Delving into the Latest Updates on Aldafermin with Synapse

Overview

Basic Info

Drug Type

Growth factors

Synonyms

(phe5>met,ser6>arg,ala8>ser,gly9>ser,his11>leu) fibroblast growth factor 19 (human fgf19) (5-194)-peptide, produced in escherichia coli, Aldafermin (USAN/INN), Engineered variant of recombinant human fibroblast growth factor 19

+ [3]

Target

FGFR1 x FGFR4 x KLB

Mechanism

FGFR1 stimulants(Fibroblast growth factor receptor 1 stimulants), FGFR4 agonists(Fibroblast growth factor receptor 4 agonists), KLB agonists(Klotho beta agonists)

Therapeutic Areas

Digestive System DisordersEndocrinology and Metabolic DiseaseOther Diseases

Active Indication

Cholangitis, SclerosingBile acid malabsorptionChronic diarrhea+ [4]

Inactive Indication

Constipation - functionalDiabetes Mellitus, Type 2Mandibuloacral Dysplasia With Type a Lipodystrophy+ [2]

Originator Organization

NGM Biopharmaceuticals, Inc.

Active Organization

NGM Biopharmaceuticals, Inc.

Inactive Organization-

Drug Highest PhasePhase 2/3

First Approval Date-

RegulationOrphan Drug (US)

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Gene Sequence

Sequence Code 9579683

Source: *****

This single-center, randomized, double-blind, placebo-controlled study is designed to compare effects of aldafermin, (NGM282), 1 mg, and placebo given daily by subcutaneous injection on bowel functions and hepatic synthesis and fecal excretion of bile acids in patients with diarrhea associated with bile acid malabsorption (BAM).

Start Date01 Dec 2021

Sponsor / Collaborator

Mayo Clinic

[+1]

NCT04828265 / CompletedPhase 1

A Phase 1, Open-Label Study to Assess the Safety, Tolerability, and Pharmacokinetics of Aldafermin in Healthy Adult Male Japanese and Non-Japanese Subjects

This is an open-label study to assess safety, tolerability, and pharmacokinetics of Aldafermin (NGM282) in healthy adult male Japanese and non-Japanese subjects

Start Date13 Apr 2021

Sponsor / Collaborator

NGM Biopharmaceuticals, Inc.

100 Clinical Results associated with Aldafermin

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100 Translational Medicine associated with Aldafermin

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100 Patents (Medical) associated with Aldafermin

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39

Literatures (Medical) associated with Aldafermin

01 Sep 2024·METABOLIC ENGINEERING

Genetic heterogeneity of engineered Escherichia coli Nissle 1917 strains during scale-up simulation

Article

Author: Woodley, John M ; Rugbjerg, Peter ; Munkler, Lara P ; Visby Nissen, Victoria ; Mohamed, Elsayed T ; Worberg, Andreas ; Sommer, Morten O A ; Feist, Adam M ; Vazquez-Uribe, Ruben

Advanced microbiome therapeutics have emerged as a powerful approach for the treatment of numerous diseases. While the genetic instability of genetically engineered microorganisms is a well-known challenge in the scale-up of biomanufacturing processes, it has not yet been investigated for advanced microbiome therapeutics. Here, the evolution of engineered Escherichia coli Nissle 1917 strains producing Interleukin 2 and Aldafermin were investigated in two strain backgrounds with and without the three error-prone DNA polymerases polB, dinB, and umuDC, which contribute to the mutation rate of the host strain. Whole genome short-read sequencing revealed the genetic instability of the pMUT-based production plasmid after serial passaging for approximately 150 generations using an automated platform for high-throughput microbial evolution in five independent lineages for six distinct strains. While a reduction of the number of mutations of 12%-43% could be observed after the deletion of the error-prone DNA polymerases, the interruption of production-relevant genes could not be prevented, highlighting the need for additional strategies to improve the stability of advanced microbiome therapeutics.

01 Sep 2024·AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM

The role of FGF19 in metabolic regulation: insights from preclinical models to clinical trials

Review

Author: Santoro, Sergio ; Izabel, Larissa dos Santos ; Magdalon, Juliana ; Carvalho, Marcela Botelho de ; Jorge, Gabriel Machado Chavez Passos ; Zanardo, Luiza Wolf ; Hamada, Leticia Miho ; Izabel, Larissa Dos Santos

Fibroblast growth factor 19 (FGF19) is a hormone synthesized in enterocytes in response to bile acids. This review explores the pivotal role of FGF19 in metabolism, addressing the urgent global health concern of obesity and its associated pathologies, notably type 2 diabetes. The intriguing inverse correlation between FGF19 and body mass or visceral adiposity, as well as its rapid increase following bariatric surgery, emphasizes its potential as a therapeutic target. This article meticulously examines the impact of FGF19 on metabolism by gathering evidence primarily derived from studies conducted in animal models or cell lines, using both FGF19 treatment and genetic modifications. Overall, these studies demonstrate that FGF19 has antidiabetic and antiobesogenic effects. A thorough examination across metabolic tissues, including the liver, adipose tissue, skeletal muscle, and the central nervous system, is conducted, unraveling the intricate interplay of FGF19 across diverse organs. Moreover, we provide a comprehensive overview of clinical trials involving an FGF19 analog called aldafermin, emphasizing promising results in diseases such as nonalcoholic steatohepatitis and diabetes. Therefore, we aim to foster a deeper understanding of FGF19 role and encourage further exploration of its clinical applications, thereby advancing the field and offering innovative approaches to address the escalating global health challenge of obesity and related metabolic conditions.

01 Jun 2024·Clinics and Research in Hepatology and Gastroenterology

Efficacy and safety of aldafermin in non-alcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials

Review

Author: Abbas, Ahmed W ; Marey, Mohamed Mahmoud ; Awad, Abdelaziz A ; Belal, Mohamed ; Nashwan, Abdulqadir J ; Hassan, Malak A ; Rabea, Eslam Mohammed

BACKGROUND:

Non-alcoholic steatohepatitis (NASH) is an advanced subtype of non-alcoholic fatty liver disease (NAFLD). NASH prevalence is increasing exponentially and carries a high risk for disease progression, cirrhosis, and liver-related mortality. Aldafermin, a fibroblast growth factor 19 (FGF19) analog, is one of the evolving therapeutic agents with the potential to regulate multiple pathways involved in the pathogenesis of NASH. We aimed to investigate the efficacy and safety of aldafermin in patients with NASH.

METHODS:

PubMed, Scopus, Cochrane Library, and Web of Science were searched till November 2023 to identify eligible randomized controlled trials (RCTs). Continuous data were pooled as mean difference (MD), while dichotomous data were pooled as risk ratios (RR) with a 95 % confidence interval. A subgroup meta-analysis was conducted to evaluate the efficacy of the two doses (1 mg and 3 mg) of aldafermin.

RESULTS:

Four RCTs with a total of 491 patients were included. Aldafermin showed a dose-dependent improvement in the ≥30 % reduction in the liver fat content (RR: 2.16, 95 % CI [1.41 to 3.32]) and (RR: 5.00, 95 % CI [1.34 to 18.64]), alanine aminotransferase levels (MD: -19.79, 95 % CI [-30.28 to -9.3]) and (MD: -21.91, 95 % CI [-29.62 to -14.21]), aspartate aminotransferase levels (MD: -11.79, 95 % CI [-18.06 to -5.51]) and (MD: -13.9, 95 % CI [-18.59 to -9.21]), and enhanced liver fibrosis score (ELF) (MD: -0.13, 95 % CI [-0.29 to 0.02]) and (MD: -0.33, 95 % CI [-0.50 to -0.17]), in the 1 mg and 3 mg subgroups respectively. No significant differences were detected in the aldafermin group regarding histologic endpoints, lipid profile, metabolic parameters, and overall adverse effects, except for the increased occurrence of diarrhea in the aldafermin 3 mg subgroup.

CONCLUSION:

Aldafermin is a promising well-tolerated therapeutic agent for NASH with evidence supporting its ability to reduce liver fat content, fibrosis serum biomarkers, and liver enzymes. However, its effectiveness in improving histologic fibrosis, while showing numerical trends, still lacks statistical significance. Larger and longer NASH trials are warranted to enhance the robustness of the evidence.

