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Intravenous Gene Transfer With an AAV9 Vector Expressing Human <=-Galactosidase in Type II GM1 Gangliosidosis

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ClinicalTrials.gov Identifier: NCT03952637
Recruitment Status : Recruiting
First Posted : May 16, 2019
Last Update Posted : August 29, 2019
Sponsor:
Collaborator:
Axovant Sciences, Inc.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Brief Summary:

Background:

GM1 gangliosidosis is a disorder that destroys nerve cells. It is fatal. There is no treatment. People with GM1 are deficient in a certain enzyme. A gene therapy may help the body make this enzyme. This could improve GM1 symptoms.

Objective:

To test if a gene therapy helps type II GM1 gangliosidosis symptoms.

Eligibility:

People ages 2 12 with type II GM1 gangliosidosis

Design:

Participants will be screened with their medical history and a phone survey.

Participants will stay at NIH for 8-10 weeks.

Participants will have baseline tests:

Blood, urine, and heart tests

Hearing tests

Ultrasound of abdomen

EEG: Sticky patches on the participant s head will measure brain function.

Lumbar puncture: A needle will be stuck into the participant s spine to remove fluid.

MRI scans, bone x-rays, and bone scans: Participants will lie in a machine that takes pictures of the body

IQ tests

Neurology exams

Central line placement

Skin biopsy: A small piece of the participant s skin will be removed.

Speech tests

Participants will have an x-ray while swallowing food.

Participants will take drugs by mouth and IV. This will get their immune system ready for therapy.

Participants will get the gene therapy by IV. They will stay at NIH for a week to watch for side effects.

Participants will have visits 3 and 6 months after treatment. Then visits will be every 6 months for 2 years. Then they will have a visit at 3 years. Visits will take 4-5 days.

Participants will return to NIH once a year for 2 years for tests in an extension study.


Condition or disease Intervention/treatment Phase
Lysosomal Diseases Gangliosidosis GM1 Biological: AAV9-GLB1 Drug: Rituximab Drug: Sirolimus Drug: Methylprednisolone Drug: Prednisone Diagnostic Test: Abdominal ultrasound Diagnostic Test: Audiology assessment with ABR Diagnostic Test: Bone density scan (DEXA) Diagnostic Test: Echocardiogram Diagnostic Test: Electroencephalogram (EEG) awake and extended overnight Diagnostic Test: Laboratory tests Procedure: Lumbar puncture Procedure: Brain MRI/MRS/fMRI Behavioral: Neurocognitive testing Other: Neurology exam Procedure: PICC line placement Procedure: Skeletal survey Procedure: Skin biopsy Procedure: Speech and modified barium swallow study Phase 1 Phase 2

Detailed Description:

This is a non-randomized, Phase 1/2 clinical trial to study the safety and efficacy of a single dose gene transfer vector AAV9/GLB1 (AAV9-GLB1) by intravenous infusion to subjects with Type II GM1 gangliosidosis. Subjects in this study will be male and female, greater than or equal to 2 years old and less than or equal to 12 years old, with genetically confirmed mutations and phenotype consistent with diagnosis of Type II GM1 gangliosidosis and be seronegative for anti-AAV9 antibodies. Other inclusion/exclusion criteria apply. Each subject will receive 1.5 x 10^13 vg/kg of the gene transfer agent. A total of 4 subjects will be treated at the NIH Clinical Center in Bethesda, MD.

The primary objective of this first-in-human study is to assess the safety of the AAV9-GLB1 vector following intravenous infusion. Secondary objectives include: 1) Assess developmental change in the Growth Scale Scores on the Vineland Adaptive Behavior Scales Third Edition (Vineland-3) instrument between pre- and post-treatment, 2) Assess brain volume using a 3T MRI, and central nervous system (CNS) metabolite levels by magnetic resonance spectroscopy (MRI) between pre- and post-treatment and compared to historical controls, 3) Assess motor function using mobility scales developed as part of the natural history study, 4) Assess change in disease severity using the Clinical Global Impressions (CGI) scale.

Exploratory objectives include: 1) Plasma, cerebrospinal fluid (CSF) and urinary biomarkers of disease progression 2) Examine differences in resting state functional connectivity (RSFC) using functional MRI (fMRI), 3) Assess neurological symptoms based on clinical and developmental rating scale scores and a structured videotaped neurologic exam pre- and post-treatment, 4) Assess immune tolerance to the gene transfer vector with antibody titers to AAV9 in serum and CSF, 5) Measure GM1-galactosidase enzyme activity in CSF pre- and post-treatment, and 6) Measure GM1 ganglioside levels in CSF pre- and post-treatment.

GM1 gangliosidosis is an autosomal recessive, neurodegenerative lysosomal storage disorder resulting from mutations in the GLB1 gene, encoding the enzyme beta-galactosidase (betagal). Betagal functions by removing terminal galactose moieties from GM1 ganglioside, a glycosphingolipid present in highest quantity in the CNS, primarily found in neurons. Betagal deficiency leads to accumulation of GM1 ganglioside and its asialo derivative (GA1) in the CNS. The age of onset and progression of GM1 gangliosidosis differs depending on the amount of residual betagal activity, but the disease is generally divided into three clinical forms: Type I (infantile), Type IIa and IIb (late-infantile and juvenile), and Type III (adult or chronic). This clinical trial will treat GM1 Type II subjects. This form of GM1 generally has onset between 3 and 5 years with plateauing, then regression of developmental milestones (juvenile) or onset of symptoms after 12 months but before 24 months, plateauing of milestones then regression (late-infantile). Clinical features vary but in addition to CNS manifestations typically include a degree of skeletal involvement and mild hepatosplenomegaly. The primary symptoms are frequent falls, poor coordination, dysarthria and cognitive decline. Disease progression is variable, with subjects surviving well into the third decade (juvenile) or into the late teens (late-infantile), but with severe cognitive and physical disabilities. GM1 gangliosidosis is extremely rare, with an incidence estimated at 1:100,000 to 1:200,000. The disease is uniformly fatal with no effective therapy. Care is limited to symptomatic medical management. Intravenous administration of a gene transfer vector to deliver a normal copy of the GLB1 gene to the CNS could potentially provide an effective treatment for GM1 gangliosidosis.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type II GM1 Gangliosidosis
Actual Study Start Date : August 19, 2019
Estimated Primary Completion Date : April 30, 2023
Estimated Study Completion Date : April 30, 2023


Arm Intervention/treatment
Experimental: 1
Single arm study only
Biological: AAV9-GLB1
The risks of administering this treatment in a subject with GMl gangliosidosis are not completely known. The major risk associated with intravenous infusion is from the subject's immunological response to the viral capsid and/or the beta-gal protein. To reduce this possibility, immune modulation therapy is being started prior to vector delivery and maintained for six months afterward. There is a theoretical risk that the integration of a small percentage of the rAAV vector DNA into the host cell genome could cause cellular transformation to cancer cells and lead to a malignancy. This has never been seen in subjects receiving intravenous AAV9 gene therapy so the risk of this complication, is likely very low.

Drug: Rituximab
We are proposing the use of immune modulation to transiently deplete B- cells using rituximab. It will be infused at -21 days, -14 days, -7 days and -1 days before gene transfer.

Drug: Sirolimus
Sirolimus is a macrocytic lactone that inhibits T lymphocyte activation and proliferation by inhibiting activation of mammalian Target of Rapamycin (mTOR) kinase that suppresses cytokine- driven T-cell proliferation. We plan to give sirolimus from day -21 to 6 months post gene transfer.

Drug: Methylprednisolone
Subjects will receive IV methylprednisolone 1 mg/kg or a maximum dose of 50 mg, 60- 120 minutes prior to vector administration on day 0 to mitigate potential acute innate immune response against the vector.

Drug: Prednisone
Prednisone (oral solution, dose 0.5 mg/kg) will be taken daily on Days 1-3.

Diagnostic Test: Abdominal ultrasound
Procedure will be performed as part of screening and safety follow-up studies. The ultrasound will be performed in the Department of Diagnostic Imaging and will take approximately 20-30 minutes.

Diagnostic Test: Audiology assessment with ABR
The Audiology assessment will be performed in the Audiology Clinic using a standard audiogram to measure thresholds for pure tones and speech, word recognition, tympanometry, and otoacoustic emissions if the subject is capable and tolerant of these measures. The assessment will take approximately 30 minutes. The ABR is a non- invasive neurophysiologic test to evaluate electrical signal transmission from the 8th cranial nerve to the brainstem and the cortex in response to specific tones. Electrodes are placed on the scalp and on each earlobe. An earphone gives off a brief click or tone and the electrodes pick up the brain's responses to these sounds and record them. This will be performed by a trained neurophysiology technician to monitor possible change in hearing during treatment. The procedure will be performed in the Interventional Radiology suite while the subject is sedated following the MRI, fMRI, and MRS of the brain.

Diagnostic Test: Bone density scan (DEXA)
This is a non-invasive enhanced form of X- ray that is used to measure bone loss. Loss of bone density is a known complication with GM1 gangliosidosis due to decrease in weight-bearing activities with disease progression. The procedure will be performed in the Nuclear Medicine Department. The subject s femur will be scanned at baseline and then yearly for 3 years. The procedure will take approximately 10 minutes and may be limited due to the subject s cooperation.

Diagnostic Test: Echocardiogram
Performed as part of screening. The Echo will be done in the Echo Lab and may take approximately 20-30 minutes. The exam may be limited due to the subject s cooperation level.

Diagnostic Test: Electroencephalogram (EEG) awake and extended overnight
Completed at baseline. The subject will also have an EEG if clinically indicated (for example encephalopathy, seizures, or other change in neurological status or if changes on the previous study are deemed to warrant a follow up study) during post treatment follow up. The procedures will be conducted in the Neurology Testing Department. The total time for an awake EEG, including lead placement, is approximately 40 minutes. An extended overnight EEG will take approximately 12 hours. The exam may be limited due to the subject s cooperation level.

Diagnostic Test: Laboratory tests
Performed on blood and urine include safety labs, clinically indicated labs and research collections. Additional specimens may be collected for the PI s biorepository or as clinically indicated. Blood volumes for clinical diagnostic testing and research will be consistent with Clinical Center laboratory guidelines.

Procedure: Lumbar puncture
Performed to obtain cerebrospinal fluid (CSF) to measure GM1 ganglioside, beta-gal enzyme, AAV antibodies, Pentasaccharide biomarkers and other research tests. CSF will also be sent for cell count and differential, glucose, protein, and culture as well as CSF neurotransmitters. The amount of CSF obtained will be less than or equal to 0.75 mL/kg body weight. The procedure will be performed while under sedation following MRI imaging. If a sedated MRI is not being performed, then the LP will be performed in consultation with the pediatric consult service using conscious sedation and local anesthesia. The procedure will take approximately 15 minutes.

Procedure: Brain MRI/MRS/fMRI

Magnetic resonance imaging (MRI), functional MRI (fMRI) and spectroscopy (MRS) - The subject will undergo non-contrast MRI, including DTI sequences, fMRI, and MRS in the 3T scanner using the same image acquisition sequences and the same MRS voxels to capture the same metabolites as prior sequencing under natural history protocol 02-HG-0107. The scans will be performed at baseline, year 1, year 2 and year 3. The MRI, fMRI, and MRS will be interpreted for signs of disease progression or stabilization and any signs of treatment toxicity by two board- certified radiologists with specialty training in neuroradiology.

The scan will require anesthesia. Sedation will be administered by the anesthesia service after a pre- anesthesia consultation to assess risk. The type of sedation and whether the subject will be intubated for the procedure will be at the discretion of the anesthesia service.


Behavioral: Neurocognitive testing
The Vineland-3 will be administered under the supervision of a psychologist. The Vineland-3 provides several types of scores, measure of personal and social independence designed to examine the domains of communication, daily living skills, social skills and motor development. Other standard neurocognitive instruments may be used depending on the subject s ability, and some visits will (may) include a measure of intelligence/cognitive development if the child is able to achieve a basal score. Neurocognitive testing will take approximately 2-3 hours depending on subject cooperation. The assessments will not address sensitive topics.

Other: Neurology exam
Neurology exam will be performed by a neurologist in the screening and follow- up appointments to monitor for any adverse reactions and to assess for clinical response to the treatment. The exam will be scripted for consistency within subject visits and between subjects and will take approximately 30 minutes to one hour. The exam will be videotaped. The exam may be limited due to the subject s cooperation level.

Procedure: PICC line placement
PICC line placement will be done under sedation in Interventional Radiology. The procedure will be done under sedation and may take 20 minutes. A chest X- ray will be done after placement to confirm correct positioning of the catheter.

Procedure: Skeletal survey
A skeletal survey will be performed to assess the degree of skeletal involvement of the disease. This will include X-rays of the cranium, long bones of the upper and lower extremities, hands, feet, chest, spine and pelvis. The X-rays will be performed in the Department of Diagnostic Imaging at baseline and year 2. The exam will take approximately 30 minutes. The exam may be limited due to the subject s cooperation level.

Procedure: Skin biopsy
Skin biopsy will be performed on subjects who have not already had a skin biopsy under the 02-HG-0107 protocol. The procedure will be done under sedation using local anesthetic. After washing the skin with chlorhexidine and numbing the skin with injectable lidocaine, a 3mm circle of skin is removed under sterile conditions and the wound is dressed. The entire procedure takes approximately 5 minutes.

Procedure: Speech and modified barium swallow study
Performed at baseline, 6 months, year 1, 18 months, year 2, and year 3 as a marker of response to treatment and safety. The swallow assessments will include a parental swallowing questionnaire and cranial nerve assessment. The NIH Swallowing Questionnaire from the Speech Language Pathology Section is designed to identify the presence and or absence of functional swallowing dysfunction as perceived by the subject and or caregiver. This 4- point scale assists with further identification of clinical/research assessments of oral pharyngeal swallowing function if indicated in the form of a modified barium swallow. In addition to swallow assessments, tape recording of speech will also be included with diadochokinetic tasks and sustained phonations as well as speech if able. Recordings will be stored on a shared drive accessible only by the study team. The assessment may take approximately 30 minutes to 1 hour.




Primary Outcome Measures :
  1. Safety [ Time Frame: Several timepoints over 3 years ]
    Assess the safety of the AAV9/GLB1 vector (AAV9-GLB1) following intravenous delivery.


Secondary Outcome Measures :
  1. Developmental changes [ Time Frame: Baseline, 6 mos, year 1, 18 months, year 2, year 3 ]
    1. Assess developmental change in the Growth Scale Scores on the Vineland Adaptive Behavior Scales Third Edition (Vineland-3) instrument between pre- and post-treatment.

  2. Brain MRI/MRS/fMRI [ Time Frame: Baseline, year 1, year 2, year 3 ]
    2. Assess brain volume using a 3T MRI, and central nervous system (CNS) metabolite levels by MR spectroscopy between pre- and post- treatment and compared to historical controls

  3. Motor Function [ Time Frame: Baseline, 6 mos, year 1, 18 months, year 2, year 3 ]
    3. Assess motor function using mobility scales developed as part of the natural history study.

  4. CGI Scale [ Time Frame: Several timepoints over 3 years ]
    4. Assess change in disease severity using the Clinical Global Impressions (CGI) scale.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Vineland-3 Adaptive Behavior composite standard score greater than or equal to 40
  • Male or female subjects greater than or equal to 2 years old and less than or equal to 12 years old at time of enrollment
  • Biallelic mutations in GLB1
  • Documented deficiency of beta-galactosidase enzyme by clinical laboratory testing
  • Phenotype consistent with a diagnosis of Type II GM1 gangliosidosis, with symptom onset after the first year of life
  • AAV9 seronegative (antibody titers < 200U/mL)
  • Agree to reside within 50 miles of the study site for at least 2 months following treatment (may include housing on NIH campus)

EXCLUSION CRITERIA:

  • Anti-AAV9 antibody titers >200U/mL
  • Contraindications to concomitant medications
  • Serious illness that would not allow travel to the study site
  • Unwilling to undergo study interventions as outlined in the Schedule of Events
  • Subjects receiving other unapproved, off-label or experimental therapies for GM1 gangliosidosis (i.e. miglustat, Tanganil) within the last 60 days
  • Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered
  • Pregnant or lactating subjects
  • Immunizations of any kind in the month prior to screening
  • Evidence of cardiomyopathy on history, exam, or additional testing (echocardiogram or electrocardiogram) or other cardiac disease that in the opinion of the investigator would deem the subject unsafe to participate in the trial
  • Indwelling ferromagnetic devices that would preclude MRI/fMRI/MRS imaging
  • Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study
  • History of infection with human immunodeficiency virus (HIV), hepatitis A, B, C or tuberculosis.
  • History of or current chemotherapy, radiotherapy or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the PI
  • Abnormal laboratory values considered clinically significant per the investigator:

    • Platelet count < 100,000 x 103 /mcL [Normal: males 2-13y=161- 403; females 2-13y=173-394]
    • Persistent leukopenia or leukocytosis [Total white blood cell count < 3,000 and > 12,000 x 103 /mcL respectively] [Normal: males 2-13y=4.23-13.38; females 2-13y=3.98-13.18]
    • Anemia [Hb <10 g/dL] [Normal: males 2-13y 10.2-17.5; females 10.2-15.7]
    • Prothrombin (PT) or partial thromboplastin time (PTT) >2X normal [Normal 11.6-15.2 seconds (PT); 25.3-37.3 seconds (PTT)]
    • Gamma glutamyl transferase > 2 X the baseline value [Normal: males 2-13y 3-22 U/L; females 2-13y 4-24 U/L]
    • Amylase >1.5 X ULN or > 2 X the baseline value [Normal < 91 U/L]
  • Failure to thrive, defined as:

    • Falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline
    • Underlying defect in immune function
    • History of multiple and severe life-threatening infections

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03952637


Contacts
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Contact: Jean M Johnston (301) 443-8628 johnstonjm@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
Axovant Sciences, Inc.
Investigators
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Principal Investigator: Cynthia J Tifft, M.D. National Human Genome Research Institute (NHGRI)

Additional Information:
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Responsible Party: National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT03952637     History of Changes
Other Study ID Numbers: 190101
19-HG-0101
First Posted: May 16, 2019    Key Record Dates
Last Update Posted: August 29, 2019
Last Verified: August 19, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
Lysosomal Diseases
Additional relevant MeSH terms:
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Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Gangliosidoses
Gangliosidosis, GM1
Sphingolipidoses
Lipidoses
Sirolimus
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Rituximab
Everolimus
Prednisolone hemisuccinate
Prednisolone phosphate
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors