The Hunt for a New Treatment Puts Huntington’s Disease in the Crosshairs: Ionis Pharmaceuticals and Roche Announce Two Clinical Studies to Begin by End of 2018

Frank Bennett



This week Ionis’ partner Roche announced their plans for two new clinical studies in people with Huntington’s disease (HD) to begin by the end of 2018 with patients enrolling by early 2019. To learn more about these plans, the Ionis partnership with Roche and the importance of finding a treatment for Huntington’s disease (HD), we interviewed Dr. C. Frank Bennett, senior vice president of research and franchise leader for the neurological programs at Ionis Pharmaceuticals for his thoughts about the latest developments in the Ionis/Roche Huntington program.

1. Two new clinical studies related to the development of IONIS-HTTRx, now known as RG6042, were announced at the 2018 European Huntington’s Disease Network (EHDN) plenary meeting in Vienna, Austria. Can you tell me a little more about the upcoming studies and what questions they are designed to answer?

For 25 years we have known what causes HD, the toxic mutant huntingtin (mHTT) protein. But until now, there has been little hope for a treatment that can address this underlying cause of the disease. Last year we completed a clinical study with IONIS-HTTRx (RG6042) in symptomatic HD patients who are early in their disease that demonstrated, for the first time, that we could reduce the production of the toxic mutant Huntington’s protein. Since December, our partner Roche has taken over development of the drug and leading the future studies.

This week, our partner Roche announced the next step in advancing this important new medicine with two new clinical studies: the HD Natural History study and the GENERATION HD1 pivotal study. Both are planned to begin by the end of 2018 with patients enrolling by early 2019.

The aim of the HD Natural History study is to further understand the correlation between mHTT protein in cerebral spinal fluid (CSF) and in other clinical measures of HD. Several studies have previously described the natural history of the disease. Many, however, have focused on specific clinical outcome measures or changes in brain volume using imaging. This 15-month study will include up to 100 symptomatic patients who are early in their disease and will be conducted at 17 sites in the U.K., U.S., Canada and Germany. This study will provide high-quality, longitudinal data to help inform patients and clinicians about the course of HD including well-validated clinical measures of HD, novel clinical outcomes, measurement of mHTT in CSF and the use of wearable devices to measure disease burden. Results from the HD Natural History study will provide valuable information in support of our Phase 3 Generation HD1 study.

The second study, the GENERATION HD1 study, is the world’s first Phase 3 study to measure the effect of a novel medicine, IONIS-HTTRx, that directly reduces the amount of mHTT in patients. The study will evaluate the long-term safety and efficacy of IONIS-HTTRx in a two-year global study that will enroll up to 660 patients exhibiting symptoms of Huntington’s Disease. The study will be conducted at 80 to 90 sites in 15 countries around the world.

2. How and why did Ionis get involved in HD research?

I have had a long-term interest in Huntington’s disease and thought that antisense technology may be a possible treatment when the gene that causes the disease was discovered. However, at the time we needed to advance our understanding of antisense technology and at the same time the basic research on HD also needed to be advanced. When we started working on HD about a decade ago, the team at Ionis working on neurological diseases was small – maybe three people. We were also collaborating with Dr. Don Cleveland and his lab at the Ludwig Institute, University of California San Diego, who were instrumental in the early preclinical work with this program. A lot has changed since then, including a partnership with Roche that has helped to produce what may potentially be the biggest breakthrough in neurodegenerative disease in the past 25 years.

However, what hasn’t changed is the excitement and passion our team has for this work. We’ve always had a team and company that believed targeting the production of mHTT with antisense technology may be a way of slowing or stopping HD progression. This is unique as other companies have been focused on creating therapies that mask the symptoms instead of targeting the cause of the disease. It was thought by many to be too difficult to target the root cause of HD, but we have demonstrated that it actually can be done.

3. Why did you choose to partner with Roche to bring IONIS-HTTRx to patients?

We considered several partners for our HD program. We ultimately chose to work with Roche because of their experience, their plan of action, and the team’s enthusiasm, commitment and the rapid pace in which we could together develop a disease modifying HTT targeting drug for HD patients. We couldn’t be happier with our collaboration and the progress of the program.

4. What would treating HD effectively with IONIS-HTTRx mean for the field of neurodegenerative diseases and patients suffering with these currently untreatable diseases?

It would be a historic moment for Huntington’s disease patients, their loved ones and the healthcare providers who treat and take care of HD patients. It also would be an important advance for the neurodegenerative field in general. Now that we have demonstrated that a targeted antisense therapy gets to its intended target in the brain for HD, the next step is to show that reducing a causative protein leads to clinical benefit in HD patients. If we can do this, the hope is that this will herald a new era for the treatment of neurodegenerative diseases, demonstrating for a second time that neurodegenerative diseases can be effectively treated with antisense drugs – SMA being the first. What we learn from Huntington’s disease may then be applied to finding treatments for those suffering with Alzheimer’s disease, Parkinson’s disease and ALS.