[Edaily Reporter KIM JI-WAN ] Mezzion Pharma Co., Ltd.(140410)is expanding the scope of “FUEL-2,” the global Phase 3 clinical trial for udenafil—a drug under development for the treatment of Fontan patients—to the United Kingdom. With patient enrollment now underway in the UK, following South Korea and the U.S., the global clinical trial aimed at securing regulatory approval for udenafil is expected to gain momentum.

According to Mezion Pharma Co., Ltd. on the 1st, the company recently completed the FUEL-2 kick-off meeting and Site Initiation Visit (SIV) with principal investigators (PIs) and pediatric cardiologists at major clinical trial sites in London and Birmingham, UK.

The kick-off meeting is an opportunity for the research team to share the trial’s objectives, overall schedule, patient recruitment strategy, and the roles and operational plans of each site, as well as to review the collaborative framework necessary for the actual conduct of the clinical trial, prior to the full-scale launch of the trial.

SIVs Completed at Three Major UK Hospitals… Patient Screening to Begin Next Week

An SIV is a procedure to conduct a final review of all clinical operations—including the trial protocol, patient management, data entry, and safety reporting—immediately prior to actual patient enrollment. Following approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA), Mezion Pharma Co., Ltd. has now completed the SIVs, finalizing preparations for actual patient recruitment.

In the UK, three major pediatric cardiology centers—including those in London and Birmingham—are participating in the FUEL-2 trial. The company plans to begin patient screening and enrollment in earnest starting next week.

A Mezion Pharma Co., Ltd. official stated, “We have completed all practical preparations and final checks for the enrollment of the first patients following approval from the UK regulatory authority,” adding, “We plan to begin screening and recruiting clinical trial patients in the UK in earnest starting next week.”

The spokesperson added, “Since the trial is being conducted at three major UK hospitals with world-class expertise in pediatric cardiology, we expect patient enrollment to proceed swiftly and smoothly.”

FUEL-2 is a confirmatory Phase 3 clinical trial evaluating the efficacy and safety of udenafil in patients with single-ventricle heart disease who have undergone the Fontan procedure. Approximately 436 patients will be randomly assigned to either the udenafil group or the placebo group and will receive treatment for 26 weeks.

The primary endpoint is the change from baseline in peak oxygen consumption (peak VO₂) during maximal exercise, as measured by a cardiopulmonary exercise test (CPET).

Which UK hospitals? The “Fontan Big 3” are strong contenders

. The specific names of the three UK hospitals participating in the FUEL-2 trial have not yet been officially disclosed.

However, based on the company’s description of them as leading pediatric cardiology centers in London and Birmingham, Great Ormond Street Hospital for Children (GOSH), Evelina London Children’s Hospital, and Birmingham Children’s Hospital are considered leading candidates.

Great Ormond Street Hospital for Children is one of the UK’s leading pediatric specialty hospitals and operates a dedicated “Single Ventricle Service” for patients with single-ventricle heart defects. It has a system in place for long-term patient care—from immediate postnatal care through staged surgeries and beyond the third surgery (the Fontan procedure)—making it a highly specialized institution capable of conducting clinical trials for Fontan patients, such as the FUEL-2 trial.

Evelina London Children’s Hospital is also a leading center for the treatment of congenital heart disease in the UK. It treats a wide range of rare and complex congenital heart conditions, performing approximately 480 to 520 congenital heart surgeries and 400 to 450 cardiac catheterizations annually. The hospital has a medical team specializing in single-ventricle circulation and actually performs Fontan procedures.

Birmingham Children’s Hospital is one of the largest pediatric cardiology centers in the UK. It treats more than 12,000 outpatients annually and performs approximately 600 cardiac surgeries. In particular, in collaboration with the University of Birmingham, it focuses on single-ventricle heart disease and the Fontan circulation as key research areas and has conducted studies on the long-term prognosis of Fontan surgery patients as well as multicenter clinical trials.

A cardiology expert noted, “If these institutions are ultimately confirmed as actual FUEL-2 trial sites, Mezion Pharma Co., Ltd. will effectively secure large, specialized pediatric cardiac centers—where Fontan patients are concentrated—as clinical hubs within the UK.”

