Aldafermin for Primary Sclerosing Cholangitis

(ALPINE-PSC Trial)

Recruiting at 2 trial locations

Overseen By NGM Study Director

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Waitlist Available

Sponsor: NGM Biopharmaceuticals, Inc

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

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

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.

What data supports the idea that Aldafermin for Primary Sclerosing Cholangitis (also known as: Aldafermin, NGM282, M 52) is an effective treatment?

The available research does not provide specific data on Aldafermin for treating Primary Sclerosing Cholangitis. Instead, it discusses other treatments like ursodeoxycholic acid (UDCA) and antibiotics such as vancomycin and metronidazole. These studies explore their effects on the condition, but there is no direct comparison or mention of Aldafermin's effectiveness in the provided information. ^{1 2 3 4 5}

What safety data is available for Aldafermin (NGM282) in treating Primary Sclerosing Cholangitis?

The safety of NGM282, an FGF19 analogue, was assessed in a multicenter, randomized, double-blind, placebo-controlled phase II trial for patients with Primary Sclerosing Cholangitis. However, the specific safety data details are not provided in the abstract. ^{6 7 8 9 10}

Is the drug Aldafermin a promising treatment for primary sclerosing cholangitis?

The information provided does not directly mention Aldafermin or its effects on primary sclerosing cholangitis, so we cannot determine if it is a promising treatment based on this data. ^{6 11 12 13 14}

Eligibility Criteria

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.

Treatment Details

Interventions

• Aldafermin (Peptide)

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.

Participant Groups

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

Who Is Running the Clinical Trial?

NGM Biopharmaceuticals, Inc

Lead Sponsor

Trials

25

Recruited

2,500+

Findings from Research

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 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 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]

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 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 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]

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]

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]

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 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]

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 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]

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]

References

1. China pubmed.ncbi.nlm.nih.gov

[A clinical and pathological analysis of 22 cases of primary sclerosing cholangitis]. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

A network meta-analysis of the efficacy and side effects of UDCA-based therapies for primary sclerosing cholangitis. [2018]

4. England 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. [2022]

5. Australia pubmed.ncbi.nlm.nih.gov

Precision medicine in primary sclerosing cholangitis. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis. [2021]

7. Netherlands 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. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. [2023]

10. United States 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. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Silymarin in the treatment of patients with primary sclerosing cholangitis: an open-label pilot study. [2021]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. [2021]

13. United States 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. [2023]

14. United States pubmed.ncbi.nlm.nih.gov

24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. [2023]