RG6042, Potential DMT in Phase 3 Trial, Named Orphan Drug in Japan

A potential treatment called RG6042, which target all forms of the mutant huntingtin protein (mHTT) — the underlying cause of Huntington’s disease, has been named an orphan drug by the Ministry of Health, Labour and Welfare (MHLW) in Japan, Chugai Pharmaceuticals announced.

The treatment, a potential first disease-modifying therapy for Huntington’s, is now a Phase 3 trial expected to end in 2022.

Orphan drug status in Japan, which grants priority review, is reserved for medicines to be used by less than 50,000 people, and which add significant value as a potential treatment of serious diseases with a need for new therapies.

“Huntington’s disease is designated as an intractable disease in Japan, and only symptomatic treatment is available for this disease,” said Yasushi Ito, MD, PhD, Chugai’s Executive Vice President, in a press release. 

RG6042, formerly known as IONIS-HTTRx, was initially developed by Ionis Pharmaceuticals and later on acquired by Roche. It was granted orphan drug status in Europe and the U.S. in 2015. (Chugai is a member of the Roche group.)

The potential therapy was also granted PRIME (PRIority MEdicines) designation by the European Medicines Agency (EMA) in 2018. 

RG6042 is currently being tested in a worldwide Phase 3 clinical trial (NCT03761849), called the GENERATION HD1. This study is evaluating the efficacy, safety, biomarkers effects of RG6042, compared with placebo, in up to 909 people with Huntington’s disease. The trial is still enrolling at select in Europe, Canada, and elsewhere; more information can be found here.

Patients are being treated with RG6042 by intrathecal (spinal cord) injection once every eight or 16 weeks.

The trial’s primary outcomes will be changes in Composite Unified Huntington’s Disease Rating Scale (cUHDRS), a uniform assessment of the disease’s clinical features and course that includes motor, cognitive, and behavioral tests. The Total Functional Capacity (TFC) score, which measures a patient’s daily abilities, will also be evaluated.

“We continue the ongoing clinical study in cooperation with Roche to deliver RG6042 to patients with Huntington’s disease, as the first disease-modifying drug,” Ito added.

RG6042 is an antisense oligonucleotide (ASO), or gene silencing therapy, designed to bind to faulty HTT mRNA — the genetic blueprint for making the abnormal huntingtin protein — targeting it for degradation. 

The potential of targeting HTT mRNA was suggested as early as 2000, when researchers demonstrated that deleting mutant HTT in mice reversed Huntington’s motor symptoms. 

A Phase 1/2a clinical trial (NCT02519036), testing RG6042 in 46 adults with early stage Huntington’s, showed a reduction in the levels of mHTT in the cerebral spinal fluid by up to 60%. An important finding was that as the dose of RG6042 was increased, levels of abnormal huntingtin protein in the participants’ spinal fluid decreased.

Although this trial was not designed to assess function, an analysis found that lower mHTT levels associated with improvements in motor, cognitive, and functional scores.