RG6042 on Horizon as a Potential Treatment for Huntington Disease

Scott Schobel, MD, MSc, associate group medical director and clinical science leader for the IONIS Roche HTT Rx program at Roche Genentech neuroscience

Scott Schobel, MD, MSc

In January, the first patient was enrolled in the phase 3 trial GENERATION HD1 (NCT03761849), studying RG6042, the first therapy in pivotal trials designed to target the underlying cause of Huntington disease by lowering production of mutant huntingtin.

Recently, Roche Pharmaceuticals updated the design of the study after a review of the 9-month open-label extension data that supported exploration of less frequent dosing. Study arms involving treatment with the study drug or placebo every 2 months will remain the same; however, the study arm that tests monthly treatment with RG6042 will be replaced with one that tests a less frequent dose of once every 4 months.

To learn more about the GENERATION HD1 study and the investigational therapy, NeurologyLive spoke with Scott Schobel, MD, MSc, associate group medical director and clinical science leader for the IONIS/Roche HTT Rx program at Roche/Genentech neuroscience.

NeurologyLive: Can you speak to the trial design of GENERATION HD1 and why these criteria were chosen?

Scott Schobel, MD, MSc: First, we are excited to be moving forward this phase 3 trial. In and of itself, this phase 3 trial represents an important step forward for the HD community.

The GENERATION HD1 trial (Global EvaluatioN of Efficacy and Safety of Roche/Genentech AnTIsense OligoNucletide for Huntington’s Disease) will evaluate the efficacy and safety of RG6042 in patients with manifest HD over a period of 25 months. Manifest HD describes the stage at which a person begins to see motor symptoms of HD, like chorea, that make day-to-day tasks more difficult.

Study Design

In this study, participants will be randomized to 1 of 3 treatment study arms (all administered intrathecally): 120mg RG6042 every 2 months, 120mg RG6042 every 4 months (placebo during alternating procedures) or placebo every 2 months. The study is also double-blinded.

Notably, this study design was recently amended following preliminary 9-month data from the open-label extension (OLE) of the phase 1/2a study, which show effects on lowering mutant huntingtin (mHTT) protein levels in the cerebral spinal fluid (CSF) that support the exploration of less frequent dosing. Based on the totality of the data, including safety and tolerability, there appears to be no overall advantage to treatment monthly versus every 2 months. As such, the original study arm that tested monthly treatment will be replaced with one that tests a less frequent dose of once every 4 months (every 16 weeks). The phase 3 GENERATION HD1 study arms involving treatment every 2 months and placebo remain the same.

While it is not yet appropriate to draw conclusions about clinical efficacy or longer-term safety, we are pleased that there are now data to support these study design changes and the exploration of less frequent dosing. We believe this will make study participation less demanding for patients, families and healthcare providers.

Primary and Secondary Endpoints

To demonstrate RG6042’s effectiveness in GENERATION HD1, we worked closely with the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) to select 2 primary endpoints. In the U.S., the primary endpoint will be measured by the Total Functional Capacity, or TFC, which tracks unilateral functional decline well when measured over longer time periods. This will be the primary endpoint in the U.S. only, as the FDA requires the primary endpoint measure changes that are clinically meaningful, including measures which focus on daily functional abilities.

Outside of the U.S., the primary endpoint will be measured using the composite Unified Huntington's Disease Rating Scale (cUHDRS), which is able to track motor, cognitive, and overall functional decline and clinically meaningful change in the manifest HD patient population intended for the planned phase 3 study.

Enrollment Criteria:

The trial is designed to investigate the efficacy and safety of intrathecally-administered RG6042 in adult patients, 25—65 years old with clinically diagnosed manifest HD. This study excludes patients with juvenile HD and those patients with prodromal or pre-manifest HD, as we need to first prove RG6042’s efficacy in adult patients, where symptom changes are most easily measurable and where changes over time can be best tracked in the manifest HD population to see if the drug works or not.

This global study will enroll up to 660 patients with manifest HD at 80—90 sites in approximately 15 countries around the world. There are several sites open already in the U.S. and Canada, with the first patient enrolled in January 2019, and we’re quickly starting up in the United Kingdom and Spain. More information on these clinical trial sites can be found here.

How long are the treatment periods? Do you have an estimated completion date?

The GENERATION HD1 study will evaluate the efficacy and safety of RG6042 treatment administered once every two months or every four months over a period of 25 months. We are aiming to complete the GENERATION HD1 trial in 2022 and will provide further updates on the status of this program as soon as we can.

What makes GENERATION HD1 exciting as a trial?

There is a significant need for new treatments in HD. Right now, there are no treatments approved that can prevent, slow or stop progression of the disease—only treatments that can help manage symptoms. Our intention with GENERATION HD1 is to determine if RG6042 will slow or stop the progression of HD in a broader HD study population.

While RG6042 is not a cure for HD, we are encouraged by the program’s early clinical trial results from the phase 1/2a study and the ongoing OLE study, and this phase 3 trial is an exciting next step for this community.

What makes RG6042 a unique therapy?

RG6042 is the first therapy in development designed to target the underlying cause of the disease by limiting production and lowering the levels of the specific toxic protein that breaks down the nerve cells in the brain, which may affect a person’s everyday functions such as mobility and thinking.

What has RG6042 shown that suggests it could potentially be approved by the FDA?

While early clinical trial findings are encouraging, we still have a lot to learn about the benefits and risks of RG6042, which can only formally be shown in a longer, controlled clinical study. As noted, preliminary 9-month data from the OLE of the phase 2/2a study showed effects on lowering mutant huntingtin protein levels in the cerebral spinal fluid that support the exploration of less frequent dosing. We look forward to sharing more detailed results of the OLE of the phase 1/2 a study at upcoming scientific meetings.

We are excited that RG6042 has been granted orphan drug designation by the U.S. FDA and PRIME designation by the EMA.

Anything else you wanted to add/mention?

In addition to GENERATION HD1, we also have 2 other studies underway in HD.

First, all 46 participants from the phase 1/2a study of RG6042 enrolled in a 15-month open-label extension study that assesses the safety and tolerability of longer use of RG6042 and provides further data in support of GENERATION HD1. Those who got the placebo originally now get the medicine.

We also have a 15-month, observational Natural History Study underway, which is evaluating up to 100 patients with early-manifest HD in the U.S., Canada, Germany and the U.K. Initial sites have opened, and the first patients have enrolled. This study—called the HD Natural History Study (NHS) — is being conducted without a drug and will gauge the natural progression of HD and help us understand the role of the mutant huntingtin protein in HD. That in turn will allow us to better evaluate the clinical outcomes and digital clinical outcomes in the ongoing study of RG6042.

Our No. 1 priority is this community of HD families who are directly impacted by the research we have underway. Together, Roche and Genentech are committed to ensuring the needs and priorities of HD families are heard and considered throughout our clinical development program. We are genuinely excited about the potential of this molecule, and we will continue to work closely with the advocacy community to share updates when we have them.

Scientific progress is only possible with collaboration and participation, and we are grateful to the patients and family members participating in clinical research, as well as everyone supporting them in the broader HD community.