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Università degli Studi di Brescia – Facoltà di Medicina e Chirurgia. U.O. di Neuropsichiatria Infantile - Spedali Civili - Brescia. Actualité dans le traitement pharmacologique de l’Ataxie Télangiectasie. Current therapeutic strategies for the treatment of Ataxia-Telangiectasia.

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Università degli Studi di Brescia – Facoltà di Medicina e Chirurgia

U.O. di Neuropsichiatria Infantile - Spedali Civili - Brescia

Actualité dans le traitement pharmacologique de l’Ataxie Télangiectasie

Current therapeutic strategies

for the treatment of Ataxia-Telangiectasia

Roberto Micheli, MD


ATAXIA-TELANGIECTASIA e Chirurgia

  • Definition: rare autosomal recessive multisystemic disorder.

  • Incidence:1: 300.000 – 1: 40.000 in newborns.

  • Etiology: biallelic mutations in the ATM gene (Chr 11q22-23), that encodes a

  • protein kinase which plays a pivotal role in DNA repair, targeting hundreds of substrates involved in cell cycle checkpoints.

  • Pathogenesis:DNA-repair defect syndromes.

  • In neuronal cells, unrepaired DNA tend to accumulate and eventually cause the death of Purkinje cells.

  • Oxidative processes, induced by release of oxygen radicals from the mitochondria, is a major contributor to neurodegeneration.

  • Patients with ataxia telangiectasia are especially prone to oxidative stress, because the ATM protein by itself is a scavenger of reactive oxygen species.


Ataxia telangiectasia clinical manifestations
ATAXIA-TELANGIECTASIA e Chirurgia : CLINICAL MANIFESTATIONS


ATAXIA TELANGIECTASIA: e Chirurgia

DIAGNOSIS

  • High serum alpha-fetoproteinlevel (95% pt.).

  • Chromosomal instability (chromosome breakage, inversions and translocations > chromosomes 7 and 14).

  • Increase in spontaneous and radiation-induced chromosomal breaks.

  • Reduced/absent IgA levels (70%) and ATM protein (98%)

  • Proven molecular diagnosis of A-T based on ATM gene mutations and/or ATM protein deficiency (Western Blot).


ATAXIA-TELANGIECTASIA: e ChirurgiaPROGNOSIS

  • Progressive neurodegeneration.

  • Dramatically affect the quality of life: wheelchair dependency toward the second decade of life.

  • Prognosis is poor: life expectancy is around 25 years, with a wide range. Pulmonary infections and cancer are the two most common causes of death in patients with A-T.


Ataxia telangiectasia neurological dysfunction
ATAXIA-TELANGIECTASIA e Chirurgia : NEUROLOGICAL DYSFUNCTION

  • Cerebellarataxia (100% pt.)

  • Generally the presentingsymptom; progressive.

  • Narrowgaitataxia.

  • Neckposturing (anterior or posterior bending).

  • Extrapyramidalinvolvement (70% pt.)

  • Disabling, in some cases prevalent manifestations.

  • Hyperkineticmovementdisorders / Parkinsonianfeatures.

  • Eyemovementabnormalities (80% pt.)

  • Oculomotorapraxia.

  • Significantmorbidity, including readingimpairment.

SM axonal peripheral neuropathy

Cognitive profile


ATAXIA-TELANGIECTASIA: e Chirurgia

TREATMENT

  • No established therapy is currently available

  • Treatments are symptomatic and supportive only

  • Therapy and prophylaxis of infections:

  • Early antibiotic treatment and continuous prophylactic therapy ;

  • Vaccines (S. pneumoniae;N. meningitidis; H. Influenzae);

  • Regular injection of immunoglobulins.

  • Rehabilitation and supportive care:

  • Physical, occupational and speech/swallowing neurorehabilitation.

  • Adaptive equipment, including braces, walkers, orthotics, wheelchairs and computers

  • X-ray exposure should be limited to times when it is medically necessary!


POTENTIAL THERAPEUTIC STRATEGIES e Chirurgia

  • Use of antioxidants

  • Mutation-targeted therapies:

  • Correction of ATM gene function by read-through of premature termination codons (aminoglycosides)

  • Correction of ATM splicing mutations with antisense morpholino oligonucleotides


POTENTIAL THERAPEUTIC STRATEGIES e Chirurgia

Oral Betamethasone


POTENTIAL THERAPEUTIC STRATEGIES e Chirurgia

Oral Betamethasone


A Randomized Trial of Oral e ChirurgiaBetamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012


A Randomized Trial of Oral e ChirurgiaBetamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012

Study design summarizing the double-blind crossover trial of BETA versus placebo


A Randomized Trial of Oral e ChirurgiaBetamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012

Association between the change in ICARS total score and plasma level of BETA in the ITT population.

  • Higher BETA plasma levels corresponded with greater decreases in ICARS total score and corresponding improvement in ataxia symptoms.

  • All 13 but 2 patients (patients 8 and 13) had improved ataxia symptoms during the BETA treatment.


A Randomized Trial of Oral e ChirurgiaBetamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012

Data are medians (ranges). Thirteen ITT A-T patients are included.

In this trial, BETA reduced ICARS total score by a median of 13 points in the ITT population and 16 points in the PP population (median percent decreases of ataxia symptoms of 28% and 31%, respectively).


A Randomized Trial of Oral e ChirurgiaBetamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012


POTENTIAL THERAPEUTIC STRATEGIES e Chirurgia

Dexamethasone Sodium Phosphate Encapsulation in Human Erytrhtocites

To avoid theside effects of long-term administration of steroidswe utilized a method for encapsulation of dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EryDex method) allowing slow release of dexamethasone for up to one month after dosing


POTENTIAL THERAPEUTIC STRATEGIES e Chirurgia

Dexamethasone Sodium Phosphate Encapsulation in Human Erytrhtocites


Erydex system
EryDex System e Chirurgia

LOAD Dexamethasone INTO RED BLOOD CELLS BY MEANS OF DEDICATED CE MARKED SYSTEM

2

WITHDRAWAL

OF

50 ml OF WHOLE

BLOOD FROM THE PATIENT

1

3

AUTOLOGOUS LOADED RBC REINFUSION TO THE PATIENT


Intra-Erythrocyte Infusion of Dexamethasone Reduces e Chirurgia

Neurological Symptoms in Ataxia Teleangiectasia Patients:

Results of a Phase 2 Trial


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

STUDY OBJECTIVES:

A single-arm, open-label, 6-month Phase II clinical trial, conducted in

22 AT patients (mean age 11.2 years) in two Italian centres (Brescia and Roma)


Inclusion criteria

Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

INCLUSION CRITERIA:

  • Neurological signs of AT

  • Patients in autonomous gait or helped by a support

  • Proven molecular diagnosis of AT

  • Males and females aged >3 years

  • Body weight >15 Kg

  • Plasma levels of CD4+ lymphocytes/mm3 ≥500 (for patients aged 3-6 years) or ≥200 (for patients older than 6 years)

  • Written IC to participate from the patient or from the parents (or from a legal acceptable representative)


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

EXCLUSION CRITERIA:

  • Current or previous neoplastic disease

  • History of severe impairment of the immunological system

  • Chronic conditions representing a contraindication to the use of steroid drugs

  • Noncompliance with the study protocol

  • Have participated in any other investigational trial within 30 days from Screening Period

  • Any previous steroid use within 30 days before starting ERY-DEX

  • Have any other significant disease that in the Investigator’s opinion would exclude the patient from the trial

  • Females of childbearing potential who were pregnant, breast-feeding or were not using adequate contraceptive methods


Study disposition

screened SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

n = 26

enrolled

n = 22

screening failure

n = 4

completed study

n = 18

premature terminations n = 4

CD4+ lymphocytes below the limit n = 3

concomitant disease

n = 1

CD4+ lymphocytes below the limit n = 1

(protocol violation)

consent withdrawal

n = 1

dropouts due to AEs n = 2

Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

STUDY DISPOSITION:


