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Newron Pharmaceuticals SpASIX: NWRN Annual media & analyst

March 1, 2016

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2015 – a year to be remembered • EU approval of Xadago® • CH approval of Xadago® • Zambon launch of Xadago® (safinamide) in Germany and (post period) in Switzerland, Spain and Italy • Xadago® - late-cycle review meeting completed with FDA – PDUFA date 29 March 2016 • Meiji Seika Pharma: initiation of Phase II/III and Phase III long-term trials with safinamide in Japanese patients • ODD for the treatment of patients with Rett Syndrome for the EU and the US • Plan for international double-blind, placebo-controlled efficacy study with sarizotan in patients with Rett Syndrome • Completion of first in man US Phase I study of NW-3509• U.S. Phase II study initiation with NW-3509 in patients with schizophrenia• Completion of EUR28.3m Private Placements with leading EU and U.S. About Newron Pharmaceuticals • CHF300m Market Cap, listed on SIX Swiss Exchange (NWRN)• Driven to deliver effective treatments to patients living with debilitating Central Nervous System (CNS) diseases • Xadago® (safinamide) for Parkinson's disease: – EU Commission grants Marketing Authorization Feb. 24, 2015 – Launched in key EU markets: Germany, Spain, Italy– Swissmedic grants Marketing Authorization Nov. 12, 2015– Launched in Switzerland: Jan. 2016– Accepted for filing by the FDA March 2, 2015 PDUFA date: March 29, 2016 • Material revenues from license agreements• Moving towards a CNS-specialty, commercial orphan company Licensing Revenues Phase II Orphan Drug Portfolio Xadago® (safinamide) for PD Development-stage assets Orphan neuropathic pain Phase II asset for schizophrenia Stefan Weber
Ravi Anand
Marco Caremi
Roberto Galli
Pipeline Overview Commercial Rights Xadago® (safinamide)1 Adjunctive to dopamine agonist early-stage PD Adjunctive to levodopa mid-to late-stage PD Orphan indication in neuropathic pain 1 Safinamide, NW-3509 and Ralfinamide all developed from Newron's ion channel based research 2 Sarizotan was licensed from Merck Germany Valuable Assets with Licensing and Commercial Opportunities Xadago® (safinamide) • Schizophrenia • Rett syndrome Marketing Authorizations – EU: Feb. 24, 2015 • World-wide anti-psychotic • Orphan patient population: – Switzerland: Nov. 12, 2015 35K-40K in U.S. and EU – US PDUFA: Mar. 29, 2016 - ODD in US and EU Phase II initiated Dec. 2015 • Material revenue generating • Initiate Phase II/III potentially pivotal study in Q2/2016 – Zambon– Meiji Seika in Japan/ Asia • Licensed worldwide; U.S.
sublicense pending • Peak sales potential: $450M+ Licensing Opportunity Launch First Orphan Product by 2018 Xadago® (safinamide) – First NCE Approved for PD in a Decade Commercial Rights Adjunctive to dopamine agonist early-stage PD Adjunctive to levodopa mid-to late-stage PD Xadago® (safinamide) – First NCE Approved for PD in a Decade Azilect (rasagiline) last NCE approved in 2006; No NCE pipeline candidates within 5 years Xadago® (safinamide) – Once daily oral Efficacy and safety adjunctive therapy for all stages of PD demonstrated as add-on to • Alpha-amino amide derivative, high solubility and bioavailability with quick onset and long • dopamine agonists lasting effects (> 2 years) through • First PD therapy working through dual
• L-dopa (mid to late mechanism; current PD treatments only enhance dopaminergic function mechanism
– Enhances dopaminergic function– Reduces glutamatergic activity Xadago® (safinamide) Offers Multiple Benefits to PD Patients with Long Duration of Effect Early PD Patients – add
Mid- to late-stage PD Patients
to dopamine agonist Long-Term Duration of Effect
add to dopamine replacement • Significant improvement of • Significant improvement of ON Time (without troublesome
