Background

PR006 is a gene-replacement therapy that uses adeno-associated virus 9 (AAV9) to deliver a functional copy of the progranulin gene GRN to the brain. Progranulin mutations are a frequent cause of familial frontotemporal dementia. Mutations result in 30 to 50 percent reductions in cerebrospinal fluid progranulin levels compared to the normal range. The loss of progranulin interferes with proper lysosomal function, leading to build-up of toxic proteins, neuroinflammation, and neurodegeneration (e.g., Sep 2017 news).

GRN is also implicated in Alzheimer’s disease. Variants that reduce progranulin levels increase risk of AD, and progranulin reduction exacerbates AD pathology in animal models (reviewed in Elia et al., 2020).

PR006 is delivered as a one-time injection into the cerebrospinal fluid in the cisterna magna at the base of the brain. At conferences, company scientists reported that PR006 increased progranulin release and improved lysosomal function of neurons derived from FTD-GRN patients, that PR006 restored brain GRN expression and progranulin secretion into the CSF in progranulin knockout mice, and that PR006 appeared safe and resulted in broad progranulin expression in the brain and periphery in nonhuman primates (see Nov 2019 news). This preclinical data have since been published (Sevigny et al., 2024), as was evidence that PR006 normalized lysosomal markers and reduced CNS inflammatory markers in the knockout mice.

Separately, one study reported T cell infiltration, as well as ependymal and hippocampal toxicity, following supra-physiological expression of progranulin from an AAV9-GRN delivered to GRN knockout mice. Some of this toxicity was also seen with progranulin overexpression in wild-type (Amado et al., 2019).

A second study comparing several AAV-GRN constructs in progranulin knockout mice and nonhuman primates reported no such toxicity (Hinderer et al., 2020).

A more recent study evaluated different PGRN-expressing AAV1/9 viruses in TMEM106b/GRN double knockout mice (Feng et al., 2023).

Findings

In July 2020, Prevail began a Phase 1/2 trial of PR006 in 23 people with FTD due to a progranulin mutation. Participants had to be living independently and have symptoms. The study is evaluating a low dose of 2.1 × 10¹³ viral genomes, and a medium dose of 4.2 × 10¹³, administered as a single intra-cisternal injection, concomitantly with an immunosuppressive regimen of steroids, sirolimus and rituximab. A third cohort will test the commercially produced drug product at either the low or mid dose. There is no placebo group. The primary endpoints are number of adverse events over a period of five years, plus immunogenicity of the virus and progranulin, and progranulin levels in blood and CSF. Secondary outcomes are one-year changes in measures of clinical decline, as well as neurofilament light chain concentrations in CSF and blood. Called PROCLAIM, the trial is recruiting at eight sites in Australia, Belgium, France, Spain, the U.K., and the U.S., and expected to run through 2029.

Interim results are published on patients on the low or mid dose who reached six months follow-up, and on low-dose patients who reached one year. Adverse events occurred in all 13 patients. Increased white blood cells in CSF, an indication of neuroinflammation, was seen in half. The increase was transient and caused no symptoms in all but one patient, who experienced a hearing impairment that later recovered. Twelve serious adverse events were noted, including multiple instances of blood clots. Deep vein thrombosis in two patients was possibly related to the immunosuppressive therapy in people with multiple risk factors for DVT. There was one death. Most patients had generated AAV9 antibodies; none developed progranulin antibodies. In all participants, CSF progranulin concentration rose, between 2.1- and 6.9-fold. Most attained normal or supernormal CSF progranulin levels at six or 12 months. There was a transient increase in neurofilament light chain in plasma and CSF; it was attributed to inflammation in dorsal root ganglia cells induced by transgene expression. Urine BMP, a candidate phospholipid marker of lysosome function, increased toward normal with treatment. Measures of clinical progression were similar to historical controls (Sevigny et al., 2024).

PR006 has orphan drug designation for FTD from U.S. and European regulators, and fast-track designation for FTD-GRN in the U.S.

In January 2021, Prevail was acquired by Eli Lilly & Company (press release, press release) and PR006 was renamed LY3884963.

For details on PR006/LY3884963 trials, see clinicaltrials.gov.