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Conatus Pharmaceuticals ENCORE-PH Trial Results - BioWatched Reactions

15:37 EST 7 Dec 2018 | Biotech Watcher


On Thursday, December 6, 2018, Conatus Conatus Pharmaceuticals (CNAT) announced its results for the ENCORE-PH trial, held a conference call, and released associated presentation slides. The following represents our initial reactions.

Brief Summary


The ENCORE-PH trial enrolled 263 patients with compensated or early decompensated NASH cirrhosisand severe Portal Hypertension. Conatus released top-line results for its main study. These patients are currently enrolled in a 24-week treatment extension study.

Compensated Patient Subpopulation
Baseline HVPG
Emricasan
5 mg BID
Emricasan
25 mg BID
Emricasan
50 mg BID
Placebo
BID
≥ 12 mmHg
-0.8
n=46
-0.8
n=47
-0.4
n=42
+0.2
n=53
≥ 13 mmHg
-0.9
n=39
-0.9
n=46
-1.0
n=37
+0.5
n=44
≥ 14 mmHg
-1.0
n=35
-1.3
n=38
-1.1
n=31
+0.5
n=39
≥ 15 mmHg
-1.2
n=30
-1.3
n=35
-1.7
n=25
+0.3
n=35
≥ 16 mmHg
-1.6
n=26
-1.7
n=30
-1.5
n=21
+0.5
n=26
≥ 17 mmHg
-1.7
n=23
-1.9
n=25
-1.6
n=19
+0.9
n=20


The trial failed its primary endpoint to show reduction in portal vein hypertension across all patients. CNAT fell $2.56 to $1.94, a grievous 43% reduction in valuation.

Does this trial show that emricasan lacks efficacy? Not really, no.

The emricasan patients all showed numerical improvements. For all categories of disease severity, the placebo patients got worse. All three emricasan dose groups showed clinically meaningful improvement, especially for severe patients.

The patients were segmented by disease severity (baseline HVPG).

Our Thoughts


The trends were clear, the patients with the worse disease had the greatest improvement. It was statistically and clinically significant for the worst patients across all three dose groups. There were also improvements in liver-related biomarkers. This is aligned with Conatus’ intent to pursue the severe groups that aren’t served by competitors.

CEO Steve Mento said that it was really a matter of sample size, that with a larger sample, the entire set of compensated patients with HPVG ≥ 12 mmHg would be statistically significant. He said it was a matter of mathematical proportionality.

In the Conatus' earlier pilot trial, the avg baseline HVPG was 21. We still maintain that there might be a relation to severity.

From a clinical science perspective, the extension results become important. This is because emricasan patients had numerical superiority over placebo patients at all disease and dosage levels. This translated into statistical significance for the “most severe” patients with compensated disease.

Will these advantages be maintained? Over time, will this translate into further advantages, e.g. survival and stable disease?

Valuation Rock & A Hard Place

The investor community understandably wants to see clinical results in which emricasan is efficacious across groups. Nuanced results in the NASH area is now met with investor disdain.

The extension results can have greater implications than the main results. Even with great extension results, we fear that the investors won’t pay attention. It’s not unexpected nor a wholly unreasonable position.

Ultimate Thoughts

Emricasan is a strong anti-inflammation, anti-apoptotic drug. We’ve seen to much evidence to support it. NASH is a “dirty disease” and we’ve had our doubts that it is wholly amenable to one drug. That’s why even the successful drugs only target meaningful subsets.

Does emricasan treat a necessary component that is insufficient alone for treating the range of NASH?

For those who have a strong science element in their investment charter, the key questions involve: does inflammation play an essential role in the NASH disease process?

The answer is likely yes.

Is it enough for Novartis to still make a serious run for emricasan? Is caspase inhibition the way to go?

The answer is: we don’t know. The animal work at Conatus and Novartis remains hidden. Unlike prior work, the combination work remains opaque.

This is enough uncertainty that it should scare most other types of investors…and it did.

Prognostication on the Final Two Trials

ENCORE-NF (NASH Fibrosis) – 330 patients with NASH fibrosis. Top-line results confirmed for 1H-2019.

ENCORE-LF (Liver Function) – 210 patients with decompensated NASH cirrhosis, with top-line results expected in Mid-2019. The primary endpoint is event-free survival with all patients treated for a minimum of 48 weeks.

We were asked off-line whether we thought the ENCORE-PH trial results would be positive. Conatus announcements seemed to indicate confidence. Years ago, we thought the portal hypertension trial would be the ultimate test. We revised our thinking.

We told the reader our gut reaction: we have greater confidence in the ENCORE-LF trial than the ENCORE-PH trial. We were worried about nuanced results as portal hypertension has multiple factors influencing it.

Don’t get us wrong. We like the experienced team at Conatus and the Novartis agreement. Nevertheless, NASH treatment is a shootout. Even the “good drugs” have a rocky development path. Despite recent success for these drugs, the odds are tough. It feels uncertain, not impossible, but definitely rough for emricasan. 

Nevertheless, we agree with the management's characterization. The evidence points towards emricasan. The trial wasn't necessarily powered to pick up statistical significance for each subgroup. Like everyone else, though, we want a grand slam. The drop may have been overdone, but we sympathize with the investor mentality. They need a clear picture that is easily captured in a single headline. 

Milestones


Conatus Pharmaceuticals - Clinical Milestones
ENCORE Trials – The ENCORE program supports the design of the Phase III program. Each Phase IIb trial explores a different indication. Robust results, however, may support an FDA or EMA filing. The first results arrive in the first half of 2018.
ENCORE-PH – Portal Hypertension – Patients with severe portal hypertension (SPH) that were cleared of Hepatitis C (HCV-SVR) and have NASH cirrhosis. The primary endpoint is a reduction of HVPG(Hepatic Venous Pressure Gradient) after 6 months of treatment, which may later serve as a valid surrogate.Includes a 6-month continuation phase to monitor continuing liver decompensation.
ENCORE-PH Extension
24-Wks Treatment Extension
Mid-2019
ENCORE-NF – NASH Fibrosis -  NASH patients with fibrosis, but not cirrhosis, are measured according to the NASH CRN Histological Scoring System.  The primary endpoint involves a biopsy-based change in the fibrosis score after 72 weeks of treatment.

Based on previous studies in HCV patients, Conatus management expects the 5 mg dose to be as effective as higher doses in fibrosis patients. The 50-mg dose is being positioned for patients with cirrhosis and the 5-mg dose for patients with fibrosis.
330 Nash Fibrotic Pts- 5mg or 50mg 2x/day, 72 Wks
  Top-line Results
1H-2019
ENCORE-LF – Liver Function – NASH Cirrhosis + Clinically Significant Portal Hypertension (CSPH) – Pts have compensated cirrhosis and portal hypertension, and will examine the long-term impact of treatment. The ongoing liver cirrhosis trial results will inform the design decisions (e.g. sample size).

The endpoints include: MELDor CPTto measure mortality risk in patients with liver disease; biomarkers (e.g. bilirubin, albumin). Event-free survival serves as the primary endpoint. Analysis is conducted after a pre-specified number of events occur. These events include: all-cause mortality, new decompensation events, or a progression of ≥4 points in the MELD score
210 NASH Cirrhotic Pts w/ Portal Hypertension
5mg or 25mg 2x/day, 48+ Wks
  Top-line Results
Q3-2019
Post-treatment Follow-up – Observational study for patients from POLT-HCV-SVR, ENCORE-NF, ENCORE-PH, and ENCORE-LF. Patients treated with placebo and emricasan will be followed to estimate the event rate for liver cancer, and to confirm safety.
 Final ResultsAbout 800 patients will be enrolled.

2021*
IDN-7314 – Like emricasan, this is also a pan-caspase inhibitor. As a liver treatment, it falls within the current Conatus-Novartis agreement.
Primary Sclerosing Cholangitis(PSC) – The company recently received orphan designation from the EMA(European Union) and the FDA (United States).
Preclinical Animal Models
Ongoing

Additional Thoughts

This represents our initial thoughts on Conatus. We want to think more about NASH and write our thoughts about other companies including Corcept, but not until visiting both companies.Corcept is early in the game, and we frankly prefer to think its pursuit of NASH as a cipher for pursuing metabolic syndrome. That’s the proper lens to view it.

For those of you who follow my personal account on twitter (@AlanHobbes), I have recently been tweeting my whereabouts for office hours. This is a deliberate change.

I believe you should know those who comment on the industry. Do not take candy from strangers. I eschew going under institutional pseudonyms and paying social media sites for the privilege of anonymity. This isn’t to insult anyone else, it’s simply my old school druthers.

I have met some of you, whether it’s in California or South Carolina. I periodically hold public office hours in Seattle, but also during my travels. You don’t have to visit, but many have commented that “just being available” is enough.

(At the time this post was written, one or more BioWatch staff held a position in CNAT)

This blog post is from The Biotech Watcher:
And about us, see http://alanhobbes.blogspot.com/2014/12/welcome-to-my-personal-thoughts-about.html


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