idorsia – reaching out for more · the purpose of idorsia is to. discover, develop and bring...

Idorsia –Reaching out for more

The following information contains certain “forward-looking statements”, relating to the company’s business, which can be identified by the use of forward-looking terminology such as “estimates”, “believes”, “expects”, “may”, “are expected to”, “will”, “will continue”, “should”, “would be”, “seeks”, “pending” or “anticipates” or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company’s investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company’s existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected.

Idorsia - Reaching out for more | July 20182

15 June 2017


The purpose of Idorsia is todiscover, develop and bring more,innovative medicines to patients.

We have more ideas, we seemore opportunities and we wantto help more patients.


Highlightsin 2018 First patients

Enrolled into the Phase 3 study with lucerastat for Fabry disease

Enrolled into the Phase 3 program with nemorexant for insomnia

First patientsEnrolled into the Phase 3 study with aprocitentan for resistant hypertension management

First patients

For development of our pipeline and keep us on track to deliver on our strategic priorities

Financing secured


Idorsia Today

>700Highly qualified professionals

11

>1 bn > 550State-of-the-artlaboratory workspaces

Compounds in the pipeline,with four progressing tolate-stage development inthe year ahead

Swiss francs in cash


Our Strategic Priorities

Deliver at least three products to market

Build a commercial organization

Bring Idorsia to profitability in a sustainable manner

Create a pipeline with a sales potential of CHF 5 billion

Utilize state-of-the-art technologies

5 key priorities to ensure the company’s success over the next 5 years

5

4

3

2

1


Diversified and balanced pipeline: CNS, cardiovascular and immunological disorders & orphan diseases

More in the pipeline –Promising compounds Vasospasm associated

with aneurysmal subarachnoid hemorrhage (aSAH)

ClazosentanEndothelin receptor antagonistStatus: Advancing to Phase 3

Resistanthypertensionmanagement

AprocitentanDual endothelin receptor antagonistStatus: Phase 3 Insomnia

NemorexantDual orexin receptor antagonistStatus: Phase 3

Fabry disease

LucerastatGlucosylceramide synthase inhibitorStatus: Phase 3

Duchenne muscular dystrophy

VamoroloneDissociative steroidStatus: Phase 2Idorsia has an exclusive optionto the worldwide rights for ReveraGen's vamorolone

Acute Coronary Syndrome

ACT-246475P2Y12 receptor antagonistStatus: Phase 2

Systemic lupus erythematosus

CenerimodS1P1 receptor modulatorStatus: Phase 2

Orphan CNS diseases

ACT-519276GBA2/GCS inhibitorStatus: Phase 1Epilepsy

ACT-709478T-type calcium channel blockerStatus: Phase 1

Anxiety

ACT-539313Selective orexin 1 receptor antagonistStatus: Phase 1

Nasal polyposis

ACT-774312CRTH2 receptor antagonistStatus: Advancing to Phase 2

In collaboration with Janssen Biotech, Inc.


Lucerastatin Fabry disease

Lucerastat is investigational, in development and not approved or marketed in any country.


Fabry disease is a rare inherited lysosomal storage disorder in which a particular lipid (a fat-like substance) can’t be broken down by the body, leading to its build-up in the cells of the body organs which results in cell and organ damage

Fabry disease is often undetected or misdiagnosed

As the disease is progressive, early diagnosis is essential to manage the symptoms as soon as possible and reduce the risk of developing serious complications

Fabry disease


• Lipids are fat-like substances such as fatty acids, oils, waxes and steroids. A well-known example is cholesterol

• Lipids are stored naturally in the body’s cells and organs and are vital to their healthy functioning

• Normally, the body is able to process lipids effectively, which keeps them within healthy levels

What is the role of lipids in the body?

What happens in patients with lysosomal storage disorders?Normal breakdown of lipids

When enzyme to break downlipid is deficient

Lipid (fatty molecules) Broken-down lipids exit cell to be processed further

Unbroken-down wasteProducts collect in cell

Lipids can’t be processed and build up in cell


Fabry diseaseBiochemical mechanism

Cer ceramideGCS glucosylceramide synthaseGlcCer glucosylceramideGb3 globotriaosylceramidelysoGb3 globotriaosylsphingosineα-GalA α-galactosidase ASM sphingomyelinSph sphingosine

Dysfunctional or absent α-galactosidase A results in accumulation of Gb3 in various organs

Plasma Membrane

Late endosome + lysosome

cis-Golgi

lysoGb3

Gb3

Gb3

Sph

Sph

Cer

SM

GlcCerGCS

α-GalA

Gb3


X-linked recessive genetic disease

Inheritance pattern in Fabry disease

• GLA gene mutation results in defective lysosomal enzyme α-GalA

• In turn, this results in Gb3 accumulation

Random X-inactivation in Fabry female ‘carriers’: both genders affected

Male have generally classical phenotype

Females have higher residual level enzyme and• are affected later • progress slower • have more variable phenotype


Large spectrum of clinical, heterogeneous manifestations

Clinical manifestations of Fabry disease

BrainStrokes (in severe

cases), and dizziness

Neuropathic pain Pain resulting from

damage to or dysfunction of the nervous system

EyesThe appearance

of the eyeschanges

EarsTinnitus,

hearing loss,and vertigo

HeartCardiomyopathy with arrhythmia,

valvular dysfunction,ischemia, left heart

failure

KidneysCysts, reduced kidneyfunction, progressive

kidney failure

SkinDark red spots orrashes, burning /

tingling sensations, sensitivity to

temperature and profuse sweating

Digestive Tract Abdominal pain,

constipation, diarrhea, and nausea

Fabrydisease

• Gradually progressing in severity from childhood to adulthood

• Major impact on quality of life

• Slow progressive damage to vital organs over decades

• Earlier death


Diagnosis of Fabry disease

Clinical symptomsNeuropathic pain, GI, hearing loss, hypohydrosis

Clinical eventsStroke, cardiac and renal events

Pedigree analysisFamily members

(between childrenand parents)

Enzyme assayLeukocyte α-GalA

Genotyping>830 mutations

BiomarkersGb3 in plasma and urine


Epidemiology of Fabry disease

Group Total Male Female

EU-28

All ages 7,324 2,509 4,815

<18 years 659 279 380

<10 years 268 75 193

US

All ages 4,607 1,578 3,029

<18 years 414 175 239

<10 years 168 47 121

Estimated prevalence of diagnosed Fabry disease in general population (2001): 1.4 per 100’000

1.0per 100.000

Incidence of Fabry disease per year

Patients diagnosed with Fabry disease in EU28 and US in 2014

1.9per 100.000

0.01 – 0.03 per 100.000

up to 0.05per 100.000


Current therapies in Fabry disease

No curative therapy

Symptomatic treatments not satisfactory

Etiological therapies limited

Enzyme replacement therapy

• Fabrazyme (agalsidase beta) (US and EU)

• Replagal (agalsidase alfa) (EU only)

• i.v. infusion, bi-weekly

• Immunogenicity

• Partial efficacy

Chaperone therapy

• Galafold (migalastat) (EU only)

• Galafold for patients with amenable mutation

• 1 capsule orally, fasted, every other day


Lucerastat in Fabry disease

Access to most tissues, including peripheral & central nervous system

Highly soluble with complete absorption

Inhibitor of glucosylceramide synthase

Oral administration

Low molecular weight iminosugar

Renal excretion of unchanged drug

Orphan drug status granted in the US and EU



Plasma Membrane

Late endosome + lysosome

cis-Golgi

lysoGb3

Gb3

Gb3

Sph

Sph

Cer

SM

GlcCerGCS

α-GalA

Gb3

Mode of action



lucerastat

By inhibiting GCS, lucerastat reduces the precursor of Gb3 (GlcCer) and Gb3 itself

