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Promise and Peril - New Hep C Drugs

An article by the always excellent Liz Highleyman editor-in-chief of HIVandHepatitis.com

For the past few years experts have predicted a revolution in treatment for hepatitis C virus (HCV), making it simpler, shorter, and much more effective. With the approval of the first two next-generation direct-acting antivirals (DAAs) -- and with several more expected over the next couple of years -- that revolution has now arrived. But cost and other factors may limit access for many.

New HCV therapies were a major theme at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) in March and the 49th EASL International Liver Congress in April. HCV treatment is undergoing a sea change comparable to the advent of effective HIV med combinations in the mid-1990s, but at a much faster pace. "It's like HIV drug development at warp speed," according to Douglas Dieterich from Mt. Sinai.

Where Are We Now?

The old standard of care, pegylated interferon plus ribavirin, required weekly injections and twice-daily pills taken for six to 18 months. It caused unpleasant and potentially dangerous side effects, including flulike symptoms, depression, and anemia -- and it cured only about half of those who took it. (The benchmark for a cure is SVR12 -- a "sustained virologic response," which means an undetectable HCV viral load 12 weeks after finishing treatment.)

The first DAAs -- the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek) -- were approved by the FDA in 2011. When added to interferon and ribavirin, they shortened treatment time by half and raised cure rates up to 75% in trials. But they require multiple daily pills and have side effects of their own (anemia with Victrelis; skin rash with Incivek). And SVR rates have been disappointing in clinical practice, especially for some of the hardest-to-treat people: those with liver cirrhosis, HIV/HCV coinfection, and those who did not respond to previous interferon.

The next-generation DAAs promise to overcome these barriers. The first out of the gate -- Janssen's protease inhibitor simeprevir (Olysio) and Gilead's polymerase inhibitor sofosbuvir (Sovaldi) -- were approved in late 2013. Other promising drugs in the final stages of testing include:

ledipasvir -- NS4A inhibitor (Gilead)
daclatasvir -- NS4A inhibitor (Bristol-Myers Squibb)
asunaprevir -- protease inhibitor (Bristol-Myers Squibb)
faldaprevir -- protease inhibitor (Boehringer Ingelheim)
"3D" combo -- three different DAAs (AbbVie)
Unlike interferon, which stimulates the body's natural immune response, DAAs interfere with enzymes the virus uses to reproduce. Like HIV meds, they work best when drugs that target different steps of the viral lifecycle are combined. They can shorten treatment to 12 or 24 weeks -- and maybe even 6 or 8 weeks for some people -- and they do not add many side effects.

Sovaldi
For people with HCV genotype 1 (the most common type in the U.S. and until now the most difficult to treat), the FDA approved both Olysio and Sovaldi for use in a 12-week regimen with interferon and ribavirin. Sovaldi has the edge since it is active against more HCV genotypes and has fewer drug interactions than Olysio.

But what most people with HCV and their providers have been waiting for is interferon-free treatment.

No Interferon or Ribavirin

For people with HCV genotype 2 or 3, Sovaldi plus ribavirin is the first FDAapproved regimen without interferon. Taken for 12 weeks for genotype 2 or 24 weeks for genotype 3, it cured more than 90% of previously untreated patients. Recognizing the eagerness -- and for many, the necessity – to go interferonfree, the FDA said people with genotype 1 who are ineligible to take interferon can use Sovaldi plus ribavirin alone for 24 weeks. Though the FDA did not define "ineligible," many providers are interpreting it to include people who are unwilling to take interferon as well as those who cannot tolerate it.

An expert panel (AASLD, IDSA, and IAS-USA) went further, saying people who can't or won't take interferon may take Sovaldi plus Olysio for 12 weeks. This regimen has not completed Phase 3 trials but led to cure rates above 90% in the Phase 2 COSMOS trial. In new guidelines released at the Liver Congress, European experts agreed, and also gave the nod to Sovaldi plus soon-to-beapproved daclatasvir.

"Recently approved medications and several others on the horizon promise to cure nearly all treated patients without the many side effects that have plagued past treatment regimens," said AASLD panel co-chair Donald Jensen.

In addition to causing anemia, ribavirin can also cause birth defects, and should not be used by pregnant women or their male partners. While research is still scarce, it is reasonable to believe safer treatments taken during pregnancy would further reduce the already low risk of mother-to-child HCV transmission.

In the Pipeline

The SYNERGY trial showed that close to 100% of people starting HCV treatment for the first time can be cured with two DAAs taken once daily for 12 weeks or three DAAs taken for just six weeks. This trial enrolled 60 African-Americans with genotype 1, including about 25% with advanced liver fibrosis or cirrhosis. "We believe this population is really reflective of the hepatitis C population in the U.S., which historically has been a difficult-to-treat population," said lead researcher Anita Kohli.

A Gilead trial of Sovaldi plus ledipasvir taken for 12 weeks produced an SVR12 rate of 100%. Adding either the polymerase inhibitor GS-9669 or the protease inhibitor GS-9451 yielded cure rates of 95% and 100% in only six weeks. And the ION trials showed cure rates above 90% for a combo pill of Sovaldi and ledipasvir in people treated for 12 or even 8 weeks.

But Gilead is far from the only player in the interferon-free game. A 12-week regimen of AbbVie's "3D" combo pill (the protease inhibitor ABT-450, NS5A inhibitor ombitasvir, and polymerase inhibitor dasabuvir) has also demonstrated high cure rates. In the PEARL-III trial, SVR rates reached 99% for previously untreated genotype 1 patients without liver cirrhosis. AbbVie expects approval by the end of 2014.

Similarly, a regimen of daclatasvir, asunaprevir, and the polymerase inhibitor BMS-791325 taken for 12 weeks cured 92% of previously untreated patients. Merck also has a promising combo in the works: the protease inhibitor MK-5172 and NS5A inhibitor MK-8742.

Daclatasvir resulted in SVR rates near 100% when taken with Sovaldi. Gilead declined to pursue this regimen, but now that Sovaldi is FDA approved, research by other companies is continuing. And once drugs are approved, providers can mix and match them as they choose. In fact, the recently released guidelines from the European Association for the Study of the Liver recommend combos that include daclatasvir, even though it is not yet approved.

More Benefit for More Patients

In the past, being African American, having a high HCV viral load, or having HIV coinfection all predicted a poor response to interferon. Fortunately, these factors don't lower cure rates as much for the new DAAs. Even liver cirrhosis does not reduce response to some of the new meds. On the other hand, genotype 3 is now known to be harder to treat than genotype 2, and genotype 1a is harder than 1b.

"All the old predictors of response are gone when you have a potent two or three drug combination," said Dieterich. He added that response rates for HIVpositive and HIV-negative people are "exactly the same."

The FDA unexpectedly included people coinfected with HIV in its approval of Sovaldi -- a group that usually has to wait. In the PHOTON-1 trial of coinfected people, Sovaldi plus ribavirin for 24 weeks cured 75% of genotype 1 patients who had no prior treatment and more than 90% of treatment-experienced genotype 2 or 3 patients.

Some HCV drugs (especially protease inhibitors) can interact with some HIV meds. Fortunately, drug companies are now testing new DAAs in people with HIV earlier in the development process. Jurgen Rockstroh from the University of Bonn and others have suggested that coinfected people be included in early HCV trials, since response rates are similar to those of HIV-negative patients.

What About the Cost?

Janssen and Gilead have both taken heat for their high prices. Sovaldi's $1,000-per-pill price tag has drawn attention well beyond the usual ranks of activists, with criticism coming from medical providers, insurance companies, and legislators.
While these advances are cause for celebration, it's unclear how they will be used in the real world. Of the three million people with HCV in the U.S., only half have been diagnosed, a third are referred to care, 10% start treatment, and only 5% are cured.

Janssen and Gilead have both taken heat for their high prices: $66,000 for Olysio and $84,000 for Sovaldi for a 12-week course. Sovaldi's $1,000-per-pill price tag has drawn attention well beyond the usual ranks of activists, with criticism coming from medical providers, insurance companies, and legislators. The New York Times even asked whether there are ways to finance research into new drugs without making profit the main reason for their development.

Some cancer drugs are priced equally high, and Gilead argues that Sovaldi is a good value. Unlike HIV drugs that must be taken for life, or cancer drugs that prolong life by only a few months, Sovaldi offers a permanent cure. Because it is so effective, its cost per cure compares favorably to Incivek, which has a higher chance of failure. And curing hepatitis C can avoid more costly long-term consequences such as a liver transplant, which runs about $500,000.

But the price of new DAAs is a major concern because so many people with HCV rely on public funding like Medicaid, Medicare, the VA, or prison budgets. A recent analysis by University of California Riverside researchers estimated that treating all U.S. prisoners with hepatitis C could cost more than $30 billion.

"We'd like to think we could make decisions about what's best for the individual [patients]," former AASLD president Gregory Fitz said, "but thinking about this on a population scale is daunting."

While the FDA and expert guidelines do not take cost into account, price will play a major role in the real world. It will be an issue in low- and middle-income countries, of course, but also in Europe, where national health programs take cost-effectiveness into account, and in the U.S., where the Affordable Care Act has increased emphasis on cost containment. "Cost is the biggest obstacle of all," said Ingo van Thiel of the European Liver Patients Association.

