The Era of Once Weekly Continuous Drug Delivery

for Parkinson’s Disease is Here

Randall Moreadith, MD, PhD

President and Chief Executive Officer

Biotech ShowcaseJP Morgan 2020

Biotech Showcase 2020

Everything begins with an idea

“The treatment of Parkinson’s disease has not changed

dramatically in the past 50 years. Patients are invariably

treated with L-DOPA to control their symptoms – and patients

invariably develop dyskinesia.

At Serina we intend to create a paradigm shift in how patients

with Parkinson’s disease may be treated.”

POZTM - Next Generation in Polymer TechnologyWe are the founding scientists and management that ushered in the first-generation technology - PEG

• Proprietary drug delivery technology platform based on poly(2-oxazoline) (POZ™)

Dominant IP estate with over 30 issued patents, and 25+ pending Global exclusive license to “click” chemistry from Scripps for POZ-therapeutics (unlimited right to

sublicense) Non-immunogenic Does not accumulate in any tissues Is not metabolized Clears entirely by renal filtration

• POZ™ provides continuous drug delivery of small molecules when administered via subcutaneous administration

Clinically validated – SC injections are safe, very well-tolerated Optimizes safety / efficacy profile of known molecules Extends interval of administration for improved half life and greater patient compliance Creates new IP and extends market exclusivity

• Serina’s pipeline of five product candidates target some of the most significant challenges in medicine today

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Immunothera

py

How we prepare “polymer therapeutics”

• A polymer of POZ is illustrated above with

Rotigotine (a potent dopamine agonist) is attached to multiple pendent groups (SER-214)

Via a cleavable ester linker (a cleavable linker is one that will release the active drug following cleavage by an

enzyme in the blood - butyrylcholinesterase)

• If the polymer has an extended profile of circulation in the body

The release of the attached drug from the polymer will also be extended = continuous drug delivery

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Immunotherapy

Chemical Structures of Pipeline CompoundsAll have an accessible chemical handle

• Candidate small molecules must have a “chemical handle”

• Linkers are attached to the –OH (creates a stable ester), an azide moiety on the end of the linker allows for permanent

“click chemistry” attachment to the pendent alkyne of the polymer backbone

• Search known structures (AdisInsight) - thousands of candidate molecules (phenolic hydroxyl, alcohols, carboxylates)

Rotigotine

Cannabidiol

CBD

Buprenorphine

Tetrahydrocannabinol

THC

Apomorphine

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Drug Candidate Indication Research Preclinical Phase I Phase II Phase III

SER-214

(rotigotine)

Parkinson’s disease

Early

SER-214

(rotigotine) Restless Leg Syndrome

SER-248

(apomorphine)

Parkinson’s disease

Advanced

SER-227

(buprenorphine)

Post-operative pain

Opioid use disorderNIH HEAL Initiative

SER-228

(cannabidiol)

Refractory epilepsy

Multiple indications

SER-232

(tetrahydocannabinol)

CINV

Spasticity in MS

Autism, Aggression

Serina PipelineA CNS-focused pipeline developing high value products for significant markets

HEAL Initiative – Helping to End Addiction Long-term

Immunotherapy

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Why is continuous drug delivery so important in PD ? Continuous delivery of dopaminergic agents invariably improves outcomes 1

Naïve MPTP-monkeys were divided into

two groups

Apomorphine rod implant, vs

Daily (x 3) apomorphine injections

Monkeys that received a rod implant

remained ON with NO dyskinesia for 6

months (!)

Monkeys that received daily SC injections

were transiently ON – and all developed

severe dyskinesia within the first two days

1 C Francesco Bibbiani, Lauren C. Costantini, Raj Patel, Thomas N. Chase Continuous

dopaminergic stimulation reduces risk of motor complications in parkinsonian primates (2004).

(The rod implant causes skin necrosis and is not currently being developed for PD.)

Immunotherapy

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The Challenge in Parkinson’s Disease None of the existing drugs used in Parkinson’s provide continuous dopaminergic stimulation

L-DOPA remains the most commonly

prescribed drug for Parkinson’s

Over 50% of patients will develop

dyskinesia within five years of therapy as

daily L-DOPA levels are increased

Over 90% of patients will develop

dyskinesia within ten years of therapy

LIDs remains one of the most troubling side

effects – and treatment challenges – in

Parkinson’s disease

What if you could administer a single

injection that provided continuous drug

delivery – for an entire week ?

Immunothera

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A Weekly SC Injection of SER-214Provides continuous drug delivery in monkeys

Cynomolgous macaque monkeys received a single SC injection of SER-214 weekly for 12 weeks

(this study was the formal toxicology study that supported

the IND)

In weeks 1/5/9/12 daily plasma rotigotine levels were determined

Following a slow rise to Tmax on day 2-3 plasma levels of released

rotigotine remained within a narrow range of ~ 6-8 ng/ml -

without accumulation or accelerated clearance

In a separate study in naïve MPTP-monkeys a weekly

injection of SER-214 fully rescued PD symptoms with no dyskinesia

liability (data not shown)

Plasma levels of Released Rotigotine following

weekly SC injections of SER-214 to Normal Monkeys7.0 mg/kg dose

(male and female; n=10, SD)

0 1 2 3 4 5 6 70.01

0.1

1

10

100

week 1

week 5

week 9

week 12

Time (days)

Pla

sm

a c

on

ce

ntr

ati

on

(n

g/m

L)

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SER-214 - Phase Ia in Stably-treated Parkinson’s Patients Assess safety, tolerability, pharmacokinetics and preliminary efficacy (N=5 per cohort)

Cohort Dose of SER-214 (SC) Data

Collected

0 Single 20 mg Safety, PK

1 50 mg (beginning of each week for 2

consecutive weeks)

Safety, PK

Efficacy

2 50 mg (beginning of Week 1)

100 mg (beginning of Weeks 2 and 3)

Safety, PK

Efficacy

3

50 mg (beginning of Week 1)

100 mg (beginning of Week 2)

200 mg (beginning of Weeks 3 and 4)

Safety, PK

Efficacy

Establish safety and tolerability of a weekly

injection of SER-214 in Parkinson’s Disease

patients

A once-weekly SC injection of SER-214 was

safe and very well-tolerated

Establish pharmacokinetics – does a weekly SC

injection of SER-214 provide predictable levels of

rotigotine within the therapeutic window for relief

of symptoms ?

Establish efficacy of SER-214 in providing

symptomatic relief of mild motor fluctuations

Motor portions of UPDRS (Parts II and III)

constitute the approvable endpoint for all new

PD drugs in development

Immunothera

py

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A Weekly SC Injection of SER-214 in Parkinson’s PatientsProvides continuous drug delivery in stably treated PD patients

Data from Cohort 3 in the multiple

dose portion of the Phase Ia trial

in Parkinson’s disease patients

Patients received: an initial

subcutaneous dose of 50 mg

SER-214 (0.25 mL); 100 mg dose

in Week 2 (0.5 mL); and 200 mg

in Week 3 and Week 4 (1.0 mL)

Plasma levels of released

rotigotine are shown for Week 3

(14-21) and Week 4 (21-28) and

compared to the 3 mg Neupro

patch (UCB published data)

Immunotherapy

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A Weekly SC Injection of SER-214 Improves Motor Scores Dose-dependent decline in UPDRS (Part III)

Effect of dose on UPDRS part III scores inParkinson's patients following weekly sc of SER-214

(mean for n=5)

Dose of SER-214 (mg)

UP

DR

S c

han

ge

fro

m p

re-d

ose

100 200 300 400

-14

-12

-10

-8

-6

-4

-2

0

2

linear r2=0.88

extrapolated

Data from Cohorts 1,2 and 3

in the multiple dose portion

of the Phase Ia trial

The predicted change in

UPDRS (Part III) at the 400+

mg doses of SER-214 would

achieve the approvable

endpoint for use of SER-214

for the PD indication

SER-214 will be developed

for patients with early

Parkinson’s disease

POZ-apomorphineApomorphine has many of the characteristics ideal for POZ

• Apomorphine The first dopamine agonist used in the treatment of Parkinson’s

disease (1884) Most potent dopamine agonist known (our KOLs call it the “holy

grail” of dopamine Rx) Reverse akinesia within minutes Binds with equal affinity as dopamine to receptors that mediate

symptomatic relief in PD (D2, D3) Limited bioavailability makes it unsuitable as an oral drug (or any

other formulation) Present formulations limited by significant skin irritation through

transcutaneous approaches that require daily administration through an insulin infusion set-up, often requiring a skilled healthcare professional to administer

• Hypothesis Attachment to POZ should keep the molecule on the polymer until it

reaches the blood (no BuChE in the SC compartment 1) – thus avoiding any skin liabilities

Upon entry into the vascular compartment the apomorphine is immediately cleaved, providing continuous drug release as long as the polymer circulates

131 Butyrylchonilesterase (BuChE) is synthesized in the liver and secreted into the vascular compartment

Apo-Go - ApomorphineApomorphine is very effective 1 … but the current formulation has significant challenges

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Severe skin reactions

Nodules

Patients with advanced PD

may have > 6 hours a day of

“OFF” time where they are

unable to perform routine

daily tasks

Patients use an infusion

device to provide continuous

delivery of apomorphine

~ 12-16 hours a day

Removed at bedtime

1 In July 2018 the only randomized, controlled trial of Apo-Go was published (TOLEDO) showing daily apomorphine was capable of providing the same reduction in daily OFF time - ~ 2 hrs –

as DBS and LCIG. Apo-Go is approved in the EU – not yet approved in the USA.

