Phase 1/2 Clinical Trial of LY3884963 in Patients With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN) (PROCLAIM)

• ClinicalTrials.gov Identifier: NCT04408625
• Recruitment Status: Recruiting
• First Posted: May 29, 2020
• Last Update Posted: January 17, 2024
• Sponsor: Prevail Therapeutics
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Prevail Therapeutics

Study Description

Brief Summary:

Study J4B-MC-OKAA is a Phase 1/2, multi-center, open-label ascending dose, first-in-human study that will evaluate the safety and effect of intra-cisternal LY3884963 administration on progranulin protein (PGRN) levels in patients with frontotemporal dementia with progranulin mutations (FTD-GRN). Two escalating dose (low dose and medium dose) cohorts are planned, as well as one bridging cohort which will allocate patients to receive either low or medium dose. The duration of the study is 5 years. During the first year, patients will be evaluated for the effect of LY3884963 on safety, tolerability, immunogenicity, biomarkers, and efficacy. Patients will follow up for an additional 4 years to monitor safety and changes on selected biomarkers and clinical outcomes.

Condition or disease	Intervention/treatment	Phase
Frontotemporal Dementia	Biological: LY3884963; Drug: Methylprednisolone; Drug: Optional Sirolimus; Drug: Optional Prednisone	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Ascending Dose Study to Evaluate the Safety and Effects on Progranulin Levels of LY3884963 in Patients With Fronto-Temporal Dementia With Progranulin Mutations (FTD-GRN)
• Actual Study Start Date: November 9, 2020
• Estimated Primary Completion Date: August 31, 2029
• Estimated Study Completion Date: August 31, 2029

Arms and Interventions

Arm	Intervention/treatment
Experimental: Initial Cohort - Low dose	Biological: LY3884963; Participants will receive a single dose of LY3884963, administered intra cisterna magna; Drug: Methylprednisolone; IV pulses every 2 weeks in the first 3 months.; Drug: Optional Sirolimus; At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Optional Prednisone; If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen
Experimental: Initial Cohort - Medium dose	Biological: LY3884963; Participants will receive a single dose of LY3884963, administered intra cisterna magna; Drug: Methylprednisolone; IV pulses every 2 weeks in the first 3 months.; Drug: Optional Sirolimus; At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Optional Prednisone; If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen
Experimental: Bridging Cohort - Low dose; Participants enrolled in the Bridging Cohort will be assigned to either low or medium dose in an alternating manner	Biological: LY3884963; Participants will receive a single dose of LY3884963, administered intra cisterna magna; Drug: Methylprednisolone; IV pulses every 2 weeks in the first 3 months.; Drug: Optional Sirolimus; At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Optional Prednisone; If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen
Experimental: Bridging Cohort - Medium dose; Participants enrolled in the Bridging Cohort will be assigned to either low or medium dose in an alternating manner	Biological: LY3884963; Participants will receive a single dose of LY3884963, administered intra cisterna magna; Drug: Methylprednisolone; IV pulses every 2 weeks in the first 3 months.; Drug: Optional Sirolimus; At the investigators discretion following steroid tolerability issues, patients may receive a loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Optional Prednisone; If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen

Outcome Measures

Primary Outcome Measures :

1. Number of Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events Leading to discontinuation [ Time Frame: 5 Years ]
2. Sum of adverse reactions (ARs) and suspected ARs [ Time Frame: 5 years ]
3. Sum of serious ARs and serious suspected ARs [ Time Frame: 5 years ]
4. Incidence of procedure or treatment-emergent AEs [ Time Frame: 5 years ]
   Measured by brain and spine MRI
5. Change in PGRN immunogenicity in blood [ Time Frame: Baseline and Month 12 ]
   PGRN: progranulin protein. Measured by level of antibodies and ELISPOT
6. Change in PGRN immunogenicity in CSF [ Time Frame: Baseline and Month 12 ]
   CSF: cerebrospinal fluid
7. Change in AAV9 immunogenicity in blood [ Time Frame: Baseline and Month 12 ]
   Measured by level of antibodies and ELISPOT.
8. Change in AAV9, PGRN, and NfL immunogenicity in CSF [ Time Frame: Baseline and Month 12 ]
   Measured by levels of antibodies.
9. Change in PGRN levels in blood [ Time Frame: Baseline and Month 12 ]
10. Change in PGRN levels in CSF [ Time Frame: Baseline and Month 12 ]

Secondary Outcome Measures :

1. Change in CDR plus NACC FTLD [ Time Frame: Baseline and Month 12 ]
   CDR: Clinical Dementia Rating staging instrument. NACC FTLD: National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains
2. Change in NfL levels in blood [ Time Frame: Baseline and Month 12 ]
   NfL: neurofilament light chain
3. Change in NfL levels in CSF [ Time Frame: Baseline and Month 12 ]

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Men or women aged 30 to 85 years (inclusive), at the time of informed consent.
• Body weight range of ≥40 kg (88 lbs) to ≤110 kg (242 lb) and a BMI of 18 to 34 kg/m2.
• Has symptomatic frontotemporal dementia (FTD), including mild behavioral, cognitive, motor or language impairment per Investigator's assessment (behavioral-variant FTD, primary progressive aphasia-FTD, FTD with corticobasal syndrome, or a combination of syndromes are allowed for enrollment).
• Score ≥0.5 and ≤15 on CDR plus NACC FTLD sum of boxes.
• Stable use of background medications at least 8 weeks prior to LY3884963 dosing.
• Carrier of a pathogenic progranulin gene (GRN) mutation.
• Negative screening test for Mycobacterium tuberculosis (MTB) or documented negative MTB test within 1year prior to screening.
• Age- and gender-appropriate cancer screenings are up-to-date and completed.
• Patient and/or patient's legally authorized representative has the ability to understand the purpose and risks of the study, and provide written informed consent and authorization to use protected health information.
• 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.
• Patient is not dependent on a walker or wheelchair.
• Patient is living in the community (i.e. not in nursing home); some levels of assisted living may be permitted at the discretion of the investigator.
• Pneumococcal pneumonia and shingles vaccines are required within 10 years of Screening (allowed to be performed during Screening but must be given at least 4 weeks prior to initiation of immunosuppressant regimen).

Exclusion Criteria:

• Diagnosis of a significant CNS (central nervous system) disease other than frontotemporal dementia (FTD) that may cause FTD symptoms or confound study objectives.
• Brain or cervical spine magnetic resonance image (MRI)/MRA imaging showing clinically significant abnormality considered to prevent intracisternal magna (ICM) injection.
• Hypersensitivity or contraindications to corticosteroid, and/or sirolimus use.
• Clinical evidence of peripheral symmetric sensory polyneuropathy (stable sensory mononeuropathies and radiculopathies are not exclusionary).
• 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
• Clinically significant laboratory test result abnormalities assessed at screening.
• Participation within 3 months prior to screening in another therapeutic investigational drug or device study with purported disease-modifying effects on FTD, unless it can be documented that the patient received placebo only.
• Any type of prior gene or cell therapy.
• Live vaccines in the 4 weeks prior to Screening. NOTE: Pneumococcal vaccine and/or shingles vaccine administration is allowed at least 4 weeks prior to initiation of immunosuppressant regimen.
• Use of blood thinners in the 2 weeks prior to screening, or anticipated use of blood thinners during the study. Antiplatelet therapies are acceptable if the patient is medically able to temporarily stop 48 hours to 7 days (depending on the antiplatelet medication used) prior to and at least 48 hours after ICM injection and LP. Note: the use of blood thinners as part of prophylaxis or treatment of an emergent VTE or another AE during the study does not exclude the patient, unless there is a baseline high risk of thromboembolic events, and use of blood thinners is highly anticipated in the opinion of the Investigator.
• Contraindications or intolerance to imaging methods (MRA, MRI, and/or computed tomography [CT]), including claustrophobia and intolerance to contrast agents used for MRI, MRA, or CT (including, but not limited to, gadolinium contrast agents and iohexol).
• Contraindications to general anesthesia or deep sedation.
• Positive urine test for drugs of abuse (including opiates, amphetamines, cocaine, barbiturates, and phencyclidine) without prescription at Screening and on Day 1.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Contacts

Contact: Prevail Therapeutics; (917) 336-9310; prevail.patients@lilly.com

Locations

United States, Florida

PPD Phase 1 Clinic, 100 West Gore Street, Suite 202; Recruiting

Orlando, Florida, United States, 32806

Contact: Sarah Poissant 689-216-3100 sarah.poissant@ppd.com

United States, Pennsylvania

Hospital of the University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Dahlia Kamel 215-662-6134 kamel.dahlia@pennmedicine.upenn.edu

Australia, New South Wales

Royal Prince Alfred Hospital, Brain & Mind Research Institute, 94 Mallet Street; Recruiting

Camperdown, New South Wales, Australia, 2050

Contact: Cassandra Kaizik 02 9515 4540 cassandra.kaizik@sydney.edu.au

Belgium

UZ Leuven, Neurologie Herestraat 49; Recruiting

Leuven, Belgium, 3000

Contact: Carine Schildermans 3126345500 carine.schildermans@uzleuven.be

France

Le Ber, Institut du Cerveau et de la Moelle Epinière; Active, not recruiting

Paris, France, 75013

Spain

Hospital Clinic de Barcelona, Villaroel 170 Servicio de Neurología; Recruiting

Barcelona, Spain, 08036

Contact: Beatriz Bosch Capdevila, PhD [+34] 934518240 ext 3088 beabc6@hotmail.com/bbosch@clinic.cat

Hospital Universitario de Donostia, Servicio De Neurologia, Consultas Externas Neurologia, San Sebastian, Guipúzcoa; Recruiting

San Sebastian, Spain, 20014

Contact: Fermin Moreno +39 443007027 fermin.morenoizco@osakidetza.eus

United Kingdom

University College London,Queen Square, Dementia Research Building, London,; Recruiting

London, United Kingdom, WC1N 3BG

Contact: Miguel Alvarez miguel.alvarez.13@ucl.ac.uk

Sponsors and Collaborators

Prevail Therapeutics

Eli Lilly and Company

Investigators

• Study Director: Olga Uspenskaya-Cadoz, MD, PhD; Prevail Therapeutics

More Information

• Responsible Party: Prevail Therapeutics
• ClinicalTrials.gov Identifier: NCT04408625
• Other Study ID Numbers: J4B-MC-OKAA (PRV-FTD101)
• First Posted: May 29, 2020
• Last Update Posted: January 17, 2024
• Last Verified: January 2024

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Prevail Therapeutics:

Fronto-Temporal Dementia; Frontotemporal Dementia; Progranulin Mutations; FTD-GRN; Gene Therapy; Dementia Gene Therapy; AAV9

Additional relevant MeSH terms:

Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Neurodegenerative Diseases; Frontotemporal Lobar Degeneration; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Aphasia; Speech Disorders; Language Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Sirolimus; Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents