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Leonardo LopianoUniversità di Torino

Nuove prospettive terapeutiche per la malattia di Parkinson (farmaci e dispositivi)

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Poewe et al. 2017

Terapia farmacologica

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Chaudhuri et al. 2016

Chaudhuri et al. 2016

In development levodopa-based strategies

ND0612

Safinamide

Safinamide TolcaponeEntacaponeEpicapone

TolcaponeEntacaponeEpicapone

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Safinamide

• Phase III, multicentre,randomised, double-blind,placebo controlled, parallelgroup, 24 week duration trial.

• To evaluate the efficacy andsafety of safinamide versusplacebo as add-on therapy to astable dose of L-Dopa (alone orwith other antiparkinsoniandrugs) in pts with mid- to late-stage PD and motorfluctuations.

• The primary efficacy measurewas the change from baselineto 24 weeks in daily ON timewith no/non troublesomedyskinesia. The addiction of safinamide 50 mg/day or

100 mg/day to L-Dopa in PD patients andmotor fluctuations increased total ON timewith no or non-troublesome dyskinesia

At six months, safinamidesignificantly reduced dailyOFF time when used as add-on to levodopa.

SETTLE STUDY

At six months, safinamidesignificantly increaseed dailyON time when used as add-onto levodopa.

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• The primary endpoint was the mean change from baseline (study016 start) to study end (2 years) in the total Dyskinesia RatingScale (DRS) score evaluated during ON time.

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• Change in Dyskinesia Rating Scale was not significantlydifferent in safinamide versus placebo, despitedecreased mean total Dyskinesia Rating Scale (DRS)with safinamide compared with an almost unchangedscore in placebo (safinamide 100 mg 31%; safinamide50 mg 27%; placebo 3%).

• Ad hoc subgroup analysis of moderate to severedyskinetic patients (242 pts, 36%) showed a significantdecrease of DRS with safinamide 100 mg/d comparedwith placebo.

• The antidyskinetic effect was independent of the L-Dopadose reduction.

• Improvements in motor function, ADL, depressivesymptoms, clinical status and quality of life at 6 monthsremained significant at 24 months.

Concomitant use of pain treatments in trials 016 and SETTLE (PooledData)

Estimated risk of concomitant use of pain medications during treatment with Safinamide or placebo

2015

Uso concomitante di trattamenti per il dolore

Cattaneo C. et al., J Park Dis, 2016 epub

Studi 016 e SETTLE: post hoc sul dolore

Variazione dal basale alla settimana 24 degli item 37, 38 e 39 della PDQ39

Cattaneo C. et al., J Park Dis, 2016 epub

Studi 016 e SETTLE: post hoc sul dolore

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Cattaneo C. et al., J Park Dis 2016 epub

Path analysis

SafinamideEffetto totale

sul dolore

Effetto diretto sul dolore

Effetto indiretto sul dolore

-0.0172 (20.3%) -0.0846 (100%)

-0.0674 (79.7%)

Studi 016 e SETTLE: post hoc sul dolore

2016

Fabbri et al. 2016

Opicapone (OPC): high COMT inhibitory potency, no liver toxicity, l ong durationof action and easy-to-administer drug for the treatment of PD motor fluctuations.

Complete inhibition of COMT with an inhibition duration higher than bothtolcapone and entacapone.

One hour after administration, COMT inhibition was 99% with OPC versus 82%with tolcapone and 68% with entacapone. 9 hours after administration,entacapone showed no COMT inhibition and tolcapone produced minimalinhibitory effect (16%), whereas OPC continued inhibiting COMT activity by91%.

Therefore, OPC behaves as along-acting and potent COMT inhibitor thatmarkedly increases systemic and brain L-dopa bioavailability, even whencompared with older COMT inhibitors, that is, tolcapone and entacapone.

No dose adjustmentseemed to be needed in patients with mild to moderatechronic hepatic impairment.

Fabbri et al. 2016

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High COMT inhibitory potency, noliver toxicity, long duration of actionand easy-to-administer drug for thetreatment of PD motor fluctuations.

Complete inhibition of COMT with aninhibition duration higher than bothtolcapone and entacapone.

No dose adjustment seemed to beneeded in patients with mild tomoderate chronic hepatic impairment.

• OPC at doses of 5 mg/day to 50 mg/day has been found to besafeandwell tolerated.

• Two Phase III double–bind RCTs have investigated the efficacy ofOPC as adjunctive therapy to L-dopa for advanced PD patientswithmoderate end of-dose motor fluctuations showing thatOPC 50 mgwas superior to placebo and non inferior to entacapone in reducingOFF time.

• OPC 50 mg obtained a meanreduction time in the OFF state ofabout 60 min daily versus placebo without increasing the ON-time.

• OPC 50 mg presented a tendency for agreater effect magnitude forOFF-time reduction.

Fabbri et al. 2016

• Dyskinesiasare the most common AE, even when compared withentacapone and placebo. Interestingly, no issues of concern wereobserved for severe diarrhoea and report of urine discoloration.

Non-levodopa-based treatment strategies

Oertel 2017

Non-dopaminergic mode of action: new compounds or new formulation

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Oertel 2017

Non-dopaminergic mode of action: drug approved in another indication, nowtested in Parkinson’s disease

Subcutaneous apomorphine infusion

This is the first clinical trial performed with the levodopa-entacapone-carbidopaintestinal gel (LECIG). The results suggest that the required levodopa dose can besuccessfully reduced with LECIG without lowering the clinical effect.

TRIGEL infusion

DEEP BRAIN STIMULATION

130 Hz

• Amplitude (max 3,6 mA)• Frequency (130 Hz)• Pulse width (60 µsec)

Monopolarcathodic

Bipolarcathodic

Double monopolar

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Box-and-arrow modelRate model

Progress in Brain Research, 2009, 175 (24), 379

DBS: mechanism of action

• Memory

• Perception

• Consciouness

Neuronal oscillations in PD

• Bradykinesia and rigidity associated withbeta oscillations (15-28 Hz)

• Beta rhythm attenuated by medications orDBS

• Gamma activity (60 Hz) associated withongoing movements

• Pro-kinetic STN-GPi-cortical network (60-80Hz)

• Anti-kinetic STN-GPi-cortical network (3-10Hz; 11-30 Hz)

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Suppression of beta activity before andduring movement

Relationship between systemperformance and neural synchrony

Best results have been reported in patients withadvanced PD and:

• excellent LD response• younger age• no or few axial non–LD-responsive motor symptoms• no or very mild cognitive impairment• absence of or well-controlled psychiatric disease

56,7

24,527,3

36,4

10,5

2,8 1,9 3,3

11,8

6,0 5,9 6,6

23,3

11,013,1

16,8

0,0

10,0

20,0

30,0

40,0

50,0

60,0

pre-op 1 y 5y 11y

UPDRS

score

UPDRS III tot

tremore

rigidità

bradicinesia

*

*

*

*

11,0

4,7

6,3

9,7

2,01,2

1,62,42,3

0,71,1

1,61,91,1 1,3

1,9

0,0

2,0

4,0

6,0

8,0

10,0

12,0

pre-op 1 y 5y 11y

UPDRS

score

assiali

linguaggio

deambulazione

stabilità posturale*

UPDRS III – Med OFF vs Med OFF/Stim On

p < 0.05 vs pre-op

• 26 patients• Mean Follow-up: 11 ys

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10,4

6,3

9,7

19,6

0,0

5,0

10,0

15,0

20,0

25,0

pre-op 1y 5y 11y

UPDRS

score

UPDRS II (ADL) - Med ON/Stim ON

*

10,4

1,4

2,2

3,3

5,2

0,61,0 0,8

3,8

0,20,8

1,3

0,0

2,0

4,0

6,0

8,0

10,0

12,0

pre-op 1y 5y 11y

UPDRS

score

UPDRS IV

*

**

*

P < 0.05 vs pre-op

Pedunculopontine area stimulation has an initial but not sustained benefit forgait related symptoms.

New technologies

• Interleaved stimulation

• Multiple-source currentsteering

• Directional DBS

New stimulation patterns

Closed-loop stimulationDifferent patterns of stimulation

Low-frequency stimulation

Variable frequency stimulation

Delivery of different waveforms

Coordinated reset modulation

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Polymeropoulos et al.

A pattern of familial aggregation has been documented for the disorder, and it wasrecently reported that a PD susceptibility gene in a largeItalian kindred is located onthe long arm of human chromosome 4. A mutation was identified in the a-synucleingene in the Italian kindred and in three unrelated families of Greek origin withautosomal dominant inheritance. This finding of a specific molecular alterationassociated with PD will facilitate the detailed understanding of thepathophysiology ofthe disorder.

• Alpha-synuclein aggregation• Lysosomal-autophagy axis change• Endoplasmatic reticulum stress

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Jia-Yi Li et al.

Oertel 2017

Therapy with compounds targeting alpha-synuclein

• Gene therapy has made severalprogresses but a lot of problems stillremain (the target area, inflammation,weigh loss, antibody against GDNF)

• With the advancing of the biology, wehope to see more help from RNAi thatrescue gene deficit. However,applications of the RNAi technique inclinical practice still have a long way togo

• Neurotrophic factor (for regeneration)

• Synthesis of neurotransmitter (forprolong the duration of L-dopa)

• Modulation of proteins

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Comparison of the major approaches to cell-based therapies in Parkinson’s disease

2015

Trapianti di cellule mesencefaliche fetali

Studio europeo coordinato dall’Università di Cambridge chevaluterà 20 pazienti per almeno un anno e terminerà nel 2020(TRANSEURO Trial)

Cellule staminali adulte mesenchimali

Prelevate dal paziente o da un donatore, amplificate ereintrodotte nell’organismo per via intra-ventricolare ointra-arteriosa

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Centro Regionale Esperto per la malattia di Parkinson e i disturbi del movimento

Dipartimento di Neuroscienze “Rita-Levi Montalcini”Università di Torino

Dipartimento di Neuroscienze e Salute MentaleAOU Città della Salute e della Scienza di Torino

SC Neurologia 2U