PR006 for Frontotemporal Dementia

(PROCLAIM Trial)

Recruiting at 8 trial locations

Overseen By Prevail Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Prevail Therapeutics

Must not be taking: Corticosteroids, Sirolimus, Blood thinners, others

Disqualifiers: CNS disease, Polyneuropathy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a new drug called LY3884963 to help people with a specific type of dementia. The drug is given directly to the brain to increase a protein that could improve their condition. The study focuses on patients with genetic mutations that affect their response to usual treatments.

Do I have to stop taking my current medications for the trial?

The trial requires that your current medications be stable for at least 8 weeks before starting the study drug. It does not specify if you need to stop any medications, but you should discuss your specific situation with the study team.

How is the treatment PR006 unique for frontotemporal dementia?

PR006 is a gene therapy that uses a virus to deliver a healthy copy of the GRN gene to cells, potentially restoring the production of progranulin, a protein that is deficient in some cases of frontotemporal dementia. This approach is different from traditional treatments as it targets the genetic cause of the disease rather than just managing symptoms. ^{1 2 3 4 5}

Who Is on the Research Team?

Olga Uspenskaya-Cadoz, MD, PhD

Principal Investigator

Prevail Therapeutics

Are You a Good Fit for This Trial?

This trial is for adults aged 30-85 with frontotemporal dementia due to progranulin gene mutations. Participants must be living in the community, not dependent on a walker or wheelchair, have up-to-date vaccinations and cancer screenings, and test negative for tuberculosis. They need a reliable informant to report on their health status.

Inclusion Criteria

Your score on the CDR plus NACC FTLD sum of boxes test is between 0.5 and 15.

I have had the pneumonia and shingles vaccines within the last 10 years.

I understand the study's risks and can give my consent.

Exclusion Criteria

I have a brain condition that is not frontotemporal dementia but could cause similar symptoms.

I am allergic or cannot take corticosteroid or sirolimus.

You have abnormal test results that are important for your health.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intra-cisternal administration of LY3884963 in escalating doses to evaluate safety, tolerability, immunogenicity, biomarkers, and efficacy

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and changes in biomarkers and clinical outcomes

4 years

Annual visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• PR006

Trial Overview The study tests LY3884963's safety and its effect on protein levels related to dementia when administered into the spinal fluid. Optional treatments include Sirolimus and Prednisone. Over five years, patients will be monitored through various doses of LY3884963 for changes in biomarkers and clinical outcomes.

How Is the Trial Designed?

Group I: Initial Cohort - Medium dose Experimental Treatment 4 Interventions

Group II: Initial Cohort - Low dose Experimental Treatment 4 Interventions

Group III: Bridging Cohort - Medium dose Experimental Treatment 4 Interventions

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

Group IV: Bridging Cohort - Low dose Experimental Treatment 4 Interventions

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

PR006 is already approved in United States, European Union for the following indications:

Approved in United States as LY3884963 for:

• Frontotemporal dementia with progranulin mutations (FTD-GRN) - Orphan drug designation

Approved in European Union as LY3884963 for:

• Frontotemporal dementia with progranulin mutations (FTD-GRN) - Orphan drug designation

Who Is Running the Clinical Trial?

Prevail Therapeutics

Lead Sponsor

Trials

5

Recruited

190+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

A case study of a patient with behavioral variant frontotemporal dementia (bvFTD) revealed a GRN mutation, but their asymptomatic parent and sibling carried protective TMEM106B gene variants, suggesting a reduced risk for developing symptoms.

Combining TMEM106B genotyping with GRN mutation screening can enhance genetic counseling for families at risk of FTD, potentially identifying individuals with lower disease risk and promoting further research into the gene's protective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family. Perneel, J., Manoochehri, M., Huey, ED., et al.[2023]

Gene therapy using adeno-associated viral vectors to deliver the progranulin gene into the cerebrospinal fluid has shown promising results in mouse models and nonhuman primates, significantly increasing progranulin levels and normalizing markers of deficiency.

The AAV1 vector demonstrated superior efficacy in increasing progranulin expression compared to other variants, and the treatment was well tolerated with no significant toxicity, supporting its potential as a safe therapeutic option for frontotemporal dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus serotype 1-based gene therapy for FTD caused by GRN mutations. Hinderer, C., Miller, R., Dyer, C., et al.[2021]

TMEM106B variants, particularly the minor allele rs3173615, have been identified as genetic modifiers that reduce the risk of developing frontotemporal dementia (FTD) in carriers of C9ORF72 expansions, with a significant protective effect observed in FTD patients (odds ratio 0.33).

The protective effect of TMEM106B is specific to FTD and does not extend to motor neuron disease (MND), suggesting its role is particularly relevant for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), highlighting its potential as a therapeutic target.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. van Blitterswijk, M., Mullen, B., Nicholson, AM., et al.[2022]

In a study of 121 patients with frontotemporal lobar degeneration (FTLD), six different mutations in the progranulin (GRN) gene were identified in eight patients, indicating a mutation frequency of 6.6% in this cohort.

Patients with GRN mutations had significantly reduced serum levels of progranulin (>50% lower) compared to FTLD patients without these mutations, suggesting a link between GRN haploinsufficiency and the disease's pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration. Chiang, HH., Forsell, C., Lilius, L., et al.[2021]

In a study involving 230 patients with frontotemporal lobar degeneration (FTLD), 104 patients with Alzheimer's disease, and 161 control subjects, decreased levels of progranulin were confirmed in FTLD patients with GRN mutations, indicating a potential biomarker for this genetic subtype.

Interleukin-6 levels were found to be elevated in FTLD patients overall, but this increase did not help differentiate between the various clinical and genetic subtypes of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma levels of progranulin and interleukin-6 in frontotemporal lobar degeneration. Gibbons, L., Rollinson, S., Thompson, JC., et al.[2018]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family. [2023]

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

Adeno-associated virus serotype 1-based gene therapy for FTD caused by GRN mutations. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration. [2021]

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

Plasma levels of progranulin and interleukin-6 in frontotemporal lobar degeneration. [2018]