Farmaci Innovativi nella Sclerosi Multipla. Prof C. Pozzilli Sant Andrea Hospital Sapienza University, Rome

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1 Farmaci Innovativi nella Sclerosi Multipla Prof C. Pozzilli Sant Andrea Hospital Sapienza University, Rome

2 MS Patients Rating of Their Most Important Functions MS <5 Years (n=84) MS >15 Years (n=82) Percentage e First Rank Walking Power Coordination of Hands Normal Skin Sensations Lack of Pain Bladder Control Bowel Control Visual Function Awakefulness and Alertness Thinking and Memory Speech Swallowing Mood Sexuality Heesen C, et al. Mult Scler. 2008;14:

3 Walking Impairment in MS 64% 1 85% 2 of MS patients report walking difficultiy 70% 1 of MS patients with walking difficulty report it to be the most challenging aspect of their MS 3 1. Harris Interactive. Experiences with Multiple Sclerosis (MS): Perspectives of People with MS and MS Care Partners [poll]. March 25, NARCOMS database.

4 Table 1. Measures of Walking Speed in MS Assessme nt T25FW 10MTW 100MTW 6MWT 2MWT What is measured (units)? Description of Test Citation Time (seconds) to walk 25 feet (feet/sec) Time (seconds) to walk 10 metres (metres/sec) Time (seconds) to walk 100 metres (metres/sec) Total distance covered in 6 minutes and distance per minute (metres or feet/sec) Total distance covered in 2 minutes and distance per minute (metres or feet/sec) Subject directed to walk as fast and safely as they can across a clearly marked linear 25-foot course (no turns); static start; may use assistive device; task is immediately repeated Subject directed to walk independently across a linear 10-metre course (no turns) either at normal or fastest speed; may use assistive device; maximum time = 180 sec if unable to complete test; task may be repeated Subject directed to walk as quickly as possible 4 times along a clearly marked 25 metre course pivoting 3 times; may use assistive devices if absolutely necessary; no running Subject directed to walk at maximal speed back and forth in a hallway pivoting at each end for 6 minutes; may use their assistive device, no permitted rest, no encouragement Same as above but for 2 minutes Fischer 1999 Vaney 1996; Kempen 2011; Paltamaa 2005 Phan-Ba 2011 Goldman 2008 Gijbels 2011 T25FW=Timed 25-foetresot Walk; 10MTW=10-Metre Timed Walk; 100MTW=100-Metre Timed Walk; 6MWT=6 minute Walk Test; 2MWT=2- Minute Walk Test.

5 Summary Shorter tests (eg, T25FW) Better for assessing walking ability in patients with greater disability The 6MWT may be a burden for patients with greater disability, eg, patients with EDSS > 6.0 (Gijbels 2011) Average (SD) distance for 6MWT in patients with MS = 421 (145) metres Subject to floor effects in patients with mild disability Longer tests (eg, 100MTW, 6MWT, 2MWT) Better for the assessment of walking fatigability and limitations in maximal walking distance Overall performance on the 6MWT, 2MWT, and 10-metre Timed Walk (10MTW) predicts levels of community ambulation. (Gijbels 2010, Kempen 2011) 6MWT and 2MWT both assess the endurance component of functional capacity. (Savci 2005) Good precision for discriminating differences in disability in patients with mild disease Variability over time less-well defined

6 Burden of Symptoms to Patients Percent of MS Patients Treated with the Following Symptomatic Therapies for Fatigue & Mobility Impairment Average Number of Symptomatic Therapies Per Patient Provigil* 9% 31% 4 Zanaflex Baclofen (oral) Baclofen (pump) Amantadine* 4% 3% 8% 20% Number of Prod ducts No drug specifically 30% adresses 34% 17% 18% walking disability % SSRIs 28% 0% 10% 20% 30% 40% US EU5 0 US EU5 Source: GMI Survey *Used off-label in MS 6

7 Fampridine Dalfampridine = USAN (generic) name of 4-aminopyridine (4-AP) C5H6N2, MW=94 Available as compounded drug in several countries Fampridine-PR (prolonged-release formulation) Longer duration of effect Avoids high plasma peaks Overcomes food effect New Chemical Entity (NCE) FDA/EMA granted MW=molecular weight; USAN=United States adopted names mg Dose Fampridine Plasma Conc. (ng/ml) No food effect on absorption IR 12.5 mg Fasted PR 12.5 mg Fasted + PR 12.5 mg Fed Time After Administration (h)

Scientific Rationale and MoA Demyelinated nerves lose ability to effectively conduct action potentials due to loss of K+ ions Fampridine reverses this by

8 Scientific Rationale and MoA Demyelinated nerves lose ability to effectively conduct action potentials due to loss of K+ ions Fampridine reverses this by blocking the repolarizing K+ currents, thus normalizing nerve conduction Shi and Blight, Neuroscience 77: , 1997 Exp. Neurol. 148: ,

9 Enhanced brain motor activity in patients with MS after a single dose of 3-4 diaminopyridine 1 2 (1) placebo, (2) 3,4-diaminopiridina MaineroC et al, Neurology 2004

10 Oral 4-aminopyridine improves fatigue: results of a randomized, double-blind, placebo-controlled, crossover trial on 54 MS patients AP Fatigue Scor re Placebo Placebo 4-AP Baseline 6 months 12 months Group 1 4-AP -> Placebo Group 2 Placebo -> 4AP (Rossini P.M., Multiple Sclerosis 2001)

11 Phase 3 Study Design Randomized, placebo-controlled Primary endpoint 3/4 visits vs. best off-drug visit T25FW MSWS 12 SGI CGI Walking Speed Responder* Validation of clinical impact** Secondary endpoints Lower Extremety Manual Muscle Test (LEMMT) Ashworth Score for spasticity 11 * Defined as faster Timed Walk speed on at least 3 of 4 on drug visits vs. the fastest speed among 5 off-drug visits ** SGI On a scale of 1-7, where 1 = terrible and 7 = delighted; CGI on a scale of 1-7, where 1 = very much improved, 7 = very much worse Goodman et al. Sustained-release oral fampridine in multiple sclerosis: a randomised double-blind, controlled trial. Lancet 2009;373: ;

12 Consistent Methology and Response Definition (MS-F202, MS-F203, MS-F204) A Timed Walk Responder is a subject whose walking speed on at least 3 of 4 on drug visits is faster than the fastest speed during any of 5 off-drug visits 5 Off-drug Visits 4 On-drug Visits Screening Randomisation 2-Wk Placebo Run-in Treatment Period 2-Wk Follow-up 12 Goodman et al. Sustained-release oral fampridine in multiple sclerosis: a randomised double-blind, controlled trial. Lancet 2009;373: ;

3% P<0.0001 34.8% Timed Walk Responders (%) 50 40 30 20 10 9.3% P<0.0001 42.

13 PIII: Timed Walk Response With Fampridine MS-F203 Timed 25-Foot Walk ITT Population MS-F204 Timed 25-Foot Walk ITT Population Timed Walk Responders (%) % P< % Timed Walk Responders (%) % P< % 0 Placebo (n=72) Fampridine-PR (n=224) 0 Placebo (n=118) Fampridine-PR (n=119) ITT=intent to treat. 13

14 Efficacy in Walking Speed Over Time of Treatment MS-F203 Walking Speed MS-F204 Walking Speed Placebo (N=72) Fampridine-SR Timed Walk Responders (N=78) Fampridine-SR Timed Walk Non-Responders (N=146) Placebo (N=118) Fampridine-SR Timed Walk Responders (N=51) Fampridine-SR Timed Walk Non-Responders (N=68) Percentage Change P< Percentage Change P< Week 2 Week 6 Week 10 Week 14 Week 2 Week 4 Week 6 Week 8 14

15 Timed Walk Responder Odds Ratio: Demographic 95% CI by Demographic Subgroups Pooled Across Studies (MS-F202, MS-F203, MS-F204) Favoring Favoring Placebo Fampridine 10 mg Variable P-Value Gender Males <0.001 Females <0.001 Race Caucasian <0.001 Non-Caucasian Age <=45 yrs < yrs <0.001 >=65 yrs Body Mass Index <25 < <0.001 >30 < Notes: P-values provided for descriptive purposes. Non-Caucasians were pooled because individually the races that comprise Non-Caucasian subgroup was < than 30 15

