ALN-HSD for NASH with Fibrosis

(NASHGEN-2 Trial)

Recruiting at 72 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Regeneron Pharmaceuticals

Disqualifiers: Chronic liver disease, Substance abuse, Diabetes, Bariatric surgery, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, ALN-HSD, to determine if it can reduce liver scarring in individuals with MASH. MASH is a liver disease characterized by fat accumulation, which causes damage, inflammation, and scarring. The trial also seeks to understand the drug's effects on liver function and its side effects. Participants must have a diagnosis of MASH with fibrosis and meet specific screening criteria. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that ALN-HSD is likely to be safe for humans?

Research has shown that ALN-HSD is safe in studies involving both healthy adults and those with nonalcoholic steatohepatitis (NASH). In a previous study, researchers reported no safety problems, indicating that the treatment was well-tolerated. Another study found positive safety results, with participants experiencing no major side effects. These findings suggest that ALN-HSD could be a safe option for people with MASH (metabolic dysfunction-associated steatohepatitis) interested in joining clinical trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for MASH?

Unlike the standard treatments for NASH with fibrosis, which often focus on managing symptoms or underlying conditions like diabetes and obesity, ALN-HSD works by targeting a novel mechanism in the liver. ALN-HSD is designed to specifically inhibit an enzyme called HSD17B13, which has been implicated in the progression of liver disease. Researchers are excited about ALN-HSD because by directly targeting this enzyme, it might slow or even reverse liver damage more effectively than current therapies. This targeted approach could lead to more precise and potentially more effective management of NASH with fibrosis.

What evidence suggests that ALN-HSD might be an effective treatment for MASH?

Research shows that ALN-HSD, which participants in this trial may receive, may help treat a liver condition called metabolic dysfunction-associated steatohepatitis (MASH). In earlier studies, ALN-HSD significantly reduced a protein called HSD17B13, linked to liver inflammation and scarring. Another study found that patients taking ALN-HSD improved liver scarring without worsening liver damage. These findings suggest that ALN-HSD could help reduce liver scarring and inflammation, major problems in MASH. Early trials also showed that ALN-HSD is generally safe and well-tolerated. ^{4 6 7 8 9}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults with a condition called NASH, where fat buildup leads to liver inflammation and scarring. Participants must have a certain level of liver damage (stage 2 or 3 fibrosis) and meet specific genetic criteria.

Inclusion Criteria

My genetic test results match the study's requirements.

Exclusion Criteria

History of Type 1 diabetes

I have a long-term liver condition.

I had or plan to have weight-loss surgery within the last 5 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the study drug ALN-HSD or placebo to assess its effect on liver scarring related to NASH

52 weeks

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ALN-HSD
• Placebo

Trial Overview The study tests ALN-HSD, an investigational drug, against a placebo to see if it can reduce liver scarring in NASH patients. It also examines how the body processes the drug and its effects on liver function and inflammation.

How Is the Trial Designed?

Group I: ALN-HSD Experimental Treatment 1 Intervention

Randomized 1:1

Group II: Placebo Placebo Group 1 Intervention

Randomized 1:1

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Published Research Related to This Trial

In a study involving Wistar rats with non-alcoholic steatohepatitis (NASH), treatment with β-hydroxyphosphocarnitine (β-HPC) for 4 weeks significantly reduced liver inflammation, necrosis, and fibrosis, indicating its potential efficacy in improving liver health.

The treatment with β-HPC also led to a notable decrease in triglyceride levels and did not cause any adverse effects on liver enzyme function, suggesting it may be a safe option for managing NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

β-Hydroxyphosphocarnitine modifies fibrosis, steatosis and improves liver function in non-alcoholic steatohepatitis induced in rats. Sánchez-Quevedo, J., Ocampo-Rodríguez, E., Alvarez-Ayala, E., et al.[2022]

Obeticholic acid (OCA), an FXR agonist, has shown significant improvement in hepatic fibrosis for patients with NASH stage 2/3 in a phase 3 trial, although it has side effects like itching and increased LDL cholesterol.

