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Simple screening may not be accurate.
These data suggest that frequent exposure to HCV could contribute significantly to increased viral diversity and cell tropism within an individual and might also result in variants that would not be readily detected should only serum/plasma be evaluated by a clinical HCV genotype assay and not by a robust, multicompartment sequencing approach.
http://jid.oxfordjournals.org/content/195/4/519.full
FDA approves MRK’s HCV combo with recommended RAV screening for GT1a patients:
#msg-120155884
This is a good outcome for ENTA.
ENTA- BlackRock reported holding 8.9% of ENTA as of 12/31/2015:
http://ih.advfn.com/p.php?pid=nmona&article=70169841&xref=newsalert
ENTA’s FY1Q16 results/CC on 2/9/16:
http://finance.yahoo.com/news/enanta-pharmaceuticals-host-conference-call-130000496.html
How many non-nucleoside NS5B polymerase inhibitors are available?
GSK Combination Study on Track; Data by Year-End 2016. In March 2016, Regulus plans to initiate a multi-center, open-label Phase II study evaluating the combination of a single subcutaneous injection of 4 mg/kg of RG-101 and daily oral administrations of 20 mg of GSK2878175, an investigational non-nucleoside NS5B polymerase inhibitor, for up to 12 weeks in treatment-naïve patients chronically infected with HCV genotypes 1 and 3. Concurrently, GSK will work on developing a "LAP" formulation of GSK2878175 as a single intra-muscular injection, providing the potential for a single-visit therapeutic treatment for HCV that could improve patient compliance through reduced dosing intervals and potentially extend opportunities for HCV therapeutic intervention. This LAP formulation of GSK2878175 may be used in additional clinical trials together with RG-101 following completion of the planned Phase II study, although any additional studies are not covered by the current collaboration agreement. Regulus expects to report safety and efficacy data from the GSK Phase II study before the end of 2016.
Today's +13% move likely due (at least in part) to short-covering:
#msg-119961699
#msg-119965328
#msg-119967041
CSO exercised and held more options yesterday: #msg-119968598.
Some of the disparity comes from the different proportions of GT1a vs GT1b in the US vs EU. Among all GT1 patients, the US is about 2/3 GT1a, 1/3 GT1b; the 5 big EU countries are just the reverse: about 2/3 GT1b, 1/3 GT1a.
Dewophile predicted a label similar to what olysio got for MRK. Will know if his analysis is worth a bar of gold in a week.
2. above 800,000 IU/mL, the virologic failures were all over the map. one at 948k, 3 between 1-2M iu/ml, 3 between 2-4M, 3 between 4-6M, 3 w VL>6M. So unlike havoni's 8 week trial where they only saw a break point post hoc above 6M baseline VL (constituting the minority of patients), MRK will forever be dogged in the marketplace with a lower efficacy for GT1a, which will be especially pronounced for the majority of GT1a patients who don't have low viral loads. I also think this adds regulatory risk since these pts as i mentioned likely have SVRs below 90%. Recall 8 weeks of Harvoni for pts with VL >6M had 91% SVR and the label only allowed consideration of 8 weeks below this level, so what are they to do with MRK?
3.directly from the paper: "NS5A RAVs were identified at baseline in 19 of 154 (12%) GT1a-infected patients. SVR12 was achieved in 11 of 19 (58%) of these patients compared with 133 of 135 (99%) patients without baseline NS5A RAVs". I'm not sure how readily available and cost effective screening for baseline NS5A RAV is, but if approved they could get tagged with a label similar to what olysio got, strongly urging testing and treating with another regimen if someone has these at baseline (one difference though Q80K is more common than these NS5A resistant variants, but in this study 12% pts had it - in GILD's ION study it was 18%, so not exactly uncommon either). Of note GILD's TE cohorts (but not naives) showed some correlation w these RAVs, but not nearly as severe as MRK. ABBV failures had higher rates of basleine RAV to NS5A, but again correlation not nearly as strong as MRK (probably due to the 3rd agent in ABBV's case).
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=113189275
Why is GT3 cirrhotics excluded in EXPEDITION-1?
Why is GT3 cirrhotics excluded in EXPEDITION 1?
