NASH! AND NOW?

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This early 2019 saw the landscape of NASH shook strongly. Year 2019 is far from over but can we already imagine the possible evolutions on this future market?


In a few days many analysts have published their comments and forecasts following the publication of the results of the STELLAR 4 trial on SELONSERTIB and the REGENERATE trial on OCALIVA.

In these publications as always, there is the worst and the best.

There are Analysts who lay their opinion without knowing the subject they are dealing with, flying over the subject, relying on 3 years old data’s and obviously disregarding, and drugs competing, and the structuring of the market potential of NASH.

I will not mention those by kindness, I just remind them every week by email, on 'seekingalpha', facebook or twitter the datas and facts they curiously ignore.

Some have a very good knowledge of the disease, they publish very well constructed and well-argued articles, and even if I do not always agree on their conclusions, I can only salute the quality of their job. They are often not professional analysts of big banks but specialized analysts with a confidential diffusion like "Vision and Value" on seekingalpha.

Me, as I recall in each article, I am neither financial analyst nor doctor, I am only what we could call an enlightened amateur, a candid impertinent who shares his research and analysis on his blog.

Despite my limited baggage, I still allow myself to criticize analyzes that seem incomplete or distorted in a utopian quest for truth.

 

To be honest, the results published by GILEAD and INTERCEPT at the beginning of the year did not surprise me. It might be pretentious to say that they were predictable, but a bundle of presumptions should have helped to anticipate them.

GILEAD, on the basis of a not very academic phase 2 study, without a placebo arm and on a ridiculous amount of patients, tried to go into direct force with two phase 3, testing the SELONSERTIB.

The clinical results of phase 2 were all but conclusive and those of phase 3 on cirrhosis are catastrophic. It remains to wait for the publication of the results of phase 3 on advanced fibrosis for confirmation but hopes are slim.

Despite the fact that specialists believe that it is better to validate the clinical benefits of each drug individually before testing them in combo, GILEAD persists in launching clinical studies with drug cocktails that have not proved anything individually.This makes reading the results very difficult. Some will say that's prevent from market sanctions in case of failure, as for the study SELONSERTIB + SIMTUZUMAB which allowed them to use the results to kill the SIMTUZUMAB and start the clinical studies of Phase 3, on SELONSERTIB, based solely on results obtained only on a small subgroup of patients.

We see the result 2 years later.

 

 

The market is a little unfair with the results published by INTERCEPT, there is a marked disappointment whereas if the analysts had done their job correctly they could have tempered the ardor of the investors on the sole basis of the analysis of the results of the previous trials.

Notwithstanding the facial values of the success rates obtained, the results of the OCALIVA in NASH are in my opinion exactly those to which INTERCEPT could have claim. In FLINT, Phase 2b, a statistically significant decrease in fibrosis was observed in the ITT population and is confirmed in phase 3 with REGENERATE.

Similarly, no resolution of NASH (old and new definition) was found on the ITT population in phase 2b, and it is the same in phase 3.

The populations profile of the two trial were quite close (85% of patients with FLINT had F1 F2 or F3 grade fibrosis), the difference may be in the huge bias that the FLINT trial suffered from, which I largely commented on here in its day.

The results of the trial can be ruled out at 10mg / day!  As soon as the Japanese study was published, I had highlighted the very low probability that this dose would be effective in NASH

 

Some analysts find the results in fibrosis worse in phase 3 than in phase 2, this is not my opinion.

It is necessary to be careful not to look at the single figure of decrease of fibrosis under OCALIVA . But the ratio between spontaneous drops under placebo and those under OCALIVA.

This ratio is better in phase 3.

PHASE 2b: OCALIVA 35% vs PLACEBO 19% p = 0.004        Ratio = 1.8

PHASE 3: OCALIVA 23.1% vs PLACEBO 11.9% p = 0.0002   Ratio= 1,94

On this point, OCALIVA has not been unworthy. 

Before publication, INTERCEPT had sent the press its expectations on the basis of a panel of FLINT patients who were close to the one recruited in REGENERATE.

Post hoc Phase 3 like, based on Phase 2b patients: OCALIVA 39% vs PLACEBO 21% p = 0.007 Ratio = 1.85

As we can see again the OCALIVA/placebo ratio is better in phase 3 than in the expectations.

The main drawback is in the side effects! OCALIVA is twice as bad in pruritus and a little less good for the increase of LDL, this strongly limits the potential for use of the drug but as we will see later there are combo's solutions to offset these effects.

 

AND NOW ?

We will start by waiting without illusions the results of phase 3 STELLAR3 of SELONSERTIB within a few months.

