Safinamide: un farmaco innovativo con un duplice meccanismo d azione

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Vincent Hensley
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1 Safinamide: un farmaco innovativo con un duplice meccanismo d azione AINAT Sardegna Cagliari, 26 novembre 2016 Carlo Cattaneo Corporate Medical Advisor CNS & Rare Diseases

2 Reichmann H. et al., European Neurological Review 2015; 10(2): GLUTAMATERGIC TERMINAL SAFINAMIDE Na+ CHANNELS Ca++ CHANNELS Non dopaminergic targets Ø Sodium channels Ø Calcium channels Ø Glutamate release DOPAMINERGIC TERMINAL MAO-B Dopaminergic target Ø Monoamine oxidase B (MAO- B) SAFINAMIDE GABAERGIC MSN (Medium Spiny Neuron) Reichmann H. et al., European Neurological Review 2015; 10(2):

3 Safinamide is a potent and highly selective MAO-B inhibitor in human tissues MAO-A MAO-B IC 50 (µm) Tissue Brain Liver Brain Liver Platelet Rat 485 ~ not evaluated Human ~80 > Rasagiline from Youdim, 2001 Selegiline Brain Ratio MAO-A/MAO-B Safinamide 1000 Rasagiline 50 Selegine 240 Kulisevsky J., European Neurological Review 2014; 9(2):

Safinamide mantains increased dopamine levels after 39 week chronic treatment in monkeys Putamen Nucleus Accumbens Increased DA levels in a specific brain region devoted to

4 Safinamide mantains increased dopamine levels after 39 week chronic treatment in monkeys Putamen Nucleus Accumbens Increased DA levels in a specific brain region devoted to the motor control (putamen nucleus) without affecting regions involved in rewarding circuitry such as mesolimbic structures. Caccia C. et al., Neurology 2006; 67(1): S18- S23

Safinamide shows state- and use- dependent block of Na+ currents in rat cortical neurons The Na + channels are cycling : State-dependent block of the channel occurs when the channel is blocked in a

5 Safinamide shows state- and use- dependent block of Na+ currents in rat cortical neurons The Na + channels are cycling : State-dependent block of the channel occurs when the channel is blocked in a defined state. Use-dependent block of the channel occurs when neurons are overexcited Under more depolarized membrane potential, there is the largest accumulation of channels in the inactivated state. Safinamide inhibits the Na + channels in a state-dependent manner (different potency at different states of the channel), and in a use-dependent manner (increased potency during high frequency stimulation) when they are in the inactivated state, reducing channel availability for re-activation and leaving normal function unaffected (= no CNS depressant effects).

targeting non-dopaminergic systems might be an alternative approach to

6 Safinamide affects both dopaminergic and non-dopaminergic targets in PD progression SAFINAMIDE Dopaminergic tone Glutamatergic overactivity.targeting non-dopaminergic systems might be an alternative approach to improve and control motor complications.. Fox S., Drugs 2013; 73:

7 Safinamide is a new drug with a unique dual mechanism of action Safinamide: dopaminergic target Potential clinical benefits MAO-B inhibition with unique features: Ø Ø Ø Reversible Highly selective Potent (nmolar range) Ø Fewer side effects Ø No main drug-drug interactions Ø No need for dietary restrictions Safinamide: non dopaminergic target Ø State- and use-dependent blockade of sodium channels Ø Modulation of calcium channels Ø Inhibition of the abnormal glutamate release Ø Potential benefits on motor complications and non-motor symptoms

8 Safinamide: clinical registration program in mid- to latestage PD fluctuating patients Study NW 016 (669 pts) L-Dopa Add-on 1218 patients SETTLE double-blind extension Study (549 pts) Study NW 018

9 Borgohain R. et al., Movement Disorders 2014; 29(10): A Phase III, Double-Blind, Placebo-Controlled 18-Month Extension Study to Determine the Efficacy and Safety of a Low (50 mg/day) and High (100 mg/day) Dose of Safinamide, as Add-On Therapy, in Patients with Idiopathic Parkinson s Disease with Motor Fluctuations Treated with a Stable Dose of Levodopa and Who May Be Receiving Concomitant Treatment with Stable Doses of a Dopamine Agonist, and/or an Anticholinergic

27) p-value vs placebo 0.0031 0.0002 Mean ON time without dyskinesia + with non-troublesome dyskinesia (hours) ** p<0.

10 Study 018: ON time with no/non-troublesome dyskinesia Safinamide 50 mg/day Safinamide 100 mg /day Clinical effect maintained over 2 years LSM LSM difference vs placebo % CI of LSM difference ( ) ( ) p-value vs placebo Mean ON time without dyskinesia + with non-troublesome dyskinesia (hours) ** p<0.01; *** p<0.001 vs placebo *** ** (Start of Study 016) Week (End of Study 018) Borgohain R. et al., Mov. Disord. 2014; 29(10):

11 Cattaneo C. et al., Journal of Parkinson s Disease 2016; 6:

12 SETTLE (pooled data) : forest plot (OFF time) of the subgroups of patients Subgroup Levodopa (a) only Levodope (a) and other meds No use of dopamine agonist Use of dopamine agonist No use of COMT inhibitor Use of COMT inhibitor No use of amantadine Use of amantadine Mild Fluctuators (b) Non-Mild Fluctuators (b) Mean Difference with 95% CI safinamide as first add-on to levodopa Safinamide Better Placebo Better Cattaneo C. et al., Journal of Parkinsons Disease 2016; 6:

SETTLE + 016 (pooled data) : total daily OFF time change from baseline in L-dopa subgroups of patients

13 SETTLE (pooled data) : total daily OFF time change from baseline in L-dopa subgroups of patients Improvement Adjusted mean change from baseline in total daily OFF time (hours) Safinamide 100 mg/day (n=43) Levodopa Only p < Placebo (n=46) * Other = other antiparkinsonian medications Levodopa + Other* Safinamide 100 mg/day (n=444) p < Placebo (n=438) Cattaneo C. et al., Journal of Parkinsons Disease 2016; 6:

14 SETTLE (pooled data) :effects on UPDRS scores and on cardinal symptoms of Parkinson s Disease Xadago 100 mg/day (n = 482) LS means ± SE placebo (n = 479) LS means ± SE p-value UPDRS Part II (ADL) ± ± UPDRS Part III (Motor symptoms) ± ± Bradykinesia ± ± Rigidity ± ± Tremor ± ± Postural stability ± ± Gait ± ± Cattaneo C. et al., Journal of Parkinsons Disease 2016; 6:

15 Cattaneo C. et al., Journal of Parkinson s Disease 2015; 5:

Study 018: % of patients with DRS change in all subjects (with and without dyskinesia at baseline of study 016) and no change in L-Dopa dose 50,0% 45,0% 40,0% 35,0% 30,0% 25,0% 20,0% Placebo SAF 50mg

16 Study 018: % of patients with DRS change in all subjects (with and without dyskinesia at baseline of study 016) and no change in L-Dopa dose 50,0% 45,0% 40,0% 35,0% 30,0% 25,0% 20,0% Placebo SAF 50mg SAF 100mg 15,0% 10,0% 5,0% 0,0% Decrease No change Increase Variable Placebo Safinamide 50 Safinamide 100 Decrease 27.2 % (37/136) 33.8 % (50/148) 39.5 % (58/147) No change 43.4 % (59/136) 41.9 % (62/148) 36.7 % (54/147) Increase 29.4 % (40/136) 24.3 % (36/148) 23.8 % (35/147) Cattaneo C. et al., Journal of Parkinsons Disease 2015; 5:

Study 018: % of patients with DRS change in subjects with dyskinesia at baseline (study 016) and no change in L-Dopa dose 70,0% SAF 100mg vs. Placebo (p-value = 0.0546) SAF 50mg vs.

