Safety and efficacy of efruxifermin in metabolic dysfunction-associated steatohepatitis: A systematic review

Table 1 Baseline characteristics of individual studies and study participants included in the meta-analysis, mean ± SD

Ref.	Study design, name of the trial, trial registration number	Major inclusion criteria	Groups	Number of study subjects	Female (%)	T2D (%)	Age (year)	BMI (kg/m2)	Hepatic parameters	Concomitant medications (%)	Duration
Harrison et al[21], 2021, Multicenter in United States	Phase 2a RCT, BALANCED, NCT03976401	Adults with biopsy-proven NASH, fibrosis stage 1–3, NAS ≥ 4, HFF ≥ 10% and E > 7.0 kPa	EFX 28 mg	19	53	37	50.4 ± 12.4	38.8 ± 9.3	HFF: 21.4 ± 8.1; NAS: 5.6 ± 1.0; ELF: 9.5 ± 0.6	MFN (37), Statin (32)	12 weeks
			EFX 50 mg	20	50	50	52.6 ± 14.2	36.7 ± 6.8	HFF: 18.3 ± 6.3; NAS: 5.1 ± 1.2; ELF: 9.5 ± 0.9	MFN (42), Statin (37)
			EFX 70 mg	20	55	50	53 ± 13.2	37.2 ± 5.5	HFF: 19.4 ± 6.3; NAS: 5.6 ± 0.7; ELF: 9.5 ± 0.8	MFN (25), Statin (45)
			Placebo	21	71	67	52.4 ± 9.6	37.6 ± 4.8	HFF: 19.3 ± 6.9; NAS: 5.1 ± 1.0; ELF: 9.5 ± 1.0	MFN (48), Statin (33)
Harrison et al[22], 2023, Multicenter in United States	Phase 2a RCT, BALANCED (expansion cohort), NCT03976401	Adults with biopsy-confirmed compensated cirrhosis due to NASH, E > 13.1 kPa, ELF > 9.8, and no evidence of worsening levels of ALT and AST	EFX 50 mg	20	80	50	61.1 ± 10	36.0 ± 5.6	E: 22.1 ± 10.8 kPa; NAS: 4.1 ± 1.7; ELF: 10.4 ± 1.2	GLP-1RA (15), Statin (30)	16 weeks
			Placebo	10	30	50	57.1 ± 14.4	39.1 ± 8.3	E: 25.8 ± 13.2 kPa; NAS: 3.3 ± 2.1; ELF: 9.7 ± 0.8	GLP-1RA (30), Statin (30)
Harrison et al[23], 2023, Multicenter in United States	Phase 2b RCT, HARMONY, NCT04767529	Adults with biopsy-confirmed NASH, defined by NAS ≥ 4 and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis	EFX 28 mg	42	69	76.2	56.5 ± 9.3	38.3 ± 6.9	HFF: 18.5 ± 6.9; E: 13.8 ± 5.2 kPa; NAS: 5.1 ± 1.0; ELF: 9.7 ± 0.8	GLP-1RA (12), SGLT-2i (14), Statin (52.4)	96 weeks
			EFX 50 mg	43	54	69.8	52.4 ± 11.4	37.2 ± 6.6	HFF: 17.5 ± 6.4; E: 16.0 ± 7.1 kPa; NAS: 5.6 ± 1.1; ELF: 9.8 ± 0.8	GLP-1RA (9), SGLT-2i (12), Statin (32.6)
			Placebo	43	63	65.1	55.0 ± 10.1	38.7 ± 7.7	HFF: 17.1 ± 6.4; E: 14.5 ± 6.2 kPa; NAS: 5.4 ± 1.2; ELF: 9.8 ± 0.7	GLP-1RA (16), SGLT-2i (19), Statin (48.8)
Harrison et al[24], 2025, Multicenter in United States	Phase 2b RCT, Cohort D, NCT05039450	Adults with MASH, F1 to F3 (confirmed by biopsy), and T2D treated with a stable dose of GLP-1RA	EFX 50 mg	21	43	100	59	35.0	HFF: 10.4; E: 10 kPa; ELF: 9.2	GLP-1RA (100), MFN (76), SGLT-2i (33), Statin (81)	12 weeks
			Placebo	10	90	100	55	35.4	HFF: 15.2; E: 12 kPa; ELF: 9.6	GLP-1RA (100), MFN (70), SGLT-2i (20), Statin (50)
Noureddin et al[25], 2025, Multicenter in United States, Puerto, Rico, and Mexico	Phase 2b RCT, SYMMETRY, NCT05039450	Adults with liver histologic features consistent with MASH and compensated cirrhosis (defined as stage 4 fibrosis with a Child-Pugh score of 5 or 6, T2D or two components of MetS	EFX 28 mg	57	68	81	61.7 ± 8.3	36.1 ± 7.1	E: 24.1 ± 12.4 kPa; NAS: 3.9 ± 1.6; ELF: 10.6 ± 0.8	GLP-1RA (19)	96 weeks
			EFX 50 mg	63	70	78	59.4 ± 8.8	34.5 ± 5.9	E: 24.5 ± 13.4 kPa; NAS: 4.1 ± 1.5; ELF: 10.5 ± 0.8	GLP-1RA (33)
			Placebo	61	62	82	61 ± 7.5	36.7 ± 6.8	E: 24.7 ± 14.2 kPa; NAS: 3.7 ± 1.6; ELF: 10.4 ± 0.8	GLP-1RA (26)

