Products

Date: 2016-02-16

Type of information: Positive opinion for the granting of a Market Authorisation in the EU

Product name: Harvoni®

Compound: ledipasvir/sofosbuvir fixed-dose combination

Therapeutic area: Infectious diseases

Action mechanism: direct-acting antiviral agent/nucleotide analog. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. This direct-acting agent interferes directly with the HCV life cycle by suppressing viral replication. Ledipasvir is a NS5A inhibitor. Harvoni® was approved by the FDA and Health Canada in October 2014 and by  the European Union in November 2014. This is the first once-daily single tablet regimen for the treatment of chronic HCV genotype 1 infection in adults.

Company: Gilead Sciences (USA -CA)

Disease: chronic hepatitis C genotypes 1, 4, 5 and 6, HCV/HIV-1 coinfection, HCV genotype 1 and 4 liver transplant recipients, and genotype 1-infected patients with decompensated cirrhosis chronic hepatitis C (CHC) in adults and in adolescents aged 12 to < 18 years

Latest news:

• • On June 22, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Harvoni®. The extension to the existing indication is as follows: “Harvoni® is indicated for the treatment of chronic hepatitis C in adults and in adolescents aged 12 to < 18 years."
• • On February 16, 2016, Gilead Sciences announced that the FDA has approved additional indications for Harvoni® (ledipasvir/sofosbuvir) for use in chronic hepatitis C patients with advanced liver disease. Harvoni® in combination with ribavirin (RBV) for 12 weeks was approved for use in chronic hepatitis C virus (HCV) genotype 1- or 4-infected liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), and for HCV genotype 1-infected patients with decompensated cirrhosis (Child-Pugh B or C), including those who have undergone liver transplantation. Harvoni® is now approved for use in a broader range of patient populations, including HCV genotypes 1, 4, 5 and 6, HCV/HIV-1 coinfection, HCV genotype 1 and 4 liver transplant recipients, and genotype 1-infected patients with decompensated cirrhosis.
• The supplemental new drug application (sNDA) approval for genotype 1 or 4 HCV liver transplant recipients without cirrhosis or with compensated cirrhosis, and for genotype 1 HCV patients with decompensated cirrhosis, was supported by data from the Phase 2 SOLAR-1 and SOLAR-2 trials. These open-label studies evaluated 12 and 24 weeks of treatment with Harvoni in combination with RBV in HCV treatment-naïve and treatment-experienced patients with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease.
• • On July 3, 2015, Gilead Sciences announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg), the first once-daily single tablet regimen for the treatment of chronic hepatitis C genotype 1 infection in adults. Harvoni combines the NS5A inhibitor ledipasvir with the nucleotide analog polymerase inhibitor sofosbuvir, approved by the MHLW under the trade name Sovaldi® in March 2015 . Harvoni is indicated for the suppression of viremia in patients with genotype 1 chronic hepatitis C virus (HCV) infection with or without compensated cirrhosis, with a treatment duration of 12 weeks. Harvoni's approval in Japan is supported by data from 318 treatment-naïve and treatment-experienced Japanese patients with genotype 1 HCV infection randomized to ledipasvir/sofosbuvir (n=157) or ledipasvir/sofosbuvir plus ribavirin (n=161) in the Phase 3 clinical trial GS-US-337-0113. Of the 318 patients enrolled in this study, 34 percent were ages 65 years or older and 23 percent had cirrhosis. Among patients receiving 12 weeks of ledipasvir/sofosbuvir without ribavirin, 100 percent (n=78/78) of treatment-naïve and 100 percent (n=79/79) of treatment-experienced patients achieved sustained virologic response 12 weeks after completing therapy (SVR12). Adverse events observed with ledipasvir/sofosbuvir without ribavirin were generally mild and included nasopharyngitis (29 percent), headache (7 percent) and malaise (6 percent).
• The approval is also supported by results from three Phase 3 studies (ION-1, ION-2 and ION-3) evaluating eight, 12 or 24 weeks of ledipasvir/sofosbuvir among genotype 1 HCV patients. Trial participants included patients from the United States , Europe and Puerto Rico who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens, and also included patients with compensated cirrhosis. Trial participants in the ribavirin-free arms (n=1,080) achieved SVR12 rates of 94 to 99 percent.
• • On November 18, 2014, Gilead Sciences announced that the European Commission has granted marketing authorization for Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg), the first once-daily single tablet regimen to treat the majority of chronic hepatitis C genotype 1 and 4 infection in adults. Harvoni® is indicated for the treatment of chronic hepatitis C virus (HCV) in adults and is recommended in treatment-naïve and treatment-experienced cirrhotic and non-cirrhotic genotype 1 and 4 patients with a treatment duration of 12 or 24 weeks depending on prior treatment history and cirrhosis status. Eight weeks of treatment with Harvoni® may be considered in non-cirrhotic treatment-naïve genotype 1 patients. In genotype 1 and 4 patients with decompensated cirrhosis, and genotype 3 patients with cirrhosis and/or prior treatment failure, Harvoni® should be used in combination with ribavirin for 24 weeks. Harvoni is also indicated for patients with HCV who have HIV co-infection.
