actualité dans le traitement pharmacologique de l’ataxie télangiectasie current therapeutic...

Actualité dans le traitement pharmacologique de l’Ataxie

Télangiectasie

Current therapeutic strategies

for the treatment of Ataxia-Telangiectasia

Università degli Studi di Brescia – Facoltà di Medicina e Chirurgia

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

Roberto Micheli, MD

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 aprotein 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: DIAGNOSIS

High serum alpha-fetoprotein level (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:

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

Cerebellar ataxia (100% pt.)• Generally the presenting symptom;

progressive.• Narrow gait ataxia.• Neck posturing (anterior or posterior

bending). Extrapyramidal involvement (70% pt.)• Disabling, in some cases prevalent

manifestations.• Hyperkinetic movement disorders /

Parkinsonian features.Eye movement abnormalities (80% pt.)• Oculomotor apraxia. • Significant morbidity, including reading

impairment.SM axonal peripheral neuropathy

Cognitive profile

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!

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

Oral Betamethasone POTENTIAL THERAPEUTIC

STRATEGIES

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

Telangiectasia Zannolli et al., 2012



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



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.

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



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).

To avoid the side effects of long-term administration of steroids we 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


Dexamethasone Sodium Phosphate Encapsulation in Human Erytrhtocites

Dexamethasone Sodium Phosphate Encapsulation in Human Erytrhtocites


EryDex System

WITHDRAWAL OF

50 ml OF WHOLE BLOOD FROM THE PATIENT

1AUTOLOGOUS LOADED RBC REINFUSION TO THE PATIENT

3

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

2

Intra-Erythrocyte Infusion of Dexamethasone ReducesNeurological Symptoms in Ataxia Teleangiectasia Patients:

Results of a Phase 2 Trial

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)

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)


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:

screenedn = 26

enrolledn = 22

screening failuren = 4

CD4+ lymphocytes below the limit n = 3

concomitant diseasen = 1

premature terminations n = 4

completed studyn = 18

CD4+ lymphocytes below the limit n = 1

(protocol violation)

consent withdrawaln = 1dropouts due to AEs n

= 2


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


STUDY DESIGN:

26 screened

22 enrolled (ITT)

4 drop-outs

18 completed (PP)

screening Visit

(days 30→0)

screening Visit

(days 30→0)

six months study (6 treatments) six months study (6 treatments)

V1V1

V2V2

V3V3

V 4V 4

V5V5

V6V6

V7 V7

ICARS

InfusionInfusion InfusionInfusion InfusionInfusion InfusionInfusion InfusionInfusion InfusionInfusion

ICARS ICARS ICARS

3 weeks3 weeks


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.

ICARS Total Score

95% CI for the mean mean (SD)

95% CI for mean median min-max p-value*

V1 50.6 (12.8) (45.2/56) - 52.5 8-72 -

V2 48.4 (11.4) (43.6/53.2) -2.2 (5.6) (-4.6/0.2) 48.5 14-68 0.107

V4 47.4 (11.5) (44/51.8) -3.4 (7.3) (-6.7/0.1) 49.0 14-62 0.054

V7 46.6 (12.3) (41.4/51.8) -4.0 (7.5) (-7.1/-0.9) 48.0 14-62 0.024


I 1. WALKING CAPACITIESI 2. GAIT SPEEDI 3. STANDING CAPACITIES, EYES OPENI 4. SPREAD OF FEET IN NATURAL POSITION WITHOUT SUPPORT, EYES OPENI 5. BODY SWAY WITH FEET TOGETHER EYES OPENI 6. BODY SWAY WITH FEET TOGETHER EYES CLOSEDI 7. QUALITY OF SITTING POSITION

III 15. DYSARTHRIA: fluency of speechIII 16. DYSARTHRIA: clarity of speech

II 08. KNEE-TIBIA TEST: decomposition of movement II 09. ACTION TREMOR in the HEEL-TO-KNEE TestII 10. FINGER-TO-NOSE TEST: decomposition and dysmetriaII 11. FINGER-TO-NOSE TEST: intention tremorII 12. FINGER-FINGER TEST: action tremor and instabilityII 13. PRONATION SUPINATION altering ovementsII 14. DRAWING the Archimedes spiral

POSTURE AND GAIT DISTURBANCE

KINETIC FUNCTIONS

SPEECH DISORDERS

OCULOMOTOR DISORDERS

ICARSTOTAL SCORE

PRIMARY END-POINT: ICARS

IV 17. GAZE EVOKED NYSTAGMUSIV 18. ABNORMALITIES OF THE OCULAR PURSUITIV 19. DYSMETRIA OF THE SACCADE


SECONDARY END-POINTS

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

Ocular MotilityStatistically significant improvements were noted at 3 and 6 months (p=0.021 and p=0.002).

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

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


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)


Exploratory analysis for dose response


Chronic treatment with ERY-DEX

Long term benefit confirmed with compassionate treatment up to 18 months

V1 V7 C1 C8

02.01 57 53 49 45

ICARS

TOTAL SCOR

E

02.02 55 58 58 51

02.05 58 56 50 43

02.08 49 42 37 38

STEROIDS in AT

Cerebellar ataxia improved

Oculomotor apraxia improved

Extrapyramidal involvement not improved

Peripheral neuropathy not improved

TREATMENT OF EXTRAPYRAMIDAL SYMPTOMS

Drugs that increase dopamine in the striatum

treat parkinsonism but exacerbate hyperkinetic

movements,and vice versa

Amantadine SulfatePOTENTIAL THERAPEUTIC

STRATEGIES


STRATEGIES

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 STRATEGIESAmantadine Sulfate

Improvement (%) P (t test)

AT score 29.3 <.01

ICARS (ataxia) 25.2 <.01

AIMS (involuntary mov.) 32.5 <.01

UPDRS (parkinsonism) 29.5 <.01


STRATEGIES

76.5% responders (mean improvement 29.3%)

Increasing the dosage 5 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

L- Dopa

screening Visit

(days 30→0)

screening Visit

(days 30→0)

Two months study (Tapering 1 MG/KG/WEEK) Two months study (Tapering 1 MG/KG/WEEK)

V1V1

V2V2

V3V3

ICARS

Up to 4 mg/kgUp to 4 mg/kg Up to 8 mg/kgUp to 8 mg/kg

ICARS ICARS

AIMS

UPDRS UPDRS

AIMS

UPDRS

AIMS

10 screened 7 enrolled


POTENTIAL THERAPEUTIC STRATEGIESL-Dopa/Amantadine

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 treatment combining 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

Patientnumber

No. of infusions

mean dose(mg/bag)

sex age (years/

months)

ATM mutations ATM protein

Center 101-01 6 9.6 F 11/7 n.d. absent01-02 6 8.5 F 7/10 n.d. absent01-03 6 4.7 F 10/7 1898+1G>T / ? 10%01-04 6 18.6 F 10/8 7517del4 / ? absent01-05 6 3.5 M 10/1 717delCCTC /

717delCCTCabsent

01-06 4 1.0 F 6/4 3894insT absent01-07 6 1.9 M 10/2 97delC / 2113del T absent

01-08 6 0.7 M 12/3 4344-4345insA / IVS47-9G>A

n.d.

01-09 6 17.8 F 6/10 126G>A / del-700Ex46+1406

n.d.

01-10 6 17.4 F 18/1 4396C>T / 9139C>T absent

01-11 6 14.5 F 18/9 3802delG / ? absentCenter 2

02-01 6 4.1 M 8/8 6679C>T / 8484del A 10%

02-02 6 2.4 M 8/7 5979del5 / 7408T>G 20%

02-03 5 6.2 M 11/6 3111delT / 3576G>A n.d.

02-04 6 6.7 F 17/8 3111delT / 3576G>A n.d.

02-05 6 17.5 M 14/2 IVS12+1G>T / 3576G>A

n.d.

02-06 3 2.7 M 12/10 R111X / L3035F n.d.02-07 6 1.8 M 13/7 1369C>T / 3576G>A absent

02-08 6 4.2 M 10/2 6679C>T / 6679C>T absent

02-09 5 7.7 M 10/7 331+2T>G / ?4-20dup absent

02-10 3 5.1 F 3/3 5932G>T / 8278C>T absent

02-11 2 F 3/8 c.3291delC / c.8977C>T

50%

ITT populationNumber 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

Demographics and clinical characteristics

age, mean years (SD) 11.2 (3.5)

female/male, # (%) 11/11 (50/50)

ethnicity (%) Caucasian (100)

weight, mean Kg (SD) 29.1 (9.5)

height, mean cm (SD) 134.8 (15.3)

BMI (SD) 15.6 (2.6)

age at diagnosis, mean months (SD) 60.0 (35.2)

age at symptoms onset, mean months (SD) 25.9 (17.5)

mean ICARS score (SD)

posture/gait disturbances

kinetic function

speech disorders

oculomotor disorders

50.6 (12.8)

20.9 (7.1)

23.1 (6.2)

3.5 (1.4)

3.2 (1.0)

mean VABS score (SD) 5.5 (2.0)

Primary efficacy end-point met

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

*(p= 0.02)

RMANOVA analysis

Secondary end-point: VABS

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

*p< 0.0001

RMANOVA analysis

Secondary end-point: Ocular Motility

Mean Ocular Motility Assessment Score by Visit (ITT Population)

(*p= 0.014)

RMANOVA analysis

actualité dans le traitement pharmacologique de l’ataxie télangiectasie current therapeutic...

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