HCV drugs - A review of 2012 and a peek at 2013
Today this blog offers a look back at the two new drugs approved in 2011 to treat hepatitis C, and a few promising therapies in development.
In May of 2011 the U.S. Food and Drug Administration approved Incivek (telaprevir) and Vicrelis/Boceprevir to treat hepatitis C patients chronically infected with genotype 1.
Among treatment-naive people with HCV genotype 1 these two new direct-acting antiviral agents boceprevir or telaprevir have increased SVR more than 75%.
Both protease inhibitors are taken with a combination of pegylated interferon and ribavirin. Treatment duration is a total of 24, 36 or 48 weeks.
Telaprevir and Boceprevir
In a study of veterans infected with hepatitis C virus (HCV) genotype 1, the direct-acting antiviral drugs boceprevir and telaprevir, in combination with pegylated interferon and ribavirin, produced robust antiviral responses at 24 weeks and at the end of therapy, read the December 2012 article from Medscape here.
Telaprevir and Boceprevir Offer Similar Efficacy For Most Patients?
Reported by (Reuters Health)
As there are no head-to-head comparison trials so far, Dr. Kiernan and colleagues used a Bayesian mixed treatment comparison model to explore the relative differences in efficacy between boceprevir and telaprevir when used as a third agent (with pegylated interferon and ribavirin) in HCV genotype 1 treatment. She added, "For patients who have experienced a previous treatment relapse, our research would suggest that telaprevir would be a better choice." .... continue reading
Incivek (Telaprevir)-Hepatitis C Geno 2 Patient Treated
Anemia (including severe anemia) and neutropenia, have been reported to be significantly higher with boceprevir triple therpay than with pegylated interferon and ribavirin alone, and telaprevir is associated with a serious rash. In clinical data a rash was reported in 56% of patients using telaprevir . We can compare that to 32% of patients reporting a rash receiving standard of care (pegylated interferon and ribavirin). The rash was found to be mild to moderate although severe in 1% of patients and resulted in stopping treatment for 6% of patients.
Recently Vertex announced that the INCIVEK® (telaprevir) label in
Included below are links to the recent updates
HCV Drug Incivek (telaprevir) - View Rash Grade 1 and 2
FDA Podcast: Serious skin reactions with Hepatitis C drug Incivek (telaprevir)
As for boceprevir anemia was seen in about 50 % of patients undergoing therapy - compared to 30% receiving standard therapy.
According to new data presented by Merck at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) drug-induced anemia during triple therapy with boceprevir can be managed by ribavirin dose reduction or by the addition of erythropoietin.
The November 2012 press release from Merck -
Merck Reports New Phase III Analyses on Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy, Including Cirrhotic Patients
Jan 6 2013 - HCV triple-therapy genotype 1: management of side-effects
How to optimize HCV therapy in genotype 1 patients: management of side-effects
Antiviral therapy for chronic hepatitis C has dramatically changed with the advent of triple therapy incorporating direct-acting antivirals (DAAs) such as the protease inhibitors (PI) boceprevir and telaprevir. Such triple-therapy is associated with a new spectrum of side-effects which can hamper quality of life. These may lead to dosage reduction and sometimes discontinuation of therapy. This review presents practical tips to help manage adverse effects appropriately and efficiently. The main adverse effects causing discontinuation of therapy are varied. Although the most common adverse effects are the ‘flu’-like symptoms of fatigue, myalgia, fever and lassitude, these are usually easily managed and do not lead to treatment discontinuation. Cytopaenia, particularly anaemia, has emerged as perhaps the most troublesome side-effect. Cirrhotic patients are especially prone to moderate or severe anaemia with boceprevir and telaprevir triple-therapy regimens. Aggressive ribavirin dosage reductions, erythropoietin and blood transfusions are effective for managing anaemia. Skin rash can be controlled with moisturization and corticosteroid ointment. Rarely, dermatology consultation is required for further management. Anal discomfort, with or without diarrhoea, sometimes responds to barrier creams and haemorrhoidal ointments. Dysgeusia is treated by sipping water frequently, oral ointments and mouth washes to maintain salivary flow and oral hygiene. Successful adherence to treatment can be enhanced by a strong support network for the patient, including specially-trained hepatitis nurses and a multidisciplinary team incorporating pharmacists, counsellors and social workers.........
Cirrhosis and Triple Therapy
In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen. The full article written by Neil Osterweil is available here.
Cirrhosis - Interferon-free
Reported by Keith Alcorn - November 2012
The first major data on interferon-free hepatitis C treatment in people with cirrhosis show that treatment using BI-201335 – now known as faldaprevir – and BI-207127 with ribavirin can be safe, and proved effective in up to 69% of patients, according to results from the SOUND-C2 study presented this week at the 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, read the full article here.
Standard Therapy Improves Survival In Patients With Cirrhosis
According to a study reported this month in the December 26, 2012, issue of JAMA, sustained virological response to hepatitis C interferon-based treatment is associated with improved survival in patients with advanced disease.
Read all updates here: Hepatitis C Cirrhosis Patients with Sustained Treatment Response Have Lower Risk of Death
A Shortfall in Statin Use.
A study from the University of North Carolina at Chapel Hill suggests that providers are hesitant to prescribe statins to patients with dyslipidemia and chronic liver disease, despite data and guidelines supporting the safe use of the drugs in this patient population.
The cross-sectional study identified 1,198,221 patients with dyslipidemia. Statin use was compared in patients with HCV without cirrhosis, patients with compensated cirrhosis of any etiology and a group of controls without liver disease. The investigators found that statins were prescribed to 1,055 (28.7%) of the HCV-infected patients, 1,092 (34.1%) of the patients with compensated cirrhosis and 710,564 (59.6%) of control patients. Patients with HCV or compensated cirrhosis thus were significantly less likely than controls to receive statins (odds ratio, 0.31; 95% confidence interval, 0.29-0.32). The authors recommended increased education to change providers’ perceptions of statin hepatoxicity risk among patients with chronic liver disease.
“This study confirms that statins are underused in the HCV population and those with liver cirrhosis. As pharmacists, we can and should do a better job in educating patients and physicians about the safety of statins in this population,” said specialty pharmacist Janet Nguyen, PharmD, BCPS, vice president of network strategy at ModernHealth in Monrovia, Calif. “We should be doing a review of their medication profile and identifying opportunities to provide interventions for patients who should be put on a statin for their cardiovascular benefits.”
Current guidelines state that patients who are coinfected with HCV and HIV should be treated for 48 weeks, especially if polymerase chain reaction (PCR) tests for HCV remain positive at four weeks. But Canadian researchers presented data suggesting that response-guided therapy (RGT)—usually with pegylated interferon plus ribavirin (PR)—can significantly shorten the duration of therapy.
In the study, researchers at Toronto General Hospital used electronic medical records to identify all patients with HCV genotype 2 or 3 with HIV coinfection. PCR tests for HCV were performed every four weeks of drug therapy until a negative result (<50 IU/mL) was achieved.
In the intent-to-treat analysis, 23 of 35 patients were treated with the RGT protocol, and 20 patients completed their treatment. According to the researchers, only one patient needed the full 48 weeks of therapy to achieve a sustained virologic response (SVR)—a finding that was especially striking, considering the fact that less than half of the patients (nine) had a negative PCR HCV test at four weeks.
Based on the results, “the use of response-guided therapy allows [treatment] to be shortened in the majority of individuals” with HIV and HCV coinfection, the researchers concluded.
Positive Telaprevir Data.
Researchers from the University of Milan in Italy presented a study on the use of telaprevir (Incivek, Vertex) for patients with HCV genotype 1 with severe fibrosis or compensated cirrhosis. In the open-label, early-access program spanning 16 countries, patients were treated for 12 weeks with telaprevir and PR, followed by PR. At four weeks, 54% of patients had undetectable HCV RNA and at 12 weeks, 79% had undetectable viral loads. Serious adverse events occurred in 14% of patients, which is similar to rates from Phase III registration trials.
“The study results are consistent with what we have seen with other telaprevir studies,” commented Dr. Nguyen. “There is still a misnomer out in the community with what telaprevir can do for patients. It is a potential cure for HCV and people still don’t realize that. In this study, and other studies, even patients who had partial or null response to therapy in the past have hope with this therapy.”
Impact on Quality of Life.
Another study presented at The Liver Meeting evaluated the quality of life (QoL) in patients with chronic HCV who achieved SVR versus non-SVR after IFN-based HCV treatment. German researchers found that SVR had a significant effect on liver-related morbidity, and improved QoL and productivity. Specifically, 759 of 1,355 patients achieved SVR after first therapy and only three of those developed a liver-related clinical event compared with 31 non-SVR patients. Increased QoL (scored on the Short Form-36 Health Survey) and productivity (measured by higher frequency of employment, higher number of working hours and lower number of outpatient and inpatient visits after HCV treatment) also were significantly associated with patients who achieved SVR.
Source - Infectious Disease Special Edition
Sofosbuvir (formerly referred to as both GS-7977 and PSI-7977) is a nucleotide analog polymerase inhibitor
November 2012 Press Release
Gilead Announces 100 Percent Sustained Virologic Response Rate (SVR4) for an Interferon-Free Regimen of Sofosbuvir (GS-7977), GS-5885 and Ribavirin in Treatment-Na ïve Genotype 1 Hepatitis C Infected Patients
Hepatitis C Medicine Trial Shows 100% Cure Rate
Nov 10 2012 (Reuters) - Gilead Sciences Inc on Saturday reported a 100 percent cure rate using a combination of drugs in a small number of patients with the most common and hardest to treat form of hepatitis C.
Rival Abbott Laboratories Inc, meanwhile, said a trio of its oral medicines to treat hepatitis C produced unprecedented cure rates in a larger number of patients who had failed to benefit from standard treatment, as well as very high cure rates for newly treated patients.
Data from both companies' mid-stage trials were released Saturday at the annual meeting of the American Association for the Study of Liver Disease in Boston. Gilead's study, dubbed Electron, examined 25 patients with genotype 1 chronic hepatitis C virus (HCV) infection who were treated for 12 weeks with a combination of three drugs: sofosbuvir, ribavirin and GS-5885....
Also in November Gilead reported results examining sofosbuvir (GS-7977) plus ribavirin in patients with genotype 2 or 3
Phase 3 POSITRON study examining a 12-week course of once-daily sofosbuvir plus ribavirin (RBV) in patients with genotype 2 or 3 chronic hepatitis C virus (HCV) infection who are not candidates to take interferon (IFN).
The study found that 78 percent of patients remained HCV RNA undetectable 12 weeks after completing therapy (SVR12). The safety profile of sofosbuvir was similar to that observed in previous studies, and there were few treatment discontinuations due to adverse events.
POSITRON is the first of three Phase 3 studies to be completed that are evaluating sofosbuvir therapy in HCV genotype 2 or 3 infected patient populations.
“We look forward to sharing data from additional Phase 3 studies in early 2013, and expect to submit our first regulatory filings for sofosbuvir by mid-2013.”, read the press release here.
HCV drugs approved and currently in development
In January 2013 - Gilead Provided An Update on Hepatitis C Development Programs Including - Sofosbuvir (GS-7977)
Gilead Update - 2nd Phase 3 Study of Sofosbuvir and GS-5885 to Begin Later this Month
-- Sustained Virologic Response Achieved with Oral Regimen of Sofosbuvir, GS-5885 and Ribavirin in 9/9 Null Responder Genotype 1 Hepatitis C Patients --
-- Second Phase 3 Study Evaluating Fixed-dose Combination of Sofosbuvir and GS-5885 to Begin Later this Month --
Stay Updated - 2013 Sofosbuvir
2013 Investment Commentary - Sofosbuvir (GS-7977)
Hepatitis C Market-Sofosbuvir's (GS-7977) Potential
Gilead's lead 'nuc' sofosbuvir anchoring what could become the first interferon-free regimen
November 2012 - Daclatasvir, Asunaprevir and BMS-791325
Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and BMS-791325 Achieved SVR12 of 94% in Treatment-Naïve Patients with Genotype 1 Chronic Hepatitis C Infection in Phase II Trial
First presentation of results from this investigational interferon-, ribavirin- and ritonavir-free regimen Phase III development anticipated to begin in 2014
In November Bristol-Myers announced for the first time Phase II data demonstrating that the 12-week Triple DAA treatment regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 achieved sustained virologic response 12 weeks post-treatment (SVR12) in 94% (15/16) of treatment-naïve, genotype 1 chronic hepatitis C patients.
The remaining one patient had undetectable viral load at the end of treatment and was lost to follow-up until approximately 24 weeks post-treatment; in preliminary data, this patient has achieved SVR24. The Phase II results from this interferon-, ribavirin- and ritonavir-free investigational regimen combining three different classes of direct-acting antivirals (DAAs) – an NS5A replication complex inhibitor (DCV), an NS3 protease inhibitor (ASV) and an NS5B non-nucleoside polymerase inhibitor (BMS-791325) – were presented today at the American Association for the Study of Liver Diseases congress in Boston, read more here.
Triple Therapy With Daclatasvir, Asunaprevir, and BMS-791325 Produces Very High SVR12 Rates in Treatment-Naive Patients With Genotype 1 HCV
In a randomized phase IIa trial, SVR12 rates of 94% were observed with the peginterferon/ribavirin-sparing regimen, and therapy was generally well tolerated.
October 2012 - ABT-450/r, ABT-267, ABT-333 and ribavirin
Abbott's Investigational Interferon-Free Hepatitis C Treatment Regimen
In October Abbott announced initial results from "Aviator," a phase 2b study of its interferon-free, investigational regimen for the treatment of hepatitis C (HCV).
