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Evaluating the Safety and Tolerability of Orally Administered DF-003 in ROSAH Syndrome Patients

PHASE1NOT_YET_RECRUITING

The purpose of this study is to evaluate the safety and tolerability of DF-003 in retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome patients.

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Study details:

This is a Phase Ib open-label, single-arm, single-dose study that will be conducted in up to 12 ROSAH syndrome patients. The study will investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DF-003 (study drug). DF-003 will be administered orally (PO), once daily (QD) for 28 days (4 weeks).

Patients will be followed up for 8 weeks after administration of the last dose of study drug. A total of 8 patients will be evaluated in one cohort. The cohort will have a minimum of 6 patients.

Additional patients (maximum of 12 patients) may be enrolled in the event of insufficient data after a review of safety data by the Study Safety Committee. Patients will receive loading doses of 140 mg DF-003 on Days 1, 2, and 3, followed by a maintenance dose of 45 mg DF-003 starting on Day 4 through Day 28. Individual dose modification is not allowed in this study.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Sufficient understanding of the purpose and procedures required for the study.

Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive.

Genetic testing for ALPK1 mutations that has been shown to be associated with ROSAH syndrome (e.g. T237M or Y254C, or T237A mutations).

Signs of uveitis (anterior and/or posterior) in the eye (e.g. macula edema, optic nerve edema, retinal vasculitis, or retinal vascular leakage).

Patients must be deemed healthy except for diagnosis of ROSAH syndrome and its clinical manifestation.

Patients must be at least 18 years of age but no older than 65 years of age at the time of Screening.

Exclusion criteria

Males who plan to father a child or donate sperm while enrolled in this study or within 90 days after the last dose of study drug.

Females who are pregnant, breastfeeding, planning to become pregnant, or planning to donate eggs while on study medication or within 90 days after the last dose of study drug.

Use of any of the following prohibited medications: * Agents that are known to have systemic anti-inflammatory responses or high risk for nephrotoxicity or hepatotoxicity * Moderate CYP3A4 inhibitors: e.g., amiodarone, amprenavir, conivaptan, delavirdine, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, miconazole, verapamil, grapefruit juice, cat's claw (Dolichandra unguis-cati), Echinacea augustifolia, wild cherry, chamomile, licorice * Strong CYP3A4 inhibitors: e.g., ceritinib, clarithromycin, cobicistat, elvitegravir/ritonavir, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir, ombitasvir/paritaprevir/ritonavir (and/or dasabuvir), posaconazole, ritonavir, saquinavir/ritonavir, telithromycin, tipranavir/ritonavir, voriconazole. * Strong CYP3A4 inducers: apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor/ivacaftor, mitotane, phenytoin, rifampin, St. John's wort. * Digoxin * Agents known to cause Torsade de Pointes: Disopyramide, procainamide, quinidine, sotalol, azithromycin, clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin, fluconazole, ketoconazole, pentamidine, voriconazole, haloperidol, thioridazine, ziprasidone, citalopram, escitalopram, dolasetron, droperidol, granisetron, and ondansetron * Investigational agents (small molecules and oligonucleotides), vaccines, or invasive medical devices within 28 days (4 weeks, or 5 half-lives, whichever is longer) prior to enrollment or having received a biological product within 6 months prior to enrollment.

History of significant hypersensitivity to products related to DF-003 (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs.

Recent (within 3 months prior to screening) or acute changes in the following laboratory values: * Platelet count ≤ 120,000/mm3, or * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN * Bilirubin (total, direct) > ULN or * International Normalization Ratio (INR) > ULN, or * Serum albumin less than the lower limit of normal, or * Estimated creatinine clearance < 70 mL/min/1.73 m2 at Screening, calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, or * Hemoglobin A1c (HbA1c) > 8%.

Moderate or severe hepatic impairment (categorized as Child-Pugh class B and C, respectively, on the Child-Pugh Score for Cirrhosis Mortality)

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-09-01

Primary completion: 2025-08-01

Study completion finish: 2025-11-01

Study type

TREATMENT

Phase

PHASE1

Trial ID

NCT06395285

Intervention or treatment

DRUG: DF-003

Conditions

• ROSAH

Condition: ROSAH
DRUG: DF-003
Sydney, New South Wales, Australia and more
Sponsor: Shanghai Yao Yuan Biotechnology Ltd. (also known as Drug Farm)

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Find a site

Closest Location:

Save Sight Institute - University of Sydney Eye Hospital

Research sites nearby

Select from list below to view details:

Save Sight Institute - University of Sydney Eye Hospital
Sydney, New South Wales, Australia
The Royal Melbourne Hospital
Parkville, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: DF-003 Oral (PO) doses of 140 mg DF-003 on Days 1, 2, and 3 followed by a maintenance dose of 45 mg DF-003 once daily (QD) starting on Day 4 through Day 28. DF-003 will be administered PO with approximately 240 mL of water in the morning once daily for 28 consecutive days.	DRUG: DF-003 140 mg on Days 1, 2, and 3 followed by a maintenance dose of 45 mg QD starting on Day 4 through Day 28. DF-003 will be administered PO with approximately 240 mL of water in the morning once daily for 28 consecutive days.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Frequency and Severity of Treatment-Emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0	Not Specified	Baseline to Day 78 (±2)
Frequency and Severity of Serious Adverse Events (SAEs) (Local and Systemic) as Assessed by CTCAE v5.0	Not Specified	Baseline to Day 78 (±2)

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Eye Uveitis as Measured by Changes in Macular Edema	Not Specified	Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
Eye Uveitis as Measured by Changes in Optic Nerve Edema	Not Specified	Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
Eye Uveitis as Measured by Changes in Retinal Vasculitis	Not Specified	Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
Eye Uveitis as Measured by Changes in Retinal Vascular Leakage	Not Specified	Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
Changes in Serum Chemokine Levels	Chemokine (C-C motif) ligand CCL2, CCL4, C-X-C motif chemokine ligand (CXCL)-1, CXCL9, CXCL10	Day 1 (±30 minutes prior to dosing), Day 29 (24 hours relative to dosing on Day 28), and Day 78 (approximately same time as Day 29 collection)
Changes in Serum Cytokine Levels	Interleukin (IL)-1b, IL-6, IL-8, IL-10, IL-2RA soluble, IL-18, Tumor Necrosis Factor (TNF)-Alpha	Day 1 (±30 minutes prior to dosing), Day 29 (24 hours relative to dosing on Day 28), and Day 78 (approximately same time as Day 29 collection)
Changes in Serum Serum Amyloid A (SAA) Levels	Serum Amyloid A (SAA) proteins are a family of apolipoproteins associated with high-density lipoprotein (HDL) in plasma	Day 1 (±30 minutes prior to dosing), Day 29 (24 hours relative to dosing on Day 28), and Day 78 (approximately same time as Day 29 collection)
Changes in Serum High-Sensitivity C-reactive Protein (hs-CRP) Levels	Not Specified	Day 1 (±30 minutes prior to dosing), Day 29 (24 hours relative to dosing on Day 28), and Day 78 (approximately same time as Day 29 collection)
Maximum Plasma Concentration (Cmax) of DF-003	Not Specified	Day 1 (-1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 2 (24 hours post-dose), 8(±2), 15(±2), 22(±2), 28(±2; -1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 29(±2; 24 hours post-dose), 36(±2), 50(±2), 64(±2), 78(±2)
Time to Reach Maximum Plasma Concentration (Tmax) of DF-003	Not Specified	Day 1 (-1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 2 (24 hours post-dose), 8(±2), 15(±2), 22(±2), 28(±2; -1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 29(±2; 24 hours post-dose), 36(±2), 50(±2), 64(±2), 78(±2)
Area Under the Concentration-Time Curve (AUC) of DF-003 from time zero to time t (AUC0-t)	Not Specified	Day 1 (-1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 2 (24 hours post-dose), 8(±2), 15(±2), 22(±2), 28(±2; -1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 29(±2; 24 hours post-dose), 36(±2), 50(±2), 64(±2), 78(±2)
Area Under the Concentration-Time Curve (AUC) of DF-003 from time zero to the time of the last quantifiable concentration (AUC0-last)	Not Specified	Day 1 (-1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 2 (24 hours post-dose), 8(±2), 15(±2), 22(±2), 28(±2; -1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 29(±2; 24 hours post-dose), 36(±2), 50(±2), 64(±2), 78(±2)
Area Under the Concentration-Time Curve (AUC) of DF-003 from time zero to infinity (AUC0-inf, first dose only)	Not Specified	Day 1 (-1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 2 (24 hours post-dose), 8(±2), 15(±2), 22(±2), 28(±2; -1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 29(±2; 24 hours post-dose), 36(±2), 50(±2), 64(±2), 78(±2)
Terminal Phase Half-Life (t1/2)	Not Specified	Day 1 (-1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 2 (24 hours post-dose), 8(±2), 15(±2), 22(±2), 28(±2; -1, 0.5, 1, 2, 4, 6, 8, and 12 hours relative to dosing), 29(±2; 24 hours post-dose), 36(±2), 50(±2), 64(±2), 78(±2)

Frequently Asked Questions

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References

Clinical Trials Gov: Evaluating the Safety and Tolerability of Orally Administered DF-003 in ROSAH Syndrome Patients