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Huntington’s Antisense Therapy Enters Phase III

In April, researchers reported that an antisense oligonucleotide (ASO) for Huntington’s disease lowered mutant huntingtin levels in cerebrospinal fluid. In this follow-up, we examine what’s happened in the field since then.

After years of preclinical development and a successful phase I/IIa trial, the first-ever pivotal study of a huntingtin-lowering drug is starting.

The phase III trial of the ASO once known as IONIS-HTTRx — now called RG6042 after Roche Pharmaceuticals bought the drug from Ionis — will investigate whether the drug can slow or improve symptoms for people with Huntington’s disease.

Huntington’s disease is caused by cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. In rodent models, suppressing HTT production delays disease progression and reverses disease phenotype. RG6042 is designed to bind to the huntingtin mRNA in a specific sequence that leads to its degradation, resulting in less mutant huntingtin protein being made.

The ASO is the first potential treatment to have lowered levels of mutant huntingtin in humans successfully, but whether it can slow disease progression is unknown.

In the next few weeks, Roche/Genentech will start GENERATION-HD1, a phase III trial of RG6042, studying 660 patients ages 25 to 65 with manifest Huntington’s disease. Co-primary endpoints include 2-year change from baseline in the Composite Unified Huntington’s Disease Rating Scale and in Total Functional Capacity score. Seventeen secondary outcomes that include clinical measures as well as biomarkers will be tracked as well.

“It is hoped that the phase III study in a larger patient population will determine if RG6042 can slow or stop the progression of Huntington’s disease in adults and further characterize the safety profile,” a Roche spokesperson told MedPage Today.

The 2-year study will enroll patients across 80 to 90 sites in about 15 countries, evaluating RG6042 administered by injection either once a month or once every 2 months, compared with placebo. “The U.S. and Canadian trial sites will be listed imminently,” the spokesperson added.

Meanwhile, all 46 patients at the nine sites involved in the phase I/IIa study have enrolled in an open-label extension study to help assess the long-term safety and tolerability of RG6042.

Other Antisense Trials

RG6042 is not the only huntingtin-lowering therapy being studied for Huntington’s disease, noted George Yohrling, PhD, senior director of mission and scientific affairs of the Huntington’s Disease Society of America in New York.

Wave Life Sciences also is testing antisense drugs in two ongoing clinical studies, PRECISION-HD1 for Huntington’s patients who carry a single-nucleotide polymorphism (SNP) at the rs362307 location, and PRECISION-HD2 for those who carry a SNP at rs362331. These trials are using a more allele-specific approach, Yohrling said: unlike RG6042, the Wave drugs target just mutant huntingtin, leaving the healthy form relatively intact.

The trade-off is that not every Huntington’s patient may be suitable for this treatment. But combined, the two Wave drugs — known as WVE-120101 and WVE-120102 — have the potential to treat over two-thirds of Huntington’s patients, trial researchers estimated.

Currently, WVE-120101 and WVE-120102 are in phase Ib/IIa studies. “We hope to see at least top-line data from these trials in 2019,” Yohrling told MedPage Today.

RNAi Approaches

Also possible in 2019 may be a trial with an RNA interference (RNAi) therapy for Huntington’s disease, Yohrling added: “This is expected to come from uniQure, which is using a viral-mediated approach.”

The uniQure agent, called AMT-130, is intended to inhibit production of mutated huntingtin protein by delivering microRNA into cells via an adeno-associated virus. Once inside the cell, the microRNA can bind to the messenger RNA molecule for huntingtin to inhibit the protein’s expression. Voyager Therapeutics also is pursuing RNAi approaches to treating Huntington’s disease, Yohrling noted.

Previously, uniQure showed that AMT-130 improved motor coordination and survival in mouse models and that the therapy could penetrate the brain and spinal cord when injected in a primate. The company recently completed a safety and toxicology study of AMT-130 in non-human primates; the findings will be incorporated in an Investigational New Drug application that uniQure plans to submit to the FDA before the end of 2018.