Cover Story

The Promise of New HCV Therapies

Your guide to the age after interferon
The Promis of New HCV Therapies

The future of treatment for hepatitis C virus infection is exciting. Many new drugs and combination therapies are moving rapidly through clinical trials and are becoming part of the conversation for FDA approval. The most recently approved tools at the disposal of clinicians are sofosbuvir and simeprevir, oral therapies that are associated with high cure rates.

The fast pace of development begs the question of whether an interferon-free future is near. Interferon has been the backbone of HCV treatment since it was approved by the FDA in 1991 for the treatment of HCV. In 1998, the addition of ribavirin to interferon was approved. Since the approval of pegylated interferon in 2001, the gold standard of treatment has been pegylated interferon with ribavirin with or without a protease inhibitor. However, the downsides associated with interferon, including adverse effects, need for careful monitoring and the fact that some patients are ineligible for treatment, and have left many desiring an interferon-free regimen.

Yet, interferon therapy is not quite a thing of the past. The approach figures into several recommended treatment options featured on HCVguidelines.org, the website recently launched by the American Association for the Study of Liver Diseases and Infectious Diseases Society of America, in collaboration with the International Antiviral Society-USA, which will serve as the clinical guidelines for HCV treatment in the United States (See Feature). However, a range of non-nucleoside polymerase inhibitors, nucleoside/nucleotide polymerase inhibitors, NS5A inhibitors, protease inhibitors and combinations thereof have demonstrated such overwhelmingly encouraging cure rates across genotypes in clinical trials that many believe the days of interferon are numbered.

The FDA has acted accordingly and provided accelerated 6-month approval status for several combination therapies. The speed with which new therapies are evolving has raised some eyebrows in the clinical community, but Donald M. Jensen, MD, said the development process is working exactly as it should.

“The duration of therapy is shorter with many of these drugs,” said Jensen, who is professor of medicine and director of the Center for Liver Diseases at University of Chicago Medical Center. Most combinations are being studied for 8 to 12 weeks of therapy and 12 weeks of follow-up.

“This has made the development of agents much quicker than with pegylated interferon and ribavirin-based therapies,” Jensen, a co-chair on the HCVguidelines.org panel, said. “The time factor has allowed for big breakthroughs and has opened the door for a number of combinations to be still in the game — not on the sideline.”

Andrew J. Muir, MD, MPH, associate professor of medicine and clinical director of hepatology at Duke University, put the issue in clinical terms: “The concern is not the pace of the FDA-approval process. The concern is that patients are dying of cirrhosis and liver cancer. We now have the tools to stop this disease and end pain and suffering.”

HCV Next spoke with several experts about the current drug pipeline. Their insights may help clinicians who treat this disease prepare for 2014 and beyond.

The Nucleoside/Nucleotide Polymerase Inhibitors

The nucleoside polymerase inhibitor sofosbuvir (Sovaldi, Gilead) was granted FDA approval in December. It was the first drug to demonstrate safety and efficacy in the treatment of certain HCV genotypes without the need for coadministration of interferon.

“Sofosbuvir could become a backbone for future all-oral therapy moving forward,” Jensen said. “It is potent, with a high genetic barrier to resistance, minimal drug-drug interactions, a good safety profile and it leads to virtually no resistance to variants.”

The key data for sofosbuvir come from Mark S. Sulkowski, MD, of Johns Hopkins University, and colleagues, who conducted an open-label study of 44 treatment-naive patients with HCV genotype 1 and 44 patients with genotypes 2 or 3. The study drug was administered combined with daclatasvir (Bristol-Myers Squibb), an NS5A inhibitor. Anna Suk-Fong Lok, MD, professor of hepatology at the University of Michigan, was an investigator on this study. According to Lok, results showed that 12-week treatment of the two HCV direct-acting antivirals without ribavirin resulted in a SVR rate of 98% in patients with genotype 1 disease who had experienced no prior treatment. “The most exciting aspect about the study is that 21 of 21 patients who failed telaprevir or boceprevir plus interferon and ribavirin achieved SVR after 24 weeks of sofosbuvir plus daclatasvir, providing hope for patients who failed telaprevir- or boceprevir-based therapy,” Lok said.

