ALPINE 4: Phase 2b study of NGM282 in Cirrhosis caused by NASH
Research type
Research Study
Full title
Evaluation of Efficacy, Safety and Tolerability of NGM282 (Aldafermin) in a Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Study in Subjects with Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (ALPINE 4)
IRAS ID
273137
Contact name
Quentin Anstee
Contact email
Sponsor organisation
NGM Biopharmaceuticals, Inc.
Eudract number
2019-002341-38
Clinicaltrials.gov Identifier
Duration of Study in the UK
1 years, 7 months, 5 days
Research summary
Research summary- Nonalcoholic Steatohepatitis (NASH) is a one of the most common causes of chronic liver disease in the western world and its estimated prevalence has risen dramatically in parallel with the rise in population levels of obesity and diabetes. NASH is defined as an excessive build up of fat in the liver (steatosis), inflammation and possible fibrosis (tissue scarring) at the time of diagnosis.
The natural history of NASH is variable from patient to patient and the presence of fibrosis has been the only highly predictive factor of patients who will progress to cirrhosis (an advanced stage of fibrosis). There are currently no approved medications for NASH and weight loss through lifestyle management is considered the first-line treatment strategy. Given the increasing disease burden and no approved treatment options, the development of pharmacologic therapies to treat NASH is critical.
Aldafermin is being developed by NGM Pharmaceuticals, Inc as a treatment for NASH. Aldafermin is 95.4% identical to FDF19, a protein found naturally in the body and thought to be involved in bile acid metabolism in the liver. Whilst the potential role of reduced FDF19 activity in the development of NASH isn't fully understood, aldafermin has demonstrated anti-steatotic, anti-inflammatory and anti-fibrotic activities in multiple animal models of NASH.
This is a Phase 2b, randomised, double-blind, placebo-controlled study to evaluate the safety and efficacy of aldafermin compared to placebo in patients with fibrosis stage 4 (F4) cirrhosis due to NASH.
Approximately 150 eligible subjects will be randomised into 1 of 4 treatment groups in a 3:2:2:3 ratio to receive either placebo, 0.3 mg aldafermin, 1 mg aldafermin or 3 mg aldafermin, respectively.
Summary of results- Full title: Evaluation of Efficacy, Safety and Tolerability of NGM282 (Aldafermin) in a Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Study in Subjects with Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (ALPINE 4)
NGM Biopharmaceuticals, Inc., the Sponsor, would like to thank the participants in this clinical study for their time and effort. Study participation allows NGM Biopharmaceuticals, Inc. and the doctors, nurses, and study staff responsible for the study, to examine how well aldafermin works and how safe it is in treating people with cirrhosis (severe liver scarring and damage) caused by nonalcoholic steatohepatitis (NASH).
1. GENERAL INFORMATION ABOUT THE STUDY/WHY WAS THIS STUDY DONE?
This was a study of aldafermin, an investigational medicine, to determine whether it helps people with cirrhosis caused by NASH. NASH is a liver disease in which fat deposits cause the liver to become inflamed and damaged. Cirrhosis occurs when the liver damage advances enough to cause severe scarring.
Aldafermin is designed to reduce liver damage. The main purpose of the study was to evaluate the safety of aldafermin and how well it works for treating cirrhosis caused by NASH. Study participants received either placebo or aldafermin (together, referred to as “study medicine”). Placebo refers to the same treatment protocol except that the study medicine does not contain any aldafermin. Placebo study participants are included to ensure that any effects observed in the study are really related to aldafermin.
The efficacy of aldafermin was measured using the Enhanced Liver Fibrosis (ELF) score. The ELF score is obtained from a blood test that measures the levels of three markers to see the severity of liver fibrosis. It results in a number that estimates the stage of liver disease (the lower the number, the better):ELF score Risk of liver disease progression
Less than 9.8 Lower risk (no to mild or moderate damage)
Between 9.8 and 11.3 Mid risk (severe damage)
More than 11.3 Higher risk (cirrhosis)2. WHEN AND WHERE WAS THE STUDY DONE?
This study started in February 2020 and ended in February 2023.
The study took place in the following countries:Country Number of participants Country Number of participants
Australia 18 participants Hong Kong 5 participants
Belgium 1 participant Poland 2 participants
France 6 participants United Kingdom 3 participants
Germany 4 participants United States 121 participants3. WHO TOOK PART IN THIS STUDY?
Male and female participants in the study had to meet the following criteria among others:
• be aged 18 years to 75 years;
• be diagnosed with cirrhosis caused by NASH;
• agree to use contraception from the beginning of the study until the end of the study.4. WHICH MEDICINES WERE STUDIED?
Aldafermin and placebo were both given as injections under the skin (subcutaneous), once a day (at similar time every day) for 48 weeks (about 11 months). The study was double-blind, what means that neither the participant nor the research team knew which treatment the participant received until the end of the study. Participants were initially assigned to one of 4 possible treatment groups:
• Placebo,
• 0.3 mg/day aldafermin,
• 1 mg/day aldafermin,
• 3 mg/day aldafermin.They had a 3 in 10 (or 30%) chance of receiving placebo and 7 in 10 (or 70%) chance of receiving aldafermin.
The treatment group of 0.3 mg/day aldafermin was closed in March 2021, so participants starting the study afterwards had a 4 in 11 (or 36%) chance of receiving placebo and a 7 in 11 (or 64%) chance of receiving aldafermin (either 1 or 3 mg/day).
Aldafermin may increase cholesterol in the blood. Because of this, participants were eligible to also receive an approved medication to treat high cholesterol called rosuvastatin. Rosuvastatin is not a medication to treat cirrhosis, but was used in the study to treat high cholesterol if needed. To keep the treatment group unknown, participants received either rosuvastatin capsules or placebo capsules (looking the same as rosuvastatin but without any active ingredient) together with the study medicine.5. HOW WAS THE STUDY DONE?
The study consisted of a screening period in which participants had certain tests to see if they qualified for the study; a double-blind treatment period in which participants received the study medicine and rosuvastatin/placebo; and a follow-up period. Participants were in the study for a maximum of 62 to 66 weeks (about 1 year and 2-3 months).
Several procedures were done during the study visits, including blood and urine tests, ultrasound scan of the liver (to get images of the liver), liver biopsy (to collect a tissue sample), questionnaires, and physical examinations, among others6. WHAT WERE THE MAIN RESULTS OF THE STUDY?
In the treatment group of aldafermin 3 mg/day, the risk of liver disease worsening was reduced after treatment. The mean ELF score was reduced (improved) from 10.629 at baseline to 10.409 after 48 weeks for the aldafermin 3 mg/day group, on average. Whereas the mean ELF score was increased (worsened) from 10.585 at baseline to 10.893 after 48 weeks in the placebo group, on average. This means a significant reduction of 4.41% in the ELF score for aldafermin 3 mg/day when compared to placebo (for example from a starting ELF of 10 to between 9.5-9.6).
No significant reduction (improvement) in the ELF score was seen in the other 2 treatment groups with lower doses of aldafermin (0.3 mg/day or 1 mg/day).7. WERE THERE ANY UNWANTED EFFECTS?
Overall, aldafermin was well tolerated in this study across all treatment groups. There were no serious adverse reactions. Adverse reactions are unwanted effects, considered related or unrelated to aldafermin by the investigator. The most common adverse reactions in the study were:
• diarrhea, seen in 25 of every 100 participants receiving aldafermin (or 25%);
• feeling sick (nausea), seen in about 21 of every 100 participants receiving aldafermin (or 21%);
• abdominal swelling (distension), seen in about 9 of every 100 participants receiving aldafermin (or 9%);
• upper abdominal pain, seen in about 8 of every 100 participants receiving aldafermin (or 8%);
• increased appetite seen in about 8 of every 100 participants receiving aldafermin (or 8%);
• headache, seen in about 8 of every 100 participants receiving aldafermin (or 8%);
• frequent bowel movements, seen in about 6 of every 100 participants receiving aldafermin (or 6%);
• tiredness (fatigue), seen in about 6 of every 100 participants receiving aldafermin (or 6%);
• reddening of the skin at the injection site (injection site erythema), seen in about 6 of every 100 participants receiving aldafermin (or 6%).8. HOW HAS THE STUDY HELPED PATIENTS AND RESEARCHERS?
This summary only shows the results from this study, which may be different to the results from other studies.
The information from this study may help the Sponsor and authorities to make decisions if aldafermin should be studied further to see if it can be used to treat cirrhosis caused by nonalcoholic steatohepatitis (NASH).9. ARE THERE ANY PLANS FOR FUTURE STUDIES?
There is a possibility for potential future studies of aldafermin in indications including NASH.REC name
London - Westminster Research Ethics Committee
REC reference
20/LO/0676
Date of REC Opinion
2 Jul 2020
REC opinion
Further Information Favourable Opinion