Interview with Prof. Dr. Trauner and Team Nor-urso at the Medical University of Vienna, Austria
The below article is intended as a lay version. However, some paragraphs of this article might be considered very technical and hard to read. We decided to publish it as such, as there are readers who want a more in- depth knowledge about the mechanisms in drugs and drug development, while others can easily skip these specific sub-paragraphs and continue reading without missing any indispensable information. Team Nor-urso was kind enough to provide us with visuals to enhance understanding of the text. And for this matter the author has also added sub-paragraphs, inserted certain synonyms (= synonym), and a glossary at the end of the article.
Nor-ursodeoxycholic acid (nor-urso): In the PSC community, many have heard of the name of this potential new drug, but what is this new drug and how does it work?
Firstly, PSC Patients Europe checked what PSCers want to know about nor-urso, by giving over 3,000 PSC forum members worldwide the opportunity via various Facebook forums to post any questions they had about nor-urso. There were 60 voters from UK, NL, USA and Australia, 7 posts and many likes, resulting in ten added questions to the interview.
Prof. Dr. Michael Trauner M.D. is Professor and Chair of Gastroenterology and Hepatology at the Division of Gastroenterology and Hepatology at Medical University of Vienna (Austria). Honoured to have the opportunity to interview Prof. Dr. Trauner and his team members, I visited the Medical University in Vienna for an interview on a sunny September afternoon. The hospital, where the research is being conducted, is located next to the tube station, very convenient. In one of these two 21-floor towers the beating heart of liver research in Europe is located. The premises is so huge, it almost covers a street block of inner city Vienna.
The warm welcome from Prof. Dr. Trauner (one of the three nor-urso inventors) and Dr. Emina Halilbasic was a great start to gain further information on the promising drug development of nor-urso, currently in Phase 2. And although no hard conclusions can be drawn from this Phase, learning more specifically about the background of nor-urso, the impact of orphan designation for a drug, as well as clinical trials in general, was interesting indeed.
The drug: nor-urso
Most PSCers are familiar with, and often use, UDCA (Ursodeoxycholic acid), aka “urso”. However it is hard to understand what the ‘nor’ stands for in this new drug. In articles, we also often see the reference ’24-nor-ursodexycholic acid’. It turns out that, simply put, the composition of the substance of nor-urso is almost equal to urso.
As such, nor-urso represents also a bile acid like urso the difference being that in nor-urso ‘the 24th carbon element with two accompanying hydrogen atoms’ (called methylene group) is missing in the chemical composition of the side chain of ursodeoxycholic acid. In chemical nomenclature
(= terminology), nor- is used as a prefix to name a structural analog that can be derived from a parent compound by the removal of one carbon atom along with the accompanying hydrogen atoms. That’s why this bile acid is called ‘24-nor-ursodeoxycholic acid’.
Thus, the active drug used in clinical trials represents a synthetically manufactured bile acid that in comparison to wide used urso has small change in chemical structure, this imparting the difference in their therapeutic properties (see Figure 1).
Figure 1: Chemical differences between urso and nor-urso
The mechanism of action of ‘nor-urso’ is complex and researchers assume, based on performed mice studies, it has multiple additional effects than urso:
· First of all nor-urso is more hydrophilic, then the other bile acids, including urso.
Hydrophilic compounds are those that tend to dissolve in water.
(In contrast to them hydrophobic ones naturally repel water, causing droplets to form, are known as hydrophobic). In general, toxicity of the bile acids, as detergents, increases with their hydrophobicity. Thanks to its hydrophilic quality, nor-urso increases the fluidity of the bile and is less toxic than the other bile acids.
· Nor-urso, in addition, increases the bile flow.
Most PSCers know urso makes the bile flow easier, “flushes the biliary system”. It’s even more for nor-urso. The latter will be partially reabsorbed by the bile duct cells and it re-enters the liver cells. This cycling of the compound inside the liver is referred to as ‘cholehepatic shunting’. The less acid there is in the liver, the less damage there will be to the liver.
· In addition, nor-urso is expected to positively influence the removal of harmful and toxic substances of the bile acids (detoxification).
‘Cholehepatic shunting’ allows ductular targeting to the inflamed bile ducts and also stimulates bicarbonate secretion helping to restore the bicarbonate umbrella protecting the bile duct epithelial cells from other toxic bile acids (see Figure 2).
Figure 2: Mechanisms of action of nor-urso
Whether all the effects of nor-urso found in pre-clinical experiments hold true in PSC patients has still to be determined and clinical studies that are going on at present may answer some of the questions. According to the existing data, nor-urso is expected to decrease jaundice, fibrosis and the number occurrence of cholangitis attacks. The researchers are also testing the influence of nor-urso on pruritus (=itch) and general well-being using validated questionnaires. The future studies should consider whether the nor-urso may improve this tiredness (= fatigue) in parallel to ameliorated liver function.
At present nor-urso is tested in adults with PSC or small-duct PSC, in early stage of the disease. The drug has not however been tested in patients with advanced liver disease (in liver cirrhosis and patients with dominant bile duct stenosis) and in children, so researchers are not able to confirm its use in these patient population at this point. When fully developed, the drug will be available worldwide in pill-form and the correct dose will need to be taken once daily. Mentioning to Team Nor-urso, whether a liquid form of the drug, which would be more convenient for a number of PSCers with the swallowing difficulties, has been considered, it was explained that it is too early in the development to know about such directions.
The compound seems to be well-tolerated. However, to know more about the safety and tolerability, the clinical trial needs to be completed. It is also too early to determine the benefits of nor-urso for other related diseases, but the researchers carefully mentioned that if nor-urso works, it could also have benefit in patients with other cholestatic disorders such as PBC, CF and in patient suffering from overlap with AIH.
The clinical trial
Clinical trials are divided into 4 phases:
Number of Participants
Approximate Success Rate
20 to 80
Up to two years
100 – 300
1 to 4 years
1.000 – 3.000
70 to 90%
Currently, the nor-urso trial is in Phase 2 and is conducted in 45 centres from 12 European countries. Only patients without dominant stenosis are considered for the trial since nor-urso will result in increased bile flow and there was a consideration of overburden the bile duct system upstream of biliary stenosis. However, new experimental results done in mice with mechanical obstruction of bile duct disarm this consideration, suggesting that nor-urso may be safe also in presence of dominant stenosis. Strict selection criteria include: 1) Confirmed PSC-diagnosis, 2) AP value more than 1,5 upper limit of normal 3) Bilirubin level not higher than 3. Every 4th patient receives placebo in the clinical trial.
Prof. Dr. Trauner and his team together with other European centres are still recruiting for Phase 2 of this clinical trial which will close by spring 2015. So far, the trial is well on its way and the final results are expected in the first half of 2015.
It is important to note that as the patients in the clinical trial are carefully selected, the results can be biased and may not be representative of all PSC patients. However, the results will determine whether or not it is worth investigating further, thereby moving on to Phase 3.
Depending on the results, it will be decided whether or not to go on with the next phase of the clinical trial. Preparations for the possible Phase 3 are at full speed behind the scenes. One of the things to consider is what an acceptable outcome will be. Possibly, fibrosis stage measured by fibroscan may be considered as valuable outcome parameter for Phase 3. Also, during Phase 3 the researchers would like to know more about the use of nor-urso in combination with other drugs and their interactions. It is expected that Phase 3 may also recruit participants from USA and Canada and is anticipated to commence at the end of 2015.
Orphan Drug Designation
In July 2014 nor-urso was granted ‘Orphan drug’ designation by the European Commission (officially referred to as ‘Orphan Designation’), which was the great news for the PSC community. Among other things, this means that the pharmaceutical company, who owns and developed nor-urso, Falk Pharma, will carry the patent for 11 years instead of the usual 10 years. Orphan drugs are used by fewer patients. Therefore it takes longer for a pharma company to receive a good return on their investment. By lengthening the patent by a year, it is more attractive for a pharma company to research orphan drugs. This is just a fact of life, an economic principle.
There are in fact benefits for both, companies and patients, to have the orphan drug designation. It is expected that administrative approval and other formalities will be easier, therefore saving precious time in the clinical trial process. Also, for certain legal and scientific endpoints that have to be reached, the threshold is lower. It speeds up the complicated and mandatory processes involved with drug development and the drug will be available earlier for patients. However, even if all goes well, it will take at least another 3 to 5 years before the drug will be available. Even though the authorities still do need to be convinced, it is expected that national health insurances will cover nor-urso, thanks to the Orphan drug designation. This will however depend on national decisions and is likely to differ in the various countries.
The researchers are asked which aspect was not covered in the interview and/or something they would like to add. Prof. Dr. Trauner stated he is also very interested in knowing if nor-urso will affect IBD as the drug is expected to also influence the body’s immunological systems. This might be a part of the research during the possible Phase 3 of the clinical trial. Since PSC also carries an increased risk for cancer in the biliary and intestinal tract, potential protective anti-cancer effects will also be explored in the future.
Dr. Halilbasic would like to point out that some patients are in denial of their PSC status and she urges all patients to take good care of themselves, pro-actively seeking the necessary procedures as per the PSC protocol, such as regular MRCPs, bi-annual Dexa scans and others as advised by their health care providers.
There was also an opportunity to discuss the ‘PSC Wish List’, which Team Nor-urso was eager to hear. These are as follows:
- Next scientific paper with a layman’s version
- Please always think of our PSC children
- International Patient Registry: let’s make it happen!
- PSC-friendly MELD score (although in Europe, thanks to the exception rules, the MELD score system is a bit better for European PSCers. For example, the MELD score during your last cholangitis episode is considered)
Team Nor-urso is doing excellent and promising research and they are very willing to inform the PSC community about the progress. At present, it is still too early to have solid conclusions and all are anxiously waiting for the final results of Phase 2, expected in summer 2015 at the latest. It is likely there will be a Phase 3 clinical trial in Europe and North America. The Orphan drug designation status is beneficial for pharmaceutical companies, researchers and patients.
Special thanks to Prof. Dr. Trauner and Dr. Halilbasic.
Natural human bile acid is composed of various bile acids, 2% of which is UDCA. Human bile acids are mainly represented by chenodeoxycholic acid and cholic acid. The UDCA component is, amongst other things, in charge of the bile flow. In all bear species bear bile acid the main component is UDCA, which consists of up to 40% of the bear bile acid. Therefore researchers decided to make a synthetic version of this bear bile, which is urso (‘ursus’ in Latin = bear)
A list of the terminology used in this article with accompanying definitions.
AIH Autoimmune hepatitis
AP / AP value Alkaline phosphatase; enzyme in (human) body / one of LFT’s measured
Bilirubin (~ level) Yellow pigment occurring especially in bile and blood and causing jaundice if accumulated in excess. A blood test shows the bilirubin level.
CF Cystic Fibrosis
Cholestatic Cholestasis = total or partial suppression of the flow of bile
Compound To form (something) by combining separate things
Detoxification To remove a poison or toxin or the effect of such from
Dexa scan Dual Energy X-ray Absorptiometry.
This measures the bone density to determine if there is ‘bone loss’ (osteoporosis)
Epithelial cells Bile duct epithelial cells are cells that form the bile ducts and, consequently, are the major barrier between tissue and bile.
Fibroscan A technique/machine used to assess liver stiffness without invasive investigation
Fibrosis The formation of excess fibrous connective tissue in an organ or tissue
Genetic research The study of human DNA to find out what genes and environmental factors contribute to diseases
Hydrophilicity Tendency to easily be dissolved in water
Hydrophobic Tendency to not dissolve in water
IBD Inflammatory Bowel Disease
Immune system A system of biological structures and processes within an organism that protects against disease
LFT’s Liver Function Test, common tests to see how the liver is functioning
(e.g. ‘blood work’)
Mechanism of action Specific biochemical interaction through which a drug substance produces its pharmacological effect.
Methylene group A divalent hybrocarbon group CH2 derived from methane
Orphan Designation Qualification used by European Medicines Agency (EMA):
check link above for details
Parameter, outcome ~ A rule that controls what something is or how something should be done
Patent Having the exclusive rights over a certain period of time
PBC Primary Biliary Cirrhosis/Cholangitis, a liver disease
Placebo A simulated or otherwise medically ineffective treatment for a medical condition
Stenosis A narrowing or constriction of the diameter of a bodily passage
UDCA Ursodeoxycholic acid
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