•Reda Elkhatib 15:05

Hi Dimitar, how are you?

•Dimitar Tonev 15:05

I’m fine, thanks How about you?

•Reda Elkhatib 15:06

I am fine, thanks!Thank you for doing this chat interview with us, to try to raise awareness on NASH during The International NASH day 2020.

•Dimitar Tonev 15:07

Thats a great idea I am privileged to support today.

•Reda Elkhatib 15:09

To start off, I must say you are one of the experts in the NASH field. Could you please describe your experience within NASH and liver diseases?

•Dimitar Tonev 15:09

Sure

I have been involved extensivelly with the clinical development and later market utilisation of new treatments for HBV and HCV, ever since the times we were using conventional interferon. In the last 6-7 years I have refocused my attention to development of agents for the treatment of NASH and smaller liver diseases like PBC and PSC.

I was one of the first medical directors of Intercept (maker of Ocaliva) in Europe and later consulted many small biotech companies on their developmental programs in NASH space, including here diagnostic technologies, devices and even big clinical research organisations like Iqvia.

•Reda Elkhatib 15:14

That’s an impressive career I must say, congratulations and thank you for all the work you have been doing!

•Dimitar Tonev 15:14

Thank you, Reda

•Reda Elkhatib 15:14

To get into it, as you know, NAFLD affects around 25% of the global population and many of these patients develop NASH. Could you describe the health and economic burden on society this disease brings forth?

•Dimitar Tonev 15:14

I agree

recently NASH became the number one reason for a liver transplantation almost everywhere in the developed world, taking this worrisome crown from HCV. Associated mortality and consumption of health care resources is unparalleled in the history of liver diseases.

Its still a subject of debate but NASH probably has a bimodal connection with T2DM-meaning that diabetes drives NASH further and NASH is making diabetes worse.

•Reda Elkhatib 15:18

That really is worrisome!

•Dimitar Tonev 15:18

I know, right?

•Reda Elkhatib 15:19

Even though many patients are affected, and as you say NASH is widely associated with T2DM, there are still many that do not know of the disease. Why do you think that is?

•Dimitar Tonev 15:19

Yes

On one hand that’s the typical issue with other asymptomatic diseases we frequently typify as “iceberg structure”. On the other it’s perhaps due to the fact that the majority of cases are a responsibility of diabetologist and GPs which are rarely focused on the liver health. Minority of these patients develop advanced fibrosis and cirrhosis and are being referred to hepatologists and gastroenterologists.So physicians that see these patients every day are rarely equipped with the tools and know how to recognise an early and perfectly treatable liver disease.

•Reda Elkhatib 15:23

That is really interesting..How should patients know they are at risk and can these patients be diagnosed in any way?

•Dimitar Tonev 15:28

I would suggest our more and better aware patients with risk factors (males, beyond 60, with obesity and T2DM) to start requiring  simple functional liver tests as ALT, AST to be done at their regular follow up sessions with their health provider. These tests are very cheap and easily available everywhere. Given their title specificity, there is a need for a secondary (sometimes called sequential or trigger) more specific biochemical test to be done as well as abdominal sonography (echo) or transient elastography (fibroscan) as a confirmatory methodology.

•Reda Elkhatib 15:30

Those are some good points. A livery biopsy is considered the golden standard by many to determine the diagnosis. Is that still the case, and which patients should go through that procedure?

•Dimitar Tonev 15:32

Yes and no. Currently liver biopsy is not widely recommended for patients in normal clinical practice because the results (so called histology reading) would not change the way these patients are being treated.

As a specific case, if there is a chance and interest on a patients side to be included in advanced Clinica trials (we call those phase IIb and phase III) he or she will have to agree to have one or more liver biopsies. For the time being regulatory drug agencies do all require this histological assessment to be the primary endpoint of all registration studies for potential anti NASH medications.Liver biopsy is a rich and classical source of information about the structure of liver tissue but it’s not without shortcomings and risks.It has been already successfully replaced by other diagnostic modalities in the successful drug development and treatment of diseases like HBV, HCV and PBC.

