December 10, 2013

Provided by ACT UP-Basel

Monday 9 December 2013
All the versions of this article: [English]

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• Press Release • December 9 • Bangkok – Paris – Basel – London – New York • On December 6, the U.S. Food and Drug Administration approved Gilead’s sofosbuvir (Sovaldi), an oral medication for the treatment of hepatitis C virus (HCV). Sofosbuvir and other direct-acting antivirals (DAAs) coming out of the drug development pipeline are more potent, have fewer side effects, and can often be taken for a shorter duration than the current standard of care. In clinical trials, sofosbuvir demonstrated high cure rates of up to 100% when combined with other DAAs. Yet its anticipated price tag of USD $80,000 will ensure that this drug remains out of reach for the vast majority of people living with HCV.

At least 185 million people worldwide have been infected with hepatitis C virus (HCV). Each year, three to four million people are newly infected and HCV-related liver complications kill an estimated 350,000 people annually, even though HCV is treatable and curable. Currently, injectable pegylated interferon is the backbone of the standard of care and, in combination with the oral drug Ribavirin (RBV), has a cure rate of between 50 and 75% of cases, depending on the HCV genotype; however, it is associated with significant side effects. Drugs like sofosbuvir — Gilead’s “blockbuster” nucleotide polymerase inhibitor — show much-improved cure rates (reaching up to 90-100% in clinical trials) and shorter treatment duration when combined with pegylated interferon or other DAAs. Using newer DAAs, especially if they can be used without the addition of pegylated interferon, may result in a drastically lower incidence of side effects and adverse reactions. Many more DAAs will enter the market over the next couple of years.

Ninety percent of people who have hepatitis C live in low- and middle-income countries (LMICs); most are not aware of their HCV status, nor do they have access to testing and counselling. Most people with chronic HCV do not have access to treatment, even under the current standard of care, as pegylated interferon can cost up to USD $18,000 per treatment course, or ten times their country’s per capita Gross Domestic Product. Advocates are already fighting for better accessibility to treatment programs and more affordable prices of pegylated interferon. Accordingly, now is the time to ensure affordable DAAs and optimized DAA combinations that reduce treatment duration and improve both adherence and treatment outcomes for everyone who needs them.

The price of sofosbuvir in high-income countries is expected to be very high, between USD $80,000 – 90,000. Like other DAAs, sofosbuvir is used in combination with other drugs, thus the total cost of a treatment course will be even higher. In France, where sofosbuvir is approved for early access, the 12-week course of treatment costs more than USD $76,000 (USD $905 per pill). Analysts expect Gilead’s drug to generate sales of USD $1.73 billion in 2014 alone.

Sofosbuvir and other DAAs coming out of late-stage development do not have to cost this much. They can be produced generically for a tiny fraction of that price, just like HIV antiretrovirals (ARVs). For example, a 12-week course of sofosbuvir, produced generically, may cost in the range of USD $68-136. Ensuring universal access to affordably priced and generic DAAs could help eradicate HCV globally.

The HIV/AIDS pandemic demonstrated that corporate greed, rather than the cost of drug development and production, caused originator drug prices to be scandalously inflated. Generic competition led to radical decreases in HIV drug prices: for some molecules they dropped by 99% once generic versions became available, allowing millions more people to access life-saving ARVs. Generic production also led to the development of optimized fixed-dose combinations that have simplified treatment, ensured access to ideal treatment combinations, and enabled the development of pediatric versions and heat stable formulations.

We, people living with HCV, HIV/AIDS, people who use drugs, and our advocates, demand that:

  • Companies, Gilead specifically, as well as generics producers must price their products close to the cost of production for all patients in all LMICs; considering the cost of production per 12-week treatment course (Ribavirin plus two DAAs) is estimated to range from USD $100 to 250.
  • Companies should not hinder the production of generic medicines and should not interfere with the obligation of governments to guarantee the access to health for their population; including the right to grant patents for real therapeutic inventions only, the right to revoke abusive patents, and the right to issue compulsory licenses in order to protect public health interests as clearly allowed by the World Trade Organization’s TRIPS agreement (Agreements on Trade related Aspects of Intellectual property rights) and reaffirmed in the Doha Declaration.
  • Governments must ensure that their intellectual property (IP) laws promote, not impede, their obligation to their people’s right to health. In particular, governments must use all safeguards to protect public health, and where IP laws are not written to promote public health, they should be revised accordingly.

We cannot allow more people to die from a treatable and curable disease and must learn the lessons from HIV advocacy by demanding affordable drug pricing for all, now! Failure to learn these lessons would be an unforgiveable scandal.

Act Up-Basel – Médecins sans Frontières – Asia Pacific Network of People Living with HIV/AIDS – Médecins du Monde – International Network of People who Use Drugs – International Treatment Preparedness Coalition

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Gilead HCV Drug May Face Price War; Rival AbbVie Up

By AMY REEVES, INVESTOR'S BUSINESS DAILY

Posted 03:08 PM ET

IT18-GILD-1211-AP_345

Gilead Sciences' (GILD) newly approved hepatitis C drug Sovaldi came under fire for its price from pharmacy benefit manager Express Scripts (ESRX) Tuesday, as rival AbbVie (ABBV) reported good data for its competing drug candidate. Gilead's stock dropped while AbbVie's rose on the stock market today.

Bloomberg reporter Drew Armstrong said on Twitter that Express Scripts' chief medical officer, Steve Miller, told him that the convenience of Sovaldi's one-pill-a-day regimen won't necessarily justify the $84,000 price tag for a 12-week regimen. "We will identify which drugs can be pitted against each other and make some really tough formulary decisions," Armstrong quoted him as saying.

This was a positive sign for AbbVie's regimen, which has so far performed as well as Sovaldi in clinical trials but involves four different drugs. Coincidentally, early Tuesday AbbVie released a second round of data from the regimen's phase-three program, showing a 96% sustained response rate among patients with the most common genotype of the virus who'd failed previous treatments.