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

ASSESSMENTS

  • International Cooperative Ataxia Rating Scale (ICARS)

  • Vineland Adaptive Behavior Scales (VABS)

  • Investigator’s Global Assessment (IGA)

  • Ocular motility (measured by an ‘ad hoc’ form)

  • Physical examination, vital signs, ECG and laboratory tests


screening Visit SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

(days 30→0)

Infusion

Infusion

Infusion

Infusion

Infusion

Infusion

V1

V2

V3

V 4

V5

V6

V7

ICARS

ICARS

ICARS

ICARS

six months study (6 treatments)

3 weeks

Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

STUDY DESIGN:

22 enrolled (ITT)

4 drop-outs

18 completed (PP)

26 screened


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

TOTAL SCORE : ICARS

Mean ICARS Total Score and Changes from Baseline (V1) by Visit

(ITT Population)

*Comparison vs. baseline (V1) using Wilcoxon non-parametric test.


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

PRIMARY END-POINT: ICARS

I 1. WALKING CAPACITIES

I 2. GAIT SPEED

I 3. STANDING CAPACITIES, EYES OPEN

I 4. SPREAD OF FEET IN NATURAL POSITION WITHOUT SUPPORT, EYES OPEN

I 5. BODY SWAY WITH FEET TOGETHER EYES OPEN

I 6. BODY SWAY WITH FEET TOGETHER EYES CLOSED

I 7. QUALITY OF SITTING POSITION

POSTURE AND GAIT DISTURBANCE

ICARS

TOTAL

SCORE

II 08. KNEE-TIBIA TEST: decomposition of movement

II 09. ACTION TREMOR in the HEEL-TO-KNEE Test

II 10. FINGER-TO-NOSE TEST: decomposition and dysmetria

II 11. FINGER-TO-NOSE TEST: intention tremor

II 12. FINGER-FINGER TEST: action tremor and instability

II 13. PRONATION SUPINATION altering ovements

II 14. DRAWING the Archimedes spiral

KINETIC FUNCTIONS

SPEECH DISORDERS

III 15. DYSARTHRIA: fluencyofspeech

III 16. DYSARTHRIA: clarityofspeech

IV 17. GAZE EVOKED NYSTAGMUS

IV 18. ABNORMALITIES OF THE OCULAR PURSUIT

IV 19. DYSMETRIA OF THE SACCADE

OCULOMOTOR DISORDERS


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

SECONDARY END-POINTS

VABS

Statistically significantimprovements were noted in adaptive behavior (total score, p<0.0001), with significant increases at 3 and 6 months (p<0.0001).

Ocular Motility

Statistically significant improvementswere noted at 3 and 6 months (p=0.021 and p=0.002).

IGA

Statistically significant improvements in global health status were noted at 3 and 6 months (p=0.003 and p=0.005, respectively).

  • Safety

  • Most Frequent AE: Cough (6), Fever (4), Otitis (3), Bronchitis (2);

  • Most events represent recurrencies of medical illness patients had experienced prior to the study;

  • None of these adverse events was considered related to the study medication


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

DATA ANALYSIS REVEALED:

  • a wide interindividual variability in the variations of ICARS scores

  • (range -16 +9)

  • a substantial variability in the patient-specific DSP-erythrocyte loading (the mean dose ranged from 0.7 to 18.6 mg per bag)

  • a greater proportion of loaders (mean doses of DSP of 5 mg or more) among females rather than males (80% vs 27%)

  • the efficiency of the erythrocytes loading was related to greater improvement  responders females > males (73% vs 18%)

  • patients with milder basal ICARS score (42 +- 1) experienced a better improvement (mean 11.3 points)


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

Exploratory analysis for dose response


Chronic SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients treatment with ERY-DEX

Long term benefit confirmed with compassionate treatment up to 18 months


Evaluation of Effects of Intra-Erythrocyte Dexamethasone SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients


STEROIDS in AT SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

  • Cerebellar ataxia improved

  • Oculomotor apraxia improved

  • Extrapyramidal involvement not improved

  • Peripheral neuropathy  not improved


TREATMENT OF SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

EXTRAPYRAMIDAL SYMPTOMS

Drugs that increase dopamine in the striatum

treat parkinsonism but

exacerbate hyperkinetic movements,

and vice versa


POTENTIAL THERAPEUTIC STRATEGIES SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

Amantadine Sulfate


POTENTIAL THERAPEUTIC STRATEGIES SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

Amantadine Sulfate

  • Open label, prospective study

  • 17 children (F:M=5:12; mean age 11.2 years)

  • 8 weeks, 3 visits, amantadine dosage gradually titrated up to 7 mg/kg/day

  • Neurological assessement: International Cooperative Ataxia Scale (ICARS);

    Unified Parkinson Disease Rating Scale (UPDRS);

  • Abnormal Involuntary Movement Scale (AIMS);

  • Severity of the neurological involvement: ad hoc AT score (sum of the 3 scales)


POTENTIAL THERAPEUTIC STRATEGIES SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

Amantadine Sulfate


POTENTIAL THERAPEUTIC STRATEGIES SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

Amantadine Sulfate

  • 76.5% responders(mean improvement 29.3%)

  • Increasing the dosage5 to 7 mg/kg/day increased response

  • Well tolerated(mild and transient side effects)

  • Compassionate treatment(9 patients, 1 year) no significant change in neurological score as compared with 8 weeks’ visit.

  • No compassionate treatment(7 patients, 1 year)  significant neurological deterioration

  • Improvement of both parkinsonism and hyperkinetic movements


screening Visit SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

(days 30→0)

V1

V2

V3

Up to 4 mg/kg

Up to 8 mg/kg

ICARS

ICARS

ICARS

Twomonthsstudy (Tapering1 MG/KG/WEEK)

POTENTIAL THERAPEUTIC STRATEGIES

L- Dopa

AIMS

AIMS

AIMS

UPDRS

UPDRS

UPDRS

10 screened

7 enrolled


POTENTIAL THERAPEUTIC STRATEGIES SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

L-Dopa/Amantadine


Conclusions
CONCLUSIONS SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

  • Efficacy of steroids in improving ataxia of AT patients has been proven in the last 5 years

  • To avoid the side effects of long-term administration of steroids, EryDex method may be a promising challenge

  • Extrapyramidal symptoms may be ameliorated by dopaminergic or NMDA antagonists, but long-term, placebo-controlled studies are needed

  • In the future we are looking for a long-term treatmentcombining both steroids and dopaminergic/NMDA antagonists, to improve both ataxia/oculomotor apraxia and parkinsonism/movement disorders.

  • Early treatment in asymptomatic children could be speculated to delay neurological degeneration


ITT population SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients

Number of patient (divided for Trial Center: 1–Roma and 2-Brescia), sex, date of birth, molecular identification, number of infusions and mean dose of DSP loaded


Demographic and clinical characteristics at baseline
Demographic SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patients and clinicalcharacteristics at baseline


Primary efficacy end point met
Primary SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patientsefficacyend-pointmet

Mean ICARS Total Score over the 6-Month Study Period (ITT Population)

*(p= 0.02)

RMANOVA analysis


Secondary end point vabs
Secondary SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patientsend-point: VABS

*p< 0.0001

RMANOVA analysis

Mean VABS Total Score over the 6-Month Study Period (ITT Population)


Secondary end point ocular motility
Secondary SodiumPhosphate on Neurological Symptoms in Ataxia-Telangiectasia Patientsend-point: OcularMotility

(*p= 0.014)

RMANOVA analysis

Mean Ocular Motility Assessment Score by Visit (ITT Population)


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