Daclatasvir and Sofosbuvir: New drug combo cures toughest cases of hepatitis C, hints to future injection-free therapies

Hello folks,
Today, the New England Journal of Medicine published results on two different Phase II studies of all-oral combination therapies for the treatment hepatitis C. One study evaluating Daclatasvir plus Sofosbuvir and the other ABT-450 with ritonavir (ABT-450/r), combined with ABT-267/ABT-333. The two studies achieved a high rate of sustained virologic response (SVR) with few side effects. 

Articles and commentary from Medscape, Johns Hopkins, NEJM Journal Watch, MedPage Today and links to NEJM are provided. 

Related: Daclatasvir Plus Sofosbuvir-Three New Clinical Trials Sponsored By Bristol-Myers Squibb 

Medscape Medical News 

HCV Therapy: High Rate of Viral Clearance, No Injections

Two phase 2, open-label studies evaluating the safety and efficacy of all-oral combination therapies for patients infected with hepatitis C virus (HCV) have shown that high rates of sustained virologic response (SVR) are possible even in the absence of interferon. Results from both studies were published in the January 16 issue of the New England Journal of Medicine.

Patients enrolled in both studies were between 18 and 70 years of age with no evidence of cirrhosis.
In the first study, Mark S. Sulkowski, MD, from Johns Hopkins University, Baltimore, Maryland, and colleagues evaluated the efficacy of combination therapy with once-daily, oral antiviral drugs daclatasvir (60 mg daily) and sofosbuvir (400 mg daily) for patients infected with HCV genotypes 1, 2, or 3. Patients were treated for 24 weeks, and use of ribavirin as part of the treatment protocol was optional.

The US Food and Drug Administration recently approved sofosbuvir for the treatment of HCV in combination with ribavirin or ribavirin and interferon, depending on the HCV genotype being treated. Daclatasvir remains an investigational agent.

Overall, 211 patients enrolled in the study. Among those with genotype 1 infection, 126 were previously untreated and 41 had failed previous therapy with telaprevir or boceprevir plus peginterferon alfa-ribavirin.

Among patients with HCV genotype 1, researchers found that 164 (98%) previously untreated patients and 40 (98%) patients who had failed traditional therapy demonstrated a SVR (HCV RNA < 25 IU/mL) at week 12 after the end of therapy. High rates of SVR were also noted at week 12 among patients with HCV genotype 2 (92% of 26 patients) and those with HCV genotype 3 (89% of 18 patients).

"Our study shows that the combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients, including patients who had persistent HCV variants conferring resistance to protease inhibitors after unsuccessful treatment with telaprevir or boceprevir," write Dr. Sulkowski and colleagues.

The authors note that response rates were similar between patient groups treated with or without ribavirin; however, patients treated with ribavirin demonstrated a greater decrease in hemoglobin.
The second study evaluated an 8-, 12-, and 24-week all-oral, interferon-free treatment regimen among 571 patients with HCV genotype 1 who were previously untreated or who had failed prior therapy. The study, led by Kris V. Kowdley, MD, from the Virginia Mason Medical Center, Seattle, Washington, evaluated various dosage combinations of the NS3/4A protease inhibitor ABT-450 with ritonavir (ABT-450/r), combined with nonnucleoside NS5B polymerase inhibitor ABT-267, ABT-333, or both. All but 1 subgroup also received ribavirin.

The researchers found that SVR ranged from 83% to 100% across all treatment groups. The SVR at 24 weeks among previously untreated patients administered ABT-450/r plus ribavirin was 88% among those treated for 8 weeks and 95% among those treated for 12 weeks. Treatment beyond 12 weeks did not appear to confer any additional benefit. 

HCV Therapy Without Injections
"The current standard of care for chronic HCV genotype 1 infection is pegylated interferon (peginterferon) and ribavirin, with a protease inhibitor (boceprevir or telaprevir)," write Dr. Kowdley and colleagues. The emergence of new oral antiviral therapies could mean the end of multipill and injectable drug regimens.

