소실 백질 환자에서 ABBV-CLS-7262의 안전성, 내약성 및 약동학을 조사하기 위한 1b상 연구

Inclusion Criteria:

1. Males and females ≥18 y of age (Cohort 1 and Cohort 1b - adults), ≥12 y and <18 y of age (Cohort 2 - adolescents), ≥6 y and <12 y of age (Cohort 3 - children), and ≥6 mos and <6 y of age (Cohort 4 - children [≥1 y and <6 y of age] and infants [≥6 mos and <1 y of age]) at the time of Screening.

2. Subject must have VWM disease defined as:

   • A clinical diagnosis by a physician experienced in the assessment of VWM disease, AND
   • A molecular diagnosis of VWM disease (Note: Subjects who can provide a verified laboratory report of previously performed VWM molecular diagnosis, including the specific mutation(s), will not be required to reconfirm diagnosis before Screening), AND
   • A magnetic resonance imaging (MRI) presentation consistent with VWM disease, as assessed by a neuroradiologist or by a physician experienced in the assessment of VWM disease except for presymptomatic homozygous carriers of Cree leukoencephalopathy (EIF2B5 R195H) or other mutation with known imminent risk of significant clinical decline or death (requires approval from Sponsor).

3. Subject must have a designated caregiver who is able to complete the respective caregiver ce ntered assessments. The caregiver must be consistently present at visits, including telehealth visits, to report on symptoms and comply with the protocol. The caregiver must be willing to provide informed consent.

4. Subject is willing and able to give informed consent. Where local regulations permit inclusion of participants deemed not able to provide informed consent, a legally authorized representative (LAR) must provide informed consent on the subject's behalf, and the subject must provide assent, in accordance with the local regulations, guidelines, and Institutional Review Board (IRB), or Independent Ethics Committee (IEC). If the subject becomes cognitively impaired (diminished capacities) during the study and is unable to provide informed consent, the subject should be discontinued from the study unless local regulations permit inclusion of participants deemed not able to provide informed consent. In such case, a LAR must provide informed consent on behalf of the subject and the subject must provide assent as per local regulations, guidelines, and IRB or IEC. Careful consideration will be given to ensure that cognitive impairment/diminished capacity does not limit the subject's right to withdraw from the study. The LAR and the caregiver can be the same person.

5. Subjects in Cohorts 1, 1b, 2, and 3 must meet criteria a and at least 1 of the other criteria listed below (b or c):

   • Medical history of at least 1 neurological symptom that is assessed by the investigator as having a reasonable possibility of being related to VWM disease
   • Motor criteria as defined below:

   All age groups:

   Inability to walk 10 or more steps with or without light support of 2 hands

   - Cognitive criteria as defined below (Note: Subjects are not required to complete testing if they meet the motor criteria or if they are able to provide source documentation of prior cognitive testing performed by a qualified psychologist and meeting eligibility criteria obtained in the past 12 months):

   Adults and adolescents ≥16 y of age must have:

   A perceptual reasoning index <50 (Wechsler Adult Intelligence Scale, fourth edition [WAIS-IV])

   Adolescents and children ≥6 y and <16 y of age must have:

   A visuospatial reasoning index <50 (block design, visual puzzles, Wechsler Intelligence Scale for Children performance, fifth edition [WISC-V]) AND A fluid reasoning index <50 (matrix reasoning, figure weights, WISC-V). Note: At the Sponsor's discretion, pediatric subjects <16 y of age who are unable to complete the subtests for calculating BOTH indices of the WISC-V due to functional impairment (e.g., due to fine motor or visual impairment) may meet inclusion criteria by a score <50 on either the visuospatial reasoning index OR the fluid reasoning index of the WISC-V.

   Pediatric subjects in Cohort 4 must meet both criteria a and b below, or criterion c:

   Medical history of at least 1 neurological symptom that is assessed by the investigator as having a reasonable possibility of being related to VWM disease

   Motor criteria as defined below:

   More than minimal head control as demonstrated by:

   While in prone position, the subject can lift his/her head and sustain the position for 10 seconds and bring his/her arms actively to weight bearing in that position Presymptomatic and homozygous for Cree Leukoencephalopathy (EIF2B5 R195H) or other mutation with known imminent risk of significant clinical decline or death (sponsor must be notified and provide approval prior to screening and enrolling a patient that meets eligibility with only this criterion).

6. All male subjects who are sexually active and not surgically sterilized must agree to use an acceptable contraceptive method. Additionally, male subjects must agree to not donate sperm during the study and until 30 days after the final dose of study drug.

7. All female subjects who are sexually active and of childbearing potential must agree to use an acceptable contraceptive method. Additionally, female subjects must agree to not donate eggs during the study and for 30 days after the final dose of study drug.

8. Canada-specific Cohort 5: Male and female infant subjects between 0 mos and <6 mos of age at the time of Screening.

9. Canada-specific Cohort 5: Subject body weight ≥5 kg at the time of the Baseline visit. The screening period can be extended by up to 30 days to ensure that this minimum weight is met at the Baseline visit.

10. Canada-specific Cohort 5: Homozygous carriers of Cree leukoencephalopathy (EIF2B5 R195H) or other mutation(s) with known imminent risk of significant clinical decline or death (the Sponsor must be notified and provide approval prior to screening and enrolling a patient that meets eligibility with only this criterion).

An MRI presentation consistent with VWM disease is not required for Cohort 5. Exclusion Criteria

1. Pediatric subjects ≥6 mos and <6 y of age must not be on any form of respiratory support at the time of Screening.
2. Subject who has any clinically significant electrocardiogram (ECG) abnormalities, including QT interval corrected for heart rate using Fridericia's correction formula (QTcF) of >450 msec for adult males, >470 msec for adult females, or >450 msec for adolescents ≥12 y and <18 y of age (Cohort 2) and children ≥6 y and <12 y of age (Cohort 3), or >414 msec for infants and children ≥0.5 y and <6 y of age (Cohort 4).
3. Subject with current or history of abnormal screening laboratory or imaging results that, in the opinion of the Investigator, are indicative of any significant cardiac, endocrinologic, hematologic, hepatic, immunologic, infectious, metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurologic, and/or other major disease (other than VWM) that would preclude administration of FGT or safe participation in the study Abnormal adrenal function, defined as confirmed abnormal random cortisol or ACTH at Screening (see Section 7.2.8 for cortisol and ACTH thresholds) Participants may undergo repeat cortisol and ACTH testing once, in order to establish normal adrenal function. If repeat cortisol and/or ACTH testing is abnormal, at the Investigator's discretion, the participant may undergo cosyntropin stimulation testing to establish normal adrenal function to meet eligibility criteria.
4. Subject who has suicidal ideation at the Screening Visit (V1). Prior medical history and/or Columbia-Suicide Severity Rating Scale (C-SSRS) may be used to inform the Investigator's decision.
5. Changes in medication use for the management of VWM disease symptoms within the 4 weeks preceding Screening.
6. Seizure disorder not considered adequately controlled by the Investigator within the 6 months preceding Screening.
7. Subject who, in the opinion of the Investigator, is incapable of completing study-required visits and procedures to assess primary and secondary endpoints (e.g., due to severe comorbid conditions or severity of VWM disease).
8. Subjects who are pregnant, breastfeeding, or providing breast milk. Note: Infant subjects are permitted to receive breast milk from a non-participant mother or caregiver (who is not receiving the study intervention).
9. Canada-specific Cohort 5: Subjects between 0 mos and <6 mos of age must not be on any form of respiratory support at the time of Screening.
10. Canada-specific Cohort 5: Subject who has any clinically significant ECG abnormalities, including QT interval corrected for heart rate using Fridericia's correction formula (QTcF) of >414 msec for infants between 0 mos and <6 mos of age