MAFLD Pandemic: Updates in Pharmacotherapeutic Approach Development

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Reviewer 1

1

It would be good to have a figure to improve the visual appearance of the manuscript

Thank you for your suggestion. We have added an illustration to improve the manuscript's appearance. 

The Figure 2 has been added.

Figure 2: Molecules trialled for Metabolic-associated fatty liver disease in respect to their most current randomized clinical trial phase.

2

There are minor grammatical and syntax errors which should either be fixed by the authors, or perhaps it will occur at the journal?

Thank you for this remark.

We have corrected the grammatical and syntax errors made in the manuscript.

3

The authors on page 2 discuss the criteria for MAFLD, the third criteria is not “other metabolic disorder” but rather, “patients who are of healthy weight according to ethnic specific criteria with 2 or more metabolic risk factors”

Thank you for pointing out this omission.

This was wrongly explained and we have now corrected this sentence.

This is how this part of the text reads now:

The focus of this new terminology is on the inclusion of "positive" disease criteria for MAFLD diagnosis: overweight/obesity or T2DM or at least 2 metabolic risk factors in patients having normal/lean weight defined by the criteria for specific ethnic group, which should be present in addition to evidence of steatosis detected via biopsy, imaging or biomarkers in the blood (8).

4

On the same page they talk of environmental factors such as metabolic syndrome, oxidative stress gut microbiota etc. This should be rephrased: metabolic syndrome is not an environmental risk factor nor is oxidative stress. These are correctly risks factors or associations of MAFLD that may have a pathogenic role.

Thank you for this remark. We have corrected the sentence.

Here is the following sentence:

Generally, MAFLD is considered to be caused by a combination of various risk factors such as metabolic syndrome, oxidative stress, gut microbiota imbalance and genetic factors such as genetic polymorphisms and epigenetic alterations (1).

5

Page three regarding “in patients who progress to NASH”, should be changed to MASH

Thank you for bringing this to our attention.

Here is the following sentence:

Additionally, in patients who progress to MASH, in parallel with the steatosis increasing, the activity of THR-β receptors in liver decreases, i.e. the receptors become less sensitive to thyroid hormones (36).

6

Page 4: the authors talk of “no aggravation of MAFLD”, it should be no aggravation of MASH”.

Thank you for pointing out this error.

Here are the following sentences:

The biopsy results demonstrated that compared to the placebo group, in which patients were advised on healthy nutrition and exercise, a larger number of patients on resmetirom therapy showed resolution or no aggravation of MAFLD/MASH or liver fibrosis (38, 39).

(...)

Additionally, patients in the 80 mg and 100 mg resmetirom group (24.2 % and 25.9% re-spectively) showed benefit in liver fibrosis and no aggravation of MASH in comparison with the placebo group (14.2%) (38, 39).

7

In the same paragraph they state that the study will be extended for 54 months “in order to provide a full safety ie clinical benefit assessment”. This is not correct. The trial has a 5 year duration in order to demonstrate clinical benefit with regards to liver related outcomes with an acceptable safety profile.

Thank you for your remark.

Here is the following sentence:

However, the sponsor still must complete 54 months of this study in order to demonstrate clinical benefit in terms of liver-related outcomes along with an acceptable safety profile (39, 40).

8

The primary outcome measure of NCT05308160 is safety (despite the title)

Thank you for pointing out this omission.

Here is the following sentence:

The safety of dapagliflozin is still being assessed in a placebo-controlled phase 3 RCT (NCT05308160), which is expected to enroll a total of 75 patients with MAFLD diagnosed with steatosis grade 2 or higher detected by FibroScan device and to be finished by the end of April 2024 (65, 76).

9

 The GPLIRAs are being investigated in pre-registration trials and perhaps this section should come before the SGLT2i section.

Thank you for your suggestion.

Section Incretin and Glucagon Receptor Agonists has been moved before section Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

10

It is stated that ESSENCE is expected to enrol 1200 by 2029. I think 2029 is the completion date not the date for enrolment of 1200 patients. These sorts of errors should be fixed throughout the manuscript.

We appreciate your comment. This sentence was inaccurately formed and we have corrected it and other sentences in the manuscript accordingly.

Here is the following sentence:

Semaglutide is currently being investigated in the ESSENCE phase 3 clinical study designed as randomized, placebo-controlled trial (NCT04822181), which is enrolling a total of 1,200 patients and is expected to be completed by 2029.

One of these is the SYNCHRONY Histology study (NCT06215716), which is expected to recruit 1000 participants and to be finalized by March 2027.

The aim of this ongoing study, with an estimated duration until the end of 2025, is to assess its efficacy in resolution of MASH without aggravation of liver scarring in a total of 300 non-diabetic patients with histologically proven precirrhotic MASH (63, 64).

The safety of dapagliflozin is still being assessed in a placebo-controlled phase 3 RCT (NCT05308160), which is expected to enroll a total of 75 patients with MAFLD diagnosed with steatosis grade 2 or higher detected by FibroScan device and to be finished by the end of April 2024 (65, 76).

Currently, scientists at the University of Florida in the United States are also investigating the efficacy and safety of pioglitazone in the RCT known as AIM 2, but at a low dose (15 mg per day) and in patients with T2DM and MASH, with the plan to enroll 166 patients and a duration until the end of 2027 (NCT04501406) (89).

Those favourable outcomes led to the launch of the NATIV3 study, a Phase 3 placebo-controlled RCT (NCT04849728), which aims to enroll 1000 patients with active NASH and liver fibrosis (stage F2 / F3) and to be completed by October 2026.

11

Regarding pioglitazone, this is hardly used because of the potential adverse effects including weight gain, fluid retention and risk of bladder cancer. This should be mentioned.

Thank you for this remark.

We added following sentence:

On the other hand, it should be pointed out that the clinical use of pioglitazone is limited due to its potential side effects including weight gain, bladder cancer, fluid retention which can cause congestive heart failure in patients having cardiomyopathy and an enhanced risk of bone loss and distal bone fractures in postmenopausal women and therefore careful selection of patients for pioglitazone therapy is required (87, 91).

[91.       Miao L, Xu J, Targher G, Byrne CD, Zheng MH. Old and new classes of glucose-lowering agents as treatments for non-alcoholic fatty liver disease: A narrative review. Clin Mol Hepatol. 2022;28(4):725-38.]

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Reviewer 2

1

The major concern is that several studies (e.g. the "MAESTRO-NASH" RCT for resmetirom) enrolled patients based on NASH criteria. However, the novel terminology is based on the presence of at least 1 of 5 cardiometabolic risk factors; thus, MASH is not identical to NASH (Rinella ME, et al. NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-86). The authors are welcome to disuss the emerging limitations  on the revised version of the manuscript

Thank you for this remark. We acknowledge the limitation of our article.

Following section was added:

To reflect the accepted new terminology and to facilitate readability of this paper, the new term MASH has been used instead of NASH. This is also the main limitation of this review, as the RCTs mentioned included patients based on NASH criteria, which are not the same as those for MASH. The main difference is that NASH patients do not necessarily have at least one of the five cardiometabolic risk factors (obesity, T2DM, hypertension, elevated plasma triglycerides and decreased plasma HDL) (106). It is therefore uncertain whether the study results would be significantly different if patients with MASH criteria were included in the study. On the other hand, it is important to emphasize that the term steatohepatitis as well as the criteria for fibrosis stages were preserved in both terminologies. In addition, patients with steatosis without cardiometabolic risk factors or other possible causes are considered cryptogenic and candidates for possible MAFLD who would benefit from regular reassessment (8, 106, 107). The sponsor of the MAESTRO-NASH study (NCT03900429) for resmetirom, which involved patients with NASH and fibrosis, announced along with the study results that the new terminology for NASH is MASH (20). However, to correctly adopt the MASH terminology, studies would need to enroll patients with MASH, which is expected in future RCTs for this indication.

[106.     Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-86.]

[107.     Liebe R, Esposito I, Bock HH, Vom Dahl S, Stindt J, Baumann U, et al. Diagnosis and management of secondary causes of steatohepatitis. J Hepatol. 2021;74(6):1455-71.]