In an interview with Medscape Medical News, William Balistreri, MD, from the Cincinnati Children's Hospital Medical Center in Ohio, said: "[T]hese 2 preliminary studies are clearly promising, offering the hope for a 'cure' of chronic hepatitis C with a less complex, shorter-duration, interferon-free, all-oral regimen."

A similarity between the studies was the finding that both treatment-naive patients and those who had failed previous therapy demonstrated high rates of SVR with these oral, interferon-free regimens. In previous studies, "only approximately one third of patients who had not had a response to prior therapy with peginterferon and ribavirin had a sustained virologic response when re-treated with the addition of a protease inhibitor," write Dr. Kowdley and colleagues. These findings provide hope that these newer regimens may be of benefit in difficult-to-treat patients with HCV.

Adverse effects were similar between the studies and included fatigue, headache, and nausea; they compare favorably with the rate of adverse effects previously documented with standard HCV therapy.

Although the results of both studies offer hope to patients infected with HCV, "[w]e await 'real-world' experience with these [agents], once full approval and widespread use occur. This will include reports of barriers encountered, including cost, efficacy, and adverse effects," concluded Dr. Balistreri.

Source - Medscape 

Funding for Dr. Sulkowski's study was provided by Bristol-Myers Squibb and Pharmasset (Gilead). Funding for Dr. Kowdley's study was provided by AbbVie. Dr. Sulkowski is a paid consultant for Bristol-Myers Squibb and Gilead. Full conflict-of-interest information for all contributors is available on the journal's Web site. Dr. Balistreri has disclosed no relevant financial relationships.
New Engl J Med. 2014;370:211-221, 222-232.
Sulkowski abstract, Kowdley abstract

New drug combo cures toughest cases of hepatitis C, hints to future injection-free therapies
Efforts to cure hepatitis C, the liver-damaging infectious disease that has for years killed more Americans than HIV/AIDS, are about to get simpler and more effective, according to new research at Johns Hopkins and elsewhere.

In a study to be reported in the Jan. 16 issue of the New England Journal of Medicine, researchers say combination treatments involving a pair of experimental, oral antiviral drugs, daclatasvir and sofosbuvir, were safe and highly effective in the treatment of hepatitis C. The combination therapy worked well even in the patients who are hardest to treat, in whom the conventional "triple therapy" with hepatitis C protease inhibitors, telaprevir or boceprevir, plus peginterferon and ribavirin had failed to cure the infection.

"This research paves the way for safe, tolerable and effective treatment options for the vast majority of those infected with hepatitis C," says study leader Mark Sulkowski, M.D., medical director of the Johns Hopkins Center for Viral Hepatitis. "Standard treatments for the disease are going to improve dramatically within the next year, leading to unprecedented advances for the treatment of patients infected with the hepatitis C virus."

The research was conducted on 211 men and women with any of the three major types of the disease who were treated at 18 medical centers across the United States and Puerto Rico. Among patients with genotype 1—the most common strain of the infection in the United States—98 percent of the 126 previously untreated patients and 98 percent of 41 patients whose infections remained even after the triple therapy were considered cured, with no detectable virus in their blood three months after the treatment had stopped. Results were similar in study participants infected with genotypes 2 or 3, strains which are less common in the United States.

The study participants took a daily combination of 60 milligrams of daclatasvir and 400 milligrams of sofosbuvir, with or without ribavirin.

On Dec. 6, the U.S. Food and Drug Administration (FDA) approved sofosbuvir in combination with peginterferon and ribavirin for the treatment of genotype 1 infection and in combination with only ribavirin for genotype 2 and 3 infection. Daclatasvir has not yet been approved by the FDA.

Sulkowski says that if declatasavir and other new drugs for hepatitis C win approval from the FDA, the dreaded weekly injections of peginterferon will be a thing of the past.

