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Aandeel Genfit PSE:GNFT.FR, FR0004163111

  • 3,235 23 apr 2024 17:35
  • 0,000 (0,00%) Dagrange 3,215 - 3,270
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Het jaar van de waarheid

1.555 Posts
Pagina: «« 1 ... 55 56 57 58 59 ... 78 »» | Laatste | Omlaag ↓
  3. felipe 20 juni 2015 15:35
    Onderstaand stuk komt van Seeking Alpha.

    Betting On The First NASH Blockbuster Drug: Dump Intercept And Buy Genfit

    Logribel Biostocks
    Long only, biotech, micro-cap, deep value
    Profile| Send Message| Follow (186 followers) | Performance
    Betting On The First NASH Blockbuster Drug: Dump Intercept And Buy Genfit
    Must Read | Jun. 18, 2015 12:37 PM ET | 15 comments | About: Intercept Pharmaceuticals (ICPT), Includes: GNFTF
    Subscribers to SA PRO had an early look at this article. Learn more about PRO »
    Disclosure: I am/we are long GNFTF. (More...)
    Summary

    NASH has no FDA-approved therapy and could represent a $35 billion untapped market.
    Intercept and Genfit are currently leading the race to get the first NASH drug approved.
    Intercept has the favors of many analysts, but a careful analysis of data and trial designs suggests that Genfit might come out first as Intercept's shortages are piling up.
    As both companies' stock prices are inversely correlated, Intercept's loss is bound to be Genfit's gain.
    Non-alcoholic steatohepatitis, or NASH, is a form of chronic liver disease caused by a build-up of fat in the liver (progressive fatty liver disease) affecting at least 2 to 5 percent of Americans. There is currently no FDA-approved therapy for NASH, even though the disease can progress to cirrhosis and ultimately lead to hepatocellular carcinoma (liver cancer), which makes it one of the major unmet medical need of the 21st century. The market for NASH drugs is currently estimated to reach $35 to $40 billion by 2025, a huge untapped market that could support one or several blockbuster drugs in the years to come.

    Several companies are currently developing NASH drugs, but until now, only Intercept (NASDAQ:ICPT) and Genfit (OTCPK:GNFTF) have demonstrated histological proof of efficacy that their compounds are able to reverse or reduce NASH symptoms in randomized controlled trials. Intercept recently announced the design of its Phase 3 trial of obeticholic acid, or OCA, while Genfit is currently preparing its own Phase 3, to be announced before the end of the year, with its leading compound, elafibranor.

    Since the announcement of Intercept's and Genfit's Phase 2b results, there has been a huge amount of speculation from investors and analysts about which of the two companies stands better chances of reaching FDA requirements in a larger pivotal Phase 3 trial - success in Phase 3 would translate in the ability to put on the market the very first specific NASH drug approved by the FDA and capture a significant share of this huge untapped market.

    In terms of pair trading, this connection between Intercept and Genfit has been demonstrated by past events: the impact on both companies' stock prices due to major announcements has been strongly (inversely) correlated - see Figure 1. For example, upon the announcement of Genfit's Phase 2b results, Intercept's stock jumped more than 10% as the market's initial reaction was clearly negative towards Genfit's prospects. On the contrary, when Intercept announced its Phase 3 design, Genfit gained about 8% as the market was digesting the implications of the trial's size and endpoints.
  4. felipe 20 juni 2015 15:36
    (click to enlarge)
    Figure 1 - Intercept

    Until now, Intercept seems to be clearly favored by most U.S. analysts. Intercept's market cap is six times greater than Genfit's, a huge gap between two companies with very similar prospects in terms of revenues and a negligible time-gap to market. However, I believe that a careful analysis of available data makes a compelling contrarian case for Genfit, as I will clearly expose below, in five points.

