This study is NOT currently recruiting participants.
Number
000957-HG
Sponsoring Institute
National Human Genome Research Institute (NHGRI)
Recruitment Detail
Type: Clinical hold/Recruitment or enrollment suspended Gender: Male & Female Min Age: 3 Years Max Age: 17 Years
Referral Letter Required
No
Population Exclusion(s)
None
Keywords
Organic Acidemia
Recruitment Keyword(s)
Condition(s)
Methylmalonic Acidemia
Investigational Drug(s)
SEL-302
Investigational Device(s)
Intervention(s)
Drug: SEL-302
Supporting Site
National Human Genome Research Institute
Methylmalonic acidemia (MMA) is a genetic disorder that affects how the body uses food. Newborn screening aids early diagnosis, but even with prompt care affected individuals develop serious complications from different organs that can be life-threatening. Children with MMA may have periods of good health with recurrent episodes of severe illness. Liver transplants can help, but gene therapy could be an alternative treatment option.
Objective: To test gene therapy (MMA-101) for mut type MMA.
Eligibility:
People aged 3 to <18 years with mut type MMA.
Design:
Participants will be screened to see if they are eligible to participate in the study. They will have consultations with cardiology, nephrology, gastroenterology and genetics doctors. They will have ultrasounds. They will have a scan that measures bone density and tests that measure their heart function and their metabolism.
Participants will have a flexible tube called a catheter placed in a vein. It will remain in place during treatment. The tube will allow blood to be drawn and medications infused without repeated use of needles.
Participants will stay in the hospital 4 days for treatment. MMA-101 will be given as an infusion over 30 to 60 minutes. They will also have other drugs to help their body accept the MMA-101. Some may receive a drug called SEL-110 for this purpose. Participants receiving SEL-110 will have 3 total infusions of this drug, one before MMA-101 and 2 more, given a month apart. They will stay in the hospital for two days each time.
Participants will visit the clinic every other day for the first week, then twice a week , then weekly for 3 months for blood draws and other testing.
Follow-up visits will be at 6 months and then yearly for 5 years.
Sponsor's website: https://reimmagine.com
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INCLUSION CRITERIA: To be eligible to participate in this study, an individual must meet all the following criteria: -Age 3 to <18 years at time of consent (assent where possible) -Confirmed diagnosis of MMUT type methylmalonic acidemia by molecular genetic testing -Clinical and biochemical diagnosis of severe MMA as defined by: -sMMA levels between 100 to 3,000 micromole/L as demonstrated by the average of 3 values from blood samples collected at least 24 hours apart during the screening or pre-dose baseline period. -A clinical history consistent with severe MMA, defined as meeting at least two of the criteria listed below: -A history of neonatal encephalopathy with or without hyperammonemia -A history of hemodialysis for hyperammonemia after infancy -One or more hospitalizations, including NICU, PICU, and/or ER visits or need for sick-day dietary adjustment for metabolic ketoacidosis in the last 24 months prior to study enrollment -Complete protein tolerance less than the recommended daily allowance for age and/or gastrostomy feeding-dependance for meeting caloric needs. -One or more disease-related complications including cognitive impairment, failure to thrive (height, weight and head circumference falls lower than the third percentile), renal disease, basal ganglia injury, optic nerve disease, history of pancreatitis, bone marrow failure -Subjects must have fully recovered from any hospitalization for metabolic ketoacidosis or surgery at least 4 weeks prior to the start of the screening period. -Parent or legal guardian are willing and able to provide informed consent. Written assent will be obtained from minors older than age seven whenever possible. -Subject must be willing to comply with study-related assessments and adhere to Lifestyle Considerations throughout study duration. EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: -History of liver transplant, or any organ transplantation -High MMUT liver enzymatic activity in the range seen in healthy subjects or MMA patients after corrective liver transplant, as demonstrated by POBT >3000 0-120 AUC or >40% cumulative 1-13C-propionate dose metabolized -Presence of NAb against AAV8 >=1:5 dilution of serum. -Presence of anti-polyethylene glycol (PEG) antibodies up to 80 days prior to dosing. -Ongoing/active infection (including current COVID-19 infection). Investigator to confirm complete resolution of infection for at least 14 days prior to dosing of MMA-101. -An eGFR < 45 mL/min/1.73 m2, as estimated by the creatinine-based bedside Schwartz eGFR equation (<chronic kidney disease stage 3a, CKD3a) -Hemoglobin <10 g/dL -Platelet count <100,000 per mm3 -Clinical or non-invasive testing indicative of advanced liver fibrosis or history of liver diseases, a pre-existing diagnosis of portal hypertension, and/or ALT elevation >2x upper limit of normal [ULN]. -Presence of liver abnormalities suspicious of malignancy at screening and/or baseline (by liver ultrasound). -History of any malignancy. -Other than as required per protocol, subject has received chemotherapy, granulocyte colony-stimulating factor (GCSF) or immune-modulating agents within 6 months before Day 1. -Serology positive for hepatitis B virus (HBV), Hepatitis C virus (HCV), or human immunodeficiency virus (HIV), CMV, EBV, or a positive T-spot. -History or presence of significant arrhythmia, long QT syndrome using Fridericia's formula (QTcF) syndrome (>=480msec) or other clinically significant ECG abnormality on 12 lead ECG at screening or baseline. -History of anaphylaxis or severe allergic reaction to drug therapy, foods, polyethylene glycol (PEG) or polysorbates. A list of tables of PEG and polysorbates containing vaccines and medications is provided. -Immunocompromised state, regardless of etiology -Concomitant medications to manage chronic condition(s) must not interfere with the mechanism of action for MMA-101 or SEL-110 in the opinion of the Investigator and dose(s) must not alter for at least 4 weeks before screening through to dosing (Day 1) -Is taking foods (eg, St John s Wort, grapefruit juice) or drugs classified as CYP3A4 or strong P glycoprotein (P-gp) inducers or inhibitors known to interact with sirolimus (RAPAMUNE ) such as cyclosporine, diltiazem, erythromycin, ketoconazole (and other antifungals), nicardipine (and other calcium channel blockers), rifampin, verapamil unless they are stopped 14 days prior to dosing through to 30 days post last dose of SEL-110. -Subject has received a live virus vaccine in the previous 6 weeks prior to screening (MMR, Varicella, Rotovirus, Varivax, oral Polio). Subjects must refrain from vaccination for 6 weeks after the last dose of SEL-110. Live vaccines should not be administered within the last 6 weeks prior or after MMA-101 administration. -Previously received gene therapy or messenger ribonucleic acid (mRNA) treatments for MMA. -Participated in a clinical trial of another (non-gene or mRNA therapy) investigational agent within 30 days prior to screening, or within 5 elimination half-lives of the investigational agent, whichever is longer. -Has any other clinically significant medical condition that in the Investigator s opinion could interfere with interpretation of study results or limit the subject s participation in the study. Consultations with the GI/hepatology, nephrology and cardiology service will be obtained to assess liver, kidney and cardiac function, interpret laboratory and clinical findings and determine study eligibility at baseline and as needed for the duration of the study.
To be eligible to participate in this study, an individual must meet all the following criteria:
-Age 3 to <18 years at time of consent (assent where possible)
-Confirmed diagnosis of MMUT type methylmalonic acidemia by molecular genetic testing
-Clinical and biochemical diagnosis of severe MMA as defined by:
-sMMA levels between 100 to 3,000 micromole/L as demonstrated by the average of 3 values from blood samples collected at least
24 hours apart during the screening or pre-dose baseline period.
-A clinical history consistent with severe MMA, defined as meeting at least two of the criteria listed below:
-A history of neonatal encephalopathy with or without hyperammonemia
-A history of hemodialysis for hyperammonemia after infancy
-One or more hospitalizations, including NICU, PICU, and/or ER visits or need for sick-day dietary adjustment for metabolic
ketoacidosis in the last 24 months prior to study enrollment
-Complete protein tolerance less than the recommended daily allowance for age and/or gastrostomy feeding-dependance for
meeting caloric needs.
-One or more disease-related complications including cognitive impairment, failure to thrive (height, weight and head
circumference falls lower than the third percentile), renal disease, basal ganglia injury, optic nerve disease, history of
pancreatitis, bone marrow failure
-Subjects must have fully recovered from any hospitalization for metabolic ketoacidosis or surgery at least 4 weeks prior to the start of the screening period.
-Parent or legal guardian are willing and able to provide informed consent. Written assent will be obtained from minors older than age seven whenever possible.
-Subject must be willing to comply with study-related assessments and adhere to Lifestyle Considerations throughout study duration.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
-History of liver transplant, or any organ transplantation
-High MMUT liver enzymatic activity in the range seen in healthy subjects or MMA patients after corrective liver transplant, as demonstrated by POBT >3000 0-120 AUC or >40% cumulative 1-13C-propionate dose metabolized
-Presence of NAb against AAV8 >=1:5 dilution of serum.
-Presence of anti-polyethylene glycol (PEG) antibodies up to 80 days prior to dosing.
-Ongoing/active infection (including current COVID-19 infection). Investigator to confirm complete resolution of infection for at least 14 days prior to dosing of MMA-101.
-An eGFR < 45 mL/min/1.73 m2, as estimated by the creatinine-based bedside Schwartz eGFR equation (<chronic kidney disease stage 3a, CKD3a)
-Hemoglobin <10 g/dL
-Platelet count <100,000 per mm3
-Clinical or non-invasive testing indicative of advanced liver fibrosis or history of liver diseases, a pre-existing diagnosis of portal hypertension, and/or ALT elevation >2x upper limit of normal [ULN].
-Presence of liver abnormalities suspicious of malignancy at screening and/or baseline (by liver ultrasound).
-History of any malignancy.
-Other than as required per protocol, subject has received chemotherapy, granulocyte colony-stimulating factor (GCSF) or immune-modulating agents within 6 months before Day 1.
-Serology positive for hepatitis B virus (HBV), Hepatitis C virus (HCV), or human immunodeficiency virus (HIV), CMV, EBV, or a positive T-spot.
-History or presence of significant arrhythmia, long QT syndrome using Fridericia's formula (QTcF) syndrome (>=480msec) or other clinically significant ECG abnormality on 12 lead ECG at screening or baseline.
-History of anaphylaxis or severe allergic reaction to drug therapy, foods, polyethylene glycol (PEG) or polysorbates. A list of tables of PEG and polysorbates containing vaccines and medications is provided.
-Immunocompromised state, regardless of etiology
-Concomitant medications to manage chronic condition(s) must not interfere with the mechanism of action for MMA-101 or SEL-110 in the opinion of the Investigator and dose(s) must not alter for at least 4 weeks before screening through to dosing (Day 1)
-Is taking foods (eg, St John s Wort, grapefruit juice) or drugs classified as CYP3A4 or strong P glycoprotein (P-gp) inducers or inhibitors known to interact with sirolimus (RAPAMUNE ) such as cyclosporine, diltiazem, erythromycin, ketoconazole (and other antifungals), nicardipine (and other calcium channel blockers), rifampin, verapamil unless they are stopped 14 days prior to dosing through to 30 days post last dose of SEL-110.
-Subject has received a live virus vaccine in the previous 6 weeks prior to screening (MMR, Varicella, Rotovirus, Varivax, oral Polio). Subjects must refrain from vaccination for 6 weeks after the last dose of SEL-110. Live vaccines should not be administered within the last 6 weeks prior or after MMA-101 administration.
-Previously received gene therapy or messenger ribonucleic acid (mRNA) treatments for MMA.
-Participated in a clinical trial of another (non-gene or mRNA therapy) investigational agent within 30 days prior to screening, or within 5 elimination half-lives of the investigational agent, whichever is longer.
-Has any other clinically significant medical condition that in the Investigator s opinion could interfere with interpretation of study results or limit the subject s participation in the study.
Consultations with the GI/hepatology, nephrology and cardiology service will be obtained to assess liver, kidney and cardiac function, interpret laboratory and clinical findings and determine study eligibility at baseline and as needed for the duration of the study.
Principal Investigator
Referral Contact
For more information:
Additional Linkshttps://reimmagine.com