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 aims to test the safety and effects of a new treatment, PR006 (a gene therapy), for individuals with frontotemporal dementia caused by progranulin mutations (FTD-GRN). Researchers seek to understand how different doses of this treatment affect progranulin levels, a protein linked to the condition. Participants will be divided into groups receiving low or medium doses to better understand the treatment's impact. Suitable candidates have symptomatic frontotemporal dementia and carry a specific gene mutation. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in humans.

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.

Is there any evidence suggesting that PR006 is likely to be safe for humans?

Research has shown that PR006, a gene therapy, is under study for its safety and effectiveness in treating a type of dementia linked to specific genetic changes. Early results provide some insight into how well patients tolerate PR006. However, more follow-up and further studies are needed to confirm these findings. The current trial remains in its early stages, with researchers still gathering crucial safety information. This process often involves closely monitoring for any side effects and adjusting doses if necessary. While early studies suggest that PR006 might be safe, ongoing trials will offer a clearer understanding over time. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for Frontotemporal Dementia, which typically involves medications to manage symptoms like behavior changes and mood swings, PR006 is designed to address the genetic root of the disease. PR006 uses a viral vector to deliver the GRN gene directly into the brain cells, potentially correcting the protein deficiency that leads to the disease in some patients. Researchers are excited about PR006 because it targets the underlying cause rather than just the symptoms, offering hope for a more effective, long-lasting treatment.

What evidence suggests that PR006 might be an effective treatment for frontotemporal dementia?

Research has shown that PR006, a type of gene therapy, could help treat frontotemporal dementia with progranulin mutations (FTD-GRN). In studies with mice lacking the progranulin gene, PR006 restored important brain fat levels to normal. This suggests the treatment might address similar issues in humans. Participants in this trial will receive varying doses of PR006. Some in the Initial Cohort will receive low or medium doses, while others in the Bridging Cohort will alternate between low and medium doses. Early results from human trials suggest that PR006 could slow the progression of FTD-GRN. Although more research is needed to confirm these effects, the initial findings are promising. ^{2 4 6 7 8}

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

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]

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]

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]

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. nature.com nature.com/articles/s41591-024-02973-0

Progranulin AAV gene therapy for frontotemporal dementia We detected a robust decrease for both BMP species in Grn-KO mice, and treatment with PR006 restored di-22:6-BMP to levels similar to that of WT ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04408625

Study Details | NCT04408625 | Phase 1/2 ... 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 ...

3. prevailtherapeutics.com prevailtherapeutics.com/ftd-trial/

FTD Gene Therapy Clinical Trial (PROCLAIM) The clinical trial will assess the safety, tolerability, and effectiveness of a gene therapy aimed at slowing the progression of frontotemporal dementia and its ...

4. ftdregistry.org ftdregistry.org/press/featured-study-proclaim-a-study-of-pr006-with-ftd-grn/

FEATURED STUDY: PROCLAIM - A Study of PR006 with ... The PROCLAIM study, sponsored by Prevail Therapeutics, is evaluating safety and effectiveness of a one-time investigational gene therapy (PR006)

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04408625?term=gene%20therapy&cond=%22Frontotemporal%20Dementia,%20Ubiquitin-positive%22&viewType=Table&rank=5

Phase 1/​2 Clinical Trial of LY3884963 in Patients With ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38745011/

Progranulin AAV gene therapy for frontotemporal dementia These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04408625

Study Details | NCT04408625 | Phase 1/2 ... Patients will follow up for an additional 4 years to monitor safety and changes on selected biomarkers and clinical outcomes. Official Title. A Phase 1/2 ...

8. theaftd.org theaftd.org/posts/aftd-partners-in-ftd-care/pic-genetic-ftd-tu/

Genetic FTD Trials Update - Approaching a Phase 3 ... After a Phase 3 trial concludes, scientists review the results to see how the drug performed relative to the overall trial's “endpoints,” or the ...