NASH ! COMBO’s ARE THE WAY

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Please remember that I am not a doctor or researcher.  the following article is a personal interpretation 


The pathways leading to NASH are multiple, and they are apparently based on different metabolic pathways.

This is why all experts agree now on the fact that there will be no universal drug in NASH, but a combination of drugs or specific drugs  targeting the diversity of metabolic mechanisms.

The following diagram attempts to symbolize different pathway used by disease and its consequences.




First observation, there are two major lethal consequences induced by NASH:

1- Cirrhosis sometimes inducing HCC

2- Cardio-metabolic diseases such as heart attacks or stroke

 

These two consequences are not equivalent in terms of deaths, cardio-metabolic related deaths are far ahead, but, although many studies were published on the link between the two diseases, as the causes of these diseases are multiple, and the clinical field present in NASH patients strongly overlaps with other clinical states already known to worsen the cardio-metabolic risk, as obesity and type 2 diabetes, it is difficult to attribute these deaths mainly to NASH.

So fibrosis / cirrhosis induced NASH is easier to attribute directly to NASH and that’s why it is pinned by all laboratories.

Nevertheless, one constraint is clearly posed: A treatment against NASH should improve or at least be neutral in terms of cardio metabolic risk.  That, in fact, should eliminate any treatment that would exacerbate the cardiometabolic risk by increasing, for example, cholesterol .

In facts, the total absence of treatment of liver fibrosis still leaves room for all therapeutic solutions, even increasing the cardio-metabolic risk. But do not be fooled, as and with the arrival of new drugs on the market, this factor will become more discriminating.

 

Following the literature, we can roughly divide the patients of NASH in major categories.

· Patients with type 2 diabetes

· Obese without diabetes

· Mixed (obesity + diabetes)

· People with a genetic predisposition to develop steatosis without being either obese or diabetic in which one can also find patients with type 1 diabetes.

It seems that the metabolic pathways leading to development of steatosis are different for these large families and, therefore, certain medications only act on some of these routes and are only usable for certain types of patients

For example, it appears, (the laboratory did not confirm it), that, in the results of the FLINT study, OCA is efficient only on diabetic patients. Other drugs such as liraglutid would act more on the way from obesity to steatosis.

Steatosis is the breeding ground for NASH, but a patient with advanced fatty liver does not always develop NASH, nor necessarily fibrosis, by cons, he is already subject to a marked increase in cardio-metabolic risk.

This will probably lead practitioners to look differently, in the future, the steatosis , previously considered benign.



About NASH !

NASH begins when steatosis causes inflammation and hepatocyte ballooning (a hepatocyte apoptosis). when this state is reached, and after a while, scar tissue appear in the liver, the fibrosis.

It was also found that in a number of patients, fibrosis is jointly developing in the first stages of NASH and not after,

Still, the leading mechanism of steatosis to NASH does not seem unique, if the majority of medications are trying to slow or stop the inflammation, that is not the only therapeutic option studied.

Once the fibrosis is recorded, its progress is measured using a fibrosis stage index (0-4) which assesses the progress of the disease.

To date, patients to be treated by future drugs are patients with advanced NASH (NAS score> = 4) and a fibrosis score between F1 and F3 with a preference for fibrosis F2 / F3.

The F4 score corresponding to Cirrhosis is the subject of specific studies because liver failure is a major risk. For those patients, treatment priority would rather be to find an effective anti-fibrotic even if the treatment of the underlying cause (NASH) should not be neglected.

It seems that treatments specifically targeting fibrosis and cirrhosis (named below pure anti-fibrotics), does not specifically target the mechanisms of NASH but are common to all kind of cirrhosis and liver fibrosis. Therefore, these drugs are often tested clinically in patients with alcoholic cirrhosis. 

This diversity of mechanisms of the pathology found a perfect example in the shift observed between the promising results of the FLINT trial (OCA in NASH) and the disappointing results in an other study conducted in Japan.

In the first study, with a daily dose of 25 mg of OCA, improvement of NAS score by  2 points was found (but no significant NASH reversion), and also an improvement in fibrosis score in about 36% of patients vs placebo 19%.

In the second study (Japanese), no statistically significant improvement is observed on the NAS score at a dose of 20 mg / day and especially no improvement in fibrosis was observed whatever the dose.

Several parameters can come into account. Intercept argued that the phenotype of the Japanese study was very different from American patients to justify this failure.

This difference is indeed a possible reason for the difference in action on the NAS score and particularly its fatty component. In the absence of complete elements of the Japanese study ever published, we do not know the rate of diabetic patients included in the study. As the action of the OCA is mainly affecting those patients, that may have had an important role on results. But if OCA have specific anti-fibrotic effect, it is difficult to understand why it does not work on the Japanese’s.

Another parameter, sometime not pleasant to hear by study sponsor, is the difference in the thoroughness of the two studies protocol. (See inset on the right)

The difference in results between the two studies got probably multiple causes, but as the complete data of the Japanese study, and the specific data's on FLINT's patients who started treatment with statins during the study were not published,  it reigns some uncertainty about the relative weight of these possible causes.

 


The NASH spectrum and treatment levers

Undoubtedly, none of the drugs under study are treating at the same level of effectiveness the mechanisms of action needed to treat all the spectrum of NASH patients.

If one tries to represent a mapping of the disease (causes, consequences stages, treatments) he could draw this:

 

NASH leviers

 


Then we could look at what levers are acting  (or are predisposed to act) in drugs in development.

In order to identify the different actions of drugs, I tried to make levers readable using a color code.

Regarding the latest interview of specialists I've read, the ideal cocktail to treat NASH patients depend on the progress of the pathology

To classify here is a table specifying the sickest and urgent to be treated first, and lighter at the end.

 

combo effects


   

 

Some drugs dealing specifically with metabolic causes of NASH showed anti-fibrotic effects in the long-term, probably related with reduction of the causes of inflammation combined with the significant liver capacity for self-regeneration.

Treatment may therefore also evolve with the patient, because if the treatment is effective, pure anti-fibrotic could be progressively removed from the cocktail, as the metabolic long-term anti-fibrotic effect is growing.

The anti-fibrotic component may be a 'one shot' treatment at medium or short-term while the metabolic treatment could be a long-term treatment, perhaps even 'ad vitam'.    

 

courbes traitements



If one looks at the most advanced drugs tested, it is worth looking the relative effectiveness on different levers.

A new color is added to the spectrum for drugs that are not pure anti fibrotic but have an indirect and long-term anti-fibrotic action.

 


Legend of colors and hatch used in the following tables

  

The ideal combo for fibrotic or cirrhotic patients should cover all the boxes. 

Some boxes could also be covered by drugs already on the market, such as metformin or statins.

 



This table could obviously evolve with the future clinical outcomes, but already, some trends emerge.


The possible Combo's

The perfect combo on paper is undoubtedly a duo  Cenicriviroc + Elafibranor which together cover the entire spectrum required to treat the disease. 


They have proven to be effective in phases 2b, are among the most advanced in the pipe,  and could be on the market in 2020/2023.

The long term effect of Elafibranor on fibrosis could gradually replace the Cenicriviroc and could allow the patient to switch, after a while, on a chronic treatment with Elafibranor alone.

 

Another possible combo available quickly (2020/2021)  if the OCA confirms its anti-fibrotic effect, is : OCA + an anti-diabetic (such as metformin) + strong statin to reverse OCA effect on cholesterol and + eventually, an anti-histamine to reduce itching generated by OCA



One can also imagine a combo Elafibranor + GS4997


Because of the potential results of the GS4997 on the rest of the spectrum (unpublished) there may be partial redundancy with Elafibranor effects. However it will be maybe be necessary for GILEAD to confirm the results of their Phase 2a in a phase 2b before moving to phase 3, which would delay the placing on the market.


 

In the longer term, other combos can be considered as a specific combo including only GILEAD compounds. 

This combo is not for now, as the GS0976 from just entered Phase 2, access to the market is difficult to envisage before 2025    

 

An hypothetical combo can be also considered using the promising MSDC-0608 from OCTETA with an anti-fibrotic (as Emricasan from CONATUS

 

There is a lot of possibles combinaisons but only a few can reach the market before the end of the decade and proved their effects in a large clinical study.


In the first 4 years of drugs commercialization, the market will be complex and the offer seems not sized to the anticipated needs.

Obviously the NASH treatment market is primarily dependent on the ability to easily diagnose the disease. In the absence of reliable and non-invasive diagnostic methods, patients first treated will be the patients with significant clinical symptoms, so with advanced fibrosis or cirrhosis.

Therefore laboratories focus their interest primarily on the active drugs on fibrosis.

Understandable!  these patients have a reduced life expectancy without treatment and are easily diagnosed. It's the perfect equation to sell an expensive treatment quickly.

So to make fast money!

The paradox is that the first drugs that are coming on the market are not mainly anti-fibrotic.

- OCA still needs to confirm its anti-fibrotic effect found in FLINT but not in the Japanese study, and its side effects worries investors.

- Elafibranor seems to have anti-fibrotic effects in the medium term, but is not to date, considered a pure anti-fibrotic (this may change with incoming publications).

 

The first pure anti-fibrotic which could reach the market is Cenicriviroc owned by TOBIRA /ALLERGAN which has not yet begun its Phase 3 and who could get, hopefully, a marketing authorization at the earliest in 2023. But the GS4997 and Emricasan are approximately in the same timing.

We therefore find ourselves in a paradoxical situation. the priority patients require anti-fibrotic drugs that would reach the market around 2 to 3 years after the drugs supposed to treat NASH metabolic disorder.

What is predictable!  That, given the urgency and pending an anti-fibrotic, drugs treating metabolic disorder of NASH showing any action, even long term, on fibrosis, will be prescribed to patients by default until an anti-fibrotic or a combo reach the market.

The labs who bet on liver fibrosis alone are not sure to win so far.

Moreover it is likely that non-invasive diagnostic tools will be available from 2020. Many progress are published and GENFIT has just validated some NASH diagnosis biomarkers on a large cohort of patients.


In conclusion, the Laboratories's craze to anything that looks to date as an anti fibrotic, is not necessarily a medium / long term winning strategy (without associated molecule on metabolic side of NASH), and because of the calendar, should not be either a short-term win.

To my opinion, the winning strategy for a laboratory is, besides the acquisition or development of anti-fibrotic molecule, an acquisition or access via a partnership at a molecule widely treating metabolic components of NASH and if possible insulin sensitivity and dyslipidemia (both can also be found in existing drugs).

With those both compounds, it will occupy the ground since 2020 on the metabolic side of NASH, which will be a growing market thanks to biomarkers diagnostic and then complete its offer from 2022/2023 with a combo targeting most patients.

As the treated patients should see fibrosis improvement after one or two years, the need for a pure anti-fibrotic will decrease and they will pursue the metabolic long-term treatment. 

An income second breath with chronic treatment widely prescribed.

Laboratories interested in NASH will have to make a move quickly now, because the opening of the NASH market will start in a few years and none of them, to date, has, alone, the right combination to take the lead. 

Testing combos take time.


G Divry


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