HCV Drugs: AbbVie's Pending FDA Approval and AASLD—Part 2, by Alan Franciscus

In this month’s column I present a basic overview of AbbVie’s 3D combination that details the baseline demographics of their phase 3 studies. In addition, there is information from the AASLD conference about Merck’s drug development program and exciting news about all-oral therapies for treating HCV post-liver transplantation.
 
AbbVie
The exciting news is that the Food and Drug Administration is scheduled to approve Abbvie’s 3D all-oral combination to treat hepatitis C (HCV) genotype 1 in the second part of December 2014.  I reported on the results of AbbVie’s 3D combination in cirrhotic patients in the December issue.  This mid-month issue provides an overview from an abstract presented at the Infectious Disease Conference held in Philadelphia, PA in October.    

Safety of Abt-450/R/Ombitasvir + Dasabuvir With or Without Ribavirin in HCV Genotype 1-Infected Patients, by Baseline Demographics–R. Nahass et al.
 
Viekirax (ombitasvir/paritaprevir/ritonavir) plus Exviera (dasabuvir) with and without ribavirin to treat HCV genotype 1 has achieved cure rates greater than 90% in phase 3 clinical trials. 
This analysis included only non-cirrhotic patients.  The side effect profile and treatment discontinuations were reported by sex, age, race, ethnicity, and diabetes status. There were 910 patients across the three PEARL clinical trials.  The majority of patients had at least one side effect, but most were mild.  The results are reported in the table on page 10. 

The majority of the side effects that occurred in more than 20% of patients in the groups were fatigue and headache.  There were 4 patients who discontinued treatment due to side effects (0.4%, 2 in each treatment group). The authors concluded that the 3D regime was well-tolerated with low rates of discontinuation.  The side effects and tolerability were similar regardless of age, gender, race, ethnicity, or history of diabetes.
 
Comments:  AbbVie’s 3D combination produces very high cure rates, low rates of side effects and a short duration of treatment–all of which will make AbbVie’s 3D combination a very welcome addition to treatment landscape of hepatitis C. 
 
AASLD 2014 – Part 2

Merck
Efficacy and Safety of MK-5172 and MK-8742 ± Ribavirin in HCV GT1 Infected Patients with Cirrhosis or Previous Null Response:  Final Results of the C-WORTHY Study (Parts A and B)–E. Lawitz et al.

Merck’s phase 2 study of grazoprevir (MK-5172) plus elbasvir (MK-8742) with and without ribavirin included HCV genotype 1 patients with cirrhosis or patients who had a null response to a prior course of HCV therapy.  There were two parts to this study—Parts A and B. A total of 253 patients were enrolled in the studies.
 
Part A: Treatment naïve, non-cirrhotic patients received 12 weeks of grazoprevir plus elbasvir with and without ribavirin.  Part B:  This part of the study included treatment-naïve non-cirrhotic patients, prior null responders (non-cirrhotic and cirrhotic), and non-cirrhotic HIV/HCV coinfected patients.
The combined overall cure rates were 90-100%.  The most common side effects that occurred in more than 10% of patients were fatigue, headache and asthenia (weakness).  

Comments:  Although there was a relatively small patient population due to the many different treatment arms and varied patient population the results are still very impressive.  This drug combination has advanced into larger phase 3 studies. Hopefully, we will have even more therapies to treat hepatitis C in the not too distant future. 

Liver Transplantation at AASLD
The hepatitis C virus is a blood-borne virus and, as a result, if someone with hepatitis C has a liver transplant the new liver will be re-infected with hepatitis C.  Now that we have these incredible drugs everyone who needs a new liver should be cured of hepatitis C prior to a liver transplant.  Until that time, the best option is to treat people with hepatitis C as soon as safely possible after the liver transplant.

AbbVie
High Sustained Virologic Response Rates in Liver Transplant Recipients with Recurrent HCV Genotype 1 Infection Receiving ABT-450/r/Ombitasvir Plus Dasabuvir Plus Ribavirin–P. Mantry et al.

This was a study of 34 genotype 1 patients who received the 3D drug therapy Viekirax (ombitasvir/paritaprevir/ritonavir) plus Exviera (dasabuvir) with ribavirin for 24 weeks after receiving a liver transplant.

The mean time since transplantation was about 40 months. The patient characteristics were:  male (80%); White (85%); age ~60 yo; Fibrosis stage F0 (18%), F1 (38%), F2 (44%); genotype 1a (85%).  The cure rate was 97% (33 of 34 patients).

There were no episodes of acute or chronic rejection.  One patient discontinued treatment due to side effects at week 18, but went on to achieve a cure.  Nineteen patients required ribavirin dose reductions but the dose reductions did not affect cure rates.
 
Comments:  These are truly spectacular results!  In the past, it was very difficult to treat post-transplant people because of all the drug-drug interactions and the very real possibility of greatly accelerating the disease process, which could lead to death.   

Gilead
Ledipasvir/Sofosbuvir with Ribavirin for the Treatment of HCV in Patients with Post-Transplant Recurrence:  Preliminary Results of a Prospective, Multicenter Study–K. R. Reddy et al.

Preliminary results were presented of patients who were treated for 12 weeks (112 patients) or 24 weeks (111 patients) with the combination of ledipasvir/sofosbuvir (Harvoni) plus ribavirin (RBV).  There were 4  treatment arms:
NOTE: CPT = Child-Pugh-Turcotte cirrhosis score
*RBV = weight based dosing
**RBV=dose escalation, 600-1200 mg/day

The patients were pretty evenly divided across the treatment arms–mean age 59-61yo; mostly male (80-100%); White (80-89%); genotype 1a (67-78%); median year from transplant (2.9 to 8.1 years) and most had prior HCV treatment. 
In those patients who completed treatment the cure rates are as follows:
There were 4 deaths among the clinical trial participants; however, the researchers did not attribute any of the deaths to the study drugs, but rather to complications from the transplants and cirrhosis.

Comments:  These results are impressive since the patients in this study had severe liver disease.    Now, we just need to get these drugs to people before the need for a liver transplant and we can all breathe a bit easier.    

Any AE
Severe AE
Serious AE
AE leading to discontinuation
3D +RBV
3D
3D + RBV
3D
3D + RBV
3D
3D + RBV
3D
n/N (%)
n/N (%)
n/N (%)
n/N (%)

Overall
332/401
(82.8)
383/509
(75.2)
4/401
(1.0)
6/509
(1.2)
9/401
(2.2)
7/509
(1.4)
2/401
(0.5)
2/509
(0.4)
Sex

Male
180/221
(81.4)
193/272
(71.0)
2/221
(0.9)
4/272
(1.5)
6/221
(2.7)
3/272
(1.1)
1/221
(0.5)
2/272
(0.7)

Female
152/180
(84.4)
190/237
(80.2)
2/180
(1.1)
2/237
(0.8)
3/180
(1.7)
4/237
(1.7)
1/180
(0.6)
0
Age

<65
296/362
(81.8)
345/461
(74.8)
3/362
(0.8)
5/461
(1.1)
8/362
(2.2)
6/461
(1.3)
2/362
(0.6)
2/461
(0.4)

≥65
36/39
(92.3)
38/48
(79.2)
1/39
(2.6)
1/48
(2.1)
1/39
(2.6)
1/48
(2.1)
0
0
Race

Black
20/25
(80.0)
31/44
(70.5)
0
2/44
(4.5)
0
2/44
(4.5)
0
0

Non-Black
312/376
(83.0)
351/464
(75.6)
4/376
(1.1)
4/464
(0.9)
9/376
(2.4)
5/464
(1.1)
2/376
(0.5)
2/464
(0.4)
Ethnicity

Hispanic or Latino
13/16
(81.3)
21/25
(84.0)
0
0
1/16
(6.3)
0
1/16
(6.3)
0
Non-Hispanic or Latino
319/385
(82.9)
362/484
(74.8)
4/385
(1.0)
6/484
(1.2)
8/385
(2.1)
7/484
(1.4)
1/385
(0.3)
2/484
(0.4)
History of Diabetes

Yes
17/22
(77.3)
24/29
(82.8)
0
2/29
(6.9)
0
3/29
(10.3)
0
0

No
315/379
(83.1)
359/480
(74.8)
4/379
(1.1)
4/480
(0.8)
9/379
(2.4)
4/480
(0.8)
2/379
(0.5)
2/480
(0.4)
n = number of patient AE’s (side effects)
N = number of patients treated
% = percentage of patients with AE’s

http://hcvadvocate.org/news/newsLetter/2014/advocate1214_mid.html#2

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