NASH ! THE INTENT TO TREAT POPULATION

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There is, to date, a fragile consensus on the NASH population to be treated (ITT).

 

First ! To have a NASH!


For this, a scoring system was proposed, the NAS Score (it should be noted that this scoring system was established for untreated patients).

This score is based on a histological analysis of a liver biopsy studied under a microscope. In this analysis, three parameters are taken into account:

· Steatosis on a score of 0 to 3, this score being calculated by a percentage of the affected area

· The lobular inflammation on a score of 0 to 3, this score being itself calculated by a percentage of the affected area

· Ballooning (cell degeneration) on a score of 0 to 2, this score calculated by a percentage of the affected area

 The NAS score is the sum of these 3 scores (components) and can therefore be between 0 (no disease) and 8 (liver totally affected).

Historically, NASH was considered to have a score of 3 or more with a score greater than or equal to 1 in each of its 3 components, but this definition has changed and it is now considered that a patient has NASH If and only if the patient has:

• A ballooning score> 0

• An inflammation score> 1

This established, all NASH patients are not considered, to date, as patients to be treated.

This subpopulation to be treated is the one targeted in the current Phase 3 clinical trials and, notwithstanding some variations between studies, it corresponds to patients with the following characteristics:

1- NAS score> = 4 on the basis of a histological analysis of a liver biopsy.

2- Fibrosis Stage 2 or 3, with patients with stage 1 fibrosis and additional risk factors such as a high BMI (BMI) or T2D. (Patients with stage 4 Fibrosis equivalent to cirrhosis are not included in clinical studies on NASH but should be treated, as we will see later).

According to the studies, this population is estimated to correspond to a share of the US population between 3% and 5% of the US adult population.

 

Is this consensus fixed ?

My opinion is that no, it was established two years ago by KOLs and taken over by the agencies on the basis of knowledge that has evolved since.

It must be understood that the equation that governs the definition of patients to be treated is complex, based on the dangerousness of the disease, the rate of its development, the known comorbidities and the risks associated with the treatment. In addition, there is an obvious but often obscured economic figure that is the cost of treatment.

The rate of progression of the disease in the population is similar to that of obesity and diabetes and can be described as a pandemic.

It is therefore urgent for health agencies to find a way to treat patients with known risk.

Numerous studies point out, day after day, the complex nature of NASH, which participates in a metabolic disorder related to obesity, diabetes, hyperlipidemias.

One of its consequences often highlighted is fibrosis and cirrhosis that can be fatal in their ultimate stage, but the main cause of death of NASH patients remains by far the deaths related to cardio-metabolic causes.

That's why the agencies and the Key Opinion Leaders have been very cautious and have decreed that NASH treatment should in no way aggravate the cardio-metabolic risk.


All of this impacts the perimeter of the population to be treated!

 

 

PRIMUM NON NOCERE

One of the main criteria examined before prescribing a treatment is recalled in the Hippocrate's epidemic treatise: "In diseases, two things must be considered: to be useful or at least not to harm

It is for this reason that defining a population to be treated rests entirely on a benefit / risk ratio which cannot be unique for a given disease because it depends heavily on treatment.

Each treatment has positive and negative effects.

Treatment with few deleterious negative side effects may be prescribed to a very large population even if its benefit is moderate, whereas a highly effective treatment with dangerous side effects can be prescribed only to a limited number of patients very sick for whom the benefit / risk ratio remains positive overall.

It is therefore understandable that the perimeter of the population to be treated defined during the design of the clinical studies is not necessarily that which will be defined at term. This will depend on the side effects of each drug.

 

OF NASH AND FIBROSIS

To date, there has been a controversy among laboratories about what should be treated as a priority in patients with NASH.

Many laboratories have focused their studies on drugs that target hepatic fibrosis. They explain that the major risk of NASH is the progression to cirrhosis, which must be treated as a priority.

Some other laboratories (Genfit, Novonordisk, ...) focus on the metabolic causes of NASH and explain that if metabolic NASH regresses, hepatic fibrosis will be stopped and will regress too, preventing the passage to cirrhosis. They put forward the absurdity of concentrating only on fibrosis without treating the underlying cause and, citing the hepatitis C as an example, that is well cured by fighting against the virus and not against fibrosis that is only its result.

This controversy is interesting because it finds one of its sources in one of the previously mentioned parameters: The ratio benefit / risk.

Patients with advanced fibrosis or compensated cirrhosis are high-risk patients, their progression to decompensated cirrhosis is only a matter of time if nothing is done to stop the progression of their fibrosis.

