OCALIVA

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NAME OF DRUG : OCALIVA

ALSO KNOWN AS : OCA

LABORATORY : INTERCEPT

STATUS AND ADVANCEMENT

Type of drug : FXR Agonist

Clinical trials advancement : Ongoing Phase 3

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

Estimated time to market : 30 months.

LABORATORY ABSTRACT ON THE DRUG

Intercept's lead product, OCALIVA  (obeticholic acid), was granted accelerated approval by U.S. Food and Drug Administration (FDA) in May of 2016 for the treatment of primary biliary cholangitis, previously known as primary biliary cirrhosis (PBC), in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. OCALIVA is the first PBC therapy that targets the farnesoid X receptor (FXR), a key regulator of bile acid, inflammatory, fibrotic and metabolic pathways. For more information, please visit ocaliva.com. Obeticholic acid (OCA) is also being evaluated for potential indications across a variety of additional chronic liver diseases, including nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), and biliary atresia.

 

HISTORY AND ANALYSIS

THE FIRST BIOTECH TO PUBLISH 2B STUDY RESULTS Intercepts Pharmaceutical is the first laboratory to have announced positive clinical results on NASH with its FXR agonist, the the obeticholic acid (OCA).

 

KNOWN RESULTS

 THE 2B PHASE CLINICAL STUDY - FLINT 

The OCA is not the first FXR agonist tested as a drug, the initial target of the drug was PBC (Primary Biliary Cirrhosis) to which they finalize phase 3.

Their study Phase 2b named FLINT with a 72 weeks duration including 283 patients originally included in two balanced arm, a Placebo and one OCA (24 mg / daily) orally. INTERCEPT was not the sponsor of this study, which had been delegated to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

In early January 2014, Intercept announced that the NIDDK had decided to discontinue the study, positive interim results having allowed to reach the first endpoint of the study. This announce was followed by intense speculation and the Intercept stock price rose from $ 70 to over $ 400 in two days.

It appeared soon after, that the company had deliberately omitted to announce the second cause of the shutdown of the clinical study by the NIDDK:  the fact that, for many patients, high cholesterol increased significantly.  in fact The NIDDK has even asked to the centers managing the study that : 

« … all patient[s] who remain on treatment (OBCA or Placebo) will be discontinued within two weeks of today ».  which could reveal, in their mind, a potential risk in pursuing the study.  

This announcement has distorted the information given to the public. As soon the truth came out, the stock value quickly lost again almost 40% of its value. 

Following, shareholders, feeling cheated by an oriented communication, suited the company in a Class Action. INTERCEPT wanted to oppose this action, but a judge has confirmed, on the evidences he got, that the class action is justified. The memorandum of his judgment is a wealth of information.

A partial release of the results of the study  was published only inJuly 2014 and the complete publication in the journal the Lancet associated with fairly critical comments was released in November 2014 

We learned, shortly after, that the publication of the study was initially refused by the New England Journal of Medicine on grounds of lack of scientific rigor, partly for non centralized reading of histological liver biopsies.

« From the BioPharm Insight report:

NEJM would not accept the FLINT data for publication because Intercept published the early findings of the DSMB, said a person familiar. The trial suffered from a loss of power due to its early stop, which is something thatnobody wants to talk about, said a second person familiar.

However, publication of the interim results was not the only reason the paper was rejected by NEJM, said the source familiar. The NEJM reviews did not like the fact thatthere were discrepancies between the liver biopsy pathologyassessments at the central lab versus the local labs, the source added.

There were alsoconcerns surrounding some of the statistical methods used to assess the data, the source said, though did not clarify further details. »

The study, due to its early termination, had to separate the patients who have not finished treatment and had not practiced the second control biopsy. Therefore, the results were based on only 200 patients vs initial 283, which makes 29% of patients had to be excluded and that in fact only 71% of the initial sample was ultimately taken into account.

The study achieved its primary endpoint (NAS  Score 2 points drop without worsening of fibrosis)  (45% vs 21% placebo OCA p = 0.0002) but failed on the secondary endpoint (Reversion of NASH without worsening fibrosis) (22% vs 13% OCA placebo p = 0.08) due to a lack of statistical significance.

It also highlighted a improvement of  fibrosis score (OCA 36% vs 19% placebo p = 0.04)

However it revealed several side effects that worry:

- An increase in LDL of 0.45 mmol / L vs placebo

- An increase in insulin resistance (HOMA-IR)

and incidentally a noticeable or significant pruritus in 23% of patients.

To complet your knowledge on the OCA mechanisms, you should read the excellent  Albert Wright Memo on the OCA paradox.

This study was not so much criticized by financial analysts, which are nevertheless expected to dig the subject for their customers. But numerous biases, some incredible, were identified.

- The non-centralized reading of biopsies which is a well recognized bias.

- The absence of stabilization of other drugs acting on the disease (Vitamin E, statins) before and during the clinical study.

- The start during the study, of other drugs treatment acting on the disease (26 started a statin treatment during clinical study)

- The study in  8 centers and only in one country (USA).

- The finding 'a posteriori' that 20% of patients enrolled had no NASH.

Some of these biases were quickly recognized and, in particular, the problem of the lack of centralized biopsy reading. 

Others have just been highlighted recently by a scientific publication of May 2015 (http://dx.doi.org/10.1016/j.jhep.2015.05.006) showing improvements in NASH and fibrosis associated with statins treatments. 

As 54% of the FLINT study of patients finished the study under statins (50 were on treatment before the study and continued, 26 have started treatment during the study) it casts a disorder on the part of results related to the OCA versus the part related to statins.

Some indépendant researchers also asked about the documents published in the Lancet.

One of the issues highlighted, always on the basis of data published in the Lancet, the OCA seemed to have no statistically significant effect on non-diabetic patients, limiting its scope.

The responses were unfortunately made on the basis of unpublished data.

INTERCEPT argued a lot on of the improvement in fibrosis seen in the FLINT study.

 Another point that deserves to be studied is the distribution of the initial fibrosis score of the FLINT study of patients who seem different from another meta study on the subject.

 

 

 

As the fibrosis score was not a criterion for recruitment of study FLINT (with the exception of the exclusion of F4), one can wonder about the possible impact of recruitment criteria or quality of histological reading on the under-representation of F1 fibrosis score and the over-representation of F3 fibrosis score in the sample of the FLINT study. The absence of F4 Fibrosis in recruitment may, perhaps, explain part of the gap, but not everything.

 

THE POST HOC FLINT STUDY

In March 2015, INTERCEPT therefore announces a Post Hoc study which, to date, only a few numbers were announced, and they bring more questions than answers.

INTERCEPT announced in a statement a Post Hoc study on a selected population in a grid according to precise criteria.

  • Patients with NASH and NAFLD score> = 4 (sic hopefully well: it was in their recruitment criteria) concomitantly with:
  • Or a fibrosis score of F2 or F3
  • Or an F1 fibrosis score associated with diabetes, obesity or elevated ALT (we do not know how).

This analysis grid deviates exactly 20% of patients finally selected in the initial FLINT study and leads us to a new sample of 160 patients exactly.

We could stop here and think that a selection of post hoc as patients could be based on simpler selection criteria. In fact we discovered later that it corresponds roughly to the selection criteria of their future Phase 3.

But curious people like me have peeled the report of the press conference following the release. Indeed, during the press conference speech on the selection of these patients has NOTHING TO SEE with the terms of the release.

Here is the verbatim transcript

« And the 200 patients were actually paired very evenly between those receiving placebo and those randomized to receive OCA dosed at 25 milligrams once a day. I'll also remind you that the way this study was conducted that each of?the eight centers submitted their slides for a local review and the local pathologists said yes, this patient has NASH and meets the entry criteria and the patient was enrolled.?The formal analyses of the results was done by two blinded observers, well blinded is wrong in the case of histology. But two independent observers who didn't know the allocation codes who then also then made a determination of whether a patient actually did or did not have NASH. And according to these two experts, Elizabeth Brunt and David Kleiner, about 20% of the patients actually didn't have NASH according to their criteria. So we have removed those patients who had crazy NASH or didn't have NASH from the study, from these analysis.? »

We find out our 160 patients but the selection method has changed: After a centralized rereading of the biopsies, two independent experts found that 20% of patients had no NASH, or 'crazy NASH').

INTERCEPT does not communicate a lot  on this point and curiously no analyst has noted the enormity of information: 20% of patients in the study FLINT, had no NASH at baseline. This shows the unreliability of the initial histological readings of the study and the need to be very suspiciously on all the initially published datas, in particular those relating to the fibrosis that depend only histological readings.

The second point is that the lack of consistency in the presentation of the selection of patients who were selected for the Post Hoc study. This give the feeling that it was done for the need of the cause and that the ensuing results are subject to all assumptions.

Another anomaly of this study Post Hoc, is the section for the lipid profile where they thoroughly detail the subgroups to demonstrate that patients who began statin treatment during processing (this fact was discovered on this occasion ) saw their LDL drop below their baseline.

The statin treatment patients began treatment before the clinical study have seen them, their LDL rise above their baseline.

