In an interview with PharmaShots, James E. Brown, President, CEO, and Director of Durect shared his views on the clinical data of DUR-928 in P-1b trial for NASH and P-I trial for Hepatic Impairment

Shots:

• The P-Ib trial evaluates DUR-928 (50/150/600mg for 4wks.) in 65 patients with NASH with stage 1-3 fibrosis which showed improvement from baseline in insulin resistance & liver stiffness, median reductions of HOMA-IR from baseline (22% & 18%) in patients with 50 & 150 mg dose
• The P-I study evaluates a single oral dose of DUR-928 (200mg) in a patient with mod. and sev. HI, which showed median reductions from baseline of the apoptosis biomarker M30 (cCK-18) @12hrs. post-dose, no AEs & dose-limiting toxicity were observed
• The therapy was safe & well tolerated in both studies. The company also plans to start new clinical trial sites and enroll patients in ongoing P-IIb AHFIRM trial for AH patients

Tuba: Discuss the data from the Phase 1b trial supporting the efficacy of DUR-928 in patients with NASH.

James: This Phase 1b randomized, open-label multi-center U.S. clinical trial assessed DUR-928 safety and early signs of efficacy in NASH patients with stage 1-3 fibrosis. DUR-928 was orally administered daily in 65 patients at 50 mg (n=23), 150 mg (n=21), or 600 mg (300 mg BID (n=21)) for 4 weeks and patients were followed up for an additional 4 weeks.

Data from the trial were presented at The Liver Meeting Digital Experience' 2020 (AASLD) and the 2021 International Liver Conference (EASL). DUR-928 led to improvement from baseline in several of the treatment groups in liver enzymes such as ALT, AST, and GGT and serum lipid profiles such as LDL-C, non-HDLC, and triglycerides, in addition to liver fat and biomarkers of liver health, such as CK-18, a cell death biomarker. Dosing of DUR-928 additionally resulted in an improvement from baseline in liver stiffness, assessed by transient elastography (TE), magnetic resonance elastography (MRE) and the liver fibrosis marker pro-C3. 

DUR-928 also showed an approximate 20% median reduction from baseline of HOMA-IR, an important indicator of insulin resistance, observed after only 4 weeks of daily oral administration at the 50 mg and 150 mg dose levels, a similar level of reductions as seen in longer-term studies of several well-established diabetes therapeutics. DUR-928 was well tolerated at all three doses with no serious adverse events reported.

Overall, the promising safety and early efficacy data presented at these two prestigious liver conferences underscore the potential of DUR-928 for the treatment of people with NASH, the most severe form of non-alcoholic fatty liver disease, affecting 3-5% of the U.S. population, with no approved drugs available.

Tuba: Give a glance at Phase 1 data of DUR-928 in Hepatic Impairment.

James: This Phase 1 open-label, multicenter US study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single oral dose of DUR-928 in subjects with moderate and severe hepatic impairment (HI).

Overall, DUR-928 was safe and well-tolerated by all HI subjects with no adverse events and no dose-limiting toxicity reported throughout the study. These safety results are impressive given how sick this patient population is. We also confirmed that, as expected, subjects with impaired liver function had higher drug exposure than matched control subjects with normal liver function and that the more impaired the liver was, the higher the drug exposure was. We believe that this is a promising finding as patients with more impaired livers may benefit from more exposure to DUR-928. An equally exciting finding was that a single oral dose of DUR-928 resulted in a statistically significant median reduction from baseline of the apoptosis (cell death) biomarker M30 (cCK-18) at 12 hours post-dose.

Tuba: What are the key takeaways of the DUR-928 posters presented at EASL 2021?

James: The totality of the safety and early efficacy data presented at EASL this year in nonalcoholic steatohepatitis (NASH) and hepatic impairment (HI) patients, together with outstanding safety and efficacy profiles observed in a previously completed Phase 2a trial evaluating DUR-928 in patients with alcohol-associated hepatitis (AH), highlights the potential of DUR-928 to treat multiple severe chronics and acute liver diseases. 

Tuba: Are you planning to evaluate DUR-928 in other indications?

James: DURECT's lead indication for DUR-928 is alcohol-associated hepatitis (AH), a life-threatening acute liver disease with no approved treatment and a 26% mortality rate within 28 days of hospitalization, higher than most cancers. What physicians have available to them today primarily involves abstinence and supportive care, which includes nutrition and hydration. Corticosteroids are used in some cases but have been shown to have no survival benefit at 90 days or 1 year. 

Unfortunately, even before the COVID-19 pandemic, the incidence of AH was increasing in younger patients and during the pandemic alcohol consumption in the US has increased by about 30%. AH has a significant economic cost to the healthcare system as well. The average hospitalization cost for an AH patient is more than $50,000 in the first year and there are about 132,000 hospitalizations per year in the US. Alcoholic liver disease is becoming a leading cause of liver transplants in the US and the cost of a liver transplant exceeds $875,000. We estimate the annual cost of AH to the US healthcare system to be as high as $6 billion. 

Results from a completed Phase 2a trial evaluating DUR-928 in 19 AH patients showed that 100% of the patients treated with DUR-928 lived past 28 days. Based on the degree of liver damage in these patients, historical data suggests that several of them were likely to not survive 28 days, yet all of them did survive. In addition, 14 of the 19 patients left the hospital within four days of receiving a single dose. DUR-928 was well tolerated in all patients with no serious drug-related adverse events reported in the trial. Based on this encouraging data and the high degree of unmet need, the FDA granted Fast Track Designation for DUR-928 in the treatment of AH.

The company is currently advancing a double-blind, placebo-controlled Phase 2b clinical trial, AHFIRM, to evaluate DUR-928's life-saving ability in approximately 300 patients with severe AH. In the US, we have now opened about 75% of the planned US clinical sites, and are on track to open additional sites in the UK, Europe, and Australia in the coming months. 

In parallel, DURECT continues to explore NASH and other potential acute and chronic indications that could benefit from DUR-928's unique mechanism of action. 

Tuba: What is DUR-928? Discuss epigenetic regulation and DUR-928's MOA and its potential to treat multiple liver diseases. 

James: DUR-928 is an endogenous epigenetic regulator. The vast majority of what is in the nucleus of a cell is not DNA but proteins and other molecules that determine which genes are expressed and are known as the epigenome. DUR-928 binds to and inhibits the activity of DNMT-1, 3a, and 3b, which are epigenetic regulating enzymes that add methyl groups to DNA in a process called DNA methylation. 

DNA methylation and demethylation regulate the expression of genes, especially clusters of master genes that further modulate crucial cellular activities. DNA hypermethylation has been associated with certain diseases, including alcohol-associated hepatitis (AH) and non-alcoholic steatohepatitis (NASH).

By inhibiting DNMT activity, DUR-928 inhibits DNA methylation thereby regulating the expression of genes that modulate crucial cellular activities including those associated with cell death, stress response, and lipid biosynthesis.

These modulations can lead to improved organ function and survival, reduced lipid accumulation, and inflammation, as we have observed in various in vivo animal models and the promising results from our completed clinical trials in AH and NASH.

Tuba: What motivates you to work on NASH and other hepatic diseases? Do you feel competition in this space?

James: Let me start with our lead indication of alcohol-associated hepatitis or AH. These patients are hospitalized and facing a high risk of mortality within a short period, with 29% mortality within 90 days of hospitalization. There are currently no treatments approved, so these patients are in desperate need of treatment. The best you can hope for when you develop a drug is that it will save patients lives. We believe that DUR-928 has that potential and that possibility drives us every day. 

NASH is a chronic disease that also has no currently approved therapeutics. The time course of the disease is much longer than AH, but some NASH patients do advance to where the disease can cause liver failure and mortality. We believe DUR-928's mechanism of action is well-suited for treating both AH and NASH and are motivated by the prospect of improving or even potentially saving the lives of many patients in need.

Regarding competition, there are no drugs approved to treat AH. The drugs used today have been shown not to improve the long-term survival of AH patients. There are other clinical trials evaluating drugs approved for other indications to see if they might be helpful in AH, but we have not seen anything comparable to the outstanding clinical benefit we saw in our Phase 2a trial. In NASH, there are several other therapeutics in development but, we do not believe any of them have demonstrated the breadth of activity combined with the safety profile we have seen with DUR-928. DUR-928 has a unique mechanism of action and is the first epigenetic regulator in development for these difficult-to-treat indications. 

 We believe it has great potential and could change the treatment landscape for AH patients and potentially many other acute organ injuries and certain chronic diseases, including NASH. 

Tuba: Do you think this drug will bring change in the lives of patients with hepatic disorders?

James: As I mentioned in the previous question, we are evaluating DUR-928's ability to save the lives of hospitalized AH patients. One aspect of this that may not be appreciated is that some AH patients at the highest risk of death receive liver transplants if they meet strict eligibility requirements and a liver is available for them. If DUR-928 can reverse the course of that patient's AH, the donated liver that would have gone to that patient would now be available for another patient waiting on the liver transplant list. So, saving one AH patient's life may also save the life of the patient who was next in line on the transplant list. 

Considering the outstanding safety and efficacy data observed for alcohol-associated hepatitis (AH) in our Phase 2a trial, DUR-928 has the potential to fundamentally change the lives of these patients. We are talking about a disease for which about a quarter of hospitalized patients die within a month, and all patients treated with DUR-928 during our Phase 2a trial survived the 28-day follow-up period. Three-fourths even went home after the first 4 days. 

The safety and initial efficacy data observed during our Phase 1 trials in nonalcoholic steatohepatitis (NASH) and hepatic impairment (HI) patients add to the body of evidence supporting the potential of DUR-928 to change the lives of many patients with hepatic disorders that currently lack treatment options. 

Tuba: Discuss the growth of the company and its plans in the coming future.

James: This is a very exciting time for DURECT. If we can demonstrate a robust mortality benefit in our ongoing AHFIRM trial, we believe it will support an NDA filing. In addition to the possibility of saving AH patients lives, one of the exciting things about AH from a corporate standpoint is that we believe it would also be an attractive commercial opportunity to create value for our shareholders and save the healthcare system significant money at the same time. Each AH patient costs the healthcare system over $50,000 on average, largely in the form of long hospital stays, sometimes in the ICU. We believe AH represents an attractive opportunity for the company to develop its commercial team and launch our first pharmaceutical product.

We also believe that DUR-928's mechanism of action may address underlying epigenetic dysregulation associated with many additional acute and chronic conditions, including NASH.

Source: Depositphotos

About Author: James E. Brown is the President, CEO, and a Director of Durect. He holds a BA from San Jose State University and a D.V.M. (Doctor of Veterinary Medicine) from the University of California, Davis where he also conducted post-graduate work in pharmacology and toxicology. He previously worked at ALZA Corporation as Vice President of Biopharmaceutical and Implant Research and Development

Related Post: Exclusive Interview with PharmaShots: Ron Elwell of IPM.ai Shares Insight on the Simplification of Patient Recruitment by Applying AI and ML to Real-World Data