Anna Suk-Fong Lok, MD

Anna Suk-Fong Lok

Sofosbuvir is approved for genotypes 1 through 4. “It may be used with pegylated interferon plus ribavirin for 12 weeks in patients with genotype 1 or 4, and with ribavirin but not interferon for 12 weeks in patients with genotype 2. For genotype 3, it is approved with ribavirin for 24 weeks,” Lok said.

Other drugs currently in this class include mericitabine (Roche) and ALS-2200 (Vertex). “Mericitabine is a little less potent in trials than sofosbuvir,” Jensen said, referencing results of the JUMP-C and PROPEL trials, which studied mericitabine plus pegylated interferon alpha 2a/ribavirin in treatment-naive patients with HCV genotype 1/4. “ALS-2200 is on hold at the moment.”

The Non-Nucleoside Polymerase Inhibitors

AbbVie currently has two non-nucleotide polymerase inhibitors in development, ABT-072 and ABT-333, according to Jensen. “ABT-333 seems to be going forward in trials as a twice-daily therapy,” he said.

Eric J. Lawitz, MD, of The Texas Liver Institute, and colleagues reported that 12 weeks of ABT-450/r, a ritonavir-boosted formulation, plus ABT-072 was associated with SVR at 36 weeks in nine of 11 patients. The combination was well tolerated.

Bristol-Myers Squibb has another drug in this class, BMS-791325. Gregory T. Everson, MD, of the University of Colorado, and colleagues reported at The Liver Meeting 2013 that BMS-791325, as part of combination with daclatasvir and the protease inhibitor asunaprevir, yielded a cure rate of more than 90% at 12 weeks in previously untreated patients with HCV genotype 1.

Other drugs in this class that have moved through phase 2 trials include once-daily GS-9669 (Gilead) and twice-daily setrobuvir (ANA-595; Hoffmann-La Roche/Genentech) and VX-222 (Vertex).

The NS5A Inhibitors

Currently, no NS5A inhibitor is approved for use in the United States. Muir cited the aforementioned study by Sulkowski and colleagues as evidence of the potential of daclatasvir.

“Daclatasvir is a potent drug,” Muir said. “There is a case building for it as combination therapy moving forward. We can see pairing it with other drugs, like sofosbuvir. How that proceeds and whether those regimens get reimbursed is something we will see in the future.”

The pangenotypic properties of daclatasvir are critical to its success, according to Jensen, who also discussed the two mechanisms of action with the viral replication process. “Daclatasvir directly inhibits replication and export of particles outside of the liver,” he said.

Ledipasvir (Gilead) has shown promise, particularly combined with sofosbuvir. Results of the LONESTAR study, conducted by Lawitz and colleagues, demonstrated that the combination yielded an SVR rate in 95% or more patients across several cohorts and treatment groups.

“These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype 1 HCV, irrespective of treatment history or the presence of compensated cirrhosis,” the investigators wrote in The Lancet.

Other investigational drugs in the NS5A class include ABT-267 (AbbVie), ACH-3102 (Achillion Pharmaceuticals), GS-5816 (Gilead), GSK2336805 (GlaxoSmithKline) and IDX719 (Idenix Pharmaceuticals), all of which are in phase 2 trials.

The Protease Inhibitors

Simeprevir (Olysio, Janssen Therapeutics), an NS3/4A protease inhibitor was approved by the FDA in November as once-daily treatment of HCV as part of an antiviral regimen in combination with pegylated interferon and ribavirin in genotype 1-infected adults with compensated liver disease, including cirrhosis.

David R. Nelson, MD, said simeprevir has an improved adverse event profile compared with previous drugs, albeit with some rash. “In genotype 1a, this has not been very effective if the patient has pre-existing Q80K mutation,” said Nelson, who is assistant vice president for research in life sciences at the University of Florida Office of Research, professor of medicine and associate dean of clinical research at the University of Florida College of Medicine, and director of the Clinical and Translational Science Institute at University of Florida. “This may limit its broad application due to the need for resistance testing in this very common genotype.” 

