Biotech Values

[dewophile]

A better explanation of the pullback in the share price, IMO, is that ABBV/ENTA are basically sitting out AASLD (#msg-92269405, #msg-92226409), while such companies as MRK will be presenting their best data

MRK is one to watch - I included their abstract below, but i couldn't reproduce the table properly. suffice to say they don't have SVR data in the body of the abstract so take it for what its worth. I personally think GILD's data is spooking some investors because data from the LONESTAR study (also pasted below) shows they may have a chance at good cures without ribavirin and/or an 8 week course of therapy. This has to be taken with some grain of salt - they had 100% SVR in gen 2/3 in phase 2 with similar numbers and we know how that data ended up after phase 3. Additionally data from ELECTRON - albeit in cirrhotics, shows that ribavirin (or a 3rd DAA) is probably of benefit. also 6 weeks of triple therapy was insufficient in non-cirrhotics. So all told i think the GILD phase 3 is going to show ribavirin is probably of some benefit in gen 1a and SVRs are going to come down to earth somewhat from 97% in phase 3, but there is a chance they can either have slightly better SVRs with full 12 weeks and/or be able to eliminate ribavirin (there is one non-rib arm in their phase 3 i believe)

ABSTRACT BODY: Background: In a prior phase 2 study, patients with HCV genotype 1 who received sofosbuvir (SOF), an HCV-specific uridine nucleotide analog, together with ledipasvir (LDV), an NS5A inhibitor, plus ribavirin (RBV) for 12 weeks, achieved a high rate of sustained virologic response (SVR), irrespective of whether the patients were treatment-naïve or prior null responders. We therefore assessed the safety and efficacy of 8 and 12-week regimens of a fixed-dose combination (FDC) of SOF and LDV with and without RBV in treatment-naïve and protease inhibitor-experienced patients with HCV genotype 1.

Methods: 60 non-cirrhotic treatment-naïve patients with HCV genotype 1 were randomized 1:1:1 to receive: 1) FDC for 8 weeks, 2) FDC + RBV for 8 weeks, or 3) FDC for 12 weeks. In parallel, 40 patients who had not achieved SVR after previous treatment with a protease inhibitor regimen (50% of whom also had compensated cirrhosis) were randomized to receive twelve weeks of: 1) FDC or 2) FDC + RBV. The primary end point was SVR 12 weeks after completion of treatment.

Results: 100 patients were enrolled. The treatment-naïve group was 88% genotype 1a and 20% were IL28B CC. The protease-inhibitor experienced group was 85% genotype 1a and 7.5% were IL28B CC. Biopsy-confirmed cirrhosis was present in 22/40 (55%) of the PI-experienced subjects. Results are tabulated below.
SOF/LDV FDC with or without RBV for 8 and 12 weeks was generally well tolerated; 1 patient discontinued treatment early. Adverse events were generally mild, and no SAEs attributed to treatment were reported. Grade 3/4 laboratory abnormalities were infrequent. Adverse events and laboratory abnormalities consistent with the safety profile of RBV were noted in groups receiving SOF/LDV FDC+RBV. SVR12 from all groups will be presented.

Conclusions:
SOF/LDV FDC elicited rapid declines in HCV RNA and high rates of SVR regardless of the presence of RBV in all treatment groups with no viral breakthrough observed. 97% of patients achieved SVR, two relapsed, and one was lost to follow up. Further evaluation of SOF/LDV FDC in treatment-naïve and treatment-experienced patients in Phase 3 studies is in progress.








Study Visit

Treatment-naïve

Protease-Inhibitor Experienced



SOF/LDV FDC
8 Weeks
(n=20)

SOF/LDV FDC+RBV
8 Weeks
(n=21)

SOF/LDV FDC
12 Weeks
(n=19)

SOF/LDV FDC
12 Weeks
(n=19)

SOF/LDV FDC+RBV
12 Weeks
(n=21)



RVR

100%

100%

100%

95%

100%



EOTR

100%

100%

100%

100%

100%



SVR4

100%

100%

100%

95%

95%*



SVR12

95%

100%

Pending

Pending

Pending

*One patient has not yet returned for post-treatment follow up.





ABSTRACT BODY: Background: In previous Phase 2 studies, the addition of an NS5A inhibitor (either ledipasvir (LDV) or daclatasvir) to the combination of the HCV nucleotide analog sofosbuvir (SOF) plus ribavirin (RBV) for 12 weeks resulted in high rates of sustained viral response (SVR) in non-cirrhotic patients infected with HCV genotype 1 (GT-1). In the ELECTRON Phase 2 study, we evaluated the safety and efficacy of a fixed-dose combination (FDC) tablet of SOF plus LDV in additional patient populations, including those with cirrhosis and with non-GT-1 infection. We also evaluated the need for RBV and for 12 weeks’ duration.

Methods: We enrolled 4 arms: prior null-responder HCV GT-1 patients with compensated cirrhosis were randomized to receive open-label SOF/LDV FDC with or without RBV for 12 weeks; treatment-naïve HCV GT-1 patients without cirrhosis received SOF/LDV FDC plus RBV for 6 weeks; and treatment-naïve HCV non-GT-1 patients without cirrhosis were assigned to receive SOF/LDV FDC plus RBV for 12 weeks.