Cer ceramideGCS glucosylceramide synthaseGlcCer glucosylceramideGb3 globotriaosylceramidelysoGb3 globotriaosylsphingosineα-GalA α-galactosidase ASM sphingomyelinSph sphingosine


Patient survey

Clinical development plan



Clinical pharmacology studies

Exploratory study

Confirmatory study

Pediatric study

Potential beyond initial plan

• SAD and MAD studies• Renal impairment study• tQT study

• Safety and proof of mechanism study

• MODIFY

• Study to run in parallel to MODIFY

• Plan agreed with EMA

• Better understand medical need from patient perspective


Clinical pharmacology



Dose-proportional exposure

Half-life: approximately 6 hours –twice daily dosing

>85% of the dose excreted unchanged in urine

Negligible food effect

Low potential for drug-drug interaction

Dose adjustment required in subjects with renal function impairment

eGFR(mL/min/1.73 m2)

Dosing regimen(mg b.i.d.)

≥ 60 1000

≥ 45 and < 60 750

≥ 30 and < 45 500

≥ 15 and < 30 250

Guérard et al. (2017) Orphanet J Rare DisGuérard et al. (2017) J Clin PharmacolGuérard et al. (2018) Clin Pharmacol Ther


Exploratory study design



lucerastat on top of ERT (10 patients)

D1 Monthly visitMonth 1

Admission Randomization

Screening Treatment Period Follow-up

D-28 / D-3 (-10)

ERT (4 patients)

EoSMonth 3

Monthly visitMonth 2

+ 2 DaysPhone Call for patients

who received lucerastat

+ 30 DaysPhone Call

Prospective, single-center, open-label, randomized, study in 14 male/female adult patients with Fabry diseasereceiving enzyme replacement therapy (ERT)

Phase 2study


Primary objective

• To assess the safety and tolerability of lucerastat 1000 mg b.i.d. for 12 weeks

Secondary objectives

• To investigate the effect of lucerastat on plasma biomarker levels following a 12-week treatment

• To assess the effect of lucerastat on renal and cardiac function

• To determine the 12-hour pharmacokinetic profile of lucerastat at steady state

• To identify metabolites in plasma

Exploratory study objectives



Phase 2 study


Exploratory study patient demographics


• All patients had comorbidities, most of them manifestations of Fabry disease

• None of these affected eligibility for the study

• Overall balanced between groups

Lucerastat group• 6 females, 4 males

• Mean age (SD): 47.7 (15.0), range from 18 to 67

• Mean ERT duration in years (SD): 4.5 (2.6)

Control group• 4 males

• Mean age (SD): 39.8 (19.1), range from 21 to 62

• Mean ERT duration in years (SD): 6.3 (4.2)


Phase 2 study

Medical history:


Exploratory study safety results


Lucerastat was safe and well tolerated in patients with Fabry disease over 12 weeks on top of ERT

One Serious Adverse Event, unrelated to lucerastat:Re-occurrence of atrial fibrillation in a patient with underlying hypertrophic cardiomyopathy

No specific pattern in the nature and distribution of Treatment-Emergent Adverse Events

No trends for changes from baseline in:Vital signs, body weight, ECG recordings, clinical laboratory parameters


Phase 2 study


Exploratory study biomarker results – Biomarker reduction


Biomarker Lucerastat group Control group

Plasma Gb3 -55.0% (10.5) -6.9% (12.6)

Urine Gb3 -52.5% (21.2) -8.6% (54.4)

GlcCer -49.0% (16.5) -6.5% (9.7)

LacCer -32.7% (13.0) -3.9% (2.8)

Mean % (SD) biomarker reduction from baseline at week 12

Day 1 Month 1 Month 2Visit

Month 3

-80

-60

-40

-20

0

20

40

% c

hang

e fr

om

Bas

elin

e

Control (n=4)Lucerastat (n=9)


Phase 2 study


Exploratory study conclusions


Lucerastat was safe and well tolerated in patients with Fabry disease over 12 weeks on top of ERT

Pharmacokinetic findings consistent with previous studies in healthy subjects

Proof of mechanism achieved with lucerastat:Lucerastat significantly reduced Fabry disease-elevated Gb3 and other relevant biomarkers


Phase 2 study


Goals

Fabry patients survey

Better understand patients’ disease and needs from the patient perspective

Investigate key aspects of Phase 3 study MODIFY with respect to symptoms: neuropathic pain and gastrointestinal symptoms

Complement existing information/data from the literature

1 2 3In addition, collect information on:• Use of enzyme replacement therapy (ERT)

• Impact on daily life

• Participation in clinical trials


Key results

Fabry patients survey

• Fabry patients experience significant Neuropathic Pain

• Combining intensity, frequency & location

• GI symptoms are heterogeneous in nature and frequency

• Large impact of neuropathic pain on quality of life

• Large majority of patients are willing to participate in a clinical trial

Moderate to severe

pain

Pain in hands and

feet

Frequent pain

51.5% (189/367) of patients report frequent pain AND

moderate/severe pain

52.0% (191/367) of patients report frequent pain AND

pain in hands & feet

74.7% (274/367) of patients report pain in hands & feet AND

moderate/severe pain

50% of the patients report all

three

N=367


Designing the confirmatory study



• Informed design based on patients survey

• Development of endpoint measurement – neuropathic pain, based on Brief Pain Inventory instrument, modified for Fabry’s neuropathic pain according to FDA guidelines for PRO

− Concept elicitation

− Cognitive debrief

− Usability testing in different languages

• Development and validation of electronic tool to collect pain and gastro-intestinal daily data

• Input from patient organization and from specialists

• Input from regulatory agencies including FDA, and in Europe through scientific advice and the VHP procedure

Phase 3 studyMODIFY


Confirmatory study objectives


Primary objective• To determine the effect of lucerastat on neuropathic pain

in patients with Fabry disease

Secondary objectives• To determine the effect of lucerastat on gastro-intestinal symptoms

(abdominal pain and diarrhea) in patients with Fabry disease and GI symptom(s) at baseline

• To confirm the effect of lucerastat on biomarkers of Fabry disease

• To determine the safety and tolerability of lucerastat in patients with Fabry disease


Phase 3 studyMODIFY


Confirmatory study design


Screening 6-7 weeks Treatment 6 months

Randomization 2:1 (N=108)

Open, uncontrolled, Extension

Lucerastat (n=72)

Placebo (n=36)

Primary/secondary efficacy endpoints

Site visitsScreening, Randomization, Months 1, 2 (phone), 3, 4 (phone), 5, 6 + 2 FU visits (phone)

Stratification by• Sex• ERT use (on ERT at screening vs

never treated/previously treated)

Lucerastat dose• 1000 mg b.i.d. • Adjusted in subjects with

moderate renal failure


Phase 3 studyMODIFY


Confirmatory study patient population


Wee

k 1

Wee

k 2

Wee

k 3

Wee

k 4

Wee

k 5

Wee

k 6

Wee

k 7

ERT bi-weekly for at least 12 months (stable dose regimen during the last 3 months)

ERT bi-weekly No ERT in at least the last 6 months

Never treated with ERT

Last ERT

Switched patients

Pseudo-naïve patients

Naïve patients

Screening period

Randomization

Diary card, no ERT

Placebo

Lucerastat

• Confirmed Fabry disease – presence of at least 1 mutation in GLA (the gene coding for α-galactosidase A) as measured with genetic test

• Neuropathic pain in the last 3 months preceding the screening period

• Three options for ERT status at baseline


Phase 3 studyMODIFY


Confirmatory study endpoints


Primary efficacy endpoint• The primary efficacy endpoint is a response to study treatment on neuropathic

pain, defined as a reduction from baseline to Month 6 of at least 30% in the “modified” BPI-SF3 score of “neuropathic pain at its worst in the last 24 hours”.

