EMJ-OCB-HEP-032-25-1 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): Reveal The Unseen Burden

Introduction

CIDP is a rare, often progressive, immune-mediated neuromuscular disorder of the peripheral nervous system.1

As an acquired inflammatory demyelinating neuropathy, it can lead to both distal and proximal weakness, along with sensory deficits.1 The condition typically causes motor and sensory impairment in the upper and lower limbs.2

for Liver Antifibrotics

MASH and The Race

Hepatology

The publication of this article was organised and funded by Ochre Bio Ltd and is intended for healthcare professionals only.

Worldwide, 1/25 deaths is due to liver disease.1

More than a quarter of the world’s adult population lives with chronic liver disease, including MASH, alcohol-associated liver disease (ALD), viral hepatitis, cholestatic disorders such as primary biliary cholangitis, and genetic conditions such as haemochromatosis.

The so-called MASH 'tsunami' fueled by increasing rates of obesity is particularly concerning.2

The consequence of MASH and other chronic liver conditions is fibrosis, scarring that progresses to cirrhosis in its most severe form. To date, fibrosis remains the strongest predictor of liver-associated morbidity and mortality, and so its regression has become a therapeutic ‘holy grail’.3

Until recently the search for agents that regress liver fibrosis has repeatedly failed across multiple therapeutic classes (Figure 1, Supplementary Tables 1 and 2).

(iv) extracellular matrix (ECM) remodellers such as lysyl oxidase homologue 2 (LOXL2) inhibitors.10

Antifibrotic Toolbox Lacking Diversity

Liver damage

Healthy

Fatty

Fibrosis

Cirrhosis

So, it stands to further reason that broader, non-metabolic, antifibrotic mechanisms are required for widespread patient impact. Non-metabolic therapies such as LOXL2 and ASK1 inhibitors have been clinically tested as far back as a decade ago, with progress remaining slow.

Antibodies have proved enticing, despite the early failure of simtuzumab, which targets LOXL2, a collagen cross-linker.10 Nevertheless, current successes remain predominantly at Phase I:

While the low MASH therapy response rates are a crucial concern, another is that steatosis is not the primary driver of disease for a large proportion of liver fibrosis patients.22 This is especially true in later-stage disease.

(i) BI 765423, an interleukin (IL-11) inhibitor with antifibrotic and cytoprotective mechanisms.23

(ii) Lixudebart, an anti-claudin-1 antibody that reduces cell adhesion and allows tissue remodelling.24

(iii) BI 770371 which activates innate and adaptive anti-tumour immune responses also relevant to fibrosis,25 recently moving into phase II development for compensated cirrhosis due to MASH.

Cell-based therapies are another promising avenue. In a phase II study, autologous macrophage therapy in cirrhosis improved transplant-free survival.26 Separately, CAR-T cell approaches, originally developed for haematological malignancies,27 have also shown the ability to clear senescent hepatic stellate cells (HSCs).28-30

As with biologics, small molecule and ribonucleic acid (RNA) therapies have yet to demonstrate clear successes.

PLN-1474, a selective αvβ1 integrin inhibitor that reduces fibrosis via transforming growth factor beta (TGF-β) signalling, has reported favourable safety, a key concern with TGF-β inhibition.31 However, with intended co-development plans terminated, the next steps are uncertain. BMS-986263, a small interfering RNA (siRNA) against collagen chaperone heat shock protein 47 (HSP47) has demonstrated early therapeutic promise in a phase II study of HCV with fibrosis.32,33

Antifibrotic Precision Medicine: The Right Combination In The Right Patient, At The Right Time

Epidemiological studies suggest that variability in response to antifibrotic agents is to be expected. It has been long recognised that while some F3 fibrosis patients progress to cirrhosis within a few years, others remain stable for over a decade.37 Varied outcomes in metabolic patients are also well documented, with one study proposing an obesity group at increased risk of cardiovascular disease and Type 2 diabetes, and a second with limited comorbidity risk despite similar liver steatosis levels.38 Intrapatient responses also vary over time, as observed in a cenicriviroc MASH Phase II study where not all patients maintained a therapeutic response after 1 year.39 Taken together, sex, ethnicity, and genetics point towards a future in which liver antifibrotics are guided by precision medicine.

While genetics, sex, and ethnicity paint a picture of metabolic and non-metabolic stratifiers, perhaps the most challenging stratifiers will be age, comorbidities, and their interaction.

For the clinician, the precision medicine mindset will mean balancing:

Therapies addressing the initial insult versus those with more general antifibrotic potential

Therapies with high-potency, low-tolerability profiles versus those with greater tolerability but potentially lower potency

At present we can only speculate which patients will benefit first from a long-term therapy gradually addressing the initial insult, versus who may benefit from a shorter induction phase using a more potent but less tolerable antifibrotic.54 What is clear is that few, if any, patients with more advanced disease will fully benefit from monotherapies. Sadly, past trials offer few lessons to guide future combination strategies (Figure 1, Supplementary Tables 1 and 2).

Perhaps the most notable failure has been the MASH phase II combinations of selonsertib (an ASK 1 inhibitor), cilofexor (an FXR agonist), and fircostat (an ACC inhibitor).56

Fibrosis ‘Cure’ And Normal Liver Function

From MASH through to HCV infection, the extent of liver fibrosis has become established as the most meaningful surrogate endpoint for liver-associated morbidity (decompensation and HCC) and mortality (transplant-free survival).3

50%

33%

And a response of as much as 50% has been reported after 3–5 years in HCV patients with sustained virological response.61

Up to 33% reduction of fibrosis of at least one stage has been reported within 1 year after bariatric surgery.60

Consequently, therapeutic reversal of fibrosis has become a central goal. As recently as 20 years ago, doubts remained as to how much reversal would be possible in significant liver fibrosis (‘F2’ portal fibrosis to ‘F3’ bridging fibrosis). Today, expectations are higher, shaped by real-world examples, including bariatric surgery for obesity, long-term hepatitis B suppression with tenofovir or entecavir, and curative antivirals for HCV.

Should full fibrosis reversal therefore be the sole therapeutic goal in MASH, especially in patients with cirrhosis?

To date, the greatest body of evidence rests with HCV studies, which have demonstrated that while some complications such as raised portal pressure may resolve even in decompensated disease,65 HCC risk does not fully return to that expected of the fibrosis level the patient regresses to.66

Phase III Study

Future outlook

Interestingly, an ongoing MASH Phase III study of belapectin (a galectin-3 inhibitor) has also suggested that fibrosis and adverse outcomes may not be fully coupled.67 Analysis of the per-protocol patient population has indicated an 11–13% risk of oesophageal varices at 18 months (versus 22% with placebo) in the absence of fibrosis reversal.67

Equally plausible is that some patients with advanced disease will benefit from regenerative therapies aimed at restoring liver function and increasing transplant-free survival. Although regenerative therapies, such as mitogen-activated protein kinase kinase 4 (MKK4) inhibitors,69 have largely yet to progress beyond animal models, a phase II trial evaluating transplantation of hepatocytes into lymph nodes to supplement liver function70 may prove another fascinating cellular therapy option.

While the suppression of regeneration in fibrotic livers, via mechanisms such as TGF-β signalling,71 have long been recognised, recent work has further demonstrated that inhibition of microfibril-associated glycoprotein 4 (MFAP4), an ECM protein that interacts with integrins, both reduces fibrosis and increases regeneration in mice.72 Perhaps as interesting will be if regenerative therapies themselves demonstrate antifibrotic potential, a response that is seen in patients whose HCV is cured.

Conclusion

We are at the beginning of what can be expected to be a challenging phase in the development of a liver antifibrotic toolbox that adequately treats all patients across aetiology, stage of disease and across the many, as yet to be fully understood, stratifiers.

Whether functional restoration is possible is still unclear.

Even so, the recent progress in metabolic therapies is worth celebrating. Several agents can reverse fibrosis in a subset of patients with MASH without worsening steatohepatitis. As development pushes into cirrhosis, we should also learn whether fibrosis reversal alone is the right goal, as longer-term morbidity and mortality data emerge over the coming decade.

References

Support: The publication of this article was organised and funded by Ochre Bio Ltd and is intended for healthcare professionals only. Disclosure: Author: Quin Wills1 Affiliation: 1Ochre Bio, Oxford, UK Disclaimer: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This article mentions investigational therapies that are not currently approved for indication. Acknowledgements: The author thanks Kenny Moore, Julian Maller, Sarah Batey, Jack Castle, Leanne Hodson, Eduardo Martins, Scott Friedman, and Chinwe Ukomadu for providing critical reading. Writing and editorial assistance was provided by Cherry Bwalya of Cherry B Enterprises Ltd and Fiona Weston of Fiona Weston Editorial Services Ltd, funded by Ochre Bio, according to the Good Publication Practice guidelines. Interactivity support provided by Yolande Chalmers, EMJ, London, UK. Keywords: Antifibrotics, combination therapies, liver fibrosis, metabolic dysfunction-associated steatohepatitis (MASH), metabolic therapies.

Metabolic dysfunction-associated steatohepatitis (MASH), along with other chronic liver diseases, leads to progressive fibrosis and, ultimately, cirrhosis. Liver fibrosis is a major cause of global morbidity and mortality. Although past efforts to develop antifibrotic drugs have largely failed, recent advances in MASH metabolic therapies offer new hope. These include both indirect-acting agents such as glucagon-like peptide 1 (GLP-1) analogues, which reduce liver fat by promoting weight loss, and therapies with direct-acting mechanisms on the liver, such as thyroid hormone receptor beta (THRβ) activators and fibroblast growth factor 21 (FGF21) analogues. This perspective summarises emerging antifibrotics, from the fast-evolving class of metabolic therapies through to the more sluggish development of non-metabolic antifibrotics. We consider future therapeutic combinations and patient stratifiers that may impact patient outcomes, and close by asking if fibrosis reversal should be the only goal.

SUMMARY

Globally, the leading causes of compensated cirrhosis in 2017 were hepatitis B (33%), hepatitis C (HCV; 25%), and alcohol (21%), compared with 8.4% due to MASH. Deaths from cirrhosis followed a similar pattern: hepatitis B (29%), HCV (26%), and alcohol (25%), with 9% attributed to MASH.22

However, a phase II trial in patients with compensated MASH cirrhosis was terminated for lack of efficacy.34 Selvigaltin (GB1211), a small-molecule inhibitor of galectin-3, has been well tolerated,35 the next liver studies have not been clearly disclosed. 26,36

The most common MASH comorbidities in older patients are, unsurprisingly:

Type 2 diabetes

Dyslipidaemia

Hypertension

Older patients live with a greater number of comorbidities, have a diminished liver regenerative capacity, and may not tolerate the effects of certain therapies (such as GLP-1 agonist-induced sarcopenia).

Diabetics, representing over half of the patients in the semaglutide Phase III MASH trial,52 tend to have more significant fibrosis with microvascular damage, although response differences between those with or without diabetes are unclear. This may be a result of semaglutide’s dual therapeutic impact on diabetes and obesity.

Notably, hypertension and dyslipidaemia have already emerged as a treatment stratifier, with the exclusion of obeticholic acid, an FXR agonist, due to its low-density lipoprotein-raising effect, unless the patient is on statins. Obeticholic acid has faced a particularly rocky path, with FDA restrictions on its use for primary biliary cholangitis, and denial of MASH approval.53

However, short study timelines (48 weeks) and inclusion of only the most significant fibrosis stages may partly explain the failure. In addition, these preclinical models and the proposed mechanistic rationales may be inadequate to elucidate the relevant outcomes. However, the reasons for the failure of these approaches remain unclear.er, the reasons for the failure of these approaches remain unclear.

Despite limited data, the enthusiasm for augmenting GLP-1 therapies remains. Multi-agonist molecules being trialled include the glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide,55 the amylin receptor agonist amycretin,56 the glucagon receptor agonist survodutide,57 and the glucagon + GIP receptor agonist retatrutide.58,59 Although some trials have focused solely on obesity, multi-agonism may improve antifibrotic potential. This is supported by survodutide’s FDA ‘breakthrough therapy’ designation for non-cirrhotic MASH,57 and tirzepatide’s ability to resolve steatohepatitis without worsening fibrosis.55

FGF21 analogues have added to the enthusiasm for rapid and extensive fibrosis reversal, with efruxifermin, pegozafermin, and efimosfermin alpha phase II trials demonstrating remarkable response rates for significant fibrosis within 6 months.62-64 These results have elicited interest in acquisition of these compounds for potential phase III development, with efruxifermin currently under investigation for MASH in three phase III clinical trials (Figure 1, Supplementary Table 1).

MASH studies over the coming years will no doubt provide more insights. Until then, a reasonable assumption would be that tissue architecture and microcirculation disturbances, ongoing inflammatory processes (such as senescent hepatocytes),68 and oncogenic changes that remain after fibrosis reversal will require a lifetime of patient surveillance.

Phase III Study

Future outlook

Premenopausal women are less prone to MASH fibrosis and HCC,40,41 although trials have yet to demonstrate clear sex differences.

Individuals of Hispanic ancestry have a greater MASH prevalence and severity, partly due to the known patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene risk allele, while individuals of some African ancestries exhibit lower liver steatosis and fibrosis.42 Population genetics offers further clues, including variants in two genes of particular therapeutic interest in MASH.43

The PNPLA3 risk variant I148M is thought to reduce its hydrolyse activity and its degradation, resulting in increased triglycerides in hepatocytes and retinyl esters in stellate cells.43 The accumulation of poorly degraded, abnormal protein that sequesters cofactors of other lipases makes this a toxic gain-of-function that is amenable to inhibitors. AZD2693, a PNPLA3 antisense oligonucleotide in phase II,44,45 and ALN-PNP, an siRNA in phase I,46 have been developed to reduce total PNPLA3, while ARO-PNPLA3, an siRNA47 targets the variant. While PNPLA3 points to the metabolic roots of fibrosis, the mechanism of a second gene, HSD17B13, remains less clear. Its loss-of-function variants reduce inflammation without a reduction in steatosis.48 HSD17B13 therapies in phase II are GSK4532990 and ALN-HSD (separate licenses of the siRNA ARO-HSD),49,50 with INI-822, a small molecule inhibitor, in Phase I.51

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Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average (Accessed December 12, 2025) Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology (2015) 149:379–88. doi: 10.1053/j.gastro.2015.04.014 Rockey DC. Fibrosis reversal after hepatitis C virus elimination. Curr Opin Gastroenterol (2019) 35:137–44. doi: 10.1097/MOG.0000000000000524 Harrison SA, Frias JP, Neff G, et al. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol (2023) 8:1080–93. doi: 10.1016/S2468-1253(23)00272-8 Loomba R, Sanyal AJ, Kowdley KV, et al. Randomised, controlled trial of the FGF21 analogue pegozafermin in NASH. N Engl J Med (2023) 389:998–1008. doi: 10.1056/NEJMoa2304286 No authors listed. Once-monthly efimosfermin alfa (BOS-580) in metabolic dysfunction-associated steatohepatitis with F2/F3 fibrosis: results from a 24-week, randomized, double-blind, placebo-controlled, phase 2 trial. Gastroenterol Hepatol (N Y) (2024) 20 (suppl 11):15–16. Sánchez-Torrijos Y, Fernández-Álvarez P, Rosales JM, et al. Recompensation of decompensated cirrhosis in hepatitis C patients after SVR: prognostic implications. J Hepatol (2025) 83:652–61. doi: 10.1016/j.jhep.2025.02.041 Ioannou GN. HCC surveillance after SVR in patients with F3/F4 fibrosis. J Hepatol (2021) 74:458–65. doi: 10.1016/j.jhep.2020.10.016 Alkhouri N, Vuppalanchi R, Noureddin M, et al. LBO-006 Belapectin at 2 mg/kg/LBW reduces varices development in MASH cirrhosis with portal hypertension: results from the NAVIGATE trial. J Hepatol (2025) 82:S12–13. https://doi.org/10.1016/S0168-8278(25)00315-0 Wijayasiri P, Astbury S, Kaye P, et al. Role of hepatocyte senescence in the activation of hepatic stellate cells and liver fibrosis progression. Cells (2022) 11:2221. doi: 10.3390/cells11142221

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MASH: Fuelling an Emerging Metabolic Toolbox

In a 52-week Phase III trial,11 resmetirom met both histological surrogate endpoints required by the FDA and the European Medicines Agency (EMA), improvement in steatohepatitis and fibrosis.12,13

In 2024, resmetirom, a direct-acting thyroid hormone receptor beta [THR-β] agonist, became the first therapy to receive US Food and Drug Administration (FDA) accelerated approval for non-cirrhotic MASH.

GLP-1

26%

Placebo

14%

26% of patients achieved fibrosis improvement by at least one stage without worsening steatohepatitis, versus 14% with placebo.11 Although most patients still failed to reach a statistically significant response within 1 year, this has proven to be a seminal moment. Other metabolic therapies, including semaglutide (a glucagon-like peptide 1 [GLP-1] analogue) and efruxifermin(a fibroblast growth factor 21 [FGF21] analogue), quickly followed.

In a 72-week phase III MASH trial, semaglutide improved fibrosis without worsening steatohepatitis in 37% of patients, versus 22% for placebo,14 resulting in its recent FDA approval.15

11%

Placebo

29%

GLP-1

Most trials have focused on non-cirrhotic MASH, but efruxifermin is the first metabolic therapy to report positive results in compensated cirrhosis. In a 96-week Phase II trial, 29% of patients had at least a one-stage improvement in fibrosis without worsening steatohepatitis, versus 11% with placebo (intention-to-treat analysis).16

Why Slowing Cirrhosis is Not Enough

While a therapeutic intervention regressing cirrhosis may be paradigm shifting, the findings of histological improvement remain a surrogate endpoint. The true impact of these results remains to be seen in phase III trials and beyond, in which morbidity and mortality outcomes, such as the risk of hepatocellular carcinoma (HCC), decompensation, and transplant-free survival, will be the ultimate tests of efficacy.17

How might this frontline evolve and be used? A key question of the toolbox is where direct-acting versus indirect-acting mechanisms may prove most useful.

With over 30 key trials expected to readout over the next 5 years (Figure 1, Supplementary Tables 1 and 2), metabolic therapies look set to become a frontline option for patients with MASH and compensated cirrhosis.

Therapies that do not promote weight loss may, for example, be preferred for the one in six patients with MASH classed as ‘lean MASH’ (those with a normal body mass index [BMI]), in whom the sarcopenic side-effect of GLP-1 analogues would be undesirable.

On the other hand, GLP-1 analogues will likely be preferred as part of broader cardiometabolic interventions in patients with BMI >30 kg/m2 and comorbidities.

Semaglutide has been linked to reduced alcohol intake

Beyond BMI and comorbidity considerations is the question of therapies with alternative metabolic mechanisms. Given today’s low therapy response rates, it is likely that multiple metabolic approaches, each with different target populations and side-effect profiles, will be needed.

There is also growing interest in targeting metabolism in non-hepatocyte liver cells. So far, many therapies appear to act mainly by increasing hepatocyte beta oxidation, but that is unlikely to be the whole story.

Denifanstat

de novo

lipogenesis

reduction

Hepatocytes

Stellate Cell

One potential complementary approach is denifanstat, a fatty acid synthase (FASN) inhibitor that reduces de novo lipogenesis in both hepatocytes and stellate cells.

>1 Stage Fibrosis Improvement

Denifanstat

Placebo

14%

30%

In the ITT analysis of its Phase II trial, 30% of patients achieved at least one stage of fibrosis improvement, versus 14% with placebo, with subgroup analysis suggesting the greatest response in F3 patients.19

All things considered, metabolic therapies across multiple mechanisms show promise, but there is no clear home run yet beyond weight loss, THRβ signalling, and FGF21 signalling.

Lanifibranor is currently in a Phase III trial for MASH patients with Type 2 diabetes,21 with pioglitazone (an insulin sensitising PPARγ agonist approved for Type 2 diabetes) in multiple Phase IV trials.

Another potential therapy known to directly inhibit stellate cell activation is lanifibranor. Interest in peroxisome proliferator-activated receptor (PPAR) agonists such as lanifibranor dates back decades, despite weight gain and oedema limiting their use.20

Frontline Evolution: Relevance to Different Patients

(ii) metabolic therapies such as acetyl-CoA carboxylase (ACC) inhibitors and farnesoid X receptor (FXR) agonists;6,7

Examples include: (i) cytoprotectants such as apoptosis signal-regulating kinase 1 (ASK1) inhibitors and pan-caspase inhibitors;4,5

(iii) chemokine inhibitors such as C-C chemokine receptor type 2/C-C chemokine receptor type 5 (CCR2/CCR5) inhibitors and galectin-3 inhibitors; 8,9

However, the field has now been re-energised with renewed optimism thanks to indirect- and direct-acting metabolic agents targeting patients with MASH.

More recently

Metabolic therapies are emerging as a critical success in chronic liver disease

GLP-1 receptors raise the possibility of a new option to support abstinence in ALD, either alone or alongside MASH (MET-ALD), without the side effects often seen with disulfiram or naltrexone.