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FDA Approves Daclatasvir for Hepatitis C Genotype 3, Technivie for Genotype 4

The U.S. Food and Drug Administration has approved 2 new treatments for hepatitis C virus (HCV) genotypes 3 and 4, which account for millions of cases worldwide. Daclatasvir (Daklinza) received the nod for use in combination with sofosbuvir (Sovaldi) for hard-to-treat genotype 3, while AbbVie received approval for its 2D paritaprevir/ritonavir/ombitasvir coformulation for genotype 4. Options remain limited, however, for people with liver cirrhosis.

The hepatitis C therapies approved over the past 2 years -- Gilead Sciences' sofosbuvir and sofosbuvir/ledipasvir coformulation (Harvoni) and AbbVie's 3D Viekira Pak regimen -- have primarily been used to treat HCV genotype 1, the most common type in the U.S. Genotype 2 can be effectively treated with sofosbuvir plus ribavirin alone, but better options are needed for people with other genotypes.

Bristol-Myers Squibb's long-awaited daclatasvir (which was already approved in Europe) is a HCV NS5A inhibitor with pangenotypic activity, meaning it works against multiple viral genotypes. Gilead's NS5A drug ledipasvir, in contrast, is primarily active against genotype 1, and the Harvoni combo is only approved for that type.

Genotype 1 was historically considered the most difficult to treat, but now that it can be cured in more than 90% of patients, that distinction has shifted to genotype 3. Sofosbuvir was approved for genotypes 3 and 4 as well as 1 and 2, but it requires the addition of pegylated interferon or extended therapy, and still does not reach the high sustained virological response (SVR) rates seen when combining direct-acting antiviral agents (DAAs) that target different steps of the HCV lifecycle.

The approval of daclatasvir now makes effective once-daily, 12-week interferon-free DAA therapy available for people with genotype 3, and it is the first drug approved specifically for this type. BMS's ALLY-3 trial showed that daclatasvir plus sofosbuvir is highly effective against HCV genotype 3 overall, though patients with liver cirrhosis had a lower cure rate than easier-to-treat groups.

Turning to the AbbVie approval, in the U.S. the Viekira Pak regimen -- known as 3D in clinical trials -- consists of the HCV protease inhibitor paritaprevir, a ritonavir booster, and the NS5A inhibitor ombitasvir coformulated in a single pill, packaged with the HCV polymerase dasabuvir as a separate pill.

The 3D regimen is effective against HCV genotype 4 as well as genotype 1, for which it is approved, but is essentially overkill since dasabuvir has minimal activity against genotype 4. The PEARL-I trial showed that a 2D regimen consisting of the paritaprevir coformulation plus ribavirin but without dasabuvir was effective for this genotype.

It was previously possible to obtain Viekira Pak for genotype 4 and just not take the dasabuvir component. But the new Technivie brand, consisting of the 2D coformulation alone, is simpler and nearly $7000 less expensive. In Europe the coformulation (Viekirax) and dasabuvir (Exviera) were already sold separately.

Below are edited excerpts from press releases issued by Bristol-Myers Squibb and AbbVie, respectively, describing the approval of Daklinza and Technivie in more detail.

FDA Approves Daklinza (daclatasvir) for the Treatment of Patients with Chronic Hepatitis C Genotype 3

Daklinza in combination with sofosbuvir is the first 12-week, all-oral therapy that offers SVR12 for the vast majority of genotype 3 patients

Hepatitis C genotype 3 is one of the most difficult-to-treat genotypes

Announcement marks the first approval of Daklinza in the United States

July 24, 2015 -- Princeton, N.J. -- Bristol-Myers Squibb Company (NYSE:BMY) announced today that Daklinza (daclatasvir), an NS5A replication complex inhibitor, has been approved by the U.S. Food and Drug Administration (FDA). This approval marks the first time patients with chronic hepatitis C virus (HCV) genotype 3 have a 12-week, once-daily, all-oral treatment option. Daklinza is indicated for use with sofosbuvir for the treatment of patients with chronic HCV genotype 3 infection. Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving this regimen. The recommended dosage of Daklinza is 60 mg in combination with sofosbuvir for 12 weeks.

"The U.S. approval of Daklinza means that chronic HCV genotype 3 patients may now complete treatment in just 12 weeks with an all-oral, once-daily regimen," said Chris Boerner, Head of U.S. Commercial, Bristol-Myers Squibb. "We believe this Daklinza-based regimen may be a solution to improving the standard of care for these patients. This approval is the result of many years of partnership with the HCV community to address the complexities of genotype 3, and an important achievement in our ongoing Daklinza development program, which focuses on patients that are most challenging to treat."

The pivotal Phase III open-label ALLY-3 clinical trial enrolled 152 patients with chronic HCV genotype 3 infection and compensated liver disease (101 treatment-naive patients and 51 treatment-experienced patients). The co-primary endpoints were sustained virologic response rates 12 weeks after completing therapy (SVR12) in each treatment group. The full study design is outlined [in the full press release]. In the trial the Daklinzaplus sofosbuvir regimen demonstrated SVR12 in 90% of treatment-naive and 86% of treatment-experienced chronic HCV genotype 3 patients. SVR12 rates were higher (96%) in genotype 3 patients without cirrhosis, regardless of treatment history. In the more difficult-to-treat patients with cirrhosis, SVR12 rates were reduced (63%). These SVR12 rates were achieved with 12 weeks of therapy without the use of ribavirin.

Daklinzais contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daklinza. Daklinza also may be associated with the risk of adverse reactions or loss of virologic response due to drug interactions. In addition, there is a risk of serious symptomatic bradycardia when coadministered with sofosbuvir and amiodarone. Please see full Important Safety Information [in the full press release] for more details.

In the pivotal Phase III trial, there were no treatment-related serious adverse events (SAEs) and no discontinuations due to adverse events (AEs). The most common treatment-related AEs at a frequency of >5% were headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).

"The treatment landscape for HCV has radically evolved in recent years, and while we have achieved impressive SVR12 rates in genotype 1, genotype 3 still represents a clinical challenge," said David R. Nelson, MD,Professor of Medicine, Molecular Genetics and Microbiology Director, UF Clinical and Translational Science Institute, and Assistant Vice President of Research for the University of Florida. "Not only are genotype 3 patients more complicated to manage, but the aggressive nature of their disease means there is a greater urgency to treat them. Daklinza in combination with sofosbuvir gives healthcare providers a new option to achieve a high overall SVR12 rate in this difficult-to-treat patient population."

Daklinzais an inhibitor of NS5A with dual modes of anti-viral activity that inhibits both RNA replication and virion assembly. In in vitro studies, Daklinza has shown anti-viral activity across genotypes 1-6, with EC50 values from picomolar (pM) to low nanomolar (nM) against wild type replicons.

Daklinza will be available and begin shipping within a week.

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TECHNIVIE (ombitasvir, paritaprevir, and ritonavir tablets) Receives FDA Approval as the First and Only All-Oral, Interferon-Free Treatment for Genotype 4 Chronic Hepatitis C in the U.S.

Technivie provides an opportunity to treat adults in the U.S. who have genotype 4 (GT4) chronic hepatitis C virus (HCV) infection without cirrhosis, a population historically considered difficult-to-treat

Approval is supported by a robust phase II clinical trial of 135 chronic HCV GT4 patients, which demonstrated 100 percent sustained virologic response rates at 12 weeks post-treatment (SVR12) in patients who took Technivie with ribavirin (RBV)

North Chicago, Ill. -- July 24, 2015-- AbbVie (NYSE: ABBV), a global, research-based biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) approved TECHNIVIE (ombitasvir, paritaprevir, and ritonavir tablets) in combination with ribavirin (RBV) for the treatment of adults with genotype 4 (GT4) chronic hepatitis C virus (HCV) infection who do not have cirrhosis. TECHNIVIE is the first and only all-oral, interferon-free, direct-acting antiviral treatment approved in the U.S. for adult patients with GT4 chronic HCV infection. The approval of TECHNIVIE marks an important advancement in providing this historically difficult-to-treat population of HCV patients an opportunity for a cure. Virologic cure is defined as a sustained virologic response (SVR), which is when the virus is no longer detectable in the patient's blood 12 weeks after treatment (SVR12). TECHNIVIE is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B).

"Physicians have previously had limited options when it comes to treating people living with GT4 chronic hepatitis C," said Tarek Hassanein, MD, professor of medicine, University of California San Diego School of Medicine. "The approval of TECHNIVIE in combination with ribavirin is important for these patients who now have an approved all-oral, interferon-free treatment option that provides a high probability of a cure."

The FDA granted priority review to AbbVie for TECHNIVIE, a designation granted to investigational therapies that treat a serious condition and provide a significant improvement in safety or effectiveness. This designation shortened the regulatory review period from the normal 10 months to six months. TECHNIVIE was also granted a Breakthrough Therapy designation by the FDA in 2014, a status given to investigational treatments for serious or life-threatening conditions with preliminary clinical evidence that may demonstrate substantial improvement on at least one clinically significant endpoint compared to available therapy.

"As demonstrated by the PEARL-I study results, TECHNIVIE delivers on AbbVie's ongoing commitment to provide curative therapies for HCV patients who have historically been considered difficult-to-treat," said Michael Severino, MD, executive vice president, research and development and chief scientific officer, AbbVie.

About the PEARL-I Study

This approval of TECHNIVIE is based on data from the PEARL-I study, which demonstrated 100 percent sustained virologic response rates at 12 weeks post-treatment (SVR12) in patients who received TECHNIVIE and RBV for 12 weeks. PEARL-I is an open-label Phase 2b study that evaluated the efficacy and safety of TECHNIVIE in GT4 chronic HCV patients without cirrhosis. The study included GT4 patients who were new to therapy (n=42/42) or who had failed previous treatment with pegylated interferon (pegIFN) and RBV (n=49/49). Additionally, 91 percent of patients who were new to therapy achieved SVR12 (n=40/44) after taking TECHNIVIE without RBV. In the treatment-naive group without RBV, on-treatment virologic breakthrough was reported in one patient (two percent), and two patients (five percent) experienced post-treatment relapse. There were no virologic failures in the other treatment arms.

There were no discontinuations due to adverse events in these patients. The most commonly reported treatment-emergent adverse events (greater than 10 percent in any group) observed in patients receiving TECHNIVIE or TECHNIVIE with RBV, respectively, were asthenia (weakness) (25-29 percent), fatigue (7-15 percent), nausea (9-14 percent) and insomnia (5-13 percent). Four patients who received TECHNIVIE with RBV experienced decreased hemoglobin (anemia) which required RBV dose reductions; however, none of these patients required blood transfusions or medication to boost their red blood cell production. All patients treated with TECHNIVIE and RBV achieved SVR12_.

Important Safety Information -- [See full press release]

7/28/15

Sources

Bristol-Myers Squibb. FDA Approves Daklinza (daclatasvir) for the Treatment of Patients with Chronic Hepatitis C Genotype 3. Press release. July 24, 2015.

Food and Drug Administration. FDA approved new treatment for chronic hepatitis C genotype 3 infections. Press release. July 24, 2015.

R Klein, K Strubble, and S Morin, Food and Drug Administration. Approval of Daklinza in Combination with Sofosbuvir for HCV Genotype 3 Infection. FDA Hepatitis Update. July 24, 2015.

AbbVie. TECHNIVIE (ombitasvir, paritaprevir, and ritonavir tablets) Receives FDA Approval as the First and Only All-Oral, Interferon-Free Treatment for Genotype 4 Chronic Hepatitis C in the U.S. Press release. July 24, 2015.

Food and Drug Administration. FDA approves Technivie for treatment of chronic hepatitis C genotype 4. Press release. July 24, 2015.

R Klein, K Strubble, and S Morin, Food and Drug Administration. Approval of Technivie to treat of genotype 4 chronic hepatitis C virus. FDA Hepatitis Update. July 24, 2015.