16 Timed Walk Response Independent from Disease Type, Disease Duration and EDSS Variable (Placebo N / F-PR 10 N) MS Type RRMS (61/104) PPMS (34/40) SPMS (91/184) PRMS (4/15) Duration of Disease <8 (66/97) 8 16 (65/129) 16 (59/117) EDSS Score 5.5 (54/71) =6 (67/140) 6.5 (69/132) 95% CI by MS Disease Subgroups Pooled Across Studies (MS-F202, MS-F203, MS-F204) Diagnosis Type P-Value < < Duration of Disease P-Value <0.001 <0.001 <0.001 EDSS Score P-Value <0.001 <0.001 < Odds Ratio Note: P-values provided for descriptive purposes. Sample size for Progressive/Relapsing subgroup less than 30. Goodman et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology 2008;71: ; Goodman et al. Sustained-release oral fampridine in multiple sclerosis: a randomised double-blind, controlled trial. Lancet 2009;373: ; Goodman 16 et al. Sustained-release fampridine consistently improves walking speed and leg strength in multiple sclerosis: a phase 3 trial. Multiple Sclerosis 2008;14:S298.

17 Spasticity is common in MS Most patients with MS experience a degree of spasticity None (16%) Minimal (31%) Mild (19%) Moderate (17%) Severe (13%) Prevents daily activities (4%) Spasticity symptoms include: rigidity, spasms, movement difficulties, disability Rizzo et al. Mult Scler 2004; 10:

18 The burden of MS spasticity in Spain 2/3 of 2029 patients with MS surveyed in the study had a certain degree of spasticity, 40% of them moderate or severe The presence of MS spasticity was associated with significantly worse symptoms MS symptom No spasticity Spasticity p-value (%) (%) Daytime spasms < Urinary dysfunction < Sleep disturbances < Woken by urinary urgency [> 2 times / night] Woken by spasms [one or more times / night] < < Oreja-Guevara et al. Int J Neurosci 2013;

19 Unmet need in MS spasticity management Physician's satisfaction with pharmacological treatment: stratified according to the MS spasticity grade MOVE 1 Germany study (42 centres, 252 cases) % Very satisfied Satisfied Partly satisfied Partly unsatisfied Unsatisfied Completely unsatisfied 20 0 Mild Moderate Severe Flachenecker et al. Mult Scler 2012; 18: S21

German MS guidelines (5th edition) Highest evidence level for antispastic medications Baclofen (on-label; evidence class Ib II) Recommendation grade A Tizanidine (on-label; evidence class Ib)

20 German MS guidelines (5th edition) Highest evidence level for antispastic medications Baclofen (on-label; evidence class Ib II) Recommendation grade A Tizanidine (on-label; evidence class Ib) Recommendation grade A Gabapentin for painful spasms Dosage mg/d (off-label; evidence class Ib) Recommendation grade A THC:CBD spray (2.7 mg THC mg CBD oromucosal spray; evidence class Ia) Recommendation grade A Dantrolene, tolperisone, benzodiazepines Not well documented

21 Cannabinoids in MS treatment First reports of cannabis use The Anatomy of Melancholy Robert Burton (1621) Sulla Canapa Nostrana e Suoi Preparati in Sostituzione Della Cannabis indica Raffaele Valieri (1887) Cannabis Sativa sub. Sativa

THC:CBD oromucosal spray definition and origin THC:CBD oromucosal spray (Sativex ) is an endocannabinoid system modulator THC It is a unique cannabinoid-based medicine derived from the active

23 THC:CBD oromucosal spray definition and origin THC:CBD oromucosal spray (Sativex ) is an endocannabinoid system modulator THC It is a unique cannabinoid-based medicine derived from the active principles of Cannabis sativa, THC and CBD The pharmaceutical form is prepared from 2 cloned chemovars of Cannabis sativa to ensure standardisation and quality One clone produces high levels of THC and the other high levels of CBD These 2 cannabinoids account for about 70% of the composition of THC:CBD oromucosal spray; the remaining 30% comprises minor cannabinoids, terpenoids, sterols and triglycerides CBD Perez. Drugs Today (Barc.) 2006; 42:

24 THC:CBD oromucosal spray pharmacokinetics THC plasma level (ng/ml) Dose-normalised comparison of smoked cannabis (33.8 mg, 8 inhalations) and THC:CBD oromucosal (dose normalised to 33.8 mg THC, equivalent to 12.5 sprays) Smoked cannabis (33.8 mg THC) THC:CBD oromucosal spray (dose normalised to 33.8 mg THC) Time (minutes) Stott et al. Eur J Pharmacol Epub

