r&d day · 2 hawkes ma et al.2019 crit. care med. 3marchi na et al.2015 crit. care med....

©2020 Marinus Pharmaceuticals. All Rights Reserved.

R&D DayJune 30, 2020

NASDAQ: MRNS

IntroductionPresenter: Sasha Damouni

VP, Investor Relations & Corporate

Communications

R&D Day June 2020 I

Forward Looking Statement Disclosure

To 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, including our expectation to dose the first patient in our Phase 3 clinical trial for SE in September 2020; 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 data from the Marigold Study in the third quarter of 2020 and from the proof of concept study in PCDH19 in the first

half of 2021; the potential safety and efficacy of ganaxolone; the therapeutic potential of ganaxolone; and our expectations regarding the effect of the

COVID-19 pandemic on our business and clinical development plans; and our commercial plans for ganaxolone. 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; 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 U.S. Food and Drug Administration 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.

3

R&D Day June 2020 I

Presenters

Marinus Management

Dr. Scott Braunstein I Chief Executive Officer

Dr. Joe Hulihan I Chief Medical Officer

Dr. Alex Aimetti I Head of Scientific Affairs

Thomas Lyons I Vice President of Business Development & Licensing

Key Opinion Leaders

Dr. Larry Hirsch I Yale Comprehensive Epilepsy Center

Dr. Henrikas Vaitkevicius I Brigham and Women’s Hospital Department of Neurology

Dr. Scott Demarest I Children’s Hospital Colorado

Dr. Darcy Krueger I Cincinnati Children’s Hospital Medical Center

4

R&D Day June 2020 I

Agenda

Timing (minutes) Topic Presenter(s)

8:00 – 8:05 am (5 mins) Welcome/Introductions Sasha Damouni

8:05 – 8:15 am (10 mins) Marinus Overview Dr. Scott Braunstein

8:15 – 9.00 am (45 mins)Status Epilepticus

Q&A (10 mins)

Dr. Joe Hulihan / Dr. Larry Hirsch / Dr. Henrikas

Vaitkevicius / Dr. Alex Aimetti

9.00 – 9.05 am (5 mins)CDKL5 Deficiency Disorder (CDD)

VideoCaregivers (CDD) / IFCR US advocacy group

9.05 – 9:30 am (25 mins)CDD Overview

(Q&A 5 mins)Dr. Joe Hulihan / Dr. Scott Demarest

9:30 – 9.35 am (5 mins)Tuberous Sclerosis Complex (TSC)

VideoCaregivers (TSC) / TS Alliance advocacy group

9.35 – 9.50 am (15 mins) TSC Overview Dr. Alex Aimetti / Dr. Darcy Krueger

9.50 – 10.00 am (10 mins) Commercial Strategy Thomas Lyons

10.00 – 10.25 am (25 mins) Q&A Marinus Management Team / Dr. Darcy Krueger /

Dr. Henri Vaitkevicius

10.25 – 10:30 am (5 mins) Closing Remarks Dr. Scott Braunstein

5

Marinus OverviewPresenter: Dr. Scott Braunstein

R&D Day June 2020 I

Evaluation of IV and Oral Opportunities

Marinus Corporate Strategy Marinus Corporate Strategy

7

• Expand clinical opportunities

from refractory status

epilepticus (RSE) to broader

SE market

• Initiate commercialization plan

• Create a global development

strategy

• Develop pharmacoeconomic

value proposition

Building Upon Status

Epilepticus (SE)

Maximizing Value for

Orphan Epilepsies

• Continue clinical development

in CDKL5 deficiency disorder

(CDD) and tuberous sclerosis

complex (TSC)

• Consider expansion

opportunities based on

biomarker strategy

• Further develop commercial

roadmap, including scientific

and clinical differentiation

Leveraging

Ganaxolone Molecule

• Evaluate reformulation and

prodrug options and

opportunities

• Prioritize clinical studies based

on unmet need, improved

product profile, new therapeutic

indications driven by

mechanistically understood

disease states

R&D Day June 2020 I

Ganaxolone (GNX)Future Opportunities for Oral Franchise

8

GNX

• Highly potent anti-epileptic

molecule

• Excellent efficacy in SE (IV); Phase

3 to initiate in Q3

• First Phase 3 readout with TID

dosing in Q3, several phase 2

studies to read out in first half 2021

• Generally well tolerated; studied in

over 1,600 patients

• 10-15% bioavailability

• TID dosing w/ cherry flavored suspension

• One-month titration schedule to maximize

tolerability

• 7-year regulatory exclusivity and method of

use application to 2038

+

• Improve bioavailability

• More consistent and extended

pharmacokinetics

• Expand clinical utility Life cycle extension

REFORMULATION & MOLECULE OPTIMIZATION

R&D Day June 2020 I

Development Objectives

• Reformulation, molecule optimization, and prodrugs approaches may offer

improved PK profile with ”narrower” peaks and troughs

• Attempt to improve current efficacy, allow expansion into new indications, and

create the potential for new therapeutic areas

Step down IV to oral

Pediatric Dosing

0

0

100

200

300

400

Pre

dic

ted

GN

X P

lasm

aC

on

cen

trati

on

(n

g/m

L)

6am 7pm12pm

600 mg TID

IV DosingOral Dosing

9

R&D Day June 2020 I

Marinus Corporate Updates

• TSC: First patient enrolled in the Phase 2 open-label trial designed to

evaluate the safety and tolerability of adjunctive ganaxolone treatment

• CDD: Fully enrolled with data on track for release in Q3. Open

Expanded Access Program pending successful CDD data outcome

• SE: On track to start Phase 3 study in Q3

• PCDH19: Enrollment expected to be between 25-30 patients

10

R&D Day June 2020 I

Status EpilepticusPresenters: Dr. Joe Hulihan,

Dr. Larry Hirsch,

Dr. Henrikas Vaitkevicius

& Dr. Alex Aimetti

Refractory Status Epilepticus

Yale University

Lawrence J. Hirsch, MD2020

12

• Definition

– > 5 minutes of continuous seizure activity

– Back to back seizures without return to baseline

– Nonconvulsive status: >10 minutes of continuous seizure (ILAE);

• Often used: >30 minutes of continuous seizure on EEG, or >50% of any

hour;

• Being changed to 20% cutoff

Basics of Status Epilepticus

13

stroke, 25

med change, 19

etoh/drugs, 12

anoxia, 11

metabolic, 9

unknown, 8

infection, 6

trauma, 5

tumor, 4

0 5 10 15 20 25 30

STROKE

MED CHANGE

ETOH/DRUGS

ANOXIA

METABOLIC

UNKNOWN

INFECTION

TRAUMA

TUMOR

percent

etiology

DeLorenzo et al, Epilepsia ‘92

Status Epilepticus: Etiology in Adults

14

Drug Success Hypovent’n Hypotens’n arrhythmia

LRZ 65% 14% 28% 12%

PB 58% 13% 34% 3%

DZ+P HT 56% 19% 33% 2%

PHT 44% 11% 29% 9%

mean55%

7% 2ND DRUG

Treiman et al, NEJM ‘98

V.A. Status Study

15

ESETT, Kapur J et al NEJM 2019

16

ESETT, Kapur J et al NEJM 2019

17

Refractory SE

Incidence

• 31-43% of SE will be refractory to first 2 meds (ie, become RSE) Hocker S, Continuum 2015

• VA study: 38% of overt SE and 82% of subtle SE were refractory to first 2 drugs Treiman 1998

Predictors of RSE Holtkamp JNNP 2005, Mayer 2002, Lowenstein 1993, Young 1996, Hocker S 2015

• Encephalitis

• Hyponatremia in 1st 34 hours

• Delayed diagnosis/treatment

• Subtle or Nonconvulsive SE

• Focal motor seizures at onset

• Non-structural cause (HIE, tox/metab, CNS infection, unknown)

Mortality in RSE

• Overall mortality in RSE: 23-48% Hocker S, Continuum 2015

• If treated with pentobarbital, propofol or midazolam: 48% (systematic review of 28 studies, Claassen

et al Epilepsia 2002)

18

www.aesnet.org; Epil Currents 2016

AES Convulsive Status Epilepticus Guideline

Treatment Algorithm: “20-40 mins, second therapy phase”

If seizures continue:

19

AES Convulsive Status Epilepticus Guideline

Treatment Algorithm:

“40-60 mins, third therapy phase” If seizures

continue:

20

www.aesnet.org; Epil Currents 2016

20

Conclusions

• After failing benzo and 1 other IV anti-sz medication (RSE), there is

no clear standard of care, and virtually no high-quality data

• Overall outcome in RSE is poor, including mortality, long term

functional outcomes, and later epilepsy

– Outcome even worse if anesthetics required

21

Phase 2 Open-label Study of Intravenous

Ganaxolone for the Treatment of Refractory

Status Epilepticus

Henri Vaitkevicius MD

Brigham and Women's Neuroscience ICU

Assistant professor, Harvard Medical School

Boston, MA

22

Refractory seizures

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.

SeizureSeizure

Status EpilepticusStatus Epilepticus



Super Refractory Status EpilepticusSuper Refractory Status Epilepticus

Most < 2.5 min

> 5 min

Failure of 2 drugs

Failure of burst suppression

~150,000/year in US

~42,000/year in US

~30,000/year in US

23

Refractory seizures

Variable Mortality

Age 1.03 (1.01-1.05)

STESS 1.56 (1.17-2.10)

Therapeutic Coma 9.10 (3.17-26.16)


SeizureSeizure





Most < 2.5 min

> 5 min

Failure of 2 drugs


~150,000/year in US

~42,000/year in US

~30,000/year in US

24

Refractory seizures


SeizureSeizure





Most < 2.5 min

> 30 min

Failure of 2 drugs


~150,000/year in US

~42,000/year in US

~30,000/year in US

NEED BETTER DRUG:-Rapid onset-Sustained efficacy -Improved Safety

25

Index Patient

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

26

Index Patient

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

Ketogenic diet

Acupuncture

Wean attempts ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑


27

Index Patient

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

Ketogenic diet

Acupuncture

Wean attempts ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑


28

Why Neurosteroids?

Psychopharmacology (2013) 230:151–188Pharmacol Exp Ther 2018;365:583-601

5a-Reductase

3α-Hydroxysteroiddehydrogenase

* NOT A “STEROID”-> neurotransmitter* No known systemic targets

29

Why Neurosteroids?

Psychopharmacology (2013) 230:151–188Pharmacol Exp Ther 2018;365:583-601

5a-Reductase

3α-Hydroxysteroiddehydrogenase

* NOT A “STEROID”-> neurotransmitter* No known systemic targets

STATUS trial

30

Why Neurosteroids?

Psychopharmacology (2013) 230:151–188Pharmacol Exp Ther 2018;365:583-601JPET (2019) 368:326-337

Rat Pilocarpine-induced SE Model

31

Phase II Multicenter Trial Design

STATUS trial

Screening Treatment Period

Loading Dose Maintenance Taper

Post-treatment Follow-up

24 hr Weeks 2, 3, 4

Endpoints:

• Primary: IV anesthetics within 24 h

• Secondary: safety and tolerability

3 min bolus6h load

2-4 days 18 h taper

32

SeizureStatus

Epilepticus

Refractory Status

Epilepticus

Super Refractory

Status EpilepticusX

Cohort Dose of GNX/day N

Low 500mg/day 5

Medium 650mg/day 4

Target 713mg/day 8

GN

X P

lasm

aC

on

ce

ntr

ati

on

(n

g/m

L)

Modeled PK curves

GN

X P

las

ma

Co

nc

en

tra

tio

n (

ng

/mL

)

Patients

33

Patients

EtiologyNeoplasm, Stroke, Metabolic,

Autoimmune, Overdose, Alcohol Withdrawal

Cohort Dose of GNX/day N

Low 500mg/day 5

Medium 650mg/day 4

Target 713mg/day 8

Total Patients 17

Females 9

Males 8

Age (Range) 56.9 (23-88)

Failed Drugs (Range) 2.9 (2-5)

Convulsive SE 6 (35%)*

Non-convulsive SE 12 (71%)*

Intubated before 8 (47%)Intubated during 3/9 (33%)

Hx of seizures 7 (41%)No Hx of seizures 10 (59%)

*1 patient had both

*all 17 patients failed LEV or LCM

34

Outcomes

Primary endpoint: 100%

◦ No escalation to

anesthetics within 24

hours

Median time to seizure

control: 5 min

3 hours

35

Outcomes

CohortNo Anesthetics for 24h

(primary endpoint)

Status free for 24h

No additional AEDs for SE relapse for 24h after taper*

Low 100% (5/5) 100% (5/5) 60% (3/5)

Medium 100% (4/4) 100% (4/4) 75% (3/4)

Target 100% (8/8) 88% (7/8) 100% (8/8)

*Includes study period and 24h after taper

36

Safety

No clinically meaningful changes in labs, vital signs, or ECG

2 related SAEs severe sedation

Intubation

◦ 9 of 17 (53%) patients not-intubated before GNX

◦ 3 of 9 (33%) patients intubated while on GNX

13 related AEs

◦ 6 mild (2 hypotension, 2 somnolence, 1 urinary retention, 1 hypercarbia)

◦ 5 moderate (4 somnolence; 1 hypercarbia)

◦ 2 severe (2 sedation)

37

Summary

Primary endpoint: 100%

Effect was reached within 5 min (median)

Target dose identified as 713 mg/day

Safety profile consistent with known mechanism of action

Looking forward to Phase 3 trial

38

Dr. Joe Hulihan

Marinus Pharma

R&D Day June 2020 I

Benzodiazepine Administered

Medically induced Coma

Established

Status

Epilepticus (ESE)

1st line 2nd line

IV AED’s

3rd line

IV Anesthetics

Super Refractory

Status

Epilepticus (SRSE)

Refractory

Status

Epilepticus

(RSE)

ESETT GanaxoloneSTATUS

Trial

Clinical Opportunities Throughout the SE Continuum

40

R&D Day June 2020 I

Overview of U.S. Phase 3 SE Study

41

Study design • Randomized, placebo-controlled (adjunctive to standard-of-care) clinical trial

Target patient

population• Status epilepticus patients (n=124) who have failed benzodiazepines and ≥ 2 IV AEDs

Dosing• 36-hour infusion followed by a 12-hour taper (48-hour treatment).

• Phase 2 dose paradigm and extends GNX plasma exposure ≥ 500 ng/mL for 12 hours

Co-primary endpoints

• Proportion of participants with SE cessation within 30 minutes of IP initiation without

medications for the acute treatment of SE

• Proportion of participants with no progression to IV anesthesia for 36 hours following IP

administration

Secondary endpoints

• No progression to IV anesthesia for 24 hours off study drug (i.e., 72 hrs)

• Time to SE cessation

• Target key areas of safety (eg, % intubated on GNX, time to extubation)

• Healthcare utilization metrics (eg, length of stay, # of days in the ICU)

• Functional outcomes

R&D Day June 2020 I

Ganaxolone Pharmacokinetics / Pharmacodynamics

-60 -45 -30 -15 0 15 30 45 60

30

40

50

60

70

80

90

100

110

Time (min)

BIS

10 mg, 5-min Slow Bolus (n=3)


PBO, 2-min Slow Bolus (n=2)


5-min bolus (10- and 30-mg groups)

2-min bolus (PBO and 20-mg groups)

Experimental PK – plasma and brain1

Brain and plasma concentration after GNX 3 mg/kg IM in mice

Human PD – EEG changes2

EEG bispectral index in healthy volunteers following IV GNX

1. Zolkowska D, Wu CY, Rogawski MA. Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment-resistant status epilepticus. Epilepsia. 2018 Oct;59:220-7.

2. Data on file, Marinus Pharmaceuticals, inc.

Human PK2

Following 20 mg GNX bolus (over 2 minutes):

Cmax 1,240 ng/mLTmax 0.08 hrs

42

R&D Day June 2020 I

Phase 3 SE Study Design

0

Patients with SE:Failed BZD and two 2nd-line AED

Endpoints

1. Seizure cessation within 30 minutes AND

2. No progression to IV anesthesia in 36 hours

R1:1

48 hours

Ganaxolone + Standard of Care

Placebo + Standard of Care

Follow up for 4 weeks

36 hours

24hours

12 hoursBolus

> 800 Taper>500 300-400| | |Infusion

Ganaxolone target plasma concentration, ng/ml

43

R&D Day June 2020 I

Clinical Opportunities Throughout the SE Continuum

Benzodiazepine Administered

Medically induced Coma

Established

Status

Epilepticus (ESE)

1st line 2nd line

IV AED’s

3rd line

IV Anesthetics

Super Refractory

Status

Epilepticus (SRSE)

Refractory

Status

Epilepticus

(RSE)

ESETT GanaxoloneSTATUS

Trial

ESE1st line SRSERSE RSE

Failure of

benzodiazepine

Failure of

> 2 IV AEDs

Failure of

1 IV AEDFailure of

anesthetic wean

44

R&D Day June 2020 I

GNX Clinical Development Strategy

• Rapid onset of action • Durable seizure control for at least 36 hours• Mitigate escalation to IV anesthetic

• Stabilize patient to address underlying medical etiology

• Preserve neuronal function• Decrease treatment risk (i.e. ICU) • Decrease anesthesia associated

morbidities and mortality

• Facilitate better Tx outcomes • Reduce overall cost of Tx • Reduce cost due to anesthesia and its

complications

CLINICAL VALUE PROPOSITION

HEALTH ECONOMIC PROPOSITION

45

Dr. Alex AimettiMarinus Pharma

R&D Day June 2020 I

Defining the Economic Burden in Status Epilepticus

The Phase 3 study of GNX in refractory SE aims to demonstrate rapid onset of

action capable of preventing escalation to 3rd-line IV anesthetics

Treatment with 3rd-line IV anesthetics has been reported to lead to increased

length of hospital admission and risk of infections, new disability, and death.1-3

Previous studies aimed at quantifying burden of disease by derivation of SE

subtypes (e.g., ESE, RSE, SRSE) by algorithms based on diagnosis and

procedural codes4,5

1 Sutter R et al. 2014 Neurology2 Hawkes MA et al. 2019 Crit. Care Med.3Marchi NA et al. 2015 Crit. Care Med.4Strzelczyk A et al. 2017 Epilepsia5Sanchez Fernandez I et al. 2019 Seizure-Eur. J. Epilep.

$ $

47

There is a need to understand cost of admission and clinical outcomes based on treatment progression which better aligns with clinical terminology

R&D Day June 2020 I

Status Epilepticus Burden of Illness Based on Disease Severity by Treatment Progression

Segment SE population using ICD-10 diagnosis codes and administration of various antiseizure medications (ASMs)

Patient Eligibility:

• ICD-10 (G40.xxx) “with SE”

diagnosis code (primary/secondary)

• Inpatient admission (2016-2018)

• Entire admission within single

hospital

Database:

• Premier Hospital Database (U.S.)

43,988eligible SE patient encounters

14,694(33.4%)

10,140(23.1%)

19,154(43.5%)

Manuscript in preparation

Foundational SE burden of illness study aimed to support ganaxolone’s value proposition

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R&D Day June 2020 I

SE Severity Correlates with Increased Clinical Consequences and Healthcare Utilization

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

Manuscript in preparation

49

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

R&D Day June 2020 I

Additional HEOR Opportunities to Expand Potential

Value Proposition of Ganaxolone in SE

Quantify total cost of care in SE patients following hospital discharge

• Many patients were discharged to long-term care or skilled nursing facilities and correlated

with more severe SE

Effective treatment options aimed at limiting the progression of SE severity may lead to

favorable discharge settings and reduce post-hospital costs

Quantify total cost of care of an inpatient episode of SE in patients that transfer

between hospitals

• 13% of patients with an SE diagnosis code were excluded due to being transferred into or

out of a Premier hospital (i.e., incomplete SE episode details and cost)

• These patients are likely high-acuity cases in need of specialized care and may result in:

− Increased duration in status epilepticus

− Increased length of hospital stay and overall healthcare utilization

Effective treatment of SE at the initial site of care has the potential to dramatically

improve outcomes and reduce costs

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R&D Day June 2020 I

Q&A

51

R&D Day June 2020 I

VIDEO: The International Foundation for CDKL5 Research (IFCR)

The International Foundation for CDKL5 Research began as a group of parents whose children were diagnosed with CDKL5 deficiency disorder.

Over the years, the global non-profit organization has established CDKL5 Centers of Excellence and continues to fund clinical research and raise awareness for CDD families

and caregivers.

Karen UtleyPresident & Co-Founder

Mother to Samantha

Heidi GrabenstatterScience Director

Amanda JakshaTreasurer

Mother to Ava

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R&D Day June 2020 I

CDKL5 Deficiency Disorder

Presenters: Dr. Joe Hulihan & Dr. Scott Demarest

R&D Day June 2020 I

Dr. Scott Demarest

Children’s Hospital Colorado

5454

R&D Day June 2020 I

Prevalence of CDD

• CDD is estimated to occur in 1:42,000 – 60,000 individuals

• Genetic testing historically was hard to get but is now much more

accessible, improving our ability to identify CDD patients

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R&D Day June 2020 I

Typical Features of CDD

• Severe and very refractory epilepsy starting in the first several

months of life which are are very hard to treat

• Severe development delay

• A minority achieve independent walking or say a single word

• 75% have impaired vision

• Disrupted sleep

• Many have GI and pulmonary symptoms also

565656

R&D Day June 2020 I

CDD is a Developmental and Epileptic Encephalopathy

• DEEs are disorders with developmental delay and severe epilepsy

where the seizures are thought to contribute to worsening development

or cognitive function.

• This raises the possibility of improving development if seizures can be

controlled.

575757

R&D Day June 2020 I

Seizure Free Periods and Chances of Seizure Freedom

58PMID: 2777071

5858

R&D Day June 2020 I

Treatment…

59

• ~20% of patients will respond to any

given drug for at least 3 months

• 69%, 45% and 24% will respond to at

least 1 drug for 3,6 or 12 months

• In other words there is a strong

honeymoon effect

• Interestingly this is very similar to the

typical placebo effect in pediatric

epilepsy (20-40%)

Muller et al. PMID: 26387070 595959

Treatment…In other words, there are currently no effective and long-

lasting epilepsy treatments for the majority of CDD patients.

60

R&D Day June 2020 I

Dr. Joe Hulihan

Marinus Pharma

R&D Day June 2020 I

Q&A

62

R&D Day June 2020 I

26 weeksganaxolone

600 mg 3x/day maximum

12 weeks

Trial Details

2 sites in US; 1 site in Italy

6 females, 1 male – ages 2-16

Confirmed CDKL5 mutation, stable background treatment, >4 seizures per 28-day period in baseline

Baseline Characteristics

Mean number seizures – 206 (range 34 to 669)

Median number seizure-free days - 4 (range 0 to 9)

Endpoints

Primary: % change in seizure frequency per 28 days relative to baseline

Secondary: % increase in seizure free days from baseline, safety and tolerability, CGI

CDD - Phase 2 Trial Design

Open-Label Phase

52 weeks600 mg 3x/day maximum

Treatment Baseline

63

R&D Day June 2020 I

CDD Phase 2: 6 Month Open-Label Treatment and 12-Month Extension

• 4 of 7 patients entered the extension period

• Ganaxolone demonstrated preliminary evidence of sustained, long-term (out to 18 months) efficacy in a

small cohort of CDD patients

*As of 12/31/18: Clinical data presented at AES 2018

44% Median reduction in seizure frequency at 6 months

Durability at 12-18 months Median change frequency improved to 66% in extension period*

Patients Entering OLE

Patient 1 Patient 2 Patient 3 Patient 4

%

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Global Phase 3 Pivotal Trial Design

Baseline 6 weeks

Historical Control 8 weeks

Double-Blind Phase Open-Label Phase

Maintenance 13 weeks

Titration 4 weeks

Titration 4 weeks

Open-Label Phase

Trial Details

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

• Global, double-blind, placebo-controlled, clinical trial has enrolled 101 patients between the ages of 2 and 21 with a

confirmed disease-related CDKL5 gene variant

• Ages 2-21, 16 major motor drop seizures/month; up to 4 concomitant AEDs

• Data expected in Q3 2020

Endpoints

• Primary endpoint of the trial is percent change in 28-day seizure frequency

• Non-seizure secondary outcome measures: Behavioral/neuropsychiatric changes correlated with domains of attention &

sleep

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R&D Day June 2020 I

VIDEO: The Tuberous Sclerosis Alliance (TS Alliance)

The Tuberous Sclerosis Alliance was founded by four mothers to provide support, generate awareness, pursue knowledge and offer

hope to tuberous sclerosis complex (TSC) community.

Their ultimate vision is to find a cure for TSC while improving the lives of those affected.

Shannon GrandiaMother to Riley, Jake and Luke

Steve RoberdsChief Science Officer

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Tuberous Sclerosis Complex

Presenters: Alex Aimetti & Dr. Darcy Krueger

Treating Epilepsy in Tuberous Sclerosis

Complex (TSC):

A Critical Unmet Need

Darcy A. Krueger, MD PhD

Director, Tuberous Sclerosis Clinic and Clack Endowed Chair in Tuberous Sclerosis

Cincinnati Children’s Hospital Medical Center

University of Cincinnati College of Medicine

Brain (95%): Cortical displasias (e.g. tubers), SEN y SEGA

Lung (40%):LAM

Kidney (80%): Angiomyolipomas, Cysts Eye (40%):

Retinal hamartomas

Heart (50%): Rhabdomyomas

Skin (90%): Hypopigmented macules, Facial

angiofibromas, cephalic plaques, Shagreen patch, ungual fibromas

Clinical manifestations of TSC

69

SEGA(24.4%)

SEN(78.2%)

Tubers(82.2%)

Patient Age

SEGA

SEN

Tuber

Kingswood et al. Orph J Rare Dis. (2017) 12:2

TSC structurally affects the brain

70

► Epilepsy occurs in TSC at very high

prevalence (85-90%)

► Seizure onset in TSC occurs early in life

• Average onset = 4.5 months of age

• Most experience first seizure before first

birthday (70-75%)

► Seizures are highly refractory to

currently available anti-seizure

medications

• 55-65% fail to achieve seizure-freedom

► Uncontrolled seizures are closely linked

to severe, life-long cognitive and

behavioral disability

Chu-Shore et al. Epilepsia 2010; 51:1236-1241.Capal et al. Epilepsy and Behavior 2017; 70:245-252..

Epilepsy in TSC

71

Current targets to treat epilepsy in TSC

72

Ganaxolone as a novel treatment strategy for targeting the GABAA receptor in TSC epilepsy

73

► Open-label, n = 30 patient study at 6-8 U.S. sites

► Primary efficacy endpoint: % change in primary seizure frequency

• Primary seizure types: focal motor seizures without impairment of consciousness or

awareness, focal seizures with impairment of consciousness or awareness, focal

seizures evolving to bilateral generalized convulsive seizures, and generalized

seizures with a motor component that are countable

► Study design16 weeks 28 weeks

Ganaxolone Phase 2 Clinical Trial: Treatment of Refractory Epilepsy in TSC

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[email protected]

Thank You

Dr. Alex AimettiMarinus Pharma

R&D Day June 2020 I

Possible neurosteroid deficiency – external validation

Increasing seizure freq

“Ganaxolone might also be considered as a potential therapeutic agent in patients

with tuberous sclerosis who have epilepsy”

Hypothesized Differentiated Mechanism of Action for

GNX in TSC

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Hypothesized Differentiated Mechanism of Action for

GNX in TSC

• Possible neurosteroid deficiency – internal validation

• Collaborated with the TS Alliance to obtain plasma samples from patients with TSC

and compare to age-matched healthy volunteer (control) samples

Allo

-S(n

g m

L-1

)

All

o-S

(ng

mL

-1)

Prospectively plan to conduct endogenous neurosteroid – response analysis in open-label Phase 2 study of GNX in TSC

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Continued Search for Genetic Epilepsies with Strong

Scientific Alignment

• Strategic exploration for other genetic epilepsies that meet the

following criteria:

• Significant unmet medical need (i.e. high seizure burden refractory to existing

treatments)

• Strong scientific and mechanistic alignment through endogenous neurosteroid

deficits or general GABAergic deficiency

79

~15 unique genetically-defined epilepsies represented

R&D Day June 2020 I

Commercial OpportunityThomas Lyons

R&D Day June 2020 I

Goal: Build a Sustainable Franchise in Rare Epilepsy

~48,900 Rare Epilepsy

~ 4,400 CDKL 5 Patients

~ 20,000 TSC patients

Addressable Patient

Population

20-40%refractory4

Phase 2 (TSC)

40,000 patients2

50-60% refractory3Phase 3

(CDD)~5,500 patients1

80-90% refractory3

~163,0005

Rare Epilepsy

Current clinical programs targeting indications with potential of ~24K addressable US patients

Opportunity to expand treated

population through future clinical development

Identification of Biomarker Sensitive Population (including PCDH19)1 Jakimeic et. al 2020

2 NORD (https://rarediseases.org/rare-diseases/tuberous-sclerosis)3 Marinus market research4 Ryan et. al 2015 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540245/)5 Quintana market research

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Disease Burden on Quality of Life of Child with CDD

and Caregiver

82

Severe Pediatric Epilepsy

Impact to gross motor

skills

Delayed speech

development

Sleep disturbances

GI issues

Vision complications

24-7 Caregiver Support

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1 Lekoubou et. al 20182 Cramer et. al 20143 Marinus HCP market research 2020

Significant Cost Burden on Top of Impact to Quality

of Life

Adjusted medical expenditures for children with Epilepsy are nearly 6X greater than

those without Epilepsy1

Uncontrolled Epilepsy in children leads to 2X higher costs than those with more stable

Epilepsy2

Higher costs driven by more frequent utilization of inpatient setting and emergency

departments2

Failure of current treatments to drive seizure reduction can lead to more invasive

treatment options such as Vagus Nerve Stimulators and potential surgery3

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<1 year from market

On Market

Potential First Approval and Early Entry in Areas

with Limited Ongoing Research

Approved

Registration

Phase 3

Phase 2

everolimus

cannabidiol

ganaxolone

ganaxoloneOV935

CDD

No FDA approved

treatment options

Potential to be first to

market and only on label

treatment in CDD for

period of time

Current pipeline program

limited to Phase 2 only

TSC

Limited on label

development programs

ongoing

Existing pipeline

programs include

multiple distinct MOAs

which provide for

differentiated profiles

Despite approved agents

or potential agents

unmet need exists in

significant percentage

who do not respond to

those agents

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Scientific & Clinical Differentiation Potentially Support Use of GNX in Rare Epilepsies

• Studies indicate neurosteroids play a role

in several orphan epilepsies such as CDD

and TSC

• Strong scientific and mechanistic

alignment through endogenous

neurosteroid deficits or general

GABAergic deficiency

Uusi-Oukari M and Korpi ER 2010

• Ganaxolone’s differentiated mechanism

may provide treaters with a new potential

treatment option for use within the rare

pediatric epilepsy space

• Modulates synaptic and extrasynaptic receptors

that maximizes inhibitory signaling in the brain

• Targets unique binding sites on the GABAA

receptor that are not susceptible to drug tolerance

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R&D Day June 2020 I

Reaction to profile / Preliminary Market Feedback1

“Wow. It sounds very promising. We need something like this. I’m very excited about this

mechanism.” – TSC MD

“These are patients who already failed 2 other AEDs so we know this is a very efficacious

therapy” – CDD MD

“This is a different MoA, a novel anticonvulsant treatment. Efficacy is very good, comparable

to novel treatments. Overall looks like a welcome addition. Enhancing inhibition then

suppressing excitation - might be able to control seizures more finely with minimal side

effects and might preserve cognatic function” – TSC MD, Private Practice

“I like the novel MoA. This is a very promising product” – TSC MD, Community Hospital

“It's a different mechanism than a lot of types we currently have. MOA: GABAA is different,

which is encouraging. Can attack the problem with multiple different receptors” – CDD KOL,

Academic

861 Marinus HCP market research 2020

R&D Day June 2020 I

“So what this does is it really shows me that there is a need for some sort of new and improved therapy,

whatever therapy that may be. The fact that it is in such a small population, obviously, puts us into the

orphan disease state…”

Pharmacy Director1

1 Marinus payer market research 201987

Early Payer Feedback

After reviewing disease

overview, payers

acknowledge CDD and

other genetic epilepsies

are critical to treat and

current available therapies

are not effective1

Similar to other orphan

products, payers will rely

on data in the label to

determine coverage

Subjects in Marigold study

reflects addressable

population

Having no approved

treatments on market

potentially limits options for

advanced utilization

management techniques1

Specialists prescribers to

use in line with data1

Unmet Need Value in label HCP support key

R&D Day June 2020 I

Preparing to Launch in the U.S.

Executing research with Payers and Physicians around TPP / Value Proposition

Identifying organizational needs for field resources, systems and processes

Developing plans to scale up Advocacy, Scientific Affairs and Commercial teams upon successful data

Readying supply chain to support packaging and scale up needs to commercialize

Potential for operational leverage across indications within concentrated rare epilepsy care

model

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Q & A

R&D Day June 2020 I

Thank You

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r&d day · 2 hawkes ma et al.2019 crit. care med. 3marchi na et al.2015 crit. care med....

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