Cellcept for Treatment of Juvenile Neuronal Ceroid Lipofuscinosis

Phase II, Randomized, Placebo Controlled Trial of the Safety and Tolerability of Mycophenolate in Children With Juvenile Neuronal Ceroid Lipofuscinosis

The primary objective of this trial is to establish the safety and tolerability of short-term (8 weeks) administration of mycophenolate mofetil in ambulatory children with JNCL. The secondary objective is to gather preliminary evidence of the short-term (8 week) impact of mycophenolate mofetil on clinically relevant features of JNCL as measured by the Unified Batten Disease Rating Scale (UBDRS), including motor features, seizures, behavior, cognitive and functional measures.

Funding source-FDA Office of Orphan Product Development (OOPD).

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a fatal disorder. Currently treatment is symptomatic. Thus, there is a real need to intervene and slow the progression of this disease. Preliminary data on genetic knock-down of the ability to mount an immune response in cln3-knockout mice is supportive of a strategy for treating JNCL with an immuno-suppressive agent. Many drugs with the ability to suppress the immune system are steroidal and deemed unsuitable for long-term administration to children. Mycophenolate mofetil (CellCept) is used as an immunosuppressive agent in allogenic transplants in pediatric patients and is therefore approved by the Food and Drug Administration (FDA) for pediatric use.

The study design is a double-blind, randomized, 22-week cross-over study of mycophenolate mofetil vs. placebo. After a 4-week washout period, subjects will undergo blinded crossover from active study drug to placebo or from placebo to active study drug.

Subjects and caregivers will be evaluated in person in the University of Rochester Batten Center (URBC) at screening/baseline, and at weeks 8, 12, and 20. In addition, subjects will be evaluated by their local clinician who is a formalized member of the research team. Such contacts will occur at Weeks 2, 4, 14, 16, and any unscheduled or early termination visits. There will also be regular telephone contact between the URBC and the local clinician.

We have selected the dosage currently FDA approved for use in children being treated for prophylaxis of renal transplant rejection.

Inclusion Criteria:

• JNCL as determined by a characteristic clinical presentation and confirmatory genetic evidence.
• Able to walk 10 feet without assistance beyond that required due to vision impairment.
• Subjects with local treating clinician (pediatrician or neurologist) willing to conduct the trial according to the protocol, good clinical practice, and applicable regulations.
• Subjects with a parent/legal guardian willing to accompany them to all study visits, oversee study drug compliance, and monitor and report to local treating clinician/investigator and the URBC investigative personnel any signs of adversity.

Exclusion Criteria:

• Inability to tolerate oral administration of medications
• Concomitant medical condition, which, in the opinion of the local treating clinician, the parent(s)/guardian, or the URBC study investigator would place the child at greater than acceptable risk from: 1) travel by plane or car to the URBC on four occasions over the course of 22 weeks, 2) exposure to mycophenolate mofetil at protocol defined dosages for periods up to 8 weeks.
• Anticipated inability of the child (on the part of the investigator, parent/guardian, or URBC study personnel) to comply with the rigors of the protocol..
• Use of disallowed concomitant medications.
• Administration of immunosuppressive medications
• History of any prior exposure to mycophenolate mofetil
• History of hypersensitivity to mycophenolate mofetil, or any other component of the product
• History of frank gastrointestinal hemorrhage, ulceration, or melena
• White blood cell count < 3000/μL, absolute neutrophil count (ANC) < 1500/μL, hemoglobin < 10g/dL, or thrombocytopenia <100,000/μL.
• Abnormal liver function (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or bilirubin greater than 3 times the upper limit of normal)
• Pregnancy or vulnerability to engage in sexual intercourse based on report of the parent/guardian, judgment of the local treating clinician/investigator or judgment of the URBC study personnel.
• Positive Tuberculosis test
• Immunizations not up to date for age according to Centers for Disease Control guidelines