    Useful links

    Phase 2b NASH trials:
    - Genfit's GOLDEN-505 preliminary results
    - GOLDEN-505 clinical trial
    - Intercept's FLINT results (Lancet publication)
    - FLINT clinical trial

    Phase 3 NASH trial:
    - Intercept's REGENERATE trial design

    1. Neither companies had a perfect Phase 2b trial design but Genfit's was better

    Genfit's Phase 2b trial demonstrated significant efficacy on its "NASH resolution" primary endpoint in the global randomized population of the trial: simply put, no post-hoc "subgroup" analysis was needed to achieve significance on this endpoint. This basic scientific fact, however, has been largely overshadowed by the debate surrounding some statistical adjustments that the company reported right away. So, here are the facts: due to the very high number of study centers (56) all across the world for a limited number of patients (n=274), Genfit feared that data reported from very small centers would create statistical imbalances impacting the study's outcome - e.g. some of the centers only had one or two patients in total, which means that not even one patient was included in each of the study arms. This is a well-known and well-studied bias in clinical statistics known as the "center effect", which is routinely accounted for in statistical analyses by performing some minor adjustments, thereby reducing the effects of the data's heterogeneity. This is nothing exceptional.

    Hence, before the readout, Genfit went to discuss with the FDA the possibility of adjusting the original statistical plan to take those imbalances into account, with the help of international experts. At the time, Genfit had no way of knowing what the results of the trial would be, as all data were still blinded: per definition, this is not a post-hoc analysis. The FDA did agree to the proposed adjustments because they made sense.

    Then, the data were "unblinded" and Genfit applied its revised statistical plan. The results from the Phase 2b trial were clear: Genfit's drug, elafibranor, demonstrated statistically significant improvement in the intent-to-treat population (p=0.016, including mild-NASH patients). In addition to this positive outcome, if mild-NASH patients (NAS=3) are removed from the analysis in order to match Intercept's Phase 2b population, then the results are even more impressive (see comparison below).

    On the other hand, Intercept's FLINT trial was literally plagued by very questionable decisions and patient selection, including:

    - 20% of patients who did not have NASH at baseline
    - 20% of patients in the OCA arm who were actually taking Vitamin E in addition to OCA (which means that improvements could possibly be attributed to concomitant medications, as Vitamin E has shown efficacy in treating NASH in previous trials)
    - 51% of patients in the OCA arm who were taking statins at baseline, and some who initiated the treatment during the trial (again, bringing questions about the real effects of OCA on cholesterol levels)

    (Source: The Lancet, FLINT trial results, appendix)

    Besides, as the trial was abruptly ended as a consequence of the vanguard analysis, it means that many patients had incomplete treatment, which could lead to a bias in the statistical analysis, which was acknowledged but not taken into account as reported by the company itself (highlights added):

    Effect estimates and precision for the primary outcome measure were done as specified in the original protocol; no adjustments were made for potential statistical bias due to the two interim monitoring analyses (the vanguard futility analysis using alanine aminotransferase as a surrogate outcome measure and the interim efficacy analysis using the histological primary outcome) - source: The Lancet

    Besides, more importantly, OCA actually failed to demonstrate statistically significant improvements on the "NASH resolution" endpoint, which is one of Intercept's Phase 3 co-endpoints. If post-hoc analysis is performed on Phase 2b results by "removing" 20% of the patients (i.e. those patients who didn't have NASH at baseline), then the trial appears to show significant efficacy on that endpoint, but there's no objective reason to state that Intercept's results are better than Genfit's in this matter (see Table 1 below and the developments in my previous article here).
  5. felipe 20 juni 2015 15:37
    Table 1: Comparison of Genfit's and Intercept's "NASH resolution" endpoint results with similar NASH patient population (NAS =4)

    Resolution of NASH w/o worsening of fibrosis
    placebo
    treatment arm
    p value
    Genfit - elafibranor
    (n=120, balanced centers subgroup)
    5%
    29%
    0.01
    Intercept - OCA
    (n=181, excluding "not-NASH" patients)
    8%
    19%
    0.0278
    (Sources: Genfit's April 2015 analyst presentation ; Intercept's March 2015 presentation)

    The bottom line is that while both Phase 2b trials were imperfect, Genfit's shortages were mainly due to a well-known statistical bias dealt with according to standard practice while Intercept's trial had many questionable fundamental aspects, which brings much more uncertainties regarding the outcome of its Phase 3 trial.

    2. Intercept's Phase 2b patients were discontinued due to safety concerns and Phase 3 will include a lower-dose arm of OCA

    One of the main arguments which propelled Intercept's stock near the $500 region in January 2014, when it announced its Phase 2b preliminary results, was that the FLINT trial was stopped early upon interim analysis because of significant efficacy. That part is true, but there's more to it.

    In perspective, the "significant efficacy" thesis appears as a partial and incomplete narrative, as demonstrated by this quote from a U.S. district judge order about the context of Intercept's announcement (highlights added):

    [Dr Averell] Sherker [NIDDK's Scientific Advisor for Viral Hepatitis and Liver Diseases] reported that "upon planned interim analysis, the stopping boundary for efficacy was crossed and NIDDK has decided not to have subjects undergo week 72 biopsies effective today." He noted that "Dr. Shapiro [Intercept's CMO] was informed that given this decision and the finding of significant lipid abnormalities (increased total cholesterol, increased LDL cholesterol and decreased HDL cholesterol), all patient[s] who remain on treatment (OBCA or Placebo) will be discontinued within two weeks of today. - source: U.S. district judge order

    What this clearly means is that the FLINT trial was indeed stopped by its investigators (the NIDDK) upon a planned interim analysis which demonstrated significant efficacy on the "NAS decrease" endpoint (but not on the "NASH resolution" Phase 3 endpoint), but that the NIDDK's decision was also motivated by fears that "significant lipid abnormalities" could have a negative impact on the patients.

    It also implies that safety is, and will always remain, a matter of concern for OCA. This was confirmed by the design of Intercept's Phase 3 trial, which included a second 10mg dosing arm, in addition to the 25mg dose similar to the Phase 2b trial - this means that Intercept had to include in Phase 3 a study arm with less than half of the dose previously tested, with the hope of reducing significant side effects.

    On the other hand, Genfit's Phase 2b trial has proven that elafibranor has a dose-dependent effect and an excellent safety profile, which means that the company has announced its intention to include at least one higher-dose arm in its Phase 3 trial (probably around 200mg compared to 120mg in Phase 2b).

    The bottom line is that while Genfit's drug stands a chance of improving on its Phase 2b results due to its outstanding safety profile which allows the inclusion of a higher dose arm of elafibranor in Phase 3. Meanwhile, Intercept will have to deal with a similar or lower dose of OCA to try and reproduce the efficacy results from its own Phase 2b, in which it already had troubles demonstrating significant efficacy.
  6. felipe 20 juni 2015 15:40
    3. Safety profile does matter in the long-term and Genfit's drug is much safer

    On top of efficacy, safety is a real matter of concern in a therapy that is deemed to become a chronic treatment: Intercept's Phase 3 design will run for at least several years to deliver complete results while the final length of the trial remains uncertain as it is tied to progression to a pre-determined number of adverse events.

    When discussing potential adverse effects of NASH therapies from a molecular biology perspective, the mechanism of action of both compounds looks quite different.

    Genfit's drug, elafibranor, is a dual peroxisome proliferator-activated receptor (PPAR) agonist: it works by activating PPARalpha and PPARdelta, which are nuclear receptors that have a totally natural effect on lipid storage and metabolism regulation in the liver. In fact, that is the very natural mechanism you would expect to activate when increasing intakes of polyunsaturated fatty acids such as omega-3, and precisely why high-calorie diets full of saturated fat are so damageable for your liver - that is actually one of the root causes of NASH.

    Besides, PPARalpha and delta have been shown to regulate glucose metabolism, lipoprotein cholesterol metabolism, liver inflammation, and amino acid metabolism (Contreras et al., 2013; Reilly et al., 2007). In brief, due to its mechanism of action, elifibranor works by improving about every possible cardio-metabolic parameter you can think of (see Figure 2), and ultimately, it does reverse NASH even in the more severely ill patients. Indeed, in Genfit's study, beneficial cardio-metabolic effects of elafibranor (GFT505) were confirmed (statistically significant) including:

    - decrease in "bad" lipids (including LDL-C), increase in cardioprotective lipids (HDL-C)
    - improvement in glycemic parameters, particularly in diabetic patients
    - improvement in cardio-vascular risk (PROCAM score)

    (source: Genfit's data)

    Figure 2: Therapeutic targets of PPAR agonists in the metabolic syndrome

    (click to enlarge)
    Figure 2 - Therapeutic targets of PPAR agonists in the metabolic syndrome

    (Source: EASL postgraduate course on metabolic liver disease)

    On the other hand, Intercept's drug, OCA, is an agonist of the farnesoid X receptor, or FXR. FXR plays a role in regulating lipid and glucose metabolism, but in particular it affects how cholesterol is converted into bile acid (Claudel et al., 2005) - that is the primary function of OCA, which was first developed by Intercept as a treatment for primary biliary cirrhosis, or PBC. Unfortunately, FXR activation leads to undesired side effects on cholesterol, which were confirmed by the results of the FLINT study: OCA naturally increases "bad" cholesterol (LDL-C) levels. Besides, as FXR activation also modulates the clearance of triglycerides in the blood, this incidentally decreases "good" cholesterol (HDL-C) levels as well. This is already bad in general, but it is even far worse for the kind of patients that Intercept intends to treat with OCA.

