New Tools May Help Assess Impact of Future AADC Therapies

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Researchers have developed and validated new tools to help evaluate health-related quality of life, or HRQoL, in people with aromatic l-amino acid decarboxylase (AADC) deficiency.

These tools can be used to assess the cost-effectiveness ratio of future treatments, according to the team.

The study, “A Discrete Choice Experiment to Derive Health Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency,” was published in the journal Patient Related Outcome Measures.

AADC deficiency, caused by mutations in the DDC gene, is characterized by intellectual disability, muscle weakness, and problems in the autonomic nervous system that controls involuntary body functions. Oculogyric crises, or involuntary upward eye movements, also are common among people with AADC.

Patients also may show behavioral problems such as mood swings, irritability, and excessive crying.

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‘Life-changing’ Gains Evident in Children Given PTC-AADC Gene Therapy

While AADC deficiency remains without approved disease-modifying therapies, several gene therapy approaches have shown promise in clinical trials. Gene therapies — in which physicians treat a disorder by inserting a gene into a patient’s cells — have the potential to halt or slow disease progression by delivering a working copy of the faulty gene to cells.

One such therapy, PTC-AADC, is perhaps closest to potential approval. Developed by PTC Therapeutics, the gene therapy — given one time in a single dose — was previously shown to result in sustained reductions in motor and non-motor symptoms in children with the disease. It is currently being reviewed for approval in Europe.

A decision is expected later this year, and PTC plans to submit, by the end of 2021, a similar regulatory application seeking the therapy’s approval in the U.S.

With a potentially imminent approval of the first disease-modifying treatment for AADC deficiency, there is an urgent need for tools that help assess a therapy’s cost-effectiveness. Such determinations are key in garnering support for treatment funding decisions — particularly in countries with publicly funded health care systems, such as the U.K.

Capturing patients’ health-related quality of life — known as HRQoL — is “critical to understanding the impact of this condition on the individual affected and in evaluating the cost-effectiveness of treatments aimed at AADC deficiency,” the researchers wrote.

However, the disease’s rarity, and the fact that its symptoms mainly appear in early infancy, challenge the assessment of HRQoL through ratings from patients or their parents/caregivers.

In cases such as these, HRQoL data can be estimated using health utilities — cardinal values of health states that may be experienced by patients. These values range from zero, indicating death, to one, signifying full health.

Developing health utilities involves two main steps: first, defining a set of health states and disease aspects of interest, and then valuing them to determine their weight.

Researchers at PTC, the University of East Anglia’s Norwich Medical School, and the York Health Economics Consortium, both in the U.K., now set out to generate — for the first time — health utilities for AADC deficiency through an online, discrete choice experiment, or DCE.

This type of survey is increasingly used in healthcare to elicit preferences from responders without directly asking them to state their preferred options.

The DCE was based on relevant health states and disease aspects (or symptoms) identified in a previous study by the same team, and based on published literature and input from patients, caregivers, and clinicians.

Responders were presented with 10 choice scenarios in which they were asked to imagine being a parent or caregiver of a child with AADC deficiency. The survey asked them to choose between two sets of six symptoms with varying levels of severity.

In each choice scenario, respondents are forced to make a trade-off between their preferred and less-preferred symptoms, as presented. One of the scenarios was specially designed to evaluate choice consistency.

The six previously identified symptoms used in the analysis were mobility, muscle weakness, oculogyric crises, feeding difficulties, cognitive impairment, and screaming/crying. Each was divided into levels of severity.

Mobility levels included bedridden, head control, sitting unsupported, standing with assistance, walking with assistance, and walking unassisted. Three levels were selected for the other symptoms to reflect mild, moderate, and severe symptoms. The exception was feeding difficulties, which was divided into patients being unable or able to feed themselves.

The online survey was completed by a representative sample of the U.K. population, in a total of 1,596 people, most (85.2%) living in England. The participants’ mean age was 43.8 years, more than half (58.3%) were women, and 28.3% reported having children aged 16 years or younger.

Most (70.7%) gave consistent responses, while 27 participants (1.7%) always chose the same alternative for every choice set and were therefore excluded from the final analysis.

Results showed that the health utility values dropped as the severity of symptoms increased, emphasizing the value of treating such symptoms.

The most important factor for responders was avoiding constant screaming/crying, followed by a change between bedridden to walking unassisted, and a change from severe cognitive impairment to none.

The fact that the lowest health utility value was associated with screaming/crying, more so than the bedridden state, suggests that participants “may have been rating parental/caregiver health-related quality of life (HRQoL) as part of the evaluation, instead of that of the child alone,” the researchers wrote.

This may also reflect “a general lack of familiarity or possible lack of understanding of symptoms such as oculogyric crises (OGC), compared to the relative familiarity of physical limitations and sign such as screaming,” they added.

Overall, “this is the first study to derive health utilities for AADC deficiency symptoms using a large sample drawn from the general population,” the team wrote, adding that the results will be used to “enable improvements in health-related quality of life to be considered in an economic evaluation of [PTC-AADC] for AADC deficiency.”