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An open-label, multi-center, switch-over study of the efficacy, safety and PK of HPN-100 compared to sodium phenyl butyrate in Japanese patients with urea cycle disorder, with a long-term safety extension

Phase 3 study of HPN-100 in Japanese patients with urea cycle disorder

18

A total of 17 patients were enrolled in the switch-over period. The age distribution was 2 patients aged 2 to <6 years, 8 patients aged 6 to <18 years, and 7 patients aged >=18 years. All 17 patients were included in the Safety Analysis Population. In the Safety Analysis Population (N=17), 7 patients (41.2%) were male and 10 (58.8%) were female. Seven patients (41.2%) were adults (>=18 years of age) and 10 (58.8%) were pediatric patients (<18 years of age). UCD subtypes included ornithine transcarbamylase (OTC) deficiency in 9 patients (52.9%), argininosuccinate synthetase (ASS) deficiency in 6 patients (35.3%), and arginase (ARG) deficiency and argininosuccinate lyase (ASL) deficiency in 1 patient each (5.9%). At enrollment, 11 patients (64.7%) were receiving sodium phenylbutyrate (NaPBA) tablets and 6 patients (35.3%) were receiving NaPBA granules. A total of 15 patients were enrolled in the safety extension period and were included in both the intent-to-treat (ITT) population and the Safety Analysis Population. The age distribution was 2 patients aged 2 to <6 years, 7 patients aged 6 to <18 years, and 6 patients aged >=18 years. Eight patients (53.3%) were male and 7 (46.7%) were female. Six patients (40.0%) were adults and 9 (60.0%) were pediatric patients. UCD subtypes included OTC deficiency and ASS deficiency in 6 patients each (40.0%), and ARG deficiency, ASL deficiency, and other subtype (citrin deficiency) in 1 patient each (6.7%).

This was an open-label study consisting of a 14-day switch-over period in which patients receiving sodium phenylbutyrate (NaPBA) were switched to HPN-100, followed by a long-term safety extension period in which HPN-100 was administered for at least 12 months. A total of 17 patients were enrolled in the switch-over period. Fifteen patients completed the switch-over period and 2 patients discontinued during the switch-over period. The safety extension period included 14 patients who completed the switch-over period and 1 newly enrolled patient. One patient discontinued during the safety extension period, while 14 patients completed 12 months of treatment. These 14 patients continued participation in the clinical study and subsequently entered the post-marketing clinical study following marketing approval. All patients completed the post-marketing clinical study.

During the switch-over period, treatment-emergent adverse events (TEAEs) were reported in 6 of 16 patients (37.5%) receiving HPN-100 and in 4 of 17 patients (23.5%) receiving NaPBA. The adverse event profile was consistent with that observed in other clinical studies of HPN-100 and with the known safety profile of NaPBA. No TEAEs were considered related to study treatment. With the exception of one severe event of hyperammonaemia observed during HPN-100 treatment, all TEAEs were mild. No deaths occurred. Serious TEAEs were reported in 2 patients receiving HPN-100: one patient experienced an abnormal feeling and one patient experienced hyperammonaemia. Neither event was considered related to study treatment. The most frequently reported TEAEs by system organ class (SOC) during treatment with HPN-100 and NaPBA were infections and infestations (25.0% and 5.9%, respectively), followed by metabolism and nutrition disorders (6.3% and 17.6%), gastrointestinal disorders (6.3% and 0%), and general disorders and administration site conditions (6.3% and 0%). During the 12-month safety extension period, TEAEs were reported in 14 of 15 patients (93.3%). Two TEAEs (nausea and electrocardiogram QT prolongation) were considered related to study treatment. Except for one severe TEAE (noroviral gastroenteritis), all other TEAEs were mild or moderate in severity. No deaths occurred.

Efficacy analyses were conducted in 16 patients in the intent-to-treat (ITT) population. HPN-100 demonstrated blood ammonia control comparable to that achieved with NaPBA in Japanese pediatric and adult patients with UCDs. The primary efficacy endpoint, AUCNH3,0-24 (mean +/- SD), was 627.4 +/- 197.9 umolhr/L during treatment with HPN-100 and 757.4 +/- 306.8 umolhr/L during treatment with NaPBA. The geometric mean ratio of AUCNH3,0-24 for HPN-100 relative to NaPBA was 0.849, with a 95% confidence interval of 0.723 to 0.997. The maximum blood ammonia concentration (Cmax) and mean blood ammonia concentration (mean +/- SD) during HPN-100 treatment were 37.266 +/- 15.511 umol/L and 26.341 +/- 8.240 umol/L, respectively, compared with 52.259 +/- 38.252 umol/L and 31.965 +/- 13.091 umol/L, respectively, during NaPBA treatment. During the safety extension period, mean blood ammonia concentrations at both the 12-month and 24-month data cutoffs were generally comparable to baseline values, indicating sustained blood ammonia control for up to 24 months.