dyskinesia) - Change from Baseline UPDRS III - motor – ON Time/OFF Time – function, regulatory regulatory endpoint – UPDRS II – activities of daily change, responder rate) – Quality of life (PDQ-39, – UPDRS III – motor function – UPDRS IV – treatment Reduction of number of interventions (first time use CGI (clinical global impression) – severity and improvement • Benefits seen after 6 and – GRID HAMD (depression) • Additional ON Time Without Any • Delay levodopa Increase In Any Dyskinesia • Dyskinesia significantly improved• Benefits seen after 6 and 24 Clinical Trials Support Long-term Patient Benefits Study NW 009 (172 pts) Study NW 015 (269 pts) Dopamine
Study 27918 (679 pts) Study NW 016 (669 pts) DB extension
Study 27919 (549 pts) Double blind (DB) Xadago ® (safinamide) – Approved in EU and CHU.S. PDUFA Date March 29, 2016 EU Marketing Authorization:
• Both dopaminergic and non-dopaminergic
EU: Marketing
Authorization Feb. • Sustained efficacy for 2 years for ON Time, OFF Time and UPDRS III • "Very much/much improved" in Clinical Global Accepted for filing by the E - Feb. 22, 2016FDA I - Feb. 29, 2016 Significant improvement in activities of daily • PDUFA Date: Mar. 29, living (UPDRS III) Launches further EU territories Q1- • Extremely well tolerated • No drug interactions; no age, gender or race • No dietary restrictions Authorization Nov. • No requirement for laboratory tests, ECG, or any other examination Launch: Jan. 12, Significant effects in early-stage PD patients Xadago ® (safinamide) – Commercial Opportunity Identifying parties for regional sublicensing Milestone and royalty revenues to Newron since 2012 Long lasting market exclusivity (patent life: 2029 in EU, 2030 in the U.S.) Sarizotan – Targeting respiratory disturbances in Rett syndrome Commercial Rights SarizotanRett syndrome Rett Syndrome Causes Severe Disability,Reduces Life Expectancy in Girls Rett Syndrome, or

71.5% chance of surviving
Unmet Need:
Severe neurodevelopmental to age 25 years (vs 99.9%)
disorder primarily affecting • No specific cure females (1:10,000) 60% survival at 37 years
Mutations in X-linked methyl Focus on symptom (vs. appr. 98%)
CpG-binding protein 2 in majority of patients Medication needed for Normal development until 6-18 months of age, then lose fine breathing irregularities, motor skills, ability for social 25% of sudden
motor difficulties, interaction, encounter seizures' control linked to cardio- Sarizotan Has Potential to Treat Respiratory & Other Symptoms • Aminomethyl chromane derivative; new chemical entity • Breathing disturbance in Rett syndrome postulated to involve neuronal hyperactivity in the brainstem (Raphe nucleus, Kölliker-Fuse nucleus, Bötzinger complex) • Dramatic effect demonstrated on respiration in null mutant MeCP2 mouse model of • Potential additional benefits in other core features of Rett syndrome Neurological deficits Sarizotan Reduced Respiratory Arrythmia in Pre-Clinical Studies Effects of single administration of Sarizotan (5 mg/kg ip) in RTT female mice (Mecp2 Jae/+ + Mecp2 Bird/+ )
Mean data
in sarizotan
Data from individual
Change vs
Plethysmograph in a vehicle treated Mecp2Jae/+ treated RTT
↓ by 86%
Plethysmograph in the same Mecp2Jae/+ female mouse after administration of Sarizotan 5 mg/kg i.p. ↓ by 82%
(p= 0.0001)
Incidence of apnea and
irregularity were significantly
reduced by sarizotan at 20

↑ by 16%
mins compared to vehicle
(p = 0.012)
Mecp2 Jae/+ n=4
Mecp2 Bird/+ n=6
Sarizotan Reduced Respiratory Arrythmia in Pre-Clinical Studies Effects of 14-day treatment with Sarizotan in RTT female mice (Mecp2R168X/+)
Change vs control
Outcomes definition
(vehicle treated)
and units
↓ by 73.9% on Day 7
14-day treatment with Sarizotan
(p < 0.05)
(13.8 ± 1.9 mg/kg per day) was
(number apneas per ↓ by 75% on Day 10
(p < 0.01)
effective in improving respiration
↓ by 75.6% on Day 14
(p < 0.01)
in Mecp2R168X/+ female mice
significant decrease
A crossover design was used so that half of the Mecp2R168X/+ female mice Frequency (breaths
(n=4) received vehicle (1.25% DMSO + 0.1% saccharin) in their drinking water and half (n=4) received sarizotan (0.0625 mg/ml). At the end of 14 days, the treatment was reversed30 min monitoring of respiratory pattern with plethysmography performed on the 4th, 7th, 10th and 14th day of vehicle or sarizotan. *p=<0.05, **p=<0.01 vs corresponding day receiving vehicle Sarizotan has Clear Clinical Development, Regulatory and Commercialization Path • EU (Germany, Spain, UK ) Health Authorities accepted proposed CMC/preclinical/clinical safety data package, agreed to single pivotal study: Q2/2015 • Similar agreements with Canadian (TPD) and US (FDA): Orphan exclusivity 7.5 years post