ISI Group analyst Mark Schoenebaum wrote in an email to clients that while Express Scripts' size (around 100 million lives covered) gives it considerable leverage on these matters, the impact on Gilead might not be felt for a few years out.

"A big price differential would likely be necessary to block GILD's regimen," he wrote. "In a two-player market (before other competitors reach the market), whether ABBV would be willing to take a large price cut is not clear. Thus, the larger risk to price could be pushed out until 2017 when other competitors are able to reach the market."

Gilead stock, which hit a new high Monday after Sovaldi was approved, shed 3.5% in afternoon trading Tuesday. AbbVie spiked briefly to a new high above 54, but in afternoon trading was up 2%. Its partner Enanta Pharmaceuticals (ENTA), which developed the technology behind the drugs, got a much bigger lift and was up 27% in afternoon trading, to what is by far an all-time high for the stock.

RELATED: Gilead Hep C Drug Wins EU Panel Approval.

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Charles Gore - why it's important to get diagnosed

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December 2013 by Azadeh Momenghalibaf Public Health Program

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 Beyond the Hype: What sofosbuvir means—and doesn’t—for global hepatitis C treatment Download the report. 429.37 KB PDF

In December 2013, authorities in the United States and Europe approved Gilead’s highly anticipated hepatitis C drug, sofosbuvir. This drug and other new treatments for hepatitis C, called direct-acting antivirals (DAAs), have created a buzz among medical and research communities, patients, and financial analysts. Taken in pill form rather than by injection, and with cure rates and side-effect profiles better than previously seen for hepatitis C, many are hailing sofosbuvir and other new oral medicines as “miracle cures.”

The new drugs, however, come with a major limitation—price. Business analysts currently estimate that Gilead could charge $80,000 USD for a single course of treatment of sofosbuvir. With nearly 90 percent of the estimated 185 million people living with hepatitis C worldwide residing in low- and middle-income countries, where government health budgets are small and where most patients have to pay for medi ines out of pocket, this price tag means that sofosbuvir and the other new hepatitis C medicines will remain out of reach for the majority of those in need.

In this new report, Beyond the Hype: What Sofosbuvir Means—And Doesn’t—For Global Hepatitis C Treatment, we examine the new hepatitis C treatment market and projected revenues, and look back at what we can learn from the fight for access to HIV medicines in the 2000s to help secure reductions in the price of these promising new hepatitis C treatments.

Cross-posted from Open Society Foundations

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Treatments With Few Serious Side Effects Strengthen Case for Increased Screening, Which Could Save Many Lives

NEW YORK, Dec. 10, 2013 /PRNewswire/ -- The American Liver Foundation fully welcomes FDA approval of two new treatments for Hepatitis C, one of which is a new class of drug. This liver disease affects approximately 3.2 million people inthe United States, and roughly 75% of those infected are unaware they carry the virus. Often referred to as a silent epidemic, those infected include baby boomers that may have contracted the virus from surgeries, blood transfusions, and other contaminated blood products before the disease was known to exist.

Sovaldi, known generically as Sofosbuvir, is the first polymerase inhibitor to be approved for treatment of Hepatitis C, in combination with other anti-virals. Olysio, known generically as Simeprevir, is the first once-daily protease inhibitor to be approved.

"This is the beginning of a new, gentler, era in the treatment of Hepatitis C," states Tom Nealon, National Board Chair of the American Liver Foundation. "We know that thousands of patients have been awaiting new, less invasive, treatment options, and this is exciting news, but we are concerned that millions of cases of infections remain undetected and therefore untreated. These new treatments give hope to existing patients, and strengthen the case for systematically screening all baby boomers," he adds.

New data from the manufacturers of these and other new drugs for Hepatitis C was presented at the recent AASLD conference in Washington DC, indicating that there are many more new treatments in the pipeline, and promising the possibility of cure.

"With these new treatments just approved, and many more being developed, we have every reason to be optimistic about the potential to cure and even eradicate this deadly virus," states Hillel Tobias, MD, a liver transplant specialist and Co-Chair of the American Liver Foundation's National Medical Advisory Committee. "With these new treatments, it may be possible to lower the overall cost of treatment due to less side effects and hospitalizations that occurred from previous treatments. If we identify and treat patients with these new medications, it will be possible to prevent the need for many thousands of liver transplants," he adds.

Both newly approved drugs promise shorter duration of treatment and reduced side-effects, with treatment regimens for some strains of Hepatitis C no longer requiring injections of Interferon, which has been the mainstay of treatment for many years, but is associated with some challenging side effects which can impact a person's ability to work outside the home.

Between 3 and 4 million Americans are infected with Hepatitis C. Many of them are baby boomers who contracted the virus before Hepatitis C was known to exist, in the decades before the commencement of identification and screening in 1992. Other risk factors include tattoos, body piercings, and intravenous drug use.

Left untreated, Hepatitis C leads to liver cirrhosis and liver failure. 75% of patients do not know they have the disease, and 90% do not get treated. The American Liver Foundation hopes that awareness of these new, better-tolerated treatments will bring increased Hepatitis C screenings, testing and treatments.

Additional Resources:

ABOUT THE AMERICAN LIVER FOUNDATION
The American Liver Foundation's (ALF) mission is to facilitate, advocate and promote education, support and research for the prevention, treatment and cure of liver disease. It carries out its mission through education to promote liver health and disease prevention. Three national core programs are targeted to reach the public, at-risk groups, and patients with liver disease. ALF is the leading source of information on liver health and liver disease, through printed materials and www.liverfoundation.org. A toll-free national HelpLine at (800) GO-LIVER and 16 chapters across the country provide support to newly diagnosed patients, families, and the general public, through phone, email, and community outreach. It funds research that has helped to begin the careers of more than 750 scientists in the field of liver health in hopes of finding treatments and cures that will lead to a world free of liver disease. ALF is on twitter at @liverUSA

SOURCE The American Liver Foundation

RELATED LINKS
http://www.liverfoundation.org

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December 9, 2013

The Fair Pricing Coalition (FPC) today condemned Gilead Sciences for the price set for its direct acting antiviral (DAA) Sovaldi™ (sofosbuvir), a once-daily, first-in-class nucleotide polymerase inhibitor approved by the U.S. Food and Drug Administration on December 6, 2013, for the treatment of chronic hepatitis C, including those co-infected with HIV. While FPC believes that all hepatitis C virus (HCV) drugs are priced too high, the coalition of HIV and viral hepatitis treatment activists is especially dismayed by the wholesale acquisition cost (WAC) of $84,000 for a 12-week course of Sovaldi™. For comparison purposes, the FPC notes the 12-week WAC for the recently approved NS3/4A protease inhibitor Olysio™ (simeprevir) is $66,360.

"Sovaldi™ is a very safe and highly effective drug that will significantly shorten HCV therapy and either reduce or eliminate the need for injected pegylated interferon," explained FPC Co-Chair Lynda Dee. "However, this does not give Gilead unconscionable pricing carte blanche, particularly when considering that Sovaldi™ still needs to be combined with ribavirin for the treatment of HCV genotype 2 for 12 weeks or genotype 3 for 24 weeks. Twelve weeks of therapy with Sovaldi™ plus both pegylated interferon and ribavirin is required for the treatment of HCV genotype 1, the most common genotype in the US, and HCV genotype 4."

The WAC for 12 weeks of HCV treatment with pegylated interferon and ribavirin is approximately $9,000, resulting in a combined WAC of $93,000 for a Sovaldi™-inclusive regimen to effectively treat a single person living with HCV genotypes 1 or 4. To treat HCV genotype 3, 24 weeks of Sovaldi™ plus ribavirin is required, resulting in a Sovaldi™ WAC of $168,000.

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Price Portends an Ominous Future

"Gilead has set the bar dangerously high as other companies determine prices for similar hepatitis C drugs as they enter the market," Dee said. The effectiveness of Sovaldi™ as a component of future pegylated interferon-free regimens for the treatment of HCV will ultimately depend on co-administration with other DAAs currently in development, and are anticipated to come with their own high price tags.

"Sovaldi™ is expected to transform the curative landscape for hundreds of thousands of people living with hepatitis C in the U.S. who require therapy or responded poorly to previous treatment," said Lorren Sandt, FPC Co-Chair. "Yet the high price will result in significant barriers to treatment access, particularly in limited and fixed-budget programs, such as Medicare and state Medicaid programs, AIDS Drug Assistance Programs, the Veterans Administration, and in correctional systems."

The high price may also lead to access challenges imposed by private insurance plans and Qualified Health Plans in the new Affordable Care Act (ACA) Marketplaces, notably those with high co-payment and other out-of-pocket requirements.

"There may be reluctance to add Sovaldi™ to formularies quickly and payers may force people living with HCV to engage in step therapy in which they are first required to try less expensive options that are less effective," Sandt added. "These options take longer to complete and are associated with serious side effects, which present a serious impediment to adherence and, ultimately, to being cured of hepatitis C."

Concessions Where They Count

Although Gilead refused FPC's demand for fair pricing of Sovaldi™, the company has agreed to all FPC requests for concessions regarding Sovaldi™ access programs. These include:

  • The SupportPath™ (www.supportpath.com) patient assistance program (PAP), with a $100,000 maximum income allowance for a household of three and 500% of the federal poverty level (FPL) eligibility criteria for larger households.
  • The SupportPath™ Sovaldi™ co-pay coupon program will provide co-pay assistance for eligible patients with private insurance, including ACA Marketplace exchange patients, who need assistance paying for out-of-pocket medication costs. Most patients will pay no more than $5 per co-pay. Co-pay assistance of up to 20% ($16,000) of the WAC price for Sovaldi™ can also be applied toward prescription deductibles and co-insurance obligations.
  • Gilead has made a contribution to the Patient Access Network (PAN) for co-pay assistance for Medicare Part D clients.
  • Gilead has initiated an emergency Sovaldi™ supply program for patients that may lose their prescriptions.

Gilead has agreed to ensure access to its PAP and co-pay assistance programs for AIDS Drug Assistance Program (ADAP) patients who are co-infected with HIV, even in states with ADAP programs that will not include Sovaldi™ on their formularies.

The FPC urges Gilead to widely disseminate the details of its SupportPath™ PAP and co-pay coupon program, which must include providing written SupportPath™ information for prescribers, prominently featured SupportPath™ information in its professional and direct-to-consumer advertisements, and clear links to www.supportpath.com via the Gilead and Sovaldi™ websites.

From The Fair Pricing Coalition

(March 2014 Issue, Journal of Hepatology)
FOCUS 

Scott L. Friedman MD
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY

Correspondence:
Scott L. Friedman, M.D.
Division of Liver Diseases
Box 1123, Mount Sinai School of Medicine
1425 Madison Ave., Room 1170C
New York, NY 10029
Tel 212-659-9501
Fax 212 849-2574
Email: scott.friedman@mssm.edu

PII: S0168-8278(13)00839-8
DOI: http://dx.doi.org/10.1016/j.jhep.2013.12.002
Reference: JHEPAT 4964

To appear in: Journal of Hepatology

Received Date: 3 December 2013
Accepted Date: 4 December 2013

Please cite this article as: Friedman, S.L., “There are decades where nothing happens; and there are weeks where decades happen.” - Vladimir Ilyich Lenin, Journal of Hepatology (2013), doi: http://dx.doi.org/10.1016/j.jhep. 2013.12.002

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Lenin could have hardly imagined that his words describing the Bolshevik revolution almost 100 years ago could be applied to the breathtaking approvals in HCV therapies in the past few weeks. Yet, if one defines ‘revolution’ (from the Latin revolutio, "a turnaround") as “a significant change that usually occurs in a short period of time”, there is little doubt that we are experiencing a revolutionary epoch in hepatology, and practitioners would be wise to mark this watershed in their collective memories. After over a decade of only modest improvements upon standard interferon-based therapies, the recent FDA approval and anticipated EMA approval of sofosbuvir and simeprevir – albeit currently in combination with interferon and ribavirin - represent the leading edge of what will be a new era of interferon-free regimens that promise to cure more than 90% of genotype 1 patients, using regimens that are well tolerated and will rescue many patients in whom interferon is either unsafe or not tolerable. These advances have generated excitement among the lay and scientific press [1, 2], patients, providers, pharmaceutical and biotech companies, and investors.