Several other treatments, including selonsertib and emricasan, were discontinued due to lack of efficacy, while new agents and combination therapies are being explored in ongoing phase 3 trials, indicating a continued search for effective NASH treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and new pharmacotherapy options for non-alcoholic steatohepatitis. Sumida, Y., Yoneda, M., Ogawa, Y., et al.[2022]

Nonalcoholic fatty liver disease (NAFLD), now also known as metabolic dysfunction associated fatty liver disease (MAFLD), affects about 25% of the global population and can progress from benign liver fat accumulation to more severe conditions like non-alcoholic steatohepatitis (NASH).

NASH is linked to serious liver complications, including fibrosis, cirrhosis, and liver cancer, with the activation of hepatic stellate cells (HSC) playing a crucial role in the development of fibrosis, highlighting the importance of understanding the cellular interactions involved in this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD). Subramanian, P., Hampe, J., Tacke, F., et al.[2022]

Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), is linked to liver damage and increased cardiovascular risk due to complex interactions between liver cells, including hepatocytes, hepatic stellate cells, and macrophages.

The activation of hepatic stem/progenitor cells (HPCs) in response to oxidative stress contributes to liver damage and fibrosis in NASH, suggesting that targeting these cellular interactions and the role of adipokines could be crucial for developing new treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of hepatic progenitor cells in nonalcoholic fatty liver disease development: cellular cross-talks and molecular networks. Carpino, G., Renzi, A., Onori, P., et al.[2021]

Leonurine hydrochloride (LH) demonstrated hepatoprotective effects in both cell and rodent models of non-alcoholic steatohepatitis (NASH), significantly improving lipid accumulation and liver enzyme levels in a dose-dependent manner over 6 weeks.

The mechanism of LH's action appears to involve the AMPK/SREBP1 pathway, as it upregulated AMPK phosphorylation and downregulated SREBP-1c and its target genes, suggesting a novel therapeutic approach for treating NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel hepatoprotective role of Leonurine hydrochloride against experimental non-alcoholic steatohepatitis mediated via AMPK/SREBP1 signaling pathway. Zhang, L., Li, HX., Pan, WS., et al.[2019]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0168827825022706

Phase I randomized double-blind study of an RNA ... In conclusion, rapirosiran exhibited an encouraging safety and tolerability profile in the phase I ALN-HSD-001 study, with robust reduction in liver HSD17B13 ...

2. investors.alnylam.com investors.alnylam.com/press-release?id=26976

Alnylam Pharmaceuticals Press Release | Sep 15, 2022 Alnylam and Regeneron report promising data from ongoing Phase 1 study of ALN-HSD in NASH patients and healthy volunteers.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05519475

Study Details | NCT05519475 | A Precision Medicine ... Improvement of non-alcoholic steatohepatitis clinical research network (NASH-CRN) fibrosis (F) stage by ≥1 stage without worsening of MASH on liver biopsy ...

4. withpower.com withpower.com/trial/phase-2-non-alcoholic-steatohepatitis-nash-9-2022-0294b

ALN-HSD for NASH with Fibrosis (NASHGEN-2 Trial) This trial is testing a new drug called ALN-HSD to help people with a liver disease called NASH. NASH causes fat to build up in the liver, leading to damage ...

5. natap.org natap.org/2023/EASL/EASL_68.htm

Early Trials of siRNA ALN-HSD for NASH Show ... - NATAP NAFLD activity score averaged 4.2 in the placebo group and 4.4 in those getting ALN-HSD. Fibrosis stage averaged 1.6 in people receiving placebo ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04565717

NCT04565717 | A Study of ALN-HSD in Healthy Adult ... No safety issues were found. A Study of ALN-HSD in Healthy Adult Subjects and Adult Patients With Nonalcoholic Steatohepatitis (NASH). ClinicalTrials.gov ID ...

7. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/regeneron-and-alnylam-report-promising-data-ongoing-phase-1

Regeneron and Alnylam Report Promising Data from ... Regeneron and Alnylam report promising data from ongoing Phase 1 study of ALN-HSD in NASH patients and healthy volunteers.

8. capella.alnylam.com capella.alnylam.com/wp-content/uploads/2023/06/ALN-HSD-Phase-1_EASL-2023_FINAL.pdf

Phase 1 Study of the RNA Interference Therapeutic ALN-HSD ... • In this phase 1 study, ALN-HSD exhibited an encouraging safety ... nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36513186/

A phase I/II study of ARO-HSD, an RNA interference ... In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH.