February 10, 2014

The End of Hepatitis C

Clinical Gastroenterology and Hepatology

Article in Press

Norman L. Sussman, Christopher H. Remien, Fasiha Kanwal

published online 30 January 2014.
Uncorrected Proof

Go on till you come to the end; then stop.

Lewis Carroll We are at a turning point in the management of the hepatitis C virus (HCV) epidemic. HCV can be cured, but treatment up to this point has required a toxic combination of drugs. This is about to change; the second generation of direct-acting antiviral agents promises high cure rates with few side effects. This gives us the historical opportunity to eradicate HCV from the entire population. Our article addresses the advantages of universal eradication of HCV infection from the United States and the steps required to achieve this goal.

Hepatitis C Virus 

HCV is a small, hepatotropic RNA virus that infects an estimated 3–7 million people in the United States1 and 170 million worldwide.2 Transmission is almost entirely parenteral, and the most predictive risk factor for chronic infection in the United States is current or past injection drug use. The transmission efficiency of HCV is high, and exposure is followed by chronic infection in 65%–85% of cases. Most HCV cases in the United States are caused by genotype 1; other genotypes may predominate in other countries. HCV genotype 1 has traditionally been the most difficult to treat because of interferon nonresponsiveness, and attempts to create a vaccine for HCV have been unsuccessful to date.

The consequences of HCV infection are serious; recent studies show a major impact on health-related quality of life, liver-related mortality, all-cause mortality, and medical resource utilization among patients with HCV infection.3, 4, 5 Studies also show that successful treatment of HCV infection improves health-related quality of life and reduces mortality in patients with HCV.6, 7

Antiviral Therapy 

HCV has 3 nonstructural proteins that are essential for viral replication, an NS3/4A protease, an NS5B polymerase, and the NS5A protein. Each of these proteins is an excellent target for antiviral therapy.

Antiviral therapy for HCV has improved incrementally since 1986, beginning with thrice-weekly interferon monotherapy and progressing to a 3-drug regimen consisting of weekly pegylated interferon injections with oral ribavirin and a protease inhibitor (boceprevir or telaprevir). These improvements have been associated with a sustained virologic response in up to 72% of patients in randomized trials.8 Treatment-induced sustained virologic response is durable; late relapse has been described but is rare.9, 10, 11 Thus, HCV is one of the few—and possibly the only—chronic viral infection that can be cured.

Exciting changes are about to take place with the recent Food and Drug Administration approval of a new class of once-daily protease inhibitor (simeprevir) and the first-in-class once-daily polymerase inhibitor (sofosbuvir).12 Other drugs including alternative protease inhibitors, polymerase inhibitors, and NS5A inhibitors are in different phases of clinical trials.13 Although interferon remains part of the antiviral arsenal for the moment, combinations of oral agents have proven effective, and interferon-free treatment is likely to become the new standard of care within the next 12–18 months.14, 15, 16

Other Infectious Epidemics 

Several epidemic or endemic diseases have been controlled or eliminated and serve as useful case studies as we make the case for HCV eradication. The most spectacular example was smallpox, a worldwide scourge responsible for millions of deaths. A primitive form of vaccination (variolation) started around 1670, but true vaccination only gained popularity after Edward Jenner’s experiments with cowpox in 1796. The last naturally acquired case of smallpox occurred in Somalia in 1977, and the last human case occurred as the result of a laboratory exposure at the University of Birmingham in 1978. Smallpox was declared officially eliminated on May 8, 1980 when the 33rd Assembly of the World Health Organization accepted the Final Report of the Global Commission for the Certification of Smallpox Eradication.17

Polio is another important case. The Global Polio Eradication Initiative of the World Health Organization was launched in 1988 at a time when polio was endemic in 125 countries, with an estimated 350,000 new cases annually. The incidence of polio has since been reduced by more than 99%, and only 3 countries (Nigeria, Pakistan, and Afghanistan) have failed to eradicate the virus.18 Despite this amazing achievement, endemic disease is a threat to other nations, as demonstrated by an outbreak in China in 2011, 17 years after the last reported case of paralytic polio in that country.19 As pointed out in the accompanying editorial, no country is safe without global eradication.20

An example of a successful national disease elimination program is universal hepatitis B vaccination in Taiwan, instituted in 1984. At the 25th anniversary of the program, the prevalence of hepatitis B surface antigen had declined from 10% to 0.9%, hepatitis B surface antibody (protective antibodies) had increased from 24.5% to 55.9%, and hepatitis B core antibody (evidence of prior infection) had decreased from 28% to 7%.21, 22 These data highlight the gains as well as the fact that vaccination takes time to change the prevalence of a disease, especially if the goal is complete elimination.

A final example with relevance to HCV is infection with human immunodeficiency virus (HIV), a virus that cannot be cured by vaccination but can be controlled with effective treatment. Unlike polio and smallpox and similar to HCV, HIV is not easily transmitted to the general population but is associated with certain types of behavior. Progress in the control of HIV has required high levels of community awareness, timely linkage to care, and highly effective antiretroviral therapy. These factors have reduced the prevailing level of HIV.23 A study of men who have sex with men in San Francisco (a group that comprises 90% of cases of HIV/acquired immunodeficiency syndrome in that city) reported a marked decline in number of patients who reported being unaware of their infection from 21.7% in 2004 to 7.5% in 2011.24 As a result, the community viral load, described as the mean, median, or total viral load of a population living with HIV, showed a similar decline, with commensurate declines in the incidence of HIV and newly diagnosed and reported cases of HIV.25, 26

How Do We Apply These Lessons to Hepatitis C Virus?

Eradication of a disease has never occurred through individual or commercial action; it has always required a concerted and large-scale population-based approach. The examples above have all been achieved by mobilizing massive resources, including funding of antiviral therapy in the Ryan White program to control HIV. These lessons can be applied to HCV with some interesting variations on the theme. On the positive side:

1. HCV can be cured, so the benefits of treatment are nearly instantaneous instead of the decades required for a successful vaccination program or the need for lifelong therapy in the case of HIV.

2. The entire epidemic in the United States is confined to 3–7 million. Identifying and treating this cohort can potentially eliminate HCV from the U.S. population27, 28 and may prevent a second epidemic that is likely to accompany drug use among teens and young adults.

On the negative side:

1. Most infected persons in the United States are unaware of their infection; ongoing education and large-scale screening will be necessary.

2. HCV therapy is currently complicated and is delivered by a relatively small number of providers, too few to manage the problem. Treatment must be simplified,29 and the number of competent treating providers must be increased through innovative programs.30, 31

3. Patients who are cured are not immune and may become reinfected, as described in a prison population.32 In the absence of herd immunity, universal eradication of HCV is the only way to prevent reinfection.

4. Worldwide elimination of HCV is a daunting task; targeted treatment has been proposed,33, 34 but it remains too complicated and costly in developing countries. Global elimination of HCV will require very simple therapy or an effective vaccine.35

Business as Usual or a Bold Step Forward? 

Enthusiasm over the availability of the new direct-acting antiviral agents is dampened by concerns about cost; sofosbuvir has a retail cost of $1,000 per tablet ($84,000 for a 3-month course). This is similar to the cost of the recently obsolete triple drug regimens, which average $84,063 per course (including adverse event management) and a median cost of $195,000 per cure.36 The newer drug regimens will have higher cure rates, shorter courses, and lower adverse events and may cost less per cure. Nevertheless, treating 3.2 million infected individuals in the United States with sofosbuvir carries a price tag of about $270 billion in drug costs alone.

Controlling the cost of HCV therapy will require a random approach to treatment (treat those who show up), rationed care (make deliberate choices about whom we treat), or an innovative plan that attempts to treat everyone. The current approach has features of the first 2 options. Calls for treating only patients with advanced or advancing liver disease ignore 3 important facts. First, HCV is associated with extrahepatic disease; focusing only on the liver ignores the effect on non-hepatic disease and mortality. Second, following infected patients is expensive, requiring decades of office visits, lab tests, scans, and intermittent liver biopsies in some patients. Third, failure to address the problem proactively has a significant cost; Centers for Disease Control and Prevention projects that costs for the 10-year period from 2010–2019 will exceed $10.7 billion, with an additional $54.2 billion in premature mortality and $21.3 billion in morbidity and disability.37

With so much money at stake, it seems that all parties might profit from universal treatment, but it will require a new way of thinking. Instead of retail sales, we might look to something like the defense industry where the government awards contracts for goods and services that serve the public interest. We could replace low-volume, high-price sales with a strategy that spreads the same money over a much larger population. Skeptics may say that universal treatment is unnecessary; not all infected persons progress to advanced liver disease. These same voices may have had the same arguments about other diseases, but we find no written opinion that mourns the disappearance of smallpox or polio.