25 THC:CBD oromucosal spray clinical efficacy 4.1 Therapeutic indications THC:CBD oromucosal spray is indicated as treatment for symptom improvement in adult patients with moderate to severe spasticity due to MS who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial therapy trial

26 THC:CBD oromucosal spray clinical experience To date, the clinical programme has involved more than 1500 patients with MS Over 1200 patient-years of clinical experience with THC:CBD oromucosal spray have accumulated during the course of these clinical trials and >660 patients have been treated continuously for six months or more In addition, over 15,000 patient-years of post-marketing use of THC:CBD oromucosal spray have been gathered in the UK, Canada, Spain, Germany and Denmark

27 THC:CBD oromucosal spray clinical trials programme One Phase I, 8 Phase II and 3 Phase III studies Phase III randomised, placebo-controlled studies in MS patients Reference Duration Patients Endpoint Phase III studies Wade et al, 2004 (pilot) 6 weeks N = 160 Secondary: spasticity VAS scores: -31.2% vs -8.4% PBO (p = 0.001) Collin et al, weeks N = 189 Primary: 0 10 NRS evolution: -1.1 vs 0.6 PBO (p < 0.05, ITT) Collin et al, weeks N = 337 Primary: 0 10 NRS evolution: -1.2 vs 0.8 PBO (p < 0.05, PP) Novotna et al, weeks N = 572 Primary: 0 10 NRS evolution: -1.2 vs 0.8 PBO (p < 0.05, ITT) Wade et al. Mult Scler 2004; 10: ; Collin et al. Eur J Neurol 2007; 14: ; Collin et al. Neurol Res 2010; 32: ; Novotna et al. Eur J Neurol 2011; 18:

28 THC:CBD oromucosal spray Phase III clinical trial (n = 572) Two-phase enriched study design Phase A (n=488) Phase B (n=244) 12 weeks THC:CBD 12 weeks Placebo End of treatment/ withdrawal 7-day baseline period 4 weeks single-blind THC:CBD Double-blind Randomised period Visit 1 Visit 2 Visit 3 Visit 4 and 5 Visit 6 Novotna et al. Eur J Neurol 2011; 18:

29 THC:CBD oromucosal spray Phase III clinical trial (n = 572) Patient disposition Screened = 670 Entered phase A = 573 Responders (>20%) = 271 (47%) Non-responders = 302 (53%) Randomised (phase B) = 241 THC:CBD = 124 Placebo = 117 Novotna et al. Eur J Neurol 2011; 18:

30 THC:CBD oromucosal spray Phase III clinical trial (n = 572) NRS evolution from phase A responders Mean spasticity 0 10 NRS (± SE) SE, standard error Non-responders Study period (week) THC:CBD Placebo p = Novotna et al. Eur J Neurol 2011; 18:

31 THC:CBD oromucosal spray adverse events (AEs) During the first 4 weeks of exposure, dizziness (14 32%) and fatigue (12 25%) were the most common Aes Usually mild to moderate and resolved quickly When the recommended gradual up-titration schedule was introduced, the incidence of AEs was reduced In clinical trials, the rates of withdrawal due to AEs was low THC:CBD oromucosal spray does not exhibit the side effects typically associated with recreational cannabis use Wade et al. Mult Scler 2004; 10: ; Wade et al. Mult Scler 2006; 12: ; Collin et al. Eur J Neurol 2007; 14: ; Collin et al. Mult Scler 2007; 13: S129 Ambler et al. Mult Scler 2009; 15: S258

32 Treatment-related AEs AEs with highest incidence rates Preferred term Most frequently reported THC:CBD (n = 805) n (%) Placebo (n = 741) n (%) Dizziness 200 (24.8) 52 (7) Fatigue 89 (11.1) 49 (6.6) Somnolence 65 (8.1) 14 (1.9) Psychiatric AEs Disorientation Euphoric mood Depression Dissociation 32 (4) 18 (2.2) 15 (1.9) 14 (1.7) 4 (0.5) 7 (0.9) 6 (0.8) 1 (0.1) Wade et al. Mult Scler 2004; 10: ; Wade et al. Mult Scler 2006; 12: ; Collin et al. Eur J Neurol 2007; 14: ; Collin et al. Mult Scler 2007; 13: S129 Ambler et al. Mult Scler 2009; 15: S258

