FDA in Action

FDA in Action

Author: Sarah M. Aldridge, MS

The US Food and Drug Administration (FDA) has been busy, rubber-stamping several drugs that promise to improve the lives of people with bleeding disorders. With the July 2015 FDA approval of ­Bristol-Myers Squibb’s Daklinza™ and AbbVie’s Technivie™, many patients with genotypes 3 and 4 can also look forward to putting hepatitis C (HCV) behind them. Further, people with hemophilia A with inhibitors may be eligible for a new drug that won’t tax their veins.

HCV drugs for genotypes 3 and 4

Daklinza contains daclatasvir, an NS5A inhibitor, which prevents RNA replication and virus assembly. It is prescribed with Gilead’s Sovaldi®, which contains sofosbuvir, a polymerase inhibitor that prevents HCV from reproducing. Daklinza is the first all-oral treatment regimen for people with HCV genotype 3, without the need for co-administration of interferon and ribavirin. Genotype 3 is the second most common type of HCV, occurring in 12% of the population. It is considered difficult to treat and is aggressive, rapidly progressing to liver disease and cancer.

Daklinza’s clinical trials included patients who were treatment-naïve (not treated previously) and treatment-experienced (those who failed previous drug regimens). In the treatment-experienced group without cirrhosis, 86% achieved sustained virologic response (SVR, an indication they had cleared the virus 12 weeks after treatment ended) vs. 63% SVR in those with cirrhosis. The most common adverse effects were headache, fatigue, nausea and diarrhea. Daklinza’s label will carry a warning about drug interactions, including taking sofosbuvir with amiodarone (a drug that treats heart arrhythmias), which can cause a serious slowing of the heart rate.

Technivie is a daily tablet containing ombitasvir, paritaprevir and ritonavir, the three drugs in AbbVie’s Viekira Pak™ (for HCV genotype 1). It is taken in combination with a twice-daily regimen of ribavirin by patients with HCV genotype 4 who do not have cirrhosis. Technivie is the first noninterferon-containing treatment for these patients.

The direct-acting antivirals in Technivie tackle HCV at different phases of its life cycle. Paritaprevir and ritonavir are protease inhibitors; ombitasvir is an NS5A inhibitor.

In clinical trials of Technivie on 135 adults, 100% of the patients on the full regimen experienced SVR; 91% of patients on Technivie without ribavirin achieved SVR. The study included treatment-naïve patients and treatment-experienced patients who had failed previous regimens with interferon and ribavirin. Side effects included weakness, fatigue, nausea and insomnia, but no patients discontinued the study. Technivie will come with a warning about elevated liver enzymes. This adverse effect was most common in women on contraceptives containing ethinyl estradiol. Note: On October 22, 2015, the FDA issued an update stating that AbbVie’s Technivie and Viekira Pak will both be required to state on the label that serious liver injury can occur in people with advanced liver disease, specifically cirrhosis. So far, only 26 cases have occurred worldwide, typically within the first 1–4 weeks after beginning treatment.

Subcutaneous inhibitor therapy on its way

The needs of patients with inhibitors are prompting drug development in creative new ways. In September, the FDA granted breakthrough therapy (BT) designation for Genentech’s ACE910, a subcutaneous (under the skin) therapy for people with factor VIII (FVIII) and an inhibitor.

In 2012, the FDA created the BT designation to put drugs on a faster track for review and acceptance. BT-designated drugs are required to treat serious or life-threatening diseases. They must provide preliminary data showing significant improvement over existing medications.

ACE910 is a monoclonal antibody that binds to factors IXa and X, imitating the function of FVIII. In phase I studies, the subcutaneous weekly dose was effective as a prophylactic treatment for people with severe hemophilia A with or without inhibitors. The study results were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) in San Francisco in December 2014. In all three arms of the study, the annualized bleeding rate (ABR) declined by 64.7%–100%, 88.9%–100% and 100%, respectively.

Phase 3 trials in adults with inhibitors launched in November 2015. Studies in pediatric patients will begin in 2016.