David R. Nelson, MD

David R. Nelson

“Simeprevir is for genotype 1 only,” Lok said. “It has a lower SVR rate compared with sofosbuvir for genotype 1a and requires a longer duration of interferon, therefore it has limited utility.”

Moving down the pipeline, Nelson said Merck has the best protease inhibitor in class with MK-5172. “This will start phase 3 trials soon in oral combinations,” he said, adding that the drug is effective with most genotypes other than 3a.

MK-5172 has demonstrated activity against resistant variants, according to Jensen.

Boehringer Ingelheim discontinued the development of its non-nucleoside NS5B polymerase inhibitor deleobuvir, which may jeopardize oral interferon-free regimens for the protease inhibitor faldaprevir, according to Nelson.

There is hope for other protease inhibitors under investigation, including once-daily ABT-450/r, GS-9451 (Gilead) and sovaprevir (Achillion Pharmaceuticals), and twice-daily danoprevir/r (Hoffmann-La Roche/Genentech).

“The ritonavir boost increases the half-life and efficacy, and decreases the potential for adverse effects,” Jensen said. “ABT-450/r is a potent combination.”

The Future of Combination Therapies

New combination treatment regimens are being explored and are expected to emerge soon.

Kris V. Kowdley, MD, of Virginia Mason Medical Center in Seattle, and colleagues conducted a phase 2b, open-label study that investigated ABT-450/r with ABT-267 or ABT-333, or both, for durations of 8, 12 or 24 weeks. Eligible participants had received at least one dose of therapy. The analysis included 14 treatment subgroups and 571 patients. SVR rates at 24 weeks ranged from 83% to 100% across all treatment groups. Jensen described this combination as “potent.”

AbbVie announced phase 3 results for the SAPPHIRE-II trial in a recent press release. Findings indicated SVR rates of more than 95% in multiple treatment subgroups for the three-drug combination.

“We anticipate that AbbVie will likely be going forward for FDA approval sometime this year,” Jensen said.

The combination of sofosbuvir with NS5A inhibitors such as daclatasvir or ledipasvir yielded SVR rates of more than 90% in just 12 weeks of therapy without the need for ribavirin, according to data from the LONESTAR study.

“The press release from the ION trials of sofosbuvir and ledipasvir in December showed encouraging results,” Muir said. “They are moving ahead with FDA submission in the United States, which will happen in the first quarter of 2014. We are looking at potential approval by the end of the year.”

This raises the question of whether patients should wait until approval or use what is available now, Muir said. “I told my patients to expect to have that combination as an option by late 2014 or early 2015. But some may not want to wait that long.”

“We should also highlight daclatasvir, which is a good NS5A inhibitor that may be used in combination with other direct-acting antivirals. Bristol-Myers Squibb is likely to get approval by 2015,” Nelson said.

The combination of daclatasvir and asunaprevir (Bristol-Myers Squibb) is also showing high efficacy in genotype 1b, Jensen said. In February, Bristol-Myers Squibb announced that the FDA granted daclatasvir and asunaprevir Breakthrough Therapy Designation for use as a combination therapy in the treatment of HCV gentoype 1b. The designation is based on data from the company’s ongoing phase 3 clinical trial program evaluating the all-oral combination regimen. The Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. In addition, the Merck combination of the protease inhibitor MK-5172 and the NS5A inhibitor MK-8742, with and without ribavirin, has shown high efficacy in preliminary results.

Donald M. Jensen, MD

Donald M. Jensen

AbbVie is also developing a four-drug regimen, which includes three direct-acting antivirals, one of which is boosted by ritonavir: ABT-450/r, ABT-267 and ABT-333. “This has also shown SVR rates of greater than 90%, and will battle sofosbuvir and ledipasvir for genotype 1 use in the near future,” Jensen said.

Although there is great enthusiasm surrounding the development of such combination therapies, Nelson offered some perspective: To date, “all of the oral direct-acting antiviral combinations have only been tested against placebo or no control. Thus, there will be no head-to-head data to help patients and clinicians choose the best regimen for individual patients.”

Yet to Come

In the end, Muir summed up the future of HCV therapy: “We can feel better that a number of combinations are moving toward approval. We are heading toward a place where there will be different regimens, which means more options. That’s a good thing.” — by Rob Volansky

References:
Everson GT. LB-1. Presented at: The Liver Meeting 2013; Nov. 1-5, 2013; Washington, D.C.
Kowdley KV. N Engl J Med. 2014;370:222-232.
Lawitz E. Lancet. 2014;338:515-523.
Sulkowski MS. N Engl J Med. 2014;370:211-221.
For more information:
Donald M. Jensen, MD, can be reached the Center for Liver Diseases, University of Chicago Medical Center, 5841 S. Maryland Ave., MC7120, Chicago, IL 60637; email: djensen@medicine.bsd.uchicago.edu.
Anna Suk-Fong Lok, MD, can be reached University of Michigan Gastroenterology, Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109; email: aslok@med.umich.edu.
Andrew J. Muir, MD, MHS, can be reached at Duke Gastroenterology, DUMC 3913, Durham, NC 27710; email: muir0002@mc.duke.edu.
David R. Nelson, MD, can be reached at University of Florida College of Medicine, Box 100214, Room M-440, Gainesville, FL 32610; email: david.nelson@medicine.ufl.edu.
Disclosures: Jensen reports research grants paid to his institution (none since Dec. 31, 2013) from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead and Janssen, and consulting or serving on advisory panels (none since April 2013) for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb and Janssen. Lok reports receiving grants from AbbVie, Bristol-Myers Squibb, Gilead, Idenix and Merck, and serving on advisory panels for Gilead and Janssen. Muir reports research grants from AbbVie, Achillion, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Roche and Vertex, and consulting for AbbVie, Achillion, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Roche, Salix and Vertex. Nelson reports receiving research grant support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Genentech, Janssen, Merck and Vertex.
The Promis of New HCV Therapies

The future of treatment for hepatitis C virus infection is exciting. Many new drugs and combination therapies are moving rapidly through clinical trials and are becoming part of the conversation for FDA approval. The most recently approved tools at the disposal of clinicians are sofosbuvir and simeprevir, oral therapies that are associated with high cure rates.

The fast pace of development begs the question of whether an interferon-free future is near. Interferon has been the backbone of HCV treatment since it was approved by the FDA in 1991 for the treatment of HCV. In 1998, the addition of ribavirin to interferon was approved. Since the approval of pegylated interferon in 2001, the gold standard of treatment has been pegylated interferon with ribavirin with or without a protease inhibitor. However, the downsides associated with interferon, including adverse effects, need for careful monitoring and the fact that some patients are ineligible for treatment, and have left many desiring an interferon-free regimen.

Yet, interferon therapy is not quite a thing of the past. The approach figures into several recommended treatment options featured on HCVguidelines.org, the website recently launched by the American Association for the Study of Liver Diseases and Infectious Diseases Society of America, in collaboration with the International Antiviral Society-USA, which will serve as the clinical guidelines for HCV treatment in the United States (See Feature). However, a range of non-nucleoside polymerase inhibitors, nucleoside/nucleotide polymerase inhibitors, NS5A inhibitors, protease inhibitors and combinations thereof have demonstrated such overwhelmingly encouraging cure rates across genotypes in clinical trials that many believe the days of interferon are numbered.

The FDA has acted accordingly and provided accelerated 6-month approval status for several combination therapies. The speed with which new therapies are evolving has raised some eyebrows in the clinical community, but Donald M. Jensen, MD, said the development process is working exactly as it should.

“The duration of therapy is shorter with many of these drugs,” said Jensen, who is professor of medicine and director of the Center for Liver Diseases at University of Chicago Medical Center. Most combinations are being studied for 8 to 12 weeks of therapy and 12 weeks of follow-up.

