Director: Prof Olivier BLINProject Manager: Lisa Otten

www.dhune.org

Key Words: NeuroDegenerative Disorders, Aging, Imaging, Biomarkers, EuroMediterranee

DHUNeuroDegenerative Diseases and AgingEuro-Mediterranee

Drug repositionning in RDOlivier BLIN

With the support of the A*MIDEX project (n° ANR-11-IDEX-0001-02) funded by the « Investissements d’Avenir » French Government program, managed by the French National Research Agency (ANR)

Olivier Blin: Personal Interests DisclosureAfssaps & ANSM (since 2004), Ministere de la Santé (since 2010)

Public

- Prof & Head Pharmacology Dpt, Marseille- Director DHUNE Neurodegenerative Dis & Aging- VP Section X of CS for CSFRS- Regional head and Member of the National Follow up CommitteeFrench National Plan against NeuroDegenerative Diseases (2014-2019)- Member French National Plan for Rare Diseases (2017-)- Member of the board Cnapec (CSIS 11)- Expert EC

Past: - One year mission in India for the French Minister of Industry- Board of the French Minister of Health

Private

- Non profit Association 1901- Share Holder: Biosqual, Arthobac, BOTS (Vect-Horus, Zion, Thelonius), Gunther Prince

Past: - Qualissima (SARL)- Industry 2011-2013: GSK global CNS discovery medicine

Juin 2016

Pharmacologie Clinique APHMPr O. Blin (MD, PhD, MBA)

PharmacométriePharmacoépidémiologie

Dr A. Marsot (PhD)E. Jouve

Q Boucherie (PhD)

Centre Régional de PharmacoVigilancePr J. Micallef (MD, PhD)

Dr A. Default (MD)

Centre Régional d’Addictovigilance Pr J. Micallef (MD, PhD)

Dr B. Frauger (PharmD, PhD)

UMR: INT to INS team 1 (2018)

PiiCi (Pr O. Blin)Pharmacologie IntégréeInterface Clinique et Industriel

OrphanDev/F-CRIN

Fédération Hospitalo

Universitaire

DHUNE

Centre d’excellence

(DHUNE-CE)

Coordonnateur

Pr. O. Blin

Centre de Pharmacologie Clinique et Evaluations

ThérapeutiquesDr C. Audebert (MD)

Dr D. Braunstein (MD)

Centre d’Investigation Clinique (CIC)

Pr Y Berland

Pharmacologie Biologique

Dr R. Guilhaumou (PharmD, PhD)Dr J. Dupouey (PharmD)

Maladies

NeuroDégénératives

et vieillissement

Context and Methods

R&D versus Repositioning: the context

Decreased in pharmaceutical researchand development productivityIncreased development costsGeneric competitionConservative regulatory policiesInsufficient breakthrough innovations

Identifiying new indications for existing drugsSalvage of compounds shown to be safe but uneffectiveDecrease costs and time to market (eg toxicology package)Reduce (not abolish) safety and PK uncertainty

Built on 4 Cornerstones• Built Confidence early on• Help decision before major investment• Pave the way for next wave assets

Mechanistic/Pathophysiological approachesClinical Efficacy Read out

From 3 pilars to 4 cornerstones

Academic coll.PPP (MRC and AZ, NCATS with 8 pharma)In house effortTimelinesIP

Morgan et al. Drug Discov Today. 2012 May;17(9-10):419-24.

Activity based Repositioning

Libraries of approved drugs and candidatesProprietary (pharma)Johns Hopkins University Clinical Compound Library of 2687 drugsNIH clinical collections through evotec (WWW.nihclinicalcollection.com)Microsource (Pharmakon 1600, Spectrum, NINDS custom collection)Sigma (LOPAC 1280), Prestwick, Selleckchem, Enzo Life Sciences, Tocris…

Target-based screeningAdvance in disease biologyRelevant if molecular target is identified

Use phenotypic in vitro and in vivo assays relevant to a diseaseBioactivity in model cells or animal (yeast, netamatode, drosophile, rodent, mamalian…)Not directly related to target engagement

Bioinformatics Repositioning

Systematic Computational analyses for drug repositioning, allowing prediction and discoveryAbility to access virtually large number of mechanisms, data related to the disease, and compoundsQuality and extent of database are crucial

Transcriptomic approaches Gene expression serves as a quantitative toolBased on « connectivity map »: database of gene expression associated with reference drugsIdentification of a disease specific « signature » of down or up-regulated genes

Ex: topiramate for Crohn Disease (Sirota M et al. Sci Transl Med 2011; 3:96 )

GWAS: list of genes associated with specific disease traitsSubset of genes considered to be « drug targets » based on the druggability of each gene productIdentification of 2 distinct groups: GWAS traits match to the drug indication OR differs from it

Ex: a marker of LINGO-1 (developped for MS) shows GWAS association with essential tremor(Stefansson H et al. Nat Genet, 2009;41:277-279

Big Data Repositioning

Emon MA, et al. J Alzheimers Dis. 2017;56(2):677-686

Mechanism-based, drug-target interaction modeling approach

to identify promising drug candidates for repositioning.

