OCTOBER 2015
Vol. 18, Issue 10
HCV DRUGS
—Alan Franciscus, Editor-in-Chief
In this month’s column, I will discuss the recently released data from Achillion, and I will touch on various issues related to current treatment—drug-drug interactions, medical providers and insurance companies, and those who are still the most difficult to treat.
Achillion1
On September 17, 2015, Achillion announced the second part of their Phase 2 study (the PROXY study) of odalasvir (ACH-3102) and sofosbuvir to treat genotype 1. The cure rates were 100% (6 of 6 patients). Earlier, Achillion had announced a 100% cure rate for 12 patients treated for eight weeks, and a 100% cure rate for 12 patients treated for six weeks. Although there was a small number of patients in the PROXY study, this is encouraging data.
The study used Gilead’s drug—sofosbuvir—as the proxy drug. A proxy drug is used as a placeholder while another drug is being developed and tested by a pharmaceutical company—in this case Achillion. Also noteworthy, Achillion and Janssen are collaborating to develop and commercialize HCV drugs worldwide. Janssen has many drugs in development to treat hepatitis C. As well, Gilead, AbbVie, and Merck have drugs in the pipeline. Merck’s new combination of two drugs is expected to be approved by the Food and Drug Administration (FDA) in early 2017.
Medical Providers
Patients are not the only ones who are having a difficult time with the insurance restrictions. Medical providers who have to tell their patients are also upset. Many providers have to spend a lot of time submitting paperwork over and over trying to get their patients’ medications approved. It takes up an inordinate amount of the medical provider and office staff’s time—many times only to be told that the insurance claim was denied. As you can imagine it breaks their hearts to tell a patient “there is a cure, but I cannot give you it because insurance will not cover it.”
Insurance
There are other issues that are difficult for patients, medical and service providers. Access to the new medications can be very difficult depending on your insurance carrier. Many people are being denied access to these life-saving HCV medications unless they have more serious disease progression. Shame on the insurance companies that are not covering HCV medications! It doesn’t help that the price of the drugs are so expensive.
The Current State of HCV Therapy
We have certainly come a long way compared to the interferon days. Additionally, many populations—HIV/HCV coinfection, Latinos, compensated cirrhosis, healthy liver-transplanted—and other groups had very low cure rates.
The current state of HCV treatment is nothing short of amazing. Current therapy cures up to 90% to 100% of people with HCV genotype 1, 2, and 4. The medications also have lower side effects and shorter treatment duration.
The improvements in cure rates are impressive especially in certain populations with hepatitis C. In the September 2015 “Mid-Month Edition” of the HCV Advocate newsletter I wrote about 3 different clinical trials using 3 different combinations of direct-acting antivirals to treat HCV in people coinfected with HIV. The patient populations in these studies included many of the patient characteristics previously considered the most difficult to treat—people with HIV, genotype 1a, cirrhosis, Black patients, previously treated patients—all who had not achieved a cure. The cure rate in the three trials ranged from 96% to 98%. Another population that has had dramatic improvements is liver transplanted patients (with moderate liver function and compensated cirrhosis). The cure rates were 96% - 98%.
Drug-Drug Interactions
A very important issue with the new direct antiviral medications is the potential for drug-drug interactions (DDIs). This is more of an issue for people of the Baby Boomer generation who may take additional medications for blood pressure, diabetes, cholesterol, etc. People who are infected with HIV/HCV are also at risk for DDIs. There is also a risk of DDIs with common over-the-counter medications and herbs. This is why it is so important to tell your medical provider(s) about anything you are taking.
Still Difficult to Treat2
A caveat: Even though we need better therapies and strategies to treat the most difficult to treat patients listed here, the DAA therapies are still vast improvements from the older therapies in the people and groups below.
People with genotype 3 with cirrhosis and who have not been cured with a previous course of treatment are an unmet medical need. Current treatments only yield cure rates in the 60 percentile. There is an option of adding pegylated interferon. I wrote about this before and advised people to think about this but I did not get a very positive reaction.
People with decompensated cirrhosis are at risk for severe disease progression, but unfortunately, current treatment does not work as well. Similarly, people with end-stage kidney disease or people who are on dialysis also have a large unmet medical need. Note: Merck’s new combination looks very promising for this group of patients. People who do not respond to a previous course of therapy are another difficult group to treat, but treatment strategies are slowly evolving.
Re-Treatment
For someone who has relapsed, coming up with a plan to prescribe the right combination of drugs to optimize the chances of re-treatment success is more difficult with the development of RAVs (see a brief overview of RAVs in this issue).
There have been many advances in hepatitis C treatment in a short period of time. Hopefully, many of the treatment issues listed above will be quickly resolved. In the meantime, we all have to advocate for ourselves and others with hepatitis C and remember to thank those medical providers who are providing such wonderful care.
References:
1 Company Press Release
2 Difficult-to-cure populations with chronic hepatitis c: Vanishing in the direct-acting antiviral era?
Norah Terrault M.D. Hepatology Volume 62, Issue 1, pages 4–7, July 2015
Wednesday, October 7, 2015
Treating 5 Percent of Hepatitis C Patients with New Drugs Would Reduce Cost, Infections: Study
Treating 5 percent of all hepatitis C patients with the latest drugs would be more effective at reducing infections and health care costs than the current approach, a new study shows.
The cost-benefits analysis by researchers from the USC Schaeffer Center for Health Policy and Economics and other institutions compares three treatment options to the current approach, or "baseline" scenario, which treats patients in the most advanced stages of the disease when they may need a costly liver transplant.
"We made a mistake with HIV by limiting access to treatment to just people who had AIDS, and we ended up with a virus that has been with us for decades," said corresponding author Dana Goldman, the Schaeffer Center director and a professor at the USC School of Pharmacy and the USC Price School of Public Policy. "We didn't initially treat HIV aggressively enough in part because the science wasn't there to justify it. With hepatitis C, we have the science. We just need to find a way to finance it."
Nurse used same syringe on 67 people at N.J. flu clinic, state says
A nurse who administered flu vaccines to employees of a West Windsor company has been reported to health officials because she re-used a single syringe for the shots.
At an employer-sponsored flu clinic at Otsuka Pharmaceuticals last week, the unnamed nurse committed an "infection control breach," according to a spokeswoman for the N.J. Department of Health.
"Full infection control practices that prevent transmission of blood-borne diseases were not used by a contracted health care agency, Total Wellness," said Donna Leusner, the spokeswoman.
Tuesday, October 6, 2015
Hepatitis C cases on rise in northeast Indiana, Allen County proposes needle-exchange program
FORT WAYNE, Ind. (October 6, 2015) — Officials in northeastern Indiana’s Allen County have taken a first step toward creating a needle exchange to combat the county’s growing hepatitis C cases.
The Fort Wayne-Allen County Board of Health unanimously approved a resolution Monday calling for a needle-exchange program to slow the spread of the disease among intravenous drug users.
Allen County has had about 270 new hepatitis C cases during the first nine months of 2015. That’s more than in any of the past three years.
Read more....
The Fort Wayne-Allen County Board of Health unanimously approved a resolution Monday calling for a needle-exchange program to slow the spread of the disease among intravenous drug users.
Allen County has had about 270 new hepatitis C cases during the first nine months of 2015. That’s more than in any of the past three years.
Read more....
Health plan tiers raise drug costs for hepatitis patients
This is important information to think about if you have open enrollment. Jacques Chambers article "Open Enrollment" will be featured in the next issue of the October Mid-Monthly HCV Advocate Newsletter - Alan
By Bob Herman | October 5, 2015
A new report says that health insurance companies discriminate against people with hepatitis B and C by charging high out-of-pocket costs for drugs, but the industry lobby has called the analysis “very one-sided” and limited in scope.
The Affordable Care Act prohibits health insurers from discriminating against people on the basis of age, gender or health conditions, and the federal government has already made it clear it will monitor health plans sold on the public exchanges to ensure they meet ACA standards.
The not-for-profit AIDS Institute examined silver-level health plans that were sold on Florida's insurance marketplace in 2015. The group found that eight of the 12 insurers that sold 2015 plans had what it deemed as discriminatory practices for hepatitis B and C drugs. For example, Aetna placed many of its hepatitis drugs on the most expensive tiers with coinsurance rates up to 50%. Humana had a $1,500 prescription drug deductible and also had many of its hepatitis drugs on the highest tiers with large cost-sharing, the report found.
Read more....
By Bob Herman | October 5, 2015
A new report says that health insurance companies discriminate against people with hepatitis B and C by charging high out-of-pocket costs for drugs, but the industry lobby has called the analysis “very one-sided” and limited in scope.