28

News (Medical) associated with Aldafermin

17 Jul 2024

·pipelinereview.com

NGM Bio Announces $122 Million Series A Financing to Initiate Registrational Trial in Primary Sclerosing Cholangitis and Fund Phase 2 Trial in Hyperemesis Gravidarum

SOUTH SAN FRANCISCO, CA, USA I July 17, 2024 I NGM Biopharmaceuticals, Inc. (NGM Bio), a privately held biotechnology company focused on discovering and developing transformative therapeutics for patients, today announced a $122 million Series A financing led by TCG with participation from a select group of investors. NGM Bio will use the proceeds from the Series A financing to initiate a planned registrational trial of aldafermin, an engineered FGF19 analog, for the treatment of PSC, and to complete a planned Phase 2 trial of NGM120, a GDF15/GFRAL antagonist, for the treatment of HG. Both trials are expected to begin in the fourth quarter of 2024. “At the beginning of this year, we unveiled our strategy to advance clinical development efforts for two serious, rare conditions characterized by significant unmet patient need. This Series A capital strengthens our financial position, enabling us to progress our planned registrational trial of aldafermin in primary sclerosing cholangitis and to evaluate NGM120 in a proof-of-concept study for hyperemesis gravidarum,” said David J. Woodhouse, PhD, Chief Executive Officer at NGM Bio. “Having just completed a take-private transaction in April to bolster our efficiency and flexibility as a company, we’re grateful to TCG and our new investors for their support of these important programs, and we look forward to sharing more details on both trials in the coming months.” “The Column Group has long championed NGM’s mission to turn extraordinary scientific discoveries into meaningful therapeutics. NGM continues to show remarkable resilience and persistence in its pursuit of life-saving medicines while maintaining the highest level of scientific rigor. With this Series A investment, TCG is delighted to extend our investment in NGM and support the compelling opportunities presented by aldafermin and NGM120 as potential treatments for PSC and HG, respectively,” said Peter Svennilson, Founder and Managing Partner of TCG. Concurrent with the Series A financing, Mr. Svennilson joined NGM Bio’s Board of Directors. Aldafermin as a Potential Treatment for PSC PSC is a rare disease that irreparably damages the bile ducts, leading to bile acid dysregulation, which ultimately can result in end-stage liver disease, liver failure and bile duct cancer. NGM Bio’s advancement of aldafermin as a potential treatment for PSC is based on a large body of clinical data that supports its differentiated potential to address the bile acid dysregulation underpinning the disease, including NGM Bio’s prior Phase 2 study in PSC. NGM Bio anticipates that the registrational trial for aldafermin in PSC will utilize proposed surrogate endpoints with the goal of obtaining accelerated approval. Learn more about aldafermin as a potential treatment for PSC here . NGM120 as a Potential Treatment for HG HG is characterized by intractable nausea and vomiting (as frequent as 10 to 15 times per day), which results in dehydration, debility, weight loss and malnutrition. HG has a significant physical and psychosocial impact on patients and leads to overall higher rates of fetal loss and termination, preeclampsia, preterm birth, low birth weight, fetal malnutrition, maternal depression, and in some cases, suicidal thoughts. This condition is the second leading cause of hospitalization in pregnancy (second to preterm labor) and typically recurs in subsequent pregnancies. Development of NGM120 as a potential treatment for HG is rooted in NGM Bio’s decade-long efforts to advance the understanding of GDF15 biology and explore its therapeutic application in a number of disease areas. Recent genetic research confirms the link between HG and higher serum levels of GDF15. NGM120 is an antibody designed to block GDF15 signaling through its cognate receptor, GFRAL, in cells at the base of the brain involved in triggering nausea and vomiting and, thereby, may have therapeutic benefit for treating patients suffering from HG. Learn more about NGM120 as a potential treatment for HG here . Aldafermin and NGM120 were both discovered through NGM Bio’s in-house discovery engine. Abbreviations (in alphabetical order) FGF19 = fibroblast growth factor 19; GDF15 = growth differentiation factor 15; GFRAL = glial cell-derived neurotrophic factor receptor alpha-like About NGM Bio NGM Biopharmaceuticals, Inc. (NGM Bio), a wholly owned subsidiary of NGM Bio Holdings, Inc., a privately held biotechnology company, is focused on discovering and developing novel, life-changing medicines for people whose health and lives have been disrupted by disease. NGM Bio’s biology-centric drug discovery approach aims to seamlessly integrate interrogation of complex disease-associated biology and protein engineering expertise to unlock proprietary insights that are leveraged to generate promising product candidates, enable their rapid advancement into proof-of-concept studies and address high unmet patient need. Visit us at http://www.ngmbio.com for more information. SOURCE: NGM Biopharmaceuticals