•Reda Elkhatib 15:37

Certainly, and considering the millions of patients that would require testing, performing a liver biopsy on everyone is not feasible at all!

•Dimitar Tonev 15:38

Exactly

we don’t have the technical ability to do that sophisticated and expensive test to everybody.

•Reda Elkhatib 15:39

Yes, I agree. Especially not on a global scale!

•Dimitar Tonev 15:39

Exactly

•Reda Elkhatib 15:40

What would current treatment options for NASH patients be, since there is no drug available today?

•Dimitar Tonev 15:43

There is currently anecdotal data to support “treatment” with traditional dietary restrictions and physical activity. If we are successful with that and decrease patients body weight with app 10% the liver status will almost completely normalise. The majority of patients would not be able to follow such recommendations for a long enough period of time. They are left with the potential benefits of some diabetic and anti-obesity medications that are currently registered and even reimbursed for these concomitant (coexisting) diseases. FDA will soon discus the potential provisional licence for the first successful Anti NASH medication called obeticholic acid (Ocaliva)

.•Reda Elkhatib 15:45

Yes, excercise and diet are usually treatment programs that do not get followed and that’s a big problem.

•Dimitar Tonev 15:46

Definitely its not easy break the pattern of little physical activity and extra caloric food we are all subjected to…

•Reda Elkhatib 15:46

Do you think it is still necessary to diagnose patients already today, even though no drug is available?

•Dimitar Tonev 15:48

I believe so. Patients with diagnosed NASH (both non-invasive and histological sense) will be ready for clinical trials and new agents when they became available in their area/country. Sometimes extreme obesity could be successfully treated with surgical interventions as balloons and bariatric techniques -some countries even reimburse this fully for patients with BMI>35 or 40.

•Reda Elkhatib 15:49

That is a good point, and I must say that I agree!To conclude, we of course must talk about the current pandemic that has shaken the world. Do you think the Covid-19 outbreak will have any effect on NAFLD and NASH prevalence? Since many people are quarantined with limited access to exercise and a healthy diet.

•Dimitar Tonev 15:50

I’m not sure we see anecdotal increase of folks exercising in parks and fields after lockdown.

•Reda Elkhatib 15:52

That is interesting, I didn’t know that!

•Dimitar Tonev 15:53

On a serious note NAFLD is perhaps an additional risk factor to get serious complications from covid-19 infection. In a recent article patients with NAFLD were 6 times more likely to get complications even if you adjust (compensate) for the underlying diabetes and obesity which are independent risk factors in their own right.The viral environment and associated public believes definitely do delay access to specialists, clinical trials or any other treatments in many cases.

•Reda Elkhatib 15:55

That is really worrisome. The liver has been discussed in research also as one of the affected organs of the virus.

•Dimitar Tonev 15:56

I agree Viral infection does activate certain typical for the liver tests which makes it difficult to control disease activity or the effects of your treatments.

•Reda Elkhatib 15:57

Yes, that is troubling. Let’s hope to see a successfull vaccine developed soon!

•Dimitar Tonev 15:58

I look forward to it as well as more investment in the somehow forgotten Virology drugs.

•Reda Elkhatib 15:59

Yes, I agree

Dimitar, thank you very much for your time and replies, it was a pleasure writing with you and much appreciated!!

•Dimitar Tonev 15:59

Likewise all the best with the rest of this important series of interviews!

•Reda Elkhatib 16:00 Thank you very much, we must all work together to try to raise NASH awareness!

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Abbreviations Used

ALT: Alanine Aminotransferase
AST: Aspartate Aminotransferase
FDA: U.S. Food and Drug Administration
GP: General Practitioner
HBV: Hepatitis B Virus
HCV: Hepatitis C Virus
NAFLD: Non-alcoholic Fatty Liver Disease
NASH: Non-alcoholic Steatohepatitis
PBC: Primary Biliary Cholangitis
PSC: Primary Sclerosing Cholangitis
T2DM: Type 2 Diabetes Mellitus