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Freeline Therapeutics Shows Promising Gaucher Disease Gene Therapy Data, Prepares for Phase III

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BALTIMORE – Freeline Therapeutics plans to launch a Phase III trial of its Gaucher disease type 1 gene therapy FLT201 next year on the back of compelling data from its ongoing Phase I/II GALILEO-1 study.

Additionally, the company anticipates selecting a candidate therapy for its Parkinson's disease program in the second half of this year, and to file an investigational new drug application for that indication with the US Food and Drug Administration next year.

In data presented at the American Society of Gene and Cell Therapy's annual meeting on Thursday, Ozlem Goker-Alpan, founder and chief medical officer of the Lysosomal and Rare Disorders Research and Treatment Center in Fairfax, Virginia, and lead investigator of the GALILEO-1 study, showed data suggesting that a single infusion of FLT201 has the potential for meaningful improvements in clinical outcomes over existing standard-of-care treatment for Gaucher patients.

Gaucher disease is a rare disorder resulting from deficiencies in the glucocerebrosidase (GCase) enzyme, which is encoded by the GBA1 gene and needed to metabolize the Gb-1 protein in the lysosome. These deficiencies result in a toxic accumulation of the substrate lyso-Gb1 in multiple organs, causing a wide range of often debilitating symptoms and reduced lifespan.

FLT201 is an investigational adeno-associated virus (AAV) gene therapy that contains a functional copy of the GBA1 gene that is under control of a liver-specific promoter. This gene encodes, though, a version of GCase called GCase-85 that is engineered to be more stable than the wild-type enzyme. With FLT201, the researchers hope to increase the expression of GCase in patients.

In the ongoing study, five adult patients have been dosed so far and data was available on four of them. These patients, ages 18 and older, each received a single infusion of the gene therapy and have been followed for 16 weeks to 38 weeks before entering long-term follow-up.

In all patients, the infusion led to high levels of plasma GCase expression for up to 32 weeks, leading to normalized levels of GCase activity in leukocytes by four weeks, which indicated an efficient cellular uptake of GCase-85 from plasma.

Lyso-Gb1 concentrations fell significantly in patients as early as four weeks following withdrawal of standard-of-care enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), and levels remained near the normal range for at least three months. Patients' hemoglobin and platelet levels stayed within normal ranges following infusion and after their last dose of ERT or SRT for up to 16 weeks.

All patients further showed improvements in bone marrow burden scoring, a semi-quantitative MRI scoring system for assessing the extent of bone marrow involvement in Gaucher disease.

In terms of clinical improvements, Patient 1, who was the first to be dosed and recently passed the eight months of follow-up mark, demonstrated clinically significant improvements in fatigue and the ability to carry out daily activities.

"This patient was a young adult who was significantly impacted by the disease," Goker-Alpan said. "He couldn't keep a job [because] he didn't have the energy, [wasn't] able to do usual activities, and felt lonely, frustrated, and was no longer socially active."

Following treatment by FLT201, she continued, this patient became able to hold a steady job and begin working out and putting on muscle mass.

No safety issues arose with FLT201. All patients tolerated it well, with no serious adverse events. Those adverse events that did arise, Goker-Alpan said, were mild or moderate in severity, with no dose-limiting toxicities observed.

Goker-Alpan said that in addition to its favorable safety profile, FLT201 is more stable in patient's bodies than wild-type GCase, which may also increase the therapy's tissue coverage compared to ERT.

"FLT201 is a promising new treatment for patients with type 1 Gaucher disease," Goker-Alpan said.

FLT201 is one of the Gaucher disease gene therapies furthest along in development.

Eli Lilly subsidiary Prevail Therapeutics is also pursuing an AAV-mediated gene therapy for Gaucher disease, which is currently in Phase I/II testing, while Avrobio paused its Gaucher disease gene therapy program last year amid plans to sell parts of its business to Novartis.

London-based Freeline expects to complete dosing in the GALILEO-1 trial this year and to report further results from the study in the second half of the year. From this, it hopes to establish the dose of FLT201 to be used in a pivotal Phase III trial, which the company plans to launch next year.

While FLT201 is the most developed candidate therapy in Freeline's pipeline, the company is also evaluating GCase-85 for use in treating GBA1-related Parkinson's disease.

Though mutations in the GBA1 gene are linked to Gaucher disease, they are also associated with Parkinson's and dementia with Lewy bodies, and Freeline is investigating a gene therapy encoding GCase-85 to reduce GBA1-related Parkinson's disease progression.

In preclinical studies, the molecule has so far demonstrated an approximately 20-fold greater activity relative to wild-type GCase in both in vitro and in vivo studies.

"Ultimately, if we establish proof of concept in this population [of] Parkinson's disease, we believe there could be potential in Lewy body dementia because the pathway is involved in the development of alpha synuclein aggregates, but that would be down the road, and we are not actively working on that yet," a company spokesperson said via email.