3 Agents to Watch for Decompensated Cirrhosis from NASH

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The development of effective treatments for the management of nonalcoholic steatohepatitis (NASH) has captivated the medical community in recent years.

However, among the 33 late-stage pipeline items in development for NASH, just 3 focus on decompensated cirrhosis due to NASH: HepaStem, BIV201, and Albutein.¹

“Notably, as the NASH market continues to see approvals for agents focusing on cirrhosis improvement and liver regeneration that are indicated for patients in the earlier stages of NASH, the need for a treatment option for DC due to NASH will decrease as fewer patients develop DC. Until that point is reached, it remains to be seen whether or not HepaStem, BIV201, and Albutein will perform and gain approval,” said Sravani Meka, senior immunology analyst at GlobalData.¹

HepaStem

• HepaStem is a therapy for the treatment of Acute-on-Chronic Liver Failure (ACLF) involving liver derived stem cells obtained from ethically donated healthy human organs and expanded in GMP culture conditions.²
• The DHELIVER study, a phase 2b clinical trial announced by Promethera on January 8, 2020, was designed to evaluate the safety and efficacy of HepaStem on overall survival 90 days post-infusion. Secondary trial objectives included additional efficacy assessments such as transplantation-free survival and continued evaluation of the treatment’s safety.²
• The randomized, placebo-controlled, double-blinded, multicenter trial targeted enrollment of 363 patients with ACLF at 110 study sites across 22 countries in Europe. The 2 treatment arms were patients receiving two weekly intravenous infusions of HepaStem and patients receiving placebo.²
• In the prior HEP101 trial, HepaStem was proven safe and tolerable in single or repeated injections in a total of 24 patients with ACLF or acute decompensation at high risk of developing ACLF. No adverse events related to HepaStem occurred in the 3 months follow-up period and no clinically significant changes were shown in platelet count, fibrinogen levels, and coagulation factors following infusion. Of note, the study also showed preliminary signs of efficacy with improvement in Model for End Stage Liver Disease score (MELD), Child-Pugh score, and bilirubin levels 28 days and three months after treatment initiation.²

“ACLF is a severe, life threatening disease, with no current available treatments. The only option for patients is organ transplant, which is a major procedure and often not accessible. HepaStem has the potential to be the first real alternative to liver transplants in such a disease, and help ACLF patients in need,” said John Tchelingerian, PhD, president and chief executive officer of the Promethera Group.²

BIV201

• The phase 2b clinical trial NCT04112199 was designed to evaluate the efficacy of BIV201 combined with standard of care for the treatment of refractory ascites due to liver cirrhosis among 30 patients treated in a home care setting.³
• Terlipressin was administered with a continuous low dose infusion through a portable pump in two 28-day treatment cycles. The primary endpoints were the incidence of complications of at least Grade 2 severity, and the change in cumulative ascites in the 12-week period following randomization compared to a 12-week pre-treatment period.³
• The phase 2b clinical trial was paused on March 13, 2023 following encouraging data from the first 15 patients. Treatment with BIV201 plus standard of care resulted in a 34% reduction in ascites fluid 28 days after treatment initiation compared to the 28 days prior to treatment (P = .0046). Patients treated with standard of care experienced a 3.1% mean increase in ascites fluid (P = .05).³
• Patients who completed the treatment with BIV201 experienced a 53% reduction in ascites fluid (P = .001), which was significantly different from those treated with standard of care (P = .007). This improvement was sustained during the 3 months after treatment initiation compared to the 3-month pre-treatment period (43% reduction, P = .06).³

“Compelling data from the first 15 patients led us to pause enrollment,” commented Cuong Do, president and CEO of BioVie.³ “Given the high unmet need for this condition, we believe the most prudent course is to initiate conversations with the FDA on proceeding to the pivotal Phase 3 trial so that we can bring this innovation to patients as quickly as possible.”

Albumin-Human Injection

• PRECIOSA is a phase 3, multicenter, randomized, controlled, parallel-group, and open-label clinical trial designed to determine the potential of long-term albumin treatment with Albutein, dosed every 10 ± 2 days for up to 12 months, to increase survival time in patients with decompensated cirrhosis and ascites.⁴
• In July 2023, the multi-center, randomized, controlled, parallel-group, open-label study enrolled more than 400 patients with decompensated cirrhosis with ascites in 69 sites across North America and Europe.⁴
• Participants included patients discharged after hospitalization for acute decompensation of liver cirrhosis with ascites, or with prior history of ascites requiring diuretic therapy, without ACLF at discharge.⁵
• The primary outcome of interest was time to liver transplantation or death through 1 year after randomization in subjects receiving standard medical treatment and Albutein 20% administration versus subjects receiving standard medical treatment alone. Secondary outcomes included total number of paracentesis through 1 year after randomization and total number of incidences of refractory ascites through 1 year after randomization.⁵
• Topline data from the study is expected in the fourth quarter of 2024.⁵

“There is great potential for albumin to improve the survival prospects of patients suffering from decompensated cirrhosis until they can get a liver transplant, a large unmet need given the limited availability of livers for patients,” said Sandra Camprubi, senior director of clinical operations for Grifols.⁴

References:

1. GlobalData. HepaStem seems most promising pipeline agent for decompensated cirrhosis due to NASH, says GlobalData. Pharma. September 13, 2023. Accessed September 14, 2023. https://www.globaldata.com/media/pharma/hepastem-seems-promising-pipeline-agent-decompensated-cirrhosis-due-nash-says-globaldata/
2. BioSpace. Promethera® Announces Initiation of Phase 2b DHELIVER Study of HepaStem™ in Patients with Acute-on-Chronic Liver Failure (ACLF). News. January 8, 2020. Accessed September 14, 2023. https://www.biospace.com/article/releases/promethera-announces-initiation-of-phase-2b-dheliver-study-of-hepastem-in-patients-with-acute-on-chronic-liver-failure-aclf-/
3. GlobalNewswire. BioVie Announces the Pausing of Patient Enrollment in Ascites Phase 2b Trial, Encouraging Efficacy Data is Announced, Initiating FDA Discussions to Conduct Pivotal Registrational Trial. Newsroom. March 13, 2023. Accessed September 14, 2023. https://www.globenewswire.com/en/news-release/2023/03/13/2625654/0/en/BioVie-Announces-the-Pausing-of-Patient-Enrollment-in-Ascites-Phase-2b-Trial-Encouraging-Efficacy-Data-is-Announced-Initiating-FDA-Discussions-to-Conduct-Pivotal-Registrational-Tri.html
4. Grifols. Grifols completes enrollment in phase 3 study of long-term Albutein® (albumin-human injection) therapy for patients with decompensated cirrhosis. Newsroom. July 18, 2023. Accessed September 14, 2023. https://www.grifols.com/en/view-news/-/news/grifols-completes-enrollment-in-phase-3-study-of-long-term-albutein-albumin-human-injection-therapy-for-patients-with-decompensated-cirrhosis
5. Clinicaltrials.gov. Effects of Long-Term Administration of Human Albumin in Subjects With Decompensated Cirrhosis and Ascites (PRECIOSA). Study Record Detail. August 22, 2023. Accessed September 14, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03451292?