Secondary efficacy endpoints• Change from baseline to Month 6 in the average daily 11-point Numerical

Rating Scale (NRS-11) score of “abdominal pain at its worst in the last 24 hours” in subjects with GI symptoms at baseline.

• Change from baseline to Month 6 in the number of days with at least one stool of a Bristol Stool Scale (BSS) consistency Type 6 or 7 in subjects with GI symptoms at baseline;

• Change from baseline to Month 6 in plasma globotriaosylceramide (Gb3).


Phase 3 studyMODIFY


• Fabry disease is a rare genetic disorder with limited therapeutic options and a high medical need

• Lucerastat is a small molecule, oral monotherapy with the potential as a new treatment approach for patients with Fabry disease, irrespective of their genetic mutation type

• Proof of mechanism achieved in exploratory study where lucerastat was well-tolerated

• Lucerastat has orphan drug status in US and EU

• Phase 3 study to assess effects of lucerastat on neuropathic pain and safety and tolerability – ongoing

• Pediatric study planned to run in parallel


Fabry diseaseCompound: Lucerastat

Mechanism of action: Glucosylceramide synthaseinhibitionStatus: Phase 3

Summary



Nemorexant in insomnia

Nemorexant is investigational, in development and not approved or marketed in any country.


Chronic insomnia disorder

Difficulty Falling Asleep

Difficulty Staying Asleep

Waking Too Early

Sleep-Onset Insomnia

Sleep-Maintenance Insomnia

Sleep-Offset Insomnia

Distress or Impairment of life

More than 1 type of disturbance present ≥ 3 nights/week for ≥ 3 months


Who gets insomnia and what is the impact ?

Risk factors• Age (more common with ageing)

• Gender (women > men)

• Lower socio-economic status

• Physical disorder

• Psychiatric disorder (depression, anxiety, alcohol and drug abuse)

Impact • Physically and mentally fatigued,

anxious and irritable

• Increased the risk of malaise, fall, accidents, and injury

• Impaired daytime performance

• Decreased memory and concentration, cognitive decline

• Leading cause of absenteeism and reduced productivity, burden to society

• Higher rate of mortality

Insomnia is a common problem


How is insomnia treated, what are the limitations?

Sleep hygiene• Active

patient participation required

Cognitive behavioral therapy• Recommended first-

line therapy but inconsistently practiced

• Not easily accessible

• Often notreimbursed

• Active patient participation required

Pharmacological therapy • Many have significant limitations

• Insufficient acute effect: lack of sustained effect through the night

• Insufficient long-term effect: lack of continued benefit over time

• Next morning residual effect

• Abuse potential, withdrawal effect and rebound

• May have significant adverse effects


The orexin system is crucial for the regulation of wakefulness

Orexin stimulates many wake-promoting pathways

Norepinephrine (LC)

Acetylcholine (LDT, PPT)

Dopamine (VTA)

Serotonin(raphe)

orexin

Histamine (TMN)

LHA / PH

LC

TMN

Raphe

LTD / PPT

VTA

Orexin

OX1R

OX2R

OX1R and OX2R

OX1R and OX2R

OX1R and OX2R

Sakurai, T. 2007LHA = lateral hypothalamic area; PH = posterior hypothalamusLC = locus coeruleus; TMN = tuberomammillary nucleus; LDT = laterodorsaltegmental nucleus; VTA = ventral tegmental area; PPT = pedunculopontine nucleus


Rationale


Potent dual orexin receptor antagonist at OX1 and OX2 receptors

Brain penetratingThe orexin system is involved in the regulation of sleep and arousal

Dual orexin receptor antagonism specifically targets excessive alertness, in contrast to treatments of insomnia that act via broad sedation of the CNS



Translation: preclinical healthy subjects patients


Desired profileHigh in vitro potency

in vivo efficacy

Quick absorption and short half-lifefast onset of action, “appropriate” duration of action to actthroughout the night, and to avoid next morning residual effect

Safety is key• No deterioration of next-day performance• No rebound, no withdrawal symptoms upon treatment cessation• No safety concerns



Clinical development


• Single and multiple ascending dose

• Adults and elderly subjects

• Night time administration

• Pharmacokinetic and pharmacodynamic characterization

• Two studies, in adults and elderly patients with insomnia

• All information required to design confirmatory pivotal studies

Entry into man studies


program

Phase 3 confirmatory

studies

Phase 2 studies

Today



0

200

400

600

800

1000

0 24 48 72 96 120 144 168

Ideal pharmacokinetic profile


Plasma concentrations(ng/ml)

• Fast absorption• Short half life• No accumulation over time

Time(h)

25 mg




Fast and time limited pharmacodynamic effect


Elderly Healthy Volunteer –Daytime dosing

Person performing eye movement test

Adult Healthy Volunteer –Daytime dosing

25 mg Speed of eye movements (degree/sec)

Time (h)




No pharmacodynamic effect on next morning


Karolinska Sleepiness Scale Score

Very sleepy

Sleepy, but no effort keeping awake

Neither alert nor sleepy

Alert, normal level

Very alert

9

8

7

6

5

4

3

2

1

Time after first dose (h) – measures 8 hours after dosing

Placebo 25 mg




Phase 2 studies – Purpose and objectives


PurposeTo provide necessary information to adequately design the confirmatory trials

Focus in particular:• Dose definition

• Patient population characterization

• Endpoint definition

ObjectivesTo characterize the dose response on objective and subjective sleep parameters

To document the safety profile including adverse events, residual effect, rebound and withdrawal

Phase 2studies



Two Phase 2 studies completed – Informative design


Adult study: classical parallel group design

• 4-week treatment to assess durability of effect

• Short treatment withdrawal at the end

• 4 dose levels (5 mg, 10 mg, 25 mg and 50 mg)

• Placebo and active arms (zolpidem)

• Objective and subjective sleep parameters

Elderly study: cross over design

• 2-night treatment

• 4 dose levels identical to adults

• Placebo-controlled

• Objective and subjective parameters

In both studies, well-characterized insomnia patientsSelf-reported insomnia at entry

≥ 30 minutes to fall asleep

Wake time during sleep ≥ 30 minutes

Total sleep time ≤ 6.5 h

Confirmed by polysomnography at baseline

Mean LPS ≥ 20 min

Mean WASO ≥ 30 min

Mean TST < 420 minutes

Sleep induction

Sleep maintenance

Total sleep time

Phase 2studies



Efficacy results in adult patients


Modified Full Analysis SetLeast Square Mean ± 95% CL

• Statistically significant dose-response on primary endpoint (objective WASO by PSG)

• Clinically relevant effect especially at 25 and 50 mg

• Other sleep endpoints and assessments at subsequent time points generally aligned to primary results

nemorexant dose (mg) Zolpidem 10 mg

Phase 2studies



Efficacy results in elderly patients


• Statistically significant dose-response on primary endpoint (objective WASO by PSG)

• Clinically relevant effect especially at 10, 25 and 50 mg

• Other objective sleep parameters generally aligned to primary results

Modified Full Analysis SetLeast Square Mean ± 95% CL

nemorexant dose (mg)

Phase 2studies



Normal sleep architecture preserved

9.8

10

9.8

10.7

10

10.7

57.9

56.2

55.4

56.8

55.1

57.4

15.4

13

12.5

12.5

15

12.6

16.9

20.8

22.3

20

19.9

19.3

Zolpidem

50 mg nemorexant

25 mg nemorexant

10 mg nemorexant

5 mg nemorexant

placebo

S1 S2 SWS REM

Sleep architecture maintained as total sleep time is dose dependently increased in exploratory endpoint

Duration as % of Total Sleep Time (TST)

Total Sleep Time (min)

357

371

384

387

403

388

Phase 2studies



Overview of adverse events in adults

Placebo

N = 60

Nemorexant5 mg

N = 60

Nemorexant10 mg N = 58


Nemorexant50 mgN = 61

Zolpidem10 mg N = 60

Subjects with at least one AE [n (%)]Treatment-emergent AE 18 (30.0) 21 (35.0) 22 (37.9) 23 (38.3) 21 (34.4) 24 (40.0)Treatment emergent AE of special interest afterSafety Board adjudication*

- - 1 (1.7) 1 (1.7) 2 (3.3) -

Treatment-emergent AE related to study treatment 6 (10.0) 11 (18.3) 9 (15.5) 12 (20.0) 8 (13.1) 9 (15.0)Treatment-emergent AE leading to premature study discontinuation of double-blind treatment

- - 2 (3.4) - 1 (1.6) 1 (1.7)

Treatment-emergent serious AE - - 2 (3.4)** - 1 (1.6)*** -Treatment-emergent serious AE related to study treatment

- - - - - -

Well tolerated at all tested doses with no evidence of dose-dependent adverse effects

* Mild excessive daytime sleepiness in 4 patients** Myocardial infarction on Day 12 in a 53 y.o. male patient with no concomitant medication; not related to study medication ** Work accident (object fell on head) on Day 8 in a 21 y.o. female patient unrelated to dizziness or sleepiness; not related to study medication *** Angioedema caused by bee venom in a cosmetic cream on Day 4; not related to study medication

Phase 2studies



Overview of adverse events in elderly

Placebo

N = 54

Nemorexant5 mg

N = 56



Nemorexant50 mgN = 56

Subjects with at least one AE [n (%)]Treatment emergent AE 8 (14.8) 13 (23.2) 12 (22.2) 10 (18.2) 16 (28.6)Treatment emergent AE of special interest after SafetyBoard adjudication

- - - - -

Treatment emergent AE related to study treatment 4 (7.4) 5 (8.9) 6 (11.1) 4 (7.3) 5 (8.9)AE leading to premature discontinuation of double-blind treatment

- - - 1 (1.8) 2 (3.6)

Treatment emergent serious AE - - - - -

Well tolerated at all tested doses with no evidence of dose-dependent adverse effects

Phase 2studies



Phase 2 conclusion


Efficacy• Dose response confirmed in adults and elderly subjects

on objective sleep primary endpoint : WASO• Other endpoints results generally aligned to primary endpoints

Safety(in the limit of the study design)• No sign of rebound or withdrawal symptoms • No clinically relevant next morning hang-over effect• Good safety and tolerability in both age groups at all dose levels

Three doses selected for Phase 3 in both age groups• 10 mg, 25 mg and 50 mg

Phase 2studies



Phase 3 program concept: adults and elderly patients – 3 dose levels selected


Efficacy1. Objective sleep parameters2. Subjective sleep parameters3. Daytime functioning assessed by a patient reported outcome instrument specifically

developed and validated by Idorsia according to FDA guidelines

Safety1. Adverse events, vital signs, biochemistry and hematology2. Next morning residual “hang-over” effect3. Withdrawal/physical dependence, and rebound

Clinical pharmacology studies including…• Driving performance, interaction (drugs, alcohol), abuse potential• Safety in specific population (COPD, obstructive sleep apnea, liver and renal impairment)

Phase 3studies



Phase 3 program overview


Design• 3 double-blind, randomized, placebo-controlled,

multicenter international studies

Doses• 301: placebo, 25 mg & 50 mg • 302: placebo, 10 mg & 25 mg• 303: placebo, 10 mg, 25 mg, and 50 mg

Main studies (12 weeks) Extension study (40 weeks)

Duration• 3-month treatment in main studies, 301 & 302,

and 9-month in extension study, 303

Sample size (combined adult and elderly)• 900 patients/study• Extension study: All subjects who complete

either 301 or 302

301: placebo, 25 mg & 50 mg 303: placebo, 10 mg, 25 mg & 50 mg

302: placebo, 10 mg & 25 mg

Phase 3studies



Main phase 3 studies – Study Design


LD nemorexant

HD nemorexant

Placebo

V1 V3V2 V4 V5 V6 V7 EODBT, V8 V9 V10 V111st month 2nd month 3rd month EOT EOSRandomization

Screening 20-31days Treatment Period 84 days Safety Follow-up 30 days

Run-in Placebo or Low (LD) or high dose (HD) nemorexantDouble-blind

Run-out

301: LD = 25 mg; HD = 50 mg302: LD = 10 mg; HD = 25 mg

Extension study

V = Visit= polysomnography

nights

EODBT = End of double-blind treatmentEOT = End-of-Treatment EOS = End-of-Study

Phase 3studies



Phase 3 extension – Study Design


V1 V2 V3 V4 EOS, V7Week 13 Week 26 Week 44Randomization

ID-078A301/02 Treatment Period 40 weeks Safety Follow up 30 days

Run out period Either Placebo, 10, 25 or 50mg nemorexantDouble-blind

Run out No treatmentNo blinding

EODBT, V5Week 40

EOT, V6Week 41Week 2

Run-out

10 mg nemorexant

25 mg nemorexant

50 mg nemorexant

10 mg nemorexant

25 mg nemorexant

50 mg nemorexant

Placebo

25 mg nemorexantPlacebo

Patients assigned to any nemorexant arms in the confirmatory studies will receive the same dosePatients assigned to placebo in the confirmatory studies will be randomized to receive either placebo or 25 mg nemorexant in a 1:1 ratio

Phase 3studies



Summary

From preclinical to phase 2: translation of product properties

• Promotes sleep and maintains a natural sleep architecture

• PK/PD profile optimized to combine effect during the night with low residual next morning plasma concentration/no “hang-over” effect

• Well tolerated at all dose levels tested (up to 50 mg)

Phase 3 confirmatory program initiated

• Assessing the efficacy of nemorexant during the night and the impact on patient’s functioning during the day

• To assess the safety, including residual “hang-over” effect, withdrawal symptoms, and rebound

• In adult and elderly insomnia patients treated with nemorexant at three dose levels, 10 mg, 25 and 50 mg, for up to 12 months

• Comprehensive clinical pharmacology program conducted in parallel


InsomniaCompound: Nemorexant

Mechanism of action: Dual orexin receptor antagonismStatus: Phase 3



Aprocitentanin resistant hypertension management

Aprocitentan is investigational, in development and not approved or marketed in any country.


