Clinical trial NCT06395285: Evaluating the Safety and Tolerability of Orally Administered DF-003 in ROSAH Syndrome Patients
Official title: A Phase Ib, Open-Label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Administered DF-003 in ROSAH Syndrome Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: ROSAH
Keywords: ROSAH syndrome
alpha-protein kinase 1
cone-rod dystrophy
macular edema
papillary edema
retinal dystrophy
uveitis
T237M
Lead sponsor: Shanghai Yao Yuan Biotechnology Ltd. (also known as Drug Farm)
Sponsor class: INDUSTRY
First posted: 2024-05-02
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: ROSAH syndrome patients will receive oral (PO) doses of DF-003 once daily (QD) for a duration of 28 days (4 weeks). In this study, 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.

Patients will receive loading doses of 140 mg on Days 1, 2, and 3, followed by a maintenance dose of 45 mg QD starting on Day 4 through Day 28. Individual dose modification is not allowed in this study. If the overall cohort dose needs modification, this will be determined based on review of all available safety and pharmacokinetics (PK) data from this study.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Sufficient understanding of the purpose and procedures required for the study.
2. Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive.
3. Genetic testing for ALPK1 mutations that has been shown to be associated with ROSAH syndrome (e.g. T237M or Y254C, or T237A mutations).
4. Signs of uveitis (anterior and/or posterior) in the eye (e.g. macula edema, optic nerve edema, retinal vasculitis, or retinal vascular leakage).
5. Patients must be deemed healthy except for diagnosis of ROSAH syndrome and its clinical manifestation.
6. Patients must be at least 18 years of age but no older than 65 years of age at the time of Screening.

Exclusion Criteria:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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%.
6. Moderate or severe hepatic impairment (categorized as Child-Pugh class B and C, respectively, on the Child-Pugh Score for Cirrhosis Mortality)

Primary outcomes:
measure: Frequency and Severity of Treatment-Emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0
timeFrame: Baseline to Day 78 (±2)
measure: Frequency and Severity of Serious Adverse Events (SAEs) (Local and Systemic) as Assessed by CTCAE v5.0
timeFrame: Baseline to Day 78 (±2)
Secondary outcomes:
measure: Eye Uveitis as Measured by Changes in Macular Edema
timeFrame: Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
measure: Eye Uveitis as Measured by Changes in Optic Nerve Edema
timeFrame: Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
measure: Eye Uveitis as Measured by Changes in Retinal Vasculitis
timeFrame: Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
measure: Eye Uveitis as Measured by Changes in Retinal Vascular Leakage
timeFrame: Baseline, Day 1, Day 2, Day 8 (±2), Day 15 (±2), Day 22 (±2), Day 28 (±2), Day 50 (±2), Day 78 (±2)
measure: Changes in Serum Chemokine Levels
timeFrame: 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)
measure: Changes in Serum Cytokine Levels
timeFrame: 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)
measure: Changes in Serum Serum Amyloid A (SAA) Levels
timeFrame: 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)
measure: Changes in Serum High-Sensitivity C-reactive Protein (hs-CRP) Levels
timeFrame: 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)
measure: Maximum Plasma Concentration (Cmax) of DF-003
timeFrame: 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)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of DF-003
timeFrame: 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)
measure: Area Under the Concentration-Time Curve (AUC) of DF-003 from time zero to time t (AUC0-t)
timeFrame: 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)
measure: Area Under the Concentration-Time Curve (AUC) of DF-003 from time zero to the time of the last quantifiable concentration (AUC0-last)
timeFrame: 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)
measure: Area Under the Concentration-Time Curve (AUC) of DF-003 from time zero to infinity (AUC0-inf, first dose only)
timeFrame: 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)
measure: Terminal Phase Half-Life (t1/2)
timeFrame: 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)
Other outcomes:
measure: Changes in Eye Anterior Chamber Aqueous Fluid Chemokine Levels
timeFrame: 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)
measure: Changes in Eye Anterior Chamber Aqueous Fluid Cytokine Levels
timeFrame: 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)
measure: Changes in Eye Anterior Chamber Aqueous Fluid Serum Amyloid A (SAA) Levels
timeFrame: 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)
measure: Changes in Eye Anterior Chamber Aqueous Fluid High-Sensitivity C-reactive protein (hs-CRP) levels
timeFrame: 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)
measure: Change in Headache Impact Test-6 (HIT-6) Scores
timeFrame: Baseline to Day 28 (±2)
measure: Change in EuroQol 5 Dimension 5 Level (EQ-5D-5L) Scores
timeFrame: Baseline to Day 28 (±2)
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: Durham
country: United States
facility: Duke Eye Center - Duke University Hospital
state: North Carolina
city: Salt Lake City
country: United States
facility: John A. Moran Eye Center - University of Utah Health
state: Utah
city: Sydney
country: Australia
facility: Save Sight Institute - University of Sydney Eye Hospital
state: New South Wales
Study officials:
References: