Polymer for Drug Development - Serina...

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