A study by Younossi et al in this month’s issue of the Journal estimates the predicted economic and clinical windfall of this revolution using Markov modeling. In this study, the authors compared the calculated incremental cost-effectiveness ratio (ICER) between patients treated with standard interferon based triple therapy (interferon, ribavirin and either telaprevir or boceprevir) with those treated with all oral regimens for 12 weeks, based on published distributions of fibrosis stage, current costs of therapy and health care, and drug efficacies. They also distinguished between predictions based on whether patients were first screened with transient elastography (e.g. Fibroscan) as the staging method in order to limit therapy to only those with more advanced fibrosis; estimates that included the cost of liver biopsy were restricted to the sensitivity analysis. Of note, the study was performed before Fibroscan was approved in the US, and as of this writing the cost is still not determined, so the authors used the cost of ultrasound as a surrogate. The authors also made the estimate that the average total treatment cost of oral therapy was equal to the average total treatment cost of triple therapy, since the actual costs were not known at the time of their study.

The model’s findings clearly favor the use of all oral regimens in all patients with HCV over the use of triple therapy, and also predict that treating all patients would be cost-effective compared to using staging-guided therapies. The all oral regimen without staging would yield an ICER of $15,709 quality-adjusted life years (QALY), well below the threshold of $50,000 often used to provide justification for new therapies. Moreover, neither a significant reduction in the cost of boceprevir / telaprevir, nor the cost of staging would have any impact on the predicted advantage to using all oral therapy without staging guidance.

As the authors point out, the findings take on added significance with an expected increase in detection of HCV in the United States following the endorsement of recommendations by the CDC and US Preventive Services Task Force to conduct widespread one-time HCV screening in patients between 45 and 65 years old. Modeling predictions like this study’s supporting the use of a ‘test and treat’ strategy could greatly simplify the linkage to care following HCV diagnosis that is so vital for effective disease eradication in at-risk populations [3].

Of course, the analysis by Younossi et al relies on major assumptions regarding drug efficacy, costs and adverse events, which could well be higher in the real world than that seen in clinical trials. This was the experience in the use of triple therapy that includes boceprevir or telaprevir, where the incidence of adverse events in clinical practice after the drugs were approved was much higher, and the events more severe than what was experienced in pre-approval studies [3, 4]. This unexpected problem arose in part because after the drugs were approved they were first given to those with the most urgent need for cure (ie., cirrhotics), even though these same patients had the least capacity to tolerate adverse events.

Moreover, treatment with all oral regimens may not be so straightforward in every patient, particularly those who previously failed interferon-based regimens or with HCV genotype 1a. For example, in the article by Lok at al, also in this issue of the Journal, the results of a phase II trial that included two experimental direct-acting antivirals (daclatasvir and asunaprevir) underscores the more labor-intensive and customized treatments that will be required in prior null responders, especially the need to distinguish between genotypes 1a and 1b. In the Lok et al study, which was a randomized open label trial testing a series of combinations with or without interferon, 99% of the patients had the non-CC IL-28 genotype associated with interferon resistance, which explains their prior non-responses. In these difficult-to-treat patients, those with genotype 1a required interferon-based combinations to achieve an SVR. Thus, prior non-response was a tipoff to the need for more detailed diagnosis (e.g, viral and possible IL-28 genotyping) and customized therapy, yet as we screen and uncover more untreated HCV, some will also have genotype 1a and a non-CC IL-28 genotype and will possibly fail an all oral combination. Indeed, the simeprevir drug label will indicate that in genotype 1a patients resistance testing should be performed for the ‘Q80K’ mutation. If present, then “other therapies should be considered.” Thus, should our initial algorithm include both HCV and IL-28 genotyping, or should we wait until such patients fail initial therapy and then consider retreatment with an interferon-based regimen? If so, will viral resistance from initial therapy limit efforts to retreat? These are the kinds of nuanced questions, which color the interpretation of the Markov modeling used by Younossi, although they do not undermine it.

As we enter this momentous transition towards an ‘interferon-free’ world, it is also worth looking back to ask which advances were absolutely critical to bringing us to this juncture. I would contend that three seminal discoveries were essential: 1) The discovery of the HCV agent by Houghton, Choo, Kuo, Bradley and colleagues [5], a Nobel-worthy achievement both because of its public health impact and for the brilliant new methodology they formulated to clone the virus; 2) The development of cell based culture systems that supported HCV, first using the replicon [6] and then later the infectious JFH1 virus systems [7, 8], which enabled high throughput drug screening and the discovery of obligate cellular receptors for HCV [9]; 3) The characterization of HCV protein structures, which greatly facilitated the design of direct-acting antiviral drugs.

Does this mean that all the other investments in HCV research were irrelevant? Not at all. The discovery of HCV could not have happened without years of clinical characterization of non-A non-B hepatitis cases and studies in non-human primates, among others. Similarly, revealing how HCV evades immune clearance and how it drives intracellular innate immune signaling have already borne fruit in helping us understand the pathogenesis of other viral infections, and will also be vital in developing a prophylactic HCV vaccine.

Another important implication of these three seminal discoveries is that they reflect a healthy synergy between the academic and commercial research spaces. Both the discovery of the virus and the development of new drugs took place in the biotech/pharmaceutical sphere, yet they could not have happened without equally important discoveries in academia, including the clinical studies before and after the discovery of the virus, and the characterization of cell culture systems to enable drug screening. In fact, one could argue that the HCV success story represents an ideal consequence of a healthy, interdependent ecosystem between academic and commercial research.

