ELAFIBRANOR, NEW PERSPECTIVES ...

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Regarding the « GOLDEN » study results, Elafibranor effects are larger than the initially targeted effects on NASH and the drug seems to be a real new class of drug with wider perspectives


Preamble

By laziness or to simplify the reasoning, we often tend to segment the problematics in small units that we try to solve one after another. It cultivates a systematic approach.

It is the same for diseases. health agencies tend to segment patthologies and, therefore, treatment.

Each drug must have a marketing authorization for each indication. A pluripotent medicine will therefore have several marketing authorizations (MA), one for each indication.

agencies made clear any unwanted or dangerous side effects of a drug .. they rarely do mention the positive effects of a drug on other conditions, to  speak about it would require the drug is a specific authorization specifying these beneficial effects and its ability to treat this other pathology.

This allows the physician to prescribe the drug for the authorized indication without risk of being accused of sorcerer's apprentice behavior, however, doctors familiar with the drugs they prescribe all noted that some drugs have positives effects out of the initial marketing authorization but they can not use them, officialy, for treatment.

A famous example is the AVASTIN, anti cancerous authorized, which was used off-label by courageous physicians for the treatment of AMD, while the laboratory ROCHE owner AVASTIN refused to request a specific marketing authorization for AMD, because he was selling otherwise the LUCENTIL, approved for the treatment of AMD, a very close molecule,  but between 10 and 30 times more expensive.

It is ultimately the French Ministry of Health that went into force authorizing the use of AVASTIN for the treatment of AMD against the advice of Roche laboratory.

One of the problems is that the beneficial complementary effects of a molecule on a different pathology  may not make the cut for the comparison with other drugs directly targeting this pathology.

For example an authorized M1 drug for a condition A, could have  a significant positive effect on pathology B, but somewhat less effective than medication M2 which itself directly target the pathology B.

Therefore, it is not profitable for a laboratory to try to seek marketing authorization for the drug M1 for pathology B, because they can not demonstrate a higher profit on the M2 drug in this disease. so it is unlikely to get it.

This leads us to this systematic approach to the treatment of patients with multiple pathologies.

A patient with a condition A and  mild B disease, may be prescribed medications M1 and M2 while M1 could handle all the two diseases properly. There is even the risk of drug interactions between M1 and M2, and induced side effects must be addressed with an M3 drug.

Thus one finds nursing home patients to take daily 6 different drugs (or more) to treat conditions with known correlations and also to treat the induced side effects all those drugs.

This debate is as old as the pharmaceutical industry and medicine. All agree that the approach  of pathologies should be systemic but he pharmaceutical industry grows to a systematic approach.


Let us back to the NASH and the metabolic syndrome.


Nash is considered by health agencies as a new disease with no known cure. their first reaction is consistent with what we saw earlier .. We need a treatment, we ask labs to launch studies with their medications, and if they have positive results, they will be given a marketing authorization for treatment of NASH.

Everything will be better in the best of worlds, the cows will be well guarded, each in its field.

But here ... most studies argue, the more we discover that NASH is only the hepatic manifestation of a set of symptoms called metabolic syndrome.

This syndrome is an attempt at a holistic approach to patient health.

What is metabolic syndrome?

To date, (but this rapidly changing), is considered that a patient has the metabolic syndrome if it has at least 3 of the following symptoms:

  • abnormally high insulin levels
  • hypercholesterolemia
  • hypertension
  • excess weight mainly in the case of an abdominal obesity
  • hyperglycemia


Now we talk of NASH and may soon add to these symptoms, the inflammation measured by the protein C-reactive and interleukin 6.

The causes of metabolic syndrome are essentially eating large amounts of refined sugar (not related to a plant matrix like a fruit), especially of processed fructose and high glycemic index foods (processed carbohydrates, including starch cooked improperly designated as "slow sugar"), associated with genetic predisposition. But the syndrome could also be the result of more subtle risk factors such as endocrine disruptor affecting fat metabolism.

There is no specific treatment for the metabolic syndrome as a whole, Rimonabant, which targeted this indication was withdrawn from the market because of its side effects.

Yet it is clear that all of these symptoms, although they can occur in isolation, are highly correlated.

But yet, each of these symptoms is treated separately.

  • Insulin resistance is treated in the case of type 2 diabetes or prediabetes by drug treatments such as metformin Seulle or associated with other diabetes or if it worsens with insulin.
  • Hypertension can be treated with diuretics, bétablocants, of Angiotensin converting enzyme inhibitors, calcium channel blockers, antagonists of angiotensin II, etc ...
  • Abdominal Orlistat tries to be treated by changes in lifestyle or in severe cases by bariatric surgery.
  • Inflammation can be multi factorial, the treatments are different. the molecules that specifically target the cellular inflammation mechanism are in clinical study phase.
  • The hypercholesterinaemia is usually treated with statins.
  • NASH has not authorized treatment, Vitamin E and a change of lifestyle inducing weight loss are the current recommendations for treatment.


This set of symptoms is clearly linked to a common metabolic disorder, and yet we still treats the symptoms as alone.

Yet, beyond diseases directly related to these symptoms, such as atherosclerotic disease, stroke, type 2 diabetes and NASH, it is also suspected that metabolic derangement to be the direct or indirect cause of cancer as suggested 'Stephanie Cowey 'of the University of Alabama.


The elafibranor, a new class of drug.

According to the systemic reading of health agencies, The elafibranor, after the first part of its Phase 3, and if the positive results of the disease is confirmed, should obtain a marketing authorization for the treatment of NASH.

Analysts expound on the size of the overall market for NASH, the share of the potential Elafibranor’s market, the likely cost of treatment, the fact that the healths system might not be able to withstand reimbursement of the cost of this new pathology, etc, etc ..

It would be helpful they try a holistic approach to this market.

look at figures found at the mercy of various publications:

  • 70% of patients with NASH are obese
  • 56% of type 2 diabetics have NASH
  • 75% of patients with NASH have type 2 diabetes
  • 25% of Americans have metabolic syndrome
  • more than 25% of the obese have NASH
  • between 20 and 80% of patients suffer from NASH hypercholesterinaemia

 

Although these figures are not always consistent with each other, the correlation between type 2 diabetes, hypercholesterinaemia, obesity and NASH is obvious .. and yet, these patients are treated separately for each of their symptoms.

But if one looks at the published results of the Golden study in Gastroenterology, we can see that the Elafibranor:


  • Induces a reversion of NASH and improves overall liver markers.
  • Reduces resistance to insulin and drops the glycated hemoglobin% (-0.46%) as well as a drug like imeglibin from Poxel (which has other advantages).
  • Significantly improves the lipids profiles, not as well as a statin but still significantly.
  • Reduce markers of cellular inflammation.


It should be noted that, according to the results of the study, Obesity is not impacted by the drug and we have not the figures on the evolution of hypertensive patients (between 47% and 62% patients according to the study arm).

maybe those data will be available in the appendices that will be attached to the paper version of the article that will be published in May.

The improvements of treatment with Elafibranor on the features of metabolic syndrome


It seems obvious that here we have a drug that targets NASH, but which impacts the majority of metabolic syndrome symptoms.

This clearly implies that the drug is not symptomatic treatment but acts on the metabolic disorder that is causing many of these symptoms. This would be an etiological treatment ..


So, to illustrate my point of view, a patient having metabolic syndrome gathering:

  • a pre diabetes (glycated hemoglobin slightly high)
  • a moderate hypercholesterinaemia (cholesterol a bit high)
  • a NASH


The usual logic would dictate that we prescribe:

  • antidiabetic of first intention as metformin (about $ 300 yearly)
  • a diet for cholesterol and if it worsens, a statin (about $ 300 yearly)
  • and a molecule to be determined for NASH (estimated price $ 5000 consensus although analyst comes to predicting a processing cost of $ 12,000 for the OCA in Nash which I find far too high for chronic treatment)


This type of combined treatment is a problem, because without prejudging the interaction of the molecule that would be used for NASH with biguanides and statins, it must be noted that these three molecules are all targeting metabolism and it seems unimaginable there is no interaction between them.

In addition, a recent study (FIELD), has shown that taking statins doubles the risk of appearing a type 2 diabetes in a patient.

A study completed by a third one showed that statin use in a diabetic patient does not reduce cardiovascular risk, which is normally the target of a statin.

Another study speaks of a double-edged sword for statins prescribed in pre diabetic !!!

Is it good idea to prescribe a statin to a prediabetic patient ??

Note that the pre-diabetic and diabetic patients with hypercholesterinaemia are a very large part of the diabetic population.


elafibranor, new perspectives 

Given the results of the studies, which are to be confirmed, one could imagine only prescribe the elafibranor for the treatment of NASH, the treatment of prediabetes and a slight hypercholesterinaemia, and all this without drug interactions !!

Moreover, this would not be symptomatic treatment of these three components but a causal treatment of all.

For treatment treating metabolic disorders, we must relativize the direct cost of treating acceptable by society by examining well the overall benefit of the molecule and not just the benefit from the only symptom targeted, and not forgetting the costs induced by a poorly treated disease.

But if Elafibranor is likely to receive a marketing authorization for the treatment of NASH in 2018, if the phase 3 is a success, and could be eligible for a marketing authorization for the treatment of type 2 diabetes (in terms of clinical outcomes), it would have little chance of obtaining a marketing authorization face to statins in the treatment of hypercholesterinaemia.

Improved lipid balance presented in the results of the elafibranor is unmistakable and consistent but still very inferior to the results of existing dedicated drugs. Treatment of cholesterol alone should therefore not be an indication of elafibranor ..

Everything could change if the metabolic syndrome became a wholly pathology and if elafibranor obtained a marketing authorization to treat a significant portion of the components of this syndrome, all related to the underlying metabolic dysregulation and where the drug appears to have action!

We could imagine, after the publication of partial results of phase 3, an application for an enlarged fields of prescription for elafibranor, beyond the simple NASH with fibrosis.

That is why we will have to carefully observe the detailed design of the study to be published on clinicaltrial.org and scrutinize all the parameters that will be measured during the study to try to guess what prepares GENFIT .


G. Divry

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