Preliminary results from patients who were given low and medium doses of HMI-102 suggest that the treatment is well-tolerated and lowers the levels of phenylalanine, the compound that accumulates in patients’ bodies and leads to PKU. The results support the continuation of the study and the testing of higher doses in patients.
PKU is caused by mutations in the PAH gene which prevent or reduce the production of an enzyme called phenylalanine hydroxylase (PAH). This enzyme is responsible for converting the amino acid phenylalanine (Phe) into tyrosine (Tyr) and its absence or deficiency causes severe intellectual disability.
Medicines approved for PKU — including Kuvan (sapropterin dihydrochloride) and Palynziq (pegvaliase-pqpz), both produced by BioMarin Pharmaceutical — work by lowering phenylalanine levels either by stimulating the residual activity of PAH or by directly breaking down phenylalanine.
Homology Medicines is developing two genetic approaches to restore PAH enzyme production: gene editing to correct the defective PAH gene and gene therapy to deliver a working copy of this gene into patients’ cells.
Both approaches are delivered by a vector platform that consists of a non-infectious version of the adeno-associated virus (AAV) derived from human blood stem cells — called AAVHSC.
The open-label, randomized, dose-escalation, Phase 1/2 pheNIX trial (NCT03952156) is the first gene therapy trial for PKU and plans to enroll up to 21 adults, 18 to 55 years old, at five sites in the U.S. During the trial, up to three ascending doses of HMI-102 will be tested. Each participant receives a single dose, injected into the vein (intravenously).
As of Dec. 2, two patients had received a low-dose (cohort 1) of HMI-102, and one patient had received a mid-dose (cohort 2).
Early data from all three patients indicated that HMI-102 was well-tolerated, with no treatment-emergent adverse events. Of note, in the patient given a mid-dose, HMI-102 treatment led to a dose-dependent reduction in phenylalanine, with an increase in tyrosine, and a drop in the Phe/Tyr ratio (a clinically relevant diagnostic measurement for PKU).
Specifically, the patient experienced a reduction in Phe of 35% at week 1 and 48% at week 4, and an increase in Tyr levels of 72% at week 1 and 85% at week 4. The patients in cohort 1 did not show a reduction in Phe from weeks 10 to 12.
Overall, these preliminary data show that the therapy is safe and can be effective in restoring PAH enzymatic activity.
“We believe that the initial efficacy from Cohort 2 suggest HMI-102 is delivering the PAH gene that produces the functional PAH enzyme and restores the biochemical pathway that converts Phe to Tyr,” Albert Seymour, PhD, chief scientific officer of Homology Medicines said in a press release.
“We are pleased with the data with HMI-102, as this trial represents the first time one of our novel, human-derived AAVHSCs has been administered to patients, and provides initial evidence supporting our vector platform,” he added. “The safety results observed and trial design allowed us to quickly execute on our plan to dose-escalate, and our wide safety margin provides potential for further dose-escalation.”
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