Udenafil Stalled at the Threshold of Phase 3… ‘Super-Fontan’ Excluded from FUEL-2

The upcoming FUEL-2 trial is effectively the key clinical trial for Mezzion Pharma Co., Ltd.’s renewed attempt to secure approval for udenafil. The previous Phase 3 FUEL-1 trial evaluated the efficacy of udenafil in 400 Fontan patients.

At that time, peak oxygen consumption (peak VO₂)—the primary endpoint—increased by 2.8% in the udenafil group, while it decreased by 0.2% in the placebo group. However, the P-value indicating the difference between the two groups was 0.071, failing to meet the standard threshold for statistical significance of 0.05.

On the other hand, significant improvements were observed in some secondary endpoints, such as oxygen consumption at the anaerobic threshold (VAT) and exercise capacity. Subsequently, the researchers noted the possibility that the overall efficacy of the drug may have been diluted due to the inclusion of so-called “Super-Fontan” patients, whose exercise capacity was already near normal.

“Super-Fontan” refers to a subgroup of patients who have undergone the Fontan procedure and exhibit exceptionally good cardiopulmonary exercise capacity. In the academic community, patients whose maximum oxygen consumption (VO₂ max) on a cardiopulmonary exercise test (CPET) is 80% or higher of the normal predicted value for their age and sex are generally classified as “Super-Fontan.” Since the VO₂ max of typical Fontan patients is known to be approximately 55–70% of the normal predicted value, Super-Fontan patients represent an exceptional subgroup with exercise capacity relatively close to that of healthy individuals.

In fact, a post-hoc analysis of the FUEL-1 study published in the Journal of the American Heart Association (JAHA) in 2025 showed that the beneficial effects of udenafil were more pronounced when analyzing only patients whose maximum oxygen uptake was less than 80% of the normal predicted value. The P-value for the difference between the two groups was 0.021, indicating statistical significance.

Consequently, the FUEL-2 trial excluded “super-fit” patients from the outset. The study is designed to re-evaluate the efficacy of udenafil by recruiting patients whose maximum oxygen uptake is between 45% and 80% of the normal predicted value. The strategy is to reduce the “ceiling effect” observed in FUEL-1 by excluding patients whose exercise capacity is already close to normal, leaving little room for further improvement.

Ultimately, FUEL-2 is not simply a repeat of FUEL-1. The key point is that it is a confirmatory trial that pre-selects patient groups likely to benefit from udenafil—based on the differences in response across patient groups identified in the previous trial—and then re-evaluates its efficacy.

Expanding from the U.S. and South Korea to the U.K. and the EU… Patient Recruitment Is the Decisive Factor

Uncertainties regarding the clinical trial process have also been partially reduced.

Mezzion Pharma Co., Ltd. conducted an independent blinded statistical review once half of the planned subjects had completed 26 weeks of treatment and concluded that there was no need to increase the number of patients further to maintain the originally established statistical assumptions.

Accordingly, the target patient enrollment for FUEL-2 remains at 436.

Mezzion Pharma Co., Ltd. plans to expand the clinical trial not only in the UK but also in other European countries. It has already submitted clinical trial protocols to some EU countries and is awaiting review by regulatory authorities.

Mezzion Pharma Co., Ltd. stated, “We have completed the submission of clinical trial protocols to swiftly initiate trials in European countries other than the UK,” adding, “We will actively respond to feedback from regulatory agencies and do our utmost to successfully complete the FUEL-2 trial across all of Europe within the target timeline.”

Ultimately, the key challenge going forward is how much the pace of patient recruitment for the FUEL-2 trial can be accelerated, with the UK and Europe joining Korea and the U.S. If global patient enrollment is completed as planned, Mezion Pharma Co., Ltd.’s Udenafil will enter the final stage of securing confirmatory data required for approval as a Fontan therapy.

A Mezion Pharma Co., Ltd. official stated, “There is no change to our plan to complete patient recruitment for the global Phase 3 FUEL-2 clinical trial for the Fontan procedure by the end of this year.”