Homology Therapeutics, HMI-102 (Gene-therapy) in adult subjects with Phenylketonuria (PKU)

Gene Therapy Clinical Study in Adult PKU (pheNIX, Phase 1/2)

Detailed Description: 
This study will evaluate the safety and efficacy of HMI-102 gene therapy in adult subjects with PKU due to PAH deficiency. Subjects will receive a single dose of HMI-102 administered intravenously. Up to 3 dose levels of HMI-102 may be investigated in this study. At a given dose level, a minimum of 2 subjects will be enrolled and dosed. The dosing of the first two subjects will be staggered. Following the evaluation of data from the first 2 subjects in a cohort, a decision can be made to either escalate to the next dose level or expand the cohort at the selected dose level. If the cohort is expanded, additional subjects will be randomized to receive HMI-102 or a concurrent delayed treatment control arm. Subjects in the delayed treatment control will be eligible to receive HMI-102 after 24 weeks.

Sponsor: Homology Medicine 

Experiment Design:
HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene to cohort 1, 2 and 3 with different dose of HMI 102

Primary Outcome Measures:
  • Incidence and severity of treatment-emergent adverse events (TEAE) and serious TEAEs
  • Subjects with at least one TEAE or serious TEAE
  • Incidence of sustained plasma Phe concentration of ≤360 μmol/L at 24 weeks post-dose 
  • Subjects achieving a sustained plasma Phe concentration ≤360 μmol/L at 24 weeks post-dose

Secondary Outcome Measures:
  • Plasma Phe Concentration 
  • Change in plasma Phe concentration at 24 weeks
  • Incidence of achieving a plasma Phe concentration to ≤360 μmol/L
  • Subjects achieving plasma Phe concentration ≤360 μmol/L at each time point during the study

Other Outcome Measures:
  • Phenylketonuria Quality of Life Questionnaire (PKU-QOL) 
  • Change in PKU-QOL

Homology Medicine Encouraging Initial Clinical Data from its pheNIX Gene Therapy Trial for PKU (Updated December 2, 2019)

  • Two patients had received investigational HMI-102 gene therapy in Cohort 1 (low-dose) and one patient in Cohort 2 (mid-dose). 
  • Preliminary safety data from Cohorts 1 and 2 showed HMI-102 was well-tolerated. 
  • Efficacy data from the first patient in Cohort 2 indicated a dose-response effect with an observed reduction in phenylalanine (Phe) levels from baseline, increase in tyrosine (Tyr), and reduction in the Phe/Tyr ratio, suggestive of increased enzymatic activity. 
  • The first patient dosed in Cohort 2 experienced a reduction in Phe of 35% and 48% from baseline at Weeks 1 and Week 4, respectively, as compared to Cohort 1, which generally did not show a reduction in Phe through Weeks 10 and 12. 
  • The first patient dosed in Cohort 2 also showed increases in Tyr levels of 72% and 85% at Weeks 1 and Week 4, respectively, suggesting increased PAH enzyme activity.
  • In addition, the patient experienced a 62% and 72% reduction in the Phe/Tyr ratio from baseline to Weeks 1 and 4, respectively.


Key Findings from Molecular Characterization of Precise in vivo targeted gene integration in human cells using AAVHSC15 

- Single I.V. administration of the AAVHSC15-based gene editing construct resulted in the efficient integration of the human PAH gene in human hepatocytes in the murine model
-Gene integration was precise without unintended de novo mutations analyzed by next-generation sequencing
-AAVHSC15-mediated gene editing occurs via homologous recombination
-No inverted terminal repeats (ITRs) integrations using long-read sequencing
- Approximately 6% of Gene integration efficiency was observed at the DNA level (characterized using ddPCR and 3-primer generation sequencing 
(PlosOne: 2020, https://doi.org/10.1371/journal.pone.0233373)

Key Results from Nonclinical Murine Model following a Single Intravenous Administration of AAVHSC15-PAH

  • Sustained Correction of a Murine Model of Phenylketonuria following a Single Intravenous Administration of AAVHSC15-PAH
  • Maintained on a phenylalanine-containing normal chow diet
  • Sustained reduction in serum phenylalanine and normalized tyrosine levels for the lifespan of Pahenu2 mice.
  • Restoration of Brain levels of phenylalanine and the downstream serotonin metabolite 5-hydroxyindoleacetic acid
  • Darkened coat color of mice after treatment, indicating restoration of the phenylalanine metabolic pathway.

Homology Therapeutics
Ahmed et al Methods & Clinical Development (Mol Therapy) 2020, vol 17
Chen et al Plos One 2020