The acceptance by the FDA of Prevail Therapeutics Inc.’s IND for the one-time, fast-tracked gene therapy PR-006 provided hope for 50,000 to 60,000 people in the U.S beset by frontotemporal dementia with the GRN mutation (FTD-GRN), and the New York-based company is moving ahead with a phase I/II experiment called Proclaim.

Progressive, neurodegenerative FTD-GRN is caused by lowered production of progranulin (PGRN), a protein critical for lysosomal function, neuronal survival and normal microglial activities. The progranulin fall-off leads not only to lysosomal dysfunction, but also ineffective protein degradation and recycling, neuroinflammation and, ultimately death, typically within three to 10 years of diagnosis. PR-006 delivers the GRN gene by AAV9 and is intended to increase PGRN levels.

There is some good in vivo evidence for the candidate, which boosted PGRN expression in GRN knockout mice as measured via mRNA levels in the cerebral cortex. It also decreased buildup of lipofuscin, an indicator of lysosomal dysfunction, and cut gene expression of proinflammatory cytokine TNF-alpha. PRL-006 upped PGRN levels in cerebral spinal fluid in nonhuman primates by way of what Oppenheimer analyst Jay Olson appreciated as “widespread transduction in the central nervous system [CNS] and periphery.” Also, PRL-006 has shown efficacy in human FTD-GRN-induced pluripotent stem cell-derived neuronal cultures. Prevail’s study will start in mid-2020, with some data on safety and biomarkers due by the end of the year or early in 2021. In his March 8 report, Olson maintained an outperform rating on the stock with a 12- to 18-month price target of $25.25, noting the 52-week range of $7.41 to $19.25.

Prevail deploys the same in-licensed AAV9 technology as Zolgensma (onasemnogene abeparvovec-xioi), enabling gene delivery to the CNS and broad distribution across the brain. In late May 2019, Zolgensma won FDA clearance to treat spinal muscular atrophy for Basel, Switzerland-based Novartis AG’s Avexis Inc. unit. Rockville, Md.-based Regenxbio Inc., which already had collected $100 million in milestone payments under an accelerated schedule from Avexis as part of the AAV9 licensing deal, reaped another $3.5 million for the approval and is eligible for $80 million more in milestone rewards if Zolgensma reaches $1 billion in cumulative sales.

With Prevail in the space is Alector Inc., of South San Francisco, which has AL-001, a humanized recombinant monoclonal antibody designed to boost PGRN, but its mechanism of action differs. AL-001 functions by shutting down the SORT1 degradation mechanism for PGRN and increasing the circulating half-life of the functional PGRN in the brain. The candidate, at the phase II stage, gained orphan drug designation in 2018. Another monoclonal antibody in Alector’s hopper for FTD-GRN is AL-101, at the phase I stage. In play, too, is Philadelphia-based Passage Bio Inc., which priced a $216 million IPO on Feb. 27. The company has gene therapy PBFT-02 in the works for FTD and expects to submit an IND in the second half of 2020. The bid by Passage involves a different serotype and strategy than Prevail, Oppenheimer’s Olson noted.

Regenxbio, Passage clash ahead?

About a third of FTD cases are inherited, and GRN represents one of three main genes implicated; the other two are MAPT and C9orf72. There’s no FDA-designated treatment and no cure for any of the FTDs. Some types of antidepressants, such as trazodone, may reduce the behavioral problems associated with the condition. Selective serotonin reuptake inhibitors such as citalopram, paroxetine or sertraline have worked for some people. Antipsychotic medications, such as olanzapine or quetiapine are sometimes used, but those should be prescribed “with caution in people with dementia due to the risk of serious side effects, including an increased risk of death,” the Mayo Clinic points out.

Lancet Neurology recently published research that combined findings from multiple observational studies in the U.S., Europe, Canada and Australia to examine age of onset and disease duration in FTD. Data came from 3,403 people from 1,492 families who had genetic mutations in one of three genes. Investigators used published papers as well as the Frontotemporal Dementia Prevention Initiative, which connects several natural history cohort studies. Included is the effort called ALLFTD, a rough acronym for the ARTFL LEFFTDS Longitudinal FTD study, which combines the data collection known as Advancing Research and Treatment for Frontotemporal Lobar Degeneration and another dubbed Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects. ALLFTD is jointly supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke. Results showed that MAPT-mutation people were younger at symptom onset and death than people in the GRN and C9orf72 groups. As the NIA pointed out, time of onset ranged from 17 years to the 80s for MAPT segment and from the 20s to the 90s for the other two groups, providing evidence that FTD can occur throughout adulthood.

Exchanges between two gene therapy drug developers have brought intrigue. In February, Passage disclosed receipt of a letter from Regenxbio attempting to extract a license for intellectual property (IP) for Passage’s AAVhu68 vector, claiming overlap with unspecified elements of the Regenxbio patent estate. SVB Leerink analyst Mani Foroohar said in a Feb. 21 report that the move was “reflective of Regenxbio’s increasingly assertive strategy to grow its patent business despite its core IP approaching expiry,” but the knife may slice another way. “While Regenxbio could secure a royalty stream from Passage, we note that this strategy opens Regenxbio’s patent claims to potential invalidation,” he wrote, adding that the filing by Passage “doesn’t tip their hand regarding their response” and he “see[s] potential litigation as high-risk for Regenxbio.”

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