    Regarding LDL-C levels, Intercept has already suggested that taking statins could help manage the adverse effects induced by OCA. However, an increasing number of recent studies seem to demonstrate that statins themselves have severe adverse effects, including a very stronger risk (+250%) of developing type 2 diabetes (Cederberg et al., 2015), damages to peripheral nerves (Otruba et al., 2011) and an increased risk of developing rheumatoid arthritis (de Jong et al., 2012).

    Besides, in addition to abnormalities in cholesterol levels, the FLINT study's complete results also showed that pruritus (itchy skin) was confirmed in 23% of patients receiving OCA (vs. 6% in the placebo arm), and that five severe or life-threatening adverse events in the patients receiving OCA were judged to be possibly related to the treatment (3 severe pruritus, 1 hyperglycaemia and 1 dysarthria and dizziness possibly due to cerebral ischaemia). Genfit's study, on the contrary, showed that no severe adverse event were associated with elafibranor and demonstrated a very favorable safety profile.

    In brief, when comparing elafibranor and OCA, what comes out is that the very rationale behind both drugs is substantially different. Elafibranor is a global, cardioprotective drug with nearly nothing but beneficial effects; OCA has some inherent adverse side effects that might prove worse in the long-term than its beneficial effect on NASH patients - in fact, NASH patients are far more likely to die from cardiovascular disease than from NASH itself (Misra et al., 2009).

    So, even though a CVOT study was not required by the FDA along with Intercept's Phase 3 trial, I believe that this is a significant risk associated with Intercept's NASH drug in the long run, that has been considerably overlooked by the market at this point.
  7. felipe 20 juni 2015 15:41
    5. …while Genfit's insiders are buying and the company has many potential upcoming catalysts

    Meanwhile, since the announcement of its Phase 2b results in March 2015, Genfit's insiders have been buying the stock, like Genfit's CEO, Jean-François Mouney, who bought for more than EUR 200,000 in shares at the end of April 2015.

    At the moment, Genfit has approximately $75 million in cash and it has repeatedly confirmed that it is discussing with several big pharma players to conclude a partnership regarding the funding of its upcoming Phase 3 trial. Should Genfit announce the backing of a big pharma company supporting its Phase 3 trial, this would be a major event that could bring the market to seriously reconsider Genfit's chances of success.

    By the end of summer 2015, Genfit expects the publication of its Phase 2b complete results in a major scientific journal. This publication, which should disclose the full details of the trial's results, should bring further clarity about the validity of Genfit's data and could lead some international analysts to reconsider their position on Genfit's prospects.

    The company has also declared on several occasions that, following its preliminary discussions with the FDA, it expects to enrol from 1,500 to 1,700 patients in Phase 3. Since Intercept's Phase 3 design surprised many investors because of its unexpected size (2,500 patients in total), the issue of patient enrolment has become fundamental in assessing the chances of both companies to finish first in the race to market… Genfit is expected to announce the design of its Phase 3 trial before the end of 2015. Elafibranor is just six months behind OCA in terms of clinical development - should the company be allowed to conduct a smaller Phase 3 trial, this would translate in a significant gain on its main competitor in terms of time to market.

    Finally, Genfit recently confirmed its plan to be listed on the NASDAQ by early 2016.

    In brief, potential short-term (6 months) catalysts abound for Genfit, and if just a few of them materialize in the coming months, this could lead to a significant reevaluation of Genfit's stock price.

    Conclusion - Strong rationale for a pair trading with a clear timing perspective

    With a careful and detailed analysis of trial designs and available data, I believe that the current valuation gap between Intercept (market cap of $6 billion) and Genfit (market cap of $900 million) is totally unjustified relative to the similarities in the development stage of their drugs, their potential market and the data collected from previous trials. If logic prevails, this gap is bound to close as investors reevaluate their positions upon deeper analyses and upcoming events clarifying the situation.