Sulkowski, a professor at the Johns Hopkins University School of Medicine, also says that the so-called "pill burden" of what had been standard therapy for genotype 1 could go down from some 18 pills per day and one injection per week to as few as one or two pills per day and no injections. Side effects from the new pill combination were generally mild, but included fatigue, headache and nausea, a safety profile that Sulkowski says compares favorably with that of the peginterferon-based therapy, which is tied to severe side effects which may include fatigue and depression.

The new study is one of the first to show that hepatitis C can be cured without the use of ribavirin, which is known to cause anemia.

The advent of simpler pill-only regimens, Sulkowski adds, should make it easier for those infected with hepatitis C to be cured, preventing the development of liver cancer and liver failure and obviating the need for liver transplant. Currently, he says, fewer than 5 percent of the estimated 3.2 million Americans with hepatitis C have been cured, according to the U.S. Centers for Disease Control and Prevention (CDC). Further, the CDC estimates that between 50 and 75 percent of people who live with chronic hepatitis C are unaware that they are infected.

Sulkowski says the arrival of simpler treatment regimens could not come soon enough. Many of the people diagnosed with the infection, mainly those born between 1945 and 1965, were infected during the 1970s and 1980s through injection drug use and tainted blood transfusions and are now suffering from cirrhosis and liver cancer tied to chronic infection. This is why, he says, the CDC recommended hepatitis C screenings in 2012 for all baby boomers.

Sulkowski says that further research is being performed by Gilead Sciences of Foster City, Calif., on a regimen that combines sofosbuvir with another experimental drug it manufactures, called ledipasvir, into a single tablet which can be taken once a day. Ledipasvir is similar to daclatasvir, which is made by Bristol-Myers Squibb of Princeton, N.J., in that it inhibits replication of the hepatitis nonstructural protein NS5A. The combination of sofosbuvir and ledipasvir has not yet been approved by the FDA.

The newly published study, which took two years to complete, was funded by Gilead Sciences and Bristol-Myers Squibb. Sulkowski is a paid consultant to both Gilead Sciences and Bristol-Myers Squibb. The terms of his arrangements are managed by The Johns Hopkins University in accordance with its conflict of interest policies.

New England Journal of Medicine Original Article - Free Abstract 

Full Text @ NATAP

Daclatasvir plus Sofosbuvir for Chronic HCV Infection

New England Journal Abstract
January 16, 2014 | M.S. Sulkowski and Others

In this study, once-daily treatment with oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients with genotype 1, 2, or 3 HCV infection, including those in whom previous therapy with telaprevir or boceprevir had failed.
(full text @ NATAP)

New England Journal of Medicine Original Article - Free Abstract

Full Text @ NATAP

Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1 
New England Journal Abstract-
 An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.
(full text @ NATAP)

Progress Toward All-Oral, Interferon-Free Therapy for HCV Genotype 1 Infection
Atif Zaman, MD, MPH reviewing Sulkowski MS et al. N Engl J Med 2014 Jan 16. Kowdley KV et al. N Engl J Med 2014 Jan 16.

Regimens tested in open-label studies achieved high virologic response with low resistance and few adverse effects.

Interferon is still currently required for treating hepatitis C virus (HCV) genotype 1 infection. Now, investigators report findings of two new studies evaluating interferon-free regimens for these patients.

In an open-label study, Sulkowski and colleagues evaluated daclatasvir (an NS5A inhibitor; 60 mg daily) plus sofosbuvir (an NS5B inhibitor; 400 mg daily) with or without ribavirin for 24 weeks in patients with genotype 1 infection (44 treatment-naive and 41 treatment-experienced with telaprevir-based or boceprevir-based regimens). Another 82 treatment-naive patients received therapy for 12 weeks. Sustained virologic response (SVR) at 12 weeks posttreatment was 98% and did not vary by ribavirin use, HCV subtype, or IL28B genotype.

