prior protease inhibitor therapy. These historically difficult-to-treat patients had outstanding response rates, and 24 weeks of therapy was superior to 12 weeks of therapy (99% vs 94% SVR). Based upon this compelling data, Harvoni® was approved by the FDA on October 10, 2014, for 12 weeks in treatment-naïve genotype 1 CHC patients with or without cirrhosis and 24 weeks or 12 weeks in treatment-experienced patients with or without cirrhosis, respectively.

    A current alternative which was recommended by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (http://www.hcvguideline.org/) in 2014 prior to approval of Harvoni® for genotype 1 patients intolerant of or ineligible for Peg-IFN was sofosbuvir and the NS3-4A inhibitor, simeprevir (150 mg daily).26 While originally an off-label use, this combination was just recently added to simeprevir’s package insert based upon data from COSMOS.27 Ninety-five percent of non-cirrhotic patients attained an SVR following 12 weeks with this combination. The SVR12 was 96% after 24 weeks of simeprevir and sofosbuvir in patients with cirrhosis (n=23), and extending treatment is advised in this population.27 In Europe, the NS5A inhibitor, daclatasvir (60 mg daily, Daklinza®), is an additional DAA, which can be combined with sofosbuvir for genotype 1 patients with (24 weeks) or without (12 weeks) cirrhosis with SVR rates comparable to Harvoni® (see also daclatasvir package insert).28

    Genotypes 2–4
    Sofosbuvir is the backbone for genotypes 2–4 treatment as well. It should be given for 12–16 weeks in combination with weight-based RBV for genotype 2 patients with or without cirrhosis. Treatment-naïve patients do slightly better than treatment-experienced patients (SVR >90% vs >80%).29 Genotype 3 patients, however, require 24 weeks of therapy with sofosbuvir and RBV. Like genotype 2, treatment-experienced patients do not fare as well as treatment-naïve patients (SVR 77% vs 93%).30 In Europe, the addition of daclatasvir to sofosbuvir and RBV is an attractive option for genotype 3 and would be a combination to choose, particularly in treatment-experienced patients with cirrhosis (see also daclatasvir package insert).28 Lastly, like genotype 1, sofosbuvir was originally approved in combination with Peg-IFN and RBV for 12 weeks for genotype 4 patients. While this combination remains a viable option for interferon-eligible patients, 24 weeks of sofosbuvir and RBV or 12-weeks of Harvoni® is probably a better alternative (http://www.hcvguideline.org) (Table 1).
    Hepatitis C treatment in special populations

    Patients with HIV coinfection represent an important subset of CHC patients to target therapy. They are at high risk for fibrosis progression compared to mono-infected patients. Thus, sofosbuvir, which can be safely administered concomitantly with antiretroviral therapy, has been a blessing to coinfected patients. Twenty-four weeks of sofosbuvir and RBV are effective in genotype 1–3 patients.31 For genotype 1 coinfected patients, 12 weeks of Harvoni® therapy resulted in an SVR rate of 98%32 and appears to be preferable to 24 weeks of sofosbuvir/RBV. However, ledipasvir increases tenofovir levels and should be avoided in patients with a creatinine clearance below 60 mL/min (http://www.hcvguideline.org). Historically, post-liver transplant outcomes in patients transplanted for CHC were inferior to other indications for liver transplant due to allograft reinfection and recurrent hepatitis C infection.33 Moreover, an aggressive form of allograft reinfection, fibrosing cholestatic hepatitis C (FCH), contributed to early graft failure within the 1st year after liver transplant. The availability of sofosbuvir is poised to change the natural history of hepatitis C after transplant. In fact, a compassionate use program with sofosbuvir for patients with FCH and allograft cirrhosis was started prior to its FDA approval, and 59% (54/92) of patients achieved an SVR12.34 While exact guidelines on when to initiate therapy post-transplant in the DAA era are not clear, patients can now be treated before transplant35 to prevent allograft reinfection or after transplant36 with truly remarkable response rates and without the risk of immune graft dysfunction associated with Peg-IFN therapy.37

    Safety profile of sofosbuvir
    Sofosbuvir is used in combination with other DAAs, Peg-IFN, or RBV. Thus, attributing side effects directly to sofosbuvir should be considered with caution. Anemia due to Peg-IFN/RBV therapy is common and should be monitored closely in regimens containing these agents. In a pooled analysis of Phase III trials of patients who received a sofosbuvir/RBV regimen, 8% of patients had a Hgb <10 g/dL, and <1% had a Hgb <8.5 g/dL. The corresponding numbers from the FISSION study in which patients also received Peg-IFN were 14% and 2%, respectively.22 Not surprisingly, patients treated with interferon-sparing, sofosbuvir-based regimens had less treatment discontinuation rates and reported better health-related quality of life.

    It is important to make note of adverse effects of sofosbuvir in combination with other DAAs. In the COSMOS trial, fatigue and headache were the most common adverse effects; however, simeprevir and sofosbuvir were also associated with pruritus (17%), rash (11%), and hyperbilirubinemia (7%). Sofosbuvir plus daclatasvir combination therapy was also associated with fatigue (11%) and headache (7.8%), as well as nausea. Only two patients required treatment discontinuation, which was likely unrelated to the study drug.28 Pooled data from Phase III trials using sofosbuvir in combination with ledipasvir revealed headache (11%–17%) and fatigue (13%–18%) as the most common side effects with very few patients (<1%) requiring treatment discontinuation due to side effects. Nausea, diarrhea, and insomnia were reported in 5%–10% of patients. Laboratory abnormalities with elevation in bilirubin and lipase levels were noted in ≤3% of patients, and may be a unique adverse effect of ledipasvir.

    Conclusion and future challenges associated with the effective treatment of hepatitis C
    The challenges in managing patients with CHC are in many ways different today in the era of highly effective DAA therapy. With the arrival of sofosbuvir ($1,000 per pill) and now Harvoni® ($1,125 per pill), concerns about cost have arisen. The cost of therapy must be further contemplated in the context of a strained US health care system where many patients with CHC are either uninsured or insured through government-sponsored plans.38 Insurance companies may decide to prioritize treating certain patients first over others (eg, those with more advanced fibrosis). Another factor both in the US and across the world involves identifying infected patients. In 2012, the US Centers for Disease Control and Prevention recommended one-time screening for CHC infection in persons born between 1945 and 1965.39 The implementation of this guideline is expected to identify a large number of previously undiagnosed patients who will require treatment. The public health mandate to find such patients is justified by our ability to now provide safe and effective therapy. While the cost of sofosbuvir or Harvoni® treatment today remains an issue, many providers feel that the real question is actually the relative cost of treating against the price paid by not treating – namely more patients at risk for complications from cirrhosis. In developing countries, where access and affordability are paramount, generic pharmaceutical companies, through licensing agreements with Gilead Sciences Inc., expect to be able to provide the drug at a fraction of the US cost. As a result, the main obstacle may become ensuring adherence to therapy.

    Future challenges still exist for special patient populations, and guidelines for treating HIV–HCV-coinfected patients with Harvoni® will require updating once ongoing clinical trials are complete. The same can be said regarding the optimal timing and duration of therapy for post-liver transplant patients. Chronic kidney disease patients with CHC infection, including those on dialysis, must await dosing recommendations for sofosbuvir and Harvoni® or seek alternative DAA combinations that are not renal cleared. Finally, a small percentage of patients will not achieve an SVR with DAA therapy containing sofosbuvir, reflecting real-world outcomes where adherence is suboptimal. Retreatment with sofosbuvir should be possible, but the decision to change to a different combination of DAA and/or adding RBV therapy will need to be individualized. While these concerns are real, when placed in perspective, the chance to prevent patients from developing cirrhosis, liver cancer, and even in some cases the need for liver transplant is truly remarkable to envision.