What Will It Take? 

Two big government programs of similar scale are the Centers for Medicare and Medicaid’s program for free access to chronic hemodialysis and the Ryan White program for HIV care. Curing HCV is a smaller project because it has a defined population that is approaching the end of an epidemic. Furthermore, unlike the existing programs, an HCV treatment program holds the promise of complete eradication of the targeted condition (HCV) from the United States. However, the plan will require a proactive and bold approach.

Safe and effective oral antiviral agents are already available,12, 15, 16 but the drugs are made by different companies, and many are not yet on the market. We must ask whether companies can be incentivized to cooperate as they have on drugs such as Bactrim/Septra and the combination antiviral agents Truvada and Atripla. In return for cooperation and reasonable pricing, the federal and state funding agencies and private insurers must agree to fund universal therapy. The government can provide additional incentives such as expedited Food and Drug Administration review of promising agents and protection from groundless lawsuits.

Conclusion

Safe oral combination therapy will allow us the historic opportunity to clear HCV from the U.S. population. The arguments can be summarized as the cost of health vs the cost of healthcare. We will hear arguments on both sides, but we must ask ourselves whether we should let a historic opportunity pass without at least considering the possibility.

References 

Conflicts of interest This author disclose the following: Dr Sussman is a speaker for Genentech, Gilead, and Janssen; receives research support from AbbVie, Biotest, BMS, Boehringer Ingelheim, Gilead, Merck, Novartis, and Vertex; and is on the advisory board for Merck. The remaining authors disclose no conflicts.

PII: S1542-3565(14)00133-5

doi:10.1016/j.cgh.2014.01.025

© 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

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HBV Tests Urged for High-Risk Groups

Published: Feb 10, 2014

By Michael Smith, North American Correspondent, MedPage Today

People at high risk for hepatitis B (HBV) should be screened for the viral infection, according to a draft recommendation from the U.S. Preventive Services Task Force.

If approved, the recommendation would apply mainly to people born in countries where the prevalence of the disease is greater than 2%, the task force said.

But it would also apply to people born in the U.S. but not vaccinated as infants and whose parents come from regions with a high prevalence of HBV infection.

People living with HIV, injection drug users, and men who have sex with men would also be considered as being at high risk for HBV infection, as would patients with a weakened immune system or undergoing treatment for kidney failure.

The draft recommendation is available for comment until March 10 on the task force Web site.

Most people born in the U.S. currently are vaccinated against the virus at birth, but there are still between 700,000 and 1.4 million people in the U.S. chronically infected with HBV, the task force notes in the draft recommendation.

"Fortunately, most people in the U.S. are no longer at risk of getting hepatitis B," commented task force member Mark Ebell, MD, of the University of Georgia in Athens.

"Because some countries have high rates of HBV infection, it is important for immigrants from those countries and their doctors to be aware of their risk status and screen them if appropriate," Ebell said in a statement.

The natural history of the illness varies, but an estimated 15% to 25% of people with chronic HBV die of cirrhosis or hepatocellular carcinoma. Those with chronic infection also serve as a reservoir for transmission, the agency noted.

After immunization programs began in 1991, the number of reported acute symptomatic cases of HBV infection decreased from more than 20,000 cases annually in the mid-1980s to 2,890 cases in 2011, the task force noted.

But because of under-reporting, the actual number of new cases every year in the U.S. is likely higher, the draft recommendation says.

The task force said screening tests are very accurate, with sensitivity and specificity both greater than 98%, and likely have small or no associated harm.

Several antiviral agents have been approved for HBV treatment, the task force noted, and there is "convincing evidence" that therapy improves intermediate outcomes, including virologic or histologic improvement or clearance of the HBV e antigen (HBeAg).

And, the task force argued, there is "moderate" evidence that treatment reduces the risk of hepatocellular carcinoma with little associated harm.

