Q&A with AbbVie's Barry Bernstein, MD: Are More FDA Warnings in the Works ?

Note:  In addition to the label change and warning about their currently approved medications Dr. Bernstein gives an estimate on a possible approval of AbbVie's new pan-genotypic combination.  Alan


The effectiveness of the new arsenal of hepatitis C antivirals has elated physicians and patients and been a triumph—and lucrative development--for pharmaceutical companies.

The announcement on Oct. 22 that AbbVie, manufacturer of two such drug products was changing labeling to include new warnings dampened the euphoria. Post-marketing reports alerted the company and the US Food and Drug Administration (FDA) of patient deaths and severe liver damage sometimes requiring transplantation in some patients who received AbbVie’s treatments.

The company, in consultation with the FDA changed its package inserts and labeling for Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) and Technivie (ombitasvir, paritaprevir, and ritonavir tablets.

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HCV Drugs: AbbVie, BMS, Merck —Alan Franciscus, Editor-in-Chief

AbbVie:

TECHNIVIE:
On July 24, The Food and Drug Administration (FDA) approved the first interferon-free combination therapy to treat HCV genotype 4. The combination called TECHNIVIE (ombitasvir, paritaprevir and ritonavir) is taken with ribavirin and for 12 weeks.  There was a total of 135 patients in the study—91 received TECHNIVIE with ribavirin and 41 received TECHNIVIE without ribavirin.  None of the trial participants had cirrhosis.  In the group that received TECHNIVIE with ribavirin there was a 100% cure rate; in the group that did not receive ribavirin there was a 91% cure rate.  Since the study did not include people with cirrhosis the FDA did not approve TECHNIVIE for the treatment of genotype 4 with cirrhosis.  AbbVie has indicated that there are on-going studies of genotype 4 cirrhotic patients and they will pursue an indication for cirrhotic patients on the TECHNIVIE product label. 

Genotype 4 is uncommon in this country—the estimated prevalence is between 1.3% to 2.3%.  There are some higher populations in areas around New York City, Los Angeles and Southern California estimated between 2 to 3%.   Genotype 4 is the fourth most common genotype worldwide.  It also accounts for 90% (6,030,000) of the hepatitis C population in Egypt.  The remaining HCV population is genotype 1.  The total HCV population of Egypt is 6.7 million. 

Source:  FDA Press Release (The total HCV population of Egypt is 6.7 million.

Be sure to check out our fact sheet on hepatitis C in Egypt: http://hcvadvocate.org/hepatitis/factsheets_pdf/HCAW_Egypt.pdf  

New Combo:
A new phase 2 study of ombitasvir, paritaprevir and ritonavir—once-a-day  combination of AbbVie drugs to treat 181 genotype 1b patients for a treatment period of 12 weeks ( without cirrhosis) or 24 weeks (with cirrhosis).   The cure rates among the groups are listed below:

• No-cirrhosis group: 95.2% cure rate among people who had never been treated (treatment naïve (42 patients); 90% cure rate among people who had been previously treated (treatment experienced  (40 patients))
• Cirrhosis group: 97.9% cure rate among treatment naïve (47 patients);  96.2% cure rate in the treatment-experienced group (52 patients)

The most common side effects were headache, lack of energy, itching, and diarrhea. There was one treatment discontinuation due to treatment-related side effects.

This combination without interferon or ribavirin in a once-a-day pill for people with HCV genotype 1b would be a welcome addition to the landscape of hepatitis C treatment. 

Source: Efficacy and Safety of Ombitasvir, Paritaprevir, and Ritonavir in an Open-label Study of Patients With Genotype 1b Chronic Hepatitis C Virus, With and Without Cirrhosis—Erica Lawtz– et al. http://dx.doi.org/10.1053/j.gastro.2015.07.001

Bristol-Myers Squibb
On July 24, 2015, the FDA approved BMS’s Daklinza (daclatasvir) in combination with Gilead’s sofosbuvir to treat HCV genotype 3.  In the phase 3 studies of patients who were treated with Daklinza and sofosobuvir for 12 weeks the cure rates broken down by cirrhosis and prior treatment response are listed below:

• Without Cirrhosis:  Treatment naïve—98%;
  Treatment experienced—92%
• With Cirrhosis:  Treatment naïve—58%;
  Treatment experienced—69%

The most common side effects were fatigue and headache.