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; E: Liver stiffness during FibroScan measurement; EFX: Efruxifermin; ELF: Enhanced liver fibrosis; GLP-1RA: Glucagon-like peptide-1 receptor agonists; HFF: Hepatic fat fraction (by Magnetic Resonance Imaging Proton Density Fat Fraction); kPa: Kilopascals; MASH: Metabolic dysfunction-associated steatohepatitis; MetS: Metabolic syndrome; NAS: Non-alcoholic fatty liver disease activity score; NASH: Nonalcoholic steatohepatitis; MFN: Metformin; RCT: Randomized controlled trial; SGLT-2i: Sodium-glucose cotransporter 2 inhibitor; T2D: Type 2 diabetes.

Table 2 Comparison of the general safety outcomes in the efruxifermin vs placebo arms

Outcome variables	EFX dose (mg)	No. of study reports	No. of participants with outcome/participants analyzed (n/N)		Pooled effect size, RR (95%CI)	P value (EFX vs placebo)	I2 (%)	P value (EFX 28 vs 50)
			EFX arm	Placebo arm
Any TEAE	28	3	110/116	113/125	1.03 (0.96-1.10)	0.39	9	0.56
	50	4	141/145	121/135	1.05 (1.00-1.11)	0.04	0
Drug-related TEAE	28	3	79/116	58/125	1.45 (1.16-1.82)	0.001	0	0.38
	50	4	110/145	61/135	1.67 (1.36-2.05)	< 0.00001	0
Severe TEAE	28	2	1/59	1/64	1.11 (0.07-16.47)	0.94	NA	0.70
	50	3	2/82	1/74	2.21 (0.22-22.47)	0.50	NA
TEAE leading to treatment discontinuation	28	3	10/116	3/125	3.15 (0.96-10.35)	0.06	0	0.97
	50	5	16/166	3/145	3.05 (1.06-8.81)	0.04	0
Serious AE	28	3	16/116	11/125	1.51 (0.77-2.97)	0.23	0	0.89
	50	5	19/166	12/145	1.35 (0.30-6.11)	0.70	40
Abdominal pain	28	2	10/76	8/82	1.35 (0.56-3.21)	0.50	0	0.84
	50	2	8/82	8 /82	1.13 (0.27-4.69)	0.87	37
Nausea	28	3	36/116	29/125	1.38 (0.66-2.91)	0.39	53	0.55
	50	5	68/166	32/145	1.78 (1.25-2.54)	0.001	0
Vomiting	28	3	28/116	12/125	2.17 (1.16-4.08)	0.02	0	0.57
	50	4	27/145	12/135	1.80 (0.95-3.39)	0.07	0
Diarrhea	28	2	29/76	22/82	1.42 (0.90-2.24)	0.13	0	0.45
	50	4	59/123	26/102	1.90 (1.04-3.49)	0.04	36
Frequent bowel movements	28	2	12/59	1/64	8.98 (1.71-47.13)	0.009	0	0.26
	50	2	2/62	1/64	1.43 (0.09-22.30)	0.80	37
Increased appetite	28	3	21/116	7/125	3.16 (1.39-7.20)	0.0006	0	0.30
	50	4	45/146	7/135	5.66 (2.71-11.82)	< 0.00001	0
Fatigue	28	2	12/76	12/82	1.04 (0.51-2.14)	0.90	0	0.73
	50	2	11/82	12/82	0.87 (0.42-1.83)	0.72	0
Headache	28	2	14/97	13/104	1.15 (0.57-2.33)	0.69	0	0.68
	50	3	22/126	14/114	1.41 (0.75-2.65)	0.29	0
Injection site erythema	28	3	23/116	14/125	1.66 (0.88-3.14)	0.12	4	0.89
	50	4	30/145	14/135	1.77 (0.95-3.32)	0.07	5
Injection site reaction	28	3	16/116	14/125	1.17 (0.60-2.28)	0.65	0	0.51
	50	4	26/145	14/135	1.71 (0.67-4.39)	0.26	21

AE: Adverse events; EFX: Efruxifermin; NA: Not available; RR: Risk ratio; TEAE: Treatment-emergent adverse event.