The Affordable Care Act prohibits health insurers from discriminating against people on the basis of age, gender or health conditions, and the federal government has already made it clear it will monitor health plans sold on the public exchanges to ensure they meet ACA standards.
The not-for-profit AIDS Institute examined silver-level health plans that were sold on Florida's insurance marketplace in 2015. The group found that eight of the 12 insurers that sold 2015 plans had what it deemed as discriminatory practices for hepatitis B and C drugs. For example, Aetna placed many of its hepatitis drugs on the most expensive tiers with coinsurance rates up to 50%. Humana had a $1,500 prescription drug deductible and also had many of its hepatitis drugs on the highest tiers with large cost-sharing, the report found.
Read more....
Olysio (simeprevir) label revised
Information about FDA Hepatitis product approvals, safety warnings, medical product labeling changes, notices of upcoming public meetings, and notices about proposed regulatory guidances.
On October 5, 2015 FDA approved revisions to the Olysio (simeprevir) label to include dosing recommendations for the treatment of HCV/HIV-1 coinfection and to expand the indications and usage to include genotype 4 infection.
The recommended dosage regimens and treatment duration for genotype 1 and HCV/HIV-1 co-infected patients was added to the following table:
| Table 1: Recommended Dosage Regimens and Treatment Duration for OLYSIO, Peg IFN alfa, and RBV Combination Therapy for Treatment of CHC Infection in HCV Genotype 1 or 4 Mono infected and HCV/HIV 1 Co infected Patients | |
| Patient Population | Treatment Regimen and Duration |
| Treatment naïve patients and prior relapsers* | |
| 12 weeks of OLYSIO in combination with Peg IFN alfa and RBV followed by an additional 12 weeks of Peg IFN alfa and RBV (total treatment duration of 24 weeks)† |
| |
| with cirrhosis, who are co infected with HIV | 12 weeks of OLYSIO in combination with Peg-IFN-alfa and RBV followed by an additional 36 weeks of Peg IFN alfa and RBV (total treatment duration of 48 weeks)† |
| Prior non responders (including partial‡ and null responders#), with or without cirrhosis, with or without HIV co infection | 12 weeks of OLYSIO in combination with Peg-IFN-alfa and RBV followed by an additional 36 weeks of Peg IFN alfa and RBV (total treatment duration of 48 weeks)† |
†HIV = human immunodeficiency virus.
* Prior relapser: HCV RNA not detected at the end of prior IFN based therapy and HCV RNA detected during follow up [see Clinical Studies (14)].
‡† Recommended duration of treatment if patient does not meet stopping rules (see Table 3).
#‡ Prior partial responder: prior on-treatment ≥ 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at end of prior IFN based therapy [see Clinical Studies (14)].
§# Prior null responder: prior on treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior IFN based therapy [see Clinical Studies (14)].
* Prior relapser: HCV RNA not detected at the end of prior IFN based therapy and HCV RNA detected during follow up [see Clinical Studies (14)].
‡† Recommended duration of treatment if patient does not meet stopping rules (see Table 3).
#‡ Prior partial responder: prior on-treatment ≥ 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at end of prior IFN based therapy [see Clinical Studies (14)].
§# Prior null responder: prior on treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior IFN based therapy [see Clinical Studies (14)].
Section 6 Adverse Reactions was updated with the following information.
OLYSIO in combination with Peg IFN alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV 1 co infection. The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono infected subjects.
OLYSIO in combination with Peg IFN alfa and RBV was studied in 107 subjects with HCV genotype 4 infection. The safety profile of OLYSIO in subjects with HCV genotype 4 infection was comparable to subjects with HCV genotype 1 infection.
Azithromycin, bedaquiline and dolutegravir were added to the list of drugs without clinically significant interactions with OLYSIO (see section 7.4 of the label).
Section 12.3 Pharmacokinetics was updated to include the following statements.
Patients co infected with HIV 1
Simeprevir exposures were slightly lower in subjects with HCV genotype 1 infection with HIV 1 co infection compared to subjects with HCV genotype 1 mono infection. This difference is not considered to be clinically meaningful.
Section 12.4 Microbiology was updated to include data on genotype 4 as follows:
Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment naïve genotype 4a-, 4d-, or 4r infected patients displayed median FC in EC50 values of 0.5 (IQR: 0.4 to 0.6; N=38), 0.4 (IQR: 0.2 to 0.5; N=24), and 1.6 (IQR: 0.7 to 4.5; N=8), compared to reference genotype 1b replicon, respectively. A pooled analysis of chimeric replicons carrying the NS3 sequences from HCV protease inhibitor naïve patients infected with other HCV genotype 4 subtypes, including 4c (N=1), 4e (N=2), 4f (N=3), 4h (N=3), 4k (N=1), 4o (N=2), 4q (N=2), or unidentified subtype (N=7) displayed a median FC in EC50 value of 0.7 (IQR: 0.5 to 1.1; N=21) compared to reference genotype 1b replicon.
In the RESTORE trial in genotype 4 infected subjects, 30 out of 34 (88%) subjects who did not achieve SVR had emerging amino acid substitutions at NS3 positions Q80, T122, R155, A156 and/or D168 (mainly substitutions at position D168; 26 out of 34 [76%] subjects), similar to the emerging amino acid substitutions observed in genotype 1 infected subjects.
Table 11: SVR12 Rates by IL28B rs12979860 Genotype in Adult Patients Receiving OLYSIO 150 mg Once Daily in Combination with Peg IFN alfa and RBV (Trials C212 and RESTORE) | |||||
| Trial (Population) | IL28B rs12979860 Genotype | Treatment- Naïve Subjects % (n/N) | Prior Relapsers % (n/N) | Prior Partial Responders % (n/N) | Prior Null Responders % (n/N) |
C212 (HIV 1 co infection) | C/C | 100 (15/15) | 100 (7/7) | 100 (1/1) | 80 (4/5) |
| C/T | 70 (19/27) | 100 (6/6) | 71 (5/7) | 53 (10/19) | |
| T/T | 80 (8/10) | 0 (0/2) | 50 (1/2) | 50 (2/4) | |
RESTORE (HCV genotype 4) | C/C | 100 (7/7) | 100 (1/1) | - | - |
| C/T | 82 (14/17) | 82 (14/17) | 60 (3/5) | 41 (9/22) | |
| T/T | 0 (8/10) | 00 (4/4) | 60 (3/5) | 39 (77/18) | |
SVR12: sustained virologic response 12 weeks after planned EOT.
Section 14 Clinical Studies was updated to include the trial results from the HCV/HIV- coinfected trial and the genotype 4 trial.
Subjects with HCV/HIV 1 Co Infection
C212 was an open label, single arm Phase 3 trial in HIV 1 subjects co infected with HCV genotype 1 who were treatment naïve or failed prior HCV therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Non cirrhotic treatment naïve subjects or prior relapsers received 12 weeks of once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) and all cirrhotic subjects (METAVIR fibrosis score F4) received 36 weeks of Peg IFN alfa 2a and RBV after the initial 12 weeks of OLYSIO in combination with Peg IFN alfa 2a and RBV.
C212 was an open label, single arm Phase 3 trial in HIV 1 subjects co infected with HCV genotype 1 who were treatment naïve or failed prior HCV therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Non cirrhotic treatment naïve subjects or prior relapsers received 12 weeks of once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) and all cirrhotic subjects (METAVIR fibrosis score F4) received 36 weeks of Peg IFN alfa 2a and RBV after the initial 12 weeks of OLYSIO in combination with Peg IFN alfa 2a and RBV.
The 106 enrolled subjects in the C212 trial had a median age of 48 years (range: 27 to 67 years; with 2% above 65 years); 85% were male; 82% were White, 14% Black or African American, 1% Asian, and 6% Hispanic; 12% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800,000 IU/mL; 68% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 13% METAVIR fibrosis score F4; 82% had HCV genotype 1a, and 17% HCV genotype 1b; 28% of the overall population and 34% of the subjects with genotype 1a had Q80K polymorphism at baseline; 27% had IL28B CC genotype, 56% IL28B CT genotype, and 17% IL28B TT genotype; 50% (n=53) were HCV treatment naïve subjects, 14% (n=15) prior relapsers, 9% (n=10) prior partial responders, and 26% (n=28) prior null responders. Eighty eight percent (n=93) of the subjects were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (except rilpivirine) were prohibited from use in this study.
The median baseline HIV 1 RNA levels and CD4+ cell count in subjects not on HAART were 4.18 log10 copies/mL (range: 1.3 4.9 log10 copies/mL) and 677 × 106 cells/L (range: 489 1076 × 106 cells/L), respectively. The median baseline CD4+ cell count in subjects on HAART was 561 × 106 cells/mL (range: 275 1407 × 106 cells/mL).