Phase 2

17 Jul 2024

·www.fiercebiotech.com

3 months after taking NGM Bio private, VC firm oversees biotech’s $122M series A

Part of the funds will go towards a registrational trial of aldafermin in primary sclerosing cholangitis. Three months after The Column Group acquired NGM Bio to take the biotech private, the VC firm has overseen a $122 million fundraise to fuel clinical trials of NGM’s two lead assets. Column swooped in to acquire publicly-listed NGM in February following a 2023 that saw a third of the biotech’s staff laid off and a sliding share price in the wake of a phase 2 trial failure for an age-related macular degeneration asset. Under the ownership of Column, NGM has been a private entity since April. Now, Column wants to inject some cash into NGM’s pipeline. Part of the $122 million series A—which involved “a select group of investors” led by Column—will go towards aldafermin. The engineered FGF19 analog failed in trials for the rare liver disease primary sclerosing cholangitis and for metabolic dysfunction-associated steatohepatitis (MASH). Despite later accruing some better MASH data, NGM is now only pursuing aldafermin for primary sclerosing cholangitis, where it has secured an orphan drug tag from the FDA, and will use part of today’s funds to launch a registrational trial in this indication. The rest of the funds will be used to complete the phase 2 trial of NGM120, a GDF15/GFRAL antagonist that is being evaluated for the treatment of hyperemesis gravidarum, a term for severe vomiting and nausea in pregnancy. Both trials are expected to begin in the fourth quarter of 2024, NGM said in a July 17 release. “Having just completed a take-private transaction in April to bolster our efficiency and flexibility as a company, we’re grateful to [Column] and our new investors for their support of these important programs, and we look forward to sharing more details on both trials in the coming months,” NGM CEO David Woodhouse, Ph.D., said in the release. Although not name-checked in this morning’s release, NGM has another clinical-stage asset in the form of NGM707. In January, the company reported “encouraging responses” from a phase 1 trial of the dual ILT2/ILT4 antagonist in combination with Merck & Co.'s Keytruda in multiple solid tumor indications. Before taking over NGM, Colum already owned almost 27% of the company’s outstanding stock, making it the biotech’s largest shareholder. The same month it announced the acquisition, Column co-launched a $400 million fund described as a “novel venture-biotech model ... to support the advancement of ideas from bench to clinical proof of concept.”

Phase 2AcquisitionOrphan Drug

17 Jul 2024

·firstwordpharma.com

NGM secures $122M, debuts new fit and focused look after going private

While NGM Bio delisted earlier this year in a take-private deal with The Column Group (TCG) after a couple of clinical stumbles, the biotech isn’t going anywhere. If anything, the company is raring to go; its newly refined, orphan disease-focused pipeline, coupled with $122 million in new funding from TCG, has put it on a path towards securing FDA approval in two indications that currently have no available treatments. “Sometimes when you see these private transitions, it’s… a quiet way of making a company disappear,” CEO David Woodhouse told FirstWord. But that’s not the case for NGM, where “it’s business as usual,” he said. “We’re firing away here on all cylinders.” Being private is a boon for NGM to focus on executing on its development programmes more rapidly because it “alleviates the costly and time consuming activities surrounding the regulatory and financial requirements of being publicly traded, as well as some of that short term market related pressures,” he added.Laser-focused pipelineWednesday’s financing will also help NGM start new studies of its two lead programmes in the fourth quarter, including a potentially registrational trial of aldafermin, an engineered FGF19 analogue, for primary sclerosing cholangitis (PSC). Also on the docket is a Phase II study of GDF15/GFRAL antagonist NGM120 to treat hyperemesis gravidarum (HG).It’s a much more slimmed down clinical pipeline than NGM has sported in the past, and that’s intentional, said Woodhouse, who’s been with the company for nearly a decade and has served as chief executive since 2018.“What’s really happened over the last year and a half is recognising the resources we have and the focus we want to have, rather than be really broad,” Woodhouse said, explaining that NGM’s pipeline was historically “broad” both in terms of the number of indications, as well as their respective population sizes. The company previously had candidates in development for “big diseases” including type two diabetes, geographic atrophy, and colorectal cancer.Liver disease needRather than going after the largest market opportunities, NGM is focused on two diseases where it can make a difference. There are no treatments for PSC, a progressive liver disease in the same category as primary biliary cholangitis (PBC) — which made headlines last month when Ipsen’s oral PPAR agonist Iqirvo (elafibranor) secured an accelerated approval from the FDA, making it the first new medicine for the disease cleared in the US in nearly a decade. Gilead Sciences also jumped into the disease space this year with the $4.3-billion takeout of CymaBay. However, while Iqirvo’s clearance was granted based on a biomarker-based endpoint — a reduction in alkaline phosphatase levels — there previously has been no clear-cut approval pathway for PSC.That regulatory irregularity had halted NGM’s development of aldafermin in PSC several years ago, despite “industry-leading efficacy” results from a Phase II study. The company then pursued the FGF19 analogue in metabolic dysfunction–associated steatohepatitis (MASH), but ended up discontinuing development in that disease due to an insufficiently competitive profile. But now, NGM has had several conversations with the FDA to establish a path forward for aldafermin in PSC. “So why not rush to a registrational study of the drug that we’ve known for a while?” Woodhouse commented. Helping severe morning sicknessNGM’s second programme, NGM120, is in development for a severe form of morning sickness that causes extreme levels of nausea and vomiting.“Calling it morning sickness is like calling a hurricane a little bit of rain,” Woodhouse said. “It’s not even in the same zip code.”The disease accounts for 400,000 emergency room visits per year due to dehydration, and can cause esophageal tears due to excessive vomiting, highlighting the need for a treatment to ameliorate symptoms. “It just takes rolling up some sleeves to do a trial in the pregnant population, but we think the unmet need is big enough to merit that,” he said.

Phase 2Drug Approval

100 Deals associated with Aldafermin

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KEGG	Wiki	ATC	Drug Bank
D11734	-	-	DB16086

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cholangitis, Sclerosing	Phase 3	US	NGM Biopharmaceuticals, Inc.	21 Oct 2024
Bile acid malabsorption	Phase 2	US	NGM Biopharmaceuticals, Inc.	01 Dec 2021
Chronic diarrhea	Phase 2	US	NGM Biopharmaceuticals, Inc.	01 Dec 2021
Irritable bowel syndrome with diarrhea	Phase 2	US	NGM Biopharmaceuticals, Inc.	01 Dec 2021
Compensated cirrhosis	Phase 2	US	NGM Biopharmaceuticals, Inc.	23 Mar 2020
Compensated cirrhosis	Phase 2	AU	NGM Biopharmaceuticals, Inc.	23 Mar 2020
Compensated cirrhosis	Phase 2	BE	NGM Biopharmaceuticals, Inc.	23 Mar 2020
Compensated cirrhosis	Phase 2	FR	NGM Biopharmaceuticals, Inc.	23 Mar 2020
Compensated cirrhosis	Phase 2	DE	NGM Biopharmaceuticals, Inc.	23 Mar 2020
Compensated cirrhosis	Phase 2	HK	NGM Biopharmaceuticals, Inc.	23 Mar 2020

