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
3
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
4
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
5
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
7
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
8
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
py
9
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
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