[Edaily Reporter KIM JI-WAN ] “When you examine the kidneys of mice with polycystic kidney disease, you can see large cysts. However, after administering Udenafil, a reduction in the size of these cysts was visible even to the naked eye.”

Mezzion Pharma Co., Ltd.(140410)The company is expanding the indications for udenafil—currently under development as a treatment for Fontan patients—to include autosomal dominant polycystic kidney disease (ADPKD). In trials progressing from cells to kidney tissue and then to live animal models, kidney cysts consistently decreased, and indicators related to kidney function and cardiac hypertrophy also showed improvement.

ADPKD is a hereditary disease caused by mutations in the PKD1 or PKD2 genes, resulting in the formation of numerous cysts in both kidneys. As the cysts continue to grow, the overall volume of the kidneys increases, compressing normal tissue and gradually impairing kidney function. Some patients progress to end-stage renal disease, requiring dialysis or a kidney transplant. Because it can be accompanied not only by kidney involvement but also by hypertension, liver cysts, cardiovascular abnormalities, and cerebral aneurysms, it is considered a systemic disease.

Kim Yong-cheol, Clinical Associate Professor of Nephrology at Seoul National University Hospital, analyzed the results of preclinical trials of Udenafil for ADPKD conducted by the Mayo Clinic in the U.S. during a Mezion Pharma Co., Ltd. corporate briefing held on the 4th at the Financial Investment Education Center in Yeouido, Seoul. Based on these animal study results, Mezion Pharma Co., Ltd. plans to proceed directly to Phase 2b clinical trials for ADPKD in both South Korea and the U.S.

Cysts Reduced by 50–60% and BUN P<0.001… “All Key Indicators Met”

The efficacy of Udenafil has been verified in stages, from cells to kidney tissue to animal models.

First, a cystic environment similar to ADPKD was created in a 3D cell model by treating the cells with forskolin (FSK). Forskolin is a standard research reagent that induces cyst growth by increasing the production of cyclic adenosine monophosphate (cAMP) within cells.

Round, swollen cysts formed in the cells treated with forskolin. However, when udenafil was co-administered, the enlarged cysts were observed to shrink again. Quantitative analysis showed that udenafil reduced cyst growth in the 3D cyst formation model by approximately 50%.

The same results were confirmed in an in vitro organ-on-a-chip assay using excised kidney tissue. When udenafil was administered to a kidney model in which cysts had been induced by phoscolin, the cyst burden was reduced by up to approximately 60%. This demonstrates that the effect observed at the cellular level was replicated in actual kidney tissue.

Professor Kim emphasized, “Under a microscope, cells swell significantly after forskolin treatment to form cysts, but when udenafil is administered, the enlarged cysts shrink again,” adding, “Consistent results were observed not only in cells but also in kidney tissue.”

Statistically Significant Decreases in Cyst Index and BUN in ADPKD Animal Model

The most notable finding in this presentation was the in vivo study using a mouse model developed by the Mayo Clinic.

Cross-sections of the kidneys in the control group with polycystic kidney disease showed cysts of various sizes widely distributed throughout the tissue. In contrast, in the groups administered 150 mg/kg and 300 mg/kg of udenafil, the area occupied by cysts decreased overall.

The cyst index, which quantifies this, decreased statistically significantly in the udenafil-treated groups. The p-value reported by KD Corporation was P < 0.003. The cyst index is a measure of the proportion of the kidney occupied by cysts. Since ADPKD is a disease in which cysts continue to grow, compressing normal kidney tissue and leading to long-term decline in kidney function, reducing the cyst burden is key to drug development.

Blood urea nitrogen (BUN), a marker of kidney function, also decreased in the udenafil group. The statistical significance was P < 0.001, indicating a stronger effect than that observed for the cyst index. Blood urea nitrogen (BUN) is the concentration of waste products generated by protein breakdown in the blood and is primarily used as an indicator to assess kidney function and dehydration status.

Professor Kim emphasized, “The two most important indicators in ADPKD research are cyst size and kidney function,” adding, “In this study, both the cyst index and BUN showed statistically significant improvements, and the statistical significance of the BUN reduction was particularly strong.”

He continued, “When nephrologists review new ADPKD clinical trials, the first question they ask is whether there is data from animal studies,” adding, “Medical professionals who reviewed this data also responded that the results are sufficient to proceed with clinical trials in humans.”

Positive signs were also observed in the secondary endpoints.

Heart weight relative to body weight (HW/BW) decreased statistically significantly in both the 150 mg/kg and 300 mg/kg udenafil treatment groups. A decreasing trend was also observed in left ventricular weight normalized by body weight (LV/BW), and the renal fibrosis index showed a tendency to decrease following udenafil administration.

Professor Kim explained, “Chronic kidney disease is not just a condition that affects the kidneys; it also places a burden on the heart due to fluid retention and elevated blood pressure,” adding, “The fact that cardiac hypertrophy markers showed statistically significant improvement following udenafil administration is also significant.”

Up to $1.7 billion for Phase 1b assets… “Udenafil, as an oral medication, will proceed directly to Phase 2b”

Park Dong-hyun, Chairman (CEO) of Mezion Pharma Co., Ltd., also highlighted the value that the global pharmaceutical industry places on the ADPKD pipeline.

Last year, Novartis acquired Regulars Therapeutics, which held the ADPKD candidate farabursen. At the time, farabursen had completed Phase 1b clinical trials. The acquisition terms included an upfront payment of $800 million (1.1397 trillion won) and an additional payment of up to $900 million (1.2813 trillion won) upon achieving regulatory milestones, bringing the total transaction value to a maximum of $1.7 billion (2.4196 trillion won).

Chairman Park stated, “Novartis valued the ADPKD asset, which had completed a Phase 1b clinical trial, at up to $1.7 billion,” adding, “This is an example that demonstrates just how much value a new treatment with proven efficacy and safety can hold in the ADPKD market, where treatment options are limited.” He continued, “Following the Phase 2b clinical trial results, we plan to pursue a technology export (L/O).”

Udenafil is also considered to have a comparative advantage in terms of convenience of administration. While Udenafil and the existing treatment Tolvaptan are oral medications, Parabursen was developed as a subcutaneous injection. Regulus’s Phase 1b trial was conducted as a multiple-dose escalation study using the subcutaneous administration route.

Kim Won-geun, Executive Vice President of Mezion Pharma Co., Ltd.’s Development Division, stated, “While a significant number of new candidate compounds being developed in the ADPKD field are injectables, Udenafil is an oral medication that patients can take daily,” adding, “Since rare chronic diseases require long-term treatment, ease of administration and medication adherence can also be important competitive advantages.”

Udenafil also differs from new drugs in its starting point. According to Mezion Pharma Co., Ltd., it has been administered to more than 4,700 pediatric and adult subjects, and the company has accumulated long-term administration data spanning up to five years, as well as extensive pharmacokinetic and toxicology data. The company also possesses an established manufacturing and quality control system, along with experience in dealing with regulatory agencies in the U.S., Europe, and Japan.

Executive Vice President Kim explained, “Since Udenafil has clinical and safety data spanning approximately 20 years, there is no need to start over from Phase 1,” adding, “We have confirmed sufficient efficacy signals in preclinical studies, and because existing human data is available, we can proceed directly to Phase 2b.”

Hepatic safety was also cited as a differentiating factor compared to existing treatments. Tolvaptan requires regular liver function tests due to the risk of liver damage. Mezion Pharma Co., Ltd. explained that, based on the clinical data accumulated to date on Udenafil, no signs of hepatotoxicity severe enough to restrict development or administration—as seen with tolvaptan—have been observed.

In a clinical trial involving Fontan patients, Udenafil reduced the LF score, a blood marker associated with liver fibrosis.

Chairman Park emphasized, “Udenafil demonstrated improvements in liver fibrosis-related markers in the Fontan clinical trial,” adding, “This sets it apart from tolvaptan, which exhibited hepatotoxicity. Safety is a crucial factor for ADPKD patients who must take medication long-term.”

Based solely on preclinical results, Mezion Pharma Co., Ltd. assessed that the efficacy signal for Udenafil was stronger than that of Tolvaptan in previous preclinical studies.

Executive Vice President Kim emphasized, “While early animal studies of tolvaptan were primarily conducted using rat models, uddenafil improved both cyst size and BUN levels in a genetic ADPKD mouse model developed by the Mayo Clinic,” adding, “The data is highly reliable because this model reflects current understanding of the disease and evaluation techniques.”

Korea-U.S. Clinical Trial with Fewer Than 100 Participants… “Patient Recruitment to Begin in Korea First, Completed by Next Summer”

Mezzion Pharma Co., Ltd. is proceeding with a randomized, double-blind, placebo-controlled Phase 2b trial targeting adult ADPKD patients at risk of rapid disease progression. The trial is expected to involve three to four hospitals in Korea and several hospitals in the United States.

Professor Kim Yong-cheol will serve as the principal investigator (PI) for the domestic trial. Professor Kim is reported to be treating and managing approximately 1,500 ADPKD patients at Seoul National University Hospital.

Executive Vice President Kim explained, “We are planning to conduct the trial simultaneously in Korea and the U.S., but will begin patient enrollment and dosing in Korea first,” adding, “Since patients in Korea are concentrated in major hospitals and researchers have a deep understanding of the disease, initial patient recruitment may be faster than in the U.S.”

There are also differences between South Korea and the U.S. regarding insurance coverage criteria for tolvaptan. In the U.S., access to treatment may vary depending on a patient’s kidney function and insurance status, so whether a patient is currently taking existing medications could potentially affect patient recruitment for the clinical trial. In contrast, the company explains that in South Korea, treatment costs and insurance coverage are relatively less likely to pose direct barriers to participation in the clinical trial.

Executive Director Kim said, “In the U.S., whether tolvaptan is used depends on kidney function and insurance criteria, so there are many factors to consider during the clinical enrollment process,” adding, “In South Korea, there are relatively fewer insurance issues related to clinical participation, and patient access is good, so we expect the initial enrollment rate to be faster.”

Mezzion Pharma Co., Ltd. aims to complete patient recruitment for the domestic clinical trial by next summer. However, since ADPKD is a chronic, progressive disease in which kidney size and function change over the long term, it is difficult to assess therapeutic efficacy based on a short-term treatment period alone.

Executive Vice President Kim explained, “We expect to complete patient recruitment for the Phase 1 trial by the second half of next year, and we should be able to obtain clinical results once the 12-month treatment period has elapsed.”

The clinical trial will evaluate renal function—including total kidney volume and eGFR—as well as disease-related biomarkers, pharmacokinetics, safety, and tolerability. Total kidney volume is a key imaging indicator for predicting the risk of ADPKD progression and assessing the efficacy of cyst growth inhibition.

Last May, Mezion Pharma Co., Ltd. received written feedback from the U.S. Food and Drug Administration (FDA) stating that, following a review of the preclinical pharmacology data for Udenafil, the ADPKD disease model is suitable for Phase 2b clinical development.

Chairman Park emphasized, “Udenafil has consistently reduced cysts in cells, kidney tissue, and live ADPKD animal models, and we already have safety data from long-term administration in humans.” He added, “Unlike the development of a new compound that starts from Phase 1, the greatest strength of Udenafil is that it can proceed directly to Phase 2b to verify its efficacy.”

He continued, “If we succeed with ADPKD following our treatment for patients who have undergone the Fontan procedure, we will be targeting two rare diseases with a single compound, Udenafil,” and added, “We will develop ADPKD into Mezion Pharma Co., Ltd.’s second core rare disease program.”