The FDA press release noted that the response rates were reduced for HCV genotype 3 patients with cirrhosis.  It should also be noted that the treatment duration is only 12 weeks as opposed to 24 weeks with the current standard of care—Sovaldi plus ribavirin.  Still there is an unmet medical need for people with HCV genotype 3 with cirrhosis. 

Source:  FDA press release. 

Merck
On July 28, 2015, Merck announced that the FDA had accepted their New Drug Application for grazoprevir/elbasvir for the treatment of HCV genotype 1, 4 and 6 infection.  Merck has been granted Breakthrough Therapy designation for grazoprevir/elbasvir for the treatment of patients with HCV genotype 1 with end stage kidney disease who are on hemodialysis, and also for those patients with HCV genotype 4.

The cure rates for grazoprevir/elbasvir (one-pill/once-a-day) are impressive:  genotype 1 up to 100%; genotype 4 up to 100% and up to 80% for genotype 6.

Merck stated that they expected a notification for drug approval from the FDA by January 28, 2016.

Source:  Company press release

http://hcvadvocate.org/news/newsLetter/2015/advocate0815_mid.html#1

2 New Easy C Treatment Fact Sheets

Be sure to check out these 2 new Easy C Facts fact sheets on treatment for Genotype 3 and Genotype 4

Click to Download

Click to Download

Bristol-Myers wins approval for 1st hepatitis C type 3 drug

TRENTON, N.J. (AP) - An experimental drug for one of the hardest-to-treat types of hepatitis C has been approved by the Food and Drug Administration, adding to the surge of new options - all much more effective but extremely costly - for patients with the liver-destroying virus.

Daklinza, developed by New York-based Bristol-Myers Squibb Co., is the first drug approved to treat genotype 3, the second-most-common form. About 10 percent of Americans with hepatitis C have genotype 3.

Because genotype 3 is so hard to cure and damages the liver more quickly than other types, Daklinza is to be taken with Sovaldi, one of two blockbuster hepatitis C drugs sold by market leader Gilead Sciences Inc., along with Harvoni.

Meanwhile, the FDA on Friday also approved Technivie, a combination drug made by AbbVie Inc. for one of the least common forms of hepatitis C, genotype 4. Technivie also must be taken with a second drug, a much-older, generic pill called ribavirin.

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FDA approves Technivie for treatment of chronic hepatitis C genotype 4

For Immediate Release

July 24, 2015

The U.S. Food and Drug Administration today approved Technivie (ombitasvir, paritaprevir and ritonavir) for use in combination with ribavirin for the treatment of hepatitis C virus (HCV) genotype 4 infections in patients without scarring and poor liver function (cirrhosis).

Technivie in combination with ribavirin is the first drug that has demonstrated safety and efficacy to treat genotype 4 HCV infections without the need for co-administration of interferon, an FDA-approved drug also used to treat HCV infection.

“Today’s approval provides the first treatment option for patients with genotype 4 HCV infections without requiring use of interferon,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop cirrhosis over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, approximately 2.7 million Americans are infected with HCV, of which genotype 4 is one of the least common.

The safety and efficacy of Technivie with ribavirin were evaluated in a clinical trial of 135 participants with chronic HCV genotype 4 infections without cirrhosis. Ninety-one participants received Technivie with ribavirin once daily for 12 weeks. Forty-four participants received Technivie once daily without ribavirin for 12 weeks. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 100 percent of the participants who received Technivie with ribavirin achieved a sustained virologic response. Of those who received Technivie without ribavirin, 91 percent achieved sustained virologic response.

Safety information was available for 316 participants with HCV treated with the recommended dose of Technivie in combination with other anti-HCV drugs in clinical trials. The three drugs included in Technivie are also included in Viekira Pak, previously approved for the treatment of HCV genotype 1 infection. Additional safety information for those drugs was available from the Viekira Pak trials. The most common side effects of Technivie with ribavirin were fatigue, weakness (asthenia), nausea, insomnia, itching (pruritus) and other skin reactions.

Technivie carries a warning alerting patients and health care providers that elevations of liver enzymes to greater than five times the upper limit of normal occurred in approximately 1 percent of clinical trial participants. The elevations occurred more frequently in females taking contraceptives containing ethinyl estradiol. Contraceptives containing ethinyl estradiol must be discontinued prior to starting Technivie. Hepatic laboratory testing should be performed during the first four weeks of starting treatment, and as clinically indicated thereafter.

Technivie and Viekira Park are marketed by AbbVie Inc. based in North Chicago, Illinois.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Press Release Source:  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455857.htm