Orphan Drug Designations obtained in EU and US: July 2015 • Interaction with Pediatric Development Committee (EMA) to extend age range to younger patients: Q3/2015 • Advocacy relationships being developed; Rett foundations for potential funding/co-sponsorship of activities • ‘Rare Pediatric Disease' voucher possibility Orphan exclusivity
12 years post approval
2016 Major Sarizotan Inititiatives • Launch of first ever Phase 3 pivotal study in Rett syndrome under a US IND – Double-blind, randomized placebo-controlled, 28 week, multi-center design in min. 90 – Primary endpoint: Reduction in number of objectively defined apnea episodes • Initiation of Global Caregiver Outreach Program – In partnership with Rett foundations – Collecting and distributing data on impact of respiratory abnormalities: • ER visits, hospitalizations, effect on development, lost school days, feeding problems, staring episodes, worsening of cardiac functioning including QTc abnormalities, cost of treatment • Development of Caregiver Satisfaction Assessment Instrument – together with Rett foundations • Discussions with Pharmacy Benefit Managers/Pricing and re-imbursement representatives of EU needs for Rett treatments • Establishing Step guidelines for Rett Syndrome with Rett experts NW-3509 – Schizophrenia Commercial Rights NW-3509 Schizophrenia NW-3509 Brings New Mechanism to Schizophrenia Treatment • First in class voltage-gated sodium channel (VGSC) blocker for add-on treatment in schizophrenia, schizo-affective and bipolar disorders • Novel small molecule, oral available, rapid onset of action, high availability in the brain • Potential to address poorly responding patients with schizophrenia/mania• Benefit shown in models of positive symptoms, aggression, cognition (schizophrenia), negative symptoms, mania, depression, obsessive behavior • IND approval from FDA as add-on to antipsychotics for patients with psychosis• Phase I study completed – Drug was well tolerated– Exposure increased with dose– Exposure overlaps with exposure in animals at doses proven to be efficacious • Phase II placebo-controlled study started • Large market opportunity (anti-psychotic market >$23bn)• Composition of matter – USPTO, 2013 - Patent life 2028 plus extension Unique MOA: selective Voltage-Gated Sodium Channel (VGSC) Blocker Inhibition of naive sodium channels expressed in rat Selectively blocks VGSCs in a
voltage-and use-dependent manner
High frequency firing Low frequency firing Modulates sustained repetitive
firing without inducing impairment
of the normal neuronal excitability
NW-3509 1µM
Add-On: Amphetamine-induced PPI Deficit Model NW-3509 augments the effect of typical and atypical antipsychotics in amphetamine-induced PPI deficit Amph (2.5 mg/kg sc) and NW-3509A (1.25 or 0.62 mg/kg po) were administered 5 min before PPI session. Haloperidol and risperidone were administered ip 30 min before PPI session at 0.05 mg/kg. Statistics: Tukey's multiple comparison test *p<0.05, ***p<0.001 vs Vehicle+Amp (n=6-18 rats per group) (Studies performed by Dr Bortolato, Dept. of Pharm. Sciences, Univ. Cagliari- USCLA) Preliminary Validation of a novel treatment concept Phase II MTD study with NW-3509 as add-on in positive symptoms of schizophrenia• NW-3509 as add-on treatment to patients with stable and adequate dose of standard therapy, experiencing break-through symptoms Double blind, placebo controlled, randomized, 4-week in/outpatient study in 2 US sites in minimally 60 patients receiving NW-3509 15-25 mg/daily (given BID) or placebo Selection Criteria: – Current diagnosis of schizophrenia in accordance with DSM-5– PANSS (Total ) < 80; CGI-S rating of mildly, moderately, or moderately severely ill – Excludes patients with hallucinatory behavior, excitement, delusions, suspiciousness/persecution and – Endpoints: Symptoms of schizophrenia, as assessed by • Positive and Negative Syndrome Scale (PANSS),• Clinical Global Impression - Change from baseline (CGI-C) and CGI - Severity of illness (CGI-S) Enrollment started: Jan 2016 Results expected by end 2016 Milestones/News Flow 2 0 1 6 / 2 0 1 7
