Abbvie (formerly Abbott Laboratories) is developing many drugs for the treatment of HCV. The corporation's first generation of drugs consists of the following agents:
ABT-450, 267 and 333 are examples of DAAs (direct-acting antiviral agents).
Many clinical trials of these drugs have taken place. One of the latest studies whose results were released is called Pearl-III. This study was a phase III trial of the drugs mentioned above with or without the nuke ribavirin in participants who had not previously been treated and who did not have severe liver injury (cirrhosis). All participants had HCV genotype 1b.
Preliminary results from Pearl-III suggest that the combination of three DAAs being developed by Abbvie is extremely powerful, resulting in very high cure rates of about 99%. Furthermore, the combination appears to be as effective with or without ribavirin. Also, the combination of three DAAs appears to be safer than regimens containing ribavirin.
The Pearl-III study is important for other reasons. Historically, many of the problems associated with HCV treatment were blamed on exposure to interferon. However, the Pearl-III study was interferon-free and compared two regimens, one containing ribavirin and the other without ribavirin. The rate of side effects in Pearl-III was greater among ribavirin users.
A total of 419 participants were randomized to receive one of the following regimens:
Although participants will only have been exposed to the study drugs for 12 weeks, researchers plan to monitor them for 60 weeks.
The doses of medicines were as follows:
All of the three drugs listed above were co-formulated (put into one pill) and taken once daily.
The dose of ABT-333 was 250 mg twice daily.
The dose of ribavirin was as follows:
The average profile of participants at the start of the study was as follows:
This difference between the two regimens suggests that a ribavirin-free regimen of three DAAs was statistically no worse than three DAAs + ribavirin (the technical term for this is "non-inferior").
Comparing both combinations to historical results based on the current standard of care -- telaprevir + interferon + ribavirin (assuming that this historical regimen resulted in a 75% cure rate) -- found that both regimens, three DAAs with and without ribavirin, were statistically superior.
Three participants in the current study did not develop SVR12 for the following reasons:
There was no impact of race, gender or genetics on the response to therapy.
Researchers must note all adverse events that occur in a study to later analyse them and determine if they were caused by the medications used. Here are some adverse reactions reported:
Headache (generally of mild intensity):
Differences in adverse events emerged as follows:
Difficulty falling asleep:
Serious adverse events (SAE) occurred in four participants on each regimen. However, only one SAE -- a case of arthritis -- appeared to be linked to exposure to the three DAAs.
Differences in lab tests were distributed among the regimens' users as follows:
Hemoglobin (a protein that helps to transport oxygen to tissues) levels less than 10 grams per dL:
The dose of ribavirin had to be decreased in 19 out of 210 people (9%) because of anemia and other problems. However, all were still able to recover from HCV.
Bilirubin (a waste product; elevated levels of which can temporarily discolour the skin and whites of the eyes) levels more than three times the upper limit of normal:
ALT (alanine aminotransferase; a liver enzyme) levels greater than five times the upper limit of normal:
AST (aspartate aminotransferase; a liver enzyme) levels greater than five times the upper limit of normal:
The results from Pearl-III are compelling and show that a regimen of the three Abbvie DAAs is very powerful and generally safe. Furthermore, it appears that in some patients with only a small degree of liver injury, ribavirin is not necessary when used with the three DAAs in this study. Further studies of these drugs will be featured in a future issue of TreatmentUpdate.
Abbvie is developing its second-generation anti-HCV therapy whereby the company hopes to simplify a regimen to one pill, once daily, perhaps without ritonavir boosting. However, it will be several years before we will know if such a regimen can work in large numbers of participants.
Ferenci P, Nyberg A, Enayati P, et al. Pearl III: SVR ≥ 99% after 12 weeks of ABT-450/r/267 + ABT-333 ± ribavirin in treatment-naïve HCV genotype 1b infection. In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections, 3-6 March 2014, Boston, U.S. Abstract 29LB.
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