NeuroVoices: Dirk Thye, MD, on Challenges and Progress in Treating Ataxia Telangiectasia With EryDex

EryDex (Quince Therapeutics) is an automated outpatient bedside technology to ex-vivo encapsulate dexamethasone sodium phosphate given into patient’s red blood cells, which are then re-infused. This allows for the circulation of controlled, slow release, low doses of dexamethasone over the subsequent several weeks following treatment. EryDex is part of a larger technology platform, the EryDex System, that is capable of expansion to other drugs or biologics, including enzyme replacement therapy. In June 2024, the FDA granted fast track designation for the EryDex System as a treatment for patients with ataxia-telangiectasia (A-T).¹

Recently published data from the phase 3 ATTeST study (NCT02770807) revealed that EryDex did not meet its primary end point of change in the modified International Cooperative Ataxia Rating Scale (mICARS) among pediatric patients with A-T following 6 months of treatment.^2,3For context, the modified intention-to-treat (mITT) population in this trial comprised of 164 participants (low-dose group, n = 56; high-dose group, n = 54; placebo group, n = 54). At the conclusion of the 6-month treatment period, investigators reported no differences identified in regard to change in mICARS score in the low-dose group (least squares mean difference, -1.37; 95% CI, -2.932 to 0.190) or the high-dose group (-1.40; -2.957 to 0.152; P = .0765) compared with the placebo group.

Following the news of publication, Dirk Thye, MD, chief executive officer and chief medical officer at Quince, had a conversation with NeurologyLive^® to discuss the specific challenges in using the ICARS scale as a primary efficacy end point in the ATTeST study, and how it has been refined for future research. During the interview, he also talked about how the variability in age and disease progression among patients with A-T affected the outcomes of the study, and why the 6 to 9-year-old age group is now the focus of the phase 3 NEAT study (NCT06193200). Further into the discussion, Thye spoke about the potential broader implications of the study’s results for the future treatment and management of A-T, particularly regarding long-term safety and disease modification.

NeurologyLive: Could you elaborate on the challenges encountered in achieving the primary efficacy endpoint and how these might inform future research on EryDex?

Top Clinical Takeaways

The ATTeST study faced significant challenges because of the lack of reliable biomarkers and variability in disease progression, leading to the need for refined measurement tools in future studies.
The 6 to 9-year-old age group with A-T has been identified as a critical population for studying the efficacy of EryDex, given their rapid disease progression.
The ATTeST study demonstrated a favorable safety profile for EryDex, differentiating it from traditional corticosteroid treatments and offering hope for long-term management of A-T.

Dirk Thye, MD: There were a few challenges that we encountered in achieving the primary efficacy endpoint in ATTeST – learnings from which we have applied to our current phase 3 NEAT study of EryDex.

One challenge centers on the lack of reliable and quantitative biomarkers of cerebellar symptoms and disease progression for the rare pediatric neurodegenerative disease, A-T. The ICARS scale, a modification of which was used as the primary efficacy endpoint in the ATTeST study, is based on detailed description of cerebellar symptoms. However, progression of different symptoms/components of this scale over time is not well understood as larger studies of disease progression measured by the ICARS scores are not available. There also is no homogeneity among patients with A-T when it comes to symptom progression. This necessitated the use of controls, which may be challenging to do over a longer period. We allowed all our control patients to switch to active treatment with the open label extension study following completion of the ATTeST study.

The ATTeST study enrolled patients with A-T that were 6 years or older. The study did not utilize a targeted age range for the primary patient population, which we believe contributed to challenges in achieving the primary efficacy endpoint. Patients with A-T ages 6 to 9 experience the most rapid clinical decline, while the progression tends to slow in patients ten and over. Studying the patient population of only 6 to 9 years olds in our current phase 3 NEAT study allows us to better understand the treatment effect compared to placebo, especially over a short duration of treatment such as six months.

Finally, in addition to the impact of the COVID19 pandemic, we encountered ATTeST trial challenges inherent in the rarity of the disease – resulting in a need to conduct the study across five different continents and in 22 centers to enroll the required number of patients. While this was time and resource consuming, we were able to confirm that the delivery of intra-erythrocyte dexamethasone sodium phosphate using our point-of-care system is a procedure that can be successfully adopted in health care centers around the world.

We have applied learnings from ATTeST and worked with the FDA to further refine the measurement scale and are utilizing the rescored modified ICARS (RmICARS) — which primarily focuses on posture and gait disturbance – in our current phase 3 NEAT study of EryDex in 6 to 9 year-old patients with A-T.

Given the adverse events reported, how do you perceive the safety profile of EryDex in this trial compared to traditional corticosteroid treatments?

The main takeaway of the ATTeST study was the excellent safety profile of EryDex, which was well-tolerated with no serious safety concerns. Reported adverse events did not mimic those seen with standard corticosteroids and were very similar between treated patients and controls.

We are encouraged with observations of continued growth in height of pre-pubertal children who received EryDex for up to 2 years, and a few patients who received EryDex for more 10 years. Additionally, we observed no excessive weight gain, Cushingoid appearance, hyperglycemia, hypertension, hirsutism, or behavioral adverse effects – essentially all the adverse effects that make steroids a challenging agent to use in children or adults for longer periods of time.

What potential implications do the findings of this study have for the treatment of A-T, particularly in the younger age subgroup identified for future research?

ATTeST showed positive effect of EryDex treatment in a subset of patients with A-T ages 6 to 9 – the age range that typically experiences rapid clinical decline – which is now the primary population for our current phase 3 NEAT study. We believe clinicians view these data as highly encouraging as we work together to bring a safe and efficacious treatment to underserved patients with A-T.

The ATTeST trial was the largest prospective study investigating treatment for A-T, data from which added meaningfully to the research of this rare pediatric neurodegenerative disease. In addition to studying the efficacy of EryDex, which has the potential to be the first approved A-T treatment, this study provided important additional data on biology, course of disease, and tools used in efficacy assessment of this devasting disease.

We also remain committed to following EryDex’s possible effects not only on neurological functioning, but also on preservation of lung function or modifications in the risk of hematologic malignancies that are very common in children with A-T as they age, in addition to exploring the potential role EryDex may have in disease modification.