PAGEREFERENCE | NASH BIOTECHS | www.nashbiotechs.com

NAME OF DRUG : ELAFIBRANOR

ALSO KNOWN AS : GFT505

LABORATORY : GENFIT

STATUS AND ADVANCEMENT

Type of drug : dual PPAR alpha delta agonist

Clinical trials advancement : Recruiting Phase 3

The drug got the Fast Track Status granted by the FDA and is eligible for Subpart H on intermediate results of Phase 3

Estimated time to market : 36 months.

LABORATORY ABSTRACT ON THE DRUG

Elafibranor (GFT505) is GENFIT's lead pipeline product. Elafibranor is an oral once-daily treatment, and a first-in-class drug acting via dual peroxisome proliferator-activated alpha/delta pathways to treat nonalcoholic steatohepatitis (NASH). Elafibranor is believed to address mutliple facets of NASH, including inflammation, insulin sensitivity, lipid/metabolic profile, and liver markers.

HISTORY AND ANALYSIS

GENFIT's LEADING PRODUCT, ELAFIBRANOR (GFT505)

Elafibranor is the generic name accepted by the World Health Organization in June 2015 for the molecule developed by the GENFIT under the code name GFT505.

This name reveals a new root "FIBRANOR" which positions the Elafibranor as the first member of a new class of drug.

Elafibranor is a new dual activator of the nuclear receptors PPARα/δ having multiple properties: modulating plasma glucose and lipid levels, anti-fibrotic, anti-inflammatory affects and other properties being studied.

According to the GENFIT website, Elafibranor has demonstrated:

- Improvement in markers of hepatic dysfunction, including liver enzymes: ALT, AST, GGT, and ALP
- Improved insulin sensitivity and glucose homeostasis
- Beneficial effects on plasma lipids, with a reduction in triglyceride and LDL-C and increased HDL-C levels
- Anti-inflammatory effects
- Beneficial effects on histological parameters NASH (steatosis, inflammation, fibrosis) in animal models - anti-fibrotic activities
- A very good safety profile with no unwanted side effects in clinical trials (reinforced profile in toxicology studies with up to two-year carcinogenicity studies).

The molecule that was initially developed to target diabetes was, because of its multiple action redirected for the treatment of NASH ( metabolic nonalcoholic steatohepatitis), a rapidly developing metabolic disease with no known treatment.

in 2014 GENFIT got from FDA the FAST TRACK Status for the Elafibranor in the treatment of NASH disease.

In many preclinical studies (on animals), the drug was tested and demonstrated strong effects on NASH disease which induced antifibrotic effects, so the results of the Phase 2b were eargerly awaited.

KNOWN RESULTS

SAFETY STUDIES

Aware that the safety of the drug is essential for chronic treatment of patients already suffering from multiple diseases, GENFIT, in contrast to the majority of its competitors, has previously conducted or during Phase 2b, a number of other studies have confirmed the safety and absence of significant or dangerous side effects.

Phase I Study to Evaluate the Effect of GFT505 on QT/QTc Interval in Healthy Volunteers

Comparative Bioavailability - Gender Effect - Single and Multiple Ascending Dose Safety and Pharmacokinetic Study of GFT505

Mass Balance Study of 14C-labelled GFT505 in Healthy Volunteers

THE CLINICAL STUDY - 2B PHASE - « GOLDEN"

The study of Phase 2b was entitled GOLDEN with a duration of 52 weeks integrating Originally 270 patients, included three balanced arms, placebo, ELAFIBRANOR 80 mg / day and a ELAFIBRANOR to 120mg / day, all orally. GENFIT was the direct sponsor of this study.

At the end of March 2015 GENFIT announced the first results of this study, which were, in contrast to those of INTERCEPT very unwelcomed, the day after the announcement, GENFIT's share price lost 40% of its value.

THE RESULTS OF THE STUDY ARE PUBLISHED HERE

One cause of this stock disaster was, to my opinion, the shape and excessive honesty of the press on the results and concerted action market for stopping value.

