Serina Therapeutics Randall Moreadith, MD, PhD President and CEO - - PowerPoint PPT Presentation

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Serina Therapeutics Randall Moreadith, MD, PhD President and CEO - - PowerPoint PPT Presentation

Jan 06, 2023 978 likes •1.18k views

Serina Therapeutics Randall Moreadith, MD, PhD President and CEO SER-214 POZ-Rotigotine A Once-per-week SC Injection that Provides Continuous Drug Delivery 1 Parkinsons Disease Do you think you could use your polymer technology to

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Serina Therapeutics

Randall Moreadith, MD, PhD President and CEO

SER-214

POZ-Rotigotine

A Once-per-week SC Injection that Provides Continuous Drug Delivery

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“Do you think you could use your polymer technology to develop a drug to treat Parkinson’s disease ?”

Serina shareholder and patient with Parkinson’s disease

Parkinson’s Disease

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Non-Confidential

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Parkinson’s Disease

Of the current drugs for Parkinson’s disease the dopamine agonists had some attractive features for a POZ conjugate approach …

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Non-Confidential

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Adapted from: Stocchi F, et al. Eur Neurol, 1996.

The “Therapeutic Window” For Treatment of Parkinson’s Disease

Current Drugs – “wearing off” and dyskinesia

4 Non-Confidential

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None of the approved drugs for PD deliver CDS … but would it work ?

5 Non-Confidential

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  • Study Design
  • Double-blind, double-dummy trial of levo-dopa gel infusion (37 patients)

versus levo-dopa sustained release capsules (34 patients) *

  • Endpoint was reduction in “off” time and corresponding increase in “on” time

(without troublesome dyskinesia) during 12 weeks of administration

  • Results :
  • Mean “off” time decreased by 4 hrs – p < 0.0015 – compared to capsules
  • Mean “on” time increased by 4.1 hrs – p < 0.0059 – compared to capsules
  • Expert Commentary
  • “This study shows that levo-dopa gel infusion provides a definite advantage in

patients with advanced Parkinson’s disease … and the results appear similar to those obtained with deep brain stimulation,” Dr. Stanley Fann

* Principal Investigator C. Warren Olanow, MD, Serina Clinical Advisory Board. This is the only study

  • f its kind in the Parkinson’s literature. It is being developed by AbbVie.

Summary

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Non-Confidential

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  • Target Product Profile
  • Subcutaneous delivery once a week in a standard insulin or tuberculin syringe

(injectate ~ 0.5-1 cc)

  • Prompt onset of dopaminergic “tone” (within 20-30 min)
  • Steady-state levels of dopamine agonist within a relatively narrow therapeutic

window

  • Sustained levels of dopamine agonist for approximately one week (“continuous

dopaminergic stimulation”)

  • Consistent levels of dopamine agonist upon repeat dosing
  • Week-to-week drug exposure and half-life do not vary widely, and do so within the

therapeutic window for control of symptoms

SER-214

Product Concept

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Non-Confidential

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SER-214

20 kDa POZ polymer with 10 rotigotine molecules

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Non-Confidential

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PK Profiles in Plasma

SER-214 “slow release”

SER-214 showed a marked difference in release rates, with a half-life of ~ 11 hours in the rat and > 3 days in monkey and human (the same linker:drug attached to PEG or polydextrans releases completely in < 10 minutes)

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Non-Confidential

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MPTP Monkey Model

Study Design

  • The study is a twelve week PK and PD study to assess the efficacy and safety
  • f a weekly SC injection of SER-214 versus a twice daily oral dose of L-DOPA

versus polymer alone

  • Adult monkeys (6-7 YOA) were treated with daily MPTP for several months
  • MPTP is a mitochondrial toxin that disrupts the electron transport chain
  • Progressive exposure to MPTP results in a profound state of

“Parkinsonism” in monkeys due to selective degeneration of the pre- synaptic dopaminergic neurons in the substantia nigra

  • This has served as the non-human primate model for every drug that has

been approved for Parkinson’s disease

  • The results are …

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Non-Confidential

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Preliminary Results PK Profiles

A weekly SC injection

  • f SER-214 delivers a

steady-state level of rotigotine upon repeat dosing

Total rotigotine refers to total amount of rotigotine released by alkaline hydrolysis

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Non-Confidential Plasma Rotigotine levels following four SC injections of SER-214 to Monkeys

(n=3; SD)

7 14 21 28 35 42 49 0.01 0.1 1 10 100 1000

Free Rotigotine Total Rotigotine (Pro-drug levels)

Time (day) Plasma concentration (ng/mL)

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Preliminary Results (Week Two)

100 200 300 activity (0-360 min, % post-MPTP) vehicle L-DOPA (15 mg/kg, b.i.d.) SER-214 (1 mg/kg equiv. 1/ weekly) study day 1 4

** * #

7 1 4 7 1 4 7

*

N=3 N=3 N=2

A single SC injection

  • f SER-214 promotes

prompt and sustained locomotor activity

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Non-Confidential

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Preliminary Results

  • SER-214 appears to be safe – no adverse events reported in the

monkeys to date

  • Polymer control is safe, and shows no evidence of efficacy
  • L-DOPA twice daily promotes prompt, but non-sustained locomotor

activity (as expected for this model)

  • Monkeys in the L-DOPA group have all developed dyskinesia
  • SER-214 promotes prompt, sustained locomotor activity in severely

impaired MPTP-lesioned monkeys

  • None of the SER-214 treated monkeys have developed dyskinesia after 12 weeks
  • f dosing
  • Plasma PK profile (first four weeks) demonstrates continuous drug

delivery with steady-state levels of plasma rotigotine in the therapeutic window for CDS

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Non-Confidential

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Formulation

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Non-Confidential

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  • IND-enabling Toxicology
  • In vitro Metabolite Profiles (GLP) – Complete
  • Rat single dose MTD and PK (GLP) - Complete
  • Dog single dose MTD and PK (GLP) - Complete
  • Rat 6 week and 12 week PK (non-GLP) - Complete
  • Rat Chronic Dose 3 Month Study (GLP) - Complete
  • Observed effect identified, and NOAEL identified
  • Rat ADME Study
  • QWBA – Complete
  • Rat 6-OHDA Efficacy – Complete (Published)
  • Planned pre-IND Meeting with the Agency in June
  • cGMP Campaign
  • Underway - Demo Batches Complete

Development Milestones And Timelines

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Non-Confidential

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  • US 8,383,093 B1 – Issued February 26, 2013
  • US 8,597,633 B2 – Issued December 3, 2013
  • Subcutaneous delivery of poly(oxazoline) conjugates
  • “… a heterofunctional POZ of a general formula containing a dopamine

agonist (all dopamine agonists)”

  • Composition of matter on SER-214
  • Which includes controlled release of the attached dopamine agonist
  • Covers all classes of dopamine agonists and some other classes of drugs
  • Method of treating a disease with a heterofunctional POZ-dopamine agonist

where the disease is a dopamine-responsive disorder

  • Subcutaneous delivery of POZ-therapeutics
  • Specifically covers Parkinson’s disease

Strong IP Position

Issued on SER-214

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Non-Confidential

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Summary

  • SER-214
  • Target Product Profile achieved
  • Parkinson’s disease models (rat and monkey)
  • At least as efficacious as levo-dopa in MPTP monkey model (Week 2)
  • All monkeys in levo-dopa:carbidopa cohort have developed dyskinesias
  • None of the monkeys in the SER-214 cohort have developed dyskinesias
  • Market Research (100 Neurologists – movement disorder specialists)
  • Twice market share of Neupro in un-blinded product profile
  • Would be used as first-line therapy in new onset patients as a levo-dopa sparing strategy
  • Transition therapy for patients experiencing “wearing off” and early dyskinesias
  • Executed partnership with AstraZeneca in January 2013
  • Executed partnership for development of polymer-ADCs with Scripps 2013
  • Exclusive license to “click chemistry” to POZ
  • Unlimited right to sublicense

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Non-Confidential

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Acknowledgements

The Serina Team Our Shareholders

  • Dr. David Standaert

Chairman, Division of Neurology, UAB

  • Dr. Warren Olanow

Chairman Emeritus, Mt Sinai Medical Center

The Atuka Team

Montreal, Canada

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Non-Confidential