ICAAC 2014: AbbVie 3D Hepatitis C Regimen Is Well-Tolerated in Phase 3 Trials

AbbVie's 3D hepatitis C regimen containing paritaprevir (ABT-450), ombitasvir, and dasabuvir was generally well-tolerated in the Phase 3 SAPPHIRE trials, according to a pooled analysis presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy last week in Washington, DC. While most patients experienced some adverse events, serious side effects were rare and few people discontinued treatment early for this reason.

Direct-acting antiviral agents (DAAs) that target different steps of the hepatitis C virus lifecycle have brought about a revolution in treatment, especially with the advent of all-oral regimens that omit interferon and its difficult side effects, which can include flu-like symptoms and depression. While the first-generation DAAs used with interferon added their own side effects, the new generation of hepatitis C drugs have few adverse effects.

Tolga Baykal from AbbVie, Donald Jensen from the University of Chicago Medical Center, and colleagues performed a combined analysis of adverse events in the SAPPHIRE-I and SAPPHIRE-II trials. SAPPHIRE-I enrolled previously untreated participants, while SAPPHIRE-II enrolled prior non-responders to interferon-based therapy. Participants in both studies had HCV genotype 1 -- including a majority with harder-to-treat subtype 1a -- and did not have liver cirrhosis.

Both trials evaluated a 12-week interferon-free regimen consisting of the HCV protease inhibitor ABT-450 boosted with ritonavir, the NS5A replication complex inhibitor ombitasvir (formerly ABT-267; 25 mg), the non-nucleoside NS5B polymerase inhibitor dasabuvir (formerly ABT-333), and ribavirin.

Unlike many recent hepatitis C treatment trials, the SAPPHIRE studies included a placebo arm, allowing direct comparison of adverse event rates. This is important because a proportion of people randomly assigned to receive placebo in clinical trials also report side effects or adverse events unrelated to treatment; the difference between the active drug and placebo arms gives a better idea of which effects are actually attributable to the drugs being studied. Overall, 770 of participants in the combined SAPPHIRE trials were randomized to receive the active 3D regimen plus ribavirin, while 255 received placebo.

Results

• As previously reported, sustained virological response rates at 12 weeks post-treatment (SVR12) were 96% in both SAPPHIRE I and SAPPHIRE-II.
• Overall, 89% of study participants receiving the 3D + ribavirin regimen reported adverse events compared with 77% of those receiving placebo in a pooled analysis.
• Most adverse events were mild or moderate in severity.
• 16 participants (2.1%) taking the 3D + ribavirin regimen and only 1 person (0.4%) taking placebo experienced serious adverse events.
• 3 people (0.4%) taking 3D + ribavirin, but none taking placebo, experienced serious adverse events considered possibly related to the study drugs.
• Drug discontinuation due to adverse events was uncommon and occurred with similar frequency in the 3D + ribavirin and placebo groups (0.8% vs 0.4%, respectively). 
• The most common adverse events -- headache and fatigue -- were reported by approximately 30% of participants across study arms.
• Roughly twice as many 3D + ribavirin recipients as placebo recipients reported insomnia (14% vs 8%, respectively), asthenia or weakness (14% vs 7%), and rash (10% vs 6%).
• The symptom with the greatest difference between the 2 groups was pruritis or itching (16% vs 4%, respectively).
• Despite the use of ribavirin, serious anemia was rare.

"The 3D + ribavirin regimen demonstrated a favorable adverse event profile as evidenced by low rates of study drug discontinuation, drug-related serious adverse events, and generally mild adverse events," the researchers concluded.

"Previous exposure to treatment did not influence the safety profile."

9/12/14

Reference

DM Jensen, T Baykal, E Lawitz, et al. Adverse Event Profile of the Interferon-Free All-Oral ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin Regimen in HCV Patients. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC 2014), September 5-9, in Washington, DC. Abstract V-477.