Table 3 Comparison of the hepatic safety outcomes in the efruxifermin vs placebo arms

Outcome variables	EFX dose (mg)	No. of study reports	No. of participants with outcome analyzed		Pooled effect size, MD (95%CI)	P value (EFX vs placebo)	I2 (%)	P value (EFX 28 vs 50)
			EFX arm	Placebo arm
ALT (U/L)	28	3	118	125	-16.52 (-29.54 to -3.51)	0.01	87	0.96
	50	5	165	145	-16.93 (-28.38 to -5.48)	0.004	92
AST (U/L)	28	3	118	125	-14.62 (-21.72 to -7.53)	< 0.0001	74	0.81
	50	5	165	145	-13.35 (-20.94 to -5.75)	0.0006	89
ALP (U/L)	28	3	118	125	-2.13 (-10.52 to 6.26)	0.62	86	0.64
	50	5	165	145	-4.46 (-9.61 to 0.70)	0.09	64
GGT (U/L)	28	3	118	125	-16.52 (-29.54 to -3.51)	0.01	87	0.96
	50	5	165	145	-16.93 (-28.38 to -5.48)	0.004	92
Urate (mg/dL)	28	3	112	124	-0.73 (-1.06 to -0.41)	< 0.0001	64	0.63
	50	5	158	134	-0.59 (-1.06 to -0.12)	0.01	85

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; EFX: Efruxifermin; GGT: Gamma-glutamyl transferase; MD: Mean difference.

Table 4 Comparison of the hepatic efficacy (continuous) outcomes in the efruxifermin vs placebo arms

Outcome variables (continuous)	EFX dose (mg)	No. of study reports	No. of participants with outcome analyzed		Pooled effect size, MD (95%CI)	P value (EFX vs placebo)	I2 (%)	P value (EFX 28 vs 50)
			EFX arm	Placebo arm
HFF (relative change) (%)	28	2	57	63	-54.06 (-71.01 to -37.11)	< 0.00001	76	0.42
	50	3	71	73	-62.00 (-71.27 to -52.73)	< 0.00001	31
HFF (absolute change) (%)	50	2	36	31	-9.30 (-16.36 to -2.23)	0.01	87	NA
ELF score	28	3	113	124	-0.67 (-0.83 to -0.51)	< 0.00001	0	0.46
	50	5	166	144	-0.75 (-0.89 to -0.61)	< 0.00001	0
Liver stiffness (kPa)	28	2	95	103	-1.90 (-3.88 to 0.08)	0.06	0	0.92
	50	4	138	123	-2.00 (-2.51 to -1.50)	< 0.00001	0
Pro-C3 (μg/L)	28	3	113	122	-5.42 (-8.15 to -2.70)	< 0.00001	68	0.69
	50	5	157	142	-6.11 (-8.06 to -4.16)	< 0.00001	53
Pro-C3 (%)	50	2	83	71	-20.85 (-36.07 to -5.64)	0.007	0	NA

EFX: Efruxifermin; ELF: Enhanced liver fibrosis; HFF: Hepatic fat fraction; kPa: Kilopascals; MD: Mean difference; NA: Not available; Pro-C3: N-terminal propeptide of type III collagen.

Table 5 Comparison of the hepatic efficacy (categorical) outcomes in the efruxifermin vs placebo arms

