The investigative therapy IONIS-HTTRx effectively reduced levels of the protein responsible for Huntington’s disease in early-stage patients, according to the findings of an ongoing Phase 1/2 clinical trial.
The results also revealed that IONIS-HTTRx is generally safe and well-tolerated by patients, further demonstrating its potential as an alternative therapeutic option for this population.
Ionis Pharmaceuticals will present the trial’s results at the 2018 Annual Meeting of the American Academy of Neurology (AAN) in Los Angeles, California, April 21-27. The presentation, titled “Effects of IONIS-HTTRx in Patients with Early Huntington’s Disease, Results of the First HTT-Lowering Drug Trial,” will be made by Sarah J. Tabrizi, PhD, University College London.
Huntington’s is characterized by mutations affecting the HTT gene that leads to the production of abnormal and toxic mutant huntingtin (mHTT) protein. Accumulation of this protein ultimately promotes gradual destruction of brain cells, leading to deterioration of mental abilities and physical control.
IONIS-HTTRx, also known as RG6042, is a disease-modifying treatment called antisense oligonucleotide (ASO) that was designed to target and destroy all forms of the huntingtin protein, including the mutated one. This strategy raises the possibility of treating all Huntington’s patients, regardless of their individual HTT mutation.
Results from preclinical studies have shown that the investigative drug could suppress huntingtin protein production in mouse models of the disease. Also, it could effectively delay disease progression and even reverse disease symptoms.
“A comprehensive drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT [protein] production,” researchers wrote.
Supported by these positive preclinical data, the investigative therapy was evaluated in the Phase 1/2 study (NCT02519036) in patients with early-stage Huntington’s disease.
The study enrolled 46 adult patients who were randomized to receive one of four doses of IONIS-HTTRx or a placebo. The therapy was administered once a month by injection in the spinal canal, followed by four months without treatment.
All tested doses were found to be safe and well-tolerated with only mild adverse effects, which were found to be unrelated to the treatment. No patients needed to discontinue the treatment prematurely.
IONIS-HTTRx was stable and could de detected in the plasma and cerebral spinal fluid of patients, which was in accordance with the preclinical data.
Importantly, IONIS-HTTRx could significantly reduce the levels of mHTT protein detected in cerebral spinal fluid samples in a dose-dependant manner. Results recently presented at the 13th Annual HD Therapeutics Conference showed that patients experienced a reduction of 40 percent, and up to 60 percent, of the mHTT protein.
Under a licensing agreement between Ionis and Roche, an open-label extension trial (NCT03342053) for the 46 participants who completed the Phase 1/2 trial will be initiated soon to evaluate the long-term safety and effectiveness of the investigative drug.