Replies to post #164591 on Biotech Values

[oc631]

There are 9 phase-3 trials in all: 6 trials that comprise the initial
NDA submission in 2Q14 and 3 trials for subsequent use.

Has ABBV elaborated on why they are running these three additional trials with Incivek/PegRiba as an active comparator? By all indications the ABBV combo should prove superior. Could the data from these trials establish the ABBV combo as the next SOC under future FDA guidance?

[jq1234]

I jumped onto ENTA bandwagon today.

[DewDiligence]

ENTA should have ample news flow in September insofar as ABBV’s SAPHIRE-1 and -2 studies are scheduled to report top-line data (see listing in #msg-90408583).

Moreover, ENTA will be increasing its visibility during September by participating in three investor conferences: Citi on 9/3, Morgan Stanley on 9/11, and Stifel Nicolaus on 9/12. This is a pretty big change for a company that has, until now, maintained a low profile by not even holding quarterly conference calls since its IPO in Mar 2013.

[DewDiligence]

Demystifying ABBV/ENTA’s SAPHIRE-1/2 Trials

ABBV/ENTA’s SAPHIRE-1 and -2 are likely to be the first two phase-3 trials of the nine (!) phase-3 trials including ABT-450 to report data (see #msg-90408583 for a description of all nine trials). What some investors may not realize is that SAPHIRE-1 and -2 are essentially safety trials insofar as there is no bona fide control arm for an efficacy comparison.

In SAPHIRE-1 and -2, half of the patients are randomized to immediately receive ABBV’s 5-drug cocktail (ABT-450, ABT-267/r, ABT-333, and ribavirin) for 12 weeks; the other half of the patients are randomized to receive only placebos for 12 weeks followed by the identical 5-drug regimen as the first arm for 12 weeks (http://www.clinicaltrials.gov/ct2/show/NCT01716585 , http://www.clinicaltrials.gov/ct2/show/NCT01715415 ).

Because HCV progresses relatively slowly and a patient’s condition does not deteriorate materially without treatment during a period as short as 12 weeks, SAPHIRE-1 and -2 have essentially no difference between the two trial arms with respect to efficacy.

With respect to safety, however, the control (i.e. delayed-treatment) arm can serve as a comparator to the immediate-treatment arm to establish the safety profile of ABBV/ENTA’s regimen, relative to placebo, during the 12-week treatment period.

Note: The only difference between SAPHIRE-1 and SAPHIRE-2 is that the former is for treatment-naïve patients and the latter is for treatment-experienced patients. All patients in both trials are genotype-1.

[DewDiligence]

ABBV/ENTA plan to run a Japanese phase-3 trial of ABT-450/r + ABT-267 without ribavirin in GT1b treatment-naïve patients. (Source: ABBV webcast at Morgan Stanley that just finished.)

[DewDiligence]

ABBV/ENTA will probably not present partial results of the 6-trial global registration program at 2013 AASLD, according to today’s MS webcast; instead, they will likely present all 6 trials together at a later medical meeting. The last of these six trials to report data is expected to be PEARL-2, which is scheduled to complete in Mar 2014 (see #msg-90408583).

Results of some or all of the six individual phase-3 trials may be reported by press release.

[DewDiligence]

ABBV/ENTA—TURQUOISE-1 (the phase-3 trial in HCV/HIV co-infection) is now listed at clinicaltrials.gov:

http://clinicaltrials.gov/ct2/show/NCT01939197

Along with MALACHITE-1 and -2, TURQUOISE-1 is one of the three global phase-3 trials of ABBV/ENTA’s HCV regimen that will not be part of the initial NDA/MAA in 2Q14. Please see #msg-90408583 for details.

[DewDiligence]

ABBV/ENTA’s Global Phase-3 HCV Program (updated)

ABBV/ENTA have 9 global phase-3 trials testing an all-oral
regimen in HCV genotype-1a/1b : 6 trials that comprise the initial
NDA/MAA submissions in 2Q14, and 3 trials for subsequent use.
(MALACHITE-1 and MALACHITE-2 are essentially phase-4 trials
that have been listed as phase-3.)

All 9 of these global phase-3 trials include the 3-DAA combination
of the protease inhibitor, ABT-450/r (licensed by ABBV from ENTA);
the NS5A inhibitor, ABT-267 (from ABBV’s pipeline); and the non-
nucleoside polymerase inhibitor, ABT-333 (from ABBV’s pipeline).
Some of these trials also include ribavirin in one or both trial arms.

