Non-alcoholic steatohepatitis or NASH and biliary cholangitis or PBC are two very serious liver diseases affecting millions of people, but with no known cures or effective therapies. The difficult and unsuccessful search so far for breakthrough remedies for these diseases has not deterred the researchers at GENFIT, a clinical stage biotechnology company based in Loos, France.  GENFIT is testing its lead compound elafibranor in both indications.

Without therapeutic intervention NASH can cause the development of fibrosis which leads to progressive loss of liver function and, ultimately, life threatening conditions such as cirrhosis, liver cancer and liver failure – in which patients have no other choice than undergoing a liver transplant. NASH today is the second leading indication for liver transplant behind hepatitis C and is expected to become the primary cause by 2020.

PBC is a relatively uncommon disease, but its prevalence has drastically increased in the US in the last decade with an 80% jump in cases between 2006-2014. Women are more likely to be affected by PBC. The FDA, recognizing the urgent patient need for effective treatments for these indications has granted elafibranor Fast Track status in PBC and Breakthrough Therapy designation for elafibranor in NASH.   

GENFIT has recently signed a $228 MM licensing agreement with Terns Pharmaceuticals – a global biopharmaceutical company based in the U.S. and China – to develop and commercialize elafibranor in Greater China, making it one of the biggest deals of the kind in the region, and a clear vote of confidence coming from experts in the field. With NASH continually growing in the region, it is essential that companies at the forefront of research and development penetrate this market and bring patients treatment options in the near future.

One of the key leaders of GENFIT’s efforts is Pascal Prigent, Executive VP of Marketing and Commercial Development. Prigent has a rich experience with more than 20 years in the pharmaceutical industry holding positions at Eli Lilly and Glaxo Smith Kline (GSK) on three continents including Europe, North America and Latin America. Prior to joining GENFIT Prigent was VP of Marketing for the Vaccines division of GSK where he led the commercial strategy for a multi-billion dollar vaccine portfolio. He holds an MBA from INSEAD  (Institut Européen d’ Administration des Affairse), and is a graduate of Reims Business School.   

WuXi AppTec Communications spoke with Prigent about the research progress of elafibranor, and its  potential as a much needed breakthrough drug product, and what these FDA programs have meant for his company as part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.

WuXi: How is elafibranor a unique compound in NASH, the main indication it’s known for?

Pascal Prigent: Elafibranor, GENFIT’s lead compound is a best-in-class PPAR alpha delta transcription factor developed specifically to treat NASH, a chronic metabolic liver condition affecting millions of people worldwide and closely associated with diabetes and obesity. Because there is no FDA or EMA-approved treatment for NASH today, both regulatory agencies have acknowledged the urgency by granting a Fast Track designation to  elafibranor, which is also evaluated under an accelerated approval process (Subpart H) in order to address the significant unmet clinical needs as fast as possible.

WuXi: How did you demonstrate the potential clinical benefit beyond existing treatments?

Pascal Prigent:  Elafibranor is currently the only therapy in an advanced Phase 3 trial targeting “NASH resolution without worsening of fibrosis” (RESOLVE-IT clinical study). As such, elafibranor could be the first monotherapy to be approved by regulatory agencies for resolving NASH, the underlying cause of disease progression potentially leading to cirrhosis or cancer.

Compelling Phase 2b data published in Gastroenterology, by Ratziu, in May 2016, have shown elafibranor’s unique potential to combine the following: first, efficacy on “NASH resolution without worsening of fibrosis”, second, the FDA/EMA regulatory endpoint that addresses the underlying cause of disease progression; third, improvement of the cardiometabolic risk profile (reduction of LDL and TG, increase of HDL, and improvement of insulin sensitivity), crucial for NASH patients; and fourth, favorable safety and tolerability profile, which is essential for a pharmacological treatment targeting a chronic and silent condition like NASH.

There is today a multitude of treatments in development for NASH, and three advanced competing programs in Phase 3, but none of them meet all of the above criteria: one has failed, one is delayed, and one has achieved fibrosis improvement but missed resolution of NASH. This is why elafibranor’s Phase 3 data, expected by the end of 2019, is considered the next major milestone for the whole NASH space.

Another key differentiation element is that elafibranor is the only drug candidate in phase 3 to be now starting a pediatric trial, based on its unique profile described above. This is an important step given that the condition is growing in this naïve population.

WuXi: Turning to PBC, another serious liver condition, how did elafibranor demonstrate the potential clinical benefit beyond existing treatments to secure the Breakthrough Designation, and what impact will this have for the company?

Pascal Prigent:   Primary Biliary Cholangitis or PBC, is a severe autoimmune liver disease, mainly affecting women. There are currently only two therapies approved for PBC. The first, ursodeoxycholic is flawed in the sense that a significant portion of patients do not respond to the treatment. The second, obeticholic acid is known to cause severe adverse events.  It is also known to generate pruritus, or itching, one of the main symptoms of PBC, which has an immense impact on patient’s quality of life.

PBC is therefore an indication with significant unmet needs with approximately 50% of patients unable to benefit from existing therapies. In a Phase 2 clinical trial, elafibranor showed impressive results on PBC with a significant reduction in alkaline phosphatase, as well as on the composite endpoint used for Phase 3, and on other markers of the disease. This compelling data, presented in detail at EASL 2019 (and selected as ‘best of ILC 2019’), has resulted in the FDA granting elafibranor the Breakthrough Therapy Designation for the treatment of PBC. This is important news for us as a company, as it is the recognition of elafibranor’s potential to become a safe and efficient therapy, but it’s also particularly important for patients, who, for the significant part, cannot benefit from existing therapies. The development of new therapies for PBC represents a real hope for these patients.