In a phase IIB study, Kowdley and colleagues randomized 571 patients with genotype 1 HCV infection without cirrhosis to receive ABT-450/r (the protease inhibitor ABT-450 plus 100 mg of ritonavir) in daily doses of 100 mg, 150 mg, or 200 mg with ABT-267 (an NS5A inhibitor; 25 mg daily) or ABT-333 (nonnucleoside polymerase inhibitor; 400 mg twice daily) or both for 8, 12, or 24 weeks. In addition, all but one of the subgroups received ribavirin (1000–1200 mg daily). Among patients receiving ABT-450/r plus ABT-267 or ABT-333 or both plus ribavirin, SVR rates at 24 weeks posttreatment ranged from 83% to 100% in treatment-naive and treatment-experienced patients. Rates were highest among patients receiving all three anti-virals plus ribavirin and those receiving 12 weeks of therapy (vs. 8 weeks). SVR varied significantly by HCV subtype, host IL28B haplotype, race, and baseline HCV RNA level.

In both studies, resistance was uncommon, and side effects were mild (e.g., fatigue, headache, nausea).

Comment
These two all-oral, direct-antiviral regimens for hepatitis C virus genotype 1 infection achieved high sustained virologic response rates with a short duration of therapy and low resistance and adverse effects. In addition, none of the traditional predictors of negative response had a significant effect on treatment response. Soon, all-oral regimens for every HCV-infected patient will be a reality.

Citation(s):
Sulkowski MS et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014 Jan 16; 370:211. (http://dx.doi.org/10.1056/NEJMoa1306218)
Kowdley KV et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014 Jan 16; 370:222. (http://dx.doi.org/10.1056/NEJMoa1306227) 

Daclatasvir-sofosbuvir combo scores in resistant hepatitis C
By: MARY ANN MOON, Family Practice News Digital Network
A combined regimen of daclatasvir and sofosbuvir achieved sustained virologic response rates greater than 90% in an industry-sponsored trial involving patients with chronic HCV, according to study published online Jan. 16 in the New England Journal of Medicine.
Read More........

HCV Combo Works Without Old Standbys
By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Published: Jan 16, 2014

Chronic hepatitis C (HCV) can be treated effectively without any of the standard drugs, researchers reported.

In an open-label study, all-oral combination therapy yielded cure rates ranging from 89% to 100% depending on patient and treatment characteristics, according to Mark Sulkowski, MD, of Johns Hopkins University, and colleagues.

Importantly, the combination of daclatasvir and sofosbuvir (Sovaldi) worked equally well with or without ribavirin, one of the mainstays of HCV therapy for years, Sulkowski and colleagues reported in the Jan. 16 issue of the New England Journal of Medicine.
The combination also worked equally well regardless of previous treatment failure, the presence of mutations associated with poor response to therapy, and viral genotypes regarded as difficult to treat, the investigators reported.

For years, chronic HCV was treated with pegylated interferon, an injectable drug with a host of difficult and dangerous side effects, and ribavirin, an oral drug with its own suite of hazards including hemolytic anemia and teratogenicity.

Therapy was usually protracted and cure rates -- sustained virologic responses (SVR), defined as no detectable HCV at a given point after the end of treatment -- were low.

The addition of drugs that block the HCV protease enzyme has improved outcomes, but clinicians and patients have been waiting for all-oral regimens that eliminate both interferon and ribavirin.
"In my view," Sulkowski told MedPage Today by email, "this clinical trial demonstrates the potential for interferon-free and ribavirin-free regimens for persons infected with HCV genotype 1."
In the trial, patients with genotypes 1, 2, or 3 of the virus were given daclatasvir/sofosbuvir, with or without ribavirin, for 12 or 24 weeks.