Outcome variables (categorical)	EFX dose (mg)	No. of study reports	No. of participants with outcome/participants analyzed (n/N)		Pooled effect size, RR (95%CI)	P value (EFX vs placebo)	I2 (%)	P value (EFX 28 vs 50)
			EFX arm	Placebo arm
Reduction in HFF ≥ 30%	28	2	48/54	11/62	4.73 (2.54 to 8.82)	< 0.00001	16	0.98
	50	2	48/52	11/62	4.79 (2.76 to 8.30)	< 0.00001	4
Reduction in HFF ≥ 50%	28	2	35/54	2/62	19.06 (4.82 to 75.40)	< 0.0001	0	1.0
	50	2	44/52	2/62	19.03 (5.68 to 63.78)	< 0.00001	0
HFF ≤ 5%	28	2	17/54	2/62	8.71 (2.06 to 36.75)	0.003	0	0.70
	50	3	41/68	3/72	12.45 (4.09 to 37.93)	< 0.00001	0
Decrease in NAS ≥ 2	50	2	17/25	2/7	1.96 (0.64 to 5.99)	0.24	0	NA
MASH resolution and improvement in fibrosis stage	28	2	15/51	2/43	4.59 (1.29 to 16.25)	0.02	0	0.72
	50	2	19/47	2/43	6.33 (1.83 to 21.90)	0.004	0
MASH resolution and no worsening of fibrosis stage	28	2	24/51	6 43	3.19 (1.47 to 6.93)	0.003	0	0.43
	50	3	36/59	6/48	4.89 (2.41 to 9.91)	< 0.0001	0
Fibrosis regression by ≥ 1 stage and no worsening in steatohepatitis	28	3	42/108	19/104	2.06 (1.28 to 3.30)	0.003	0	0.61
	50	4	55/122	19/109	2.44 (1.55 to 3.83)	0.0001	0
Fibrosis regression by ≥ 2 stage and no worsening in steatohepatitis	28	2	9/51	2/43	2.68 (0.70 to 10.18)	0.15	0	1.00
	50	2	9/47	2/43	2.68 (0.69 to 10.38)	0.15	0

EFX: Efruxifermin; HFF: Hepatic fat fraction; MASH: Nonalcoholic steatohepatitis; NA: Not available; NAS: Non-alcoholic fatty liver disease activity score; RR: Risk ratio.

Table 6 Comparison of the metabolic outcomes in the efruxifermin vs placebo arms

Outcome variables	EFX dose (mg)	No. of study reports	No. of participants with outcome analyzed		Pooled effect size, MD (95%CI)	P value (EFX vs placebo)	I2 (%)	P value (EFX 28 vs 50)
			EFX arm	Placebo arm
Body weight (kg)	28	3	113	124	0.05 (-1.48 to 1.57)	0.95	0	0.13
	50	5	158	144	-1.49 (-2.74 to -0.25)	0.02	0
HbA1c (%)	28	3	113	124	-0.24 (-0.46 to -0.02)	0.03	0	0.24
	50	5	158	144	-0.40 (-0.55 to -0.25)	< 0.00001	0
HOMA-IR	28	3	113	124	-5.70 (-8.21 to -3.19)	< 0.00001	0	0.72
	50	4	135	130	-5.13 (-6.94 to -3.32)	< 0.00001	0
C-peptide (μg/L)	50	2	54	50	-1.16 (-1.59 to -0.73)	< 0.00001	0	NA
Adiponectin (mg/dL)	28	2	55	53	1.95 (0.13 to 3.76)	0.04	76	0.17
	50	3	72	72	3.65 (2.06 to 5.24)	< 0.00001	85
TG (mg/dL)	28	3	111	124	-53.83 (-86.82 to -20.84)	0.001	83	0.68
	50	4	137	134	-63.21 (-92.07 to -34.35)	< 0.0001	82
Non-HDL-C (mg/dL)	28	2	92	103	-16.10 (-29.92 to -2.29)	0.02	68	0.78
	50	3	117	113	-18.40 (-26.99 to -9.81)	< 0.00001	7
LDL-C (mg/dL)	28	3	111	124	-11.10 (-17.84 to -4.35)	0.001	14	0.37
	50	4	137	134	-6.99 (-12.90 to -1.08)	0.02	8
HDL-C (mg/dL)	28	3	111	124	10.77 (7.51 to 14.03)	< 0.00001	46	0.31
	50	4	137	134	12.77 (10.68 to 14.86)	< 0.00001	0
Apo-B (mg/dL)	28	2	56	53	-15.08 (-22.02 to -8.14)	< 0.00001	0	0.39
	50	3	75	73	-11.10 (-17.01 to -5.19)	0.0002	0
Apo-C3 (mg/dL)	28	2	55	63	-2.24 (-4.10 to -0.38)	0.02	69	0.90
	50	2	56	63	-2.44 (-4.89 to 0.01)	0.05	82

Apo-B: Apolipoprotein B; Apo-C3: Apolipoprotein C3; EFX: Efruxifermin; HbA1c: Glycated hemoglobin; HDL-C: High-density lipoprotein cholesterol; HOMA-IR: Homeostatic model assessment for insulin resistance; LDL-C: Low-density lipoprotein cholesterol; MD: Mean difference; NA: Not available; TG: Triglycerides.