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Poly(oxazoline) - POZTM – The Next Generation
Polymer for Drug Development
Company History Founded 2007
Raised $20 M Since
Inception
Ten employees
Technology
Pipeline
Lead Clinical
Candidate SER-214
Summary
Unparalleled Track Record of Excellence in
Innovative Drug Delivery
Serina Founders and Management Milton Harris and Michael Bentley developed first generation PEGs at Shearwater Polymers Acquired by Nektar Therapeutics* in 2001 Licensed for research and therapeutic
applications (multiple products today use this same technology)
Almost all of Nektar’s current technology originated from Harris/Bentley lab e.g. $1.5 B AZ deal with Nektar for
Movantik™ (2015 launch)
> $130 B in sales
POZ vs PEG
Safe, inexpensive starting materials
Does not form peroxides
POZ – “one pot synthesis”
Stable at RT, refrigerator, - 20 C
Relatively low viscosity
High, programmable drug loading
Active targeting of pendent POZ
Excreted unchanged (renal)
Non-immunogenic Absence of pre-formed antibodies to POZ
is anticipated
Minimal tissue accumulation Only observed in monkey at 20X HED
Patent estate (largely to Serina)
Explosive, toxic starting materials
Forms peroxides (must add BHT)
Limited suppliers of quality PEG
Stable only at < - 20 C
Relatively high viscosity
Low drug loading
Difficult to actively target
Major route of elimination renal
Pre-formed Abs in ~ 25 % population Antibodies to PEG are suspected to alter
response to some products
Tissue accumulation (multiple)
Immunogenicity of mPEG products
Crowded patent estate
Pipeline
4
Drug Indication(s) Formulation Research Preclinical Phase I
SER-214 Parkinson’s Disease and RLS SC
SER-226 Schedule III POZ-analgesic, post-op pain SC
SER-228 / SER-232Schedule I POZ-cannabidiolSchedule I POZ-tetrahydrocannabinol SC
POZ-polymer ADCs (multi-target, multi-toxin) IV
POZ TM-platform (targeted and non-targeted) SC, IV, IM
4Strictly Confidential
Undisclosed Partner
Polymer SynthesisHow we make pendent POZ
Programmable loading of polymer determined by the ratio of pentynyl * : neutral monomers at initial synthesis (example above is a 20 kDa 10 pendent POZ)
IEC for purification takes advantage of the –COOH on the terminus of the polymer (Typically > 70% yields, PDI < 1.02, currently at 3 kg cGMP scale and scaling up for partnered programs)GLP and cGMP)
*
Polymer SynthesisHow we make pendent POZ-therapeutics
Programmable loading of polymer during initial synthesis – Controlled drug loading at the “click chemistry” step
Single-step Cu(I)-catalyzed “click chemistry” at pendent alkyne (Scripps Research Institute Global Exclusive License to Serina)
Drug release is tuned by the nature of the linker attached to the drug (this requires a “chemical handle” for attachment)
Let’s take a look at how we accomplish this to build POZ-therapeutics … kg (GLP and cGMP)
*
Parkinson’s Disease
Current Treatment
Patients take a variety of medications at multiple doses and frequencies to manage the disease
Compliance, “wearing off” anddyskinesia are common
Commonly used drugsMAO-B inhibitors/COMT inhibitors
Levo-dopa : carbidopaDopamine agonists(oral, transdermal)
None of these drugs providecontinuous dopaminergic
stimulation
SER-214 Target Product Profile(20 kDa POZ with 10 rotigotine molecules)
Once weekly SC dosing that does not change week-to-week
Week-to-week levels stay within the “therapeutic window”
Provide prompt onset of dopaminergic “tone”
PK profile provides continuous drug delivery with steady-state levels = continuous dopaminergic stimulation (CDS)
Rapid clearance upon cessation of dosing
Weekly SC Injection of SER-214
Provides Continuous Drug Delivery
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)
Cynomolgous macaque monkeys (~ 3 kg) received a single weekly SC injectionof ~ 58 mg SER-214 (~ 7 mg equivalents rotigotine) / kg in a final volume of ~ 0.5 cc
“ON-time without dyskinesia”(Week two data from MPTP-monkey study)
dy
sk
ine
sia
v eh ic le
S E R -2 1 4 (1 m g /k g e q u iv .)
m o d e ra te
m ild
a b s e n t
m a rk ed
sev e re
L -D O P A (1 5 m g /k g )
*
ON
-ti
me
(m
in)
0
5 0
1 0 0
1 5 0
2 0 0
v eh ic le
S E R -2 1 4 (1 m g /k g e q u iv .)
L -D O P A (1 5 m g /k g )
A single weekly SC injection of SER-214 provides good“ON-time” (comparable to L-DOPA) without inducing dyskinesia
11Non Confidential
PK Data From Cohort 1Cmax Day 3-4 Approximates 0.2-.3 ng/ml – 4 X = 1-1.2 ng/ml
12
SER-214 Ia: Pharmacokinetic profile of rotigotine
following a subcutaneous administration of SER-214[Cohort 1: Dose 50mg (6 mg equiv); n=5, SD]
0 4 80.0001
0.001
0.01
0.1
1
10
100
24 72 120 168 216 264 312 360 408 456 504
day 7day 14
0.05ng/mL
dose
released drug
total drug
day 21
S401 released
S402 and S501 released
S401, S403 and S404 released
S501 released
S401 Total
S402 and S501 Total
S401, S403 and S404 Total
S501 Total
Time (h)
Plas
ma
conc
entr
atio
n (n
g/m
L)
Serina Oncology PlatformAntibody-targeted POZ-toxins
Programmable loading of the polymer allows for very high drug antibody ratios (DAR) –multiple site attachment to resident – SH in the antibody
May prove to be particularly important for low-density targets POZ polymers are stable – do not break down in plasma (thus do not release toxin, which
may narrow the therapeutic index) POZ polymer ADCs may have improved therapeutic index and enhanced half-life = greater
engagement of target cancers
POZ Polymer ADCsIncreased DAR Employing POZ Improves Cell Kill
of Low Density Antigen-expressing Tumor Cell Lines
14
0.1 1 10 100 10000
20
40
60
80
100
Concentration (nM)
Ce
ll V
iab
ilit
y (%
)
CD79b-vc-PAB-MMAE (●) DAR=1, CD79b-POZ-(vc-PAB-MMAE)1 (♦) DAR=1 via POZ, and CD79b-POZ-(vc-PAB-MMAE)5 (■) DAR=5 via POZ
Summary POZ polymer technology represents a unique injectable platform
technology with distinct advantages
SER-214 for Parkinson’s Disease / RLS – SC
Oncology – IV and IM {Extensive pre-clinical data, multiple oncolytics}
Pain, epilepsy, CINV, inflammation, others – SC
POZ polymer technology may can be applied to many drug development challenges
Half-life extension for proteins and small molecules
Programmed loading and release
Targeting by small molecules and polypeptides (antibodies, others)
New COM, solubility, ease of synthesis, non-immunogenic, renal clearance
Strong IP – 15 issued patents worldwide, 28 pending
Executed partnership to develop POZ-polymer ADCs in September 2015 – multi-target, multi-toxin (Undisclosed partner)
Exclusive license to “click chemistry” to develop POZ-therapeutics
Unlimited right to sublicense
Thank You