• This marketing authorization is based on the clinical development program that included more than 2,000 patients with HCV infection, and follows an accelerated assessment by the European Medicines Agency, a designation that is granted to new medicines of major public health interest. It allows for the marketing of Harvoni® in all 28 countries of the European Union. The marketing authorization is supported primarily by data from three Phase 3 studies, ION-1, ION-2 and ION-3. These studies evaluated eight, 12 or 24 weeks of treatment with Harvoni®, with or without ribavirin, among nearly 2,000 genotype 1 HCV patients with compensated liver disease. These studies included non-cirrhotic treatment-naïve patients (ION-3), cirrhotic and non-cirrhotic treatment-naïve patients (ION-1) and cirrhotic and non-cirrhotic patients who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor (ION-2). The primary endpoint for each study was sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV. In these studies, ribavirin was not shown to increase response rates. Trial participants in the ribavirin-free arms (n=1,080) achieved SVR12 rates of 94 to 99 percent.
• The approval was also supported by preliminary data from the SOLAR-1 trial, which evaluated difficult to treat patients with decompensated cirrhosis and patients who have undergone liver transplantation, and from the ERADICATE trial, which evaluated genotype 1 HCV patients co-infected with HIV. The primary endpoint in these studies was SVR12. At the time of submission, only preliminary results were available. In the SOLAR-1 trial, participants with decompensated cirrhosis receiving a 12-week treatment regimen of Harvoni plus ribavirin had an SVR4 rate of 90 percent (n=45/50). In post-liver transplant patients without decompensated liver disease, SVR4 rates were greater than 95 percent (n=109). In an interim analysis of the ERADICATE trial, 40 of the 50 patients had reached 12 weeks post treatment and had SVR12 rates of 98 percent (n=39/40).
• The ELECTRON-2 trial, a Phase 2 open-label study, provided preliminary data on genotype 3 infected HCV patients demonstrating 100 percent (n=26/26) SVR12 when Harvoni was used in combination with ribavirin for 12 weeks. In these clinical studies, fatigue and headache were more common in patients treated with Harvoni compared to placebo.
• • On October 10, 2014, the FDA approved Harvoni® (ledipasvir and sofosbuvir) to treat chronic hepatitis C virus (HCV) genotype 1 infection. Harvoni® is the first combination pill approved to treat chronic HCV genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin. Harvoni® is the third drug approved by the FDA in the past year to treat chronic HCV infection. The FDA approved Olysio® (simeprevir) in November 2013 and Sovaldi® in December 2013. Harvoni®’s efficacy was evaluated in three clinical trials (ION-1, ION-2 and ION-3) enrolling 1,518 participants who had not previously received treatment for their infection (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants with cirrhosis. Participants were randomly assigned to receive Harvoni with or without ribavirin. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response, or SVR), indicating that a participant’s HCV infection has been cured.
• In the first trial, comprised of treatment-naive participants, 94 percent of those who received Harvoni for eight weeks and 96 percent of those who received Harvoni for 12 weeks achieved SVR. The second trial showed 99 percent of such participants with and without cirrhosis achieved SVR after 12 weeks. And in the third trial, which examined Harvoni’s efficacy in treatment-experienced participants with and without cirrhosis, 94 percent of those who received Harvoni for 12 weeks and 99 percent of those who received Harvoni for 24 weeks achieved SVR. In all trials, ribavirin did not increase response rates in the participants. The most common side effects reported in clinical trial participants were fatigue and headache. Harvoni® is the seventh new drug with breakthrough therapy designation to receive FDA approval.
• • On September 26, 2014, the European Medicines Agency has recommended the authorisation of Harvoni® (ledipasvir / sofosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection in adults. The product is a combination of the active substances sofosbuvir and ledipasvir, which block the action of proteins which are essential for HCV to replicate - the protein NS5B for sofosbuvir and NS5A for ledipasvir. Harvoni® was evaluated under the EMA’s accelerated assessment mechanism.
• • On September 24, 2014, Gilead Sciences announced that the company has submitted a New Drug Application (NDA) to Japan's Pharmaceutical and Medical Devices Agency (PMDA) for approval of an once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg for the treatment of chronic genotype 1 hepatitis C virus (HCV) infection in adults. The data submitted in the NDA, which include a Japanese Phase 3 study (GS-US-337-0113) among 341 treatment-naïve and treatment-experienced genotype 1 patients. In the study, 100 percent (n=83/83) of treatment-naïve and 100 percent (n=88/88) of treatment-experienced patients receiving 12 weeks of LDV/SOF without RBV achieved SVR12. Adverse events observed with LDV/SOF without RBV were generally mild and included nasopharyngitis (28 percent), headache (6 percent) and malaise (5 percent).
