Photo by Kyriakos Kaziras - PowerPoint Presentation

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Photo by Kyriakos

Kaziras

Lipid Nanoparticle (LNP)

Systems for RNA Delivery

Lipid Nanoparticle (LNP) SystemNucleic Acid Delivery by LNP

Photo from Precision

Nanosystems

Lipid Nanoparticle (LNP) SystemGeneral Properties

Size: diameters less than 100 nm Basic constituents

Structural lipidIonizable amino lipidPEG-lipid conjugate

CholesterolNucleic acid (siRNA, mRNA,

etc

)

pKa

of

ionizable amino lipid less than pH 7 Prepared using microfluidics (ethanol/water mixing in flow system) AdvantagesIncreased half lifeProtection from nucleasesAids in endocytosis and endosomal escapeDisadvantagesElevated risk of toxicity with introducing excipient materials

Lipid Nanoparticle (LNP) System

Basic Constituents & Structural ElementsPhoto from Arbutus Biopharm

Lipid Nanoparticle (LNP) SystemBasic Constituents: Cationic Lipid

Pros

Efficient delivery

Condense plasmidCons

Toxicity

Dissociation from DNA

Pros

Lower toxicity

Cons

Dissociation from DNAPros Low/no toxicity Dissociates from DNACons Low efficiency

Lipid Nanoparticle (LNP) SystemBasic Constituents: Cationic Lipid

Cullis

PR, Hope MJ. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol Ther. 2017 Jul 5;25(7):1467-1475.

Lipid Nanoparticle (LNP) SystemEffect of Cationic Lipid Structure on

pKa

Jayaraman et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed Engl. 2012 Aug 20;51(34):8529-33.

Lipid Nanoparticle (LNP) SystemEffect of

pKa on LNP Delivery

Wan C, Allen TM, Cullis PR. Lipid nanoparticle delivery systems for siRNA-based therapeutics. Drug Deliv Transl Res. 2014 Feb;4(1):74-83.

One of the key findings from these studies was the optimum lipid pKa value of 6.2–6.5 as a dominating factor in determining hepatic gene-silencing activity in vivo.

Photo by Kyriakos

Kaziras

cGMP manufacturing initiated in 1985

Supplied the first semi-synthetic phospholipid for an approved drug product in 1990

Dipalmitoyl phosphatidylcholine (DPPC)

Exosurf

®

Neonatal, synthetic lung surfactant replacement for neonates with

respiratory distress syndrome

Currently support ~25 active drug master files for clinical trials and commercial products

Manufacture cGMP quality materials from 50g to 25kg batches

Maximum annual capacity: 2 MT per shift

Manufacturing suites available for production:

General lipid production 10

Small scale lipid production 1

Adjuvant production 2

Formulations 1

cGMP Manufacturing

API, Excipient, & Contract Manufacturing

In general, lipids are non-toxic, flexible, biocompatible, completely biodegradable, and

non-immunogenic for systemic and non-systemic administrations.

Classical drug delivery systems (drug depot) Encapsulation of hydrophilic drugs (passive and remote loading)

Sequestration and dispersion of hydrophobic drugs

Targeted drug delivery systems via coupling with site-specific ligands

Delivery of genetic material (cationic lipids)

Plasmid

siRNA

mRNA

Liposomal adjuvant systems for vaccine development and immunotherapy Contrast agents for MRI (targeted and untargeted)

Nasal and pulmonary delivery of drugs

Topical delivery of drugs (enhanced penetration)

Opthalmic

delivery of drugs

Lipid-coated microbubbles for ultrasound imaging or treatment

Applications

Drug Product Patent Expires Active Drug Lipid Components

DaunoXome® 2009

Daunorubicin

DSPC, Cholesterol

Doxil

®

2010 Doxorubicin HSPC, Cholesterol, DSPE-

mPEG(2000)

Epaxal

® 2012 Inactivated hepatitis A virus DOPC:DOPE

Inflexal

® V 2012 Inactivated hemagglutinin of

DOPC:DOPE

influenza virus strains A and B

Depocyt® 2015

Cytarabin

/Ara-C DOPC, DPPG, Triolein

, Cholesterol

Ambisome®

2016 Amphotericin B HSPC, DSPG, Cholesterol

Amphotec

® 2016 Amphotericin B Cholesteryl

sulphate

Visudyne

®

2016

Verteporphin

DMPC, EPG

DepoDur

™ 2017 Morphine sulfate DOPC, DPPG,

Triolein

, Cholesterol

Mepact

®

2019

Mifamurtide

DOPS, POPC

Abelcet

®

2019 Amphotericin B DMPC, DMPG

Marqibo

®

2020 Vincristine SM, Cholesterol

Exparel

®

2021 Bupivacaine DEPC, DPPG,

Tricaprylin

, Cholesterol

Onivyde

™ 2028 Irinotecan DSPC, DSPE-

mPEG

(2000), Cholesterol

Myocet

®

N/A Doxorubicin EPC, Cholesterol

Approved Liposomal Drug Products

Phospholipids (Semi-synthetic, plant-derived) Phospholipids (Natural)

DMPC DLPE DMPG Egg PC (>95%) DPPC DMPE DPPG

DSPC DPPE DSPG

DEPC DSPE POPG

DOPC DOPE

POPC

Adjuvants (Synthetic MPLA)

PHAD

®

3D-PHAD

®

3D(6-acyl)-PHAD

®

Other

Tricaprylin

Semi-synthetic Cholesterol (plant-derived)

Triolein

DSPE-

mPEG

(2000)-

Maleimide

DOTAP

cGMP Lipids Currently Available

Synthetic Monophosphoryl Lipid A (MPLA)

PHAD® 3D-PHAD®

3D(6-acyl)-PHAD®

Equivalent to bacterial-derived MPLA (native)

Toll-like receptor 4 (TLR4) agonist

Elicits a strong T

H

1 immune response

Used in multiple clinical trials

Adjuvant system formulations available (research & cGMP)

Available in gram to kilogram scale

Adjuvants

Vaccine Development & Immunotherapy

From research to early phase clinical Products Liposomes

Emulsion Lyophilized lipid formulations Scaled from milliliters to > 100L

Most Avanti lipids can be incorporated into liposomal formulations Custom synthesis lipids can also be

used in formulations

Formulations

Liposomes & Nanoparticles

Contract Manufacturing

Proven Partner for Development to Commercialization

Over 150 combined years of lipid synthesis experience Route scouting and process development for proprietary lipids

Small-scale batches available (<100g) Scale-up support for multi-kilo production

Custom packaging options

Full analytical support with

method

development and validation Regulatory support for clinical trial

and commercial filings

People do

amazing

things with our lipids!

What will you

do?