FDA Grants LX1001 Fast Track Designation for Alzheimer Disease


The FDA has granted a fast track designation to LX1001 as a potential treatment for adult patients with APOE4-associated Alzheimer disease.

R. Nolan Townsend, chief executive officer of LEXEO Therapeutics

R. Nolan Townsend

The FDA has granted a fast track designation to LX1001 as a potential treatment for adult patients with apolipoprotein E4 (APOE4)-associated Alzheimer disease, according to a statement from LEXEO Therapeutics, the developer of the AAV-mediated gene therapy.

The fast track designation is meant to facilitate and expedite the development of treatments for serious conditions that fill an unmet need. With the Alzheimer designation, LEXEO will benefit from more frequent interaction with the FDA. Additionally, if clinical studies are successful, the company will be eligible for an accelerated approval, priority review, and the ability to submit a rolling biologic license application.

“The fast track designation granted by the FDA will expedite the development and review of LX1001 and we look forward to working closely with the Agency moving forward as we continue to advance this transformational gene therapy,” R. Nolan Townsend, chief executive officer of LEXEO Therapeutics, said in a statement. “While other treatments in development focus on the pathogenesis of Alzheimer’s disease, LX1001 is the first investigational gene therapy designed to correct the underlying genetics of the disease thereby addressing the most significant risk factor for developing Alzheimer’s disease.”

LX1001 is a single dose gene therapy that is administered as an intracisternal injection. The agent utilizes a serotype rh.10 AAV that expresses the cDNA for the APOE2 gene and is targeted toward APOE4 homozygotes in the central nervous system/cerebral spinal fluid (CSF). The goal of the gene transfer therapy is to convert APOE4 homozygotes to dual APOE2-APOE4 alleles on chromosome 19.

A phase 1 study (NCT03634007) is currently exploring LX1001 for adult patients with APOE4 homozygote of Alzheimer disease. The primary goal of the study is currently focused on the safety of the gene therapy, with a secondary outcome of uncovering a maximum tolerated dose. The trial plans to enroll 15 participants with mild cognitive impairment.

The open-label trial will consist of 3 cohorts, each exploring a different dose of the gene therapy in the CSF. In the first cohort of the study, patients will receive LX1001 at 5.0 x 10^10 gene copies (gc)/mL CSF. In the second cohort, the treatment will be administered at 1.6 x 10^11 gc/mL CSF. The third cohort will examine LX1001 at 5.0 x 10^11 gc/mL CSF.

The company noted that recruitment was on schedule, with all 15 individuals expected to be enrolled by the end of the year. Initial clinical data from the trial are expected in the second half of 2021, according to LEXEO.

The startup gene therapy company LEXEO was launched in January 2021, following $85 million in series A funding. The initial drug pipeline includes 3 clinical stage therapies for monogenic diseases, with an additional 15 indications also under consideration. These medicines were primarily developed at Weill Cornell Medicine and the company was founded by Ronald G Crystal, MD, who is a professor and chairman of Weill Cornell’s Department of Genetic Medicine and Director of the Belfer Gene Therapy Core Facility. Crystal will act as the company's scientific advisor.

“I am excited to work with LEXEO Therapeutics to move our extensive academic portfolio into clinical development and ultimately bring it to patients,” said Crystal. “LEXEO’s AAV-mediated gene therapy programs have the potential for broad applicability across a range of therapeutic indications, and in a single company pipeline present an opportunity for the natural evolution of gene therapy from rare genetic conditions to more common diseases.”

In addition to LX1001, the company is also exploring LX2006, an IV-administered gene therapy, for cardiomyopathy associated with Friedreich ataxia. Additionally, LX1004, which is administered to the CNS, was explored in a phase 1/2 study for patients with CLN2 Batten disease. Findings from this study were published in December 2020 in Science Translational Medicine showing a slower loss of gray matter volume in 4 of 7 children treated with the gene therapy. Overall, LX1004 elicited a 42.4% decline of motor and language function compared to Weill Cornell natural history cohort (P <.04).

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