Homology Medicines has announced the next steps for its gene therapy and gene editing clinical programs for the treatment of phenylketonuria (PKU).
“We ended 2020 with positive data from the dose-escalation phase of the world’s first PKU gene therapy clinical trial, pheNIX, and validation of both our PKU gene therapy and gene editing programs with an equity investment from Pfizer, a leader in genetic medicines,” Arthur Tzianabos, PhD, Homology’s president and CEO, said in a press release.
The company now is focused on patient recruitment for advancing and completing the Phase 2, dose expansion part of the pheNIX Phase 1/2 study (NCT03952156), which is testing its investigational gene therapy HMI-102 in adults with PKU, and whose results are expected “by the end of the year,” Tzianabos said.
The company also plans to launch a similar Phase 1/2 trial to evaluate HMI-103, its gene editing candidate for children with PKU, by late this year, Tzianabos said in a webcast.
Homology’s gene therapy and gene editing candidates for PKU are designed to target its underlying cause — insufficient activity of the phenylalanine hydroxylase (PAH) enzyme due to mutations in the PAH gene.
Since PAH is required to break down the amino acid phenylalanine (one of the building blocks of proteins) into another amino acid, tyrosine, PAH deficiency results in the toxic buildup phenylalanine throughout the body, causing intellectual disability and other serious health problems.
Both investigational therapies, meant to be given once via an into-the-vein injection, use a modified and harmless adeno-associated virus — AAVHSC15 — to deliver a functional copy of the PAH gene to cells in the liver.
However, the copy delivered through HMI-102 is not integrated in the patient’s DNA — lingering outside the cell’s nucleus (where the genetic material is stored) — while that of HMI-103 is meant to replace the mutated PAH gene copy through a natural DNA repair process called homologous recombination.
Given that liver cells divide more rapidly during childhood, a healthy gene copy siting outside the cell’s nucleus likely would be lost in the cell division process, losing its therapeutic effect. As such, HMI-103 is thought to be the most adequate candidate for a potential cure of PKU in children.
HMI-102 represents the world’s first gene therapy for PKU in clinical trials and it received orphan drug and fast track designations in the U.S. and orphan drug status in Europe; all meant to speed its development and review.
Promising preclinical data showing that HMI-102 resulted in a rapid and sustained increase in PAH activity and reduction of phenylalanine levels prompted the launch of the two-part pheNIX study to evaluate the therapy’s safety and effectiveness in up to 21 adults, ages 18–55, with PKU.
The Phase 1, dose-escalation part of the trial tested three doses (low, mid, and high) of HMI-102 in six patients (two per dose) to determine the optimal doses to be tested in the Phase 2, dose-expansion part, which will include a larger number of patients.
Based on results from the initial part, Homology selected the mid-dose and a dose between the mid- and high-doses for the next phase. The company expects the latter dose to reduce phenylalanine levels while limiting the amount of steroids — used to suppress immune responses against the virus — needed with the high dose.
In pheNIX’s second part, additional patients will be assigned randomly to receive one of the two doses of HMI-102, or no intervention (treatment delayed control group), for 24 weeks (nearly six months), after which all participants will be given the therapy.
Its main goals are to assess the proportion of patients achieving a sustained blood phenylalanine concentration of 360 micromoles per liter or lower (target levels), and safety measures. Secondary goals include changes in phenylalanine levels and in the phenylalanine/tyrosine ratio, as well as the proportion of patients achieving target levels at any point during the trial.
Patients’ diets also will be monitored more closely during this phase to better control factors that can influence the study’s results, Tzianabos noted in the webcast.
According to the company, this portion of the trial has the potential to be converted into a registrational trial that supports applications to regulatory agencies seeking HMI-102’s approval.
In the webcast, Tzianabos reinforced that the upcoming Phase 1/2 trial of HMI-103 likely will have a similar design to pheNIX, with a dose-escalating phase followed by a randomized, dose-expansion portion that also will include a delayed treatment control group.
He also noted that with this study, HMI-103 will become the first homologous recombination-based, gene editing therapy in clinical studies.
“We are also leveraging our technology platform to expand our pipeline and plan to name another development candidate focused on a new therapeutic indication in 2021,” Tzianabos said in the release.