DNL593 for Frontotemporal Dementia

Recruiting at 29 trial locations

Overseen By Clinical Trials at Denali Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Denali Therapeutics Inc.

Disqualifiers: Neurologic, Psychiatric, Cardiovascular, Malignancy, others

Compensation: Varies

Number of Visits: Unknown

106 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in two parts followed by an optional open-label extension (OLE) period. Part A will evaluate the safety, tolerability, PK, and PD of single doses of DNL593 in healthy male and healthy female participants of nonchildbearing potential. Part B will evaluate the safety, tolerability, PK, and PD of multiple doses of DNL593 in participants with frontotemporal dementia (FTD) over 25 weeks. Part B will be followed by Part C, an optional 18-month OLE period available for all participants who complete Part B.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What makes the drug DNL593 unique for treating frontotemporal dementia?

DNL593 is unique because it targets progranulin (PGRN) levels, which are often reduced in frontotemporal dementia due to genetic mutations. By potentially restoring PGRN levels, DNL593 may address the underlying cause of the disease, unlike other treatments that do not target this specific mechanism. ^{1 2 3 4 5}

Research Team

Amy Berger, MD

Principal Investigator

Denali Therapeutics Inc.

Eligibility Criteria

This trial is for healthy adults and those with frontotemporal dementia (FTD), specifically caused by a granulin mutation. Healthy participants must be 18-55 years old, non-childbearing women or men, with a BMI of 18-32 kg/m². FTD patients should be aged 18-80 and have a certain score indicating dementia severity. All must agree to use effective contraception if applicable.

Inclusion Criteria

Have a Clinical Dementia Rating® plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration global score ≥ 0.5

I am either not able to have children, a man, or using reliable birth control.

I am a man or a woman unable to have children, aged 18 to 55.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Evaluation of safety, tolerability, PK, and PD of single doses of DNL593 in healthy participants

Duration not specified

Treatment Part B

Evaluation of safety, tolerability, PK, and PD of multiple doses of DNL593 in participants with frontotemporal dementia over 25 weeks

25 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Optional 18-month open-label extension period available for all participants who complete Part B

18 months

Treatment Details

Interventions

• DNL593
• Placebo

Trial Overview The study tests DNL593's safety and effects on the body in two parts: single doses in healthy individuals (Part A) and multiple doses in FTD patients over 25 weeks (Part B). Participants who finish Part B can join an optional open-label extension for another 18 months to continue observing the drug's long-term effects.

Participant Groups

Group I: DNL593 (Participants with FTD) Experimental Treatment 1 Intervention

Group II: DNL593 (Healthy Participant) Experimental Treatment 1 Intervention

Group III: Placebo (Healthy Participant) Placebo Group 1 Intervention

Group IV: Placebo (Participants with FTD) Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Denali Therapeutics Inc.

Lead Sponsor

Trials

24

Recruited

1,900+

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Findings from Research

A novel mutation in the PGRN gene, identified as A303AfsX57, is linked to late-onset frontotemporal dementia, highlighting a genetic factor in this condition.

The mutation results from a deletion in exon 8 of the PGRN gene, leading to a frameshift and a premature stop codon, which may disrupt normal protein function and contribute to disease pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late-onset frontotemporal dementia associated with a novel PGRN mutation. Lladó, A., Sánchez-Valle, R., Reñé, R., et al.[2018]

Induced pluripotent stem cells from a patient with a specific GRN mutation (PGRN S116X) showed reduced levels of progranulin, establishing a model for studying frontotemporal dementia (FTD) related to PGRN deficiency.

Neurons with the PGRN S116X mutation were more sensitive to certain stress inducers and exhibited downregulation of the S6K2 kinase, but these defects could be reversed by restoring PGRN levels, highlighting potential therapeutic targets for FTD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects. Almeida, S., Zhang, Z., Coppola, G., et al.[2021]

Frontotemporal degeneration (FTD) is a serious brain disease linked to mutations in the GRN gene, which leads to reduced levels of progranulin (PGRN), causing cell dysfunction and neuron death.

Research is focusing on developing therapies that can restore PGRN levels in the brain, which could not only help patients with GRN-linked FTD but also potentially benefit those with other neurodegenerative diseases like Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches to develop therapeutics to treat frontotemporal dementia. Elia, LP., Reisine, T., Alijagic, A., et al.[2021]

In a study of 210 frontotemporal dementia (FTD) patients, 4.8% were found to have PGRN null mutations, indicating that these mutations are a significant cause of FTD, especially in familial cases (12.8%).

Interestingly, 3.2% of sporadic FTD patients also carried PGRN mutations, suggesting the potential for de novo mutations, and highlighting the need for genetic testing even in those without a family history of dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progranulin null mutations in both sporadic and familial frontotemporal dementia. Le Ber, I., van der Zee, J., Hannequin, D., et al.[2018]

Frontotemporal lobar degeneration (FTLD) is a major cause of dementia in younger individuals, primarily linked to mutations in the progranulin gene (GRN), which leads to reduced levels of the progranulin protein (PGRN) and contributes to neurodegeneration.

Recent studies have identified receptors for PGRN and potential pharmacological regulators, paving the way for new therapeutic strategies to address PGRN haploinsufficiency and FTLD, highlighting the importance of understanding PGRN biology in developing effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progranulin axis and recent developments in frontotemporal lobar degeneration. Nicholson, AM., Gass, J., Petrucelli, L., et al.[2021]

References

1. Austria pubmed.ncbi.nlm.nih.gov

Late-onset frontotemporal dementia associated with a novel PGRN mutation. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Approaches to develop therapeutics to treat frontotemporal dementia. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Progranulin null mutations in both sporadic and familial frontotemporal dementia. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Progranulin axis and recent developments in frontotemporal lobar degeneration. [2021]