An Open-Label Exploratory Study of Fosigotifator in Subjects with Vanishing White Matter Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Calico Life Sciences LLC

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

22 Mar 2024 → ongoing

Decision date (initial)

2024-02-19

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AbbVie Inc.

External identifiers

EU CT number

2023-505704-30-00

WHO UTN

U1111-1292-2118

ClinicalTrials.gov

NCT05757141

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Therapy

Evaluate the safety and tolerability following Fosigotifator administration in adult and pediatric subjects with VWM disease during the Safety Evaluation Period

Evaluate the PK of A-1684909 (the pharmacologically active compound) following multiple doses of Fosigotifator (the prodrug) in adult and pediatric subjects with VWM disease

Secondary objectives 1

1. Evaluate the safety and tolerability following Fosigotifator administration in adult and pediatric subjects with VWM disease during the Maintenance Dose Period and the Follow-up Period

Conditions and MedDRA coding

Vanishing White Matter disease

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003344-PIP01-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Males and females ≥18 y of age (Cohort 1 and Cohort 1b), ≥12 y and <18 y of age (Cohort 2), and ≥6 y and <12 y of age (children Cohort 3), 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]
2. Have VWM disease defined as: a. A clinical diagnosis by a physician experienced in the assessment of VWM disease; AND b. A molecular diagnosis of VWM disease (Note: Subjects can provide a verified report of molecular diagnosis including the specific mutation(s), will not be required to reconfirm diagnosis), AND c. An 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-centered 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 (ab or bc): a. 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 b. Motor criteria as defined below: i. All age groups: (1) Inability to walk 10 or more steps with or without light support of 2 hands c. 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): i. Adults and adolescents ≥16 y of age must have: (1) A perceptual reasoning index <50 (Wechsler Adult Intelligence Scale, fourth edition [WAIS-IV]) ii. Adolescents and children ≥6 y and <16 y of age must have: (1) A visuospatial reasoning index <50 (block design, visual puzzles, Wechsler Intelligence Scale for Children performance, fifth edition [WISC-V]) AND (2) 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 (eg,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: a. 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 b. Motor criteria as defined below: i. More than minimal head control as demonstrated by: (1) 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 c. 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 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 a 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.

Exclusion criteria 10

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. Because metallic orthodontic devices may generate image artifacts during MRI scans, subjects with such devices will undergo further evaluation by the Sponsor to determine their inclusion or exclusion from the study.
3. 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).
4. Current 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 disease) that would preclude administration of FGT or safe participation in the study
5. Subject who has suicidal ideation at the Screening Visit (V1). Prior medical history and/or C SSRS may be used to inform the Investigator’s decision
6. Changes in medication use for the management of VWM disease symptoms within the 4 weeks preceding Screening
7. Seizure disorder not considered adequately controlled by the Investigator within the 6 months preceding Screening
8. Subjects who, in the opinion of the Investigator, is incapable of completing study-required visits and procedures to assess primary and secondary endpoints (eg, due to severe comorbid conditions or severity of VWM disease)
9. Adult female subjects who are pregnant, breastfeeding, or providing breast milk.
10. Treatment with any other investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to Study Day 1 and during the study. Current participation in another trial is not permitted unless it is a non-interventional study and the sole purpose of this study is for long term follow-up describing clinical features or survival data (registry). Non interventional studies that include biomarker assessments (including, but not limited to, sampling of blood, urine, CSF, or neuroimaging) are not allowed.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. AEs and SAEs during the Safety Evaluation Period
2. Vital signs, ECGs, clinical laboratory tests, and suicidality assessments during the Safety Evaluation Period
3. Plasma concentrations of A-1684909 at pre-specified visits from Baseline up to Week 96 for all cohorts
4. CSF concentrations of A-1684909 at Week 12, Week 48, and Week 96 for all cohorts
5. Plasma PK parameters of A-1684909 following dosing at V4 (Study Day 14) for Cohorts 1 and 1b: Cmax; Tmax; AUC0-24h; Ctrough; and t1/2, functional

Secondary endpoints 2

1. AEs and SAEs at last visit (Week 197)
2. Vital signs, ECGs, clinical laboratory tests and suicudality up to last vist (Week 197)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Calico Life Sciences LLC

Sponsor organisation

Calico Life Sciences LLC

Address

1170 Veterans Boulevard

City

South San Francisco

Postcode

94080-1985

Country

United States

Scientific contact point

Organisation

Calico Life Sciences LLC

Contact name

Anna Rodriguez

Public contact point

Organisation

Calico Life Sciences LLC

Contact name

Anna Rodriguez

Third parties 8

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 39 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications