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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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Actualité dans le traitement pharmacologique de l’Ataxie Télangiectasie

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Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

ATAXIA-TELANGIECTASIA

  • 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 : CLINICAL MANIFESTATIONS


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

ATAXIA TELANGIECTASIA:

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).


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

ATAXIA-TELANGIECTASIA: PROGNOSIS

  • 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 : 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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

ATAXIA-TELANGIECTASIA:

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!


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

  • 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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

Oral Betamethasone


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

Oral Betamethasone


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

A Randomized Trial of Oral Betamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

A Randomized Trial of Oral Betamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

A Randomized Trial of Oral Betamethasone 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.


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

A Randomized Trial of Oral Betamethasone 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).


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

A Randomized Trial of Oral Betamethasone to Reduce Ataxia Symptoms in Ataxia Telangiectasia

Zannolliet al., 2012


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

Dexamethasone Sodium Phosphate Encapsulation in Human Erytrhtocites


Erydex system

EryDex System

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

Intra-Erythrocyte Infusion of Dexamethasone Reduces

Neurological Symptoms in Ataxia Teleangiectasia Patients:

Results of a Phase 2 Trial


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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)


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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

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:


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

screening Visit

(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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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.


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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)


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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

Exploratory analysis for dose response


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

Chronic treatment with ERY-DEX

Long term benefit confirmed with compassionate treatment up to 18 months


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

STEROIDS in AT

  • Cerebellar ataxia improved

  • Oculomotor apraxia improved

  • Extrapyramidal involvement not improved

  • Peripheral neuropathy  not improved


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

TREATMENT OF

EXTRAPYRAMIDAL SYMPTOMS

Drugs that increase dopamine in the striatum

treat parkinsonism but

exacerbate hyperkinetic movements,

and vice versa


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

Amantadine Sulfate


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

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)


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

Amantadine Sulfate


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

screening Visit

(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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

POTENTIAL THERAPEUTIC STRATEGIES

L-Dopa/Amantadine


Conclusions

CONCLUSIONS

  • 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


Actualit dans le traitement pharmacologique de l ataxie t langiectasie

ITT population

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 and clinicalcharacteristics at baseline


Primary efficacy end point met

Primaryefficacyend-pointmet

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

*(p= 0.02)

RMANOVA analysis


Secondary end point vabs

Secondaryend-point: VABS

*p< 0.0001

RMANOVA analysis

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


Secondary end point ocular motility

Secondaryend-point: OcularMotility

(*p= 0.014)

RMANOVA analysis

Mean Ocular Motility Assessment Score by Visit (ITT Population)


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