Hypertension as a cardiovascular risk factor

30% of adult population is hypertensive

20% of them are unaware of hypertension

Hypertension, or high blood pressure, remains the most frequent addressable risk factor of cardiovascular morbidity/mortality outcomes, ahead of smoking and obesityReported by the 2015 Global Burden of Disease, Injuries, and Risk Factor Project collaborating with WHO

The definition of hypertension was recently updated to be a persistently elevated blood pressure above 130/80 mm Hg ACA/AHA Task Force on Clinical Practice Guidelines 2017


What is resistant hypertension?Definition

Resistant hypertension Patients whose blood pressure remains high, despite receiving at least three antihypertensive medications from different classes, including a diuretic, at maximal tolerated dose

Not resistant hypertension Pseudo-resistant hypertension due to:• White coat effect• Medical inertia• Poor adherence to treatment• Inappropriate blood pressure

measurementTreatable secondary hypertension


Clinical phenotypes

Resistant hypertension

Cum

ulat

ive

inci

den

ce (%

)

Time Until CVD/MI/Stroke (Months)

Medication usage:

REACH Registry n = 53,530

Poorer prognosis: higher incidence of major cardiovascular events

Typical characteristics of patients with resistant hypertension

Excessive dietary sodium

Older age; especially > 75 years

Ethnicity (black)

Sex (women)

Aortic stiffening

High baseline blood pressure and chronicity

of uncontrolled hypertension Target organ

damage (left ventricular

hypertrophy, chronic kidney

disease)

Diabetes

Atherosclerotic vascular disease

Obesity


Therapeutic options

Resistant hypertension

Current (2018) Medical Treatment Principles

Pharmacological therapy

• Check that each drug is used at the maximum tolerated level

• Optimize diuretic treatment

• Add antihypertensive drugs with different mechanism of action

• Aldosterone receptor antagonist (PATHWAY 2) or B1-blockers if not contraindicated

Device-based therapy (need confirmation of their benefit)

• Renal denervation

• Baroreflex activation therapy

“There is an urgent public health need for additional therapies acting on pathways different from those currently used, in line with the underlying disease mechanism.” Prof. John Chalmers, MD


Rationale

Aprocitentan in resistant hypertension

Resistant hypertension is often a salt- and volume-dependent hypertension

ET system may play a role in vascular remodeling, cardiac hypertrophy and the complications of resistant hypertension

ET-1 increase is associated with most risk factors linked to resistant hypertension

ET system is activated in hypertension and especially in salt-and volume-dependent hypertension

Endothelin (ET) System is involved in resistant hypertension



Rationale


Orally-active, potent dual ETA and ETB receptor antagonist

Synergistic effect with other antihypertensive drugs (RAAS blockers) in animal models

Low potential for drug-drug interaction

Demonstrated efficacy of aprocitentan on blood pressure, renal and cardiac protection in animal models of salt-dependent hypertension

Evidence of blockade of both receptors in vivo in humans

Demonstrated blood pressure decrease in patients with essential hypertension


Partnered with Janssen Biotech, Inc.


• Janssen Biotech, Inc. and Idorsia are collaborating in respect of the development and commercialization of aprocitentan and any of its derivative compounds or products

• Idorsia has received a one-time milestone payment of USD 230 million

• Both parties will have joint development rights over aprocitentan, while Janssen Biotech, Inc will have the sole manufacturing and commercialization rights

• The development costs will be shared equally between both partners

• Idorsia will oversee Phase 3 development and regulatory submission for the first indication

• Janssen will oversee the Phase 3 development and submission for any additional indications

Collaboration with Janssen Biotech, Inc.




Clinical development


Phase 2 study

Today


Phase 3 confirmatory

study

• Confirmation of dual ETA and ETB receptor blockade

• No dose adjustment in patients with any degree of renal impairment

• Low potential for drug-drug interaction

• Clinically relevant, dose-dependent lowering of blood pressure in essential hypertension patients

• Doses selected for further development

• To characterize the RHT patient population

• To identify sites where these patients are managed

SPIRIT survey




Week-6 -4 -2

Day 12 4 8 10

Period IScreening and run-in

Period IITreatment

Safety Follow-up

Placebo

Aprocitentan 5 mg

Aprocitentan 10 mg

Aprocitentan 25 mg

Aprocitentan 50 mg

Lisinopril 20 mg

Randomization 12

Design

Prospective, multi-center, double-blind, double-dummy, randomized, monotherapy, placebo- and active-reference, parallel group, Phase 2 dose-finding study in mild to moderate hypertension

Patient population

• Mild-to-moderate essential hypertension(Systolic BP/Diastolic BP ≥ 140/90 to < 180/110)

• Background medication stopped at screening

• Mean diastolic BP ≥ 90 to < 110 mmHg at randomization


6

Period IIIWithdrawal

Phase 2studies


Aprocitentan dose-dependently decreases blood pressure



Aprocitentan dose (mg) Lisinopril (mg)

5 10 25 50

Placebo

5 10 25 50

Mea

n ch

ange

fro

m b

asel

ine

in S

BP

(mm

Hg)

-5

-10

-15

-20

-4

-6

-8

-10

-12

-14

20

Mea

n ch

ange

fro

m b

asel

ine

in D

BP

(mm

Hg)

Diastolic Blood Pressure Systolic Blood Pressure

Aprocitentan dose (mg) Lisinopril (mg)Placebo

20

Phase 2studies


Safety results


Placebo Aprocitentan Lisinopril

5 mg 10 mg 25 mg 50 mg 20 mg

N 82 82 82 80 81 81

Patients with at least one AE 30 (37%) 18 (22%) 24 (29%) 33 (40%) 22 (27%) 26 (32%)

Headache (12) 1 1 2 2 2 4

Nasopharyngitis (10) 1 1 2 2 0 4

Upper respiratory tract infection (9) 1 0 4 1 2 1

Arthralgia (7) 2 0 1 1 3 0

Pain in extremity (5) 1 1 0 1 2 0

Constipation (4) 0 0 2 1 0 1

Hemoglobin decreased (4) 0 0 2 1 0 1

Edema peripheral (4) 0 0 0 2 2 0

Orthostatic hypotension (4) 1 0 0 1 0 2

AE leading to study treatment discontinuation

5 (6%) 1 (1%) 2 (2%) 3 (4%) 3 (4%) 3 (4%)

Patients with at least one SAE 0 0 0 2 (2%) 0 1 (1%)

AE = Averse Event; SAE = Serious Adverse Event


Phase 2studies


Phase 2 conclusion


Efficacy• Dose response was consistent across all parameters measured• Efficacy observed at 10 and 25 mg, with no additional effect at 50 mg• The effect of aprocitentan covers the 24 h period

Safety(in the limit of the study design)• well tolerated across all doses• overall frequency of adverse events on aprocitentan was similar to placebo

Two doses selected for Phase 3• 12.5 mg and 25 mg


Phase 2studies


Benefitting from consultation with regulatory agencies

Aprocitentan – Confirmatory study

PRECISION will assess the short-term efficacy of aprocitentan as well as the durability of the effect.It will provide replication of clinical evidence in a single study


Phase 3 studyPRECISION


Confirmatory study design



Screening

Randomization

Screening Run-in

1 to 8 weeks

25 mg Aprocitentan

12.5 mg Aprocitentan

Placebo

25 mg Aprocitentan25 mg Aprocitentan

Placebo

Part I Part II Part III Safety Follow-up

4 weeks 4 weeks 4 weeks 32 weeks Withdrawal 12 weeks 30 days

Re-Randomization End of treatment

End of study

Continue standard background therapy

RHT confirmationStandardizationStabilization

Efficacy and safety of aprocitentan

Individual background

antihypertensive medication

Standard background

antihypertensive therapy

Stabilization on standardized medication



Confirmatory study objectives



• Double-blind treatment

• 12.5 mg aprocitentan or 25 mg aprocitentan or placebo

• Period of 4 weeks

• To demonstrate the blood pressure lowering effect of aprocitentan when added to standard-of-care in true resistant hypertension patients

• Single-blind treatment

• 25 mg aprocitentan


• To evaluate long-term safety and tolerability of aprocitentan when added to standard-of-care in true resistant hypertension patients

• Double-blind, randomized, withdrawal treatment

• 25 mg aprocitentan or placebo


• To demonstrate that the effect of aprocitentan on blood pressure is durable when added to standard-of-care in true resistant hypertension patients

Part I Part IIIPart II





Confirmatory study patient population: True resistant hypertension patients on standardized triple therapy

Mean systolic blood pressure ≥ 140 mmHg (measured by unattended automated office blood pressure measurement - AOBPM), despite a background antihypertensive medication of at least 3 different pharmacological classes (including a diuretic)

Confirmed diagnosis of resistant hypertension, mean blood pressure ≥ 140 mmHg by AOBPM, who are on standardized background medication therapy for at least 4 weeks

Standardized therapy• Calcium channel blocker, amlodipine• Angiotensin receptor blocker,

valsartan• Diuretic, hydrochlorothiazide

Entry into screening Entry into run-in Randomization

Mean systolic blood pressure ≥ 140 mmHg by AOBPM, despite stable standardized therapy



Confirmatory study endpoints


Primary endpoint

• Change from baseline to week 4 of double-blind treatment in mean trough sitting systolic blood pressure by AOBPM

Key secondary endpoint

• Change from week 36 (start of withdrawal period) to week 40 in mean trough sitting systolic blood pressure by AOBPM

Other important endpoints

• Other clinically important blood pressure parameters at week 4 and week 40

• Diastolic blood pressure by AOBPM

• Systolic and diastolic blood pressure by 24-hr ambulatory blood pressure monitoring

• Safety assessments

• Pharmacokinetic assessment




• Aprocitentan has great potential in difficult to control hypertension – resistant hypertension – as an oral, once daily treatment based on:

− Pathophysiology of resistant hypertension

− Mode of action of aprocitentan

− Efficacy in essential hypertension (Phase 2)

• We are collaborating with Janssen Biotech to jointly develop and commercialize aprocitentan

• Phase 3 study ongoing to evaluate initial and long-term effects of aprocitentan on systolic and diastolic blood pressure in patients requiring resistant hypertension management

• This registration program has benefitted from inputs from health authorities, in particular the US FDA


Resistant hypertension managementCompound: Aprocitentan Mechanism of action: Dual endothelin receptor antagonismStatus: Phase 3


Summary


Clazosentanin cerebral vasospasm post-aneurysmal subarachnoid hemorrhage

Clazosentan is investigational, in development and not approved or marketed in any country.


A sudden life-threatening bleeding occurring in the subarachnoid space

Aneurysmal subarachnoid hemorrhage (aSAH)

• aSAH is caused by the rupture of an aneurysm – a weak, bulging spot on the wall of a cerebral artery

• Prevalence: 9 in 100’000 worldwide –it is an orphan disease

• Emergency repair (endovascular coiling or microsurgical clipping) is required to stop the hemorrhage

Subarachnoid space

Scalp

Skull

Brain


Two options for the treatment of aSAH

Ruptured aneurysm

Brain artery

Pre-treatment Brain surgery: Clipping of the aneurysm

Catheter intervention: Releasing of platinum coils

Clip Catheter

Coil


Can occur between 4 and 14 days after aSAH securing

Cerebral vasospasm post-aSAH

• Cerebral vasospasm is a strong contraction of the arteries in the brain surrounding the hemorrhage

• Narrowing of the blood vessel limits blood flow decreasing the amount of blood supplied to the brain

Baseline aSAH: normal MCA

7 day after SAH: cerebral vasospasm

Blood

Artery spasm


Numbness or weakness of the face, arm or leg,

especially on one side of the body, or in more severe cases,

paralysis

Dizziness

Blurred or double vision

Loss of consciousness

Mood change, agitation

Confusion

Worsening of headache

Difficulty speaking or being unable to speak

From asymptomatic detected by systematic angiography to serious neurological symptoms

Symptoms of vasospasm

Cerebral vasospasm


• Necrosis of an area of brain tissue

• Physical deficit

• Social and emotional impact, affecting all aspects of someone’s life

Long-term consequence of vasospasm

Brain infarct due to vasospasm


Hemodynamic therapy

• Inducing high blood pressure in an attempt to force a blood supply to the brain region affected by the vasospasm

No pharmacological therapy for cerebral vasospasm

• Except for fasudil in Japan and Korea

• Nimodipine approved in most countries for preventing ischemic events secondary to aSAH (but whether it acts on cerebral vasospasm is unproven)

Rescue therapy

• Invasive neurovascular intervention

− balloon angioplasty

− intra-arterial administration of vasodilators

• Often needs to be repeated multiple times over the course of several days

• Requires highly-trained specialists in an intensive care setting

• Clinical efficacy unproven in randomized controlled trials

• Is associated with medical risks

Available therapy for vasospasm


Role in cerebral vasospasm

Endothelin release

Cerebral vasospasm is caused by the release of vasoactive mediators after a bleed on the brain triggering vessels to contract

Endothelin is one of the most powerful, long-acting vasoactive mediators that causes blood vessels to contract

Patients with cerebral vasospasm show high levels of endothelin in their cerebral spinal fluid

Blood


Highly soluble ETA selective endothelin receptor antagonist

Clazosentan in cerebral vasospasm

>1’800 patients treated with clazosentan providing significant experience in vasospasm post-aSAH and a well documented safety profile


Fast onset of action

ETA selective ERA

Highly soluble

Ideal for intravenous administration


Learning from clazosentan program

Initial SAH event

Aneurism secured

Asymptomatic vasospasm

Vasospasm-related symptoms

Hospital discharge

Delayed, 3 to 6 month

outcome

Vasospasm ≈ day 4 to 14

From this program, we know:• Which patients would benefit most• What dose should be given• How to manage the treatment and in particular the safety of clazosentan• How to measure treatment benefit short-term and long-term

This acquired knowledge is incorporated into the design of the REACT study

CONSCIOUS

REVERSE



What we have learned through our experience with clazosentan…




0

10

20

30

40

50

60

70

80

Placebo

1 mg/h 5 mg/h 15 mg/h

Clazosentan

n = 85 n = 95 n = 95 n = 79

Pat

ient

s w

ith

mo

der

ate/

seve

reva

sosp

asm

(%)

*p < 0.0001

*p = 0.0003

*p = 0.0027

All patients (per-protocol)

Dose-dependent prevention of vasospasm

Phase 2 study –angiographic endpoint

• Clazosentan 1 to 15 mg/h versus placebo post-clipping and coiling


Stroke 2008 39:3015-21

Phase 2 studyCONSCIOUS-1


5mg/hr dose is not high enough


Even

t ra

te (%

)

Phase 3 study –clinical morbidity / mortality endpoint

• Patients who received surgical clipping treated with 5mg/hr clazosentan

Overall incidence of death and vasospasm-related morbidity


The Lancet. Neurology, 2011; 10(7):618-625



15mg/hr showed significant effect on morbidity / mortality



• Patients who received endovascular coiling treated with 5 or 15mg/hr clazosentan



Stroke. 2012; 43(6):1463-9



15mg/hr showed significant effect on primary endpoint


Placebo

Clazosentan5 mg/h

Clazosentan15 mg/h


• Consistent effect at 15 mg/hr on all morbidity events25

20

15

10

0

Even

t ra

te (%

)

Death (within 6 weeks)

New cerebral infarct

Delayed ischemic neurological deficits

Rescue therapy

5

Vasospasm-related

53

6

1316

7

2118

10

7

15

21

Incidence of death and each component of vasospasm-related morbidity


Stroke. 2012; 43(6):1463-9



10mg/hr dose showed similar results to CONSCIOUS-3in Japanese patients

Phase 2 study –exploratory endpoint

• Clazosentan significantly reduced vasospasm-related morbidity and mortality events




Cerebrovasc Dis 2017;44:59–67

Japanese study


In patients with established vasospasm


Pilot study –angiographic endpoint

Key findings:

• Clazosentan acts on some large brain arteries but the real benefit is in the effect on smaller arteries not accessible to endo-arterial therapy

• Clazosentan has a considerable impact on vasospasm when caught early enough

Admission Baseline (prior to clazosentan) 3h post clazosentan

Indicates moderatevasospasm


Pilot studyREVERSE


Well documented safety profile


Main side effects are manageable

Side effects of clazosentan Risk mitigation

Hypotension

Lung complications (pulmonary edema)

Peripheral edema

Blood pressure control with vasopressors in ICU

Euvolemia,iv fluid restriction

> 1’800 patients treated

Euvolemia, iv fluid restriction



Which patients are at highest risk of vasospasm?

• Characterized by large amount of subarachnoid blood on hospital admission cerebral CT scan

• Represents approximately 50% of overall aSAH population


Patients with “thick and diffuse” clot

Normal CT Thick and diffuse SAH


Which patients are at highest risk of vasospasm?Patients with “thick and diffuse” clot

0% 10% 20% 30%

Death

New Cerebral Infarcts

DIND

RescueTherapy

Proportion of patients with event

Thick and diffuse

Other

• Data from previous CONSCIOUS program demonstrates the high event rates for vasospasm and related ischemic complications


CONSCIOUS-2CONSCIOUS-3


In high-risk patient population


Placebo

Clazosentan5 mg/h

Clazosentan15 mg/h

Phase 3 studies –clinical morbidity / mortality endpoint

Clot size impacts the absolute treatment effect (individual morbidity / mortality components)


DIND = Delayed ischemic neurological deficits

CONSCIOUS-2CONSCIOUS-3

Thick and Diffuse Clots

40%

35%

30%

25%

20%

15%

10%

5%

0%

Death New Cerebral Infarcts

DIND Rescue Therapy

Pro

po

rtio

n o

f p

atie

nts

wit

h an

eve

nt


REACT study design incorporates these learnings

Selection of the high-riskpatientpopulation

Selection of the dose

Selection of the best measure to demonstrate efficacy

Optimized patient management guidelines to ensure patient safety


Phase 3 studyREACT


Primary objective• To determine the efficacy of clazosentan in preventing

clinical deterioration due to delayed cerebral ischemia, in patients with aSAH

Secondary objectives• To evaluate the effect of clazosentan on the incidence of all-cause

new or worsened cerebral infarction ≥ 5 cm3 in volume at Day 16 post-study drug initiation

• To evaluate the effect of clazosentan on long-term clinical outcome, cognition, and health-related Quality of Life at Week 12 post-aSAH

• To evaluate the safety and tolerability of clazosentan in the selected population up to 24 hours post-study drug discontinuation

Study objectives



Phase 3 studyREACT


Clazosentan in cerebral vasospasmStudy design

400 patients (200 placebo/200 clazosentan) from 100 trial sites across 15 countries

Screening

Clazosentan 15mg/h Treatment & Observation

Extended Follow-up24h Safety Follow-up

Aneurysm rupture (aSAH)

Hospital admission

Aneurysm securing

within 72h post-aSAH

Randomization End ofstudy drug

End of 24hFollow-up

Week 12post-aSAH

EOS

Observation: 14 days post-study drug initiation

Placebo Treatment & Observation


Phase 3 studyREACT


Elevated risk of developing delayed cerebral ischemia (DCI)

Target patient population

Objective to prevent DCI, subsequent

clinical deterioration, and related ischemic

complications

High-risk for developing cerebral vasospasm • “thick and diffuse” clot on

hospital admission CT scan

• clazosentan administered in prevention of vasospasm

Early vasospasm without neurological deterioration• clazosentan administered

in treatment of vasospasm


Phase 3 studyREACT


The occurrence of clinical deterioration due to DCI, from study drug initiation up to 14 days post-study drug initiation

• Worsening of 2 points on neurological scales, lasting for at least 2 hours

• Entirely or partially due to cerebral vasospasm

• Centrally adjudicated

Episodes of neurological worsening must be avoided because they may:

• lead to brain infarcts, if left untreated

• aggravate or degrade into further ICU complications (e.g., coma with pulmonary complications)

• increase the length of stay in ICU

• trigger the performance or administration of invasive endovascular therapies (angioplasty or multiple sessions of intra-arterial vasodilators)

Clazosentan in cerebral vasospasmPrimary endpoint – highly relevant


Phase 3 studyREACT


• Occurrence of all-cause new or worsened cerebral infarction ≥ 5 cm3

at Day 16 post-study drug initiation

• Long-term clinical outcome assessed by the GOSE at Week 12 post-aSAH, dichotomized into poor (score ≤ 4) and good outcome (score > 4)

• Instruments used to assess long-term effect:

− Glasgow Outcome Scale (extended)

− Montreal Cognitive Assessment

− Modified Rankin Scale

− Quality of life instruments (Stroke Specific QOL, the EQ-5D, and the Oxford Participation and Activities Questionnaire)

Secondary endpoints



Phase 3 studyREACT


• Two identically designed studies (one in clipped patients, one in coiled patients) evaluating the effect of clazosentan 10 mg/h versus placebo on vasospasm-related morbidity and mortality and all-cause morbidity and mortality

− Death, new cerebral infarcts, delayed ischemic neurological deficits

• Study design and main endpoints similar to CONSCIOUS-2 and -3 studies

• 160 patients (80 per treatment arm) in each study

• Study expected to report results before year-end

Japanese registration program



Summary

• Developed as intravenous infusion for prevention and treatment of cerebral vasospasm in patients who have suffered an aSAH

• Has potential to prevent ischemic complications of cerebral vasoconstriction and to decrease the need for invasive intervention

• Registration studies in Japan expected to complete in second half of 2018

• REACT – Phase 3 study evaluating the safety and efficacy of clazosentan in an enriched aSAH population to start later in 2018


Cerebral vasospasmCompound: Clazosentan

Mechanism of action: Endothelin receptor antagonismStatus: Advancing to Phase 3



Cenerimodin systemic lupus erythematosus

Cenerimod is investigational, in development and not approved or marketed in any country.


• Complex, systemic, autoimmune disease of unknown etiology• Characterized by tissue damage across multiple organ systems• Severe organ damage and significant mortality in subset of patients• Limited treatment options with a high need for a new approaches

Scientific rationale for S1P1 receptor modulation in SLE: • T and B cells play a key role in pathogenesis• S1P1 receptor modulators have shown efficacy

in different preclinical models of SLE: MRL/lpr and BXSB mice

Medical need

Systemic lupus erythematosus


NO

NNO

O

HO OH

A novel S1P1 receptor modulator

Cenerimod in systemic lupus erythematosus

Very potent, highly selective, S1P1 receptor modulator

Prevents lymphocytes from leaving lymph nodes and reaching target tissues

Induces rapid and reversible, dose-dependent blood lymphocyte count reduction

Pharmacokinetic profile suitable for once-daily oral dosing with no need for initial up-titration regimen

Potential in multiple autoimmune diseases




Phase 2 randomized, double-blind, placebo-controlled, dose-response study to investigate the biological activity, safety, and tolerability of cenerimod in adult patients with systemic lupus erythematosus

67 patients were enrolled to receive either placebo or 0.5, 1, 2 or 4 mg/day of cenerimodover a treatment period of 12 weeks


Phase 2 study


Study design


Randomization EOT EOS

Week

Visit 1 2 3 4 5 6 7 8 9

Day -30 Day 1 2 4 8 12 18 23 28

Screening 30 days

Treatment period 12 weeks

Follow-up 6 weeks

Phone calls FU10 weeks

Safety interim review (IDMC)

EOT EOS

Week

Visit 1 2 3 4 5 6 7 8 9

Day 1 2 4 8 12 18 23 28

Screening 30 days

Treatment period 12 weeks

Follow-up 6 weeks

Phone calls FU10 weeks

Randomization

Placebo 12 pts

Cenerimod 0.5 mg 12 pts



Placebo 4 pts


Day -30


Part B

Part A

Phase 2 study


• A dose-response relationship for cenerimod was demonstrated, based on circulating lymphocyte counts

• Cenerimod was well tolerated at all dose levels

• The occurrence of adverse events was similar in all five treatment groups

• As a result, cenerimod is ready to move into an exploratory, dose-finding study to deliver all the information required to design the Phase 3 program

Study results



Phase 2 study


Vamorolone in Duchenne Muscular Dystrophy

Vamorolone is investigational, in development and not approved or marketed in any country.


Vamorolone is a novel compound for the treatment of Duchenne Muscular Dystrophy

• It holds potential to better preserve muscle function and prolong ambulation for the patient, without some of the side effects associated with glucocorticoid therapy

• A Phase 2a program is currently underway to investigate the safety and efficacy of vamorolone in 4-7 year old steroid-naïve boys with Duchenne(patients that have not taken prednisone or deflazacort)

• Idorsia has the option to obtain the exclusive worldwide license rights on vamorolone from ReveraGen

Vamorolone in Duchenne Muscular Dystrophy



Idorsia’s other clinical development assets



In development for the prevention of myocardial damage in acute coronary syndrome

• Targeted for individuals at risk of a myocardial infarction

• Meets a very specific pharmacokinetic profile, which requires the product to be well-absorbed subcutaneously after self-administration

• Rapid onset of action and 3 to 4 hours duration of action

• ACT-246475 has completed Phase 1, and a Phase 2 study was initiated in January 2018

P2Y12 receptor antagonist for acute coronary syndrome

ACT-246475

ACT-246475 is investigational, in development and not approved or marketed in any country.


There is a significant need for new oral therapies totreat nasal polyposis in patients whose disease is not fully controlled with current therapies

• Current evidence suggests that disease pathogenesis in nasal polyposis involves type-2 inflammatory processes and that a CRTH2 antagonist can be effective in reducing ongoing inflammation and nasal polyp burden

• A proof-of-concept Phase 2 study has been initiated.

CRTH2 receptor antagonist for the treatment of nasal polyposis

ACT-774312



In development for the potential treatment of anxiety disorders

• Potent antagonist, brain-penetrating

• Shown anxiolytic (anxiety inhibiting) effects after oral administration in four different preclinical models representing different sub-types of anxiety disorders

• In these models, it did not induce sleep at anxiolytic doses

• Phase 1 trials are ongoing

Selective orexin 1 receptor antagonist (SORA) for anxiety disorders

ACT-539313



In development for certain forms of generalized epilepsy

• ACT-7091478 is a selective, orally available triple T-type calcium channel blocker.

• The compound exhibits good tolerability after single-dose administration in humans and PK properties that warrant further investigations.

• A study was initiated to evaluate the effect of ACT-709478 in photosensitive epilepsy patients following single dose administration.

T-type calcium channel blocker for epilepsy

ACT-709478



More science –Bursting with ideas


Idorsia’s drug discovery approach

Few platforms of expertise

Single-center approach

Fully integrated research informatics

Focus on small molecules

Multiple therapeutic areas

High medical input


More joy – Transforming the horizonOur drug discovery process

Targets Hits

Molecular-Biology(Target Finding)

Biochemistry (High Throughput Screening)

Structural BiologyAnd Molecular Modeling

MedicinalChemistry

Pharmacokinetics &MetabolismChemistry

Process R&D

Pharmacology

ResearchInformationManagement

Preclinical DevelopmentClinical DevelopmentRegistrationLaunch

Compound Library


Financial information


Operating results - 6 monthsHY 2018

Non-GAAP

US-GAAP

Financial results as of June 30, 2018


Net results

-139 -139

-16

-4-20

Operating results Financial results Income Tax results Non-ControllingInterests

Net results

Non-GAAP

US-GAAP

HY 2018



Cash flow

-61-77

-138-11

14 3

-2 -3

-5

Cash flowQ1 2018

Cash flowQ2 2018

Cash flowHY 2018

Capex / other

Working capital requirements

HY 2018


-75 -67

-141

Funds from operations


LiquidityHY 2018


622 615

21885

250

250

1'091

949

Liquidity @Dec 31, 2017

Liquidity @Jun 30, 2018

Cash deposits> 12 months

Cash deposits< 12 months

Cash andcash equivalents


Cash raise in July 2018HY 2018


119.1 131.0

38.744.6

5.7

5.7

@ June 30, 2018 Proforma

Equity instruments

Equity derivatives

Issued common shares

CHF 505 million raised Impact on share count

New registered shares CHF 305 million

Convertible BondCHF 200 million

+ 5.9 mio

+ 11.9 mio

163.6181.4


Financial Guidance

Unforeseen events and potential milestone expenses excluded, we expect non-GAAP operating expenses for 2018 to be around 390 million Swiss francs.

HY 2018


More experience –Driving innovation


Idorsia has a strong and visionary leadership teamwith the power and drive to create more remarkable innovations and more new medicines


Idorsia management team

Jean-Paul ClozelChief Executive Officer

Martine ClozelChief Scientific Officer

Guy BraunsteinHead of Global Clinical Development

André C. MullerChief Financial Officer

Andrew C. WeissHead of Investor Relations & Corporate Communications

Alex KhatuntsevHead of Human Resources

Oliver PeineltGeneral Counsel

Olivier LambertHead of Pharmaceutical Development

Thomas WellerHead of Drug Discover Chemistry

Ulrich MentzelHead of Pharmacology & Preclinical Development

Markus RiedererHead of Drug Discovery Biology


Idorsia Board of Directors

Jean-Pierre GarnierChairman of the board of directors

Robert J. BertoliniMember of the board of directors

Jean-Paul ClozelChief Executive Officer

John J. GreischMember of the board of directors

David StoutMember of the board of directors

Viviane MongesMember of the board of directors


Be prepared for more


idorsia – reaching out for more · the purpose of idorsia is to. discover, develop and bring...

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