“This has made the development of agents much quicker than with pegylated interferon and ribavirin-based therapies,” Jensen, a co-chair on the HCVguidelines.org panel, said. “The time factor has allowed for big breakthroughs and has opened the door for a number of combinations to be still in the game — not on the sideline.”

Andrew J. Muir, MD, MPH, associate professor of medicine and clinical director of hepatology at Duke University, put the issue in clinical terms: “The concern is not the pace of the FDA-approval process. The concern is that patients are dying of cirrhosis and liver cancer. We now have the tools to stop this disease and end pain and suffering.”

HCV Next spoke with several experts about the current drug pipeline. Their insights may help clinicians who treat this disease prepare for 2014 and beyond.

The Nucleoside/Nucleotide Polymerase Inhibitors

The nucleoside polymerase inhibitor sofosbuvir (Sovaldi, Gilead) was granted FDA approval in December. It was the first drug to demonstrate safety and efficacy in the treatment of certain HCV genotypes without the need for coadministration of interferon.

“Sofosbuvir could become a backbone for future all-oral therapy moving forward,” Jensen said. “It is potent, with a high genetic barrier to resistance, minimal drug-drug interactions, a good safety profile and it leads to virtually no resistance to variants.”

PAGE BREAK

The key data for sofosbuvir come from Mark S. Sulkowski, MD, of Johns Hopkins University, and colleagues, who conducted an open-label study of 44 treatment-naive patients with HCV genotype 1 and 44 patients with genotypes 2 or 3. The study drug was administered combined with daclatasvir (Bristol-Myers Squibb), an NS5A inhibitor. Anna Suk-Fong Lok, MD, professor of hepatology at the University of Michigan, was an investigator on this study. According to Lok, results showed that 12-week treatment of the two HCV direct-acting antivirals without ribavirin resulted in a SVR rate of 98% in patients with genotype 1 disease who had experienced no prior treatment. “The most exciting aspect about the study is that 21 of 21 patients who failed telaprevir or boceprevir plus interferon and ribavirin achieved SVR after 24 weeks of sofosbuvir plus daclatasvir, providing hope for patients who failed telaprevir- or boceprevir-based therapy,” Lok said.

Anna Suk-Fong Lok, MD

Anna Suk-Fong Lok

Sofosbuvir is approved for genotypes 1 through 4. “It may be used with pegylated interferon plus ribavirin for 12 weeks in patients with genotype 1 or 4, and with ribavirin but not interferon for 12 weeks in patients with genotype 2. For genotype 3, it is approved with ribavirin for 24 weeks,” Lok said.

Other drugs currently in this class include mericitabine (Roche) and ALS-2200 (Vertex). “Mericitabine is a little less potent in trials than sofosbuvir,” Jensen said, referencing results of the JUMP-C and PROPEL trials, which studied mericitabine plus pegylated interferon alpha 2a/ribavirin in treatment-naive patients with HCV genotype 1/4. “ALS-2200 is on hold at the moment.”

The Non-Nucleoside Polymerase Inhibitors

AbbVie currently has two non-nucleotide polymerase inhibitors in development, ABT-072 and ABT-333, according to Jensen. “ABT-333 seems to be going forward in trials as a twice-daily therapy,” he said.

Eric J. Lawitz, MD, of The Texas Liver Institute, and colleagues reported that 12 weeks of ABT-450/r, a ritonavir-boosted formulation, plus ABT-072 was associated with SVR at 36 weeks in nine of 11 patients. The combination was well tolerated.

Bristol-Myers Squibb has another drug in this class, BMS-791325. Gregory T. Everson, MD, of the University of Colorado, and colleagues reported at The Liver Meeting 2013 that BMS-791325, as part of combination with daclatasvir and the protease inhibitor asunaprevir, yielded a cure rate of more than 90% at 12 weeks in previously untreated patients with HCV genotype 1.

Other drugs in this class that have moved through phase 2 trials include once-daily GS-9669 (Gilead) and twice-daily setrobuvir (ANA-595; Hoffmann-La Roche/Genentech) and VX-222 (Vertex).