The study included patients with GOLDEN NASH NAFLD with a score of 3 to 8 inclusive while studying Intercept excluded the NAS score <4. This inclusion, which had been validated by the FDA, these little ill patients played a trick on GENFIT. Indeed this small group of patients (15%) had the bad idea to heal all alone with placebo and lifestyle advocated in this type of study. Thus the statistical impact of these patients prevented GENFIT to have a statistically significant result in the entire study population. GENFIT, for honesty, has placed this point early in his press release, and this was immediately and opportunely announced by some as a complete failure of the study.

However, if the NAS score = 3 patients had sealed the statistical impact of the results, GENFIT had anticipated this possibility and had discussed with the FDA, even before the results of the study, statistical treatments used to rule a subpopulation if necessary.

This is common practice and regularly accepted, the only requirement being to validate statistical reprocessing prior to accessing data selections to avoid 'ad hoc' and 'post hoc' which could then be considered oriented data manipulation.

In the case of GENFIT two different data restatements were anticipated:

Remove patients with NAS < 4.
Remove the small unbalanced centers (with no patient in each arm) which is also a statistical standard that will be used to create a subset of the criteria of near future phase3. (this was not needed to reach the primary endpoint)

The mere withdrawal of NAS < 4 patients immediately exchange the results of the GOLDEN study, which then achieved its objectives with a statistically acceptable result.

Remove NAS patients with <4 is simply align with the population of INTERCEPT FLINT study had not included in its patient recruitment criteria with a NAS <4.

By removing these patients, it remains to GENFIT 74% of the initial study patients (compared with 71% remaining in the FLINT study of INTERCEPT because of his early stop). It is totally acceptable as a statistical basis and detractors of this method are not without ulterior motives.

The main end point of the study was the reversion GOLDEN NASH no worsening of fibrosis.

On an identical population to the FLINT study, GOLDEN study GENFIT has succeeded in 52 weeks on this criterion (22.4% vs 12.7% GFT505 placebo, p = 0.046, RR = 1.9) when INTERCEPT had failed in 72 weeks on this identical criterion.

We have not all the results of the GOLDEN study, which will be published shortly and that will give us more material to analyze, but the other information previously released on the results are very encouraging.

The results obtained are on the dose to 120 mg / day, the dose to 80 mg / day did not show any statistically sufficient effects, but the correlation of the two was able to demonstrate the dose / effect relationship of ELAFIBRANOR, this which is an essential factor in clinical studies and accepted a proof of the effectiveness of a drug.

The ELAFIBRANOR is significantly lower LDL and HDL levels up, it increases the sensitivity to insulin, and even if it does not show, the whole population, histological improvement of fibrosis , the set of metabolic markers of fibrosis is decreased sharply. According to experts, the 52 weeks of treatment were too short to hope for a significant reduction of fibrosis histologically, but the metabolic results make it possible to seriously consider a potential regression of fibrosis beyond 72 weeks.

A few days after the news release and when financial analysts were bent on value, a prominent scientist, a leader in the study of NASH, Professor Jean François Dufour, Switzerland, wrote in a tweet: « GFT505 which is a dual PPARα/δ agonist shows impressive results in phase 2b randomized controlled clinical trial »

In a publication in Hepatology (October 2015), one can read :

It is a clear support of the Golden Study results by some of the major KOL on NASH in the world.

But the most important is that the phase IIb GOLDEN study, applying the new consensual definition of reversion accepted now by the FDA to the incoming Phases III, was a total success whithout any statistical retreatment of the patients ( it means on all the 273 patients of the study) and Elafibranor is the only drug reaching this endpoint.

19% vs 12% placebo on all the patients (NAS 3 included)
21% vs 11% placebo on NAS >=4
22% vs 12% placebo on NAS >=4 with fibrosis.

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.

the conclusion of the article is :

"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."

THE GOLDEN STUDY - 3 ARM SITE

GENFIT has therefore adapted its communication to demonstrate that the negative reading of his first statement had no place to be, for this, it relied on the opinions of KOL (Key opinion leader) in NASH, which were very positive

GENFIT published in April at EASL Congress further data on a smaller population comprising only major centers with a NAS> = 4.

In doing so they are close to the best of the future population and conditions for future Phase 3. The exclusion of small centers leads to a drastic reduction in the patient base which is reduced to 120 in this subgroup. It should be noted that this statistical treatment had been imagined before access to data and therefore does not involve an ad hoc population.

On this small subpopulation results are stunning:

The reversion of NASH no worsening of fibrosis (29% GFT505 vs 5% placebo, p = 0.001) or 5.8 times better than placebo (odds score)

And to compare with the study of INTERCEPT FLINT, decreased 2 points NAS score with no worsening of fibrosis (48% versus 21% GFT505 for placebo; p = 0.02) or 2.29 times better than placebo.

TRIALS IN COURSE AND PLANNED

The design of the ELAFIBRANOR Phase 3 in NASH was announced by GENFIT the November 16th, 2015 after obtaining the approval from the FDA and EMA. and published on clinicaltrials.org the 10 of March 2016

This is an extremely favorable design GENFIT for several reasons as it accompanies the new consensus definition of NASH.

the recruitment asked for the GENFIT’s subpart H (1000) is lower than the ICPT’one (1400)

I mentioned this evolution of the definition of NASH in my previous articles citing the symposium speakers on NASH, which was held last June in Paris.

A world expert questioned what defined him best the NASH answered "the balloning and portal inflammation".

I recalled that on these two points, GENFIT announced very good results while the OCA Intercept had an efficiency almost zero on the balloning.

the design of the study announced is :

A total number of patients will be 1800 in total and two arms (the final design published refer to 2000 patients)

An arm 120 mg / day elafibranor
A placebo arm

What is interesting is that GENFIT has obtained eligibility for Subpart H on the basis of an interim study of 900 (1000 now) patients over 72 weeks only.

One histological criteria, the reversion of the NASH with no worsening of fibrosis.

But it is a new definition of reversion criteria:

A balloning score of 0
Inflammation score between 0 and 1

This design is incredibly favorable for GENFIT

The relative small size of the sample means will drastically limit the cost of this first phase of part 3 before applying for a marketing authorization and therefore to start returning cash.

It is far from the $ 200 million initially announced, if one follows the current design statistical publications of this type, the Phase 3 cost should not exceed a total of $ 150 million and may be only $ 80 million for the first phase which would consistent with a cost assessable to 5 times the cost of Phase 2b which included 270 patients for 12 months.

The second point is the histological criterion which is cut exactly on the known performance of the ELAFIBRANOR (an important action on the balloning and inflammation) and which deviates steatosis as a criterion on which the elafibranor was iless efficient.

Regarding GOLDEN study on ELAFIBRANOR

« Compared to PLB, the 120 mg arm improved ballooning (45% vs. 23%, p=0.02),

inflammation (55% vs. 33%, p=0.05) and steatosis (35.5% vs. 18%, NS) »

It is interesting to see that the results are in line with the new consensual definition of reversion ( good results in inflammation and balloning, NS in steatosis

With the new consensual definition of NASH, the GOLDEN study show significant results on reversion of NASH on the overall studied population (NAS 3 included)

Elafibranor 19% vs 12% p = 0.045 placebo

Professor Arun Sanyal, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, commented: “The Phase 2b GOLDEN-505 study demonstrated that, in patients with clearly established NASH with high disease activity, Elafibranor safely led to resolution of steatohepatitis as well as improvement in cardiometabolic risk factors. Of particular importance is the efficacy of Elafibranor on the new consensual definition of resolution of NASH without worsening of fibrosis. Using this new consensual definition which emphasizes the role of cell injury and inflammation as the main drivers of fibrosis evolution, the GOLDEN-505 trial demonstrated that Elafibranor-treated patients who cleared their NASH also experienced a significant reduction in liver fibrosis. Thus, the design of the Phase 3 trial is optimal to confirm the good efficacy/safety ratio of Elafibranor on resolution of NASH at an interim analysis after 72 weeks, and on prevention of cirrhosis in the long-term.”

PAEDIATRIC TRIALS

GENFIT Initiates Paediatric NAFLD/NASH Program in Europe Further to the Approval of elafibranor’s Paediatric Investigation Plan by the EMA

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