Antisense Oligonucleotides

Dr. Jeff Carroll

Fresh Updates from First Huntingtin Lowering Study Publication-May 7, 2019
By Dr. Carroll

Hot off the presses – New publication gives more details about the results of Ionis and Roche’s safety study with a Huntingtin-lowering ASO

Today saw the publication of the first manuscript describing a huntingtin lowering trial in Huntington’s disease patients. This study, sponsored by Ionis and Roche, provided clear evidence of researchers’ ability to safely reduce mutant huntingtin protein in the spinal fluid. An overview of these results has previously been shared, but this manuscript provides important new information about the results of this remarkable trial. What’d we learn?

Huntingtin lowering: a little background

Huntington’s disease (HD) is caused by a single mutation in a gene we refer to as the HD gene. Like most genes, the HD gene is used by cells as instructions to create a little cellular machine called a protein, which we call huntingtin. The genetic mutation that causes HD also changes this protein, which we refer to as mutant huntingtin.

While HD symptoms are complex, it has pretty simple genetics – if you inherit a single mutant copy of the HD gene from either your mother or father, you will develop HD. Since we know that one has to inherit a mutant HD gene to develop HD symptoms, could we interfere with the process of making the mutant huntingtin protein? If so, would that slow or prevent the progression of Huntington’s disease?

That general approach, which we refer to as huntingtin lowering has been a major focus of HD researchers for a number of years, and several companies are pursuing this target. Two companies – Ionis and Roche Pharma – are running the most advanced program, in collaboration with a number of academic researchers around the world led by Prof. Sarah Tabrizi, University College London.

We’ve previously discussed the early results of the first human study by Ionis and Roche here, subsequently updated here and here.

Excitingly, today saw the release of the first official manuscript describing these huntingtin lowering efforts in HD patients, and it provides new information about the first trail. This trial was focused on understanding whether treatment with a huntingtin lowering drug called an antisense oligonucleotide or ASO is safe.

Endpoints, Endpoints, Endpoints

As in any clinical trial, this study included a number of endpoints. Endpoints are just the target, or goal, that you want your study to accomplish. In future HD trials, this might include things like improved movement or thinking. But for a new drug that has never been tested in people, the endpoint is always safety, safety, safety.

Formally, researchers say that safety is the primary endpoint of the study. This just means it’s the sole criteria we’ll use to judge whether the trial is a success or failure. If the drug turns out to be unsafe, the trial fails. If there are no safety concerns, the study is a success.

While we’d obviously like be able to tell whether a drug is safe and whether it helps HD symptoms at the same time, we can’t achieve both goals in the course of a single study. This is because it takes large numbers of participants – many hundreds – to tell whether a drug is influencing HD symptoms. But for a safety study, we want to treat the smallest reasonable number of people to reduce the number of people exposed to the risk of testing a drug for the first time.

While trials usually have one primary endpoint, researchers are curious about other possible impacts of their drug on HD-related changes. These other measurements are called secondary endpoints – this term helps us remember that the main, or primary, goal of the trial is to determine safety, but we have many secondary measurements we’re interested in examining.

This study included a large number of secondary endpoints, focused on participants’ HD symptoms, brain scans and lab tests to measure specific markers in the blood and spinal fluid. The new manuscript is exciting, because it’s the first chance we’ve had to look at the raw data produced in the study. The interesting results of some secondary endpoints are discussed below, but it’s important to remember that determining safety was the primary goal of everyone working on this trial.

To read the full article, go to:  https://en.hdbuzz.net/273