In 2004, the task force rejected the idea of screening in the general population, arguing at the time that the potential benefits were smaller than the risks.

Since then, the CDC and the American Association for the Study of Liver Diseases have recommended screening for HBV infection in high-risk individuals, with definitions similar to those of the task force.

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Gilead hands its hep C combo to the FDA as AbbVie race heats up

Provided by FierceBiotech

February 10, 2014 | By Damian Garde

Right on schedule, Gilead Sciences ($GILD) has submitted for FDA approval for its combination hepatitis C treatment, inching toward the era of interferon-free treatment and widening its lead on rival AbbVie ($ABBV).

Gilead handed in an NDA for its fixed-dose cocktail of the NS5A inhibitor ledipasvir and the polymerase inhibitor sofosbuvir, approved on its own last year as Sovaldi. In three Phase III studies on patients with the tough-to-treat genotype 1 variant of the virus, Gilead's combo notched cure rates as high as 99.1%, all without the need for painful interferon or ribavirin. The company expects its breakthrough-designated drug to win approval this year.

"Today's filing brings us one step closer to our goal of offering all patients with hepatitis C a simple, safe and highly effective all-oral treatment regimen," R&D chief Norbert Bischofberger said in a statement.

Meanwhile, rival AbbVie is preparing an interferon-eschewing combo of its own, planning to submit to the FDA next quarter and launch its contender by year's end, thus setting up an eventual battle for market dominance. Bringing up the rear is Bristol-Myers Squibb ($BMY), whose daclatasvir got the cold shoulder from Gilead when the biotech chose to advance its in-house combo instead of pairing Sovaldi with that NS5A blocker.

Analysts expect Sovaldi to notch peak sales of around $7 billion, assuming the now-filed combo therapy takes off. AbbVie's contender is expected to top out at just $3 billion a year, but the prospect of an eventual price war could well shift the balance of power between the two, and AbbVie could grab a bigger market share if it can woo payers away from Gilead's much-maligned pricing structures.

But once the two go head to head, Gilead will likely have a leg up in the convenience department: Its combination, developed as LDV/SOF, is a fixed dose in a single pill, while AbbVie's--which includes the antiviral agents ABT-267, ABT-333 and ABT-450/ritonavir--requires multiple treatments per day.

Notably, despite both expecting 2014 launches, neither company deigned to include sales from the two combos in their recent full-year revenue guidances.

- read the announcement

Source

Also See: Gilead Files for U.S. Approval of Ledipasvir/Sofosbuvir Fixed-Dose Combination Tablet for Genotype 1 Hepatitis C

Poor Nations Seek New Hepatitis C Drug

FEB. 10, 2014

Global Health

By DONALD G. McNEIL Jr.

GLOB-blog225

Now that wealthy nations have a simple pill regimen that can cure hepatitis C, calls are mounting from representatives of poor nations for the same drugs.

In December, the Food and Drug Administration approved sofosbuvir, from Gilead Sciences. Under the brand name Sovaldi in the United States, it is expected to cost $84,000 per treatment. Four other companies are developing similar pills expected to reach the market in the next three years, with similarly high price tags.

Worldwide, at least 150 million people — nearly five times the number with H.I.V. — are believed to have hepatitis C, which can cause liver damage and cancer.

The Access Campaign of Doctors Without Borders has estimated that cocktails of sofosbuvir and similar drugs can be made for $250 or less, and it is lobbying to make that possible, said Rohit Malpani, the campaign’s policy chief.

It will ask the World Health Organization to put sofosbuvir on its list of drugs the agency tests for countries too poor to have their own drug regulatory agencies.

It is opposing Gilead’s patent application for sofosbuvir in India. Gilead, meanwhile, hopes to license Indian drug companies to make a $2,000-per-treatment version.

The campaign also plans to ask the three top funders of the war on AIDS — the Global Fund to Fight AIDS, Tuberculosis and Malaria; the President’s Emergency Plan for AIDS Relief; and Unitaid — to agree to pay for hepatitis drugs too if the prices become affordable, which will let Doctors Without Borders start pilot treatment projects in several countries.

Source

Also See: Gilead to license hepatitis C drug to lower-cost manufacturers in India

-- If Approved, Fixed-Dose Combination Would be First Oral Treatment Regimen for Patients with Genotype 1 HCV Infection, Eliminating Need for Both Interferon and Ribavirin --

FOSTER CITY, Calif., Feb 10, 2014 (BUSINESS WIRE) -- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg for the treatment of chronic hepatitis C genotype 1 infection in adults. The data submitted in the NDA support the use of LDV/SOF in patients with genotype 1 hepatitis C virus (HCV) infection, with a treatment duration of eight or 12 weeks depending on prior treatment history and whether they have cirrhosis. Approximately 75 percent of people infected with HCV in the United States have the genotype 1 strain of the virus.

“Today’s filing brings us one step closer to our goal of offering all patients with hepatitis C a simple, safe and highly effective all-oral treatment regimen,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer. “Based on the data from the Phase 3 ION studies, the LDV/SOF combination may have the potential to cure HCV in genotype 1 patients in as little as eight weeks and without the need for interferon injections or ribavirin.”

The FDA has assigned LDV/SOF a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. The NDA for LDV/SOF is supported by three Phase 3 studies, ION-1, ION-2 and ION-3, in which nearly 2,000 genotype 1 HCV patients were randomized to receive the fixed-dose combination, with or without RBV, for treatment durations of eight, 12 or 24 weeks. Trial participants included patients who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens, and also included patients with compensated cirrhosis.

Gilead plans to file for regulatory approval of LDV/SOF in other geographies, including the European Union, in the first quarter of 2014. Gilead has submitted an application to the European Medicines Agency (EMA) for accelerated assessment of LDV/SOF, a designation that is granted to new therapies and medicines of major public health interest. If accepted, accelerated assessment could shorten the EMA’s review time of LDV/SOF by two months, although it does not guarantee a positive opinion from the Committee for Medicinal Products for Human Use or approval by the European Commission.

LDV/SOF is an investigational product and its safety and efficacy has not yet been established.

SOF as a single agent was approved by the FDA under the tradename Sovaldi® on December 6, 2013 and by the European Commission on January 17, 2014.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that FDA may not approve the LDV/SOF fixed-dose combination, and that any marketing approvals, if granted, may have significant limitations on its use. In addition, Gilead may be unable to file for regulatory approval of LDV/SOF in other geographies in the currently anticipated timelines. Further, additional clinical studies of LDV/SOF, including results from the 24-week arms of ION-1, may produce unfavorable results. As a result, Gilead may not be able to successfully commercialize LDV/SOF, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at www.Gilead.com .

Sovaldi is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com , follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

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PUBLIC RELEASE DATE: 7-Feb-2014

Contact: Leila Gray
leilag@uw.edu
206-685-0381
University of Washington

newlyfoundta

This is a schematic on the window board of Dr. Ram Savan's lab at UW Medicine South Lake Union in Seattle. The schematic outlines how a genetic variant produces a robust antiviral response to the hepatitis C virus. Credit: Ram Savan/University of Washington

The hepatitis C virus (HCV) has a previously unrecognized tactic to outwit antiviral responses and sustain a long-term infection. It also turns out that some people are genetically equipped with a strong countermeasure to the virus' attempt to weaken the attack on it.

The details of these findings suggest potential targets for treating HCV, according to a research team led by Dr. Ram Savan, assistant professor of immunology at the University of Washington. The study was published in Nature Immunology.

HCV infects more than 150 million of the world's people. The virus is notorious for evading the body's immune system and establishing an infection that can continue for decades, despite treatment. A lasting infection can damage the liver, and in some cases produce liver cancer. HCV infection is a major cause of liver failure requiring an organ transplant.

The virus, hiding in other tissues, can return in the transplanted liver. HCV and the human immune system are engaged in a seemingly never-ending duel, each trying to overcome the others latest move. Several HCV mechanisms for defying the body's immune system have already been uncovered.

Present treatments are about 70 percent effective in curing the infection, Savan said. The triple combination treatments consist of interferon, ribavirin and direct-acting antiviral agents.

He added, however, that resistant strains of HCV are emerging in antiviral treated patients. Also troubling, he said, is that certain patients can undergo almost a year of treatment weeks – and still be infected. They've endured the unpleasant, flu-like side effects of the regimen with little benefit.

After observing that patients of Asian descent reacted better to HCV treatment than did those of African descent, other research teams searched entire human genomes to identify gene clusters associated with response to therapy.

On chromosome 19, the scientists found different, single-letter DNA code changes linked to treatment response and the natural ability to clear HCV infection.

These tiny genetic variations are located near an area that encodes for interferon-lamda3 (IFNL3), also called interleukin-28B. Viruses can trigger blood cells and other cells to produce this potent substance, which is released to protect against virus invasion.

The mechanism aligning this genetic finding with clearance of HCV had been elusive, Savan's group noted in their paper. His team discovered how the single-letter variation in the IFNL3 gene was responsible for the differences between those who could and those who could not effectively clear HCV.

Individuals who carry the T (for thymidine) variant have an unfavorable outcome in fighting HCV, while those who carry the G (for guanosine) variant have a favorable outcome.

Their data showed that HCV could induce liver cells to target the activities of the IFNL3 gene with two microRNAs. MicroRNAs are silencers: They stop the messengers who transmit information to produce a protein from a gene, in this case the production of the antiviral interferon lambda-3.

These two particular microRNAs are generally turned off in liver cells, until HCV coerces them to act on its behalf. Normally, these so called myomiRs are associated with myosin-encoding genes in skeletal and heart muscle.

"This is a previously unknown strategy by which HCV evades the immune system and suggests that these microRNAs could be therapeutic targets for restoring the host antiviral response," the researchers wrote in their paper. Adding support to this suggestion is the researchers' observation that the bad-acting microRNAs in question could not land on and repress interferon lambda-3, if the host carried the favorable "G" variant.

In those cases, the host is able to escape adverse regulation by HCV, the researchers observed. Savan pointed out that this particular escape variant has been found only in humans, and not in other primates. He said it is not yet known if the G variant arose in humans as a response to selective pressure by infection with HCV.

###

Savan came to the University of Washington in late 2011 from the National Institutes of Health. The first author on the paper, Adelle McFarland, was a research scientist in Savan's lab and is now a graduate student in the Molecular and Cellular Biology Program at the UW.

Funding for this project came from a start-up grant from the UW Department of Immunology and from the National Institutes of Health (HHSN261200800001E, AI060389, AI88778, and CA148068)

Other researchers on the project, reported in the article "The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAS," were Stacy M. Horner, Abigail Jarret, Rochelle C. Joslyn, all at the UW Department of Immunology at the time of the study; Eckart Bindewald and Mary Carrington of the Frederick National Laboratory for Cancer Research, Bruce A. Shapiro of the National Cancer Institute, and Don A. Delker and Curt H. Hagedorn, both of the University of Utah. Michael Gale, Jr., a collaborator in this study, is from the UW department of Immunology.

A Nature Immunology News & Views commentary, "Outflanking HCV." by Zhigang Tian of the University Of Life Sciences Of China in Hefei, gives a perspective on the research findings.

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The Hep C Race Is Heating Up: AbbVie Vs. Gilead

Provided by Seeking Alpha

Feb. 10, 2014 7:47 AM ET  |  About: ABBV, GILD

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Peter Geschek

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

In January, AbbVie (ABBV) released positive results from the remaining Phase 3 studies of its all-oral hepatitis C regimen and said it will start submitting applications to the FDA early in the second quarter. Assuming a favorable response, AbbVie could start marketing the drugs in late 2014.

Meanwhile, Gilead (GILD) is planning to submit in the first quarter an FDA application for a fixed-dose combination of the recently approved Sovaldi with the NS5A inhibitor ledipasvir.

Both companies have a breakthrough designation from the FDA.

Both the AbbVie and Gilead hepatitis C regimens appear effective, with cure rates in the high 90 percent range for both new-to-treatment and previously treated patients. AbbVie's combinations seem especially effective for the seriously ill segment of the patients.

The Gilead regimen consists of a single pill taken once daily plus ribavirin, if needed, which adds an additional pill taken twice daily.

AbbVie's regimen requires two pills to be taken in the morning, plus another pill at night. Again, if ribavirin is necessary, it's additional. AbbVie said it is working on a coformulation, to consolidate the pills in the future.

AbbVie

AbbVie calls its multinational HCV program the largest all-oral interferon-free clinical program in Genotype 1 patients conducted to date.

Genotype 1 is the most prevalent genotype in the developed world, and is roughly evenly distributed between Genotype 1a and 1b. AbbVie's Phase 3 program enrolled 2,300 patients at clinical sites in 25 countries.

The goal was to maximize SVR (sustained virologic response) rates across various patient types, from patients who are new-to-treatment to the most difficult ones to treat, such as nonresponders to interferon-based therapy and patients with advanced liver fibrosis or cirrhosis.

Late last year AbbVie released results from the Sapphire trials, which showed that the therapy plus ribavirin, in both new and previously treated patients, produced very high SVR rates of 96 percent.

In January the company reported results from the four remaining Phase 3 trials.

The 380-patient Turquose-2 study is the only dedicated trial of an all-oral therapy in the difficult to treat cirrhotic patient population. Results from the trial show that 92 percent of the patients treated with AbbVie's combination for 12 weeks achieved SVR12 and 96 percent of the patients treated for 24 weeks also achieved SVR12.

These results represent a competitive advantage in marketing. Cirrhotic patients have traditionally been the hardest to treat, and certainly with the aging of the population, the rates of cirrhosis will rise. The data from this trial are going to be of critical value to clinicians, patients and payers. The results are unprecedented, and superior to anything currently available.

Results from the Pearl 2 study showed that 100 percent of Genotype 1 previously treated patients treated with AbbVie's combination without ribavirin achieved SVR12.

Results from the Pearl 3 trial showed that 99 percent of Genotype 1b new-to-treatment patients treated with or without ribavirin achieved SVR12. The efficacy in the Genotype 1b population is particularly encouraging as it represents roughly half of the Genotype 1 patients in the G7 markets.

The Pearl 4 study involved an even more difficult to treat segment of the Genotype 1a patients. 97 percent of patients treated with the therapy and ribavirin achieved SVR12, and 90 percent of the patients in the ribavirin-free arm achieved SVR12.

Once the drugs approved, the most advanced Hep C patients, who have fibrosis or cirrhosis are the most likely to be treated first and AbbVie's combination will likely be high on the physicians' list.

Japan is the second largest HCV market globally, therefore AbbVie pays special attention to it. A Phase 3 was recently started with a 12-week, ribavirin-free treatment focusing on Genotype 1b. Submission of the regulatory application in Japan is expected in 2015.

Gilead

The U.S. launch of Gilead's Sovaldi was a success: sales in December totaled $136 million.

A little over half of that amount is attributable to the initial inventory build-up by the big three wholesalers, amounting to nearly $70 million. A one-off order for $15 million was for a clinical trial. The balance of the revenue, about $50 million, is the actual patient demand.

Sovaldi prescribing has been broad-based across physician groups: hepatologists, gastroenterologists, IMs, and infectious disease specialists have all begun using Sovaldi.

Sovaldi for Genotypes 2 and 3 were expected to be the most popular use since these patients can be given an all-oral regimen, without the use of interferon.

But it turns out, from a survey conducted at the beginning of the year, Genotype 1 is the most widely used category. This is in line with the majority of the U.S. HCV population, of which approximately 70 percent Genotype 1.

The most popular treatment regimen for these people was the Neutrino approach, a combination of Sovaldi with pegylated interferon and ribavirin for 12 weeks. Some patients were given a combination of Sovaldi and Olysio, another newly approved drug made by Johnson & Johnson (JNJ).

Gilead is not aware at all of any sort of secondary warehousing of patients by doctors, meaning to let them wait for the next generation of interferon free drugs to arrive. Physicians, both in the U.S. and Europe, are happy about the availability of Sovaldi and use it to the maximum.

In January the European Commission approved Sovaldi and it was launched in the U.K., Germany, and France.

On the payer front, it typically takes between 3 to 6 months to complete a formulary listing, but currently, almost without exception, Sovaldi prescriptions are approved by commercial plans, with prior authorization. There is already some use by state Medicaid plans and by the Department of Defense's Tricare program.

Gilead has a U.S. patient assistance program for Sovaldi, called Support Path, which has been very active since launch. This program helps patients to navigate benefits coverage, as well as provide assistance with copays and foundation grants. It is anticipated that 30 to 50 percent of commercial patients will utilize the copay assistance program.

In Europe, bottles of Sovaldi began shipping immediately after approval, and so far orders have been filled in the U.K., Germany, France, Austria, Sweden, and Finland.

In some countries, like France, orders from hospitals were received and filled even before approval, on the basis of a temporary authorization program. The urgency is not surprising, since patients with advanced disease have very limited alternatives.

What about the high price of the drug?

Gilead does not see any problem with payers. The company says that Sovaldi is not a high priced drug that extends the life of patients by a few months: it is a cure. And cures are respected by payers everywhere.

Next

The Hep C developers are not slowing down, 2014 is going to be a busy year for them.

Gilead: Based on the promising data obtained from the studies of ION1, ION2, and ION3, application to the FDA and the European Marketing Authorization will be filed this quarter. The studies investigated the fixed-dose ledipasvir/sofosbuvir combination in Genotype 1, new-to-treatment and previously-treated patients, combined with or without ribavirin for a duration of 8, 12, or 24 weeks.

The response rates in the 8- and 12-week arms evaluating the once-daily combination of ledipasvir and sofosbuvir without ribavirin ranged from 93.6 to 97.75 percent.

But the company is not stopping there. They are busy working on another fixed dose combination for Genotype 1, the so-called 5816 compound combined with Sovaldi. Early data will be presented at the EASL, the International Liver Congress in April.

Gilead is also making efforts to shorten the treatment duration even further, to six weeks, by adding a third drug.

Gilead is also planning an educational and advertising campaign, starting in mid-2014, to reach the huge potential audiences affected by Hep C. The campaign will be addressing first the diagnosed population, an estimated 1.7 million people, and later an even larger audience of an estimated 4 million, who are not or vaguely aware of their problem and of the new treatment options now available. For the campaigns some collaboration will be given by governmental agencies.

AbbVie is working on a Phase 2 program of its next-generation compounds, which include a potent protease inhibitor, ABT493, and the new NS5A inhibitor, ABT530.

The goal is to develop a ribavirin-free once daily combination that can be uniformly used for all genotypes.

In preclinical studies, the next-generation assets have shown good activity against key resistant mutants. They also support once daily dosing without ritonavir and have the ability to coformulate. AbbVie will present data about them later this year.

AbbVie is also working on creating a fixed dose combination for its current treatment, by taking all three of the current direct acting antivirals and coformulate them into a once-daily pill. The prototype formulation is ready and being tested. The program is aggressively advanced by the company.

Markets

In Hep C Gilead's Sovaldi leads the pack, with sales expected to top out at $7 billion a year once the company rolls out its fixed-dose combo.

AbbVie's three-drug regimen is expected to bring in about $3 billion at its peak, but the prospect of an eventual price war could shift the balance of power once the two companies get a chance to fight it out side-by-side in the marketplace.

According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with the hepatitis C virus.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure.

Most people infected with the hepatitis C virus have no symptoms of the disease until liver damage becomes apparent, which may take several years. Most of these people then go on to develop chronic hepatitis C. Some will also develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer.

The viral infection can lead to liver cirrhosis, and U.S. health officials recommended every American born from 1945 to 1965 to get tested for the disease.

The new combinations are projected to broaden the Hep C market which analysts estimate may reach $100 billion over a decade.

Investors' summary

AbbVie's full year 2013 earnings were $3.14 per share. Revenues grew 2.2 percent to $18.79 billion.

Humira, its principal product, sold $10.66 billion in 2013, or 56 percent of the total revenue.

In 2014 AbbVie expects a revenue of approximately $19 billion. The guidance excludes any potential revenue from the expected 2014 U.S. launch of the new HCV therapy as the approval date cannot be ascertained. The cost of investment however is already included in the expenses.

For the full-year of 2014 AbbVie's diluted earnings-per-share is forecast at $3.00 to $3.10 on an adjusted basis, or $2.63 to $2.73 on a GAAP basis.

AbbVie's pipeline represents significant potential. The company's late-stage pipeline includes several compounds in Phase 3 development targeting therapeutic areas like hepatitis C, immunology and endometriosis.

AbbVie is closing its first full year as an independent company since its separation from Abbott Laboratories (ABT). The company has several promising new endeavors, Hep C being the brightest among them.

The Hepatitis C race is heating up with Gilead in the leadership position, but AbbVie is not far behind.

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