Prospective clinical trials and novel therapies in the medical management of severe alcohol‐associated hepatitis

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INTRODUCTION

Within the spectrum of alcohol‐associated liver disease (ALD), severe alcohol‐associated hepatitis (sAH) represents the most acute and severe manifestation. This clinical syndrome is characterized by jaundice, abdominal pain, and a systemic inflammatory response that carries significant morbidity and mortality. Rates of alcohol‐associated hepatitis (AH) have been increasing, particularly during the coronavirus disease 2019 pandemic, which saw online sales of alcohol increase by 477% in 1 year. ¹

Few effective therapeutic options for AH exist. Corticosteroids have persisted as the mainstay of treatment for sAH despite considerable limitations, highlighting an unmet need for effective pharmacological therapies. Agents targeting the underlying pathogenic pathways implicated in AH provide new hope for therapeutic advances. Activation of cytokine signaling and inflammatory cascades, altered mechanisms of hepatic regeneration in response to oxidative stress, and increased gastrointestinal tract permeability facilitating systemic bacterial translocation have all been implicated in the complex pathophysiology of AH ² (Figure 1). This review highlights novel therapeutic agents for sAH currently under study through the lens of their proposed mechanism of action.

FIGURE 1.

Pathogenesis of liver injury in AH and proposed agents acting on mechanisms for its management. G‐CSF, granulocyte colony stimulating factor; IgG, immunoglobulin G; IL, interleukin; LPS, lipopolysaccharide; TNF, tumor necrosis factor.

DEFINING AH

The National Institute of Alcohol Abuse and Alcoholism (NIAAA) defines sAH as the onset of jaundice within 60 days of heavy alcohol consumption for at least 6 months, serum bilirubin exceeding 3 mg/dl, aspartate aminotransferase (AST) elevation <400 U/L, and AST:alanine aminotransferase (ALT) ratio >1.5 in the absence of an alternative etiology ³ (Figure 2). Making the diagnosis of AH and stratifying its severity is critical in guiding medical management. Liver biopsy confirms a “definite” diagnosis, but a diagnosis of “probable” AH can be used for clinical decision making. ³ In “possible” cases of AH, where multiple confounding conditions cause clinical uncertainty, a liver biopsy may be helpful to confirm a histological diagnosis. The Maddrey discriminant function (MDF) and Model for End‐Stage Liver Disease (MELD) score use laboratory markers to stratify disease severity, guide therapy, and estimate short‐term mortality. ⁴ sAH carries a mortality rate of up to 30%–50% within 90 days of diagnosis ⁵ and is defined by MDF score > 32, MELD score > 20, or the concurrent presence of hepatic encephalopathy. Societal guidelines recommend corticosteroids and nutritional supplementation in patients with sAH. ⁶ , ⁷

FIGURE 2.

Clinical presentation of severe alcohol‐associated hepatitis and NIAAA diagnostic classification. AH, alcohol‐associated hepatitis; ALT, alanine transaminase; ANA, anti‐nuclear antibody; a‐SMA, anti‐smooth muscle antibody; AST, aspartate aminotransferase; DILI, drug induced liver injury.

CURRENT AH MANAGEMENT

Corticosteroids are recommended as the first‐line treatment for sAH in the absence of active infection. ⁶ , ⁷ Their use remains controversial, because prior studies have shown a modest improvement in short‐term mortality (28 days), but no demonstrable long‐term survival benefit. ⁸ , ⁹ The 2015 STOPAH trial of prednisolone with or without pentoxifylline demonstrated a modest improvement in 28‐day mortality that nearly reached statistical significance but no reduction in long‐term survival. ⁸ A systematic review of 16 trials that studied 927 patients with sAH who received corticosteroids found no benefit to all‐cause mortality at 90 days and expressed a strong concern for publication bias. ² Moreover, corticosteroids are not without risk, with adverse effects (AE) such as infection ⁸ recognized.