Mechanistic cause-and-effect models consolidate relevant prior

knowledge on drugs, targets and pathways from the scientific

literature and integrate insights derived from experimental

data.

Failure and Success Story

The Challenge of a Rare Disease: Charcot- Marie-Tooth disease type 1A

Epidemiology

A rare disease with high prevalence

Symptoms

A gap to be filled

There is no cure for CMT targeting the underlying cellular disease process.

Current treatments are symptomatic and supportive: pain medications, physical therapy and corrective surgery

there are no European guidelines for CMT management due to large diversity of disease progression and symptoms

Tackling the Pathophysiology

one of the most common degenerative neurological disorders with increasing incidence

2016: 2.6 in 10,000 people in EU 2014: 1.4 in 10,000 people in EU

CMT1A subtype most common form of CMT: 40-50% of all cases CMT1A physiopathology:

Transmitted as an autosomal dominant trait Duplication of 1.4 Mb region on the short arm chromosome 17

Source: Ekins et al, 2014

Source: Committee for Orphan Medicinal Products (COMP)

C3 PMP22 overexpressing mouse model PMP22 overexpressing rat model stable, low nerve conduction velocities similar to human CMT1A gait abnormalities caused by a peripheral hypomyelination, Schwann

cell hypertrophy and muscle weakness. Sereda et al, 1996

Disrupted interactions between Schwann cells and axon cause axonal degeneration and neuromuscular dysfunction

autosomal dominant 1.4 Mb

duplication

excess accumulation of PMP22 protein in the ER of Schwann cells

prolonged and intense ER stress & swamped

adaptive UPR

restore proteostasis to enable cells to deal with misfolded proteins using

IFB-088

Distal motor deficit Progressive muscular atrophy Sensitive deficit Areflexia Cramps, pain, tremor Deformations - Pes cavus - Scoliosis

Burden

Faced with a clear unmet medical need A heavy burden for patients & families (often several members of a

same family affected)

Animal models

AFM, CMT France

TreatNMD

CMT US, NMI

Patient’s advocacy groups & Experts networks

Modify cAMP using AA Pleiotherapy

Pleiotherapy

Success Story CMT1A

Ph II CMT 1A180 patientsFrance PI Micallef J

2005

Micallef J et al 2009Lancet Neurol

Ph II CMT 1AFrance80 patientsPI Attarian S

ODD Pharnext(EMA &FDA, 2014) CMT1A

PHRC CMToolsObtenu 2013

EC CMT 1A 2016 Endpoints60 patientsFrancePI Attarian S

Attarian S et al 2014Orphanet JORD

EC CMT BMK, 201430 patientsPI Attarian S

Ph I, Volontaires sains

Clinical DevelopmentPlan

Protocol assistance

Call center59%

Active list of patients

41%

Call center “pre screening tool” for the recruitment of patients

Colomban C et al 2014J Neurol Sci

International Ph III CMT1A, (2015-2018)300 patients, EU and USA,7 countries, 26 centres PI Attarian S in France

ODD Inflectis Bioscience(FDA EMA, 2015)CMT

2010 2015

Meta Analyse EC CMT1ARash analysis CMTNSWang et al, 2017

H2020: 2017RHU 3

Ph II, CMT1A

PharmacoEconomical Aspects

Repositioning and R&D

Decreased costsDiscovery, CMC, Analytics, Préclinical package, Phase 1Accumulated Knowledge

New specificities to be taken into accountAnimal modelsSafetyDose determinationPediatric preclinical & clinical R&D (and PIP)

Evaluation in FranceEx: hydrocarbamide

HYDREA (BMS): Antineoplasic drug (5,28€)SIKLOS (Addmedica): Drepanocytosis : ASMR IV (2011)

Initial Price: Siklos 100 mg at 13,40€, and Siklos 1000 mg at 67 €Rapid and small price increase: 18,71 € for 100 mg and 84,12 € for 1000 mg Price increase of 65 % on 25 june 2014 : 85,48 euros and 402,42 euros

Multiples indications for the same molecule

SavingsCMCPreclinical DossierPhase 1Staged Development efforts

For Several Rare DiseasesAn Orphan Drug with several indication is it still Orphan?

For a Rare and a Not Rare DiseaseRisk of de-priorization for the rare diseaseFirst RoI in Not Rare Disease

Original Orphan Drug for single rare disease302Orphan that served the mass market first72Orphan approved for multiple rare diseases84

http://www.npr.org/sections/health-shots/2017/01/17/509506836/drugs-for-rare-diseases-have-become-uncommonly-rich-monopolies

UnAuthorized drugs and Rare Diseases

More than 500 drugs could be prescribed for Rare Diseases due to the lack of alternatives

In France, the system of Recommandations Temporaires d’Utilisation (RTU) provides a regulatory and safe frame with reimbursement costsfor the patients

Some pharma are ready to invest in repositioning for unauthorizeddrugs: a system for RoI is still to be framed