Home Blog The Race to Commercialize a NASH Treatment Requires Money, Execution, and Results

The Race to Commercialize a NASH Treatment Requires Money, Execution, and Results

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France-based biotech venture Genfit S.A. (OTCPK: GNFTF) recently filed a preliminary prospectus for an initial public offering (IPO) of 5 million American Depository Shares (ADSs) applying for the ticker symbol GNFT.

Overview

Genfit describes itself as a biopharmaceutical company focused on discovering and developing drug candidates and diagnostic solutions targeting liver diseases, in particular those of metabolic origin, and hepatobiliary diseases. They concentrate their R&D programs in direction of high unmet medical needs corresponding to a lack of approved treatments. Their lead proprietary compound, elafibranor, is a drug candidate currently being evaluated in a Phase 3 study worldwide (RESOLVE-IT) in nonalcoholic steatohepatitis (NASH). NASH is considered by regulatory authorities as urgent because it is silent, with potentially severe consequences, and with a prevalence on the rise. Elafibranor has also obtained positive preliminary results in a Phase 2 clinical trial in primary biliary cholangitis (“PBC”), a severe chronic liver disease. As part of its comprehensive approach to clinical management of NASH patients, the firm is conducting an ambitious discovery and development program aimed at providing patients and physicians with a blood-based test for the diagnosis of NASH, i.e. They position that it will eventually be non-invasive and easy-to-access. Genfit maintains offices in Loos, Lille and Paris, France, and Cambridge, MA (USA), the company has approximately 150 employees.

Genfit was founded in 1999 by current CEO, Jean-Francois Mouney, as well as Bart Staels. Mr. Mouney had been incubating the company since 1997. For several years prior, he had established M&M, a consulting firm focused on health economics as well as an executive with a French economic development agency. Mr. Staels is a world-renowned expert in nuclear receptors. Genfit’s shares were listed on Euronext Paris first on Alternext and thereafter on the regulated market under GNFT since 2006.

Primary Therapeutic Targets

Genfit’s primary therapeutic target is NASH, which has been identified by medical communities worldwide as an emerging health threat. TrialSite News produced an article on the emerging NASH crisis. We noted that with no cure, NASH overlaps with the obesity epidemic. The overall population with NASH ranges from 9% to 36.9%, depending on which part of the world. Some researchers believe that the numbers afflicted with NASH could total 20% to 25% in the U.S. by 2022. We reported that the Wall Street Journal recently interviewed an Allergan executive who noted, “nearly a third of adults in the U.S. have fatty liver while as many as 12% have NASH.” If true, 40 million with NASH makes for a true crisis is in the making—as well as a large treatment market. Genfit is also developing a NASH diagnostic technology that they target for FDA approval by 2020.  

Another Genfit focus area is primary biliary cholangitis (“PBC”), a severe chronic liver disease. It is considered an autoimmune disease of the liver. It is the result of a slow, progressive destruction of the small bile ducts of the liver, thereby causing bile and other toxins to build up in the liver—known as cholestasis. This degradation over time can lead to fibrosis and ultimately cirrhosis. A relatively rare disease, it affects up to 1 in 3-4,000 people. This disease impacts women far more than men, with a 9:1 ratio.

Financials

Upon first glance, Genfit represents a classical pre-profit drug development outfit. In 2018, they generated a net loss of $79.5 million; in 2017 they reported a net loss of $55.7 million. However, upon a further review it is clear that they evolved along a different trajectory. For many of its earlier years the firm was actually profitable—based on a number of co-research partnerships with industry sponsors.

However, over the past decade they have not earned any profits—and the losses have started accumulating to $135.2 million in just the last two years. Any reported income derives from a tax credit as well as proceeds from a sublease of a portion of their corporate headquarters to a third party.

Currently, they hold about $207 million cash and total outstanding debt is $169.5 million primarily in the form of convertible bonds. The prospectus precludes financials from their Euronext listing. TrialSite News estimates their fixed cost structure to be in the neighborhood of $30 million in addition to the capital required for their ongoing critical clinical trials (addressed under pipeline).  

Genfit plans on allocating $50 million of its IPO proceeds for the completion of the elafibranor program in NASH, “through to, at least the submission of an NDA to the FDA and EMA and the launch of a Phase 4 (post market) clinical trial” as reported in its F-1/A. It also plans on spending $15 million on commercial infrastructure and $35 million on a planned Phase 3 trial of elafibranor in PBC. The remainder, upon successful market acceptance of the offering, can potentially be allocated to research on combination therapies involving elafibranor and development of the NASH in-vitro diagnostic test. This latter activity represents, in our opinion, a critical differentiator.

Presently Genfit is valued at $22.90 per share for a total market capitalization of $713.42 million on essentially under $10 million in revenues. 52 week high/low equals $15.54 to $25.88. 31.6 million shares are outstanding.