This brings us back to the words of Lenin and the exciting times we live as investigators or clinicians devoted to liver disease. We can only hope that decades do not pass again before witnessing another revolution in our specialty, but just in case let’s enjoy this rare view while we can.

Acknowledgement

I greatly appreciate the helpful advice of Drs. Douglas Dieterich and Jean Michel Pawlotsky in writing this article.

References

[1] Pollack A. Hepatitis C, a Silent Killer, Meets its Match. New York Times. November 4, 2013.

[2] Mole B. Targeted drugs to tackle hepatitis C. Nature 2013;497:18-19.

[3] Hezode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013;59:434-441.

[4] Bichoupan K, Schwartz JM, Martel-Laferriere V, Giannattasio ER, Marfo K, Odin JA, et al. Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir. Aliment Pharmacol Ther 2013 (in press).

[5] Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-362.

[6] Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999;285:110-113.

[7] Lindenbach BD, Meuleman P, Ploss A, Vanwolleghem T, Syder AJ, McKeating JA, et al. Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci U S A 2006;103:3805-3809.

[8] Sainz B, Jr., Chisari FV. Production of infectious hepatitis C virus by welldifferentiated, growth-arrested human hepatoma-derived cells. J Virol 2006;80:10253- 10257.

[9] Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B, et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 2007;446:801-805.

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Clinical Gastroenterology and Hepatology

Article in Press

Zobair M. Younossi,Maria Stepanova, Linda Henry, Edward Gane Ira M. Jacobson, Eric Lawitz, David Nelson, Lynn Gerber, Fatema NaderSharon Hunt

Received 7 November 2013; accepted 17 November 2013. published online 09 December 2013.
Accepted Manuscript

Abstract

Background

& Aims: Interferon-based treatment of chronic hepatitis C virus (HCV) infection can negatively affect patient-reported outcomes (PROs) and work productivity (WP). We assessed these factors in patients with chronic hepatitis C treated with sofosbuvir and ribavirin, with or without pegylated interferon.

Methods

The HCV-specific Quality of Life (CLDQ-HCV), Functional Assessment of Chronic Illness Therapy-Fatigue, and WP and Activity Index: Specific Health Problem questionnaires were completed before, during, and after treatment of patients infected with HCV genotypes 2 or 3 who received sofosbuvir and ribavirin for 16 or 12 weeks (the FUSION study, n=201), or patients infected with HCV genotype 1 who received pegylated interferon, sofosbuvir, and ribavirin for 12 weeks (the NEUTRINO study, n=327).

Results

Patients in each group of the FUSION study had similar PRO and WP scores at each time point (all comparisons, P>.05). Compared to baseline, patients had modest reductions in fatigue, HCV-specific quality of life, and WP and Activity Index scores during treatment (P=.02 to <.0001). However, by 4 weeks after treatment, all scores returned to baseline levels or higher. Subjects in the NEUTRINO study had greater reductions in these scores during treatment; most remained significant through 4 weeks after treatment (P<.05). Significant improvements in PROs were observed among patients with sustained virologic responses 12 weeks after treatment (SVR12) in the FUSION and NEUTRINO studies (all P<.05). In multivariate analyses, after adjustment for confounders, interferon therapy was independently associated with worse PROs after 12 weeks of treatment.

Conclusions

Based on an analyses of 2 large clinical trials (FUSION and NEUTRINO), patient outcome and productivity are more negatively affected by the inclusion of pegylated interferon in treatment than by interferon-free regimens. Patients with SVR12 had significant reported improvements in outcome in both studies.

Key Words: CLDQ-HCV, WPAI, FACIT-F, quality of life, liver disease, hepatitis C

No full text is available. To read the body of this article, please view the PDF online.

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-RESULTS FURTHER CONFIRM PHASE II STUDIES, WITH CONSISTENT VIROLOGIC RESPONSE AND TOLERABILITY PROFILE-

- SAPPHIRE-II IS THE SECOND OF SIX PHASE III TRIALS STUDYING THE INVESTIGATIONAL 3D REGIMEN-

- FUTURE DATA ANTICIPATED FROM ABBVIE'S CLINICAL TRIALS EXAMINES 3D REGIMEN WITH AND WITHOUT RIBAVIRIN, AS WELL AS TREATMENT OF HEPATITIS C IN PATIENTS WITH CIRRHOSIS-

Dec 10, 2013

NORTH CHICAGO, Ill., Dec. 10, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) released phase III results for the investigational three direct-acting-antiviral (3D) regimen plus ribavirin in patients with chronic, genotype 1 (GT1) hepatitis C virus (HCV) infection. In the 394-patient SAPPHIRE-II study, 96 percent of patients who previously failed pegylated interferon and ribavirin treatment, including approximately 49 percent of who were prior null responders, achieved sustained virologic response at 12 weeks (SVR12) with the regimen. The majority of patients were GT1a, considered a difficult-to-treat subtype, and the SVR12 rates of GT1a and GT1b were 96 percent and 97 percent, respectively. Virologic relapse or breakthrough was noted in 2 percent of patients receiving the 3D regimen plus ribavirin. In addition, the discontinuation rate due to adverse events was 1 percent.

Globally, approximately 160 million people are chronically infected with hepatitis C[1]. AbbVie's multinational HCV program is the largest all-oral, interferon-free clinical program in GT1 patients being conducted to date[2]. GT1 (with subtypes 1a and 1b) is the most prevalent genotype worldwide, with a higher prevalence of 1a in the U.S. and 1b in Europe.

"SAPPHIRE-II demonstrates that treatment-experienced genotype 1 HCV patients achieved high rates of virologic response with AbbVie's interferon-free, all-oral 3D regimen plus ribavirin," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "Completion of the two placebo-controlled SAPPHIRE studies is an important step in AbbVie's HCV clinical development program.  We look forward to the results of studies looking at AbbVie's 3D regimen with and without ribavirin in different patients, as well as data from our dedicated study in patients with cirrhosis."