Advocates are concerned that not only will many patients die without treatment, but many others will be required to try interferon first, before being considered for more effective and well tolerated DAAs as second-line treatment.

Despite its high price, Sovaldi has been "flying off the shelves" according to Dieterich, at a rate of more 4,000 prescriptions per week in February. After years of "warehousing" HCV patients waiting for interferon-free treatment, doctors are now starting to work through ther backlogs, starting with the sickest patients first.

Some experts estimate Sovaldi sales for 2014 could reach $10 billion (compared with $9 billion for all of Gilead's HIV meds combined). That would make it one of the top-selling drugs ever and allow Gilead to quickly recoup the $11 billion it spent to acquire Pharmasset (which discovered the drug).

Who Needs It?

Only about 25% people with chronic hepatitis C develop severe liver disease, and it's difficult to predict who they will be. While Sovaldi may be a costeffective alternative to liver transplants, most people with HCV will never need a transplant.

But with the new meds, some experts think more people should be eligible for treatment. This is especially true for HIVcoinfected people, who often have more rapid liver disease progression. As with HIV, treating HCV early may prevent other problems like heart disease, and may reduce deaths even among people who do not develop severe liver damage. Plus, curing hepatitis C prevents transmission, leading some to favor a universal "test-and-treat" approach.

But cost could make such expansion impossible. Already, some private insurers and state Medicaid programs are requiring prior authorization or seeking supplemental funding for Sovaldi and Olysio. Express Scripts, for example, has asked doctors to delay prescribing Sovaldi to people who do not need immediate treatment. America's Health Insurance Plans, an industry trade group, called Sovaldi's price "unsustainable."

A report prepared for the California Technology Assessment Forum found that treating all HCV patients with advanced liver disease would cost the state more than $6 billion in a year, and treating everyone currently in care would cost at least $18 billion. The panel stated that at current prices, people with little or no liver damage generally should not be treated.

The National Association of Medicaid Directors went further, questioning whether studies -- most of which were funded by Gilead -- provide strong enough evidence that Sovaldi is really better than older treatments. The "unprecedented nexus of cost and widespread demand threaten to disrupt the healthcare landscape in the near term," said the group's executive director Matt Salo.

The World Responds

Sovaldi protest
But people with hepatitis C are concerned about their own health -- not the impact on the healthcare landscape.

In March, representatives Waxman, Pallone, and DeGette (all Democrats) took the unusual step of sending a letter to Gilead stating, "Even in cases where public or private insurers pay for the medication, it will impose substantial costs on taxpayers and could cause premium increases for those with employer or individual coverage."

The following week, Gilead agreed to give federal health plans a 23% discount, with further price reductions for the V.A. (which treats a large number of HCV patients). Gilead then agreed to license Sovaldi to drug makers in India at $2,000 for a 24-week course. And Gilead could price its Sovaldi/ledipasvir combo pill at less than the two drugs used separately, as Abbott did with Kaletra for HIV.

Production costs for DAAs can be quite low. A recent study from Liverpool University estimated manufacturing costs topping out at $136 for Sovaldi and $270 for Olysio for a 12-week course.

Outside of legislative action and negotiated discounts, the best hope for lowering the cost of new HCV drugs is increased competition. AbbVie's "3D" regimen will require more pills per day than Gilead's combos, but this may be an acceptable trade-off for a lower price.

In May, the WHO's World Health Assembly passed a hepatitis resolution supporting the use of global trade provisions to allow low- and middle-income countries to produce or import generic versions of DAAs if companies won't offer them at affordable prices. The first Hepatitis C World Community Advisory Board meeting, held in Bangkok in February, brought together advocates from around the world. They hope to get the price for a course of DAA treatment below $500, similar to the annual cost of HIV treatment in developing nations.

"We are witnessing a revolution in the treatment of HCV with powerful molecules capable of curing the infection," as Françoise Barré-Sinoussi stated in a recent report by Médecins du Monde. "There is no question that these treatments that can save millions of lives must be made universally available at an affordable price."

AASLD/IDSA/IAS-USA Recommendations for Testing, Managing, and Treating Hepatitis C are available at hcvguidelines.org.

EASL guidelines are available at http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html.

Liz Highleyman is editor-in-chief of HIVandHepatitis.com and has written about HIV and hepatitis for various publications for 20 years.

From AIDS Community Research Initiative of America - http://www.thebody.com/content/75183/promise-and-peril-the-new-hep-c-drugs.html?getPage=2

SOURCE HCVADVOCATE.COM