For close observers, one notices that this time the basis of patients studied by Intercept includes all of the recruited sample, all 142 patients in the arm receiving the OCA:

Even patients who discontinued treatment during the study are taken into account in this analysis !!

Notwithstanding the bias induced which is not even mentioned, these results are given 'versus baseline' and not 'versus placebo', which greatly improves the results.

For information, increased LDL published in the original study 'versus placebo' was nearly double what it 'versus baseline'. (It is true that the baseline average of the subsamples might be difficult to establish, because, for example, we can assume that patients who started treatment with statins during the study are only or predominantly present in the arm processed by the OCA and not in the placebo arm).

It could extend to all the sights of this study FLINT well as the study Post Hoc still unpublished, but it simply must be noted that the number of shortcuts and recognized bias incentives to take the data published with great caution.

This corroborates what we could see inset in the paper reporting the results, published in the Lancet:

« Despite the improvement in the key features of non-alcoholic steatohepatitis, including fibrosis, these improvements were not enough to reduce the number of patients with a diagnosis of non-alcoholic steatohepatitis. The positive findings are tempered by the observation of pruritus in 23% of patients and an increase in total cholesterol and LDL cholesterol, and a modest decrease in HDL cholesterol. Long-term studies are needed to confirm the beneficial effects of obeticholic acid in patients with non-alcoholic steatohepatitis, and to determine the clinical relevance of the changes in circulating lipids induced by farnesoid X receptor ligands »

Based on this study, in late January 2015, INTERCEPT received FDA Breakthrough Therapy status for the OCA in treating NASH WITH FIBROSIS and may thereby potentially accelerate its marketing after the Phase 3.

 

Phase 2b Japan Study

It is noteworthy that another Phase 2b study was conducted in Japan on the OCA in NASH by SUMITOMO, their partner. This study of 200 patients and having four arms (placebo, a 10 mg / day, a 20 mg / day, a 40 mg / day) 

The trial was a total failure (more data HERE)

 INTERCEPT management has already build a firewall on this issue by stressing the non transposable feature of the US population study because of the supposed  particular trend in the Japanese population to have bad lipid balance sheets without being related to weight gain! 

The study is also criticized because of the small size of each arm (50 patients). 

 

TRIALS IN COURSE AND PLANNED

 

  • THE PHASE 3 STUDY - REGENERATE

IMPORTANT LAST UPDATE 

The 10 of february, 2017,   INTERCEPT announced some modifications in the protocol and endpoints, they say it was done with the endorsement of the FDA and will increase their chance of success !!!

1-    The Nash resolution definition was not previously defined in the trial design ( we noticed that for months)  Now it is clear, they will use the consensual definition of reversion already used by GENFIT in their RESOLV’IT NASH study.

2-     The two endpoints on fibrosis and reversion could now be reached separately, they changed the rule between it from AND to OR .

3-    The easyness induced by this second change allow Intercept to reduce the number of patients needed for Intermediary results (needed for subpart H ) to 750 patients versus 1400. And they announced the end of this recruitment mid 2017.

 

 

 

History of the trial:

In June 2015, INTERCEPT announced that it submitted to the FDA and validated the design of their Phase 3 named REGENERATE

The targeted patients are patients with NASH NAFLD with a score> = 4 a fibrosis score of F2 or F3.

The study will include 3 arms

  • An OCA arm to 24 mg / day
  • An arm OCA 10 mg / day
  • A placebo arm

2,500 patients will be enrolled in 250 international centers and the study will last at least 24 months or more (because the statement does not specify), an intermediate point on 1,400 patients will be done after 72 weeks to try to get the Subpart H of FDA.

Criteria targeted by the phase 3 study are almost identical to those of the Phase 2b study of GENFIT and not those of Phase 2b of INTERCEPT.

1- The reversion of NASH without worsening fibrosis

2- Improving Fibrosis without progression of NASH

Note that criterion 1 was the second criterion of the FLINT study that had not been achieved in phase 2 b. This will require that INTERCEPT improve its statistical impact during this second study.

The high number of patients requested by the FDA may be related to the need for assessment of risk related to the increase of cholesterol.

INTERCEPT ad can begin his study late 2015. Given the number of patients recruited and the lack of experience of INTERCEPT in conducting this type of study (remember that this is the NIDDK who led the study FLINT) this seems ambitious.

The 15 of september 2015,  INTERCEPT published the Phase 3 design on the website clinicaltrials.gov and we discover many new points not mentionned in the  june press release:

The 16th of september , the design was silentely updated to modify the biopsy interval from every 6 to 18 months.

The targeted patients are patients with NASH NAFLD with a score> = 4 a fibrosis score of  F1, F2 or F3.

The study will include 3 arms

  • An OCA arm to 24 mg / day
  • An arm OCA 10 mg / day
  • A placebo arm

2,500 patients will be enrolled in 250 international centers and the study will last 60 months with intermediate points each 18 months.

Criteria targeted by the phase 3 study are not exactly identical to those described in the press release:

Primary Outcome Measures:

  • Clinical outcomes composite endpoint of any of the listed adjudicated events [ Time Frame: Time to accrue a pre-specified number of adjudicated events, estimated to be 5 years ] [ Designated as safety issue: No  

Primary endpoint events include:

Death (all cause), model of end stage liver disease (MELD) score ≥15, liver transplant, hepatocellular carcinoma (HCC), ascites, histological progression to cirrhosis, hospitalization (as defined by a stay of ≥24 hours) for onset of: variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis.

Evaluate the effect of Obeticholic Acid compared to placebo on fibrosis stage in non-cirrhotic nonalcoholic steatohepatitis (NASH) subjects with stage 2 or 3 fibrosis by assessing the following co-primary endpoints [ Time Frame: Samples will be measured at Baseline and every 6 months up to 5 years ] [ Designated as safety issue: No ]

Co-primary endpoints include

  • The proportion of Obeticholic Acid treated patients relative to placebo achieving at least one stage of liver fibrosis improvement with no worsening of NASH
  • The proportion of Obeticholic Acid treated patients relative to placebo achieving NASH resolution with no worsening of liver fibrosis.

 

Secondary Outcome Measures:

  • To evaluate the effect of Obeticholic Acid compared to placebo on fibrosis improvement in NASH [ Time Frame: Samples will be measured at Baseline and every 18 months up to 5 years ] [ Designated as safety issue: No ]

Using NASH CRN scoring criteria:

  • Improvement of fibrosis and NASH as a composite endpoint and as defined by improvement in fibrosis by at least 1 stage and improvement in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) by at least 2 points.
  • Resolution of fibrosis
  • Improvement in NAS by at least 2 points with no worsening of fibrosis

 

Those information are critical :

1- The primary endpoint is safety before efficacy  ( this enpoint was not mentionned in the press release)

2- Regarding the time frame, the patients will have a liver biopsy every 18 month, during 5 years !!! 

 

Moreover, the study exclude many patients, with cardiovascular disease, high LDL level, uncontroled diabetes… wich exclude more than 50% of the NASH population in the OCA initial target.

The 29 of september , a preass release announced the initiation of the study with only 2000 patients, The 7 of october 2015, the design was silentely updated on the clinicaltrials.gov another time to modify many parameters .

THE MAIN PARAMETERS MODIFIED WERE :

  • -THE NUMBER OF PATIENTS  REDUCED TO 2000
  • -THE DURATION OF STUDY INCREASED TO 6 YEARS

 

and many other data you ou can check HERE.

 

Intercept launched another phase2 study on OCA and lipids in NASH the 7 of december 2015

http://ir.interceptpharma.com/releasedetail.cfm?ReleaseID=945804

To my opinion this study is needed to obtain a positive advice from the FDA and its results are 'as important' as the phase 3 results for the future of Intercept in NASH

 

 

 

 

NASHBIOTECHS OPINION AND LITTLE STORY

ANALYSTS QUESTIONING

On August 8, 2015 the Bank Morgan Stanley last incited its coverage of the INTERCEPT title by a fairly documented report which concluded their questions about the future of the OCA in NASH and fixed a price target 30% lower than the current day.

Unfortunately we have to date, only excerpts of the report.

The latter refers to a survey allegedly carried out by analysts of the bank with practitioners on the possible limitation of the OCA to their patients. You have to take it with caution as I know, neither the sample size nor the questions put nor the context provided to ask the questions. However, the result of this survey provided in the extracts is eloquent and confirms my personal opinion.

« In our survey, 44% of clinicians would limit OCA prescriptions to NASH patients with no cardiovascular disease/risk, or not prescribe the drug at all," Berens wrote. "The survey also found 50% of NASH patients have cardiovascular disease/risk factors. »

The report does not say whether the issue was raised in the context of total lack of alternative treatment but, in light of the response, this should be the case.

I think that,  if the question had been asked about the position of a doctor for prescribing the OCA in the presence of cardioprotective alternative treatment, the 44% would be increased to almost 100%.

The report also included the question on the size of the OCA alternative market in the PBC and generously concluded that it was not involved in over 20% of the valuation of INTERCEPT.

This issue of Morgan Stanley's analysis resulted in a curious episode.

The day after its release, the bank Barclays, notorious support of stratospheric price targets for INTERCEPT, felt compelled to issue a statement to reassure its own investors ..

This rather confusing statement, is mainly focusing on the absence of cardiovascular risk in the treatment of PBC was downright surreal to minimize cardiovascular risk OCA in NASH.

The reasoning supported initially referred to recent studies on LDL of different molecular weights having unequal impacts on cardiovascular risk and assumed that LDL generated by taking OCA was limited to those with an LDL molecules minimal risk

 

I looked forward to a scientific study published on the subject concerning the OCA. It is amazing that it is a bank that allows to spread this kind of information or assumptions without even INTERCEPT confirm or reject the reality of that which is essential scientific information.

The second reasoning argued by Barclays is a tautological fallacy.

According to them, as it is found that the cured patients of NASH have their cardiovascular risk notoriously decreased, the obvious conclusion is that because OCA should cure NASH (which still has to prove , Phase 2b failed on this point), OCA will therefore lower the cardiovascular risk, not increase it.

I leave you to ponder the seriousness of this kind of argument willfully obscures the risk of the treatment phase which, like KOL point out, is likely to be lifelong treatment.

But above all, their assertion on the fact that cured patients of NASH have less cardiovascular risk associated with increased LDL contradicts a recent study that concludes:

« NASH resolution is associated with improvements in TG and HDL but not in other cardiovascular disease risk factors including LDL and non-HDL-C levels. Individuals with resolution of NASH may still be at increased risk of cardiovascular disease. ClinicalTrials.gov identifier: NCT00063622. »

 

 

RECENT NEWS ON OCALIVA

2017-02-10 : The 10 of february, 2017 INTERCEPT Announced a modification of the protocole and endpoints, theu say it was done with the endorsement of the FDA and will increase their chance of success, ate this time we do not know the changes in detail . if the reversion definition vas modified to fulfill with the one used by GENFIT , it id definitively not a good news for OCALIVA, they never reached it in the previous studies.

SOME PUBLICATIONS RELATED WITH OCALIVA

April 2017 : Combination drug therapy allows synergistic therapeutic dose reduction in NASH: a case study of elafibranor (GFT505) and an FXR agonist combination in a model of severe NASH

March 2017 : Effect of miR-146 targeted HDMCP up-regulation in the pathogenesis of nonalcoholic steatohepatitis

January 2017 : Mice species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15 (necessity to monitor HCC risk with FXR agonists )

January 2017 : Therapies in non-alcoholic steatohepatitis (NASH)

September 2016 : FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

March 2015 : Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

May 2013 : Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

February 2013 : Dual actions of fibroblast growth factor 19 on lipid metabolism

January 2013 : The FXR agonist obeticholic acid normalizes lipid droplet and triglyceride handling in visceral adipose tissue preadipocytes from a non-genomic rabbit model of metabolic syndrome

February 2012 : Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma

January 2012 : FGF19 and Cancer

March 2011 : Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening

SOME NASHBIOTECHS POINTS OF VIEW RELATED WITH OCALIVA

February 2017 : REGENERATE, A BIG CHANGE REVEALING A BIG MESS

October 2016 : NASH COMBOs ARE THE WAY

September 2016 : NASH CLINICAL TRIAL PARTICULARISMS

September 2016 : ALLERGAN / TOBIRA DEAL REVEAL A HUGE GAP BETWEEN FINANCIAL ANALYSTS AND BIG PHARMAS FORECAST ON NASH MARKET

September 2016 : NASH ! SLIDES WAR IS DECLARED!

August 2016 : STATUS REPORT ON NASH (August 2016)

May 2016 : UPDATE ON THE RACE TO NASH MARKET (May 2016)

April 2016 : OCA AND THE LDL CHOLESTEROL !

December 2015 : PHASE III REGENERATE RECRUITMENT ! A REASON OF HOURS ?

November 2015 : GILEADs POSSIBLES STRATEGIES IN NASH

October 2015 : THE FUTURE OF INTERCEPT PHARMACEUTICAL IN NASH ?

October 2015 : THE NEW DEFINITION OF NASH STRIKE THE NASH PLAYERS

October 2015 : INTERCEPT PHARMA, PBC AND FDA

October 2015 : A SECOND ANALYSIS ON THE INTERCEPT PHASE 2 ON NASH IN JAPAN

October 2015 : INTERCEPT'S STUDY CURIOSITIES

September 2015 : NASH ! TREATMENT’S STRATEGIES AND COMPETITION


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