17 Study 018: % of patients with DRS change in subjects with dyskinesia at baseline (study 016) and no change in L-Dopa dose 70,0% SAF 100mg vs. Placebo (p-value = ) SAF 50mg vs. Placebo (p-value = ) 60,0% 50,0% 40,0% 30,0% Placebo SAF 50mg SAF 100mg 20,0% 10,0% 0,0% Decrease No change Increase Variable Placebo Safinamide 50 Safinamide 100 Decrease 45.1 % (37/82) 51.5 % (50/97) 61.7 % (58/94) No change 22.0 % (18/82) 24.7 % (24/97) 12.8 % (12/94) Increase 32.9 % (27/82) 23.7 % (23/97) 25.5 % (24/94) Cattaneo C. et al., Journal of Parkinsons Disease 2015; 5:

18 Post-hoc analysis on pain

Studies 016 + SETTLE (pooled data): concomitant use of pain

19 Studies SETTLE (pooled data): concomitant use of pain treatments Barone P. et al., 19 th MDS Congress San Diego (USA), 2015

20 Studies SETTLE (pooled data): estimated risk of concomitant use of pain medications RRR 95% lower CL 95% upper CL p-value 23.6% 41.1% 1,0% RRR = Risk Ratio Reduction; indicates the % of reduction in the number of pain treatments with safinamide 100 mg/day vs placebo Barone P. et al., 19th MDS Congress San Diego (USA), 2015

Studies 016 + SETTLE (pooled data): changes from baseline to week 24 in the items

21 Studies SETTLE (pooled data): changes from baseline to week 24 in the items 37,38 and 39 of the PDQ-39 scale Barone P. et al., 19 th MDS Congress San Diego (USA), 2015

22 Studies SETTLE (pooled data): path analysis diagram of variables contributing to pain in patients Baseline OFF Time 6-month OFF Time Baseline Pain (PDQ-39) 6-month Pain (PDQ-39) Safinamide Baseline UPDRS IV 6-month UPDRS IV Baseline GRID- HAMD 6-month GRID-HAMD

23 Studies SETTLE (pooled data): results of the path analysis Exogenous variable Endogenous variable p-value Interpretation Pain at Baseline Pain at 6 month Magnitude of the effects of baseline values OFF Time at Baseline OFF Time at 6 month GRID-HAMD at Baseline GRID-HAMD at 6 month UPDRS IV at Baseline UPDRS IV at 6 month Treatment OFF time at 6 month Magnitude of the indirect effect of Xadago on pain mediated by OFF time OFF time at 6 month Pain at 6 month Treatment GRID-HAMD at 6 month Magnitude of the indirect effect of Xadago on pain mediated by GRID-HAMD GRID-HAMD at 6 month Pain at 6 month Treatment UPDRS IV at 6 month Magnitude of the indirect effect of Xadago on pain mediated by UPDRS IV UPDRS IV at 6 month Pain at 6 month Treatment Pain at 6 month Direct effect of of Xadago on pain % of the effect INDIRECT EFFECT OF XADAGO ON PAIN 20.3% DIRECT EFFECT OF XADAGO ON PAIN 79.7%

24 Post-hoc analysis on mood

25 Studies 016 and 018: changes in PDQ-39 «Emotional wellbeing» scores Cattaneo C. et al., 20th MDS Congress Berlin (Germany), 2016

26 Studies 016 and 018: changes in GRID-HAMD scores Cattaneo C. et al., 20th MDS Congress Berlin (Germany), 2016

27 Studies 016 and 018: proportion of patients reporting «depression» as adverse event Cattaneo C. et al., 20th MDS Congress Berlin (Germany), 2016

28 Progression of PD Safinamide as add-on therapy Preclinical Honeymoon- Period Motor Complications Wearing-off On-Off Resistent Symptoms Cognitiver Decline -5? Years

Anand R, 1 Borgohain R, 2 Stocchi F, 3 Giuliani R, 4 Rice P, 5 Forrest E, 4 Lucini V, 4 for the Study 016/018 Investigators IL, USA

First 2-year, placebo-controlled study in Parkinson s disease patients with motor fluctuations indicates safinamide may benefit patients with more severe dyskinesia Anand R, 1 Borgohain R, 2 Stocchi F,