    At the moment, while Intercept's trial has shown many shortages and questionable data, I believe that Genfit's drug has clearer prospects and is more likely to succeed as a broad, cardioprotective NASH-targeted drug. Opportunities abound in the short term for Genfit to confirm this status, starting with the design of its Phase 3 trial and the signing of a significant partnership deal.

    In terms of trading, as many investors are looking to pick one winner in the "NASH race", the share price of both companies is likely to remain closely correlated. And in this game, Intercept's loss is bound to be Genfit's gain.

    The author wishes to thank Dr. Albert Wright for his insight on molecular biology and the mechanism of action of PPAR and FXR.
  12. [verwijderd] 21 juni 2015 10:09
    quote:

    Biogen schreef op 20 juni 2015 22:05:

    Eens alles zwart op wit staat en de fda het bevestigd zie ik niet hoe dot spel kan blijven duren.

    Ik ga er van uit dat genfit op zoek is naar een sterke partner het verbaasd me enigszins dat Sanofi nog niet is ingestapt
    Je kunt wel een goed produkt hebben maar je moet wel de juiste kanalen (lobbyen) hebben en weten om het produkt goed in de markt te zetten En de concurrentie zit ook niet stil (icpt) en probeert hun eigen produkt beter te maken dan het is en het produkt van de concurrent de grond in te boren En icpt heeft een aantal grote banken achter zich staan (citybank) met een groot aantal (onafhankelijke) annalisten en die blijven tot het uiterste hun eigen belangen beschermen
    Wiens brood men eet wiens woord men spreekt
  13. forum rang 10 DeZwarteRidder 21 juni 2015 10:38
    quote:

    BP66 schreef op 21 juni 2015 10:09:

    [...]
    Ik ga er van uit dat genfit op zoek is naar een sterke partner het verbaasd me enigszins dat Sanofi nog niet is ingestapt
    Je kunt wel een goed produkt hebben maar je moet wel de juiste kanalen (lobbyen) hebben en weten om het produkt goed in de markt te zetten En de concurrentie zit ook niet stil (icpt) en probeert hun eigen produkt beter te maken dan het is en het produkt van de concurrent de grond in te boren En icpt heeft een aantal grote banken achter zich staan (citybank) met een groot aantal (onafhankelijke) annalisten en die blijven tot het uiterste hun eigen belangen beschermen
    Wiens brood men eet wiens woord men spreekt
    Als Genfit eind dit jaar nog steeds geen grote partner heeft, dan weten we dat ze een waardeloos geneesmiddel hebben.
  14. [verwijderd] 21 juni 2015 12:06
    quote:

    Biogen schreef op 20 juni 2015 16:35:

    www.portail-ie.fr/article/1256/Are-Eu...

    Zo nu lees je het wat ik hier al een tijdje dacht.
    De grote bekendheid van de (Europese) bio bedrijven laat te wensen over vooral in de VS een introductie kan helpen op de nasdaq maar bij oa gala zie je de omzetten na een paar weken inzakken na introductie
  17. Biogen 21 juni 2015 15:30
    Gesprekken starten met fda eind juni begin juli. Kort daarna bevestiging van de fda.

    Daarvoor misschien nog een breaktrough...

    Fda zijn geen analysten. Ze gaan Genfit noet weigeren aangezien itcp ook kan en mag starten.
    Trouwens niemand let er op maar niemand die ook weet hoelang de fase 3 van intercept eigenlijk totaal duurt.
    Toch een knap staaltje techniek van die mannen ??
  20. forum rang 10 DeZwarteRidder 27 juni 2015 13:11
    quote:

    tophound schreef op 27 juni 2015 12:52:

    [...]
    Sinds jij hier je negativisme botviert is dit forum naar de filistijnen.
    We gaan jou maar eens laten verwijderen, dan kan je thuis verder je vrouw (die zal je wel niet hebben) afzeiken, en op je werk (zal je ook niet hebben) je baas frustreren.
    www.iex.nl/Column/135825/Trending-op-...

    www.iex.nl/Column/136306/Trending-op-...
1.555 Posts
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