Roche Halts Phase III Trial of Tominersen, an Antisense RNA Therapy for Huntington's Disease

Compiled by River

To address Huntington’s disease, Roche entered into a patent licensing agreement with Ionis as early as 2017 for a novel antisense therapy targeting the protein associated with Huntington’s chorea. Now, following early safety warnings and under the directive of the data monitoring committee, Roche has announced the discontinuation of a Phase III clinical trial.

Roche stated that it has halted dosing in the Phase 3 clinical trial of tominersen, an antisense drug targeting huntingtin protein and its mutants, following recommendations from the Independent Data Committee “based on the potential benefit and risk profile of the investigational therapy for study participants.”

Roche licensed tominersen (formerly IONIS-HTTRx) in 2017, paying Ionis Pharmaceuticals a $45 million licensing fee. Prior to halting administration, Roche had enrolled 791 patients across 18 countries in the GENERATION HD1 Phase III clinical study. This double-blind, placebo-controlled study evaluated tominersen in patients with Huntington’s disease for over 25 months, with participants randomized to receive either 120 mg of the drug every two months, 120 mg every four months, or placebo.

Roche also discontinued the open-label extension study named GEN-EXTEND, which employed the same high-dose and low-dose regimens. The company stated that it would further update the development plan for the drug after additional evaluation of the data, and intended to continue monitoring safety signals in patients through the study’s trial window.

Roche pointed out that the committee’s decision did not involve new safety risks. This will alleviate some concerns, allowing another Phase I clinical study to proceed to later-stage trials. In March last year, Roche suspended the study, named GEN-PEAK, after researchers identified two cases of intrathecal catheter-related infections unrelated to the drug. The study later resumed, and Roche stated that there are currently no plans to halt it.

Tominersen is an antisense oligonucleotide (ASO) drug that binds to huntingtin mRNA and facilitates its degradation via the RNA degradation pathway, thereby reducing the expression of toxic proteins and potentially modifying disease progression. In a Phase I/II clinical trial, the drug significantly reduced levels of mutant huntingtin protein in cerebrospinal fluid; however, current trial results indicate that this reduction did not translate into clinical efficacy. As no new safety concerns have emerged, the primary limitation appears to be insufficient efficacy. Similar to Spinraza, another blockbuster ASO for spinal muscular atrophy (SMA) developed by Ionis, Tominersen requires intrathecal administration.

Reference Source:

1.Roche cuts bait on late-stage study of Huntington's med tominersen, an Ionis import with prior safety flags

2.Roche Suspends Early-Stage Huntington's Disease Trial After Catheter-related Infections