Nutritional supplementation (1–1.5 g protein and 30–40 kcal/kg body weight) is recommended in AH. ¹¹ , ¹² Multiple studies suggest that maintaining adequate nutrition improves hepatic encephalopathy and reduces risk for infection with no effect on mortality. ¹³ Zinc has been shown to decrease gut permeability and protect against oxidative stress, also prompting consideration of zinc supplementation. ¹⁴

N‐acetylcysteine (NAC) is an antioxidant therapy that is often used as an adjuvant therapy to corticosteroids. A French multicenter trial comparing NAC plus corticosteroids with corticosteroids alone showed significantly lower mortality in the combination group at 1 month. ¹⁰ In addition, significant reductions in the incidence of hepatorenal syndrome and infections were observed. Although larger trials to confirm its efficacy are needed, some guidelines recommend its consideration. ¹¹

RECENTLY INVESTIGATED NOVEL THERAPIES

Anti‐inflammatory and antioxidative stress agents

Proinflammatory cytokines play a well‐established role in modulating inflammatory pathways in the liver, activating stellate cells that deposit collagen and promote the development of fibrosis. ¹⁵ Several trials studying novel agents have recently been completed and have demonstrated safety (Table 1). Unfortunately, these agents did not show improvements in the primary efficacy endpoint: short‐term mortality. Emricasan, a caspase inhibitor, showed promise in animal models but was withdrawn from clinical trials because of toxicity. Similarly, a phase 2 study with obeticholic acid was terminated for hepatotoxicity concerns. Metadoxine, an antioxidant, showed improved survival rate at 3 and 6 months and increased likelihood of sustained abstinence at 6 months when combined with prednisone or pentoxifylline, but it has not been further studied. ¹⁶

TABLE 1.

Ongoing trials in the management of AH

Primary mechanism	Study drug	Trial identifier (ClinicalTrials.gov)	Trial name	Trial status	Study phase	Primary outcome
Modulation of inflammation and oxidation	Omega‐5 fatty acid	NCT03732586	Effect of Omega 5 Fatty Acid as an Adjuvant Treatment to Prednisone in Patients With Severe Alcoholic Hepatitis	Recruiting	N/A	30‐Day survival
	Canakinumab	NCT03775109	IL‐1 Signal Inhibition in Alcoholic Hepatitis (ISAIAH)	Active, not recruiting	Phase 2	Histological improvement on biopsy at treatment day 28
	Anakinra	NCT04072822	Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis (AlcHepNet)	Active, not recruiting	Phase 2	90‐Day survival
	Vitamin C	NCT03829683	Vitamin C Infusion for Treatment in Sepsis and Alcoholic Hepatitis (CITRIS‐AH)	Active, not recruiting	Phase 2	MELD score at baseline and 96 hours from treatment
	DUR‐928	NCT03917407	DUR‐928 in Patients With Alcoholic Hepatitis (DUR‐928/AH)	Recruiting	Phase 2	AEs, biomarkers of inflammation and death, liver enzymes, MELD score
	NAC	NCT03069300	N‐Acetylcysteine to Reduce Infection and Mortality for Alcoholic Hepatitis (NACAH)	Recruiting	Phase 3	24‐Hour monocyte oxidative burst improvement and 5‐day ex vivo monocyte oxidative burst improvement; rates of infection and 28‐ and 90‐day mortality are secondary endpoints
	Digoxin	NCT05014087	Digoxin in Treatment of Alcohol Associated Hepatitis (DIGIT‐AlcHep)	Recruiting	Phase 2	Four patients per month recruitment (feasibility); 7‐, 14‐, 28‐, and 90‐day mortality as secondary endpoints
	TAK‐242 (TLR4 blockade)	NCT04620148	TAK‐242 in Patients With Acute Alcoholic Hepatitis	Pending recruitment	Phase 2	Change in CLIF‐C ACLF score from baseline to day 8
Gut‐liver axis modification	Fecal transplant	NCT04758806	Fecal Microbial Transplantation in Severe Alcoholic Hepatitis (FMTH7)	Recruiting	Phase 3	28‐Day, 90‐day, and 1‐year mortality
	Bovine colostrum	NCT02473341	Comparison of Bovine Colostrum Versus Placebo in Treatment of Severe Alcoholic Hepatitis: A Randomized Double Blind Controlled Trial (BASH)	Recruiting	Phase 3	90‐Day survival
Regenerative potential	G‐CSF	NCT02442180	Efficacy and Safety of G‐CSF in Patients With Severe Alcoholic Hepatitis With Null or Partial Response to Steroid (GraCiAH)	Recruiting	Phase 3	2‐Month survival in steroid null responders and 6‐month survival in steroid partial responders