33 THC:CBD spray: Latest form ECTRIMS 2013 Effects on driving ability Prospective, observational, 4 6 week study conducted in 3 German centres Effects on cognition and mood 50-week, double-blind, randomised, parallel group, placebo-controlled Phase IV study in 6 Czech Republic centres Friedel et al. ECTRIMS 2013: P1111; Wright et al. ECTRIMS 2013: P1206;

34 Effect of THC:CBD spray on driving ability Pilot, prospective observational study conducted in 3 German centres Driving ability tests were assessed before and after 4 6 weeks of THC:CBD spray treatment for MS spasticity N Patient characteristics 33 (60% female) Mean age (range), years 48 (33 68) Time since diagnosis (range), years 11.5 ( ) Time with MS spasticity (range), years 6.6 ( ) Mean EDSS score (SD) 4.5 (1.5) Poster by Freidel et al. Treatment of specific symptoms session. Fri 4 Oct 15:30 17:30. P1111. ECTRIMS 2013

35 Study driving ability tests Standardised, validated computer-based Test applied Visual Pursuit (LVT) Skill tested Visual orientation Cognitrone (COG) Determination (DT) Reaction (RT) Attention and concentration Reactive stress tolerance Attention and reaction speed Effectiveness and Adaptive safety Tachistoscopic results were also recorded Observational ability and Traffic Perception (ATAVT) general traffic perception

36 Percent tage difference from bas seline test scores THC:CBD spray: no effect on driving ability -1,5 Visual Pursuit (LVT) * p= vs baseline 1,2 Cognitrone (COG) Mean dose 5.2 sprays/day No significant changes in 4 out of 5 tests after 4 6 weeks Small but statistically significant improvement in DT scores (reactive stress tolerance; p=0.0255) 1,6 Reaction (RT) 6,1 * 3 2,1 Determination Adaptive Overall (DT) Tachistoscopic Traffic Perception (ATAVT) Poster by Freidel et al. Treatment of specific symptoms session. Fri 4 Oct 15:30 17:30. P1111. ECTRIMS 2013

37 THC:CBD spray: cognition and mood Double-blind, randomised parallel group, placebo-controlled Phase IV study in 6 Czech Republic centres 50-week study in 120 patients with MS of any sub-type and at least moderate spasticity Primary endpoint: Change in cognitive function, assessed by the total Paced Auditory Serial Addition Test (PASAT I and II), between baseline and end of treatment Secondary endpoints: Effect on mood (Beck depression inventory), severity of spasticity and safety / tolerability Poster by Wright et al. Late Breaking News session. Fri 4 Oct 15:30 17:30. P1206. ECTRIMS 2013

38 THC:CBD spray: No effect on cognition or depression over 50 weeks Mean dose 6.4 sprays/day Cognition: no statistically significant effect compared with placebo Beck Depression Inventory: no statistically significant effect vs placebo PASAT score (m max.120) ,1 Cognitive ability 59.4 Baseline Placebo (n=52) THC:CBD spray (n=55) 68, Final visit Poster by Wright et al. Late Breaking News session. Fri 4 Oct 15:30 17:30. P1206. ECTRIMS 2013

39 Summary: THC:CBD spray: Cognition and mood study After 50 weeks of treatment with THC:CBD spray: Cognition not affected Not associated with depression Improvements in spasticity confirmed by patient, physician and carers Well tolerated; no new tolerability issues Few withdrawals Poster by Wright et al. Late Breaking News session. Fri 4 Oct 15:30 17:30. P1206. ECTRIMS 2013

40 Conclusions THC:CBD oromucosal spray in clinical practice THC:CBD oromucosal spray in clinical practice provides relevant relief of MS spasticity in patients previously resistant to treatment Clear improvements were noted in associated symptoms (e.g. sleep disturbances due to MS spasticity, bladder, mobility) No AEs were reported for > 80% of patients. There was a limited risk of serious AEs Long-term data support that response to THC:CBD oromucosal spray is maintained without the need to increase dose and without the risk of AEs

THC:CBD Observational Study Data: Evolution of Resistant MS Spasticity and Associated Symptoms

Review Published online: February 23, 2016 THC:CBD Observational Study Data: Evolution of Resistant MS Spasticity and Associated Symptoms Maria Trojano Department of Basic Medical Sciences, Neurosciences