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Differentiated Medicines from Polymeric Nanoparticles

Ijeoma F. UchegbuUCL School of Pharmacy

Nanomerics Ltd

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Academic Collaborations - Acknowledgements• University College London

– Andreas G. Schätzlein– Simon Gaisford– Gary Parkinson– John Malkinson– Lorenzo Capretto– George Wang– Aikaterini Lalatsa– David Workman– Vicky Lozano– Lisa Godfrey– Antonio Iannitelli– Jay Freeman– Mariarosa Mazza– Dolores Lopez– Funmilola Fisusi– Margarida Carlos – Ramesh Soundararajan– Abdullah Alamoudi– Sunish Patel– Nicholas Hobson– Xiang Wen Jen– Abdulrahman Halwani

• School of Pharmacy, University of London– Marie Christine Jones– Kar Wai Chooi– Adeline Siew– Thi Bich Hang Le– Steven McLellan – Natrah Arifin – Anja Mirenska – Jayanant Iemsang-Arng

• Exeter University– Julian Moger– Natalie Garrett– Nick Stone– Francesca Palombo

• Strathclyde University– Wei Wang– Vitaliy Khutoryanskiy– Xueliang Hou– Xiaozhong Qu– Lee Martin – Maureen Brown– Christine Dufes– Tony Brownlie– Lubna Sadiq– Soryia Siddique– Pei Lee Kan – Abdul Elouzi– Bernd Zinselmeyer – Woei Ping Cheng– Dennis Wong– Pui Ee Wong– Mazen El-Hammadi– Katherine Bolton– Samina Ahmad

• University of Arizona– Frank Porrecca

• University of New England– Tamara King Deeney

• University of Nottingham– Martyn Davies– Clive Roberts

• Universidad Complutense De Madrid– Juan Torrado

• Universidad Cardenal Herrera-CEU– M. Auxiliadora Dea-Ayuela

• Universitat Rovira i Virgili– Josep Guarro

• Cambridge University– Jeremy Baumberg

• Rutherford Laboratories– Pavel Matousek

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Summary

• Academic investigations– Nanoparticle fabrication and characterisation

• Commercialisation– Strategy– Technology– Licensing

• Nasal and ocular assets– Oral dosage form case Studies

• Current academic focus– Diagnostics

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Building Blocks

OO

OO

NHO

O

HO

NH

O

HO

O O

NH2

O

HO

OHOO

NH2

O

HO

HOO

O

uv

wx

HOO

N

O

HO

HO OO

O

HO

NHHO

O

yz

Cl

N

N

NN

NH2N

HN

H2NH2N

NH2N

NH2N

H2N

H2N

N

N

N N

N HN

NH2

NH2NH2

NNH2

N NH2

NH

NH2

OO

O

Wang et al (2004) Macromolecules, 37: 9114 - 9122.Qu et al (2008) Langmuir, 24: 9997–10004Chooi et al (2010) Langmuir, 26: 2301 – 2316Ahmad et al (2010) J Royal Society Interf, 2010, 7: S423 – S433 Siew et al (2012) Mol Pharmaceutics, 9: 14 – 28.Lalatsa et al (2012) Mol Pharmaceutics, 9: 1665-1680Mazza et al (2013) ACS Nano, 7, 1016 – 1026Lalatsa et al (2015) J Control Rel, 197: 87 – 96Fisusi et al (2016) Pharm Res, 33: 1289-1303.Godrey et al (2017) J Control Rel, 270, 135-144Hobson et al (2019) Nanomedicine, 14, 1135-1152

Dendrimer amphiphiles

Carbohydrate combs

Claws

OH

O

NH

HN

NHH2N

O

HN

O

NH

OHN

O

NH

O

H2N

O

O

Peptide amphiphile prodrugs

O OOH

O

O

OH

N

x

OOOH

O

O

OH

N

y

CH3CH3CH3

O

OH

CH2OH

CH2

O

OOH

O O OH

N

x

O

O

OH

O O OH

N

y

CH3

CH3

CH3

OOH

CH2OH

O

OOH

OOOH

N

x

O

CH2

O

OOH

O

O

OH

N

x

O

O

OH

O

O

OH

N

y

CH3CH3

CH3

O

OH

CH2OH

NHCH2

O

OOH

O

O

OH

N

x

O

O

OH

O

O

OH

N

y

CH3

CH3

CH3 O

OH

CH2OH

C

y

OOH

CH2OH

NHCH2

O

OOH

O

O

OH

N x

O

O

OH

O

O

OH

Ny

CH3CH3

CH3

O

OH

CH2OH

NH2

N

NH2

NN

NH2

NH

N

N

N

NH

NH2

NH

N

NH

NH2N

NH

NH2

N N

N N

NH2

N

N

N

NH2

CH2

OOOH

O

O

OH

N

x

O OOH

O

O

OH

N

y

CH3

CH3CH3

O

OH

CH2OH

HCH2

CH2

O

O OH

O

O

OH

N

x

O

O

OH

O

O

OH

N

y

CH3

CH3

CH3O

OH

CH2OH

H2

O

OH

OOOH

N CH3

CH3

CH3

+

+

+

+

+

+

+

+

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Polymeric, Dendrimer and Peptide Nanoparticles

Dense Spheres

200nm500nm

Vesicles

100nm

Polymeric Micelles

200nm

Discs

1000nm

Worm-like Wang et al (2004) Macromolecules, 37: 9114 - 9122.Qu et al (2008) Langmuir, 24: 9997–10004Lalatsa et al (2012) J Control Rel, 161: 523 – 536. Mazza et al (2013) ACS Nano, 7: 1016-1026

200 nm

Peptide Nanofibres

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Intracranial Tumours

Fisusi et al, 2016, Pharm Res, 33, 1289-303.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40

Pro

port

ion

of

an

imals

su

rviv

ing

Time (Days)

CONTROL ETOH QLOM

Tumour

0

200

400600

800

1000

1200

1400

1600

Day 1 Day 7 Day 14 Day 21 Day 28Pla

tele

t co

unt

(X

106 m

L-1

)

Time

* §§

Nanoparticles prolong survivalNo differences in femoral, white and red cell countsBoth treatments cause a change in platelets

Lomustine polymer Nanoparticles (13 mg kg-1) nEthanolic lomustine (1.2 mg kg-1) nUntreated animals �

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Pharma Market Challenges as Drivers

Loss of patent protection• US$194 billion in lost sales 2017-2022 • US$31 billion in lost sales in 2018 alone

Increasing cost of NEW drugs• Low Productivity• Total cost increase to >US$ 2.5 billion

Wrapping drugs with Nanomerics’ Molecular Envelope Technology (MET) creates:

• improved ‘known’ medicines, rescued new chemical entities• Patent protected and premium pricing

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Solution: Molecular Envelope Technology (MET) Engineered from scratch for enhanced delivery

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Molecular Envelope Technology

1. Non-covalent Encapsulation 2. High drug loading: 9 – 50% w/w3. Highly stable nanoparticles: low micromolar CMC

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MET Formulation Space• Data mapped on www.drugbank.ca

11

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Nanomerics Solution• Molecular Envelope Technology (MET) wrapping of

known drugs: – Creates better medicines for patients– Gives patent protection and retains/creates value

Poorly soluble drugs + Molecular EnvelopeTechnology

= Better Drugs + Patent protection

5-38 x

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Royal Society of Chemistry Award 2017

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MET Safety Demonstrated in GLP Regulatory Toxicology Studies Test OutcomeSingle intravenous dose in the rat Maximum tolerated dose = 150 mg kg-1

7 Day repeat intravenous dose study in the rat Maximum tolerated dose = 100 mg kg-1

GLP Mutagenicity testing Ames test NegativeGLP Mutagenicity testing Mouse Lymphoma Test NegativeGLP Intravenous Rat Irwin Study Nothing abnormal detected at 100 mg kg-1

GLP Intravenous respiratory safety pharmacology in the rat

NOAEL = 40 mg kg-1

Oral 7 day repeat dose ranging dog study NOAEL = 300 mg kg-1 (top dose studied)GLP oral 28 day repeat dose dog study NOAEL = 150 mg kg-1 (top dose studied)Oral 7 day repeat dose ranging rat study NOAEL = 200 mg kg-1

GLP oral 28 day repeat dose rat study NOAEL = 200 mg kg-1 (top dose studied)

Intranasal 7 day repeat dose ranging rat study NOAEL = 30 mg kg-1 (Reduced weight gain at 50 mg kg-1)

GLP 28 day intranasal dose in the rat NOAEL = 18 mg kg-1

6 day topical Ocular tolerability study in the rabbit NOAEL = 40 mg mL-1 (top concentration studied)

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FDA 505(b)(2) FDA Pre-IND Guidance Summary

ü Polymer sufficiently characterised ü Target product profile and specifications ü Preclinical PK data ü First in Human Safety and Tolerability Study Designü Manufacturing guidance and pilot batch data for NDA

statedü Pivotal study design

– Two clinical efficacy studies with a limited number of primary end points

ü Advice on analytical qualification & later stage CMC meeting

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Licensed assets

16

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Nose-to-brain delivery

Spray dried micro-particles

①

②

③

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Loaded Nanoparticles Naltos™ Powder Device

Cyclonic Plume

⑤ Olfactory deposition into nano-particles

⑥

Olfactory bulb

Brain transport & activity

Thalamus Cortex

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NM127 – Peptide replacement of opiates

Nose to brain 505(b)(1) NCE - endogenous API

– opiate analgesic replacement– Fast pain relief for the

treatment of acute and chronic pain

– Endogenous peptide delivered non-invasively to the brain

– As potent as opiates but avoids the side effects

– No habit forming potential– Enkephalin is active in humans

0.0

5.0

10.0

15.0

20.0

25.0

30.0

-10 40 90 140 190 240

Paw

With

draw

al Th

resh

old in

a Co

mple

te Fr

eund

's Ad

juvan

t Pain

Mod

el (g

)

Time (minutes)

Intravenous vehicle

Intranasal NM0127 (7.5 mg/ kg)

Intravenous morphine (2.5mg/ kg)

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Opioid sparing pain killer

• NM127

– Enkephalin based pain killer for acute and chronic pain

– No analgesic tolerance or risk of addiction– Active in all preclinical pain models– Licensed to Virpax Pharmaceuticals

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MET Application - Ocular delivery

Proposed mechanism

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Non-irritant ocular medicine

• NM133

– Cyclosporine A eye drops for dry eye disease– Superior to the market leader• Vehicle is non-irritant• Delivers 5 – 8 times more drug to tissues• Clear aqueous liquid – oil free

– Clear regulatory pathway: FDA pre-IND guidance – Licensed to Iacta Pharmaceuticals

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The oral route

22

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Oral Griseofulvin

0

1

2

3

4

5

0 4 8 12 16 20 24

Bloo

d co

ncen

tratio

n(µ

g m

L-1 )

Time

Griseofulvin

MET GriseofulvinFormulation

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Oral Cyclosporine

0

1000

2000

3000

4000

5000

6000

0 4 8 12 16 20 24

Blo

od

cycl

osp

ori

ne A

con

cen

trati

on

(ng

mL-1

)

Time (hours)

Cyclosporine

Neoral

Cyclosporine Ananoparticles

*

*

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Oral Amphotericin B

0102030405060708090

-10 10 30 50

Plasm

a Co

ncen

tratio

n (n

g m

L-1)

Time (h)

METAmphizone

Ambisome

NM0147

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Oral formulation of Phase II anti-cancer drug

01020304050607080

0 4 8 12 16 20 24Plas

ma

Conc

entra

tion

(ng

mL-1

)

Time (Hours)

MET Formulation

Clinical Formulation

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MET – Proposed Mechanism

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Mucus penetration

Control 30 min 1 h

2h 4 h

Siew et al, Mol Pharm, 9, 14-28 (2012)

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~ 250 µm

A B

DC

X-Y

X-Y

X-Y-Z

Y-Z

25 µm

25 µm

MET particle uptake in intestinal villi

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MET Particles by CARS Microscopy in the GITLiver Stomach Jejenum

Ileum Duodenum Gall Bladder

Garrett et al (2012) J Biophotonics, 5: 458-468Garrett et al (2012) J Raman Microscopy, 43: 681-688

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MET Particle Bioavailability

0.00E+002.00E+014.00E+016.00E+018.00E+011.00E+021.20E+021.40E+021.60E+021.80E+022.00E+02

0 4 8 12 16 20 24

Plasm

a Lev

els (m

g mL-

1)

Time (h)

OralIntravenous

Bioavailability = 24%

Lalatsa et al (2012) Mol Pharm, 9: 1764-1774.

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MET Competitive Advantage – Nanoparticle Technologies

Attributes MET Pegylated Liposomes

Poly-(L-lactide-co-glycolide)-co-poly(ethylene glycol) nanoparticles

Albumin stabilised nanoparticles

Oral particle uptake and tablet formulationsNose to brain deliveryNon-irritant ocular drug delivery and penetration enhancementIntravenous drug deliveryHydrophobic drug deliveryHydrophilic drug deliveryAmphiphilic drug deliveryEase of manufacture Unknown UnknownMarketed Products

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Summary of MET Advantages– GLP safety studies conducted - no safety issues– High API payload: 10 – 50% w/w– Stable system: micromolar CMC– Liquid and solid formulations– Bioavailability enhancement: 5 - 38 fold higher– Drug targeting

• Oral to the lung and spleen• Nasally to the brain

– Enables peptide bioavailability• Limits degradation of drug cargo• Enhanced transport across epithelial barriers

– Multiple routes of administration• Topical to the eye• Intranasal to the brain• Oral to the liver, lungs and spleen

– Multiple molecules• Hydrophobic drugs• Amphiphilic peptides

Qu, et al (2006) Biomacromolecules, 7, 3452-3459Siew et al (2012) Mol Pharmaceutics, 9: 14 – 28.Lalatsa et al (2012) Mol Pharmaceutics, 9: 1665-1680Serrano et al (2015) Mol Pharmaceutics, 12,: 420-431,Lalatsa et al (2015) J Control Rel, 197: 87 – 96Fisusi et al (2016) Pharm Res, 33: 1289-1303.Godrey et al (2017) J Control Rel, 270, 135-144

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Iron Oxide Imaging

Good visualisation of the liver vasculature 1 hour after dosing

Hobson et al (2019) Nanomedicine (Lond), 14, 1135-1152

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RaNT Programme Grant

EPSRC Raman NanoTheranostics Programme Grant£5.7 million

Nick StoneExeter University

Julian MogerExeter University

Pavel MatousekRutherford Laboratories

Jeremy Baumberg Cambridge University

Andreas Schätzlein UCL

Ijeoma UchegbuUCL

Francesca PalomboExeter University

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Thank you