2019, THE NASH LANDSCAPE

UPDATED the 20 of february 2019


IMG 1728

 

Feb 2019 , what is the updated NASH landscape ?


2019 is a pivotal year in NASH treatment, to date, two Phase 3 trials published their intermediate results and one Phase 3 will be publised in fall and the NASH landscape is still modified.

Four compounds are in Phase 3 to date, but Tobira (Allergan) delayed their results to september 2020, to date only 3 compounds are still in course for 2019:

  • OCALIVA (Intercept)
  • ELAFIBRANOR (Genfit)
  • SELONSERTIB (Gilead)


§ OCALIVA (INTERCEPT) :

Previous 

This drug suffered from a bad start in PBC, the agreement of the drug by the FDA was not obvious and it seems that patients associations pushed hard to obtain it. Last September a warning was published by the FDA after 21 deaths of patients under treatment. For many of the fatal events, link with the treatment could not be established but FDA regards some with suspicion.

At the end of 2017, the number of deaths raised to 63. FDA asked for a ‘blackbox' warning on the OCALIVA package but with limited restrictions. 

To my opinion, it is difficult to assess is the degree of risk carried by OCALIVA treatment for PBC patients because they are mainly in bad condition with a bad pronostic therefore some deaths are likely to occur. We need more analysis to estimate the actual risk.

Nevertheless, the bad safety profile of the drug seems confirmed. To me, it should withdraw OCALIVA from the list of potential 'backbone' treatments of NASH ( and also because of the induced prurit which reduces the compliance of the treatment)

The Phase 3 trial recruitment for interim results was reduced by Intercept from 1400 patients to 750 patient one year ago (ie early 2017). But two months ago (ie in November 2017), the total amounts of patients to recruit in the trial has been changed from 2000 patients to 2350 patients with no further explanations. To date we don’t know whether this change will have any impact (or not) on the interim trial result timeframe. 


What's new for OCALIVA

In the last months, INTERCEPT communication was insisting on targeting advanced fibrosis in NASH instead metabolic NASH itself.

With the published results (19th of february) we now know why.

Intermediate results of their Phase 3 show mixed results in fibrosis (F2 F3) below the expected projections done on the basis of phase 2b.

As expected by NASHSBIOTECHS.COM , the dose of 10mg / day is ineffective, the dose of 25mg / day, equivalent to that tested in phase 2b has a moderate efficiency on the decline of fibrosis of 1 grade without aggravation of NASH.

OCALIVA 23,1% vs  PLACEBO 11,9% p=0,0002 estimated RR= 1,94

In a previous projection based on a post hoc analysis including FLINT patients with the recruited profile of Phase 3, INTERCEPT published their expectations on that endpoint

OCALIVA 39% vs  PLACEBO 21% p=0,007 estimated RR= 1,85

Expected values were double those finally achieved but the Relative Risk ratio  is almost identical. Many facts could explain the gaps, but to my opinion FLINT bias distorted reality.

Again, as expected by NASHBIOTECHS,  OCALIVA action on the NASH reversion  is a failure , by far, especially with regard to the projections published by INTERCEPT on the basis of the FLINT Study.

for the 25mg/day dose (equivalent as FLINT)

the results of Phase 3 are :

OCALIVA 11,7% vs  PLACEBO 8,0%  p=0,1268   estimated RR=1,46

as INTERCEPT published their expectations on that endpoint :

OCALIVA 18% vs  PLACEBO 5,0%  p=0,014  RR=3,6

As OCALIVA never met that endpoint previoulsy in any trial, it is maybe a surprise for some Analysts but not for me. However, the gap is huge with the projections based on phase 2b, again, the huge bias of the FLINT study should be the main cause.

The bad news come from adverse effects,

The announced pruritus rate for the only effective dose (25mg/day) is twice that found in phase 2b at equivalent dose.

Half of the patients under OCA  suffered from pruritus, as this drug is intended to be prescribed to patients for long durations, such a significant side effect is redibitory and will prompt patients to switch to any other medication as soon as it is available.

The safety of Ocaliva could be also a concern, three times more patients under OCALIVA have suffered serious events compared to placebo, especially related to gallstones in the liver. To complete LDL peak levels increase +22,6 mg/dl vs 17,4 mg/dl in FLINT

Intercept is surely trying to find a complement to regulate LDL and to propose some treatment for metabolic NASH, they recently announced they acquired the rights of bezafibrate in NASH.

Bezafibrate is a PPAR alpha with also delta and gamma components used in many countries to regulate hypercholesterolemia. Many publications showed a direct action of PPAR alpha, delta and gamma on metabolic NASH. 

It seems a good complement to OCALIVA as one of the side effects of OCALIVA is to increase LDL levels. It confirm also that Intercept is now interested in PPAR action on NASH.

As bezafibrate in NASH is not yet in Phase 2, it could delay a combo solution with OCALIVA and Bezafibrate by years. 

This could conduct to a intermediate solution, a combo  with OCALIVA and the only PPAR in phase 3 , Elafibranor.

OCALIVA is classified by NashBiotechs.com as possible complementary treatment and not a backbone treatment because of its side effects, as pruritus, that do not promote long-term treatment.


§  ELAFIBRANOR (GENFIT) :

Again, no bad news for Elafibranor, the DSMB supported the pursuing of the trial at the end of 2018 : no safety problem has been detected. The interim result recruitment of 1000 patients was completed in may 2018 and the phase 3 intermediate results are expected Q4 2019.

The results recently published by GENFIT on PBC (phase 2) are amazing and show a clear action of Elafibranor on Liver. 

A contrario of OCALIVA, ELAFIBRANOR has already demonstrated a statistically valid resolution of NASH in phase 2b (GOLDEN), which augurs well for its phase 3.

GENFIT annonced a licence agreement with Covance in the NASH biomarkers diagnostic kit  development ! This is very important because all the specialists and the FDA are insisting on the urgent need of basic blood NASH diagnostic.

GENFIT annonced also a first step to introduce itself on NASDAQ. one can expect an IPO H1 2019

ELAFIBRANOR is classified by NashBiotechs.com as the first NASH ‘backbone’ treatment that could reach the market.

 


§  SELONSERTIB (GILEAD)

Selonsertib potential was  mainly based on expectations because the phase 2 used as reference to claim its antifibrotic potential was far from academic, with a very small amount of patients and no trustworthy placebo (Simtuzumab was used as placebo by default).

GILEAD decided to push their luck a bit and to push forward directly a Phase 3 with a short duration (11 months).  Their compound is an ASK1 reducing globally apoptosis of cells in the body and some specialists seem concerned by a possible cancerigen-induced effect.

GILEAD announced a failure of  STELLAR 4 and  we are waiting for STELLAR 3 results H1 2019.


The failure was not a surprise for NASHBIOTECHS regarding the lack of scientifical evidences for selonsertib on fibrosis. A recent publication showed that selonsertib action was specific to murine models, not human.

to my opinion the chances of positive results in STELLAR 3 are tiny.

 To date, SELONSERTIB was removed from the potential treatments list in NASHBIOTECHS database.



§  CENICRIVIROC (ALLERGAN)

At the beginning of 2019 , Phase 3 AURORA trial intermediate results were delayed by 14 months !

It could be a recruitment problem but as no explanation whas given on this delay it is only expectations.

This jeopardize the potential access of CENICRIVIROC on the market.

CENICRIVIROC is classified by NashBiotechs.com as possible complementary treatment to another backbone treatment.



Other advanced compounds in the competition 

(mainly in Phase 2)

BELAPECTIN   (GR-MD-02 ) (GALECTIN)

GALECTIN announced that they will start discussions with FDA to launch a Phase 3 in cirrhosis but, to date, no clear announcement was done.

However, scientific publications are multiplying on the direct action of belapectin on fibrosis. This medicine is to watch closely because it could surprise in the coming months.

BELAPECTIN is classified by NashBiotechs.com as possible treatment complementary to another backbone treatment.

 

§  MGL-3196 (MADRIGAL)

Madrigal published very good results on NASH . With those good results, MGL-3196 could become a backbone treatment for NASH on the market by 2025. 

MGL-3196 is classified by NashBiotechs.com as possible backbone treatment.


§  VK2809(VIKING)

VIKING published encouraging results on liver fat reduction in november 2018, as the histology analysis of liver biopsy was not included in the design of their trial, they now should confirm the action of  NASH resolution in a longer trial ( FDA whish is 12 months for a Phase 2b).

 If results are confirmed, VK2809 could become a backbone treatment for NASH on the market by 2028. 

VK2809 is classified by NashBiotechs.com as possible backbone treatment.

 

§  IMM124E (IMMURON)

Last Immuron interim results of Phase 2 showed mainly nothing, no real difference with placebo. Last results published in March 2018 show improvements for LPS and CK18 serum levels  but only on a sub group of patients. The primary and secondary endpoints are not reached on ITT population.

Detailled analysis of IMM-124E results by NASHBIOTECHS is here

It is not sure that they have a future on the NASH market. Waiting for the complete results and the publication to confirm this point of view.

IMM124E is classified by NashBiotechs.com as possible backbone treatment.


§  EMRICASAN (CONATUS)

Apr-4-2018  Conatus annonced results from Phase 2b POLT-HCV-SVR Clinical Trial, this trial was not targeting NASH but liver transplanted patients with residual fibrosis or cirrhosis. The primary Endpoint on fibrosis improvement was not reached on ITT population but the trial show some improvements on a small sub population. 

ENCORE -PH results on NASH patients with compensated cirrhosis were published in december 2018.

The primary endpoint was not met but some encouraging improvements were noticed on patients  with HVPG of 16 mmHg or higher.

It is difficult to see if those results prefigures the results expected on NASH population in ENCORE-NF and ENCORE-LF trials, but they are not very encouraging !

ENCORE-NF results are expected Q1 2019

ENCORE-NF results are expected H2 2019

EMRICASAN is classified by NashBiotechs.com as possible complementary treatment to another backbone treatment.


§  ARAMCHOL (GALMED)

Results of ARRIVE Ph 2a (evaluated the safety and efficacy of Aramchol™ at 600mg/day versus placebo in 50 patients with HIV-associated lipodystrophy and non-alcoholic fatty liver disease) were published the Feb 14 2018 and the primary endpoint ( improvement of liver fat at 12 weeks, as measured by MRI-PDFF) was not reached !

Results of ARREST (phase 2b  study with 248 NASH patients assessing Aramchol™ 400 and 600mg/day following 52 weeks treatment, with endpoints measured by MRS and liver biopsies)   were published and, as the reduction of liver fat mesured by MR Spectrorcopy  was noticable , the resolution of NASH whithout worsening of fibrosis (consensual endpoint for a phase 3 in NASH) was not reached by few: Aramchol 600 vs. 16,7% vs 5% Pbo p=0.051 OR 4.74 (95% CI: 0.99-22.7).

the 16% are also not as good as the competitors, so I am still skeptical on the future of ARAMCHOL in NASH. 

ARAMCHOL is classified by NashBiotechs.com as possible backbone treatment.


Regarding the delayed results of CENICRIVIROC, the failure of SELONSERTIB, the desapointings results of EMRICASAN and ARAMCHOL, only two drugs could dominate the market from 2020 to 2025, OCALIVA, and ELAFIBRANOR.

The last results of OCALIVA open a large field to Elafibranor on Backbone treatment of metabolic NASH.  

OCALIVA is more and more to be considered  as complementary treatment, 

This point of view is conforted by the recent acquisition by ICPT of bezafibrate rights, a PPAR alpha (delta gamma) that confirm the objective interest of labs in PPAR action in NASH, supported for years by GENFIT.

If ELAFIBRANOR confirm the results on NASH reversion reached in Phase 2b, the NASH market of the 4 next years will be shared between ELAFIBRANOR as a metabolic backbone treatment combined with OCALIVA on advanced NASH induced fibrosis.

A free forecast  NASH market survey including all the compounds in course  is HERE


G Divry

Notice that I am neither a physician nor a biologist, my point of view is only that of an enlightened amateur, so it must be taken for what it is, a questionable point of view




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