Apo-Go infusion versus POZ-apomorphineNo skin reactions at end of a 12-hr infusion of Apo-Go

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Group I - Apo-Go infusionSignificant skin reactions – all monkeys in the Apo-Go group developed abscesses by day three

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Group 3 – POZ-apomorphine (SER-241)No skin reactions at any time point following injection of POZ-apomorphine 1

171 Biopsy of the injection site revealed no evidence of inflammation

Apo-Go infusion vs POZ-apomorphinePOZ-apomorphine conjugates – provide continuous drug delivery for approximately 7 days

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Apo-Go was

administered by

continuous infusion over

12 hours

SER-240 and SER-241 1

were administered as a

single SC injection

Plasma levels of

apomorphine were

measured as shown

All doses were at 1.5 mg

eq Apo-Go / kg (the

human equivalent dose)

P K P r o f i l e o f R e l e a s e d A p o m o r p h i n e a f t e r S C d o s i n g

o f A p o m o r p h i n e , S E R - 2 4 0 a n d S E R - 2 4 1 i n F e m a l e M o n k e y s

( 1 . 5 m g / k g , n = 3 , S D )

T i m e ( d a y s )

Co

nc

en

tr

atio

n (n

g/m

L)

0 1 2 3 4 5 6 7 8 9 1 0

0

5

1 0

1 5

2 0A p o m o r p h i n e H C l

S E R - 2 4 1 ( f r e e )

S E R - 2 4 0 ( f r e e )

1 SER-240 and SER-241 differ only by the linker attaching apomorphine to the polymer

Modeling – Human PK PredictionMulti-dose PK of SER-241 simulated from monkey PK

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Monkey PK of SER-241 was

modeled using a 1- compartment fit

to predict human PK 1

A weekly dose of ~ 0.5 mg eq/kg

SER-241 is predicted to yield

plasma levels ~ 10 ng/mL free

apomorphine

This will require a device to deliver

~ 5 mL over ~10 minutes each week

1 1-compartment model predicted the human PK

of SER-214 based on multi-dose PK in monkey

Will advanced Parkinson’s patients be able to dose themselves ?Yes. Our development strategy is designed to avoid use of a syringe or needle.

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Attach WFI vial to sterile

needleless transfer system (West)

Attach to vial of lyophilized

SER-241 (under slight vacuum)

Water is drawn into vial

instantaneously, SER-241 goes

into solution within 3-5 minutes

Avoids exposure to needle injury

Enable InjectionsCustomized suite of injection devices designed for ease of use – without risk of needle injury

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Attach resuspended vial of

SER-214 to port on vial

transfer system

Nitrogen is pumped into vial,

which filters and loads the

enFuse device automatically

In less than one minute

Does not need a healthcare

provider to administer

Avoids exposure to needle

Enable InjectionsInjection systems designed for ease of use, compliance, and avoidance of needle injury

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Remove device from filling station -

adhesive is exposed automatically

Press onto clean skin area

Press button, infusion begins

automatically

Device retracts needle when

infusion is complete, button pops up

Connectivity – sends a text

message to your cell phone to tell

you it is OK to remove device

Send data to your physician

SummaryThe era of once weekly continuous drug delivery for Parkinson’s disease is here

• SER-214 - POZ-rotigotine Improved compliance, markedly improved tolerability without skin reactions, improved QoL

In blinded product profile SER-214 was chosen over Neupro

KOLs believe it would be used primarily in early PD Treat or prevent dyskinesia in patients with early motor complications 505(b)(2) – rely on the established safety/efficacy of Neupro Potential for a single Phase 3 trial Commercial launch as early as 2025 - Readily penetrable market in US of $150-300 M

• POZ-apomorphine

Potential breakthrough in therapy for advanced disease - without need for a healthcare provider to administer a daily SC injection through an infusion device, and no onerous skin reactions

KOLs believe it would be used primarily in advanced PD

Is a preventive therapy (not a rescue therapy) that has potential to arrest/prevent dyskinesia

May allow some patients to titrate off all L-DOPA 1

Eventually advance to mid-stage PD as a L-DOPA-sparing strategy

Addresses a market of 350,000 patients in US - market potential exceeds $1 B

231 Alice J. Manson, MRCP, Kirsten Turner, BSc(Hons), and Andrew J. Lees, MD, FRACP Apomorphine Monotherapy in the Treatment of

Refractory Motor Complications of Parkinson’s Disease : Long-Term Follow-Up Study of 64 Patients (2002)

FinancingUse of proceeds advances POZ-apomorphine into Phase 2a

• History of financing Raised $35 M since inception (2007, all private shareholders) Established a proprietary and clinically-validated platform for

programmed release of small molecules (does not exclude proteins) Pipeline of five CNS-focused assets of high value addressing large

markets• Seeking first institutional financing $30 M on a pre-money of ~ $80 M

Use proceeds to advance POZ-apomorphine into Phase 2a Advance SER-227 (post-op pain) through IND-enabling in concert

with NIH HEAL Initiative New NIH application for clinical grant in 2021

Plan is license SER-214 and POZ-cannabinoids

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Thank YouRandall Moreadith, MD, PhD

President and Chief Executive Officer

JP Morgan 2020

Biotech Showcase 2020