GILEAD’s POSSIBLES STRATEGIES IN NASH (updated october 2018)


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PREAMBLE This not a news or some insider data’s, it is only an analytic view of the market, strengths in presence and logical projections. 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!



What could be GILEAD’s futures strategies in NASH


To date,  GILEAD have officially three programs in NASH :


  • The GS9674 (ex Px104) is a FXR agonist as is the OCA from INTERCEPT which was originally developed by Phenex  before its acquisition by Gilead, this compound is currently in phase 2a clinical study. 


Despite earlier claims that non bile acid FXRs do not have the same side effects as FXRs like OCA, it is found that patients have also seen itching increase. For LDL, its increase is inherent to all agonist FXRs.

As a result, it is unclear what competitive advantage the drug could offer compared to OCA.

  • Access to market possible if all goes well, 2023.


  •  The SELONSERTIB (GS4997) is a ASKI (Acetyl-CoA Carboxylase (ACC) inhibitor ) that was tested in phase 2a alone or in combination with simtuzumab, it demonstrated in mices a reduction of steatosis, fibrosis and inflamation of the markers liver.  The 20 of October 2016 , GILEAD released first data's on the trial results. The trial was enrolling 72 patients in 5 arms, so the arms were including only a few patients ( 20 to 10 ), it is typically a 2a Study, the Primary Outcome Measures were


Adverse event profile of GS-4997 [ Time Frame: Up to 28 weeks ] 

Reported adverse events will include:

  • Incidence of treatment-emergent serious adverse events
  • Incidence of worsening of treatment-emergent liver laboratory abnormalities for alanine aminotransferase (ALT) and aspartate aminotransferase (AST), defined as at least 1 toxicity grade increase from baseline


Percentage of participants who prematurely discontinued study drug or study due to adverse events

The results announced show a good  efficacy on fibrosis of  GS4997  but we should stay cautious because of  the very small number of patients included in the trial  regarding the great variability of hepatic biopsy readings and the absence of a placebo arm.  

A Phase 3 ist ongoing and GILEAD managed to fulfill their recruitment in a very short time.

Nevertheless, recent results of selonsertib in severe alcoholic hepatitis cast a worrying veil over the future of the drug. Indeed the number of deaths in the arm of the selonsertib (prednisolone + selonsertib) was three times higher than that of the placebo (prednisolone alone). 

This creates serious uncertainty about the results in advanced NASH and the safety of the drug.

Access to market possible if all goes well, 2020.


  • The GS0976  ex NDI-010976 is an ACC inhibitor (apoptosis signal-regulating kinase inhibitor) which was originally developed by NIMBUS  before the acquisition by Gilead of their Apollo program . The drug just started a Phase 2a clinical study .  It have the potential to prevent production of new lipids within the liver and stimulate their breakdown. In animal models of fatty liver, ACC inhibition reduces hepatic fat content, inflammation and fibrosis (scarring), all of which are important hallmarks of NASH progression.  A  report revealed by Bloomberg explained that the half life of the NIMBUS drug is very short and do not exceed 10H for the highest doses, which could imply multiple doses per day for the treatment, and concluded that it is not a good configuration  for a market agreement by the agencies. 


Results publised in april 2018  "Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis »

in a a trial beased on very small cohorts  (10+10), show a small effect on liver fat reduction 15,7% vs 9,1% mesured by MDI-PDFF.  this is far behind MGL 3196 or VK 2809 and, to date, the competitive advantage of GS0976 is not clear by far.

  • Access to market possible if all goes well, 2023.



ANALYSIS 

One can notice that the first treatment that Gilead could have bring to the market was simtuzumab  but as the programm is halted now , GILEAD lost its main program in NASH about two years ago.


SELONSERTIB phase  2 results were encouraging but based mainly on imagery and only 70% of the patients got end of trial biopsies, the number of patients was very small and there were no placebo arm. The results expected are now jeopardized by the alarmous results of  SELONSERTIB in advanced alcoholic hepatitis.

In addition, the GS9674  is a FXR agonist which seems to have some side effects as the OCA (LDL increase), that is to say an increase in LDL cholesterol which could pose a similar problem as OCA of  INTERCEPT in terms of cardiovascular profile worsening but also an increase in pruritus. So competitive advantage on OCA is not clear! 

To complete, GS0976 results seems to be far behind MGL 3196 or VK 2809 in liver fat reduction. ( the small sample is not helping ).


GILEAD, who has announced plans to be a leader in the NASH, is far from its goal with its current programs. It was the case a year ago, it is worst today!

As they halted their admiral program, in the best projections, and if everything goes well, they could reach the market one or two years after their competitors except with a drug targeting  fibrosis induced by NASH (SELONSERTIB). 

As they will not have a metabolic (backbone)  treatment of the disease on the market before years but only a drug targeting fibrosis  , they’ll not able to cover the large spectrum of the disease. Regarding this configuration, it is difficult to claim the leadership in NASH.

The strategy develloped by GILEAD seems curious to observers. Why do they acquire preclinical NASH program when it is obvious that they need to come back on  competitors ?

To date, it is clear that GILEAD is the great looser of the last year in NASH. they lost all their potential competitive advantages of combos and are sticked with drug showing a possible safety concern or with no competitive advantages on the most advanced drugs.

It is now time for them to use the only advantage left to them, their CASH, to aquire as quickly as possible one of the few most advanced molecules that have not yet been bought by a big Pharma. 

The closer the clinical results come, the greater the competition between large pharmas will increase to enter the NASH market. They do not have much time left if they do not want to be the stuffing turkeys.

if you examine the following list, their choice is limited !




 these are few leading the race :

  • INTERCEPT and OCA
  • GENFIT and ELAFIBRANOR
  • ALLERGAN and CENICRIVIROC (not available for sale) 
  • GALMED and ARAMCHOL
  • GALECTIN and GR-MD-02 (missed the NASH trial, expecting better results on cirrhosis Ph2b)
  • BRISTOL MYERS SQUIBB and BMS 986036 (not available for sale as far i know) 
  • CONATUS and EMRICASAN (not available for sale because of Novartis deal) 
  • MADRIGAL and MGL-3196 




The ideal deal would be to complete the expected action of the most advanced drug in their pipeline (SELONSERTIB) on cirrhosis and fibrosis by a molecule that treat metabolic NASH to offer a combination covering the spectrum of disease (read here why).

To my previous opinion GILEAD could exclude molecules targeting only fibrosis and cirrhosis, maybe covered by the SELONSERTIB 

Again, the anti fibrotic promising results of SELONSERTIB, if they are confirmed in a bigger trial could be a solution for GILEAD tot take a place on the market, but the new safety issues jeopardize this scenario  and time is missing to put the SELONSERTIB on the market before the competitors.

So the most advanced drugs still available to buy are: OCALIVA, ELAFIBRANORARAMCHOL and now MGL-3196 !


OCALIVA

The OCA is in the same family as Px104 (FXR agonist) who claims to be more powerful with fewer side effects (this remains to be proven). 

The OCA is one of the most advanced in NASH clinical studies but conversely, bet on a second FXR agonist while recent studies have cast doubt on its ability to treat NASH could be risked. To complete INTERCEPT now focuses its communication on NASH induced advanced fibrosis (and by extension Cirrhosis) and not on the metabolic disorders so it does not seem consistent strategically for GILEAD.

The REGENERATE Phase III study was late in its recruitment  (I explain why here) , to accelerate and take the lead they took the risk to reduce the inital number of patients needed for intermediate results  from 1400 to 750 and declared closing the recruitment of those 750 firsts patients  in july 2017,  it mean intermediate results at the beginning of 2019 and a possible agreement and access to the market at the beginning of 2020.

Moreover, INTERCEPT got an accelerated agrement for OCA in PBC, but the full release of the PBC studies revealed some liver adverse effets in OCA higher doses wich conduct FDA to propose a limitation of OCA doses at 10mg/day. 

Regarding the studies on NASH, this dose seems too low to impact the NASH disease, the publication of the JAPAN study is clear, no any effect at 10 mg/day is notable, similar as placebo.. The analysts have not yet mesured the implications of OCA dose limitation in the PBC on the future NASH agreement  but it will come.

The last Trial ‘CONTROL’ confirmed the serious adverse effects of the drug, pruritus affected 55% of patients and LDL level increase vas also confirmed.

Nevertheless INTERCEPT seems to try to sell itself and the ticket may not exceed $ 10 billion. 

Regarding the FDA last safety communication on OCALIVA it is not sure that GILEAD could take the risk to pay for OCALIVA.



ELAFIBRANOR

ELAFIBRANOR seems the dreamed complement for SELONSERTIB, the GOLDEN phase 2b studies now prove its strong action on NASH and on the main components of the metabolic syndrome. the drug is now the most advanced in clinical studies and is likely to be the first treatment that will access the market. 

The RESOLV IT Phase III study already started its recruitment and plan to finish the recruitment of the first 1000 patients needed for the subpart H accelareted agreement before spring 2018. It mean intermediate results at end  2019 and a possible agreement and access to the market at the end of 2020.

ELAFIBRANOR is a perfect complementary to a treatment targeting advanced fibrosis and cirrhosis. 

To date, GENFIT, at less than 1b$,  is clearly underevaluated , however GENFIT knows very well the value of the gold nugget that have in their hands with ELAFIBRANOR. They are not for sale !  except maybe for a very substantial offer that could exceed maybe $ 10 billion.

It remains the option of an hostile takeover  but it could imply to pay more than the required price because other laboratories seems also very interested in GENFIT and an hostile takeover would generate an expensive battle on the price offering. 

Nevertheless ELAFIBRANOR  is the most advanced compound on NASH treatment with a good safety and no noticable adverse effects, if GILEAD  are ready to put  more than $ 10 billion on the table to buy GENFIT,  it probably worth the gamble to be the first on the market. The alternative is a licence deal with GENFIT or a co development  deal as they have done with GALAPAGOS.

They could choose to wait for the Ph3 intermediatre results, but then, with positives results, the drug could become priceless !


ARAMCHOL

the ARAMCHOL couldhave been an interesting option, but, to my opinion, their phase 2 results are not good enough to make a blockbuster.


MGL-3196

MGL3196 got histological confirmation of the published encouraging data’s on liver fat. As confirmed, MADRIGAL’s compound would be an interesting option, predicted drug action remains complementary to  simtuzumab.

But MADRIGAL valuation is very high now  regarding the facts that MGL3196 is only finishing phase 2 and, at best, the drug could reach the market 18 months  after the leaders !


CONCLUSION

A few month ago, GILEAD announced in an interview that they do no plan anymore an acquisition in NASH, they argued that they have enough drugs in development  to provide combo on this market.  It is clear that they have to move on that point if they want to stay a major actor on the liver disaese market!

Indubitably, with 3 programs left, they are one of the most  involved companies in the future treatment of NASH but, to my opinion, their pipeline is very poor, incertain  and late on main competitors.

They should rush now on OCA , Elafibrabor or maybe MGL 3196 and use their ultime argument, their CASH !

Otherwise partnership could be the way,  the most logical and promising partnership on the core NASH market would be MADRIGAL or GENFIT but they’ll have to pay the good price, and the price increase day after day !


The detailled lists of compounds targeting NASH is here 


G Divry 2018





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