EXPEDITION-1—TN/TE cirrhotic patients (Child-Pugh A) of all genotypes except GT3
EXPEDITION-4—TN/TE renal-impairment patients (including cirrhotics) of any genotyp
Global phase-3 program for ABT-493/ABT-530 (updated for EXPEDITION-4):
#msg-119900756
4 million shares shorted @ 12/31/2015. SS expects Merck to take ABBV's market share in 2016. Luly expects increasing earnings due to:
2D (2-DAA) regimen marketed in Japan without RBV
Viekira QD: Regulatory decision 3Q16
Viekira: RBV-free in GT1b cirrhotic patients
Will 1/28 be the drop dead date for the SS?
Look at how much respect ACHN got with all their proxy studies with Sovaldi. In order for EDP-494 to make Pujols' money, it will have to clean up after weak nukes in it's POC. If it passes physical in P1, it is supposed to hit the home run for the team.
Well, we will see. First it has to complete phase 1 work. In that time they will scrutinize other nukes for a combo
Picking a companion nuke is a double edged sword.
A weak nuke could mean a weak combo
Sovaldi might mean success for the combo, but could make the drug less affordable.
IF ENTA could partner with or acquire a successful nuke (how many have failed here?), it could have great commercial success.
It has a long way to go, but the slides look very encouraging. There is at least one nuke available commercially (sovaldi) that could make this (potentially) a best in class treatment. I would think this could make ENTA attractive for acquisition, or to partner with.
If it has a viable POC I would think there would be plenty of suitors.
--------------------
There is a lot of data on Sovaldi, so I would guess that it would be a reasonable place to start a proof of concept.
----------------------
Understood. Since POC studies with Sovaldi have been done by so many companies, analysts/MDs have concluded that no effective regiment can be without it or another nuke. In order to break that entrenched belief, ABBV is doing the P3 GT3 study(ENDURANCE 3). I think ENTA should do the same. Doing a POC without Sovaldi will show what EDP-494 can do wihout the gold standard.
Thanks for the compliment, but I'm not a wizened successful investor. I'm a newbie myself; not to HCV though. I was DX'ed 15 years ago, have been on HCV forums that long. I most recently was cured about 2.5 years ago in a Gilead (what would become Harvoni) trial.
Furthermore, I added shares to my ENTA and have about a 40 dollar per share average; so I'm a tad in the red (with my current stake, not my long term profits). I didn't get stopped out or sell in the October crash. I feel that the share price should come back up.
"does ENTA need a nuke as good as Sofosbuvir?"
If EDP-494 wipes out NS5B RAVs as shown on slide 14 of JP presentation, does ENTA need a nuke as good as Sofosbuvir? I wonder if ENTA has already tested EDP-494 + Sofosbuvir vs. EDP-494 + Dasabuvir.
Thank you for answering newbie question.
The textbook answer is what Luly said; A nuke is the best likely choice for a partner since it too would have a high barrier to resistance. With a nuke it may be a two compound treatment.
A NS5a or a PI would not be ideal choice since they create their own RAVs.
This would be a salvage treatment for those groups who had already been exposed these compounds and had a host of NS5a and PI prevalent resultant RAVs.
ENTA wants EDP-484 to be used in a cocktail controlled by ENTA, not by ABBV; this means the EDP-484 cocktail won't contain ABT-493 (which is licensed to ABBV).
EDP-239 isn't potent enough to form a 2-drug combination with EDP-484, although it could be used as a third drug if it turns out that three drugs are needed.
If EDP-494 can wipe out all the RAVs, does it need the best in class NS5A/NS5B to make a combo? How about ABT-433 + EDP-239 + EDP-494?
According to Luly, it is
"Additive to synergistic with DAAs (PI, NS5A and NS5B inhibitors)"
Sovaldi is readily attainable for a POC and might lend itself to "apples to apples" comparisons to display the potency of 494.
There could be a number of unattached nukes looking for a compound to couple with which could be superior to Sovaldi or a superior fit w/ 494
You have to also wonder about treatment duration.
Very impressive slides.
It still needs to be proven safe and effective on human subjects, of course. Even so; looks good.
Over all it was a pretty impressive talk; one of the best I think I've heard from ENTA.
Potential combo: MIV-802 + EDP-494??
MIV-802 displayed pan-genotypic potency in HCV replicons GTs 1-6 with
an EC50 range of 17-58 nM (EC50 range for sofosbuvir: 48-210 nM)
ENTA’s JPM webcast slides:
http://jpmorgan.metameetings.com/confbook/healthcare16/stash/slides/19782/confbook_slideshow.php
Slides 24, 26, 27 compare EDP-305 to ICPT’s OCA.
I don't think the RSV program is necessarily a consequence of the apparent discontinuation of the HCV nuke.
Thank you for pointing that out. Are you surprised by Enta ventured into RSV graveyard? Could that be related to the discontinued HCV nucleoside program?
"AL-8176 is a nucleoside analog which is being developed by Alios BioPharma as an orally administered antiviral therapy for the treatment of infants infected with RSV. AL-8176 is designed to inhibit the replication of the RSV by acting on the viral polymerase. In vitro studies of the compound showed potent and highly selective inhibition of both RSV laboratory-adapted A and B strains as well as a range of diverse clinical isolates. Similar to other nucleoside analogs, AL-8176 demonstrates a high barrier to the development of viral resistance."
Those aren’t option exercises, but rather 2013 option grants that became exercisable on 1/9/16—see the footnotes.
CEO, CSO, CFO exercised options @ $14, could have waited til 3/20/2023. What's the hurry??
PT = 16 according to Barclays, is their research worth a bar of clay?
ENTA is planning a EDP-239 + EDP-494 combo, their version of Havoni
"Enanta has also discovered EDP-239, an NS5A inhibitor for HCV infection. EDP-239 has successfully completed phase 1 studies in 2015, including a proof-of-concept study, but its further development will depnd upon its potential utility as an additional component of an EDP-494 containing therapy, which will be determined after early clinical trials of EDP-494"
The HCV nucleoside, which is not in the new pipeline chart, has apparently been dropped.
Preclinical data on EDP-305 and EDP-494 to be presented at the 34th Annual J.P. Morgan Healthcare Conference.
http://www.enanta.com/research/enanta-pipeline/
EDP-494 P1 started
A Randomized, Double-Blind, Pbo-Controlled, Study of EDP-494 to Evaluate the Safety and PK of SAD/FE in Healthy Subjects and MAD in Healthy and in Subjects With CHC Infection (POC)
The first phase explores single ascending doses of EDP-494 (active drug or placebo) in healthy subjects. A 'fasted' vs 'fed' two-part cohort will also assess food effect.
The second phase involves multiple ascending doses (active drug or placebo) for 14 days in healthy subjects.
The third, proof of concept, phase will assess two different doses for 14 days each in Hepatitis C patients.
Each cohort within each phase will consist of 8 subjects randomized to either EDP-494 or placebo in a 3 to 1 ratio, with the exception of the food effect cohort, which will consist of 10 subjects randomised in a 4 to 1 ratio.
https://www.clinicaltrials.gov/ct2/show/NCT02652377?term=EDP-494&rank=1
ENTA announces early-stage programs in HBV/RSV—phase-1 for EDP-494 (HCV cyclophilin inhibitor) has started:
#msg-119746650
EXPEDITION-4 started
A Single-Arm, Open-Label, Study to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in Renally Impaired Adults With Chronic Hepatitis C Virus Genotype 1 - 6 Infection (EXPEDITION-4)
The purpose of this study is to assess the efficacy and safety of 12 weeks of treatment with the ABT-493/ABT-530 combination regimen in adults with chronic HCV genotype 1 - 6 infection and chronic renal impairment.
Estimated Enrollment: 100
Study Start Date: December 2015
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
https://www.clinicaltrials.gov/ct2/show/NCT02651194?term=ABT-493&rank=11
How negative will FDA view grazoprevir/elbasvir on January 28, 2016?