    Disclosure
    Dr deLemos has received support for clinical trials from Vital Therapies. The remaining authors have no disclosures.


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    Helping doctors predict what's next for patients diagnosed with Hepatitis C

    • Posted by HCV New Drugs
    • File Under

    Helping doctors predict what's next for patients diagnosed with Hepatitis C

    Patient risk model can help target costly HCV treatment to those with most urgent need

    UNIVERSITY OF MICHIGAN HEALTH SYSTEM


    ANN ARBOR, Mich. -- A team of researchers at the University of Michigan Health System has developed a risk prediction model that helps identify which hepatitis C patients have the most urgent need for new anti-viral drugs.

    Rallying baby boomers to be screened for hepatitis C took off as effective treatments emerged to wipe out the liver-damaging virus. But high costs that can rise to more than $80,000 for a round of treatment have complicated the promise of providing curative treatment for the estimated 3.2 million people in the United States with hepatitis C.

    For most patients, the disease will remain stable without treatment, perhaps for years and years, while one-third will have high risk of complications and need immediate care to prevent the virus from causing further liver damage, according to the U-M research.

    The model, described in the June issue of Hepatology, uses routine lab values and machine-learning methods to help doctors predict the health outlook of patients diagnosed with hepatitis C.

    "Offering immediate treatment to patients identified as high risk for poor health outcomes would allow these patients to benefit from highly effective treatments as other patients continue to be monitored and their risk assessment updated at each clinic visit," says lead study author Monica Konerman, M.D., MSc., a fellow in gastroenterology at the University of Michigan Health System.

    Using a dataset from a previous National Institutes of Health study the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial, the U-M team used clinical data such as age, body mass index and virus type and routine lab measurements to estimate patients' risk of progression of liver disease.

    The strength of the new model includes incorporation of many more lab values than most traditional models can handle. Plus, machine learning methods help analyze how lab values change over time, including the slope and acceleration of lab values such as platelet count, hepatic panel and AST to platelet ratio index (APRI), lab markers of liver injury and liver health.

    Among the patients predicted as low-risk, only 6 percent will have cirrhosis (liver scarring) complications in the next year, compared to 56 percent in the high-risk group, according to the U-M study model.

    "Ideally we would treat all patients. Until logistic and financial barriers are solved, clinicians and policy makers are faced with trying to target these therapies to patients with the most urgent need," Konerman says. "The model allows us to identify these patients with greater accuracy."

    The risk prediction tool can be added to an existing electronic medical record as a health care decision guide for doctors. It can establish how often patients come in for doctor visits or and have monitoring tests.

    The groundwork is being laid to make care accessible and affordable, including drug cost discounts for certain health care programs, and increased competition among drug companies that could potentially drive down prices.

    Additional authors: Senior author Akbar K. Waljee, M.D., Anna S.F. Lok, M.D., Peter D.R. Higgins, M.D., Yiwei Zhang, of the University of Michigan Division of Gastroenterology and Ji Zhu, Ph.D., professor of statistics at the U-M College of Literature Science and Arts.

    Reference: "Improvement of predictive models of risk of disease progression in chronic hepatitis by incorporating longitudinal data," Hepatology, official journal of the American Association for the Study of Liver Disease, Vol. 61, Issue No. 6, June 2015.

    Funding: Researchers were supported by the National Institutes of Health and a Veterans Health Services Research and Development career development award.

    Learn more about the Hepatology Program at the University of Michigan.

    About U-M's Division of Gastroenterology: The U-M is one of the largest gastroenterology practices in the country and is a leader in the prevention, diagnosis, and treatment of diseases of the gastrointestinal tract and liver. Our 50-plus physicians are experts in the diagnosis and treatment of all diseases of the gastrointestinal system, from simple to complex, including those of the esophagus, stomach, small intestine, colon, rectum, liver, gallbladder, pancreas and biliary tract.