Results: 54 patients were enrolled. Of the GT-1 prior null-responder group, 79% were genotype 1a, and 32% were IL28B CC. Of the treatment-naïve GT-1 group, 84% were genotype 1a, and 20% were IL28B CC. Of the non-GT-1 group 20% were GT-2, and 80% GT-3. Efficacy results are tabulated. SOF/LDV FDC with or without RBV was generally well tolerated; There were no SAEs or treatment discontinuations. Adverse events were generally mild, and Grade 3/4 laboratory abnormalities were infrequent and consistent with the safety profile of RBV. No toxicity attributable to SOF/LDV FDC was identified.

Conclusions:
SOF/LDV FDC elicited rapid decline in HCV RNA in all patient populations with no viral breakthrough observed. In treatment-naïve GT-1 patients without cirrhosis, reduction in duration from 12 to 6 weeks increased the rate of relapse. In the prior null responder GT-1 patients with cirrhosis, the addition of RBV to SOF/LDV FDC decreased the rate of relapse, suggesting that either RBV or a third DAA may be useful in this difficult-to-treat patient population. Promising SVR rates achieved in genotype 2 or 3 patients support further evaluation of SOF/LDV FDC in patients with HCV GT-2 or GT-3.











Randomized GT 1 Prior Null Responders (Cirrhotics)

GT 1 Treatment Naïve (Non-Cirrhotics)

GT 2/3 Treatment Naïve (Non-Cirrhotics)



SOF/LDV FDC x 12 weeks (n=10)

SOF/LDV FDC+RBV x 12 weeks (n=9)

SOF/LDV FDC+RBV x 6 weeks (n=25)

SOF/LDV FDC x 12 weeks (n=10)



RVR

80%

66%

100%

100%



EOTR

100%

100%

100%

100%



SVR4

80%

89%*

88%

80%



SVR12

Pending

Pending

68%

80%

*One subject was lost to follow up without post-treatment data.



ABSTRACT BODY: Purpose: To assess the efficacy and safety of a 12-week regimen of MK-5172 (a potent hepatitis C virus [HCV] NS3/4A protease inhibitor) and MK-8742 (a potent HCV NS5A replication complex inhibitor) ± ribavirin (RBV) in patients with genotype (GT) 1 HCV infection. In in vitro studies, both agents have demonstrated a high barrier to resistance and activity against GT1 variants that are resistant to other first-generation agents in the same classes. This is the first report of the combination of MK-5172 and MK-8742 in an all-oral regimen with or without RBV.
Methods: Treatment-naive, non-cirrhotic (F0-F2) patients with HCV GT1 infection were randomized to one of three 12-week treatment arms: 1. MK-5172 (100 mg QD), MK-8742 (20 mg QD) plus RBV (600-1400 mg/d); 2. MK-5172 (100 mg QD), MK-8742 (50 mg QD) plus RBV; 3. MK-5172 (100 mg QD) and MK-8742 (50 mg QD). Arms 1 and 2 were stratified by GT1a vs. GT1b. Arm 3 (RBV-free) included only GT1b-infected patients. Virologic response was assessed each week during treatment and at 2, 4, 8, 12, and 24 weeks after end of treatment. HCV RNA samples were assessed using COBAS TaqMan v2.0 (lower limit of quantitation [LLOQ] <25 IU/mL).
Results: A total of 65 patients were enrolled: 45% were male, 11% were African American, and 58% had GT1a infection. Mean baseline HCV RNA was 6.1 log10 IU/mL. The most frequently reported adverse events (>10%) were headache (13/65, 20%), fatigue (15/65, 23%), and nausea (8/65, 12%). ALT was elevated at baseline in 50 patients and normalized on treatment in all but 1 patient (ALT = 42 IU/mL). Twenty patients had transient, mild (grade1-2) total bilirubin elevation on treatment. On-treatment response (HCV RNA <LLOQ) at weeks 1, 2, 4, and 8 are presented in the table. The trial is ongoing: end-of-treatment response, SVR4, and SVR12 will be presented in November.
Conclusion: Treatment with MK-5172 / MK-8742 ± RBV was associated with robust virologic suppression. No viral breakthrough was detected and in all patients HCV RNA was <LLOQ by week 4. Although some differences were noted at treatment week 1, there were no differences in on-treatment response at treatment week 4 in GT1a compared to GT1b patients, or in GT1b patients according to the presence or absence of RBV. These data warrant further evaluation of MK-5172 + MK-8742 in IFN-free and IFN/RBV-free regimens.








HCV
Genotype

Regimen

TW1

TW2

TW4

TW8



1a

MK-5172/MK-8742 (both doses) + RBV (N = 38)

19/37 (51%)

33/37 (89%)

36/36 (100%)

32/32 (100%)



1b

MK-5172/MK-8742 (both doses) + RBV (N = 14)

10/13 (77%)

14/14 (100%)

14/14 (100%)

8/8 (100%)



MK-5172/MK-8742 50 mg (N = 12*)

5/12 (42%)

10/11 (91%)

11/11 (100%)

5/5 (100%)

*Excludes one patient who received RBV due to a dosing error.
TW, treatment week.