Pipeline

As reported in their prospectus, the pipeline includes the following:

Programs

Program Indication Dev Stage Timeline
Elafibranor Adult NASH

PBC

Pediatric NASH

Phase 3

Phase 2

Phase 2

Publication of Phase 3 interim results (end of 2019)

Positive Phase 2 data announced Dec 2018

In progress; enrollment expected in early 2019

Nitazoxanide Fibrosis Phase 2 Phase 2 POC initiated; Dec 2018
TGFTX1 Autoimmune Disease Pre-Clin Pre-IND studies (mild to moderate psoriasis)
Diagnostic NASH N/A Finalizing analytical and clinical study designs

2018: alignment with FDA on path forward to validate NIS4

Discovery of two key miRNA biomarkers in 2015

 

TrialSite News provides a more detailed overview of their current clinical trials taken from Clinicaltrials.gov.

Program: Elafibranor

Phase 3 Trial

The primary objectives of this study are to evaluate the effect of elafibranor treatment compared to placebo on 1) histological improvement and 2) all-cause mortality and liver-related outcomes in patients with nonalcoholic steatohepatitis (NASH) and fibrosis.

They estimated a total enrollment of 2000 participants in what is titled “A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and Fibrosis.”  The study started in 2016, was scheduled to end in 202,1 however, they have stated interim results will be ready by end of 2019. Primary and secondary outcome measures are listed on the government site. 316 research sites are listed and range from major academic medical centers to specialty physician sites.   TrialSite News considers this an impressive array of diversified research sites worldwide—with a focus on a NASH program. The Study Director is Pascal Birman, who is also Chief Medical Officer. Dr. Birman has an impressive professional bio, having worked at both Servier in multiple R&D positions, as well as VP Clinical for Ipsen.

Genfit recently completed a PBC Phase 2 trial titled “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy and Safety of Elafibranor at Doses of 80 mg and 120mg After 12 Weeks of Treatment in Patients With Primary Biliary Cholangitis and Inadequate Response to Ursodeoxycholic Acid.” In the table above we highlight that they reported positive results. The French sponsor noted:

  • Elafibranor successfully met primary endpoint with high statistical significance of p<0.001
  • Substantial reductions in alkaline phosphatase in patients receiving elafibranor; 52% (80 mg) and 44% (120 mg) when compared to placebo
  • Significant response rate on composite endpoint used for regulatory approval with 67% (80 mg) and 79% (120 mg) responders vs 6.7% for placebo (p≤0.001)
  • Potential for improved efficacy and tolerability compared to existing second-line PBC therapy, supports advancement to the next stage of development

Genfit presently runs two Phase 1 Elafibranor—both of which are directed by Dr. Birman:

  • Open Label, Phase I Study to Assess and Compare the Pharmacokinetic Parameters After Single Oral Administration of Elafibranor 120 mg in Renal Impaired Patients and Healthy Subjects with Normal Renal Function, a Phase 1 with 24 participants scheduled to complete July 2019. Genfit is working with two primary research sites, including Eurofins Optimed (outsource test company) and ARENSIA Exploratory Medicine Unit, Nephrology Hospital with Carol Davilla in Romania.
  • An Open-label, Phase 1, Single-dose Study to Evaluate the Pharmacokinetics of Elafibranor 120 mg in Adult Subjects with Hepatic Impairment and Adult Healthy Control Subjects.  Genfit is conducting this study in order to assess the need for dose adjustment for elafibranor in patients with hepatic impairment. Pharmacokinetic parameters of elafibranor and its active metabolite (GFT1007) will be compared in hepatic impaired patients (mild, moderate and severe according to Child-Pugh categories) versus healthy participants after a single oral administration of elafibranor 120 mg. They targeted 42 participants and the targeted end date is August 2019.

The study is being conducted in collaboration with two research centers (one being a CRO) including 1) University of Miami, Division of Clinical Pharmacology, Richard A. Preston, MD and 2) Syneos Health, David J. Wyatt, MD.  

NASH Therapy Competitors

NASH represents Genfit’s primary target. The global market is could reach $20 billion by 2025 according to their prospectus. 

