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

NCT04408625 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: J4B-MC-OKAA (PRV-FTD101)
• Study Type: interventional
• Target: 35
• Locations: 6 countries
• Sites: 12

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.

Conditions

Frontotemporal Dementia

Keywords

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

Outcome Measures

Primary Outcomes (8)

• Number of Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events Leading to discontinuation

  5 Years

• Sum of adverse reactions (ARs) and suspected ARs

  5 years

• Sum of serious ARs and serious suspected ARs

  5 years

• Incidence of procedure or treatment-emergent AEs

  Measured by brain and spine MRI

  5 years

• Change in AAV9, PGRN, and NfL immunogenicity in blood

  PGRN: progranulin protein. Measured by level of antibodies and ELISPOT

  Days 7, 14, and 21 and at Months 1, 1.5, 2, 3, 6, 9, 12, 18, and 24

• Change in AAV9, PGRN, and NfL immunogenicity in CSF

  Measured by levels of antibodies.

  Months 2, 6, 12, 18, and 24

• Change in PGRN levels in blood

  Days 7, 14, and 21 and at Months 1, 1.5, 2, 3, 6, 9, 12, 18, and 24

• Change in PGRN levels in CSF

  Months 2, 6, 12, 18, and 24

Secondary Outcomes (3)

• Change in CDR plus NACC FTLD

  Months 3, 6, 9, and 12

• Change in NfL levels in blood

  Days 7, 14, and 21 and at Months 1, 1.5, 2, 3, 6, 9, and 12

• Change in NfL levels in CSF

  Months 2, 6, and 12

Study Arms (5)

Initial Cohort - Low dose

EXPERIMENTAL

Biological: LY3884963; Drug: Methylprednisolone; Drug: Optional Sirolimus; Drug: Optional Prednisone

Initial Cohort - Medium dose

EXPERIMENTAL

Biological: LY3884963; Drug: Methylprednisolone; Drug: Optional Sirolimus; Drug: Optional Prednisone

Bridging Cohort - Low dose

EXPERIMENTAL

Participants enrolled in the Bridging Cohort will be assigned to either low or medium dose in an alternating manner

Biological: LY3884963; Drug: Methylprednisolone; Drug: Optional Sirolimus; Drug: Optional Prednisone

Bridging Cohort - Medium dose

EXPERIMENTAL

Participants enrolled in the Bridging Cohort will be assigned to either low or medium dose in an alternating manner

Biological: LY3884963; Drug: Methylprednisolone; Drug: Optional Sirolimus; Drug: Optional Prednisone

Cohort 5-Medium Dose

EXPERIMENTAL

Will enroll up to 10 participants with early phase of disease

Biological: LY3884963; Drug: Methylprednisolone; Drug: Optional Sirolimus; Drug: Optional Prednisone

Interventions

LY3884963 BIOLOGICAL

Participants will receive a single dose of LY3884963, administered intra cisterna magna

Bridging Cohort - Low dose; Bridging Cohort - Medium dose; Cohort 5-Medium Dose; Initial Cohort - Low dose; Initial Cohort - Medium dose

Methylprednisolone DRUG

IV pulses every 2 weeks in the first 3 months.

Bridging Cohort - Low dose; Bridging Cohort - Medium dose; Cohort 5-Medium Dose; Initial Cohort - Low dose; Initial Cohort - Medium dose

Optional Sirolimus DRUG

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

Bridging Cohort - Low dose; Bridging Cohort - Medium dose; Cohort 5-Medium Dose; Initial Cohort - Low dose; Initial Cohort - Medium dose

Optional Prednisone DRUG

If needed and at the investigator discretion, Oral Prednisone may be added to the immunosuppression regimen

Bridging Cohort - Low dose; Bridging Cohort - Medium dose; Cohort 5-Medium Dose; Initial Cohort - Low dose; Initial Cohort - Medium dose

Eligibility Criteria

• Age: 30 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 (Cohorts 1-4 only). Note: In Cohort 5 only patients with CDR plus NACC FTLD with sum of boxes ≥0.5 and ≤9 AND global score of 0.5 or 1 will be enrolled.
• 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.
• 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 postmenopausal, 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.
• 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 patients of childbearing potential:
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormonal contraception associated with inhibition of ovulation.
• Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation.
• Intrauterine device.
• Intrauterine hormone-releasing system.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Prevail Therapeutics: lead
• Eli Lilly and Company: collaborator

Study Sites (12)

k2 Medical Research-Maitland

Maitland, Florida, 32751-5669, United States

Location

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

Orlando, Florida, 32806, United States

Location

Lahey Hospital & Medical Center, 41 Burlington Mall Road

Burlington, Massachusetts, 01805, United States

Location

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

Philadelphia, Pennsylvania, 19104, United States

Location

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

Camperdown, New South Wales, 2050, Australia

Location

UZ Leuven, Neurologie Herestraat 49

Leuven, 3000, Belgium

Location

AP-HM Hôpital de La Timone

Saint-Pierre, Marseille, 13386, France

Location

Centre Mémoire de Ressources

Lille, 59000, France

Location

Le Ber, Institut du Cerveau et de la Moelle Epinière

Paris, 75013, France

Location

Hospital Clinic de Barcelona, Villaroel 170 Servicio de Neurología

Barcelona, 08036, Spain

Location

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

Donostia / San Sebastian, 20014, Spain

Location

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

London, WC1N 3BG, United Kingdom

Location

Related Publications (2)

• Sevigny J, Uspenskaya O, Heckman LD, Wong LC, Hatch DA, Tewari A, Vandenberghe R, Irwin DJ, Saracino D, Le Ber I, Ahmed R, Rohrer JD, Boxer AL, Boland S, Sheehan P, Brandes A, Burstein SR, Shykind BM, Kamalakaran S, Daniels CW, David Litwack E, Mahoney E, Velaga J, McNamara I, Sondergaard P, Sajjad SA, Kobayashi YM, Abeliovich A, Hefti F. Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results. Nat Med. 2024 May;30(5):1406-1415. doi: 10.1038/s41591-024-02973-0. Epub 2024 May 14.

  PMID: 38745011 DERIVED

• De BP, Rosenberg JB, Selvan N, Wilson I, Yusufzai N, Greco A, Kaminsky SM, Heier LA, Ricart Arbona RJ, Miranda IC, Monette S, Nair A, Khanna R, Crystal RG, Sondhi D. Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease. Hum Gene Ther. 2023 Sep;34(17-18):905-916. doi: 10.1089/hum.2023.067.

  PMID: 37624739 DERIVED

Related Links

• Progranulin AAV gene therapy for frontotemporal dementia

MeSH Terms

Conditions

Frontotemporal Dementia

Interventions

Methylprednisolone

Condition Hierarchy (Ancestors)

Frontotemporal Lobar Degeneration; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; TDP-43 Proteinopathies; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Travis Lewis, MD, PhD

  Prevail Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2020
• First Posted: May 29, 2020
• Study Start: November 9, 2020
• Primary Completion (Estimated): November 30, 2029
• Study Completion (Estimated): November 30, 2029
• Last Updated: April 30, 2026

Record last verified: 2026-04

Locations

GB (1); ES (2); BE (1); US (4); FR (3); AU (1)