Sarizotan in Rett syndrome • Market approval/launch • Phase II/III pot. Pivotal efficacy study initiate: Q1/2016
– EU next launches: Q1,2/2016
• Results from Phase II/III pot. pivotal study: 2017 – US PDUFA date: March 2016
• Commercialization by Newron: 2018 • US sublicense by Zambon: 2016 NW-3509 in Schizophrenia • Phase II results Q4/2016
• License transaction Group Consolidated Financials 2015 (IFRS) Financial Highlights 2015 – Income statement • First time ever, Newron P/L shows royalties (German sales from May 15, 2015 on)• Substantial increase in R&D investments Research and development (18,449) (6,017)
Marketing and advertising expenses
General and administrative expenses Financial result, net Loss per share
Financial Highlights 2015Balance Sheet and Cash flow statements Net cash used in operating Non-current assets Net cash flows from/(used in) investing activities Total shareholders' equity Net cash flows from/(used in) Non-current liabilities financing activities Current liabilities Net increase/(decrease) in cash and cash equivalents Cash used in operating activities below 2015 Current assets increased because of capital increases (newly issued shares and options' Total funds available: €41m (beyond key value inflexion points) AGM/EGM March 22, 2016 Approval of the balance sheet as at 31 December 2015 Appointment of the statutory auditors for the three year time 2016-2018 Appointment of the auditing company for the period 2016-2018 Share capital increase pursuant to article 2443 of the Civil Code, in one or more time, severally (in via scindibile), even with the exclusion of the option right pursuant to article 2441, parts 4, first section, 5, 6 and/or 8 of the Civil Code, provided that in the whole the increases in the share capital can be executed for a maximum par value not higher than Euro 711.177,20 and therefore for a maximum of n. 3.555.886 ordinary shares Share capital increase pursuant to article 2420-ter of the Civil Code, to issue convertible bonds in one or more time, severally (in via scindibile), even with the exclusion of the option right pursuant to article 2441, part 5 and 6 of the Civil Code, provided that in the whole the increases in the share capital can be executed for a maximum par value not higher than Euro 711.177,20 and therefore for a maximum of n. 3.555.886 ordinary shares Increase in the share capital, severally (in via scindibile), for payment, with the exclusion of the option right, within the limit of 10% of the share capital pursuant to article 2441, part 4, second section, of the Civil Code, provided that in the whole the increases in the share capital can be executed for a maximum par value not higher than Euro 711.177,20 and therefore for a maximum of n. 3.555.886 ordinary shares Subject to approval and execution, even partial, of resolutions under points 4, 5 and 6 above, revocation: of the resolution adopted on 27 March 2014, drafted by Notary Public Filippo Zabban of Milan, rep. 66.143/11.351 granting to the Board of Directors, pursuant to article 2443 of the Civil Code, the power, within 27 March 2019, to increase the share capital for payment, severally (in via scindibile), in one or more time, up to a maximum par value of Euro 375,844.00 and therefore up to maximum no. 1,879,220 Newron Pharmaceuticals S.p.A. ordinary shares having the same characteristics of the already issued ones, with exclusion of the option right pursuant to Article 2441, part 5, of the Civil Code; of the resolution adopted on 2 April 2010, minuted by Notary Public Stefano Rampolla of Milan, rep. 34893/8887, upon the several (in via scindibile) share capital increase in option up to a maximum par value of Euro 375,844.00 through the issuance of maximum no. 1,879,220 ordinary Newron Pharmaceuticals S.p.A. shares

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Draft agenda sia standards committee meeting - 2009/04/0

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