Should be Sceptical with OCA?

[Betonarme]

Sorry...

first, I don't want to make People unnecessarily scared especially because of my very limited Knowledge reading Articles / Reports here and there and try to bind the pieces of Information.

If I understand it correctly....following are my thoughts and questions on this recently approved Drug which shows great Benefit for many and I cannot imagine that so many scientific Experts cannot be already aware of these risks. But anyway I wanted share my thought and trigger a discussion. May be some of you also can talk about these concerns when you meet your medical consultant next time.

Since long time the word "FXR" is familiar to me. This looks like the be the target Receptor for OCA. Below is the copy & paste text from the following link:

accessdata.fda.gov/drugsatf...

Pharmacodynamic Markers

"Pharmacodynamic Markers In Trial 1, administration of OCALIVA 10 mg once

daily was associated with a 173% increase in concentrations of FGF-19, an FXR-inducible enterokine involved in bile acid homeostasis, from baseline to Month 12. Concentrations of cholic acid and chenodeoxycholic acid were reduced

2.7 micromolar and 1.4 micromolar, respectively, from baseline to Month 12. The clinical relevance of these findings is unknown."

You can read the complete text if you wish to.

Now...how and why I came to search such a stuff suddenly. First We were happy that Ocaliva finally is available. But my wife once stated that We should better wait and see long term effects of the new drug. She said Urso is relatively safer because it's in use since about 20 years or so. But Oca is new she said....who knows may be it can cause serious consequences like cancer etc.

And I started reading around, searching whatever I can find. And looks like this Hormone FGF-19 (Fibroblast Growth factor 19) is the consequence of FXR activation which in turn shows positive effects in Liver. But it has also negative effects. Here is the text from a Company Web page who is also working on a novel Drug targeting PBC and the Drug is a derivative of FGF-19 which some people call M70 which should be safer than FGF-19. Here is a text cut from the Page of NGMBio:

" However, overexpression of FGF19 has been shown to promote liver tumor development in transgenic mice. NGM282, accordingly, has been engineered to eliminate the elements of FGF19’s signaling that are associated with those tumorigenic properties while retaining both the FGFR1c- and FGFR4-mediated signaling activities of the native hormone that direct the regulation of metabolism and bile acid synthesis..."

ngmbio.com/pipeline/ngm282/

You can read the complete description at the link above.

Here is another text from a longer Article appeared in the Nature :

"Although the pharmacological effects of exogenous FGF19 in human diseases have only recently begun to be explored, investigation of the biological functions of FGF19 in rodents has identified areas of concern that need to be considered for the translation of FGF19-based therapies into the clinical setting, particularly with regard to the mitogenic potential of FGF19 and implications in hepatic tumorigenesis96, 97, 98, 99, 100, 101, 102. In mice, ectopic expression of FGF19 promoted hepatocyte proliferation, hepatocellular dysplasia and neoplasia96, whereas in HCC specimens, upregulated FGF19 expression was associated with tumour progression and poor prognosis97. This tumorigenic activity has been ascribed to FGFR4, as Fgfr4 deletion or the use of an FGFR4-neutralizing antibody was able to reduce tumour burden upon ectopic FGF19 expression in mice103, 104. Therefore, targeting the FGF19–FGFR4 pathway was found to be effective at inhibiting HCC development in preclinical animal models104, 105.

These studies indicate that FGF19–FGFR4 blockade is a potential approach for the treatment of HCC. However, given the key role of this signalling pathway in bile acid synthesis, potential safety issues (such as on-target toxicity) must be considered, especially in those patients with cholestatic HCC or HCC with partial bile duct obstruction."

nature.com/nrd/journal/v15/...

Published online 16 November 2015

Here is another Article appeared on Science Mag dated 30 Jul 2014

"Abstract

Hepatic accumulation of bile acids is central to the pathogenesis of cholestatic liver diseases. Endocrine hormone fibroblast growth factor 19 (FGF19) may reduce hepatic bile acid levels through modulation of bile acid synthesis and prevent subsequent liver damage. However, FGF19 has also been implicated in hepatocellular carcinogenesis, and consequently, the potential risk from prolonged exposure to supraphysiological levels of the hormone represents a major hurdle for developing an FGF19-based therapy. We describe a nontumorigenic FGF19 variant, M70, which regulates bile acid metabolism and, through inhibition of bile acid synthesis and reduction of excess hepatic bile acid accumulation, protects mice from liver injury induced by either extrahepatic or intrahepatic cholestasis. Administration of M70 in healthy human volunteers potently reduces serum levels of 7α-hydroxy-4-cholesten-3-one, a surrogate marker for the hepatic activity of cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for catalyzing the first and rate-limiting step in the classical bile acid synthetic pathway. This study provides direct evidence for the regulation of bile acid metabolism by FGF19 pathway in humans. On the basis of these results, the development of nontumorigenic FGF19 variants capable of modulating CYP7A1 expression represents an effective approach for the prevention and treatment of cholestatic liver diseases as well as potentially for other disorders associated with bile acid dysregulation."

Authors of the text are seems to be from NGMbio.

Now I cannot know if this is a Marketshare fight between Intercept and NGMbio but....looks like there is a concern about FGF-19. If this concern is real or not is the Job of Scientists.

From this Table

(nature.com/nrd/journal/v15/...

one can see that OCA and NGM282 are being trial in case of PBC.

Should We be now concerned about high levels of FGF-19 during OCA treatment or not?

Sorry for the lengthy message but I thought it could be of interest for some....

Thanks

Beton

[Hidden]

Hello Betonarme.

I've read through your posting but haven't clicked any of the links. (I'm wary of certain links and sometimes my pc either blocks me or warns me re certain sites so I tend to stick with what I know...)

My first thought is quite rightly, it seems that any new drug to the market is to me still a bit experimental and it can be some years before certain things are more known about a drug if there are to be any. Back in the 1960s one drug that was thought to safe for pregnant women who were very nauseous was thalidomide which then turned up disabled children. (My mother was very sick she said years ago when I was expecting my first child. She said she didn't want anything at all possible in pregnancy and didn't.)

With the new OCA (I am in the UK nd it has yet to be marketed here), I do think that it's a case of a patient perhaps taking it due to the fact that there might be nothing else if the urso isn't suitable or perhaps found to be of not much use any longer. The frstrating part and worrying fact is that once we have PBC currently there is no cure and I think that for some, maybe more, as a doctor will say, "the risks outweigh the benefits". I've not thought about one day perhaps some doctor saying to me the urso is of nouse any longer.

[Betonarme in reply to Hidden]

Thanks for your Comments Peridot.

You're right in saying that at one point it comes down to Risks vs. Benefits and one has to decide.

Web sites are all ok...they are all official sites: Nature, FDA, NGMBio(Pharma company).

[Hidden]

Reading your post you have obviously done a lot of reasearch from this I can see that NGMbio have NGM282 that has been engineered to eliminate any potential tumourigenic properties of FGF19.

However I could not see or find anywhere that discusses this from Intercepts perspective regarding OCA, is it not possible they also engineered the FGF19 to eliminate any tumourgenic properties that may or may not be of relevance. Without that it feels to me personally that the publications were just part of the pharmaceutical race to get the product to market.

Iam from the Uk we are not in a position to be offered OCA yet and I think before any such release all of these factors will be taken into account. I am more concerned that we would not get the offer of OCA due to cost.

[Betonarme in reply to Hidden]

"However I could not see or find anywhere that discusses this from Intercepts perspective regarding OCA, is it not possible they also engineered the FGF19 to eliminate any tumourgenic properties that may or may not be of relevance. Without that it feels to me personally that the publications were just part of the pharmaceutical race to get the product to market."

I think OCA is just an Acid (natural or synthetic....I think it's synthetic) and it binds to FXR on the Cell surface. FXR in turn regulates the FGF19 production. So OCA has no control of FGF19s properties but only activates FXR. Looks like the company NGMBio with it's in Lab engineered FGF19(allegedly with no tumourgenic property) bypasses the FXR. This is what I so far understood.

Anyway.....I hope that OCA has no negative side effects if used long time. But I'll keep digging this

Thanks

[Jlruggie in reply to Betonarme]

Thank you Betoname! There's another auto immune drug low dose Naltrexone used for addicts so heroin won't have same effect. They are finding positive results with aids patients. Have you come across this?

Jlruggie

[Betonarme in reply to Jlruggie]

Hi Jlruggie,

No, not heard of it.

Beton

[Jlruggie]

Beton

Thanks for researching Ocaliva. I'm supposed to take it upon recommendation of my hepatologist after she rules out auto immune hepatitis. I didn't take it for fear of side effects but now think I should just for a few months to make my enzymes and liver bile damage reduce. Then just keep taking Urso til enzymes go back up, take Ocaliva lisa again. Then I'd have the least exposure and risk of liver cancer.

Have you heard of anything like this?

Jlruggie

[Betonarme in reply to Jlruggie]

Hi Jlruggie,

not so sure if I understood you well....but as I stated in the beginning of my post,

I'm far from being Expert in the field. So, as a regular person after reading things I just raised a concern to make up a issue. Surely all those Experts working in the Field of Liver will be much better Address to ask.

Let's wait....and see.

Regards

Beton

[PBCRobert Partner]

Thank you for this post.

I have had many conversations about OCA with countless (independent) clinicians and I have never heard of any concerns about FGF-19 and cancer in humans.

I have seen countless presentations, clinical and academic, and not heard the subject raised there either.

Even in being a part of the process of seeing OCA gaining approval by FDA and EMA, I have heard no long-term concerns raised about OCA.

I do know that medicine would be a much simpler sphere if everything that happened in mouse medicine occured in humans. However, this is absolutely not the case.

However, I shall go and find what I can and come back here to answer the question.

Yours,

Robert.

[Karaliz in reply to PBCRobert]

Hello Robert and above posters. I am entering my 4th year on OCA as part of the long term safety extension arm of the trial. ( I live in Australia where OCA is not yet available). I have not heard of any of the concerns raised above in all the time I have been on the trial - was on the placebo for the first year so technically this is my 5th year of being involved with OCA. I would be interested to hear from the PBC experts at the Foundation on this matter.

Best wishes

Karaliz

[Betonarme in reply to PBCRobert]

Thanks Robert!

will be very appreciated.

Best,

Beton