Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN) MedDRA version: 21.1 Level: PT Classification code 10068968 Term: Frontotemporal dementia System Organ Class: 10029205 - Nervous system disorders
Conditions
Interventions
Product Name: PR006A
Product Code: PR006A
Pharmaceutical Form: Solution for injection
INN or Proposed INN: TBC
Current Sponsor code: PR006A
Other descriptive name: Adeno-associated viral vector seroty
Sponsors
Prevail Therapeutics, a wholly-owned subsidiary of Eli Lilly and Company
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Men or women aged 30 to 80 years (inclusive), at the time of informed consent. 2. Body weight range of =40 kg (88 lbs) to =110 kg (242 lb) and a BMI of 18 to 34 kg/m2. 3. Has symptomatic FTD as per Investigator assessment (bvFTD, PPA-FTD, FTD with corticobasal syndrome, or a combination of syndromes are allowed for enrollment). 4. Score =1 and =15 on CDR plus NACC FTLD SB. 5. Stable use of background medications at least 8 weeks prior to PR006A dosing. 6. Carrier of a pathogenic* GRN mutation confirmed by the central laboratory. *All null mutations including nonsense, frameshift, splice site mutations, and complete or partial (exonic) gene deletions: - All previously published pathogenic mutations, with proven functional deleterious effect (selected missense mutations may be included provided they are known to be pathogenic) - All pathogenic mutations listed in Molgen FTD database (http://www.molgen.ua.ac.be) - All new mutations with low plasma PGRN level (<70 ng/mL) based on central laboratory measurement. 7. Negative screening test for mycobacterium tuberculosis (MTB) or documented negative MTB test within 1 year prior to Screening. 8. Age- and gender-appropriate cancer screenings are up to date and completed as per the Investigator’s judgment and local standard of care prior to Screening. 9. Patient and/or patient’s legally authorized representative (LAR) (where applicable by local regulation) has the ability to understand the purpose and risks of the study and provide written informed consent and authorization to use protected health information in accordance with national and local privacy regulations. The patient or LAR may also provide consent for future biomedical research in accordance with their national regulations; however, the patient may still participate in the study without providing consent for future biomedical research. 10. Patient has a reliable study partner/informant (e.g., family member, friend) willing and able to participate in the study as a source of information on the patient’s health status and cognitive and functional abilities (including providing input into the rating scales). The study partner should have regular contact with the patient (in person or via phone/video communication). The study partner must sign a separate partner informed consent form (ICF) indicating that she/he understands the study requirements and is willing to participate and attend study visits requiring study partner input. 11. Women of nonchildbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before Screening) or post-menopausal, defined as spontaneous amenorrhea for at least 2 years, with follicle-stimulating hormone level in the postmenopausal range at Screening based on the central laboratory’s range. 12. Men and women of childbearing potential (i.e., ovulating, premenopausal, and not surgically sterile) must use a highly effective method of contraception consistently and correctly for the duration of the study including the long-term follow-up. Highly effective methods of contraception are those that, alone or in combination, result in a failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) and include the following for female participants of childbearing potential: a. Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormon
Exclusion criteria
Exclusion criteria: 1. Diagnosis of a significant CNS disease other than FTD that may be a cause for the patient’s FTD symptoms or may confound study objectives. 2. Brain or cervical spine MRI/magnetic resonance angiography (MRA) imaging indicating clinically significant abnormality, including evidence of prior hemorrhage, infarct >1 cm3 or >3 lacunar infarcts, or a structural or vascular abnormality deemed a contraindication to intracisternal injection. 3. Hypersensitivity or contraindications to corticosteroid, rituximab, and/or sirolimus use (including but not limited to osteoporosis with vertebral fractures within 1 year prior to Screening, poorly controlled diabetes [see Exclusion Criterion 5c], uncontrolled hypertension [see Exclusion Criterion 5f]), uncontrolled hyperlipidemia or hypercholesterolemia as per Investigator assessment, uncontrolled interstitial lung disease, or uncontrolled renal insufficiency). 4. Clinical evidence of peripheral symmetric sensory polyneuropathy (stable sensory mononeuropathies and radiculopathies are not exclusionary). 5. Concomitant disease or condition within 6 months of Screening that could interfere with, or treatment of which might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable safety risk to the patient or interfere with the patient's ability to comply with study procedures; including, but not limited to, the following: a. Evidence of clinically significant liver disease b. Unstable autoimmune disease requiring chronic immunosuppression c. Poorly controlled/not adequately managed diabetes (Screening hemoglobin A1c =7%) d. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening e. Clinically significant 12-lead ECG abnormalities at Screening, as determined by the Investigator f. Uncontrolled hypertension defined as: average of 3 systolic blood pressure [SBP]/diastolic blood pressure [DBP] readings >165/100 mm Hg at Screening, or persistent SBP/DBP readings >180/100 mm Hg within 3 months prior to Screening that, in the opinion of the Investigator, are indicative of chronic uncontrolled hypertension g. History of cancer, including B-cell cancers, within 5 years of Screening or current presence of pre cancer lesions, with the exception of fully excised nonmelanoma skin cancers and fully excised prostate carcinoma in situ that have been stable for at least 6 months h. History or current alcohol or drug abuse within 2 years of Screening i. Any current psychiatric diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, International Statistical Classification of Diseases and Related Health Problems Tenth Revision, or equivalent, that may interfere with the patient’s ability to perform study procedures and all assessments (e.g., psychosis, major depression, bipolar disorder, mental retardation, and schizophrenia). NOTE: Psychiatric manifestations of FTD are not exclusionary j. At imminent risk of self-harm, based on clinical interview and responses on the C-SSRS. Patient must be excluded if they report ideation with intent, with or without a plan or method (i.e., positive response to item 4 or 5 on the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months k. Any medical disorders that, in the opinion of
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - Evaluate the safety, tolerability and immunogenicity of 3 dose levels of PR006A administered via suboccipital injection into the cisterna magna. - Quantify PGRN levels in blood and CSF.;Secondary Objective: To evaluate the effect of PR006A on: • Clinical Dementia Rating staging instrument plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains (CDR® plus NACC FTLD) • Neurofilament light chain (NfL) levels in blood and CSF;Primary end point(s): - Change from baseline in PGRN levels in blood at Months 1, 2, 3, 6, 9, and 12 - Change from baseline in PGRN levels in CSF at Months 2, 6 and 12. ;Timepoint(s) of evaluation of this end point: 1, 2, 3, 6, 9, and 12 Months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Change from baseline in CDR plus NACC FTLD SB at Months 6 and 12 - Change from baseline in NFL levels in plasma and serum at Months 2, 6, 9, and 12 - Change from baseline in NFL levels in CSF at Months 2, 6 and 12;Timepoint(s) of evaluation of this end point: 3, 6, 9, and 12 Months | — |
Countries
Australia, Belgium, France, Spain, United Kingdom, United States
Contacts
Public ContactRegulatory Department
Prevail Therapeutics, Eli Lilly and Company
Outcome results
None listed