Frontotemporal dementia: from genetics to therapeutic approaches

Figures & data

Figure 1. Tree diagram of FTLD heterogeneity. Association of genetics and proteins to the clinical phenotypes and underlying pathology in FTLD.

Abbreviations: ALS: Amyotrophic lateral sclerosis, bvFTD: Behavioral Frontotemporal Dementia, C9orf72: Chromosome 9 Open Reading Frame 72, CBS: Corticobasal syndrome, CHMP 2B: Charged multivesicular body protein 2B gene, FUS: Fused in sarcoma gene, GRN: Progranulin gene, MAPT: Microtubule Associated Protein Tau gene, MND: Motor neuron disease, PNFA: Progressive non-fluent aphasia, PSP: Progressive supranuclear palsy, SD: Semantic dementia, TAU: Tau protein, TDP: TAR DNA-binding protein, Ubi: Ubiquitin, UPS: Ubiquitin proteasome system, VCP: Valosin Containing Protein.

Table 1. Summary of the ongoing clinical trials for FTD-GRN and FTD-C9ORF72 (clinicaltrials.Gov).

NCT Number	Overview	Acronym Sponsor name	Study design	Primary outcomes	End date
FTD-GRN
NCT04374136	A phase 3 double-blind, placebo-controlled study evaluating the efficacy and safety of AL001 in participants at risk for or with frontotemporal dementia due to heterozygous mutations in the progranulin gene.	INFRONT-3 (Alector Inc)	Experimental: AL001 (IV infusion, 60mg/Kg) every 4 weeks Placebo Comparator: Placebo (IV infusion) every 4 weeks Randomization: 3:2 Experimental: Open label AL001 (IV infusion, 60mg/Kg) every 4 weeks	Evaluation of efficacy of AL001 as measured by the Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease Coordinating Center frontotemporal lobar degeneration Behavior & Language Domains Sum of Boxes	2023–12
NCT04747431	A Phase 1b Open-Label, Multicenter, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacodynamic Effects of a Single Dose of PBFT02 Delivered Into the Cisterna Magna of Adult Subjects With Frontotemporal Dementia and Mutations in the Progranulin Gene	upliFT-D (Passage Bio, Inc)	Experimental: Cohort 1 Drug: PBFT02 Dose 1: 3.3 x 10^10 GC/g* Single dose of PBFT02, via intra cisterna magna Experimental: Cohort 2 Drug: PBFT02 Dose 2: 1.1 x 10^11 GC/g* Single dose of PBFT02, via intra cisterna magna Experimental: Optional Cohort 3 Drug: PBFT02 Dose 3: 2.2 x 10^11 GC/g* Single dose of PBFT02, via intra cisterna magna *GC/g: gene copy per gram of estimated brain weight	Incidence of adverse events(AEs) and serious AEs (multiple visits) Change in Nerve Conduction Velocity and amplitude from Baseline on Nerve Conduction Studies (multiple visits) Assess Humoral Response Against the Vector and Transgene in Serum and in CSF (multiple visits) Assess serum and CSF antibody titers against AAV1 and against progranulin following ICM administration of PBFT02.	2027–08
NCT05262023	A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants with Frontotemporal Dementia (FTD-GRN) Followed by an Open-Label Extension	(Denali Therapeutics Inc)	Experimental: DNL593 (Healthy Participant) Interventions: Drug: DNL593 Placebo Comparator: Placebo (Healthy Participant) Interventions: Drug: Placebo Experimental: DNL593 (Participants with FTD) Interventions: Drug: DNL593 Placebo Comparator: Placebo (Participants with FTD) Interventions: Drug: Placebo	Incidence, severity, and seriousness of treatment-emergent AEs. Clinically significant abnormalities in safety laboratory values. Change from baseline in vital sign measurements: systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature, ECG results including PR, QRS, and QTcF intervals, abnormalities in physical/neurological examination findings. Change from baseline in Columbia-Suicide Severity Rating Scale	2025–11
NCT04408625	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).	PROCLAIM (Prevail Therapeutics)	Experimental: Initial Cohort - Low dose Biological: LY3884963 Methylprednisolone, Optional Sirolimus, Optional Prednisone Experimental: Initial Cohort - Medium dose Biological: LY3884963, Methylprednisolone, Optional Sirolimus, Optional Prednisone Experimental: Bridging Cohort - Low dose Participants will be assigned to either low or medium dose in an alternating manner. Biological: LY3884963, Methylprednisolone, Optional Sirolimus, Optional Prednisone Experimental: Bridging Cohort - Medium dose Participants will be assigned to either low or medium dose in an alternating manner. Biological: LY3884963, Methylprednisolone, Optional Sirolimus, Optional Prednisone	Incidence of AEs, Serious AEs, and AEs Leading to discontinuation. Sum of adverse reactions (ARs) and suspected ARs. Sum of serious ARs and serious suspected Ars. Incidence of procedure or treatment-emergent AEs measured by brain and spine MRI. Change in PGRN immunogenicity in blood and CSF. Change in AAV9 immunogenicity in blood. Change in AAV9, PGRN, and NfL immunogenicity in CSF. Change in PGRN levels in blood and in CSF	2029–08
NCT06064890	A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of an investigational gene therapy called AVB-101 administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN).	ASPIRE-FTD (AviadoBio, Ltd)	Experimental: Cohort 1 (dose 1) Initial dose, delivered as a one-time only, intrathalamic administration. of AAV-PGRN (AVB-101) Experimental: Cohort 2 (dose 2) Escalated dose, delivered as a one-time only, intrathalamic administration of AAV-PGRN (AVB-101)	Number and incidence of adverse events (AEs) and type and incidence of. Change from baseline in the Mini-Mental State Examination (MMSE). Time to achieve clearance of vector genomes, in plasma and semen (males only) Incidence of treatment emergent suicidal ideation or behavior (Columbia-Suicide. Incidence of treatment-emergent clinically significant abnormalities in clinical examination, in safety laboratory values. Change from baseline in brain structure (MRI findings at post treatment visits including brain swelling or bleeding)	2030–10
NCT06226064	Phase 1, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of orally administered VES001 The study is designed in two part followed by a multicenter, open-label Phase 1b study in asymptomatic GRN mutation carriers. Part A will evaluate the safety, tolerability, PK, and PD of single doses of VES001 in healthy volunteers. Part B will evaluate the safety, tolerability, PK, and PD of multiple doses of VES001 in healthy volunteers.	SORT-IN-1 (Vesper Biotechnologies ApS)	Experimental: VES001 (Healthy Participants) Part A: Ascending single doses and Part B: Multiple ascending dose (seven days of treatment), for healthy volunteers. Placebo Comparator: Placebo (Healthy Participants) Part A: Ascending single doses and Part B: Multiple ascending dose (seven days of treatment), for healthy volunteers. Part A will include six cohorts, with eight participants per cohort. Randomized in a 6:2 ratio (VES001 vs. placebo) Part B will include three cohorts, with ten participants per cohort. Randomized in a 8:2 ratio (VES001 vs. placebo)	Incidence, severity, and seriousness of treatment-emergent AEs. Incidence of clinically significant abnormalities in safety laboratory values. Change from baseline in vital sign measurement: Pulse Rate (bpm), Systolic and Diastolic blood pressure, Electrocardiogram parameter: Heart Rate, beats per minute, PR Interval, QRS Interval, QT Interval, QTcB, Incidence of clinically significant abnormalities in physical/neurological examination findings. Change from baseline in Columbia-Suicide Severity Rating Scale	2024–08
FTD- C9ORF72
NCT04993755	Phase 2a multi-center, randomized, double-blind, placebo-controlled parallel-group, 2-arm study with a long-term, open-label treatment phase with investigational drug TPN-101 in patients with Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) Associated with Hexanucleotide Repeat Expansion in the C9orf72 gene C9orf72.	(Transposon Therapeutics, Inc)	Experimental: TPN-101, 400 mg/day once daily for 24 weeks (double-blind treatment) followed by 400 mg/day TPN-101 for 24 weeks (open-label treatment) Placebo Comparator: Placebo once daily for 24 weeks (double-blind treatment) followed by 400 mg/day TPN-101 for 24 weeks (open-label treatment)	Assess the safety and tolerability of TPN-101 in patients with C9ORF72 ALS/FTD Incidence and severity of spontaneously reported treatment-emergent adverse events associated with TPN-101 v. placebo administered for up to 48 weeks in patients with C9orf72 ALS/FTD	2023–09
NCT04220021	Small-scale Phase 2 clinical trial to assess Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD	University of Florida	Experimental: C9orf72 positive ALS Metformin at a dosage of 500mg with an escalation of dosage by 500mg every week to a maximal dosage of 2000mg. Dosing will be twice daily for 24 weeks	The safety and tolerability of Metformin in participants with C9orf72 ALS currently treated with Metformin will be evaluated by the number of subjects with treatment-emergent AEs Assess the RAN protein levels in cerebrospinal fluid (CSF) samples from participants at specific intervals	2024–05
NCT04931862	Phase 1b/2a study of intrathecal injection of WVE-004 antisense oligonucleotide in Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)	FOCUS-C9 (Wave life Sci, ltd)	Experimental: WVE-004| (dose A or B or C or D) or Placebo	Safety: Proportion of patients with adverse events (AEs), severe AEs, serious AEs. Number of patients who withdrawn due to AEs	discontinued
NCT05683860	Open-label Extension (OLE) Study of intrathecal injection of WVE-004 antisense oligonucleotide in Patients with C9orf72-associated ALS and/or FTD. Patients must have successfully completed Phase 1b/2a WVE-004-001 study.	(Wave life Sci, ltd)	Experimental: Experimental: WVE-004 (Dose A)	Safety: Proportion of patients with adverse events (AEs), severe AEs, serious AEs, number of patients who withdrawn due to AEs	discontinued

Abbreviations: Abbreviation list: AAV: Adeno‐Associated Viral, AE: Adverse Events, ALS: Amyotrophic Lateral Sclerosis, AR: Adverse Reactions, bvFTD: behavioral variant of FTD, C9orf72: Chromosome 9 Open Reading Frame 72, CSF: cerebrospinal fluid, FTD: Frontotemporal Dementia, FTLD Frontotemporal Lobar Degeneration, GRN: Progranulin, MRI: Magnetic Resonance Imaging, MMSE: Mini-Mental State Examination, PGRN: progranulin, RAN: repeat associated non-ATG translation.