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ALPINE 4 (GlobeNewswire) Manual	Phase 2	Nonalcoholic Steatohepatitis	-	aldafermin 3 mg	maxmxwliro(vkknhuprgo) = patients treated with aldafermin 3 mg showed a statistically significant reduction in ELF score compared to the placebo arm after 48 weeks of treatment. bsaijhpwmm (asfwhjbnnx ) View more	Positive	13 Nov 2023
				placebo
NCT04210245 (ALPINE 4, AASLD2023)	Phase 2	Compensated cirrhosis T2D	160	Aldafermin 1mg	izszhztjxr(jkxvgjnylk) = nzfnbtojef jwtshtlpiz (zhmellkvyj )	Positive	10 Nov 2023
				Aldafermin 3mg	izszhztjxr(jkxvgjnylk) = qllhnfwwmy jwtshtlpiz (zhmellkvyj )
NCT05130047 (CTgov)	Phase 2	Irritable bowel syndrome with diarrhea \| Chronic diarrhea \| Bile acid malabsorption	30	Aldafermin (Aldafermin (NGM282))	wqbubajylj(zqnfnmmdxm) = hzapjsidqn jawimzwbxa (btbzqlufly, bqanaahjnp - oclnaxolcc) View more	-	12 Oct 2023
				Placebo (Placebo)	wqbubajylj(zqnfnmmdxm) = jlycqifpvp jawimzwbxa (btbzqlufly, ivcjhekipq - dqgovvgxuw) View more
NCT04210245 (Pubmed \| Hepatology) Manual	Phase 2	Nonalcoholic Steatohepatitis \| Compensated cirrhosis	160	Placebo	unlfsajxuq(exhihrsegf) = voczselhos rqwqmdmejl (qurfdgogvu ) View more	Positive	21 Sep 2023
				Aldafermin 0.3 mg	-
NCT03912532 (ALPINE 2/3, Pubmed \| Lancet Gastroenterol Hepatol)	Phase 2	Nonalcoholic Steatohepatitis	171	Placebo	jsfyrfzceg(yltkgwdyfc) = Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. sxepdphkjf (lzevnkrdsa )	Negative	21 Mar 2022
				Aldafermin 0.3 mg
EASL2021	Not Applicable	Nonalcoholic Steatohepatitis cT1 \| liver fat content \| MRI-PDFF ... View more	78	Aldafermin 1 mg	yciwnqqhyb(ndlefilbxn) = wakojlxjnz thqxgqpurz (abdvlnkcge )	Positive	23 Jun 2021
				Placebo	yciwnqqhyb(ndlefilbxn) = ucpgaacbcc thqxgqpurz (abdvlnkcge )
EASL2021	Not Applicable	Atherosclerosis	78	Aldafermin 1 mg	mshthdaqdr(jcicgyexmm) = whujhqncdb lgbbahaxrp (uutwdzbcxu ) View more	Positive	23 Jun 2021
				Placebo	mshthdaqdr(jcicgyexmm) = olvohxmpcu lgbbahaxrp (uutwdzbcxu )
EASL2020	Phase 2	Nonalcoholic Steatohepatitis	78	Aldafermin 1 mg	gwtunuxiwm(nuthzmdwkt) = A greater proportion of subjects on aldafermin achieved fibrosis reduction of â¥ 1-stage without NASH worsening (38% [aldafermin] vs 18% [PBO]), and NASH resolution with no worsening of fibrosis (24% [aldafermin] vs 9% [PBO]). 22% (aldafermin) vs. 0% (PBO) of subjects achieved both histological endpoints (P = 0.015). ALT, AST and fibrogenesis biomar- kers (Pro-C3 and ELF) declined rapidly and significantly from BL with aldafermin therapy. AEs were mostly mild and moderate in severity. No difference in gastrointestinal AE was observed between arms. Incidences of SAEs were 12% (PBO) vs 4% (aldafermin), and discontinuations due to AE 4% (PBO) vs 0% (aldafermin). All SAEs were unrelated to drug. spjfunqfle (vqmdctbdfz )	Positive	27 Aug 2020
				Placebo
phase 2 aldafermin trial (EASL2020)	Phase 2	Cholangitis, Sclerosing serum bile acids	62	Aldafermin 1 mg	pwqzfdaivc(fheehdtgcp) = iriuuhfgiq cuxkhdsgyt (xuyduacbad )	Positive	27 Aug 2020
EASL2020	Phase 2	Nonalcoholic Steatohepatitis \| Cholangitis, Sclerosing PRO-C3X	-	Aldafermin 1 mg	okoswzpmbi(bfwibdivku) = xksdmujbtr htxfuecgei (xadicnphvq )	Positive	27 Aug 2020
				Aldafermin 3 mg	okoswzpmbi(bfwibdivku) = rdxviixidu htxfuecgei (xadicnphvq )