FDA Advisory Committee Meeting

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

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