The NS5A Inhibitors

Currently, no NS5A inhibitor is approved for use in the United States. Muir cited the aforementioned study by Sulkowski and colleagues as evidence of the potential of daclatasvir.

“Daclatasvir is a potent drug,” Muir said. “There is a case building for it as combination therapy moving forward. We can see pairing it with other drugs, like sofosbuvir. How that proceeds and whether those regimens get reimbursed is something we will see in the future.”

The pangenotypic properties of daclatasvir are critical to its success, according to Jensen, who also discussed the two mechanisms of action with the viral replication process. “Daclatasvir directly inhibits replication and export of particles outside of the liver,” he said.

Ledipasvir (Gilead) has shown promise, particularly combined with sofosbuvir. Results of the LONESTAR study, conducted by Lawitz and colleagues, demonstrated that the combination yielded an SVR rate in 95% or more patients across several cohorts and treatment groups.

“These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype 1 HCV, irrespective of treatment history or the presence of compensated cirrhosis,” the investigators wrote in The Lancet.

Other investigational drugs in the NS5A class include ABT-267 (AbbVie), ACH-3102 (Achillion Pharmaceuticals), GS-5816 (Gilead), GSK2336805 (GlaxoSmithKline) and IDX719 (Idenix Pharmaceuticals), all of which are in phase 2 trials.

The Protease Inhibitors

Simeprevir (Olysio, Janssen Therapeutics), an NS3/4A protease inhibitor was approved by the FDA in November as once-daily treatment of HCV as part of an antiviral regimen in combination with pegylated interferon and ribavirin in genotype 1-infected adults with compensated liver disease, including cirrhosis.

David R. Nelson, MD, said simeprevir has an improved adverse event profile compared with previous drugs, albeit with some rash. “In genotype 1a, this has not been very effective if the patient has pre-existing Q80K mutation,” said Nelson, who is assistant vice president for research in life sciences at the University of Florida Office of Research, professor of medicine and associate dean of clinical research at the University of Florida College of Medicine, and director of the Clinical and Translational Science Institute at University of Florida. “This may limit its broad application due to the need for resistance testing in this very common genotype.” 

PAGE BREAK
David R. Nelson, MD

David R. Nelson

“Simeprevir is for genotype 1 only,” Lok said. “It has a lower SVR rate compared with sofosbuvir for genotype 1a and requires a longer duration of interferon, therefore it has limited utility.”

Moving down the pipeline, Nelson said Merck has the best protease inhibitor in class with MK-5172. “This will start phase 3 trials soon in oral combinations,” he said, adding that the drug is effective with most genotypes other than 3a.

MK-5172 has demonstrated activity against resistant variants, according to Jensen.

Boehringer Ingelheim discontinued the development of its non-nucleoside NS5B polymerase inhibitor deleobuvir, which may jeopardize oral interferon-free regimens for the protease inhibitor faldaprevir, according to Nelson.

There is hope for other protease inhibitors under investigation, including once-daily ABT-450/r, GS-9451 (Gilead) and sovaprevir (Achillion Pharmaceuticals), and twice-daily danoprevir/r (Hoffmann-La Roche/Genentech).

“The ritonavir boost increases the half-life and efficacy, and decreases the potential for adverse effects,” Jensen said. “ABT-450/r is a potent combination.”

The Future of Combination Therapies

New combination treatment regimens are being explored and are expected to emerge soon.

Kris V. Kowdley, MD, of Virginia Mason Medical Center in Seattle, and colleagues conducted a phase 2b, open-label study that investigated ABT-450/r with ABT-267 or ABT-333, or both, for durations of 8, 12 or 24 weeks. Eligible participants had received at least one dose of therapy. The analysis included 14 treatment subgroups and 571 patients. SVR rates at 24 weeks ranged from 83% to 100% across all treatment groups. Jensen described this combination as “potent.”

AbbVie announced phase 3 results for the SAPPHIRE-II trial in a recent press release. Findings indicated SVR rates of more than 95% in multiple treatment subgroups for the three-drug combination.

