A SECOND  ANALYSIS ON THE INTERCEPT PHASE 2 ON NASH IN JAPAN (by Gery DIVRY)

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OCA  FAILED TO PROVE EFFICACY ON NASH AND FIBROSIS IN JAPAN


We had some informations, in the INTERCEPT's published results. but SUMITOMO published by itself the 9 of december 2015 more informations on the OCA japanese study ( from page 25 to 30)

Regarding those new data,  the study is a big failure in NASH


The clinical study in Japan was designed with 4 arms

50 patients in each arm 

  • One placebo
  • One 10mg/d OCA
  • One 20mg/d OCA
  • One 40mg/d OCA

 

The main endpoint is se same as FLINT : the reduction of 2pts of the NAS score with no worsening of fibrosis

one can notice that this criteria was not accepted by the FDA who ask now for a NASH reversion criteria, more difficult to reach.

The results published on the initial endpoint today are the following:

 

It is not easy to read this figure because the p values at the bottom are not computed on the same statistical treatment than the p value on the right of the figure

A first reading is a failure of the study with no statistical significance evidence but we should examine the details to see the positive in thoses results


The 10 mg arm is a failure : 22% OCA vs 20% placebo mean no measurable effect of OCA on the NAS score reduction.

It would be a problem because the endpoint of the Japan study (NAS improvement ≥2 points  with no worsening of fibrosis)  was not as difficult to reach as the endpoint of the future Phase 3 REGENERATE  (NASH reversion with no worsening of fibrosis ) and one arm of the future REGENERATE study will be also a 10mg/day dose.

Regarding those results it would be very difficult to reach the endpoint on this arm in the future Phase 3.

 

The 20 mg arm is still a kind of failure :  28% OCA vs 20% placebo is a very limited effect RR =1,4

the Pruritus was high and consistent with the FLINT Study (24%)

It is the dose approaching the dose used in the FLINT Study ( 24mg)  and curiously the results are very different it can maybe explained by the ethnicity ot the patients

 The press release include à statement on that point

“There were distinct differences in baseline characteristics in this study population when compared to the Western patients in the previously conducted FLINT trial »

 

The 40 mg arm is interesting: 38% OCA vs 20% placebo is a significant effect RR =1,9 but the Pruritus was very high (50%)  and 13 patients on 50 discontinued the study (26%)

We do not have the lipidic balance induced by the treatment but they declare the changes in lipid parameters, including LDL-C, HDL-C and triglycerides, appeared to be consistent with previously reported lipid changes in Western NASH patients.

This is not good news to my opinion because they do not say if the increase of LDL is correlated to the dose.


Two possibilities:

1 - They are talking about average change on all the arms and it could mean that the 10 mg arm patients had small lipidic balance changes, and the 40 mg arm had bigger changes than in the FLINT Study.

2 - The changes are not dose dependents

In the both cases, it is a bad news :

In the Phase 3 they planned a 10mg arm, explaining that they would have less side effects on lipidic and pruritus. If it is the case we see now that they also have less effect on NASH .. so I am not sure they will still go on that arm in REGENERATE.

And if they have a better effect on NASH with the 40 mg dose they have more adverse effects too. They declared the 10% of the patients discontinued the treatment in the 40 mg arm because of pruritus.


The press release confirm the failure of the study

Dose-dependent trends not reaching statistical significance were also observed for several other pre-specified histologic endpoints, including the proportion of patients with steatosis and inflammation improvement, ballooning resolution and NASH resolution. No difference was seen in fibrosis improvement in the OCA groups compared to placebo.


Failure even in fibrosis wich is the OCA advantage alleged by Intercept .. the bias we discovered in th FLINT study seems to be confirmed by the Japanese study on OCA .. 


OCA FAILED IN ALL DOSE TO PROVE ANY IMPROVEMENT IN FIBROSIS !!!


In NASH REVERSION wich is the criteria requested now by the FDA and applied in the future Phase 3 REGENERATE the results are disastrous .


OCA FAILED IN NASH REVERSION FOR ALL DOSE AND ALL REVERSION DEFINITIONS !!!

THOSE TWO CRITERIAS (REVERSION AND FIBROSIS) ARE THE CRITERIAS SELECTED BY INTERCEPT AS ENDPOINTS IN « REGENERATE »  THE STARTING PHASE 3 FOR OCA IN NASH !!!



THE PRURIT IS CONFIRMED AS A REAL PROBLEM FOR A CHRONICAL TREATMENT



SO ! What is the real effect of OCA on NASH .

When you know all the bias of the FLINT study you can be very pessimistic because the Japan results do not confirm any of the supposed positives FLINT results. 

To my opinion, the only good news  is the supposed proved Effect/Dose relation wich would be a proof of OCA efficacy on the disease, but the doses needed to obtain results are not possible to use because of the strong adverses effects. 


INTERCEPT is wedged between a minimum dosage to be effective and unmanageable side effects at this minimum.


Analysts very involved ( and positionned) on the value declare those results Irrelevants?

I dont agree with them, it is so easy to declare irrelevant a study wich is not positive for Intercept , but they reacted as usual, protecting the value against evidences.. why ?

The absence of results in Japan should be explained quikly otherwise the path to success on the NASH market will be very tiny.


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