April 9, 2012
Jeffries
Key Takeaway
CORRECTION: We are correcting our note for the response rates in G1 patients combining both Arms A and B. EASL abstract data disclosed an encouraging 97% 12-week response and safety profile for the two-drug 7977+daclatasvir (NS5a) regimen in genotype 1 treatment-naives. We remain optimistic on 7977 although valuation keeps us on the sidelines.
Positive 12-Week Data For Two-Drug Oral Regimen Of 7977+Daclatasvir
Without Ribavirin. The Street is closely watching data for the highly anticipated Phase 2 study of GILD’s 7977 (nucleoside NS5B inhibitor) and Bristol’s (BMY, $33.68, Buy) daclatasvir (NS5a, DCV). In the first part of this open-label study, 44 genotype 1 (G1, of which 73% were 1a) and 44 genotype 2/3 (G2/3) treatment-naïve patients were randomized to either 7977 for 7 days then DCV + GS-7977 for 23 weeks (n=31, 15 G1), DCV +7977 for 24 weeks (n=28, 14 G1), or DCV +GS-7977 + ribavirin (rbv) for 24 weeks (n=29, 15 G1). DCV+7977 showed undetectable rapid virological responses (RVR) of 90% in G1 and 83% in G2/3. Overall, DCV+7977 and DCV+7977+rbv showed 93% undetectable responses after 12 weeks of treatment. For the two-drug regimen, 12-week response rates were 97% in G1 (28/29) and 90% in G2/3 (27/30). Virologic breakthrough occurred in one GT3 patient. For the three-drug regimen, the response rates were 100% in G1 (15/15) and 86% in G2/3 (12/14). The most frequent AEs were fatigue, headache, and nausea. Grade 3-4 laboratory abnormalities included elevated cholesterol (n=1), elevated glucose (2), low hemoglobin (6), lymphopenia (1), and low phosphorus (2). Two patients discontinued therapy for nondrug related AEs (fibromyalgia, CVA).
Our Take: 7977+Daclatasvir 12-Week Data Promising But Focus Remains SVR4 Data. As a reminder, key data in April at the EASL meeting will be the 4-week sustained virologic response (SVR4) data for GS7977 in G1 treatment-naïve patients in the ELECTRON study, further data from the Phase 2 study of DCV+7977, and early data for GILD’s own NS5a inhibitor 5885+7977. While the key efficacy endpoint to watch remains the post-treatment SVR rates, we are encouraged that a two-drug oral regimen of GILD’s 7977+ BMY’s DCV showed high 12-week responses in treatment-naives. Given the high relapse rate previously observed with 7977-rbv in G1 null responders, it remains to be seen whether the 7977+NS5a regimen can achieve attractive SVR rates in G1 patients, particularly in G1a patients.
SVR Of ~65% Seen For GILD’s 4-drug Oral Regimen In Genotype-1 (G1) Treatment Naives— Focus Remains On 7977 Combination Data. EASL abstract data were released for the higher GS5885 dose “arm 2” (90mg, n=94) of GILD’s 4 drug HCV regimen in 12-week treatment of G1-naives: GS-5885 (NS5a)+30mg bid tegobuvir (non-nucleoside NS5b)+200mg daily GS-9451 (protease inhibitor)+1000-1200mg daily ribavirin (rbv). The results for the 4-drug oral regimen showed 2-week virologic response of 79% (74/94). 64 of Arm 2 patients remained viral undetectable through the end of 12- week treatment with 11% virological breakthroughs (8/74) in post-RVR treatment. Of these 64 patients, 33 were randomized to post-treatment assessment of 4-week sustained virological responses (SVR4) and 31 were randomized to 24-week SVR (SVR24) assessment. 27 patients have reached 4-week post-treatment mark and 96% (26/27) achieved SVR4, of which 18/19 were genotype G1a and 8/8 were G1b. On safety, the most common reported AEs for the GILD quad regimen were headache (21%), fatigue (16%), diarrhea (14%), nausea (13%), and rash (11%) and there were no deaths, decreases in blood counts, or serious AE’s noted. Two patients withdrew from the study in the post-RVR treatment period but there were no discontinuations due to drug related AEs. Overall, on-treatment response rates were not as high as we had hoped for, calling into question the activity of the PI and the NS5a. As a reminder, a triple combination of Abbott’s (ABT, Buy, $61.30) PI and non-nuc yielded much higher SVR rates in G1 naïve patients. No concerning safety issues arose, which is promising as this represents the longest dosing data for 5885, the NS5a that is being tested in the critical regimen with 7977, which the Street is looking to provide even higher SVR rates in G1 patients.
Data For Mericitabine+ Ritonavir-Boosted Danoprevir Regimen Opens Opportunity For Other Regimens. As a reminder, Roche (ROG VX, Buy, CHF157.50)initiated the Phase 2b INFORM-SVR trial in 1Q11, studying mericitabine (MCB, 1000mg BID) + ritonavir-boosted danoprevir (DNVr, 100mg/100mg BID) +/- Peg-IFN/ribaviri(RBV, 1000/1200mg daily) for 12/24 weeks in treatment-naïve, non-cirrhotic, G1 patients. At week 4, 91% of patients on MCB+DNVr+RBV and 93% of MCB+DNVr+placebo had HCV RNA ≤ 15IU/mL. The 8-week SVR (SVR8) in MCB+DNVr+RBV for 24 weeks of treatment was 41% overall (26/63), with 71% (15/21) in G1b and 26% (11/42) in G1a patients. Randomization to the 12 week arm was stopped early due to unacceptable relapse rates. Furthermore, MCB+DNVr +/- RBV was noted to be safe and well tolerated with only four SAEs and two discontinuations due to AEs were observed across arms, although the nature of the SAEs were not disclosed. While the SVR rate was promising for this interferon-free regimen in G1b, the necessity for a 24-week regimen and relatively low SVR for G1a would leave open the opportunity for other regimens.
Inconvenient Dosing Schedule And Rash Issues With BI201335+BI207127 For Compensated Cirrhosis, But 335 Remains An Attractive Asset. In the interim analysis of its SOUND-C2 open-label Phase 2b study evaluating interferon-free regimens of protease inhibitor BI201335 (335) + non-nucleoside inhibitor BI207127 (127), given either three times daily (TID) or twice daily (BID),+/- ribavirin (rbv) for up to 40 weeks, 12- week SVR (SVR12) of up to 60% SVR12 in G1a and up to 83% in G1b was observed in treatment-naïve patients with compensated liver cirrhosis. Specifically, SVR12 rates of 60% was seen in G1a patients (3/5) and 56% of G1b patients (9/16) on 335+127 TID+rbv for up to 40 weeks, while 29% (2/7) of G1a and 83% (5/6) of G1b was observed for 28 weeks of 335+127 BID+rbv. On safety, mild skin and gastrointestinal were noted to be the most common, and we note that all five patients in the G1a pooled arm treated with 127 TID up to 40 weeks discontinued drug because of a rash, and two of those patients had also developed photosensitivity. We believe that the length of dosing, more than once daily dosing of 127, and rash-related discontinuations will likely prevent this regimen from becoming attractive, but the study serves as another proof of concept for a triple regimen in G1 patients and 335 remains an interesting asset for a more potent combination.
Continue Reading for more reports from Thomas Wei, Equity Analyst (stock analysis)…
No comments:
Post a Comment