“We anticipate that AbbVie will likely be going forward for FDA approval sometime this year,” Jensen said.

The combination of sofosbuvir with NS5A inhibitors such as daclatasvir or ledipasvir yielded SVR rates of more than 90% in just 12 weeks of therapy without the need for ribavirin, according to data from the LONESTAR study.

“The press release from the ION trials of sofosbuvir and ledipasvir in December showed encouraging results,” Muir said. “They are moving ahead with FDA submission in the United States, which will happen in the first quarter of 2014. We are looking at potential approval by the end of the year.”

This raises the question of whether patients should wait until approval or use what is available now, Muir said. “I told my patients to expect to have that combination as an option by late 2014 or early 2015. But some may not want to wait that long.”

“We should also highlight daclatasvir, which is a good NS5A inhibitor that may be used in combination with other direct-acting antivirals. Bristol-Myers Squibb is likely to get approval by 2015,” Nelson said.

PAGE BREAK

The combination of daclatasvir and asunaprevir (Bristol-Myers Squibb) is also showing high efficacy in genotype 1b, Jensen said. In February, Bristol-Myers Squibb announced that the FDA granted daclatasvir and asunaprevir Breakthrough Therapy Designation for use as a combination therapy in the treatment of HCV gentoype 1b. The designation is based on data from the company’s ongoing phase 3 clinical trial program evaluating the all-oral combination regimen. The Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. In addition, the Merck combination of the protease inhibitor MK-5172 and the NS5A inhibitor MK-8742, with and without ribavirin, has shown high efficacy in preliminary results.

Donald M. Jensen, MD

Donald M. Jensen

AbbVie is also developing a four-drug regimen, which includes three direct-acting antivirals, one of which is boosted by ritonavir: ABT-450/r, ABT-267 and ABT-333. “This has also shown SVR rates of greater than 90%, and will battle sofosbuvir and ledipasvir for genotype 1 use in the near future,” Jensen said.

Although there is great enthusiasm surrounding the development of such combination therapies, Nelson offered some perspective: To date, “all of the oral direct-acting antiviral combinations have only been tested against placebo or no control. Thus, there will be no head-to-head data to help patients and clinicians choose the best regimen for individual patients.”

Yet to Come

In the end, Muir summed up the future of HCV therapy: “We can feel better that a number of combinations are moving toward approval. We are heading toward a place where there will be different regimens, which means more options. That’s a good thing.” — by Rob Volansky

References:
Everson GT. LB-1. Presented at: The Liver Meeting 2013; Nov. 1-5, 2013; Washington, D.C.
Kowdley KV. N Engl J Med. 2014;370:222-232.
Lawitz E. Lancet. 2014;338:515-523.
Sulkowski MS. N Engl J Med. 2014;370:211-221.
For more information:
Donald M. Jensen, MD, can be reached the Center for Liver Diseases, University of Chicago Medical Center, 5841 S. Maryland Ave., MC7120, Chicago, IL 60637; email: djensen@medicine.bsd.uchicago.edu.
Anna Suk-Fong Lok, MD, can be reached University of Michigan Gastroenterology, Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109; email: aslok@med.umich.edu.
Andrew J. Muir, MD, MHS, can be reached at Duke Gastroenterology, DUMC 3913, Durham, NC 27710; email: muir0002@mc.duke.edu.
David R. Nelson, MD, can be reached at University of Florida College of Medicine, Box 100214, Room M-440, Gainesville, FL 32610; email: david.nelson@medicine.ufl.edu.
Disclosures: Jensen reports research grants paid to his institution (none since Dec. 31, 2013) from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead and Janssen, and consulting or serving on advisory panels (none since April 2013) for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb and Janssen. Lok reports receiving grants from AbbVie, Bristol-Myers Squibb, Gilead, Idenix and Merck, and serving on advisory panels for Gilead and Janssen. Muir reports research grants from AbbVie, Achillion, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Roche and Vertex, and consulting for AbbVie, Achillion, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Roche, Salix and Vertex. Nelson reports receiving research grant support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Genentech, Janssen, Merck and Vertex.