It also further increases our level of confidence for the ongoing NASH Phase 3 with elafibranor, as it provides a few strong and positive read across elements, although PBC and NASH populations are different.

WuXi: What role, if any, have patients played in your drug development and clinical trials?

Pascal Prigent: Patients are at the centre of our thoughts and our strategic decision-making process as a company. We have, from our creation to where we are today, always focused our research in areas of significant unmet needs, like NASH and PBC.

Our first goal is to provide patients with safe, tolerable and efficient therapies to improve their health, but also to improve their quality of life.

But one area where we, as a leader in NASH, have an essential role to play is awareness. Liver disease is relatively unknown to the public, and still associated with strong prejudice like alcohol and substance abuse, or sexually transmitted diseases.

This is why we created in 2016 The NASH Education Program, in order to gain essential insights from patients, patients’ families and the medical community and raise awareness in the public. Our goal is also to raise awareness in the medical community, especially for diabetologists, endocrinologists, cardiologists and general practitioners, as they are in the front line for the identification of patients at risk.

The first International NASH Day we organized in 2018 – together with patient advocacy groups, top NASH experts from around the world, and learned societies – has been a tremendous success in more than 25 cities in the US, Europe, Latin America, and Asia. You can also find a rich educational content online, which has been specifically produced for that day.

WuXi: What lessons can other companies learn from your successful drug development experience, and what makes your company different than others in the field of NASH?

Pascal Prigent:  We’ve discussed our therapeutic program as well as our disease awareness program, which are two essential pillars in our strategy. The first reason for success in these programs is related to our innovative thinking, which is part of our DNA as a company. The second reason is that we strive to develop comprehensive approaches to any issue/situation we face. And that’s actually how we came across our decision to work on a third essential piece of the puzzle– our diagnostic program.

Today NASH patients can only be diagnosed with a liver biopsy, an invasive procedure that has a number of limits including potential pain and bleeding. It is also a costly procedure that can only be performed by trained professionals, the number of which is far too limited to identify patients at risk given the magnitude of the problem characterized by the high prevalence of NASH which is up to 12% of the adult population.

To overcome this bottleneck, GENFIT has developed an innovative blood based diagnostic test aimed at identifying patients eligible for treatment, and monitoring them along their medical journey.

To this end, we have signed a deal with LabCorp – a major international player in the diagnostic field – earlier this year to make the test widely available in the clinical community, which is a first step towards commercialization, and we expect to be completed by 2020.

While – as a key player in the space – we’re also part of large consortiums focusing on non-invasive diagnostic (both in the US and in Europe), our diagnostic program is really unique and differentiates us from these large initiatives. Our program capitalizes on a unique databank developed and consolidated by GENFIT over time, and derived from blood samples and biopsies acquired through GENFIT’s pioneering clinical trials in NASH. It uses innovative miRNAs, as key variables used in a patented algorithm and is being developed to answer the most specific and relevant questions in the clinical field, such as “who are the patients eligible for treatment?”

WuXi: What will be the one or two most significant advances in your programs over the next year or two?

Pascal Prigent: 2019 is a very exciting year for us. First, we should be reading out on data at the end of this year or the beginning of next year, and this is a huge milestone that the NASH field has been expecting for many years now. If the trial is successful and elafibranor approved, this means we can move forward with commercialization and follow our expansion as a biopharma company on a world scale. Then, elafibranor should enter a Phase 3 trial in PBC later this year, enter a combination program with GLP1 analogue and/or SGLT2 inhibitor in 2H 2019, and recruit the first pediatric patients.

We should also start commercialization of our blood test in the form of a Laboratory Development Test.

In addition, the results from our nitazoxanide study, a Phase 2 proof of concept study evaluating our proprietary compound NTZ for the treatment of NASH fibrosis, should be announced towards the end of the year or next year.

WuXi:  Finally, have FDA initiatives such as breakthrough therapy and fast track designations, changed the paradigm of clinical drug development? If so, how did it impact your company?

Pascal Prigent: Breakthrough Therapy Designation and Fast Track Designation were initially created by the FDA to fill clinical gaps, and are designed to answer essential unmet medical needs. An area of clinical need is either an area where there is no approved treatment, or where, in the absence of treatment, the risk of progression to a more severe condition is high, as it is the case for NASH today. They can also be given to molecules aiming at treating patients who cannot, for various reasons such as intolerable side effects, benefit from existing therapies, as is the case for PBC.

The main goal for these designations is to bring essential drugs to patients as fast and as safely as possible. This is why they are often closely associated with expedited tools, such as accelerated approval or priority review, which we also benefit from, as it allows the FDA to review the drugs faster and in turn accelerate pre-market development and commercialization efforts.

These processes have truly changed the paradigm of drug development in the sense that they are proof that the FDA recognizes patients’ needs, and that an earlier approval is essential in some indications. For us as a company, both of these designations has meant that we have had facilitated and frequent contacts with the FDA, and that we benefit from seamless communications with the agency. These FDA designations may ultimately allow GENFIT to get approved therapies to patients with unmet medical needs in a more timely fashion.