Experts Seeking Tools to Assess Effectiveness of Targeted Huntington’s Therapies

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by Alice Melão |

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measuring targeted therapies

Improved measures to accurately determine the effectiveness of treatments targeting Huntington’s disease are necessary, according to clinical neurologists and Huntington’s specialists.

The editorial, “Improved metrics for Huntington’s disease trials,” reflects on recent advances made for the development of targeted agents that can effectively change the course of Huntington’s disease. Written by Kat Arney, a London-based science writer, It was published recently as part of the Nature Outlook: Huntington’s disease supplement in the journal Nature.

For many years the scientific community was focused on developing strategies that could provide patients with a certain degree of symptom relief. However, recent discoveries have opened new possibilities of engineering products that can attack the root cause of the disease.

While these advances have brought hope to the Huntington’s community, they also have raised questions about how to accurately evaluate the potential and effectiveness of new therapies to truly modify the course of the disease.

For other diseases, such as cancer, the effectiveness of therapies can be assessed more easily in clinical trials by changes in the size of tumors or amount of malignant cells. However, establishing ways to definitively demonstrate improvements in progressive neurological conditions is not as straightforward.

To date, researchers have used the Unified Huntington’s Disease Rating Scale (UHDRS), a system developed in 1996 by the Huntington Study Group. This scoring system allows physicians to evaluate a person’s overall physical and neurological fitness.

“We’ve used the UHDRS for many years,” Blair Leavitt, MD, consulting neurologist at the University of British Columbia in Vancouver, Canada said in the Nature editorial. “You can see reliable progression over a certain period, but we need better ways to measure it.”

Symptoms such as movement difficulties or cognitive impairment can vary in severity from day to day, making it difficult to tell whether a treatment is having an affect on the disease or if the patient is just having a good or bad day. Also the subjective nature of the UHDRS system makes it more susceptible to the power of the placebo effect, Leavitt said.

However, despite its limitations, the UHDRS has been used as the primary measurement tool of choice in clinical trials for two decades.

“Objective, quantitative measures will give us more sensitivity,” said Leavitt, who, in collaboration with Sarah Tabrizi, MD, a clinical neurologist at University College London, and other researchers conducted the TRACK-HD trial in 2012, in which they followed more than 100 Huntington’s patients for more than two years.

The ‘composite UHDRS’

During the trial, researchers used a broad panel of evaluation methods to determine disease progression biomarkers, including brain imaging and cognitive, motor, and psychiatric assessments.  Results of the  study, together with results from other group studies, allowed researchers to generate a new measurement for future trials.

Known as the “composite UHDRS,” it comprises some of the original assessments in addition to further cognitive, motor, and physiological tests that can evaluate the progression of Huntington’s disease more accurately.

“Huntington’s is a slowly progressive disease, but we showed that we could measure progression in almost everybody over just two years,” Tabrizi said.

Researchers agree that the composite UHDRS is an improvement on the standard disability scale. Still, the scientific community continues to seek biomarkers that can be used to define changes in Huntington’s disease progression.

The most obvious candidate would be the mutated huntingtin protein, which is the hallmark of Huntington’s disease. But other markers have been proposed recently, such as the neurofilament light (NfL).

Different tests to measure these elements in the cerebral spinal fluid, blood, and even saliva have been developed. Although they have demonstrated great potential to predict the onset of symptoms and track disease progression, some limitations need to be overcome.

Still, these biomarkers are only surrogate measures for the real events that progressively damage the brain. A more direct assay would involve imaging mutant huntingtin in the brain to determine whether treatments are able to reduce it.

This is not yet possible but researchers have been developing new ways to track biomarkers and patients’ symptoms in real-time. Radioactive “flags” to identify the mutant protein, wearable devices to measure gait, cognitive function or sleep patterns, are just a few systems being investigated.

While all these theories are being developed, the need for improved effectiveness measures and new primary endpoints in clinical trials has not yet been fulfilled. To validate any new measures it is necessary to confirm they are indeed accurate to track disease progress. However, without accurate scales to determine effectiveness, this task may become a challenge.

“It’s a circular problem. We have exciting new measures and therapies, but we don’t have a good way of comparing them to prove that they work,” Leavitt said. “Our main clinical endpoint is still the old UHDRS, which isn’t that great. We’re at the point now where we need an effective therapy to show how things respond.”

As Huntington’s disease enters an era of targeted molecular treatments, such as with antisense oligonucleotides, Tabrizi believes that researchers owe it to those affected by the disease to design the best possible trials to test those therapies.

“We’ve spent years studying the natural history of the disease to develop our armamentarium for these trials, and we’re just waiting for really good drugs,” she said. “Huntington’s is a terrible disease with a huge unmet need, and patients and their families desperately want treatments that work. We cannot afford to mess this up.”