Aldafermin for Primary Sclerosing Cholangitis

(ALPINE-PSC Trial)

No longer recruiting at 2 trial locations

Overseen By NGM Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: NGM Biopharmaceuticals, Inc

Disqualifiers: Chronic liver disease, Renal impairment, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called aldafermin (also known as NGM282 or M 52) to determine its potential benefits for individuals with Primary Sclerosing Cholangitis (PSC), a disease affecting the bile ducts and liver. The study compares aldafermin to a placebo (a substance with no active drug) to assess its effectiveness and safety over time. Suitable candidates for this trial should have a confirmed diagnosis of PSC and exhibit signs of liver fibrosis (scarring of the liver tissue) without other major liver or kidney issues. Participants will receive daily injections for up to six years. As a Phase 2, Phase 3 trial, this study evaluates aldafermin's efficacy in a smaller group and represents the final step before FDA approval, offering participants an opportunity to contribute to advancing treatment options.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications.

Is there any evidence suggesting that aldafermin is likely to be safe for humans?

Research has shown that aldafermin, a treatment for Primary Sclerosing Cholangitis (PSC), appears safe. In one study, patients with PSC who took aldafermin showed improved liver health markers. Importantly, the treatment proved safe for patients. An independent board reviewed the safety data and reported that it was well-tolerated, meaning participants experienced few serious side effects. These findings suggest that aldafermin could be a safe option for those considering joining a clinical trial for PSC. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for primary sclerosing cholangitis, which often focus on managing symptoms and complications rather than altering the disease course, aldafermin offers a different approach. Aldafermin is a modified version of the natural protein fibroblast growth factor 19 (FGF19), which plays a role in bile acid regulation and liver growth. Researchers are excited about aldafermin because it targets the underlying causes of liver damage by modulating bile acid levels and reducing inflammation. This mechanism has the potential to not just alleviate symptoms but also slow down or even reverse liver damage, offering hope for a more effective long-term solution.

What evidence suggests that aldafermin might be an effective treatment for Primary Sclerosing Cholangitis?

In this trial, participants will receive either aldafermin (NGM282) or a placebo. Research has shown that aldafermin effectively reduces bile acid production in individuals with Primary Sclerosing Cholangitis (PSC), helping to lower harmful acids in the liver. Additionally, studies have found that aldafermin reduces signs of liver scarring. However, it has not significantly changed levels of alkaline phosphatase (ALP), an enzyme often elevated in liver disease. These findings suggest that aldafermin might help manage liver damage in PSC patients by targeting bile acids and reducing scarring. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

This trial is for people with Primary Sclerosing Cholangitis, a liver condition. Participants should have at least moderate liver fibrosis, normal bilirubin levels unless they have Gilbert's Syndrome, and stable liver function tests. They must not have severe kidney or other serious liver diseases, nor recent bile duct procedures.

Inclusion Criteria

My liver has been diagnosed with stage F2 fibrosis or higher.

Laboratory parameters: TBL ≤2.5 mg/dL unless known for Gilbert's Syndrome, ALT and ALT <5x ULN, MELD score ≤12

Able and willing to give informed consent

Exclusion Criteria

My kidneys do not work well.

I do not have liver disease caused by PSC.

My sclerosing cholangitis is not caused by IgG4.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive aldafermin or placebo subcutaneously, daily, for up to 6 years

6 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Aldafermin

Trial Overview The study is testing Aldafermin against a placebo to see if it helps with Primary Sclerosing Cholangitis. It's conducted across multiple centers where participants are randomly assigned to receive either the actual drug or a dummy drug without knowing which one they get.

How Is the Trial Designed?

Group I: aldafermin Experimental Treatment 1 Intervention

Aldafermin 3mg given subcutaneously, daily, for up to 6 years

Group II: placebo Placebo Group 1 Intervention

Placebo given subcutaneously, daily, for up to 6 years

Aldafermin is already approved in United States for the following indications:

Approved in United States as Aldafermin for:

• Orphan designation for Primary sclerosing cholangitis
• Orphan designation for Primary biliary cirrhosis

Who Is Running the Clinical Trial?

NGM Biopharmaceuticals, Inc

Lead Sponsor

Trials

25

Recruited

2,500+

Published Research Related to This Trial

In a phase II trial involving 62 patients with primary sclerosing cholangitis (PSC), NGM282 did not significantly reduce alkaline phosphatase (ALP) levels, which was the primary endpoint, but it effectively decreased markers of bile acid synthesis and fibrosis, indicating potential benefits in managing PSC.

NGM282 treatment led to significant improvements in fibrosis biomarkers that predict transplant-free survival, suggesting it may help in reducing liver damage despite not affecting standard liver injury markers like ALP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial. Hirschfield, GM., Chazouillères, O., Drenth, JP., et al.[2020]

In a pilot study involving 30 patients with primary sclerosing cholangitis (PSC), treatment with silymarin for one year led to significant improvements in liver enzyme levels, specifically serum alkaline phosphatase and aspartate aminotransferase.

Approximately 34% of patients showed a positive response to silymarin, indicating at least a 50% improvement in liver tests, suggesting that silymarin may be a promising candidate for further research in PSC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Silymarin in the treatment of patients with primary sclerosing cholangitis: an open-label pilot study. Angulo, P., Jorgensen, RA., Kowdley, KV., et al.[2021]

Pemigatinib (PEMAZYRE) received FDA accelerated approval for treating adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion, based on a trial involving 107 patients, showing an overall response rate of 36% and a median duration of response of 9.1 months.

The most common side effects of pemigatinib include hyperphosphatemia and ocular toxicity, highlighting the importance of monitoring these risks during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement. Patel, TH., Marcus, L., Horiba, MN., et al.[2023]

Antibiotic therapy in primary sclerosing cholangitis (PSC) significantly reduced key health markers, including serum alkaline phosphatase (ALP), Mayo PSC Risk Score (MRS), and total serum bilirubin (TSB) by 33.2%, 36.1%, and 28.8%, respectively, based on a systematic review of 5 studies involving 124 patients.

Vancomycin was particularly effective, showing a 65.6% reduction in ALP, while adverse events leading to discontinuation of therapy occurred in 8.9% of patients, indicating that while antibiotics can improve PSC symptoms, they may also cause side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Antibiotic Therapy in Primary Sclerosing Cholangitis with and without Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Shah, A., Crawford, D., Burger, D., et al.[2023]

In a study of 22 patients with primary sclerosing cholangitis (PSC), common symptoms included fatigue, dark urine, and weight loss, with significant biochemical abnormalities observed at admission, such as elevated alkaline phosphatase and bilirubin levels.

Treatment with ursodeoxycholic acid (UDCA) did not show a statistically significant improvement in patient outcomes compared to those not receiving UDCA, indicating that while some patients improved, the therapy may not enhance prognosis overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A clinical and pathological analysis of 22 cases of primary sclerosing cholangitis]. Liu, HH., Fu, JL., Luo, SQ., et al.[2018]

In a review of 10 randomized controlled trials, the combination of metronidazole (MTZ) and ursodeoxycholic acid (UDCA) showed the best outcomes for patient survival and liver histological progression in primary sclerosing cholangitis (PSC).

While UDCA alone significantly reduced bilirubin and alkaline phosphatase (ALP) levels compared to observation, the combination therapy (UDCA plus MTZ) was associated with a higher incidence of adverse events, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A network meta-analysis of the efficacy and side effects of UDCA-based therapies for primary sclerosing cholangitis. Zhu, GQ., Shi, KQ., Huang, GQ., et al.[2018]

In a study of 34 patients with both primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), treatment with the α4 β7 integrin antibody vedolizumab did not lead to significant changes in liver biochemistry, specifically serum alkaline phosphatase levels, after 30 weeks.

Despite the lack of improvement in liver function, vedolizumab was associated with clinical remission in 55% of Crohn's disease patients and 29% of ulcerative colitis patients, indicating its efficacy in managing bowel disease with a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease. Christensen, B., Micic, D., Gibson, PR., et al.[2022]

In a study of 87 newly diagnosed primary sclerosing cholangitis patients, 40% experienced normalization of alkaline phosphatase levels, which was linked to better clinical outcomes.

Patients with normalized alkaline phosphatase had a significantly lower rate of severe outcomes (like liver transplantation or death) compared to those with persistently elevated levels, indicating that normalization may be a positive prognostic indicator.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Stanich, PP., Björnsson, E., Gossard, AA., et al.[2021]

In a 12-week pilot study involving 16 patients with primary sclerosing cholangitis (PSC), oral rifaximin did not significantly change serum alkaline phosphatase levels or other secondary health measures, indicating it may not be effective for treating PSC.

While some patients experienced mild adverse effects, the study concluded that rifaximin appears inefficacious for PSC, suggesting the need for further research into other antibiotics and their potential therapeutic roles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis. Tabibian, JH., Gossard, A., El-Youssef, M., et al.[2021]

In the Phase 2b GLIMMER study involving 147 adults with primary biliary cholangitis and moderate-to-severe itching, linerixibat showed a dose-dependent reduction in itch scores, particularly at higher doses, although the primary analysis did not show significant differences from placebo.

Diarrhea was the most common side effect associated with linerixibat, and its incidence increased with the dose, indicating a need for careful dose management in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Levy, C., Kendrick, S., Bowlus, CL., et al.[2023]

In a study of 35 patients with primary sclerosing cholangitis (PSC), oral vancomycin significantly reduced alkaline phosphatase levels, achieving the primary endpoint with a 43% decrease in the low-dose group and a 40% decrease in the high-dose group.

Both vancomycin and metronidazole showed efficacy in treating PSC, but vancomycin had fewer adverse effects, making it a potentially safer option for patients compared to metronidazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study. Tabibian, JH., Weeding, E., Jorgensen, RA., et al.[2022]

In a pilot study involving 18 patients with autoimmune sclerosing cholangitis (ASC) or primary sclerosing cholangitis (PSC), metronidazole (MTZ) treatment for at least 14 days led to significant reductions in liver enzymes (AST and ALT) and C-reactive protein (CRP), suggesting its potential effectiveness in managing these conditions.

Patients in remission showed an increase in hydrophilic bile acids after MTZ treatment, indicating a possible mechanism of action that could contribute to long-term benefits, especially when administered in the early stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric Autoimmune or Primary Sclerosing Cholangitis: Metronidazole Effectiveness on Biochemical Data, Bile Acid Profile, and Gut Microbiota: A Pilot Study. Karemera, M., Verce, M., Roumain, M., et al.[2023]

Primary sclerosing cholangitis is a rare autoimmune disease with no current treatment options, leading to high rates of severe liver disease and the need for transplants.

Recent advances in understanding the disease's genetics and natural history have paved the way for targeted drug development, with new treatments entering clinical trials, offering hope for patient-specific therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision medicine in primary sclerosing cholangitis. Maurice, JB., Thorburn, D.[2020]

In a study using Mdr2(-/-) mice, 24-norUrsodeoxycholic acid significantly improved liver function and histology, reducing inflammation and fibrosis compared to standard treatment with ursodeoxycholic acid.

The therapeutic effects of 24-norUrsodeoxycholic acid are attributed to its ability to enhance bile acid hydrophilicity, stimulate bile flow, and induce detoxification mechanisms, making it a promising treatment for primary sclerosing cholangitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Fickert, P., Wagner, M., Marschall, HU., et al.[2023]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0168827818325194

Effect of NGM282, an FGF19 analogue, in primary ... In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06654726

NCT06654726 | A Multi-center Evaluation of Aldafermin in ... A multi-center evaluation of aldafermin in a randomized, double-blind, placebo-controlled study in subjects with Primary Sclerosing Cholangitis.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30414864/

Effect of NGM282, an FGF19 analogue, in primary ... In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels.

4. hal.sorbonne-universite.fr hal.sorbonne-universite.fr/hal-02050565v1/document

Effect of NGM282, an FGF19 analogue, in primary ... Lay summary. We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine.

5. jhep-reports.eu jhep-reports.eu/cms/10.1016/j.jhepr.2021.100255/attachment/4f2adcac-fb13-44f5-835e-87772a3b9b0a/mmc4.pdf

a phase 2, randomized, double blind, placebo controlled Significant reductions in serum C4 levels were also observed after administration of NGM282 in normal volunteers (Study 12-0101) as well as in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8056274/

Potent suppression of hydrophobic bile acids by aldafermin ... In a phase II trial in patients with primary sclerosing cholangitis (PSC), aldafermin improved serum markers of fibrosis without affecting alkaline phosphatase ...

7. ngmbio.com ngmbio.com/pipeline/aldafermin/

Aldafermin A potential treatment for patients with primary sclerosing cholangitis. A rare disease with serious unmet need.