Marinus AES Investor Meeting

NASDAQ: MRNS @MarinusPharma

Marinus AES Investor MeetingDecember 7, 2020

Introduction

Sasha Damouni VP, Investor Relations & Corporate Communications

1

Marinus – AES Investor Meeting – December 7, 2020 ©2020 Marinus Pharmaceuticals. All Rights Reserved I 2

Forward-Looking Statement DisclosureTo the extent that statements contained in this presentation are not descriptions of historical facts regarding Marinus, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “may”, “will”, “expect”, “anticipate”, “estimate”, “intend”, “believe”, and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Examples of forward-looking statements contained in this presentation include, among others, statements regarding our clinical development plans for ganaxolone; expected dosing in our clinical trials; the clinical development schedule and milestones; our expected timing to begin and complete enrollment in our clinical trials; the expected trial design, target patient population and endpoints for our clinical trials; interpretation of scientific basis for ganaxolone use; timing for availability and release of data, including the expected release of topline data from our Phase 3 trial in status epilepticus (SE) in 1H 2022; from our proof of concept study in PCDH19 in the first half of 2021, and from our Phase 2 tuberous sclerosis complex (TSC) trial in mid 2021; the potential safety and efficacy and therapeutical potential of ganaxolone; timing and expectation regarding submissions of regulatory applications, including our expectation to submit an NDA for ganaxolone in CDD in mid-2021 and an MAA by the end of Q3 2021; expectations regarding commercial launch of ganaxolone in CDD in 1H 2022; expectations regarding our agreement with BARDA; expectations regarding the potential market opportunities for our product candidates, including oral ganaxolone; potential commercial alliances; and our expectations regarding the effect of the COVID-19 pandemic on our business and clinical development plans. Forward-looking statements in this presentation involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, uncertainties and delays relating to the design, enrollment, completion, and results of clinical trials; interpretation of results of clinical trials; unanticipated costs and expenses; early clinical trials may not be indicative of the results in later clinical trials; clinical trial results may not support regulatory approval or further development in a specified indication or at all; actions or advice of the FDA or other regulatory agencies may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional clinical trials; our ability to obtain and maintain regulatory approval for our product candidate; our ability to obtain and maintain patent protection for our product candidates; delays, interruptions or failures in the manufacture and supply of our product candidate; our ability to raise additional capital; the effect of the COVID-19 pandemic on our business, the medical community and the global economy; and the availability or potential availability of alternative products or treatments for conditions targeted by us that could affect the availability or commercial potential of our product candidate. Marinus undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of the Company in general, see filings Marinus has made with the Securities and Exchange Commission. You may access these documents for free by visiting EDGAR on the SEC web site at www.sec.gov.

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©2020 Marinus Pharmaceuticals. All Rights Reserved I Marinus – AES Investor Meeting – December 7, 2020 3

Agenda Topic Lead

Marinus Overview Dr. Scott Braunstein, Chief Executive Officer & Director

CDKL5 deficiency disorder (CDD) Introduction Dr. Elia Pestana Knight, Pediatric Epileptologist in the Pediatric Epilepsy Section, Epilepsy Center at the Cleveland Clinic

Video Dr. Orrin Devinsky, Director of the NYU Comprehensive Epilepsy Center and The Institute of Neurology and Neurosurgery at Saint Barnabas

Heidi Grabenstatter, Science Director at the International Foundation for CDKL5 Research

CDD posters Dr. Alex Aimetti, Vice President, Scientific Affairs

Status Epilepticus (focus on ESE & SRSE) Dr. Joe Hulihan, Chief Medical Officer

Dr. Henrikas Vaitkevicius, Vice President, Clinical Development

Commercial Strategy / Market Opportunity Christy Shafer, Chief Commercial Officer

Q&A Marinus Management Team

Marinus Overview

Scott Braunstein, M.D., Chief Executive Officer & Director

4


Corporate Update► Late Breaker Presentation for Marigold Phase 3 CDD trial:

• Consistent efficacy signal across multiple subgroups, including a 36.7% estimated difference in major motor seizure frequency relative to placebo in U.S. patients (n=41)

• Preliminary Open Label data from the Marigold study suggests potential for durable effect - for example 52.7% reduction in seizure frequency shown in a number of patients at roughly year 1 post initiation of therapy“

• PK analysis suggests strongest reduction in seizure burdens linked to serum blood concentrations of GNX, with those patients in highest grouping having an approximate 45% reduction in major motor seizure burden

► Launch of CDKL5 EAP program in conjunction with AES meeting

► Pipeline clinical development work on track:

• PCDH-19 and Tuberous Sclerosis Complex (TSC) program readouts in Q2 2021 and mid-2021, respectively

• Refractory Status Epilepticus (RSE) Phase 3 site enrollment continuing, despite COVID-19 challenges

• Established Status Epilepticus (ESE) Phase 2 study to begin 2H 2021

• Super Refractory Status Epilepticus (SRSE) first published abstracts showing successful treatment with

ganaxolone (GNX)

©2020 Marinus Pharmaceuticals. All Rights Reserved I Marinus – AES Investor Meeting – December 7, 2020

Increasing Opportunities to Drive Company and GNX Franchise Growth

Clinical Development

CommercializationLifecycle

Management

• TSC Phase 2• PCDH19 Phase 2

• RSE Phase 3

• Reformulation/ Prodrug Work• Indication Expansion

• ESE Expansion • Indication Expansion• IM development work

Commercial Build, Scientific Expansion

ParallelFranchise Strategies

Oral

IV

• CDD Launch Readiness• Prepare for TSC Phase 3 and

Potential Launch

• Prepare for Potential RSE Launch

Infrastructure

Financing and Strategic Global Opportunities

Strategic Partnerships, Financing Opportunities, Monetization of Priority Review Voucher on CDD Approval

6


Clinical Development Timeline of Pipeline Indications by Franchise

2020 2021 2022 2023

Indication Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3

CDD

TSC

RSE

End of

Phase 2

Meeting

Ph3

CompletionPotential

Approval /

Planned Launch

Expected

Phase 3 Start

Phase 2 Start –

Open Label

Phase 3

Completion

Potential EU and

US Approval

DEA Sched /

Planned Launch

Planned

NDA

Submission

Phase 3

Completion

Potential Approval /

Planned LaunchPhase 3

Start

Planned NDA

Submission

Planned

NDA

Submission

• PCDH-19 readout in Q2 2021• Initiation of Phase 2 work in ESE to begin 2H 2021• Commercial assessment of new clinical opportunities for ganaxolone IV underway • Continued investment in second generation oral program; targeting several lead

candidates by the end of 2021

EAP

StartPlanned

EU submission

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CDKL5 Deficiency DisorderTreatment StrategiesElia M Pestana Knight, MD

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Disclosures

► CO-PI Marigold Study / Cleveland Clinic CDKL5 Center of Excellence

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► Mutation in the Cyclin-dependent kinase-like 5 gene

► Kinase protein that promotes the production of proteins needed for brain development

► Role in microtubule dynamics

► Gene location: X chromosome

► More females affected than males

Zhu YC, Xiong ZQ. Dev Neurobiol. 2018.Ricciardi S et al. Nat Cell Biol. 2012Rusconi L et al. J Biol Chem. 2008Zhu YC et al. Proc Natl Acad Sci US A. 2013Baltussen LL et al. EMBO J. 2018

10

CDKL5 Deficiency Disorder


► ~1:40,000 -75,000 live births

Lindy AS et al. Epilepsia. 2018 Kothur K et al. Seizure. 2018

11

Epidemiology


Key Clinical Features: Central and Peripheral Nervous System

Early onset Epilepsy

Abnormalities of muscle tone / Gross motor

problems

Language and communication

problems / Intellectual

disability

Stereotypes / Movements

disorders

Sleep difficulties

Cortical visual impairment /

Sideways gaze / Social

avoidance

Fine motor problems

Olson H et al. Pediatric Neurol 2018Fehr S et al. J Neurodev Disrod. 2015Fehr S et al. Neurology 2016


Seizures are Refractory to Medical Treatment

Spasms

Tonic

Multiple phase

i.E HTSS

Clonic

Myoclonic

Tonic clonic

Absence

Focal

► Asymmetric seizures

► Autonomic features present during seizures

► Movement disorders associated to seizures

► Absence of hypsarrhythmia on EEG

Olson H et al. Pediatric Neurol 2018Demarest S et al. Epilepsia 2019


Other Systemic Symptoms

Gastrointestinal Symptoms• GERD• Vomiting• Constipation

Respiratory symptoms• Irregular breathing• Respiratory infections

Musculoskeletal symptoms• Scoliosis• Join deformities• Contractures

Olson H et al. Pediatr Neurol 2018Takahashi Y et al. J Peditr Epilepsy 2018


Care Team

Pediatrician

Complex Care Team

Neurologist and Epileptologist

Gastroenterologist

Pulmonologist

PM&R and PT, OT, Speech Therapy

and Visual Therapy,Orthopedics

Geneticist

Patient and

Family

School SystemAdvocacy Groups

CommunityIndustry


► Antiseizure Medications (Muller A et al. Eur J Paediatr Neurol 2016; Amis S et al. Hippokratia 2017; )• Lack of efficacy and loss of efficacy

– Felbamate, Vigabatrin, Clobazam, Valproate, Steroids, Lamotrigine, Zonisamide, Levetiracetam

– Withdraw of all AEDs due to lack of efficacy (Evans JC et al. Eur J Hum Genet 2005)

► Diet therapies (Lim Z et al. Epilepsia 2017)

► Palliative surgeries• Vagus Never Stimulator (Lim Z et al. Epilepsy Res 2018; Baba S et al Brain Dev 2017)

• Callosotomy (personal experience)

► Immunotherapy• Prednisone

► I VIG (personal experience)

► New therapies• Epidiolex, sustained reduction of seizures after 48 weeks (Devinsky O et al. Epilepsy Behav

2018)16

Treatments


► Ganaxolone (NCT03572933)

► Altaluren (NCT02758626)

► Fenfluramine (NCT03861871)

► TAK-935/OV-935 (NCT03694275)

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Clinical trials for CDD ClinicalTrials.gov

Marinus – AES Investor Meeting – December 7, 2020 ©2020 Marinus Pharmaceuticals. All Rights Reserved I NASDAQ: MRNS @MarinusPharma

Results of the Phase 3

Marigold Study Evaluating

Ganaxolone in CDKL5

Deficiency Disorder

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Marinus – AES Investor Meeting – December 7, 2020 ©2020 Marinus Pharmaceuticals. All Rights Reserved I

Global Phase 3 Pivotal Trial Design

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Trial Details

• Evaluated the use of oral ganaxolone in children and young adults

• Global, double-blind, placebo-controlled, clinical trial

• Ages 2-21 eligible, confirmed disease-related CDKL5 gene variant, ≥16 major motor seizures/month; up to 4 concomitant AEDs

• Primary endpoint was percent change in 28-day major motor seizure frequency in Double-Blind Phase relative to Baseline*

* Major motor seizures were defined as bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral clonic, or focal to bilateral tonic-clonic


Marigold Enrollment & Subject Baseline Demographics

20

United

States

Italy

Russia

United

Kingdom

Poland

France

Australia

Israel

42

15

14

10

7

6

6

1

Enrollment by Geography Demographic Placebo (n=51)

Ganaxolone (n=50)

Total (n=101)

Age, median, Q1-Q3 7.0, 4.0-11.0

5.0, 3.0-10.0

6.0, 3.0-10.0

Gender, n (%)

Male 10 (19.6) 11 (22.0) 21 (20.8)

Female 41 (80.4) 39 (78.0) 80 (79.2)

Ethnicity, n (%)

Hispanic or Latino 6 (11.8) 4 (8.0) 10 (9.9)

Not-Hispanic or Latino 43 (84.3) 44 (88.0) 87 (86.1)

Unknown 1 (2.0) 1 (2.0) 2 (2.0)

Not reported 1 (2.0) 1 (2.0) 2 (2.0)

Race, n (%)

White 47 (92.2) 46 (92.0) 93 (92.1)

Asian 3 (5.9) 2 (4.0) 5 (5.0)

Other 1 (2.0) 2 (4.0) 3 (3.0)


Subject Baseline Clinical Characteristics & Prior/Concomitant Medications

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Characteristic Placebo Ganaxolone Total

Baseline Primary Seizure Frequency, per 28 days (median, Q1-Q3)

50.0,18.7 – 120.0

57.332.8 – 156.0

-

Number of AED Medications Taken Prior(median)

7 7 7

Number of Concomitant AED Medications

(median)2 2 2

Concomitant AED Medications,

n (%)

Valproate 16 (31.4) 18 (36.0) 34 (33.7)

Levetiracetam 13 (25.5) 13 (26.0) 26 (25.7)

Clobazam 13 (25.5) 12 (24.0) 25 (24.8)

Vigabatrin 12 (23.5) 10 (20.0) 22 (21.8)

Baseline seizure frequency and prior AED use highlight unmet need


Ganaxolone Achieves Primary Efficacy Endpoint in the Marigold Study

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Ganaxolone Placebo

0

10

20

30

40

Med

ian

Perc

en

t R

ed

ucti

on

28-d

ay

Fre

qu

en

cy o

f M

ajo

r M

oto

r S

eiz

ure

s

32.2%

4.0%

= 29.7%*

p = 0.002**

*Hodges-Lehman Estimate of Median Difference

**Wilcoxon Rank-Sum Test

Titration + Maintenance relative to Baseline


Seizure Reduction in Titration and Maintenance Phases

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Titration Maintenance

0

10

20

30

40

Med

ian

Perc

en

t R

ed

ucti

on

28-d

ay

Fre

qu

en

cy o

f M

ajo

r M

oto

r S

eiz

ure

s

Ganaxolone

35.1%33.8%

(4 weeks) (13 weeks)


Notable Percent Reductions in Major Motor Seizure Frequency

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25% 50% 75%

0

20

40

60

80

100

Percent Reduction 28-day Frequencyof Major Motor Seizures

% o

f P

ati

en

ts

Ganaxolone

Placebo

57.1%

23.5% 24.5%

9.8% 10.2%3.9%

p=0.064

*Fisher's Exact Test

p=0.001


Preliminary Subgroup Analyses – Gender & Age

25

Female Male

-10

0

10

20

30

40

Gender

Med

ian

Perc

en

t R

ed

ucti

on

28-d

ay

Fre

qu

en

cy o

f M

ajo

r M

oto

r S

eiz

ure

s GanaxolonePlacebo

31.8%

10.2%

-7.8%

33.3%

6 years old > 6 years old

0

10

20

30

40

Perc

en

t R

ed

ucti

on

in

Med

ian

Majo

r

Mo

tor

Se

izu

re F

req

ue

ncy

(p

er

28

da

ys) Ganaxolone

Placebo

31.3%

7.0%

36.1%

4.0%

Age


Clinical Global Impression of Improvement (CGI-I)

26

Odds Ratio (95% CI) =

1.41 (0.68 – 2.94)

Odds Ratio (95% CI) =

1.87 (0.89 – 3.91)

Very much improved

Much improved

Minimally improved

No change

Minimally worse

Much worse

Very much worse

0

10

20

30

40

50

CGI-I (Caregiver)

% o

f P

ati

en

ts

Ganaxolone

Placebo

p=0.097

*Logistic Regression

Very much improved

Much improved

Minimally improved

No change

Minimally worse

Much worse

Very much worse

0

10

20

30

40

50

CGI-I (Clinician)

% o

f P

ati

en

ts

Ganaxolone

Placebo

*Logistic Regression

p=0.352


Caregiver Global Impression of Change in Seizure Intensity/Duration

27


Safety Summary

28

Treatment Emergent Adverse Events (TEAE)

Preferred Term Placebo (n=51)

Ganaxolone (n=50)

Any TEAE, n (%) 45 (88.2) 43 (86.0)

Somnolence 8 (15.7) 18 (36.0)

Pyrexia 4 (7.8) 9 (18.0)

Upper Respiratory Tract Infection

3 (5.9) 5 (10.0)

Constipation 3 (5.9) 3 (6.0)

Salivary Hypersecretion 1 (2.0) 3 (6.0)

Sedation 2 (3.9) 3 (6.0)

Includes AEs that occurred >5% of subjects in ganaxolone arm and

ganaxolone > placebo

Preferred Term Placebo (n=51)

Ganaxolone (n=50)

Any Serious TEAE, n (%) 5 (9.8) 6 (12.0)

Bronchitis 0 (0.0) 1 (2.0)

Rhinovirus Infection 0 (0.0) 1 (2.0)

Urinary Tract Infection 0 (0.0) 1 (2.0)

Pneumonia Mycoplasmal 1 (2.0) 0 (0.0)

Pneumonia Viral 1 (2.0) 0 (0.0)

Respiratory Syncytial Virus

Bronchiolitis1 (2.0) 0 (0.0)

Oxygen Saturation Decreased 0 (0.0) 1 (2.0)

Food Refusal 0 (0.0) 1 (2.0)

Pneumonia Aspiration 0 (0.0) 1 (2.0)

Hypoxia 1 (2.0) 0 (0.0)

Faecaloma 1 (2.0) 0 (0.0)

Hypotonia 1 (2.0) 0 (0.0)

Seizure 1 (2.0) 0 (0.0)

Unresponsive to Stimuli 1 (2.0) 0 (0.0)

Serious Treatment Emergent Adverse Events


Marigold Study Summary

• Ganaxolone met primary efficacy endpoint and demonstrated a significant reduction in major motor seizure frequency

• Ganaxolone was generally well tolerated and patients experienced less than a 5 percent discontinuation rate in the treatment arm

− Somnolence was the most common adverse event.

• Expanded analyses have provided supportive evidence of ganaxolone’s effect in CDD

• Currently developing comprehensive publication plan

29

Results of the Phase 3 Marigold Study Evaluating Ganaxolonein CDKL5 Deficiency Disorder Dr. Alex Aimetti, Vice President, Scientific Affairs

31


Expanding the Knowledge of Ganaxolone’s Effect in CDD

► The Marigold Study provides a high quality and rich dataset within the CDD patient population

► Committed to leverage these data to further the knowledge of the natural history of CDD and ganaxolone’s (GNX) clinical effects

► New Marigold Study analyses presented at AES 2020 provide supportive evidence of ganaxolone’s beneficial effects in CDD patients

Sub-group Analyses

Preliminary Open-Label Analysis

PK/PD Analysis

32


Ganaxolone Performed Similarly Across the Broader CDD Population

► Previously presented consistent findings across gender and age subgroups.

► Extended those findings across baseline seizure frequency and number concomitant antiepileptic drugs (AEDs) subgroups.

<35 35 - 93 >93-10

0

10

20

30

40

50

Pe

rce

nt

Re

du

ctio

n in

Me

dia

n M

ajo

rM

oto

r S

eiz

ure

Fre

qu

en

cy (

pe

r 28

da

ys)

GanaxolonePlacebo

20.9%

Baseline Major Motor Seizure Frequency(per 28 days)

11.1%

32.2%

-4.1%

35.9%

16.5%

(n=32) (n=34) (n=34) 2 > 2

-10

0

10

20

30

40

50

Pe

rce

nt

Re

du

ctio

n in

Me

dia

n M

ajo

rM

oto

r S

eiz

ure

Fre

qu

en

cy (

pe

r 28

da

ys)

GanaxolonePlacebo

26.1%

Number of Concomitant AEDs

-4.1%

33.3%

13.5%

(n=57) (n=43)

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Strong Signal of Seizure Reduction Observed in U.S. Patients

► Data collected in U.S. patients showed a stronger GNX effect with a 36.7% estimated difference in major motor seizure frequency relative to placebo

► Supports beneficial effect in U.S. patient population

U.S. AU/FR/IL/IT/UK RU/PL

0

10

20

30

40

Pe

rce

nt

Re

du

ctio

n in

Me

dia

n M

ajo

rM

oto

r S

eiz

ure

Fre

qu

en

cy (

pe

r 28

da

ys)

GanaxolonePlacebo

35.9%

-1.4%

31.4%

7.0%

(n=41) (n=35) (n=24)

17.5%

27.3%

U.S. – United StatesAU – AustraliaFR – FranceIL - IsraelIT – ItalyUK – United KingdomRU – RussiaPL - Poland

34


Ganaxolone’s Potential to Provide Durable Seizure Improvements in CDD

► Seizures associated with CDD are often refractory to treatment with existing AEDs and improvements may be short-lived (<3 months)1

► Preliminary analysis* of the open-label extension (OLE) provides insights into the extended duration effects of GNX in CDD

1. Müller A, et al. Eur. J. Paediatr. Neurol. 2016

*Data as of September 1, 2020

Primary Endpoint(17 wks)

1-2 3-4 5-6 7-80

10

20

30

40

50

60

70

Time in OLE (Months)

Pe

rce

nt

Re

du

ctio

n in

Me

dia

n M

ajo

rM

oto

r S

eiz

ure

Fre

qu

en

cy (

pe

r 28

da

ys)

GanaxolonePlacebo (DB) Ganaxolone (OLE)

32.2%

4.0%

Open-Label Ganaxolone

33.3%n=39

12.7%n=38

37.2%n=36

44.5%n=26

52.7%n=17

22.6%n=34

29.6%n=20

35.0%n=24

Placebo (DB)

Patients treated with ganaxolone for approximately 12 months experienced a median 52.7% reduction in major motor seizure frequency

Patients transitioning from placebo to ganaxolone demonstrated seizure frequency improvements

No new safety findings emerged in the OLE to date

35


Average Ganaxolone Levels Correlate with Seizure Reduction

► Logarithms of plasma GNX level and percentage change in major motor seizure frequency were negatively correlated

► Patients in the Medium and High GNX level groups had an average GNX concentration of 120 ng/mL and a median 43% reduction in seizure frequency• Incidence of CNS-related adverse events was similar across GNX dose level groups

Low (40 ng/mL*)

Medium(70 ng/mL*)

High(170 ng/mL*)

-100

-75

-50

-25

0

25

50

75

100

Pe

rce

nt

Ch

an

ge

in M

ajo

r M

oto

rS

eiz

ure

Fre

qu

en

cy

**p = 0.01

*mean GNX level within Group**Kruskal-Wallis Test

n=13 n=13 n=12

3.0 3.5 4.0 4.5 5.0 5.5 6.02.5

3.0

3.5

4.0

4.5

5.0

5.5

Loge GNX Level (ng/mL)

Log

e P

erc

en

t C

ha

ng

e M

ajo

r

Mo

tor

Se

izu

re F

req

ue

ncy

Eq

uiva

len

t % C

ha

ng

e in

Ma

jor

Mo

tor S

eizu

re F

req

ue

ncy

r = -0.499p = 0.001

*Pearson correlation

*145

48.4

-10.0

-45.4

-66.9

-79.9

-87.8

Equivalent GNX Level (ng/mL)

20.1 33.1 54.6 90.0 148 245 403

Loge percentage change in major motor seizure frequency was calculated as loge(percentage change + 100) 36


Efforts to Improve Ganaxolone Exposure in Chronic Epilepsies

► Dosing regimen: Marigold Study was the first Phase 3 study of ganaxolone to evaluate three times a day (TID) dosing• Predicted pharmacokinetic (PK) curves for TID and BID dosing demonstrate increase

trough GNX levels which may provide improved seizure control

► Support the continued study of ganaxolone TID dosing in other epilepsies

► Formulation development: new oral ganaxolone formulations that aim to improve PK properties to better achieve target ganaxolone levels.

Dose regimen

Cmax

(ng/mL)AUC0-24

(ng ∙ h/mL)% time (>100 ng/mL GNX)

TID 281 3763 78

BID 286 3135 53

37


Initiation of Expanded Access Program in CDD

► Allows U.S. patients with CDD who were not enrolled in the Marigold Study to begin receiving GNX under a treatment IND

► Initiated in the U.S. first yet actively exploring geographic expansion opportunities

► Process:• Physicians identify potentially eligible patient (CDD diagnosis, ≥ 2 years of age, inadequate

seizure control on current anti-seizure mediations at therapeutic doses, etc.)

• Physicians go to website / portal to submit a request for ganaxolone and provide appropriate clinical details for Sponsor medical review / approval

marinuspharma.com/expanded-access-program

38

Status EpilepticusJoe Hulihan, M.D., Chief Medical Officer

39


Continuum of Status Epilepticus

Benzodiazepine Administered

Established Status

Epilepticus (ESE)

1st line 2nd line

IV AEDs(antiepileptic

drugs)

3rd line

IV Anesthetics

Super Refractory Status

Epilepticus (SRSE)

Refractory Status

Epilepticus (RSE)

IV GNX


Convulsive vs. Nonconvulsive Status Epilepticus

Convulsive SE Nonconvulsive SE

Neurologic symptoms Tonic-clonic seizures Coma or confusional state, subtle or no movements

Usual treatment setting EMT/ED ICU

Common etiologiesUnderlying epilepsy,

decreased AED levels, acute illness

Stroke, CNS lesions, head trauma, CNS infections/inflammation

Diagnosis Clinical EEG (based on clinical suspicion of NCSE)

Treatment for uncontrolled SE

Rapid escalation to IV anesthesia after failure of single second-line

AED (minutes to less than one hour)

Two or more second-line AEDs attempted

(difference in practice US and Europe)


Phase 3 SE Plan

• Target dose range extends GNX exposure ≥ 500 ng/mL to 12 hours; IV bolus followed by 36-hour infusion followed by a 12-hour taper (48 hours in total)

• SE cessation within 30 minutes, No progression to IV anesthesia for at least 24 hours

• Focus on clinically meaningful effects: rapid onset of action, durability of effect, and prevention of treatment escalation

• Randomized, double blind, placebo-controlled trial (added to standard-of-care)

• Patients may present with convulsive or nonconvulsive SE (all or virtually all will be NCSE at time of study drug administration)

• Failure of benzodiazepine therapy and two additional antiseizure medications

• Healthcare utilization metrics, e.g., hospital/ICU length of stay

• Additional clinical and functional outcomes

TrialDesign

Target Patient Population

Dosing

Co-Primary Endpoints

Secondary Endpoints


Introduction – Henrikas Vaitkevicius, M.D., Vice President, Clinical Development

► Previously an attending neurologist in the Neurocritical Care, Stroke and Hospitalist Divisions of Brigham and Women’s Hospital Department of Neurology, and an Assistant Professor at Harvard Medical School.

► Has published over 40 peer-reviewed manuscripts, and multiple other scientific and medical materials and chapters.

► Served as the director of Brain Hub: Studio for Research and Innovation in Critical Care Neurology, with a focus on fostering collaborations among academic departments and pharmaceutical industries to bring novel treatments to the bedside.

► Principal investigator for the Phase 2 trial in refractory status epilepticus at Brigham and Women’s hospital in Boston

Henrikas Vaitkevicius, M.D., Vice President, Clinical Development

44

Status Epilepticus


Seizures and Treatment Approach

Epilepsia.2010;51(2):251–6DeLorenzo, Pellock et al. 1995Crit Care Med. 2015 May;43(5):1003-9Neurocrit Care (2013) 18:374–385Arch Neurol. 2010;67(8):931-940Neurocrit Care. 2012 Aug;17(1):3-23.

Seizure

Status Epilepticus

Refractory Status Epilepticus

Super Refractory Status Epilepticus

Most < 2.5 min

> 5 min

Failure of 2 Anti-seizure drugs

Failure IV anesthesia

Clinical convulsion and EEG

• Dosing based on environment-Peak exposure-Length of exposure

• Unique safety concerns

• Concomitant medications

• Impact of EEG and interpretation


Status Epilepticus Progression

Emergency Room

ICUTertiary Center

ICU

>48 h6 h

Pro

bab

ility

of

mo

rtal

ity

or

mo

rbid

ity

30 min 24 h

100%


Super Refractory Status Epilepticus (SRSE) – Clinical Story

Days 1 2 3 4 5 6 7 9 10 11 13 15 16 20 23 24 26 27 30 31 37 42 47 48 53 56 57 58 60 78 82 87 92 93 94 95 96 151

Propofol

Midazolam

Lacosamide

Phenytoin

Phenobarbital

Ketamine

Clonazepam

Levetiracetam

Valproate

Pentobarbital ** ** ** ** ** ** ** ** **

Topiramate

Steroids

pyridoxine

CoQ-10

Lidocaine

ECT

Bromides

Hypothermia

Ketogenicdiet

Acupuncture

Weanattempts ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑

Ann Clin Transl Neurol. 2017 Apr 26;4(6):411-414.

3 months ...


Super Refractory Status Epilepticus (SRSE) – After Treatment


GNX SRSE eIND Patient Cases Presented at AES

IV Ganaxolone in Pediatric Super-Refractory Status Epilepticus: A Single Patient Case StudyR. Singh, et al.Poster #209Saturday, December 5, 20209:00 to 10:30 AM EST

Treatment of Super Refractory Status Epilepticus Using Intravenous Ganaxolone in a Patient with Lennox-Gastaut Syndrome and Angelman SyndromeM. G. Chez, J. Hulihan, and M. GasiorPoster #86Saturday, December 5, 20209:00 to 10:30 AM EST

► 17 y.o. woman with known refractory epilepsy presented with SRSE after a febrile episode

► 7-month hospitalization with 4 episodes of IV anesthesia for seizure control

► 4-day ganaxolone infusion

► Rapid clinical improvement and initiation of PO ganaxolone

► 1 month post infusion patient is home

► 3 months post initiation of Ganaxolone patient has only minor epileptic events and remains home

► 4 y.o. girl with known epilepsy presented with convulsive SRSE

► Seizures recurred despite 4.5 days of IV anesthesia therapy

► Patient received 5-day ganaxolone infusion

► Extubated 48 hours after initiation of IV ganaxolone

► Discharged on oral ganaxolone

https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/2422556

https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/2422434


Lessons learned from eIND cases for SRSE

• Dosing paradigm focused on long exposures

• Systematic approach to the patient condition optimization

• Consistent EEG interpretation and provider education

SRSE Patients

IV sedation

Standard of care

GNX infusion +/- PRN bolus

Wean

GNXWean

EEG driven criteria

Treatment optimization


Emergency Room

ICUTertiary Center

ICU

Established Status Epilepticus – Use of Ganaxolone in Emergency Room

• Unique Environment: -No EEG-Risk of rapid escalation of care-Convulsive patients: new dosing paradigm – bolus and short infusion time (2-24 hours)


Continuum of Status Epilepticus

Benzodiazepine Administered

Established Status

Epilepticus (ESE)

1st line 2nd line

IV AEDs(antiepileptic

drugs)

3rd line

IV Anesthetics

Super Refractory Status

Epilepticus (SRSE)

Refractory Status

Epilepticus (RSE)

IV GNX


Established Status Epilepticus – Use of Ganaxolone in Emergency Room

• Not enough time for consent-Exception from Informed Consent (EFIC)-Community consent activities

• First patient expected to be enrolled in 1H of 2022

Failed

benzodiazepineOpen bolus IV ganaxolone infusion

Screening Double-blind treatment (2-24h)

Failed

benzodiazepine

Randomization

1:1

Standard of care

IV AED

Placebo

bolus

bolus

Placebo

IV ganaxolone:

<30 min

Pilot: N = 4-5 per cohort

Blinded: N = 40 per arm

Standard of care

IV AED

2-24h

Commercial Strategy / Market OpportunityChristy Shafer, Chief Commercial Officer

54


Introduction – Christy Shafer, Chief Commercial Officer

► 20 years commercial experience in biotech, pharma, and medical device

► Most recent position as Business Director of Neurology at Alexion

Pharmaceuticals where she led transformational growth in first-in-class

neurology product launches

► Positions of increasing responsibility at Pacira BioSciences, where she

was responsible for multimillion-dollar sales forecasts, operational

budgets, and sales management

► Previously held roles of Regional Sales Director for Sanofi Biosurgery and

Regional Vice President at I-Flow Corporation

► Post-Baccalaureate degree in Immunology and Pharmacology and

Bachelor of Life Science in Cell/Molecular Biology and Genetics from the

University of Maryland, College Park


Oral Franchise Model is Driven by Ganaxolone Scientific Rationale and Unmet Need in Debilitating Rare Epilepsy Disorders

24-30K addressable patients

Overlapping prescribers and similar behavior across each disease state

Physicians seeking safe, effective, and durable treatment options

• 4-5K addressable patients in US and 50-100 newborn cases per year1

• Genetic testing in major global markets driving diagnosis rates

• Severe, difficult to manage patients with high medication reliance and need for more durable options

• No indicated treatments available or clinical trials conducted

• 20-25K addressable US patient population2

• Large refractory population despite available treatment options

• Severe patients still in need of more efficacious medications

• Given refractory population, opportunity exists for later stage treatments (eg, 3rd line)

CDKL5 Deficiency Disorder (CDD) Tuberous Sclerosis Complex (TSC)

Given CDKL5 and TSC patient seizure burden, overlap of CDKL5 and TSC prescribers, and common market dynamics, we group both indications under a franchise go to market model

1. Jakimeic et. al 20202. NORD (https://rarediseases.org/rare-diseases/tuberous-sclerosis)

https://rarediseases.org/rare-diseases/tuberous-sclerosis


Key Findings from Recently Conducted Market Research Show that Ganaxolone is Well Suited for Broad Clinical Adoption Across Indications

Awareness

Mechanism of Action

TPP Reactions

Primary Usage Drivers

More Neuros were aware of ganaxolone than any drug in development for CDD or TSC

Ganaxolone’s extrasynaptic mechanism of action well understood and viewed as differentiable

Many HCPs are excited about the opportunity to use ganaxolone, especially for CDD, given favorable reactions to its efficacy and durability data, and safety profile

• Disease-specific indication, response rate, and durability of response

• Ability to be used with antiseizure medications across mechanisms (i.e., sodium channel blockers, GABA transmission inhibitors, cannabidiol) in refractory patients

Source: ZS Associates Primary Research and Analysis (N=35 HCP Interviews)*TPP – Target Product Profile


Key Focus Areas Driving Franchise Commercialization Strategy for Potential Launch in 2022

HCP Profiling & Account

Segmentation

Positioning, Messaging, & Branding

Market Access,

Pricing, & Distribution

Advocacy Groups & Societies

Commercial Organization

Commercial Partnership

Process


Ganaxolone provides us an opportunity to avoid general anesthesia and associated

complications and reduce hospital cost by changing how medicine is practiced

Utilization and Cost Outcomes

Metric Cohort 1 (≤ 1 IV AED)

Cohort 2 (> 1 IV AED)

Cohort 3(≥ 1 IV anesthetic)

All

Unique SE patient encounter, N

(%)

14,694

(33.4)

10,140

(23.1)

19,154

(43.5)

43,988

(100)

Hospital length of stay (LOS) (days)

Mean* 4.7 7.2 12.0 8.4

Median* 3 4 8 5

ICU LOS (for ICU patients only)

Mean* 2.7 3.1 6.6 5.4

Median* 2 2 4 3

Total hospital cost* ($USD)

Mean* $11,532 $18,328 $41,858 $26,304

Median* $6,812 $10,592 $24,105 $13,201

Clinical Outcomes

Metric Cohort 1 (≤ 1 IV AED)

Cohort 2 (> 1 IV AED)

Cohort 3(≥ 1 IV anesthetic)

All

Unique SE patient encounter,

N (%)

14,694

(33.4)

10,140

(23.1)

19,154

(43.5)

43,988

(100)

Discharge disposition (%)

Expired* 4.6 6.3 18.9 11.2

Hospital-acquired condition (%Y) 14.0 19.4 23.1 19.2

Catheter-associated UTI (%) 12.0 17.4 18.3 16.0

Miscellaneous infectionŦ (%) 1.6 1.7 4.3 2.8

Vascular catheter-associated

infectionŦ (%)0.2 0.2 0.4 0.3

Mechanical ventilator -associated

complication (%)0.2 0.2 1.6 0.8

*Indicates p<0.05 across all pairwise comparisonsŦindicates p<0.05 C1 or C2 vs. C3

Effective therapeutics that prevent progression to SRSE (i.e., treatment with IV

anesthetics) may reduce mortality rates by ~70% and $30,000 in hospital cost

Manuscript in preparation

SE is a Neurological Emergency With Significant Unmet Need in a Severely Impaired and Costly Patient Population


Potential Launch Into the Hospital Setting Designed to be Driven by Data, Customer Collaboration & Protocolization of Ganaxolone in RSE

•Phase 3 data to support clinical adoption and budget model

•Clear clinical benefit eg, SE cessation, IV escalation

•Economic advantage –LOS, ICU duration

Compelling Clinical and HEOR Data

•Partner with KOLs and societies to update RSE treatment guidelines

•Collaborative approach to protocol augmentation with health systems and local hospitals

Society Guideline & Account Protocol

Inclusion •Early engagement with Pharmacy to best frame value proposition

•Determine formulary process and requirements

•Reimbursement, logistics and operational processes

C-Suite, Pharmacy, & Admin

Engagement

•Navigate and influence hospital decision makers

•Educate and generate customer usage data

•Collaborate with physicians to protocolize usage

Experienced Hospital Sales

Force

Clinical and Economic Evidence Access

Pull-ThroughClinical Adoption

Critical Success Factors for RSE Launch

LOS – Longer length of stayHEOR – Health economics and outcomes research


Additional Commercial Opportunities Along SE Continuum

Ability to leverage existing hospital sales force to address > 3x patient population in ESE and SRSE

1. DeLorenzo RJ Pellock JM Towne AR Boggs JG. Epidemiology of status epilepticus. J Clin Neurophysiol. 1995; 12: 316-325

2. Kapur et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus N Engl J Med 2019;381:2103-13.

3. Rossetti and Lowenstein. Management of refractory status epilepticus in adults Lancet Neurol. 2011 Oct; 10(10): 922–930

ESETT


Key Upcoming Events for Commercial Planning

► Market Research Completion – Patient Journey, Account Segmentation,

Global Pricing and Reimbursement

► Marketing Work Completion – Positioning, Messaging, Branding, Packaging, Distribution

► Finalize Global Commercialization Plan

► TSC Phase 2 Data Readout

► CDD Launch

Q&A

63

Thank You

64

Documents

Marinus AES Investor Meeting