COMMENTS ON THE PUBLICATION OF GOLDEN STUDY RESULTS
 By Géry Divry

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 Youl find here some extracts from the original article:

Ratziu V, Harrison S, Francque S, Bedossa P, Lehert P, Serfaty L, Romero- Gomez M, Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee Q, Hum D, Hanf R, Roudot A, Megnien S, Staels B, Sanyal A, on behalf of the GOLDEN505 investigator study group, Elafibranor, an Agonist of the Peroxisome Proliferator-activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening, Gastroenterology (2016), doi: 10.1053/j.gastro.2016.01.038. 


Elafibranor, an Agonist of the Peroxisome Proliferator-activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening,

My Comments are in Blue


INTRODUCTION

Of all chronic liver diseases, non-alcoholic steatohepatitis (NASH) is of increasing concern, as it is highly prevalent, potentially severe and without approved therapy. NASH defines a subgroup of non- alcoholic fatty liver disease where liver steatosis co-exists with hepatic cell injury (apoptosis and hepatocyte ballooning), and inflammation 1. It occurs in close association with overweight/obesity, type 2 diabetes and cardiometabolic conditions that define the metabolic syndrome 2. Because of the prevalence of these comorbidities, NASH is emerging as the most common chronic liver disease  

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No specific comments on the introduction recalling the context of the rapid development of the disease and the need to find treatments

 

METHOD

  

Study design

This international, multicenter, randomized placebo-controlled study tested elafibranor at the dose of 80mg and 120mg QD vs. placebo over 52 weeks and was conducted at 56 sites, 19 in the United States and 37 in 8 European countries. The study had a staggered design as requested by the regulatory agencies to test the safety of elafibranor over a 6 month period at the lower dose before exposing patients for one year the highest dose. During the first recruitment phase, 172 patients were screened between September 2012 and June 2013 for treatment with 80mg/d of elafibranor or placebo (allocation 2:1). The second recruitment period at the dose of 120 mg/d started in July 2013, when 179 patients were screened in 1 week. 

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Useful reminder when we know that some experts considered, as Dr. Dohit Looba in a recent interview, that this spread 80 mg and 120 mg was due to poor design of the study.

 

Patients.

The inclusion criteria included: age 18-75 years and a histological diagnosis of non-cirrhotic NASH confirmed by a central pathologist. Patients were excluded if daily alcohol consumption was higher than 2 drink units/day (equivalent to 20 g.) in women and 3 drink units/day (30 g.) in men, if steatohepatitis was due to secondary causes, or if any other chronic liver disease was identified. 

The internationally recognized threshold that distinguishes an alcoholic steatosis to nonalcoholic one is respected here. An interesting article for understanding the problems of these thresholds  is available HERE for those interested

 

Randomization and masking

Randomization was obtained through a computer generated coding list, and treatment allocation was performed centrally for all sites 

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No stratification was made on investigation sites. Elafibranor and placebo were provided as identical capsules in wallets labeled with code numbers. Patients, investigators, clinical site staff and the pathologist were masked to treatment assignment. 

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We are here in the definition of "double blind": neither the doctor nor the patient knows if the pill is the drug or placebo. Note the reference to the lack of stratification by site that will be corrected in phase 3 as it was at the origin of the effects of unbalanced centers that disrupted the reading of study results

 

Procedures.

Patients were followed every 2 months with clinical and laboratory evaluations throughout the one year treatment period. An end-of-treatment biopsy and a 3-month post-treatment follow-up visit were performed. Screening and end-of-treatment biopsies were all read centrally by a single pathologist in a blinded manner (PB). At end of study, all slides (baseline and end-of-study) were read in scrambled order. 

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Non-invasive panels for steatosis or fibrosis (Fatty Liver Index, SteatoTest, Fibrotest and the NAFLD Fibrosis score) were measured at baseline, 6 months and 12 months (end of treatment). Biological assessments were all centralized and performed at each visit for efficacy and safety purposes 

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On this point, the methodology was more stringent than the FLINT study. It included a centralized reading of biopsies and serology.