About Study M13-098 (SAPPHIRE-II)

Following SAPPHIRE-I, SAPPHIRE-II is the second placebo-controlled trial and the second of six phase III trials supporting AbbVie's investigational 3D regimen for the treatment of GT1 hepatitis C patients. AbbVie will disclose detailed SAPPHIRE-II results at future scientific congresses and in publications.

SAPPHIRE-II is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with ABT-333 (250mg), ribavirin (weight-based), both dosed twice daily, and the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg) and dosed once daily in non-cirrhotic, GT1a and GT1b HCV-infected, treatment-experienced adult patients who previously failed treatment with pegylated interferon and ribavirin.

The study population consisted of 394 GT1 treatment-experienced patients with no evidence of liver cirrhosis with 297 patients randomized to the 3D regimen plus ribavirin for 12 weeks, and 97 patients randomized to placebo for the initial 12 weeks. Patients initially randomized to placebo for the first 12 weeks then received open-label treatment with the 3D regimen plus ribavirin for 12 weeks. In the study, 49 percent of patients were prior null responders to pegylated interferon and ribavirin, generally considered among the most difficult to treat successfully.

Following 12 weeks of treatment with AbbVie's 3D regimen plus ribavirin, 96 percent (n=286/297) of patients achieved SVR12 based on intent-to-treat analysis where patients with missing values for any reason were considered treatment failures. The SVR12 rates in GT1a and GT1b patients were 96 percent (166/173) and 97 percent (119/123), respectively. One subject had HCV genotype 1 and achieved SVR12, but was unable to be subgenotyped.

The most commonly reported adverse events in both the 3D and placebo arms were headache, fatigue and nausea. Discontinuations due to adverse events were reported in three (1 percent) patients receiving the 3D regimen and no patients receiving placebo. Virologic relapse or breakthrough was noted in 2 percent of patients receiving the 3D regimen plus ribavirin.  

Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.

AbbVie's HCV Development Program

The clinical program supporting our 3D regimen includes more than 2,300 GT1 patients in more than 25 countries around the world. The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral 3D regimen with or without ribavirin with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis. Results from the remaining four studies in AbbVie's phase III program will be available in the coming months, supporting regulatory submissions starting in the second quarter of 2014.

Overview of AbbVie's phase III clinical program is as follows:

Overview of AbbVie's phase III clinical program is as follows:

Study

Patients (N)

Treatment Regimen

Treatment Duration

SAPPHIRE-I

GT1, treatment-naive

(631)

  • ABT-450/rb +ABT-267c
  • ABT-333
  • Ribavirin

12 weeks

  • Placebo

12 weeks, then active treatment for 12 weeks

SAPPHIRE-II

GT1, treatment-experienced

(394)

  • ABT-450/r +ABT-267
  • ABT-333
  • Ribavirin

12 weeks

  • Placebo

12 weeks, then active treatment for 12 weeks

PEARL-II

GT1b, treatment-experienced

(210 a)

  • ABT-450/r +ABT-267
  • ABT-333
  • Ribavirin

12 weeks

  • ABT-450/r +ABT-267
  • ABT-333

12 weeks

PEARL-III

GT1b, treatment-naive

(400 a)

  • ABT-450/r +ABT-267
  • ABT-333
  • Ribavirin

12 weeks

  • ABT-450/r +ABT-267
  • ABT-333
  • Placebo

12 weeks

PEARL-IV

GT1a, treatment-naive

(300 a)

  • ABT-450/r +ABT-267
  • ABT-333
  • Ribavirin

12 weeks

  • ABT-450/r +ABT-267
  • ABT-333
  • Placebo

12 weeks

TURQUOISE-II

GT1, treatment-naive and treatment-experienced (with compensated cirrhosis)

(380 a)

  • ABT-450/r +ABT-267
  • ABT-333
  • Ribavirin

12 weeks

  • ABT-450/r +ABT-267
  • ABT-333
  • Ribavirin

24 weeks

a projected study population

b ABT-450/ritonavir

c ABT-267 is co-formulated with ABT-450/r, administered as two pills once daily

The 3D regimen consists of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's investigational 3D regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA).

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.

Safety Information for Ribavirin and Ritonavir

Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, automimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥6.

See approved product labels for more information.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow@abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements

Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements.

Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

[1] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15. 

[2] Comparison based on review of data from clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as ofNovember 15, 2013

SOURCE AbbVie Inc.

For further information: Media: Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com, or Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com, or For Investor Relations: Elizabeth Shea, +1 (847) 935-2211, elizabeth.shea@abbvie.com

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Stockholm, Sweden—Medivir AB (OMX: MVIR) Based on the recent approvals in Japan, Canada and USA, simeprevir is now available in all three markets. Simeprevir is administered once-daily for 12 weeks in combination with pegylated interferon and ribavirin, followed by pegylated interferon and ribavirin alone for an additional 12 or 36 weeks.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 8.30 a.m. CET on 10 December 2013.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB for the treatment of chronic hepatitis C infection in combination with other antivirals in HCV genotype 1 & 4 infected patients with compensated liver disease, including cirrhosis.

Simeprevir was approved for the treatment of genotype 1 hepatitis C in September 2013 in Japan and in the USA and Canada in November and has now been launched in all three markets. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C.

To date, more than 3,700 patients have been treated with simeprevir in clinical trials. Simeprevir is also being studied in several interferon-free regimens using selected combinations of direct-acting antiviral agents with different mechanisms of action.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

Medivir is a collaborative and agile pharmaceutical company with an R&D focus on infectious diseases and a leading position in hepatitis C. We are passionate and uncompromising in our mission to develop and commercialize innovative pharmaceuticals that improve people’s health and quality of life.

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Dec. 9, 2013 — Diabetes was associated with an increased risk for developing a type of liver cancer called hepatocellular carcinoma, and this association was highest for Latinos, followed by Hawaiians, African-Americans, and Japanese-Americans, according to results presented here at the Sixth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held Dec. 6-9.

"People with diabetes have a two- to threefold higher risk for hepatocellular carcinoma compared with those without diabetes," said V. Wendy Setiawan, Ph.D., assistant professor in the Department of Preventive Medicine at Keck School of Medicine of the University of Southern California. "We also found that the interethnic differences in the prevalence of diabetes were consistent with the pattern of hepatocellular carcinoma incidence observed across ethnicities: Ethnic groups with a high prevalence of diabetes also have high hepatocellular carcinoma rates, and those with a lower prevalence of diabetes have lower hepatocellular carcinoma rates."

The number of new cases of hepatocellular carcinoma in the United States tripled in the past three decades, with Latinos and African-Americans experiencing the largest increase in incidence. Prior research has suggested that diabetes may be a risk factor for hepatocellular carcinoma, and its increasing incidence may be contributing to the rising rate of hepatocellular carcinoma.

"People with diabetes should be aware that their condition is associated with a higher risk of developing hepatocellular carcinoma," Setiawan said. "Maintaining a healthy weight, managing their diabetes, preventing and treating hepatitis infection, and limiting alcohol and tobacco use should be in their priority to-do list."

In addition, Setiawan said that public health efforts encouraging obesity/diabetes prevention and effective diabetes management should be directed at high-risk populations.

Setiawan and colleagues examined if the association between diabetes and hepatocellular carcinoma differed by race/ethnic group. They analyzed data from more than 150,000 people enrolled in the Multiethnic Cohort Study between 1993 and 1996. During the study follow-up period of about 15 years, 506 cases of hepatocellular carcinoma were reported: 59 cases in non-Hispanic whites, 81 in African-Americans, 33 in Hawaiians, 158 in Japanese-Americans, and 175 in Latinos.

Compared with non-Hispanic whites, Latinos had 2.77 times the risk for being diagnosed with hepatocellular carcinoma, the highest risk identified. Native Hawaiians had 2.48 times the risk; African-Americans, 2.16; and Japanese-Americans, 2.07.

The prevalence of diabetes was consistent with that of hepatocellular carcinoma. Sixteen percent of Hawaiians, 15 percent of Latinos and African-Americans, 10 percent of Japanese-Americans, and 6 percent of non-Hispanic whites had diabetes. Compared with those without diabetes, Latinos with diabetes had 3.3-fold higher risk for hepatocellular carcinoma; Hawaiians, 2.33-fold higher risk; Japanese-Americans, 2.02-fold higher risk; African-Americans, 2.02-fold higher risk; and non-Hispanic whites had 2.17-fold higher risk.

Hepatocellular carcinoma was attributed to diabetes in 26 percent of cases in Latinos, 20 percent of Hawaiians, 13 percent of African-Americans, 12 percent of Japanese-Americans, and 6 percent of non-Hispanic whites, the researchers estimated. According to Setiawan, eliminating diabetes could potentially reduce hepatocellular carcinoma incidence in all racial/ethnic groups, with the largest potential reduction possible in Latinos.

Story Source:

The above story is based on materials provided by American Association for Cancer Research (AACR).

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

A Better Treatment for Hepatitis C

Provided by The New Yorker

DECEMBER 9, 2013

POSTED BY CELINE GOUNDER

GILEAD SCIENCES

Two years ago, the pharmaceutical company Gilead Sciences paid eleven billion dollars for Pharmasset, a small biotechnology firm based in New Jersey. Pharmasset did not have a single major drug on the market, but the company had developed a drug called sofosbuvir, which promised to do for hepatitis C what protease inhibitors did for H.I.V. in the mid-nineties: transform a hard-to-treat illness into an easily managed disease. The Food and Drug Administration officially approved sofosbuvir, also known by the brand name Sovaldi, last week, six years after it was first synthesized. It is now all but guaranteed to become a blockbuster drug and generate billions of dollars in sales for Gilead.

Hepatitis C, the target of sofosbuvir, is behind what the magazine’s Jerome Groopman described as a “shadow epidemic” of liver disease and cancer: rates of liver cancer are increasing faster than rates for any other type of cancer in the United States. Hepatitis C, which inflames and scars the liver, is thought to account for half of this rise. Worse, up to three quarters of the three million Americans who are infected with hepatitis C are not aware of it. By the time they become symptomatic, they may have been infected for decades. All the while, the hepatitis-C virus has been silently doing its terrible work. About a third of the six thousand Americans who get liver transplants each year now do so as a result of hepatitis C, as the late Lou Reed did.

Hepatitis C is one of a number of viruses that infect the liver. It, along with hepatitis B and D, are transmitted through sex and blood exposure. There is no vaccine for it. In 1998, the Centers for Disease Control and Prevention began recommending screenings for hepatitis C based on risk and exposure. But, because patients don’t always own up to or remember their potential exposures, and because many physicians are embarrassed to ask patients about drug use and sex, the C.D.C. now recommends that all Americans born between 1945 and 1965—the baby boomers, who make up three-quarters of those infected—also be screened. Even so, many clinicians remain reluctant to test patients, because the treatment is so difficult to endure.

The existing treatment regimen involves weekly injections of a substance called interferon combined with other drugs. Interferon is naturally produced by the body to combat viral infections; it’s what makes you feel tired, feverish, and generally miserable when you have the flu. In the treatment of hepatitis C, it boosts the immune system. But the injections have brutal side effects: reduced appetite and hair loss, and, over long periods of time, anemia, fatigue, and depression. If the side effects of interferon don’t sound bad enough, the other drugs often cause more anemia, fatigue, chills, nausea, vomiting, diarrhea, hair loss, and rash.

The months of misery do not guarantee that the patient will emerge cured, either, since some strains of hepatitis C—there are six genotypes—are more responsive to current treatment than others. Because hepatitis C and H.I.V. are transmitted similarly, patients are often infected with both, which further complicates treatment because of toxicities, drug interactions, and difficulties getting the doses right.

Sofosbuvir, on the other hand, is the first hepatitis-C treatment that does not require interferon injections, can be taken simply as a pill with other drugs—like the antiviral ribavirin—and typically works in a fraction of the time of existing treatment cycles. According to Alan Franciscus, the executive director of the Hepatitis C Support Project, a patient-advocacy group that educates patients and clinicians about hepatitis C, “Sofosbuvir has the potential to change the treatment of hepatitis C because of the ease of use—one-pill-a-day therapy, very high cure rates, shorter treatment duration, and fewer side effects.” After enduring his own year and a half of interferon treatment before finally being cured of hepatitis C, “I am a bit envious,” Franciscus admitted.

Sofosbuvir was invented by, and named after, Michael Sofia, the kind of person who daydreams about enzymes metabolizing drugs. Sofia was raised in a rowhouse on the northeastern side of Baltimore. His parents, a barber and a payroll clerk, were both children of Italian immigrants, and born within a block of each other in Baltimore’s Little Italy. Although they instilled an immigrant’s appreciation for education in their three children, who would all go on to work in science, Sofia’s reading skills were so poor as a child that in the fourth grade he was put in a remedial reading class. Sofia credits the nun who taught him with transforming into a “completely different student.”

Sofia eventually enrolled at Cornell and went on to earn his Ph.D. from the University of Illinois, before leaving academia to focus on drug development. Early in his career, at Squibb, he worked on cholesterol-lowering drugs. But he preferred working at small biotech companies, which function more like Internet startups, to Big Pharma. “You have an idea, you discuss it, you make a decision, you move forward,” Sofia explained to me. So, in 2005, Sofia took a risk and joined Pharmasset, then a minor biotech firm.

When Sofia arrived at Pharmasset, the company had already started moving away from the H.I.V.-drug development that it was initially known for, since the market had become saturated with “nucleoside” drugs that worked reliably with manageable side effects. Nucleosides are the building blocks of D.N.A. and R.N.A.; they can be chemically altered to terminate chains of genetic code early, producing something like a defective Lego that can’t be build onto, stopping the growth of the virus. Though this chemistry had been used successfully to treat H.I.V., only a few labs were trying this approach with hepatitis C. Sofia noted that one of the company’s test drugs, PSI-6130, showed activity against hepatitis C.

Sofia realized that any effective hepatitis-C drug not only needed to get into the liver, where the virus was replicating, but stay there, to avoid unintended side effects elsewhere in the body. It is relatively easy to transport a drug to the liver: when you eat or drink something, it is absorbed into the bloodstream by the stomach and intestines, and in turn flows directly to the liver, the body’s metabolic engine. The problem is that, in their active form, nucleoside drugs don’t enter liver cells. Sofia hypothesized that if he could shroud a nucleoside with an “invisibility cloak” to get it into liver cells he could then count on the liver’s enzymes to break down the cloak and activate the drug. Once the cloak has been shed, the nucleoside would be trapped inside, protecting the rest of the body from exposure. “A lot of people were telling me when I had this idea that this is never going to work,” he told me. “People have been trying to do this for a long time, this is a hopeless cause.”

Sofia explicitly engineered sofosbuvir with this and a number of other goals in mind—that the drug would be taken orally, ten times more potent than PSI-6130, and effective against all six genotypes of hepatitis C. Beginning with a modified version PSI-6130, after three years of development, Sofia and his colleagues arrived at sofosbuvir in 2007. What’s remarkable, according to Sofia, is that it was not in fact a happy accident, but a product of explicit engineering. “It does exactly what we designed it to do, which is one of those things that hardly ever happens,” he said.

Sofia’s clinical colleagues at Pharmasset began testing sofosbuvir in human patients between 2010 and 2011. When Pharmasset’s medical advisory group reviewed the data, they realized for the first time that sofosbuvir could potentially treat hepatitis patients without interferon—considered a heresy at the time. Since then, others have conducted larger trials of sofosbuvir—studies named POSITRON, FUSION, FISSION, NEUTRINO, and VALENCE, playing on the idea that sofosbuvir is a nucleotide—which showed that the drug is effective against all six genotypes of hepatitis C, with minimal side effects. Last month, at The Liver Meeting in Washington, D.C., scientists presented studies showing that sofosbuvir could also help cure hepatitis C in harder-to-treat patients, like those who also have H.I.V. or more advanced liver disease. There will be more studies of sofosbuvir to come, including post-marketing trials that will look for previously undetected side effects—as well as research on how sofosbuvir can best be used in combination with other new drugs in the pipeline.

Sofosbuvir does have limits, however. The first genotype of hepatitis C has always been the most difficult to treat, and remains so, even with the advent of sufosbuvir. Most patients infected with that genotype still need a combination of interferon injections and ribavirin, at least until other, new drugs hit the market, which is anticipated to happen in the next year or two. More problematically for the hundred and fifty million people worldwide who suffer from hepatitis C, Franciscus and other advocates are worried that sofosbuvir and other new drugs in the pipeline may be too expensive. Gilead announced that the wholesale cost of sofosbuvir will be a thousand dollars a pill, with the total cost of treatment easily exceeding a hundred thousand dollars per patient. Insurance companies, meanwhile, may only cover treatment for hepatitis-C patients who already have liver damage.

Following the acquisition in 2011, Sofia worked with Gilead for about a year to manage the transition process, a time he doesn’t recount fondly. “When you develop something and you take very personal ownership of it, and see it move on to where you’re no longer involved in a direct way to what’s happening to that drug,” Sofia said, “well, it’s very difficult to go through that.”

Afterward, Sofia and some of his old Pharmasset colleagues started a new company, OnCore BioPharma, to develop cures for hepatitis B. Hepatitis B is another leading cause of liver cancer, and is far more transmissible from mother to child, during pregnancy and birth, than hepatitis C; many who succumb to hepatitis B were infected as infants. Currently, we only have drugs that suppress hepatitis B, but you may have to take them for the rest of your life to keep the virus in check.

I asked Sofia what he’d be calling his next drug. “I consider myself very lucky to have one drug, he replied. “When I was doing undergraduate research at Cornell, I was told that I had to be comfortable with failure because eighty per cent of what you’re going to do is going to fail.”

Celine Gounder is a physician, public-health specialist, and medical journalist.

Photograph: David Paul Morris/Bloomberg via Getty

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