There are a number of novel agents currently in phase 2/3 of study (Table 2). A clinical trial studying interleukin (IL)‐1 receptor antagonist anakinra with pentoxifylline and zinc showed no difference in mortality compared with methylprednisolone (ClinicalTrials.gov: NCT01809132), although a similar phase 2 trial investigating changes in 90‐day mortality of anakinra with zinc compared with standard of care for sAH may yield more promising results (NCT04072822). Another current phase 2 trial seeks to study the effect of canakinumab, a monoclonal antibody targeting IL‐1, on histological improvement and 90‐day mortality (NCT03775109). Apart from blocking IL‐1‐mediated pathways, studies are underway to evaluate Toll‐like receptor 4 (TLR4) inhibition with TAK‐242 (NCT04620148) and intravenous vitamin C supplementation as an anti‐inflammatory agent in steroid‐ineligible patients with concurrent infections (NCT03829683). Another recruiting phase 2 trial will evaluate whether daily digoxin administration during hospitalization improves short‐term mortality in sAH (NCT05014087). In the rodent model, digoxin suppressed PKM2‐HIF‐1α, a transcription factor upregulated with steatosis and liver injury, and led to significant reductions in sterile inflammation and macrophage activation. ¹⁷ DUR‐928, also known as Larsucosterol, is an endogenous oxysterol shown to control hepatic lipotoxicity. ¹⁸ It has the potential to epigenetically antagonize proinflammatory and proapoptotic responses. DUR‐928 demonstrated safety in an initial trial (NCT03432260), leading to a promising current trial (AHFIRM) comparing DUR‐928 with placebo (NCT03917407). Currently, more than 64 study locations across the United States are recruiting patients.

TABLE 2.

Completed trials in the management of AH

Study drugs	Trial identifier (ClinicalTrials.gov)	Trial name	Study phase	Primary outcome	Main results
DUR‐928	NCT03432260	A Research Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of DUR‐928 in Patients With Alcoholic Hepatitis (AH)	Phase 2	28‐Day AEs	Safe without significant AEs
Metadoxine (antioxidant)	NCT02161653	Metadoxine as a Therapy for Severe Alcoholic Hepatitis	Phase 4	30‐Day survival	Significant improvement in 3‐mo and 6‐mo survival
F‐652 (recombinant IL‐22)	NCT02655510	Use of F‐652 in Patients With Alcoholic Hepatitis (TREAT 008)	Phase 1/2	6‐Week AEs	Safe without significant AEs
Selonsertib (ASK‐1 inhibitor)	NCT02854631	Selonsertib in Combination With Prednisolone Versus Prednisolone Alone in Participants With Severe Alcoholic Hepatitis (AH)	Phase 2	28‐Day (plus 30‐day) AEs	Safe but without significant change in survival at 24 weeks
Amoxicillin with clavulanic acid	NCT02281929	Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone (AntibioCor)	Phase 3	2‐Month survival	No significant improvement in survival
Anakinra, pentoxifylline, and zinc	NCT01809132	Efficacy Study of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis	Phase 2/3	6‐Month survival	No significant improvement in survival
IMM 124‐E (bovine colostrum)	NCT01968382	Safety and Efficacy of IMM 124‐E for Patients With Severe Alcoholic Hepatitis (TREAT)	Phase 2	30‐Day AEs	Safe without significant AEs
Lactobacillus subtilis/Streptococcus faecium (probiotics)	NCT01501162	Effect of Probiotics on Gut‐Liver Axis of Alcoholic Liver Disease (EPALD)	Phase 4	ALT at 7 days	7‐Day liver enzyme reduction
Lactobacillus rhamnosus GG (probiotics)	NCT01922895	Novel Therapies in Moderately Severe Acute Alcoholic Hepatitis (NTAH‐Mod)	N/A	30‐Day MELD score	Terminated (lack of funding)
Emricasan (IDN‐6556)	NCT01912404	Study of IDN‐6556 in Patients With Severe Alcoholic Hepatitis and Contraindications to Steroid Therapy (AH)	Phase 2	28‐Day survival	Concern for high systemic drug levels/toxicity—terminated
Obeticholic acid (farnesoid X‐activated receptor antagonist)	NCT02039219	Trial of Obeticholic Acid in Patients With Moderately Severe Alcoholic Hepatitis (AH) (TREAT)	Phase 2	6‐Week MELD score and AEs	Hepatotoxicity concerns—terminated

Regenerative agents

The cytokine cascade implicated in AH simultaneously activates both deleterious proinflammatory and protective anti‐inflammatory cytokines. Studies have demonstrated that anti‐inflammatory cytokines may also improve hepatic regenerative potential. IL‐22 activation in animal models has been shown to increase hepatocyte regeneration through upregulated hepatic cell migration and proliferation in addition to its antiapoptotic properties. ¹⁹ A recently completed phase 2 study on F‐652, a recombinant IL‐22 fusion protein, demonstrated safety without significant AEs. Further studies are underway (Table 1). Granulocyte colony‐stimulating factor (G‐CSF) is implicated in activation of bone marrow–derived stem cells and hepatocyte progenitor cells. In a recent study, G‐CSF increased CD34⁺ cells and hepatocyte growth factor levels. At 90 days, treated patients had reductions in MELD and MDF scores, as well as 90‐day survival. ²⁰ G‐CSF is being studied as a potential regenerative agent in sAH with steroid partial responders (NCT02442180); primary outcomes are 2‐ and 6‐month survival (Table 2).