This seems overly aggressive to us. We believe that although the NASH crisis is real, it will take further time for new investigational treatments, once approved, to ramp up in the market. As mentioned, we wrote about NASH a few months ago. In May of 2018, Biopharmdive produced a valuable NASH clinical pipeline reports. They noted that BioMedTracker (Informa) generated “48 NASH drugs in clinical trials: 14 at phase I, 30 at Phase 2 and four at Phase 3.” Phase 3 included:

  • Gilead (selonsertib)—an inhibitor of apoptosis signal-regulating kinase 1
  • Allergan (cenicriviroc)—a dual diagnostic of C-C chemokine receptor types 2 and 5
  • Intercept Pharmaceuticals (ocaliva)—obeticholic acid—an agonist of farnesold X receptor
  • Genfit (elafibranor)—a dual diagnostic of peroxisome proliferator-activated receptors alpha & delta 

Analysis

For the rest of our NASH pipeline breakdown follow the link

Yahoo Finance reported on Keith Speights breakdown of Genfit vs. Intercept from Motley Fool. He assigned the following advantages: 

Intercept

  • Intercept’s Ocaliva is already on the market as a treatment for PBC (it is expected to generate north of $170 million in sales), Intercept has a present market capitalization of over $3 billion
  • Ocaliva is the first investigational NASH therapy to be designated “breakthrough therapy” by the FDA making it eligible for expedited review
  • Ocaliva shows promise for improving fibrosis and resolving NASH
  • Intercept reported positive top-line results from a Phase 2 clinical study evaluating the drug in treating primary sclerosing cholangitis (PSC)
  • Intercept is generating revenue from Ocaliva and cash position has accumulated to $489 million—far more than Genfit.
  • Elafibranor Phase 2 results for treating NASH wasn’t what Genfit had planned for—apparently the primary endpoint of significant NASH resolution without a worsening of fibrosis compared to placebo wasn’t achieved.  

Genfit

  • Dual mechanism of action that could reduce triglycerides and promote the metabolism of fatty acid
  • In the Phase 2 trial that evidenced some challenges, “Genfit saw promise for elafibranor in treating patients with more severe fibrosis and modified its design for its phase 3 study” according to the Motley Fool’s Speights.
  • Elafibranor evidenced positive results in the targeting of PBC—both primary and secondary endpoints met
  • Genfit’s NASH diagnostic tool could represent a competitive advantage. As NASH symptoms hide, a diagnostic breakthrough would benefit Genfit positioning in the market. The French sponsor targets 2002 for FDA approval.

Seeking Alpha wrote a report articulating that Intercept has a slight advantage. Additionally, they reported in March 2019 that Intercept was starting to win the NASH battle. According to an Investors.com article, Gilead’s NASH investigational product lagged behind Intercept by at least two years according to RBC Analyst Michael Yee. Just last month, the Xconomy reported that Gilead’s most advanced NASH candidate “failed the first of two Phase 3 trials.” They further reported that Gilead and Allergan “shelled out hundreds of millions of dollars to acquire NASH drug candidates.” Roche has also made NASH purchases. Late last year the FDA published NASH drug development draft guidelines.

The agency has recognized the importance of this emerging health crisis and has proposed endpoints and patient populations. It encourages industry sponsors to focus on in Phase 2 and 3 trials. Factoring in growing health risks, the FDA is considering accelerated approval conditional on Phase 3 data, evidencing that treatments resolve steatohepatitis on overall histopathological readings while maintaining liver fibrosis. On the other hand, the agency may also open up accelerated approval options if investigational NASH treatments improve liver fibrosis by a stage or greater, and in parallel prevents the worsening of steatohepatitis.

Conclusion

Genfit faces other standard drug development risks that the TrialSite News audience knows well. However, they are one of a few ventures that are on the cusp of the opportunity to submit a New Drug Application (NDA) to the FDA for a treatment that will address an emerging health crisis. Moreover, the development of a NASH diagnostic tool with the potential to be approved by the FDA in 2020 represents an intriguing layer to the story. They have assembled an impressive, seasoned leadership team. Their Phase 3 global trial includes an impressive array of over 300 research sites—from major research centers to niche provider networks. They do face some considerable competition—most notably from a bigger, more endowed venture in Intercept. If their Phase 3 trial results are substantially positive, their valuation will undoubtedly soar. Large suitors, such as Gilead, are undoubtedly following this one. Obviously, drug development is a complex, risky affair and many things can go wrong—and often do. The good news is that there is serious drive by market actors to treat NASH. They will be rewarded handsomely if they are successful.

 

Author

Daniel O’Connor

Mr. O’Connor has spent nearly 20 years providing technology and value-added services to the clinical trials and health technology industry. An entrepreneur, he has been instrumental in building different ventures focusing on FDA 21 Part 11 enterprise document management, technology-enabled patient recruitment services, clinical safety data exchange, as well as population health and community care coordination for at-risk populations with Eccovia Solutions. He is a co-founder of a public benefit corporation launching a global clinical research site accreditation standard–ACRES ReServ. At TrialSite News Mr. O’Connor and team have developed a comprehensive clinical research site data base and intelligent clinical news curation engine to contribute to clinical research transparency with a focus on sites and investigators. He earned his combined MA and JD from the University of California (Los Angeles and Hastings College of the Law) and undergraduate from San Francisco State University.

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