Concerning OCALIVA, INTERCEPT will ask for a marketing authorization for OCALIVA in NASH with advanced fibrosis in the second half of the year with a possible obtaining and placing on the market at the beginning of 2020

For this, INTERCEPT will face two major difficulties.

As much as it seems likely that INTERCEPT can convince the FDA, it will be more difficult to convince the EMA that its intermediate results are sufficient to qualify for markey authorization.

Recall that the EMA has made it clear recently in its interim document on NASH trials and endpoints that for intermediate outcomes, a 2-stage decrease in fibrosis seemed necessary to obtain authorization:

"If an intermediate endpoint strategy is used in such compounds, it is currently recommended to use a stronger endpoint as a composite at the individual patient level such as" fibrosis regression of at least 2 stages without worsening of NASH ", in which stage 2 fibrosis patients would need to achieve complete resolution of fibrosis, and patients with stage 3

 15 November 2018 EMA / CHMP / 299976/2018

 The lack of market treatment and the health emergency may be enough to weaken the EMA position, but nothing is gained so far. The lack of access to the European market, equal in size to the US market, would be highly detrimental to the sales of OCALIVA.

 

The second problem that INTERCEPT will be facing is  the price of treatment:

Currently OCALIVA is sold in the PBC for an annual cost of about $ 70,000.

It is not conceivable for OCALIVA to be distributed at this price in NASH, the size of the affected population as well as the relative benefit of the molecule will not allow the payers to accept this cost.

The analysts mention for the treatments of NASH a consensual annual price of $ 15,000 in NASH in the US, and $ 8,000 in Europe.

In NASHBIOTECHS market forecast calculations, I was even more conservative and estimated that the average selling price of drugs specifically targeting fibrosis would be only $ 1,000 per month in the US, or $ 12,000 for just $ 8,000 in Europe.

We understand quickly the problem, INTERCEPT will not be able to continue to sell doses of 5 and 10 mg to $ 70 000 in the PBC, if they sell 25 mg doses for $ 15 000, patients know how to cut tablets in piece!

With the price of $ 15,000 for 25 mg, a 5 mg treatment in PBC will be $ 3,000 or 10 to 20 times less than currently, less expensive than the generic drug UDCA. 

INTERCEPT is therefore facing a big dilemma, the launch of OCALIVA in NASH-induced fibrosis can divide by 20 its income from PBC. It will be interesting to see how they will solve this problem.


The big wait is now for the ELAFIBRANOR Phase 3 results to be released next fall.

As we did for SELONSERTIB and OCALIVA, we can try to imagine the results of ELAFIBRANOR in phase 3 on the basis of previous studies.

Contrary to what many analysts continue to believe, ELAFIBRANOR has achieved a statistically significant resolution of NASH on the GOLDEN ITT population (Phase 2b) and without any statistical reprocessing.

This success was achieved with the new definition of reversion of NASH, as currently used in Phase 3 studies (the old definition was more lax and had artificially led to a large number of spontaneous reversion in placebo patients, who which initially disturbed the readings of the phase 2b results ).

This success was obtained in a population including 15% of NAS 3 patients without fibrosis and therefore much less favorable than the population recruited in phase 3 (NAS> = 4 with Fibrosis F2 - F3). The analysis of the results having shown that the efficacy of ELAFIBRANOR increased with the severity of the disease.

These earlier results make it possible to approach the future phase 3 results with confidence even if, as we know, nothing is sure in terms of clinical studies.

The drug therefore targets, unlike SELONSERTIB and OCALIVA, the heart of the disease. It is an etiological treatment and not a symptomatic one. So it is intended to serve as a backbone treatment to which it may be added complementary treatment, specifically anti-fibrotic.

What is very interesting to note is that, in addition to its total safety, ELAFIBRANOR has demonstrated an action on the decrease of LDL, on the decrease of hyperglycemia, and on pruritus.

Given the latest results of OCALIVA, it seems the ideal candidate for a combined prescription. There is even a preclinical study demonstrating a synergy between the two molecules to lower the equivalent effects.


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If the results of the ELAFIBRANOR are at the rendezvous, It may be that for once, the luck is on the side of the patients, because if one can imagine, in the case of a co-prescription of the two drugs, that it is possible to lower the doses of OCALIVA and at the same time compensate the side effects of pruritus and elevation of LDL, while treating metabolic NASH and lowering fibrosis, then practitioners would be offered a new therapeutic tool close to their expectations.

And this, 3 years before any new competition on the market.

Of course if ELAFIBRANOR's results on fibrosis are positive, OCALIVA’s future could be jeopardized !

It may be time for observers, analysts and investors to objectively examine what tomorrow's winners' strategies might look like with today's data.



G Divry 2019

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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