Administration of HPN-100 at a PBA molar equivalent dose to NaPBA demonstrated a favorable safety profile and achieved blood ammonia control comparable to that of NaPBA in Japanese pediatric and adult patients with UCDs. In addition, treatment with HPN-100 for up to 24 months maintained a favorable safety profile and sustained control of blood ammonia concentrations.

June. 15, 2026

June. 15, 2026

https://doi.org/10.1002/jmd2.70082

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071220110

Hiroiku Furukawa

OrphanPacific, Inc.

1-1-1 Shibaura, Minato-ku

hiroiku-furukawa.yg@orphanpacific.com

Hiroiku Furukawa

OrphanPacific, Inc.

1-1-1 Shibaura, Minato-ku

+81-80-3538-2119

hiroiku-furukawa.yg@orphanpacific.com

Complete

Mar. 07, 2023

Interventional

single arm study

open(masking not used)

active control

single assignment

treatment purpose

- Patients diagnosed with urea cycle disorder (UCD) by genetic testing, enzymatic testing, and/or biochemical testing.
- If participating in the switch-over part, patients being treated for UCD with NaPBA and who has not changed dosage and administration of NaPBA for at least one week prior to the start of study drug administration (Day 1).
- If newly participating in the extension part, NaPBA has not been administered for at least 30 days prior to the start of study drug administration (Month 0).
- Patients who are judged to be sufficiently capable of undergoing the tests and observations conducted in this study.

- Patients who have a blood ammonia level 100 micro mol/L (170 micro g/dL) or more at screening or has symptoms and/or signs of hyperammonemia within at least 2 weeks prior to the screening visit. If ammonia level is controlled and stable for at least 14 days, re-screening may be allowed at the discretion of the Investigator etc.
- Patients with active infections (viral and bacterial) or other diseases that may affect blood ammonia levels.
- Patients who have received sodium benzoate within 1 week prior to the start of study drug administration.
- Patients with history of hypersensitivity to phenylbutyrate and/or phenylacetic acid.
- Patients who have undergone liver transplantation (including hepatocellular transplantation)

Both

Urea cycle disorder

- The switch-over part of the study will last 2 weeks during which subjects will be switched from sodium phenylbutyrate (NaPBA) to HPN100 (NaPBA for the first 7 days and HPN-100 for the next 7 days). The extension part is administered HPN-100 for 12 months.
- The dosage of NaPBA is determined depending on the patients based on previous therapeutic dose. The dosage of HPN-100 equivalent to the dosage of NaPBA will be calculated using the following formula:
- NaPBA tablets daily dose (g) x 0.86=HPN-100 daily dose (mL)
- NaPBA granules daily dose (g) x 0.81=HPN-100 daily dose (mL)
-Newly enrolled subjects in the extension part will start treatment with HPN-100 at a dosage of 4.5 mL/m2/day and the dosage will be adjusted according to blood ammonia levels, protein intake, and symptoms. The recommended dose range approved in the US and Europe is 4.5 to 11.2 mL/m2/day (5.3 to 12.4 g/m2/day).
- Blood ammonia levels will be measured according to the schedule of study assessments.

The blood ammonia levels 24-hour area under the curve at the last day of NaPBA administration (Day 7) and the last day of HPN-100 administration (Day 14)

- Maximum blood ammonia levels on the last day of NaPBA and HPN-100 administration
- Mean blood ammonia levels on the last day of NaPBA and HPN-100 administration
- During NaPBA and HPN-100 administration period, the number and percentage of patients whose ammonia levels exceeded the upper limit of reference (ULN)
- NaPBA and PK parameters of the main metabolites of HPN-100 (PAA, PBA and PAGN)
- Cumulative 24-hour urinary PAGN (U-PAGN0-24) excretion on the last day of NaPBA and HPN-100 administration
- The correlation between U-PAGN0-24 excretion and AUCNH3, 0-24
- Glutamine values on the last day of NaPBA and HPN-100 administration
- Adverse events

+81-942-35-3311

Dec. 19, 2022

Dec. 19, 2022

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