Outcomes

The primary outcome was reversal of NASH without worsening of fibrosis. This was defined as per protocol, before study start, as the absence (score of 0) of at least one of the 3 components of NASH, i.e. steatosis, ballooning, and inflammation; worsening of fibrosis was defined as the progression to bridging fibrosis (i.e. stage 3) or cirrhosis in patients without bridging fibrosis at baseline or to cirrhosis in patients with bridging fibrosis at baseline

After the study was completed a modified and more stringent definition was proposed by academic and regulatory experts and recommended by regulatory agencies for ongoing trials. It defines resolution of NASH as disappearance of ballooning (score=0) together with either disappearance of lobular inflammation or the persistence of mild lobular inflammation only (score=0 or 1) and resulting in an overall pathological diagnosis of either steatosis alone or steatosis with mild inflammation; any stage increase in fibrosis is considered fibrosis progression. Because this more stringent definition is now used for current and future trials, we will here report on both the protocol-defined and the post-hoc analysis of the modified definition. 

This point is very important: it explains well the rigorous analysis of the results according to the two definitions of the reversion. One that was consensus at the beginning of the study and included in the protocol, and the more strict, consensually appeared at the end of the study required for future studies.

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Secondary outcomes included: changes in NAS between end-of-treatment and baseline biopsy (including the proportion of patients with a 2-point decrease); changes and improvements in individual histological scores of steatosis, ballooning, inflammation, and fibrosis; changes in liver enzymes, in non-invasive markers of steatosis and fibrosis, in lipid and glycemic parameters, in surrogate markers of insulin resistance (fasting insulin and HOMA scores); changes in systemic inflammatory markers; safety and tolerability of elafibranor at both doses. 

It is also important to understand that the secondary criteria are very important for a poorly understood disease which, as we have seen, the definition changes with the knowledge.

Furthermore, we shall see later that the results on liver markers are very important, if not more, than the simple histological score with a large variability that makes its very shuffle if taken alone.

 

Statistical methods

The main selection was the population of all randomized patients that received at least one dose of study drug (Intention to treat, ITT sample). To assess the robustness of findings sensitivity analyses were performed using the per protocol population (PP) defined as the ITT population with available liver biopsy at the end of the study. For sensitivity purposes, four post-hoc selections were considered: (1) Patients with bNAS>4 (moderate or high disease activity) which are similar to those included in previous NASH trials 11, 21; (2) Patients with bNAS>4 and fibrosis of any stage at baseline; (3) patients with bNAS>4 and fibrosis stage 2 or higher at baseline (target patient population for current phase 3 trials) and (4) patients with bNAS>4 recruited in centers that randomized at least one patient in each treatment arm (justified by the strong treatment-center imbalance)

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I'm not an expert on statistical methods, if a player masters the subject he can put a comment at the bottom of this article

 

Role of the funding source 

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No comment


RESULTS

A total of 276 patients were randomized, 92 in the placebo group, 93 in the elafibranor 80mg group and 91 in the elafibranor 120mg group 

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Results of the secondary histological outcomes  show no significant difference between elafibranor and placebo. Nonetheless, the efficacy of the 120mg dose to reduce the NAS by 2-points and to improve steatosis, ballooning, and lobular inflammation was more pronounced with increasing baseline severity, in contrast to the absence of a clear pattern in the placebo or 80mg groups.

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Here, the reminder of the lack of significance of the results for the histological criteria and for the total population integrating NAS 3 with the old definition of reversion 

BUT significant for the 120 mg dose with the new definition of reversion NASH that will be used for future clinical studies. 

According to this new definition which is the criterion for the Phase 3 study, the GOLDEN study is successful on the entire sample of patients treated with a 120mg dose (NAS 3 included) and with no statistical reprocessing .


A number of post-hoc, secondary analyses were performed. Importantly, there was a strong interaction effect between baseline severity and elafibranor dose which was significant for 120 mg for both the protocol-defined (OR:2.63, 95%CI[1.25-5.52], p=0.012) and modified definition (OR:2.76, 95%CI[1.33-5.76], p=0.007) 

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The significant interaction effect with baseline severity indicated that the efficacy of elafibranor 120 mg vs. placebo increased with baseline severity. Hence the exclusion of patients with mild disease activity (bNAS=3, N=40) revealed a significant direct effect of elafibranor 120 mg vs. placebo (OR=3.16, 95%CI [1.22-8.13] and 3.52, CI95%[1.32-9.40], for the protocol-defined and modified definitions, respectively) in the remaining population of 234 pts with bNAS>4 (85% of the ITT population);  

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Overall, the 120 mg elafibranor dose doubled the proportion of responders vs. placebo in patients with bNAS>4. 