Initial results show sustained virological response at 12 weeks post treatment (SVR12) in 99 percent of treatment-naïve (n=77) and 93 percent of null responders (n=41) for genotype 1 HCV patients taking a combination of ABT-450/r, ABT-267, ABT-333 and ribavirin for 12 weeks, based on an observed data analysis. Read the press release here.
December 2012 - Simeprevir (TMC435)
In December Medivir announced phase III data for Simeprevir (TMC435), administered with pegylated interferon and ribavirin - demonstrating efficacy and safety in genotype 1 hepatitis C patients
Top-line results from three pivotal phase III trials examining the one pill, once-daily, investigational protease inhibitor, simeprevir (TMC435), administered with pegylated interferon and ribavirin.
Results from the QUEST-1 and QUEST-2 trials found that 80% and 81% of treatment-naive patients with chronic genotype 1 hepatitis C infection who were treated with simeprevir achieved sustained virologic response 12 weeks after the planned end of treatment (SVR12).
Results from the PROMISE trial found that 79% of prior relapsed patients treated with simeprevir achieved SVR12. All three studies utilized response-guided treatment (RGT) criteria and 85%, 91% and 93 % of the patients, respectively, were eligible to stop all treatments after 24 weeks, press release available here.
Jan 2013 New Publications
Hepatitis C-Interferon free therapy with direct acting antivirals:asunaprevir; daclatasvir; faldaprevir; simeprevir; NS5A inhibitors; NS5B polymerase inhibitors; protease inhibitors; ribavirin; sofosbuvir
The current treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct-acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen. Major progress has been made in the past few years: numerous ongoing trials with different compounds, increasing sustained virological response (SVR) rates with oral regimens and shortened treatment duration. Combinations of antivirals with additive potency that lack cross-resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN......
HCV Studies Give Hope for Interferon-Free Therapy
Investigational agents that act directly against the hepatitis C virus (HCV) may allow previously untreated patients to avoid interferon therapy, long a standard of care, researchers said.
Two phase IIa studies, reported in the Jan. 3 issue of the New England Journal of Medicine, found promising results with different agents, either without interferon or with reduced use of the drug.
Both studies also found less impressive outcomes among patients previously treated unsuccessfully with the standard combination of ribavirin and pegylated interferon.
The investigational drugs were ABT-450, an inhibitor of the viral NS3 protease, boosted with low-dose ritonavir, and ABT-333, a non-nucleoside NS5B polymerase inhibitor.
Also see: Hepatitis C - 2013 Interferon Free Combinations
HCV: second-generation protease inhibitors
Simeprevir (TMC435; Tibotec, Beerse, Belgium; Medivir Pharmaceuticals, Stockholm, Sweden; Janssen, Beerse, Belgium) is a once-a day-oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection.
Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor.
Sovaprevir (ACH-1625; Achillion Pharmaceuticals, New Haven, CT) is another NS3 protease inhibitor with very high potency, reporting a half-maximal inhibitory concentration of ~1 nm. A phase IIa study reported that ACH-1625, with PEG-IFN/RBV, resulted in a RVR in 75–81% of subjects compared with a RVR of 20% in patients receiving PEG-IFN/RBV alone
ABT-450/r (Abbott, Abbott Park, IL; Enanta Pharmaceuticals, Watertown, MA) ABT-450 is being evaluated with ritonavir boosting to increase plasma concentrations and enable once-a-day dosing
MK-5172 and ACH-2684, are in various stages of clinical development. These true second-generation PIs are expected to have broader genotype coverage and higher barriers to resistance, which represents a significant shift from the second-wave PIs.
ACH-2684 (Achillion Pharmaceuticals) is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and a safety profile at high drug exposures that strongly supports once-a-day dosing. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. It has preclinical activity against the six known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b
|Simeprevir||Phase 3||Second wave|
|BI1335||Phase 3||Second wave|
|Asunaprevir||Phase 3 (all oral)||Second wave|
|Danoprevir/r||Phase 2||Second wave|
|Sovaprevir||Phase 2||Second wave|
|ABT450/r||Phase 2||Second wave|
|MK 5172||Phase 2||Second generation|
|ACH 2684||Phase 2||Second generation|
Jan 2013 Investment Commentary - ACH-2684, 2928, 3102 and 1625
Achillion: Poised For Growth And Now Is The Time To Buy
What is notable is that Achillion has 4 drugs in the mix; ACH-2684, 2928, 3102 and 1625. Each of which are showing strong promise at various phase I and II trials, and can either work independently or in combination in an oral fashion, not injections.
Additional Information On Key Developments
This review only touches on a hand full of drugs in development to treat HCV. For more information visit NATAP with detailed information on all the investigational drugs currently making their way down the pipeline.
HCV Advocate - Top News of 2012
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