Table 17 shows the response rates in treatment naïve, prior relapsers, prior partial responders and null responders.
| Table 17: Response Rates in Adult Subjects with HCV Genotype 1 Infection and HIV 1 Co Infection (C212 Trial) | ||||
| Response Rates | Treatment Naïve Subjects N=53 % (n/N) | Prior Relapsers N=15 % (n/N) | Prior Partial Responders N=10 % (n/N) | Prior Null Responders N=28 % (n/N) |
| Overall SVR12 (genotype 1a and 1b) Genotype 1a Genotype 1b | 79 (42/53) 77 (33/43) 90 (9/10) | 87 (13/15) 83 (10/12) 100 (3/3) | 70 (7/10) 67 (6/9) 100 (1/1) | 57 (16/28) 54 (13/24) 75 (3/4) |
| Outcome for all subjects without SVR12 | ||||
| On treatment failure* | 9 (5/53) | 0 (0/15) | 20 (2/10) | 39 (11/28) |
| Viral relapse† | 10 (5/48) | 13 (2/15) | 0 (0/7) | 12 (2/17) |
150 mg OLYSIO for 12 weeks with Peg IFN alfa 2a and RBV for 24 or 48 weeks.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12.
Eighty nine percent (n=54/61) of the OLYSIO treated treatment naïve subjects and prior relapsers without cirrhosis were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 87%.
Seventy-one percent (n=37/52), 93% (n=14/15), 80% (n=8/10) and 36% (n=10/28) of OLYSIO treated treatment naïve subjects, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these subjects the SVR12 rates were 89%, 93%, 75% and 90%, respectively.
Table 18 shows the SVR rates by METAVIR fibrosis scores.
| Table 18: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection and HIV 1 co Infection (C212 Trial) | ||||
| Subgroup | Treatment Naïve Subjects % (n/N) | Prior Relapsers % (n/N) | Prior Partial Responders % (n/N) | Prior Null Responders % (n/N) |
| F0 2 | 89 (24/27) | 78 (7/9) | 50 (1/2) | 57 (4/7) |
| F3 4 | 57 (4/7) | 100 (2/2) | 67 (2/3) | 60 (6/10) |
Two subjects had HIV virologic failure defined as confirmed HIV 1 RNA ≥ 200 copies/mL after previous < 50 copies/mL; these failures occurred 36 and 48 weeks after end of OLYSIO treatment.
Adult Subjects with HCV Genotype 4 Infection
RESTORE was an open label, single arm Phase 3 trial in subjects with HCV genotype 4 infection who were treatment naïve or failed prior therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Treatment naïve subjects or prior relapsers received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 36 weeks of Peg IFN alfa 2a and RBV.
RESTORE was an open label, single arm Phase 3 trial in subjects with HCV genotype 4 infection who were treatment naïve or failed prior therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Treatment naïve subjects or prior relapsers received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 36 weeks of Peg IFN alfa 2a and RBV.
The 107 enrolled subjects in the RESTORE trial with HCV genotype 4 had a median age of 49 years (range: 27 to 69 years; with 5% above 65 years); 79% were male; 72% were White, 28% Black or African American, and 7% Hispanic; 14% had a BMI greater than or equal to 30 kg/m2; 60% had HCV RNA levels greater than 800,000 IU/mL; 57% had METAVIR fibrosis score F0, F1 or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 33% (n=35) were treatment naïve HCV subjects, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders.
Table 19 shows the response rates in treatment naïve, prior relapsers, prior partial responders and null responders. Table 20 shows the SVR rates by METAVIR fibrosis scores.
| Table 19: Response Rates in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial) | ||||
| Response Rates | Treatment Naïve Subjects N=35 % (n/N) | Prior Relapsers N=22 % (n/N) | Prior Partial Responders N=10 % (n/N) | Prior Null Responders N=40 % (n/N) |
| Overall SVR12 | 83 (29/35) | 86 (19/22) | 60 (6/10) | 40 (16/40) |
| Outcome for all subjects without SVR12 | ||||
| On treatment failure* | 9 (3/35) | 9 (2/22) | 20 (2/10) | 45 (18/40) |
| Viral relapse† | 9 (3/35) | 5 (1/22) | 20 (2/10) | 15 (6/40) |
150 mg OLYSIO for 12 weeks with Peg IFN alfa 2a and RBV for 24 or 48 weeks.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at actual EOT.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at actual EOT.
| Table 20: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial) | ||||
| Subgroup | Treatment Naïve Subjects % (n/N) | Prior Relapsers % (n/N) | Prior Partial Responders % (n/N) | Prior Null Responders % (n/N) |
| F0-2 | 85 (22/26) | 91 (10/11) | 100 (5/5) | 47 (8/17) |
| F3-4 | 78 (7/9) | 82 (9/11) | 20 (1/5) | 35 (7/20) |
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Office of Health and Constituent Affairs
Food and Drug Administration
For more information about the Hepatitis Liaison Program visit the FDA Patient Network
U.S. FDA Grants Priority Review For Daklinza (daclatasvir) sNDA
Three applications are under review for Daklinzain combination with sofosbuvir with or without ribavirin to treat chronic hepatitis C patients with decompensated cirrhosis, post-liver transplant recurrence of HCV, and coinfection with HIV-1
Bristol-Myers Squibb’s U.S. registration focus for Daklinza is based on addressing the treatment needs of challenging HCV patient populations
October 06, 2015 07:00 AM Eastern Daylight Time
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the U.S. Food and Drug Administration (FDA) has accepted for filing and review three supplemental New Drug Applications (sNDAs) for Daklinza (daclatasvir), an NS5A replication complex inhibitor, for use with sofosbuvir with or without ribavirin. The applications are for the treatment of patients with chronic hepatitis C (HCV) coinfected with human immunodeficiency virus (HIV-1), patients with advanced cirrhosis (including decompensated cirrhosis), and for patients with post-liver transplant recurrence of HCV.
In the U.S., the FDA grants priority review status when an investigational medicine, if approved, would offer a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions. The FDA will review the three Daklinza sNDAs within a six-month timeframe.
“Hepatitis C is not a one-size-fits-all, monolithic disease. Our focus for the Daklinza-sofosbuvir regimen centers on addressing the needs of HCV patient subpopulations who need new options even in light of the extraordinary advances that have occurred in HCV treatment,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “We look forward to working with the FDA toward the goal of eventually helping many difficult-to-treat HCV patients.”
Daklinza was initially approved in the U.S. in July 2015 and is indicated for use with sofosbuvir for the treatment of patients with chronic HCV genotype 3 infection. The new sNDAs accepted by the FDA for review include data from the ALLY-1 and ALLY-2 clinical trials. ALLY-2 evaluated the once-daily 12-week combination of Daklinza and sofosbuvir for the treatment of patients with HCV coinfected with HIV-1, a patient population that historically has been challenging to treat, in large part due to the complexities of the overlapping therapeutic regimens used to treat each infection. ALLY-1 evaluated a 12-week regimen of daclatasvir and sofosbuvir once-daily with ribavirin for the treatment of patients with HCV with either advanced cirrhosis or post-liver transplant recurrence of HCV.
In May 2015, Daklinza with sofosbuvir received FDA Breakthrough Therapy Designation for HCV genotype 1 patients with advanced cirrhosis (Child-Pugh Class B or C) and those who develop genotype 1 HCV recurrence post-liver transplant. Breakthrough Therapy Designation, according to the FDA, is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for this designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.
About Bristol-Myers Squibb in HCV
Bristol-Myers Squibb’s research efforts are focused on advancing compounds to deliver the most value to HCV patients with high unmet needs. At the core of our portfolio is Daklinza, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with high disease burden.
In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic HCV. Since then, daclatasvir-based regimens have been approved in more than 50 countries, including the United States, across Europe, and in numerous other countries in Central and South America, the Middle East and the Asia-Pacific region.
Indication and Important Safety Information - Daklinza™ (daclatasvir)
INDICATION
Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.
Limitations of Use:
Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Drugs Contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).
WARNINGS and PRECAUTIONS
-- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
Bradycardia generally resolved after discontinuation of HCV treatment.
Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
ADVERSE REACTIONS
The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).
DRUG INTERACTIONS
CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.
Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.
Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.
Please click here for the Daklinza full prescribing information.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information please visit www.bms.com or follow us on Twitter at twitter.com/bmsnews.
Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that Daklinza will be approved for the additional indication mentioned above. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Contacts
Bristol-Myers Squibb Company
Media:
Robert Perry, 609-419-5378
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rob.perry@bms.com
or
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ranya.dajani@bms.com
or
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william.szablewski@bms.com
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