First in Human: PROCLAIM and upliFT-D Trials Bring Gene Therapy to Frontotemporal Dementia


With up to 20% of incidences of FTD driven by genetic mutations, multiple gene therapy companies have initiated clinical trials of AAV-mediated treatments for a patient population with little to no options.

Frontotemporal dementia (FTD) is the second most common form of dementia and typically affects patients under 65 years of age.1 FTD usually presents in either a behavioral or language variant, the latter of which can cause either a semantic type of dementia or a nonfluent aphasia type.

There are currently no approved disease-modifying treatments specifically indicated for FTD, and as Rebekah Ahmed, MD, PhD, told CGTLive™, “essentially, there are no treatment options for FTD, and currently, there are no real treatment options for neurodegenerative dementias.”

Rebekah Ahmed, MD, PhD

Rebekah Ahmed, MD, PhD

“Many of the patients who develop FTD are under 65 years of age, so they’re still working, they still have young children, and so it's devastating when they get this diagnosis. We have to tell them that there's no potential treatment options—we can only manage the symptomatic symptoms with behavioral modifications or speech and language therapy,” Ahmed, who is a clinical associate professor at the University of Sydney and the director of the Memory and Cognition Clinic, continued. “To be able to offer patients a potential treatment is revolutionary because it gives them hope that maybe they may not die from this disease, or they may live longer. It could meet a huge unmet need because there aren't treatments for these conditions.”

Although much remains to be understood about the disease, the most recent research has identified 3 main gene mutations responsible for 10% to 20% of FTD cases: GRN, MAPT, and C9orf72. Of these gene-related cases, approximately 30% are caused by the progranulin mutation (GRN), which is often associated with serious, progressive, nonfluent aphasia.

“Up until probably 10 or 15 years ago, we weren't aware of all the gene mutations that cause FTD. And I think in the future, we will find other genes because we still have cases where we know that patients have a genetic mutation in their family, because multiple generations are affected, but we don't find one of the common mutations," Ahmed said.

PROCLAIM Trial of PR006

One approach to GRN mutation is from Prevail Therapeutics, which has developed an adeno-associated virus vector (AAV9) gene therapy designed to deliver a healthy copy of the GRN gene, PR006, to patients with FTD caused by GRN mutations. This treatment is delivered via intracisternal magna (ICM) injection to restore granulin production in the lysosomes. In FTD-GRN, GRN mutations cause an insufficient production of progranulin, leading to impacted lysosomal function, neuronal survival, and microglia activity. The FDA and European Commission have granted PR006 orphan drug designation, andthe FDA has also granted the therapy fast track designation.

PR006 is being evaluated in the phase 1/2 PROCLAIM trial (NCT04408625), which dosed its first patient in 2020 and which Prevail plans to complete enrollment in this year. The trial is primarily investigating the safety and tolerability of PR006 via incidence of adverse events (AEs) or serious AEs, and GRN and AAV9 immunogenicity levels in blood and cerebrospinal fluid (CSF). Secondary outcomes include change in Clinical Dementia Rating staging instrument scores, National Alzheimer's Coordinating Center frontotemporal lobar degeneration domain scores, and neurofilament light levels in blood and CSF.

“[PR006] works by increasing progressive levels by delivery of a healthy GRN gene copy into the central nervous [CNS] system. Ultimately, what we're trying to achieve is to restore the normal progranulin protein production to give patients healthy level of progranulin and improve their lysosomal functions through the delivery of this healthy GRN gene,” Olga Uspenskaya, MD, PhD, vice president of clinical development at Prevail, told CGTLive. “We hope that we will be able to correct this underlying genetic mutation through the treatment we are administering and slow down the disease progression and hopefully, in some cases, delay or stop the progression of the disease."

PROCLAIM has a planned enrollment of 15 patients between 30 and 80 years of age with FTD-GRN. Patients must be mobile and those with other CNS diseases, MRI abnormalities, recent blood thinner use, polyneuropathy, prior receipt of cell or gene therapy, recent participation in another trial for FTD, or other laboratory test abnormalities or confounding existing conditions will be excluded. Participants will receive 3 escalating doses of PR006. Participants will receive methylprednisolone, sirolimus, prednisone, and rituximab as concomitant medications. 

“This trial is actively recruiting in multiple locations... we are working very closely with patient advocacy groups to raise awareness about the disease in general and genetic testing, in particular,” Uspenskaya said.

upliFT-D Trial of PBFT02

Although there is no surplus of cell or gene therapies in development for FTD, Prevail is not quite alone in investigating its therapy for FTD-GRN. Passage Bio’s gene therapy candidate PBFT02 uses an AAV1 vector to similarly deliver GRN via ICM administration. Its phase 1/2 upliFT-D study (NCT04747431) dosed its first patient in August 2022, with data from cohort 1 expected by the end of 2023.2,3 The timeline pulls the trial ahead of PROCLAIM, which has not released any interim data since its initiation; enrollment progress was likely slowed after Prevail was acquired by Eli Lilly in 2021.4 upliFT-D opened its fourth trial site in May 2023, whereas PROCLAIM currently has 7 clinical trial sites listed as recruiting (FIGURE).

(Click to enlarge)

(Click to enlarge)

Genetic Testing, Other Research Efforts

“We have a sponsored genetic testing program where we work with healthcare providers, just informing them about the value of genetic testing, not just for our trial, but for all trials that are for FTD. There are multiple genetic mutations. So, we have this testing program that helps enhance the genetic testing rate, which is historically quite low in FTD. It's a big effort between us and patient advocacy groups to enhance that genetic testing. And then we also work to enhance genetic testing locally within regions associated with our various sites,” Mark Forman, MD, PhD, chief medical officer of Passage Bio, told CGTLive.

Outside of FTD-GRN, an early clinical trial (NCT04931862) for C9orf72-associated FTD was recently discontinued by Wave Life Sciences in July 2023 after the RNA therapy WVE-004 showed no benefit for FTD or its other investigational indication, amyotrophic lateral sclerosis.5 Although that program has been discontinued, the recent expansion of gene therapy into the clinical trial landscape of FTD makes it clear that genetic testing needs to be become more widespread as trials become available to patients with no currentdisease-modifying treatment options.

"The evolution of gene therapy has allowed us to provide patients with information, so we can say to families, this is the gene that causes the condition in your family, and that gives them options. One of the good things that has developed is often families will decide to go through in-vitro fertilization, for example, when they have their next child, so they can stop the gene mutation from being passed,” Ahmed said. “[Genetic testing] allows patients to be able to plan their lives and potentially enter clinical trials when they’re early or presymptomatic and gene therapy will have the strongest effect.”

1. Prevail Therapeutics announces first patient dosed in phase 1/2 PROCLAIM clinical trial evaluating PR006 for the treatment of frontotemporal dementia patients with GRN mutations. News release. Prevail Therapeutics. December 11, 2020. Accessed July 18, 2023.
2. Passage Bio doses first patient in global clinical trial of PBFT02 gene therapy for frontotemporal dementia with granulin mutations. News release. Passage Bio. August 11, 2022. Accessed July 21, 2023.
3. Passage Bio reports first quarter 2023 financial results and provides recent business highlights. News release. Passage Bio. May 11, 2023. Accessed July 21, 2023.
4. Lilly completes acquisition of Prevail Therapeutics. News release. Eli Lilly. January 22, 2021. Accessed July 26, 2023.
5. Wave Life Sciences announces topline results from phase 1b/2a FOCUS-C9 study of WVE-004 for C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia. News release. Wave Life Sciences. May 23, 2023. Accessed July 26, 2023.
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