Agents focused on the gut‐liver axis

The gut‐liver axis refers to the reciprocal relationship of the gastrointestinal tract and its microbiota with the liver. The direct toxicity of alcohol mutes the gut's innate defense mechanisms, disrupting normal gut flora and increasing gastrointestinal permeability. These changes facilitate translocation of bacterial lipopolysaccharide (LPS), which activates an inflammatory cascade causing hepatic necrosis, apoptosis, and fibrosis. ²¹ The use of both antibiotics and probiotics has been studied to varying effect. The addition of amoxicillin with clavulanic acid to corticosteroids showed no improvement in 60‐day mortality (NCT02281929). Probiotics merit further investigation; although one trial demonstrated significant reduction in measured LPS (NCT01501162), another was terminated early because of lack of funding (NCT01922895) (Table 1).

The use of fecal microbial transplantation for sAH in patients unresponsive to or ineligible for corticosteroids is currently being studied in a phase 3 trial (NCT04758806) after multiple small studies demonstrated improvements in disease severity and 1‐year mortality. ²² , ²³ Bovine colostrum, which contains IgG antibodies against bacterial LPS and has been shown to decrease gut permeability and lower serum endotoxin, ²⁴ is also being investigated. Building off an earlier study that demonstrated safety in purified bovine colostrum (NCT01968382), a current trial aims to assess the effect of purified bovine colostrum on 90‐day survival with secondary outcomes of 30‐day survival and change in MDF, endotoxin, and cytokine levels (NCT02473341) (Table 2).

CHALLENGES OF CONDUCTING CLINICAL TRIALS IN AH

There are unique challenges in conducting clinical trials in patients with sAH. One such challenge is the increasing adoption of liver transplantation (LT) as a rescue therapy in cases of sAH unresponsive to medical management. ²⁶ Whether the outcome of LT constitutes treatment success or failure influences event rates and the determination of drug efficacy. It also strongly influences sample size, and careful consideration of this factor is necessary to avoid a type 2 error. Another challenge faced by investigators is the need to consider the effects of alcohol relapse on clinical outcomes. As time from onset of treatment for sAH lengthens, mortality becomes more closely related to an individual's ability to maintain abstinence. ²⁵ Many studies have adopted time point–specific mortality as the primary outcome of treatment efficacy. Differential rates of alcohol relapse between treatment groups may confound this metric. Considering this, current clinical trials are focused on treatment endpoints within 3 months of presentation and have encouraged sites to have a standardized approach in managing alcohol use disorder among trial participants. Finally, diversity of race and ethnicity among clinical trial participants is an important goal in all arenas of clinical research. Among clinical trials in sAH conducted in the United States, participants have been predominantly white, and in several landmark clinical trials, the variable of race/ethnicity is not included. ⁸ , ¹⁹ Thus, to ensure generalizability of results from clinical trials in sAH, enhanced efforts to recruit a study population reflective of those most at risk for the condition are important.

CONCLUSION

Most of the current recruiting trials for sAH have short‐term (28‐day) mortality as the primary endpoint or as a key secondary endpoint. This is appropriate given the known natural history of sAH and the importance of obtaining short‐term survival benefits as a first step to gains in longer‐term mortality. Safety is a major concern with any new drug but is particularly important in the setting of severe liver disease, as is the case in sAH. The early termination of trials because of hepatotoxicity concerns underscores this issue.

The lack of FDA‐approved therapies for sAH highlights a significant unmet need, particularly given the increasing rates of AH in the United States. Advancements in our understanding of AH inform the development of pharmacological agents currently being investigated, and promising therapies are on the horizon. Outside of pharmacotherapy, abstinence from alcohol remains the cornerstone of therapy and is recognized as the key factor in long‐term survival.

CONFLICT OF INTEREST

Nothing to report.

Pimienta M, Tien C, Terrault NA. Prospective clinical trials and novel therapies in the medical management of severe alcohol‐associated hepatitis. Clin Liver Dis. 2022;20:202–208. 10.1002/cld.1265