• The NDA is also supported by SVR12 results from three Phase 3 studies (ION-1, ION-2 and ION-3) evaluating eight, 12 or 24 weeks of LDV/SOF among genotype 1 HCV patients. Trial participants included patients from the United States, Europe and Puerto Rico who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens, and also included patients with compensated cirrhosis. Trial participants in the ribavirin-free arms (n=863) achieved SVR12 rates of 94 to 99 percent. LDV/SOF is currently under regulatory review in the United States and European Union.
• • On April 7, 2014, Gilead Sciences has announced that the FDA has granted priority review to the company's New Drug Application (NDA) for a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg for the treatment of chronic hepatitis C genotype 1 infection in adults. Gilead filed the NDA for LDV/SOF on February 10, 2014, and the FDA has set a target action date under the Prescription Drug User Fee Act (PDUFA) of October 10, 2014. The FDA has also assigned LDV/SOF a Breakthrough Therapy designation. The FDA grants Breakthrough Therapy designation and priority review status to investigational medicines that may offer major advances in treatment over existing options.
• • On March 27, 2014, Gilead Sciences has announced that the company's Marketing Authorisation Application (MAA) for a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection, has been fully validated and is now under assessment by the European Medicines Agency (EMA). The data included in the application, which was submitted on February 27, 2014, support the use of LDV/SOF among adult patients with genotype 1 HCV infection for eight or 12 weeks, depending on prior treatment history and whether they have cirrhosis. The MAA for LDV/SOF is supported by three Phase 3 studies, ION-1, ION-2 and ION-3, in which nearly 2,000 genotype 1 HCV patients were randomized to receive the fixed-dose combination, with or without RBV, for treatment durations of eight, 12 or 24 weeks. Review of the MAA will be conducted under the centralized licensing procedure, which, when finalized, provides one marketing authorization in all 28 member states of the European Union. The EMA has accepted Gilead's request for accelerated assessment of LDV/SOF, a designation that is granted to new medicines of major public health interest.
• • On February 21, 2014, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has given an opinion on the use of a fixed-dose combination of ledipasvir and sofosbuvir in the treatment of chronic hepatitis C virus infection in a compassionate-use programme. In this specific case, Sweden requested an opinion from the CHMP on the conditions under which early access through compassionate use could be given to a combination of ledipasvir and sofosbuvir, with or without ribavirin, for adult patients with genotype 1 HCV infection and advanced liver disease, who are at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated. In clinical trials, the combination of ledipasvir and sofosbuvir, with or without ribavirin, used for 12 or 24 weeks, has shown high efficacy in treating patients with genotype 1 virus, including patients with compensated cirrhosis (scarring of the liver but normal liver function) and patients who have previously failed treatment with the protease inhibitors telaprevir or boceprevir (other treatments for hepatitis C). This is the third opinion provided by the CHMP since October 2013 on compassionate use of medicines in development for the treatment of hepatitis C.
• • On February 10, 2014, Gilead Sciences has announced that the company has submitted a New Drug Application (NDA) to the FDA for a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg for the treatment of chronic hepatitis C genotype 1 infection in adults. The data submitted in the NDA support the use of this combination in patients with genotype 1 hepatitis C virus (HCV) infection, with a treatment duration of eight or 12 weeks depending on prior treatment history and whether they have cirrhosis.
• The FDA has assigned LDV/SOF a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. The NDA for LDV/SOF is supported by three Phase 3 studies, ION-1, ION-2 and ION-3, in which nearly 2,000 genotype 1 HCV patients were randomized to receive the fixed-dose combination, with or without RBV, for treatment durations of eight, 12 or 24 weeks. Trial participants included patients who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens, and also included patients with compensated cirrhosis.
• Gilead plans to file for regulatory approval of LDV/SOF in other geographies, including the European Union, in the first quarter of 2014. Gilead has submitted an application to the European Medicines Agency (EMA) for accelerated assessment of LDV/SOF, a designation that is granted to new therapies and medicines of major public health interest. If accepted, accelerated assessment could shorten the EMA’s review time of LDV/SOF by two months, although it does not guarantee a positive opinion from the Committee for Medicinal Products for Human Use or approval by the European Commission.

Patents:

Submission of marketing authorization application USA : 2014-02-10

Submission of marketing authorization application UE: 2014-02-27

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2014-10-10

UE authorization: 2014-11-18

Favourable opinion UE: 2014-09-26/2017-06-22

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes