Homology Medicines is adding an immunosuppressive regimen to a phase 1/2 trial for its phenylketonuria gene therapy, hoping to quell FDA concerns that triggered a clinical hold in February.
The agency placed a hold on the clinical trial for HMI-102, called pheNIX, in February, asking for the company to modify risk mitigation measures after reviewing liver function test data from patients. The gene therapy is being tested in adults with phenylketonuria, a rare inherited disorder that causes an amino acid to build up in the body, sometimes leading to brain damage and other severe complications.
When Homology originally disclosed the clinical hold, it didn't include many details beyond stating that it was waiting for more information from the FDA. Now, the company has more information, thanks to a letter from the agency, according to a fourth-quarter earnings update released Wednesday afternoon. But submitting a revised risk mitigation strategy will take some time, the biotech warned.
The company plans to implement a new, shorter and more targeted immunosuppressive treatment that includes T-cell inhibitors and a steroid-sparing regimen to improve patient compliance. This regimen has already been added to Homology’s phase 1 pheEDIT trial, which launched in the fourth quarter to study the gene-editing treatment HMI-103.
Adding T-cell inhibitors to treatment that uses adeno-associated virus capsids, the most common gene therapy delivery mechanism, has proven effective at dampening the immune response that is a known risk of AAV gene therapies. Homology said the patients who experienced elevated liver biomarkers have all recovered and no hospitalizations were required.
With this new risk mitigation strategy in the works, Homology said it will need more time to submit to and receive feedback from the FDA. The study protocol for pheNIX will need to be amended as well. The company will provide an update when the strategy is shored up with the agency.
A readout from the pheNIX trial was originally expected mid-year 2022, according to RBC Capital Market analysts. While RBC believes the hold is likely to be lifted, expectations for the data release are "modest." Patients who had elevated liver function tests are likely to be non-responders, RBC said. Homology had previously lowered the dose for HMI-102 in addition to upping the steroid dose.
"Threading the needle between efficacy (mixed so far) and safety (liver tox) is becoming increasingly difficult," the firm said.
As for the immunosuppressive strategy Homology is implementing, RBC said it makes sense; companies such as Rocket Pharmaceuticals and Freeline Therapeutics have done the same in their gene therapy studies. RBC noted that Novartis also saw a similar liver toxicity concern with its now-approved medicine Zolgensma.
As Homology worked to address the clinical hold, interest in the pheEDIT study has picked up. Fifteen sites have already been selected and several are being evaluated. Homology plans to provide an update on the program by the end of the year. HMI-103 is a gene-editing therapy, whereas HMI-102 is a gene therapy. Homology also has an investigational gene therapy in development for Hunter syndrome called HMI-203.
Homology is up against BioMarin in phenylketonuria, although the larger company’s gene therapy was similarly placed on clinical hold in September. As of February, BioMarin was still working on a plan to address the FDA’s concerns about a preclinical mouse model that showed treatment with BMN 307 rendered mice in one arm of the early study immunodeficient.
The agency has asked BioMarin for additional information on the theoretical risk of cancer in humans, which the company said will take “several quarters” to provide.