SAPHIRE-1 and SAPHIRE-2 are essentially safety studies, as
explained in #msg-91739317.

(ABBV/ENTA are testing the 2-DAA regimen of ABT-450/r + ABT-267
in a phase-3 trial for genotype-1b patients in Japan [#msg-91870291]
and in various phase-2 trials globally.)


Six phase-3 trials comprising initial NDA/MAA submissions:

SAPPHIRE-1—(see #msg-91739317 for discussion)—treatment-naïve GT1a/1b w/o cirrhosis; ABT-450/r + ABT-267 + ABT-333 + ribavirin for 12w vs. identical regimen delayed by 12 weeks of placebo use; 600 patients; expected completion Sep 2013:
http://www.clinicaltrials.gov/ct2/show/NCT01716585

SAPPHIRE-2—(see #msg-91739317 for discussion)—treatment-experienced GT1a/1b w/o cirrhosis; ABT-450/r + ABT-267 + ABT-333 + ribavirin for 12w vs. identical regimen delayed by 12 weeks of placebo use; 400 patients; expected completion Sep 2013:
http://www.clinicaltrials.gov/ct2/show/NCT01715415

PEARL-2—treatment-experienced GT1b w/o cirrhosis; ABT-450/r + ABT-267 + ABT-333 ± ribavirin for 12w; 210 patients; expected completion Mar 2014:
http://www.clinicaltrials.gov/ct2/show/NCT01674725

PEARL-3—treatment-naïve GT1b w/o cirrhosis; ABT-450/r + ABT-267 + ABT-333 ±ribavirin for 12w; 400 patients; expected completion Dec 2013:
http://www.clinicaltrials.gov/ct2/show/NCT01767116

PEARL-4—treatment-naïve GT1a w/o cirrhosis; ABT-450/r + ABT-267 + ABT-333 ±ribavirin for 12w; 300 patients; expected completion Dec 2013:
http://www.clinicaltrials.gov/ct2/show/NCT01833533

TURQUOISE-2—DAA-naïve GT1a/1b with cirrhosis; ABT-450/r + ABT-267 + ABT333 + ribavirin for 12w vs. identical regimen for 24w; 380 patients; expected completion Dec 2013:
http://www.clinicaltrials.gov/ct2/show/NCT01704755


Three phase-3 trials not part of initial NDA/MAA submissions:

TURQUOSE-1—DAA-naïve GT1a/1b with HIV co-infection; ABT-450/r + ABT-267 + ABT333 + ribavirin for 12w vs. identical regimen for 24w; 300 patients; expected completion Dec 2014:
http://clinicaltrials.gov/ct2/show/NCT01939197

MALACHITE-1—5-arm trial including 3 DAA arms and 2 control arms—treatment-naïve GT1a/1b; ABT-450/r + ABT-267 + ABT-333 + ribavirin for 12w vs. Incivek + peg-IFN + ribavirin for 12w plus an additional 12w or 36w of peg-IFN/ribavirin on a response-guided basis; separate DAA and control arms for GT1a and GT1b; additional DAA arm for GT1b without ribavirin; 314 patients; expected completion Jul 2015:
http://www.clinicaltrials.gov/ct2/show/NCT01854697
(Note: This is essentially a phase-4 trial.)

MALACHITE-2—treatment-experienced GT1a/1b; ABT-450/r + ABT-267 + ABT-333 + ribavirin for 12w: vs. Incivek + peg-IFN + ribavirin for 12w plus an additional 12w or 36w of peg-IFN/ribavirin on a response-guided basis; 150 patients; expected completion Jul 2015:
http://www.clinicaltrials.gov/ct2/show/NCT01854528
(Note: This is essentially a phase-4 trial.)

[oc631]

Cheat Sheet for ABBV/ENTA Phase-3 HCV Program

The TURQUOISE-1 study is currently enrolling so you might want to add it to the cheat sheet.



http://www.clinicaltrials.gov/ct2/show/NCT01939197?term=ABT-450&rank=9



There's no direct correlation between the TURQUOISE-1 and TURQUOISE-2 studies. Do you think TURQUOISE-1 was originally designed to stratify GT1A and GT1B cirrhotic patients?