The primary endpoint -- reached by 201 of 211 patients -- was a sustained virologic response 12 weeks after the end of therapy, or SVR₁₂.
SVR₁₂ rates were:

• 98% in previously untreated genotype 1 patients and the same in genotype 1 patients who had failed previous therapy with interferon, ribavirin, and HCV protease inhibitors
• 92% of patients with genotype 2, and 89% of those with genotype 3 infection
• 98% and 100%, respectively, among patients with HCV subtypes 1a and 1b
• 93% and 98%, respectively, for those with CC and non-CC IL28B genotypes, where the non-CC genotypes are regarded as predicting poor response
• 94% among those who also got ribavirin, and 98% among those who did not

The study heralds an "exciting time for HCV treating physicians," commented Paul Pockros, MD, of the Scripps Clinic in La Jolla, Calif., who was not part of the study.

"We can cure most patients finally," he told MedPage Today by email.

Whether those cures will come from the daclatasvir/sofosbuvir combination, however, is an open question.

As data from this trial was revealed at successive medical meetings, Pockros and others hailed the outcomes as a "home run" for HCV treatment.

Fears for the Future
But there were fears it would be a strikeout for patients -- the two drugs are owned by different companies and were being tested under a collaborative agreement that has now ended.
Among other things, that means the drugs are unlikely to be co-formulated as a single pill or approved as a combination with a broad indication.

But Sulkowski noted that three phase III trials have been registered, although they are not yet recruiting, for relatively narrow indications -- genotype 3 patients, those with concurrent HIV, and people with cirrhosis or recurrent HCV after liver transplant.

The two drugs are so-called direct-acting anti-virals -- they target aspects of the virus itself, rather than boosting the immune system as interferon does.

Daclatasvir blocks the action of the viral NS5A replication complex, while sofosbuvir, approved last year, is a nucleotide analog NS5B polymerase inhibitor.

Both of the companies involved in the trial -- Bristol-Myers Squibb with daclatasvir and Gilead with sofosbuvir -- have their own versions of the other's medication.

Gilead is testing the combination of sofosbuvir and ledipasvir, its own NS5A inhibitor. BMS is testing triple therapy with daclatasvir, an NS5B blocker dubbed BMS-791325, and asunaprevir, a protease inhibitor.

But if daclatasvir is approved on its own, Pockros said, it's likely some doctors at least will prescribe it with sofosbuvir off label.

Indeed, the two most recently approved HCV drugs are sofosbuvir and the protease inhibitor simeprevir (Olysio) -- neither indicated for use with the other.
But, Pockros said, they are being widely used together based on data from a clinical trial that has been reported but not yet published.

"Support for the (daclatasvir/sofosbuvir) regimen will be even firmer," he said, although it's not clear how gladly insurers would support such use.

A Practice-Changing Regimen?
The bottom line, Sulkowski said, is that the study suggests that the combination -- or one using similar medications -- has the potential to make an important impact on HCV therapy.

"The combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients," he and colleagues argued.

A separate open-label phase 2b study in the journal evaluated triple or quadruple drug regimens given for eight, 12, or 24 weeks in a cohort of 571 patients divided into 14 treatment subgroups.

The research groups overlapped -- Sulkowski, for instance, was part of both studies -- but with the exception of ribavirin, none of the drugs, all direct-acting anti-virals, were the same.

The primary analysis was the rate of SVR₂₄ among treatment-naive patients who got three direct-acting agents plus ribavirin for eight weeks, compared with those who got the same therapy for 12 weeks, according to Kris Kowdley, MD, of Virginia Mason Medical Center in Seattle, and colleagues.

Kowdley and colleagues studied the HCV protease inhibitor ABT-450 boosted with ritonavir, the non-nucleoside polymerase inhibitor ABT-333, the NS5A inhibitor ABT-267, and ribavirin in patients with genotype 1 infection.
The key finding, they reported, was that 88% of those who got eight weeks of therapy and 95% of those who got 12 weeks reached an SVR₂₄.

The seven percentage-point difference was not statistically significant, the researchers reported.
Over all treatment groups, SVR₂₄ rates ranged from 83% to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia.