DNL593 for Frontotemporal Dementia

Recruiting at 37 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called DNL593 (also known as PTV:PGRN or TAK-594) for individuals with frontotemporal dementia (FTD), a condition that affects the brain and can alter personality and behavior. Researchers aim to assess the safety, tolerability, and behavior of this treatment in the body. The study consists of two parts: one involves healthy participants receiving a single dose, and the other involves individuals with FTD receiving multiple doses. Those diagnosed with FTD and possessing a specific genetic mutation (granulin, or GRN) may be suitable candidates for the trial. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is investigating the safety and tolerability of DNL593 in both healthy individuals and those with frontotemporal dementia (FTD). Earlier studies have examined how the body processes the drug and its effects. This treatment aims to deliver a protein called progranulin, which may be important for brain health.

While specific safety details remain unavailable, ongoing research in this phase indicates that scientists continue to collect safety information. As a Phase 1/2 trial, researchers closely observe participants' responses to the drug and monitor for any side effects. This phase is crucial for understanding the safety of DNL593 in humans before broader use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for frontotemporal dementia?

Unlike the standard treatments for frontotemporal dementia, which often focus on managing symptoms through medications like antidepressants and antipsychotics, DNL593 offers a novel approach. It targets the underlying disease mechanisms, potentially slowing or halting progression rather than just alleviating symptoms. Researchers are excited about DNL593 because it could address the root causes of the condition, offering hope for more effective and lasting outcomes.

What evidence suggests that DNL593 might be an effective treatment for frontotemporal dementia?

Research has shown that DNL593, a treatment under study in this trial, could be promising for treating frontotemporal dementia (FTD). In studies with mice lacking the protein progranulin, DNL593 corrected disease signs also found in human FTD patients. This suggests that DNL593 might work by replacing progranulin in the brain, which is crucial for brain health. Although this research remains in the early stages, the findings offer hope that DNL593 might help people with FTD by addressing the disease's root cause. ^{2 3 6 7 8}

Who Is on the Research Team?

Amy Berger, MD

Principal Investigator

Denali Therapeutics Inc.

Are You a Good Fit for This Trial?

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.

My BMI is between 18 and 32.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05262023

NCT05262023 | A Study to Evaluate the Safety, Tolerability ... 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 ...

2. memory.ucsf.edu memory.ucsf.edu/research-trials/dnl593

Phase 1/2 Study of DNL593 for Frontotemporal Dementia ... This study evaluates the safety, tolerability, pharmacokinetics (how the drug is absorbed, distributed, metabolized, and eliminated in the body), and ...

3. researchgate.net researchgate.net/publication/376816346_Safety_and_pharmacokinetics_of_single_ascending_doses_of_TAK-594DNL593_a_brain-penetrant_progranulin_replacement_therapy_in_healthy_volunteers_Interim_results_from_Part_A_of_a_Phase_12_clinical_trial

Interim results from Part A of a Phase 1/2 clinical trial In PGRN‐deficient mice, TAK‐594/DNL593 corrected age‐dependent elevations of disease biomarkers that are also observed in patients with FTD‐GRN ...

4. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effects-of-dnl593-for-patients-with-frontotemporal-dementia/

Study on the Safety and Effects of DNL593 for Patients ... This study investigates the safety and effects of DNL593 in treating Frontotemporal Dementia, with a focus on understanding its impact on ...

5. theaftd.org theaftd.org/posts/1ftd-in-the-news/b-denalitakeda-upenn-ftd-grn/

Denali and Takeda Open FTD-GRN Clinical Trial Site at ... The multicenter study is evaluating the safety and tolerability of the drug DNL593 in people with and without FTD. DNL593 Reintroduces ...

6. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.075068

Safety and pharmacokinetics of single ascending doses of ... TAK-594/DNL593 is a novel PGRN replacement therapy that has been engineered to deliver PGRN across the blood brain barrier (BBB) and into lysosomes.

7. progranulinnavigator.org progranulinnavigator.org/trials/a-study-to-evaluate-the-safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-dnl593-in-healthy-participants-and-participants-with-frontotemporal-dementia-ftd-grn

Prograngulin Information Navigator The study will collect data to evaluate how safe DNL593 is, as well as how well the body handles it (pharmacokinetics), what it does in the body ...

8. orpha.net orpha.net/en/research-trials/clinical-trial/690547?name=&mode=&country=&recruiting=0&terminated=0

FTD-GRN: A Phase 1/2, Multicenter, Randomized, Placebo ... ... Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 ... Frontotemporal Dementia Followed by an Open-Label Extension - PT. Geographic ...