These are perfect candidates for effective treatment against fibrosis even though it has many side effects!

It is therefore necessary to examine carefully the risks induced by the medicines put forward in order to find that the latter often have good and bad reasons to target as a priority the patients most affected.

Another parameter that should not be overlooked is that the cost of treatments for patients with their life-threatening prognosis is much higher than average and that they are more cost-effective for laboratories. The inconsistency of treating only the consequences of an illness without treating its cause is obscured by the pure commercial strategy.

Are these medicines useless? No, they will find their place in combination with background treatments of metabolic disturbance for shock treatments fighting NASH and an advanced fibrosis and will be gradually reduced if the background treatment is effective.

 


THE IMPACT OF THE NASH CLINICAL FIELD

The clinical field of the NASH presents many co-pathologies:

 A NASH patient often presents the following co-pathologies:

• Hyperlipidemia

• Cardio-vascular risk (related to hyperlipidemia but not only)

• Type 2 diabetes (T2D)


This greatly affects the population to be treated according to the side effects of the NASH treatment.

Let us take as an example the two most advanced drugs in their development: Ocaliva and Elafibranor, both in phase 3.

What are the effects of Ocaliva on these 3 co-pathology :

 

Hyperlipidemia

The OCA has a side effect confirmed by numerous studies; it increases the hyperlipidemia by raising the LDL of about 10% to 15% and lowering the HDL. It therefore aggravates the co-pathology. The recently published CONTROL study, however, shows that this risk can be partially offset by statins but no data were provided on patients already treated with statins.

 

Cardio-vascular risk

For reasons previously seen, the OCA increases the metabolic cardio risk associated with the increase in LDL. In the FLINT Study There were 3 major cardiovascular events in the arms treated with OCA and several secondary cardiovascular events.

 

Type 2 diabetes (T2D)

In the Phase 2b FLINT trial, the OCA did not demonstrate any significant action on Glycated Haemoglobin GHA1c, but increased the HOMA-IR score, which, despite of the high variability of this index, does not imply an improvement in the diabetes of the patients. One of the curiosities of the results of FLINT is that almost all patients who had their NAS Score decline were diabetic, regarding this study it could be a problem on the statins effects on CV risk.

 

Therefore, in order to be positioned in a correct benefit / risk ratio, OCALIVA should be prescribed to patients with advanced NASH, by excluding patients with identified cardio-vascular risk and with statin prescriptions to counteract the rise of LDL. An adjunct treatment for type 2 diabetes will also be required, if present

The potential ITT population of OCALIVA is therefore, in my opinion, a reduced sub-population of NASH patients.



Now, let's look at the effects of Elafibranor on these 3 co-pathologies:


Hyperlipidemia

Elafibranor has demonstrated in the GOLDEN trial its ability to lower hyperlipidemia. The pro-atherogenic lipid profile of patients suffering from NASH has been improved with a significant reduction in total and LDL-C, and increase in HDL-C. Remarkably, improvements in lipid parameters have been obtained in patients already treated with hypolipidemic therapies.

The co-pathology is thus reduced by the treatment, even in patients already treated with statins.

 

Cardiovascular risk

For the reasons discussed above Elafibranor significantly reduces cardiovascular risk in patients. In the GOLDEN Study There were no cardiovascular events or deaths in the arms treated with Elafibranor.

 

• Type 2 diabetes (T2D)

In the GOLDEN Phase 2b Study, Elafibranor demonstrated a significant decrease in fasting glucose, decreased Glycated Haemoglobin (GHA1c) by -0.46%, and decreased the HOMA-IR score. Remarkably, improvements in glycemic parameters have been obtained in patients already treated with conventional molecules. The co-pathology is therefore reduced by the treatment.

 

ELAFIBRANOR is therefore positioned in an excellent benefit / risk ratio because, in addition to its effect on NASH, it significantly improves the most commonly encountered co-pathologies. It can therefore be prescribed sereinely to patients with advanced NASH while allowing reducing joint prescriptions such as statins and anti-diabetics.

 The potential ITT population of ELAFIBRANOR is therefore, in my opinion, all NASH patients extended to patients with advanced disease, cardiovascular risk and diabetes or pre-diabetes.

 

This comparison shows how two drugs targeting the same disease have an ITT target population that can vary from single to triple only because of side effects.

 

 

CONCLUSION

The intent to treat population of patients with NASH will be adapted to the profile of the future drugs. The more drugs will have a high safety profile, the more likely it will be admitted to treat patients early, inducing increase of the ITT population.



 G.Divry



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