The correlation between the severity of the disease and the effectiveness of elafibranor is raised by removing the patients with mild disease (NAS 3) On this sample reduced to 85% of the initial sample, the study shows a significant efficiency elafibranor on the reversion of NASH with the old and the new definition of reversion.


Overall, the 120 mg elafibranor dose doubled the proportion of responders vs. placebo in patients with bNAS>4. 

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 Because of a heterogeneous center effect and the unbalanced treatment-center distribution (due to the staggered design and an unexpected high rate of recruitment), we performed an analysis in the subset of bNAS>4 patients recruited in centers that randomized at least one patient in each treatment arm (N=120, Supplementary Table 4). The response rates were 29% and 26% (protocol- defined and modified definitions) vs. 5% placebo (p=0.01 and 0.02, respectively). 48% of patients improved the NAS by >2 points (vs. 21% in the placebo arm, p=0.013). 

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The unbalanced center effect is well explained here: this will be resolved in phase 3 where the centers will all be balanced

 

Finally, we tested whether patients that achieved resolution of NASH without worsening of fibrosis in the 120 mg elafibranor arm also experienced improvement in fibrosis. shows strong reductions in fibrosis, hepatocyte ballooning and the NAS (all p<0.001) as well as in lobular inflammation and steatosis (both p<0.05), when compared to non-responders to the same regimen. These findings were similar with both definitions of response. 

This is very important because it confirms what several experts expressed for some time: The patients that treated their NASH naturally see their fibrosis to regress , so no need for a specific antifibrotic. We must treat NASH first

 

/ Patients treated with both elafibranor doses (80mg and 120mg) improved liver function tests (ALT, GGT and alkaline phosphatase,) and lipid parameters (triglycerides, LDL- cholesterol, HDL-cholesterol,). In diabetic patients (40% of the EES population) elafibranor improved fasting serum glucose (-0.98±0.56mmol/L for 120mg vs. placebo, p=0.08) and HbA1c (-0.46% for 120mg vs. placebo, p=0.038,) as well as markers of insulin resistance (fasting insulin) /




This should be read and reread, it is to my eyes the most important of all: it is essential to read the very didactic article from Albert Wright that explains  the implications of these measures. 

Liver biopsy is by default the 'Golden Standard’ for NASH diagnosis and severity but the very high reading variability may lead to false negative detection or very important false positives (a study talking about 50%).

The rate of patients achieving histological reversion proven by biopsy is approximately 20%, twice the placebo, which might suggest a moderate effectiveness of elafibranor but simultaneously there is an improvement of all markers liver of all treated patients. The improvement of all these markers is a clear sign that the liver is healing, which seems contradictory with only 20% of reversions observed histologically. Two conclusions. Either biopsies performed poorly reflect the actual improvement of liver status (size or the biopsy site variations) , or the processing time was too short for improvements to improve liver histology. For me, the answer is a combination of both, and a longer duration of the phase 3 study should view seriously increase the rate of histologically observable reversions. 

 

/ Elafibranor was safe and well tolerated. Clinical adverse events were mostly mild and similar in the placebo and elafibranor arms. There were no cardiovascular events or deaths in the elafibranor arms. /...


 / ...Neoplastic SAEs were reported in 6 patients during the study and the 3-month follow-up periods: one bladder cancer in the elafibranor 80mg arm (unlikely related to study drug), in a patient with previous doubtful cytological lesions, and 5 cancers in the placebo arm (the four described above and one esophageal cancer considered unlikely related to study drug).  /...

 

These points are important because they emphasize the safety of elafibranor.

The point to watch is the slight increase in creatinine and the fact that several elafibranor treated patients had defects in renal function. It is specified that these patients had elevated creatinine before the start of the study, which could be a sign of a previous kidney problem which was exacerbated by treatment.

The final point that should not be statistically significant, even if it still seems to emphasize, is the number of cancers that are declared by the arm during the study.

5, for the placebo arm

1, for the arm 80 mg / d

0, for the arm 120 mg / day

The purpose of the study was no way to identify in vivo anticancer effect of elafibranor already noted in an in vitro study, but it still seems that this track is to explore, because these figures challenge.

 

 

 

 

DISCUSSION

This randomized controlled trial provides evidence of efficacy of the dual PPARα/δ activator elafibranor on both histological reversal of NASH and metabolic improvement in patients with NASH. Both are important objectives on the path of controlling NASH. Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD 5, 23. It drives fibrogenesis, a slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver failure, portal hypertension and hepatocellular carcinoma. Consequently clearance of steatohepatitis 24, i.e. reversal to a normal liver or to steatosis without steatohepatitis -a condition not associated with increased hepatic morbidity or mortality-, is expected to improve hepatic prognosis and is now accepted as the best, short-term surrogate for histological improvement in NASH trials 

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The authors of the article here clearly express their belief about the effectiveness of elafibranor. They put out the importance of correlating metabolic and histological results in their analysis

 

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Second, based on older data showing that bridging fibrosis but not earlier stages is associated with liver-related mortality23, 27-29, only progression to bridging fibrosis (or to cirrhosis) was considered "worsening of fibrosis" in the protocol-based definition. Instead, the modified definition defines worsening of fibrosis as any one stage increase based on recent data showing that even early fibrosis is associated with global and liver-related mortality7

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This is interesting because it shows the evolution of the consensus. initially only NASH with fibrosis F2 orgreater than seemed likely to be treated, while the latest studies show that the risk remains significant for patients with any type of fibrosis this implies that F1 patients are likely to be reinstated in the patients to be treated ..

 

 

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Importantly, this more stringent definition led to a lower placebo effect. 

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This shows that the new definition of strict and demanding reversion does not reduce the number of patients reaching the reversion criterion under the old definition, but did strongly reduce the number of placebo patients who appeared to have healed spontaneously and therefore eliminates a number of false positives that disrupted the reading of the study. This implies that these new criteria seem more relevant

 

 

 

/ Regardless of the definition of response, elafibranor at 120 mg was significantly superior to placebo in the post-hoc analysis after excluding the 15% of patients with mild steatohepatitis (i.e. bNAS of 3). 

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As well, the observation that elafibranor is more efficient in more severe disease is consistent with recent data showing that hepatic PPARα expression is reduced in advanced inflammatory and fibrotic NASH and that resolution of NASH is associated with a recovery of PPARα expression

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Again, the authors of the article here clearly find the effectiveness of elafibranor.

 

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The two previous large trials in NASH that had NAS reduction as a primary outcome, only included patients with a NAS of 4 or higher 11, 21 and current practice for drug development is to include only patients with moderate or severe disease defined by a NAS4. 

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The authors emphasize the effectiveness of elafibranor found on a similar population to that of other studies, and especially remember that the improvements in metabolic parameters and leading indicators are more sensitive and predictive signs of subsequent histological improvement.

To me, this suggests a much greater responder rate in Phase 3 as in phase 2b

 

 

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In order to randomize 270 patients, 56 sites were selected, with competitive recruitment and centralized randomization. Due to the unexpectedly high recruitment rates and the staggered design, treatment distribution across the sites was imbalanced.  

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Interestingly, the 21% response rate of the placebo arm for a 2-point NAS reduction is comparable to previous studies thus suggesting that this subgroup of the population is representative of patients included in previous trials.

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The authors point out the relevance of retreat unbalanced centers by noting that statistically this more homogeneous population gets a response rate of improvement of two points of the NAS score of placebo consistent with other studies, which confirms the statistical relevance of this population.

NB: please note that this retired population, then the responder rate of elafibranor is close to 30%

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Since prevention of the occurrence of cirrhosis is the ultimate goal, both from a clinical and a regulatory standpoint 26, drug therapies for NASH should ideally impede fibrogenesis, either directly or indirectly, as a consequence of clearing steatohepatitis.. 

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Responders for the primary endpoint, at the 120mg elafibranor dose, experienced a significant reduction in fibrosis, which was not seen in the overall group of treated patients. Whether a direct anti-fibrotic potency of elafibranor, reported in experimental murine models of fibrosis 16, can be reproduced in humans deserves specific testing in longer trials. Future phase 3 trials will evaluate the effect of elafibranor on the rate of progression to cirrhosis as a result of the resolution of NASH or also through a direct anti- fibrotic effect. 

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Very important: the authors find an indirect anti fibrotic effect related to the resolution of  NASH but do not rule out a direct antifibrotic effects of elafibranor in humans  as this effect was already found when tested on mice. They recommend that this approach be explored during the longest phase 3, which is actually anticipated by GENFIT

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An equally important aspect when treating patients with NASH is the requirement for absence of deterioration (or at best improvement) of the cardiometabolic comorbidities that contribute to overall mortality 25, 26. Moreover, insulin resistance, an almost constant feature of NASH, could be causally related to the hepatic build-up of fat, induction of lipotoxic compounds within the liver and systemic and adipose tissue inflammation. 

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Remarkably, the improvements in glycemic and lipid parameters were achieved in patients already treated with conventional glucose and lipid-lowering therapies which suggests an additional, direct effect of PPARα/δ agonism.  

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The effect of cholesterol on elafibranor was complementary to that produced by statins, which opens a complementary therapy to track the treatment of cholesterol, because the mechanism of action of elafibranor on the lipid profile looks different.

And THAT is also true for the insulin resistance: the elafibranor effect stacks with existing treatments ... a standalone track opens for the treatment of diabetes … to follow


It is interesting to note that contrary to placebo-induced resolution of NASH, patients that met the primary endpoint on elafibranor also exhibited a greater degree of improvement of metabolic and inflammatory parameters than non-responders. The temporal interaction and dose-dependency between the metabolic effects and the histological response of elafibranor remains to be elucidated in larger trials. 

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You have to read this topic  on histological false positive and false negative placebo treated patients. Analysis leads logically to imagine that the effective response rate of patients with elafibranor well above the 20% observed histologically.

 

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Elafibranor showed a very good tolerability and safety profile throughout the one year exposure in this trial. This is of paramount importance as NASH therapies are expected to be taken on a long term basis. Moreover, these patients often have asymptomatic liver disease and therefore are less willing to tolerate drug-induced side-effects in the long-term. 

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Here is one of the critical advantage of elafibranor on OCA

 

This trial has several other strengths and some limitations. The rigorous centralized pathological reading for both inclusion and end-of-treatment biopsies avoided inclusion of patients without clearly defined NASH 24 and provided uniformity and lack of inter-observer variability for the assessment of histological endpoints. The proportion of screen failures for histology was low, thus ensuring that included patients were representative of most real-life NASH patients seen in tertiary centers. 

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Is that a subtil critcism of the FLINT Study ?? mmm

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Importantly, a detailed definition of "resolution of steatohepatitis" is not available from FLINT or PIVENS. In addition, there was no requirement for the absence of “worsening of fibrosis” when defining resolution of NASH as an endpoint for either PIVENS or FLINT, which further limits comparisons between rates of response with the GOLDEN trial 

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Comparison is not reason … but the absence of reversion definiton in the REGENERATE Ph III study conducted by INTERCEPT is curious ! 

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Only large, phase 3 trials will provide reliable estimates of treatment response for obeticholic acid and elafibranor, but what is clear so far is that a majority of patients are non-responders and that additional pharmacological strategies will be necessary to optimize the response rate. 

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This is important because they clearly express the need for a treatment panel to cover the diversity of NASH. On this subject, read my article on treatment strategies

 

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In conclusion, this randomized controlled trial provides evidence that pharmacological modulation of the PPARα/δ nuclear receptors results in substantial histological improvement in NASH, including resolution of steatohepatitis, and improvement of the cardiometabolic risk profile, with a favorable safety profile. Larger phase 3 trials of elafibranor in the target population of patients with moderate to severe NASH are warranted. 

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What's more, the conclusion is clear: elafibranor is effective against NASH and this is now scientifically proven

 

 

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