NS5A RAVs were identified at baseline in 19 of 154 (12%) GT1a-infected patients. SVR12 was achieved in 11 of 19 (58%) of these patients compared with 133 of 135 (99%) patients without baseline NS5A RAVs. SVR12 in patients with baseline GT1a RAVs with a 5-fold or smaller shift to elbasvir was 90% (9 of 10) versus 22% (2 of 9) in patients with baseline GT1a RAVs with a greater than 5-fold shift (Appendix Table 5). An association of GT1a RAVs with virologic failure was observed only in patients with baseline viral loads greater than 800 000 IU/mL (Appendix Table 6). In 18 of 130 (14%) patients with GT1b infection and baseline NS5A RAVs, SVR12 rates were 94% (17 of 18) versus 100% (112 of 112) in those without baseline NS5A RAVs. Among the 6% (16 of 280) of GT1-infected patients with both NS3 and NS5A RAVs at baseline, SVR12 was achieved in 12 of 16 (75%) (Appendix Table 7).
Modest but positive development; I commented in #msg-119660716.
No Ribavirin on top of 1 pill for GT 1b. 100% SVR12
Enanta Pharmaceuticals Announces the U.S. FDA Grants Priority Review to AbbVie’s Supplemental New Drug Application for VIEKIRA PAK® Without Ribavirin in Genotype 1B Chronic Hepatitis C Virus Patients with Compensated Cirrhosis
TURQUOISE-III study showed 100 percent sustained virologic response at 12 weeks post-treatment (SVR12) in patients with genotype 1b (GT1b) chronic hepatitis C virus and compensated cirrhosis (Child-Pugh A)
AbbVie Announces FDA Acceptance of New Drug Application for a Once-Daily Formulation of VIEKIRA PAK
CSO exercised and held $2.7M of stock yesterday: #msg-119622892.
Global phase-3 program for ABT-493/ABT-530: #msg-119515332.
ENTA presenting at JPM 1/13/15, 2pm ET:
http://finance.yahoo.com/news/enanta-pharmaceuticals-present-34th-annual-130000619.html
ABBV presents at JPM a couple of hours earlier, which is helpful for ENTA by allowing Jay Luly to comment on any disclosures ABBV may make regarding the HCV programs.
ABBV 2nd gen will be as good as SOF/VEL, based on this move and what Luly said in last CC:
'There was no virologic failure in the naïve subjects and there was only one virologic failure in the experienced patients that were in either genotypes 1, 2 or 3'
GILD POLARIS-1,2 and P3(genotype 3)
A Phase 3, Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 12 Weeks in Direct-Acting Antiviral-Experienced Subjects With Chronic HCV Infection(POLARIS-1)
Estimated Enrollment: 380
Study Start Date: November 2015
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
======================================================================
A Phase 3, Global, Multicenter, Randomized, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 8 Weeks Compared to Sofosbuvir/Velpatasvir for 12 Weeks in Direct-Acting Antiviral-Naïve Subjects With Chronic HCV Infection(POLARIS-2)
Estimated Enrollment: 780
Study Start Date: November 2015
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
========================================================================
A Phase 3, Global, Multicenter, Randomized, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 8 Weeks and Sofosbuvir/Velpatasvir for 12 Weeks in Subjects With Chronic Genotype 3 HCV Infection and Cirrhosis
Estimated Enrollment: 200
Study Start Date: December 2015
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Gild triple combo P3
A Phase 3, Global, Multicenter, Randomized, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 12 Weeks and Sofosbuvir/Velpatasvir for 12 Weeks in Direct-Acting Antiviral-Experienced Subjects With Chronic HCV Infection Who Have Not Received an NS5A Inhibitor
SOF/VEL/GS-9857 (400/100/100 mg) FDC tablet administered orally once daily with food
SOF/VEL (400/100 mg) FDC tablet administered orally once daily without regard to food
Estimated Enrollment: 380
Study Start Date: December 2015
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
EXPEDITION-1 started
A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in Adults With Chronic Hepatitis C Virus Genotype 1, 2, 4, 5 or 6 Infection and Compensated Cirrhosis (EXPEDITION-1)
ABT-493/ABT-530 for 12 weeks
Estimated Enrollment: 175
Study Start Date: December 2015
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Very expensive data to go with the $350 million voucher. Patients must be lining up for this trial, free $1000 pill + DCV/day for 12 weeks.
Did FDA request this?
Did FDA request this?
Will MRK P3 triple combo go head-to-head against Sofosbuvir (SOF) and Velpatasvir (VEL) in GT3 patients?
Going head-to-head against Solvaldi + Daklinza in GT3 patients is a gutsy move.
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