Intra Erythrocyte Dexamethasone in the treatment of Ataxia Telangiectasia

Aim of this project is to provide a safe and efficacious treatment (EryDex) of the neurological symptoms to patients affected by Ataxia Telangiectasia (AT), a rare progressively disabling and life-shortening genetic disease; currently no therapy is available on the market. To achieve this objective EryDel s.p.a developed EryDex, an investigational product used to load dexamethasone sodium phosphate (DSP) into autologous erythrocytes, creating the EDS end product (EDS-EP), which is infused into the patient. EryDel has just designed a worldwide pivotal Phase III study to obtain marketing authorization in EU and USA. The protocol and the regulatory path to registration has been discussed and agreed with FDA, EMA and the other National Regulatory Authorities involved and adapted to cope with COVID pandemic emergency.
Aside of the clinical study, an international patient registry has been established by the patients’ association AT Society, with the aim of creating and maintaining a comprehensive clinical database of patients with AT.
The AT NEST, the first scale to assess symptoms specific to AT patients, coordinated by the AT center at the John’s Hopkins University, has been tested in the study and will represent the 1st scale assessing specific AT’s areas of impairment. Preliminary data analysis shows A-T NEST widens the description of a patient’s neurologic status given by the presently adopted ICARS scale.
Investigations into the mechanisms of action of EryDex on neurological symptoms of AT has been performed in conjunction with the University of Urbino, Italy. The patient’s DNA samples collected permitted to correlate miniATM expression to patients’ well-being at basal condition, at the time of screening visit, supporting the present knowledge on the Ataxia Telangiectasia causes.

The study (IEDAT-02-2015) has been designed as a multi-center, one-year, randomized, prospective, double blind, placebo-controlled, phase III trial, to assess the effect of two non-overlapping dose ranges of EryDex, administered by IV infusion once per month, on neurological symptoms of patients with AT. Following completion of 6 months in the trial, all patients who completed the assessments as designed continued in an additional 6-month, double-blind, placebo-controlled extension, to collect information on the long-term safety and efficacy of the trial treatments.
The study involved 22 study sites in 12 different countries: 90 local operators have been trained, about 10000 EryKit_01 for patient treatment have been assessed, 175 patients have been enrolled, 1773 treatments have been delivered. Despite the COVID emergency, 132 patients reached six months of treatment (efficacy evaluation step) and 108 twelve months of treatment (safety evaluation step).
The data analysis conducted after the six-month efficacy evaluation period showed significant efficacy of the treatment on the group of patients 6 to 9 years old when compared with placebo. No clinically meaningful differences in Severe Adverse Events (SAEs) were observed between treated groups and placebo. A request to FDA for a Type B Pre-NDA Meeting has been submitted.
Along the clinical study, a total of 474 blood samples were handled and MiniATM was quantified by PCR. The target was detected in almost 50% of tested specimens. Statistical analysis revealed a collation between some ICARS scores and the amount of miniATM at screening visit. Dexamethasone effects on miniATM and patients’ outcomes are still under investigation.
A-T Nest scale was validated based on taped neurologic exams from 477 patients, ranging in age from 5 to 62 years. Based on data collected in the clinical study A-T nest have shown a convincing statistical correlation with full ICARS and derived scales; a multivariate analysis shows A-T NEST cluster Learning and Power domains isolate from the overall data variability, improving the description of a patient’s neurologic status.

The project has the ambition to bring a satisfactory treatment for a rare disabling disease as no treatment is currently available. This ambition, to provide treatment for unmet medical need, is also supported by the complementary project objectives pursued during the study, i.e. the creation of an AT EU patient registry, the potential validation of a molecular biomarker of treatment efficacy, and the validation of the new AT NEST scale specific for the symptoms of AT.
The project’s results enhance the further understanding of the disease potentially opening to new treatment opportunities. The objective of creating an AT EU registry has been achieved, thanks to the participation of the UK A-T Society coordinating the initiative. EryDel decided to continue funding the maintenance of the Registry as a useful tool supporting the patients and investigators community.
The sample collection for miniATM measurement and time points of AT-NEST assessments to coincide with other efficacy endpoints in the phase III study, and the clinical study database, will allow consolidating information for further statistical relationship analysis of parameters of interest. Research on these two tasks will continue after the end of the project, thanks to the progresses achieved with its conduction.
The project, therefore, advances science, creates the opportunity for the development of new therapies by the introduction of meaningful tools to monitor and understand the pathophysiology and clinical presentation of AT, and delivers a treatment for children with AT for whom no treatment is available today. Market approval is being requested to the regulatory agencies.

Periodic Reporting for period 4 - IEDAT (Intra Erythrocyte Dexamethasone in the treatment of Ataxia Telangiectasia)

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