Orla Hardiman BSc MD FRCPI FTCD MRIA Professor of Neurology Trinity College Dublin

Transcription

1 Orla Hardiman BSc MD FRCPI FTCD MRIA Professor of Neurology Trinity College Dublin

2 ALS IS A HUMAN DISEASE

3 ALS: A Gene-environment Interaction (in 6 steps) 3-5 additional events Hardiman & Al-Chalabi Nat Rev Neurol 2013 Al-Chalabi et al Lancet Neurol 2015

4 FINDING THE GENES

5 ALS IS A SYNDROME: SUBCOHORTS CAN BE IDENTIFIED BASED ON CLINICAL PHENOTYPING & GENOMICS

6 ALS TRIALS > 40 negative trials Animal-based approach has not been successful Effective treatments likely to be in subgroups of patients Better biomarkers required Trial design and outcome measures need to be refined

7 EVENTUALLY, ALS WILL BE SEGREGATED BY SPECIFIC CHARACTERISTICS

8 IMPLICATIONS FOR FUTURE CLINICAL TRIALS

9 Over 20 compounds now in late pre-clinical phase

10 CLINICAL TRIALS (Currently Recruiting) 24 Phase 2 Trials 4 Phase 3 Trials

11 PRECISION MEDICINE Precision Medicine refers to the tailoring of medical treatment to the individual characteristics of each patient..it relates to the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment.

12 Treatment Research Initiative to Cure ALS

13 MISSION THE RIGHT DRUG, FOR THE RIGHT PATIENT, IN THE RIGHT DOSE, AT THE RIGHT TIME

14 OBJECTIVES

15 BETTER PATIENT SELECTION

16 DISEASE PROGRESSION IS HETEROGENEOUS Human ALS Patients VARIATONS IN RATE OF CLINICAL DECLINE

17 ALS PROGRESSION: PREDICTIVE FACTORS Age of onset Cognitive & behavioural status Site of onset Rate of progression Genetic background

18 Hierarchical Clustering identifies 3 groups Elamin et al J Neurol 2015

19 30 GENES OF MAJOR EFFECT

20 BETTER PATIENT SELECTION

21 BETTER BIOBANKING Lymphocytes Fibroblasts ips cells Brain & spinal cord

22 RECOGNITION OF EXTRA- MOTOR COMPONENTS

23 COGNITIVE & BEHAVIOURAL SUBPHENOTYPES

24 BETTER MEASURES OF PROGRESSION

25 ALSFRS-R Vital Capacity

26 Graph of longitudinal total ALSFRS-R and ALSFRS-R subscores. James Rooney et al. J Neurol Neurosurg Psychiatry 2017;88: by BMJ Publishing Group Ltd

27 BETTER BIOMARKERS INCLUDING MARKERS OF COGNITIVE AND BEHAVIOURAL CHANGE

28 BETTER NEUROIMAGING CAN NOW RELIABLY DISTINGUISH ANATOMIC REGIONS OF INVOLVEMENT

29

30 NEW NEUROPHYSIOLOGIC MEASURES

31 !

32 HARNESSING SOURCE LOCALISATION TECHNOLOGY Source-localisation Sensor-space Source-space

33 Results: Using eloreta Provides activity for sources throughout the brain, low resolution 10*log 10 (Deviant power / Standard power) Top 75% of differences between ALS and Patients

34 BETTER LABORATORY BIOMARKERS Neurofilament light & Heavy Chain Other blood biomarkers serum folate uric acid, L-ferritin Chitotriosidase, NOX2 enzyme activity, LDL/HDL ratio, creatine kinase, creatinine, albumin, vitamin D Neuroinflammatory markers MicroRNAs

35 BETTER DATA COLLECTION

36 REALTIME DATA UPLOADS for TRIAL READINESS A pan-european Electronic Patient Record

37 PRECISION MEDICINE Precision Medicine refers to the tailoring of medical treatment to the individual characteristics of each patient..it relates to the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment.

38 NEW DESIGNER TREATMENTS Based on genetics Anti-sense oligonucleotides SOD1 C9orf72 repeat expansion Based on pharmacogenomics

39 EARLY WINS: 3 NEW INVESTIGATOR-LED TRIALS LIGHTHOUSE 2 Triumeq targeting HERVK in ALS ADORE Oral Edaravone PRELUDE UNC13Allele determines response to Lithium therapy

40 LIGHTHOUSE II 10% of the human genome encodes for endogenous retroviruses (HERVs) HERV-K is the most recent HERV to be integrated into the human genome. Reverse transcriptase elevated in motor neurons from some patients with ALS

41 LIGHTHOUSE II Triumeq (an HIV antiretroviral drug) inhibits HERV-K A Phase IIa open-label, safety and tolerability trial of Triumeq was conducted in 40 patients with ALS Triumeq is safe and showed a strong potential for biological activity. Phase 3 double blind trial scheduled in Europe, Australia & US with better enrolment and outcomes

42 ADORE Oxidative stress markers are higher in patients with ALS and may relate to disease progression. Edaravone is a free-radical scavenger that has been shown to inhibit motor neuron death by reducing oxidative stress. Licensed by FDA in IV formulation for ALS (but not by the EMEA)

43 ADORE Oral formulation may improve the effectiveness of Edaravone by a more constant exposure. Better recruitment Better outcome measures

44 NEW DESIGNER TREATMENTS Based on genetics Anti-sense oligonucleotides SOD1 C9orf72 repeat expansion Based on pharmacogenomics

45 PHARMACOGENOMICS PRELUDE: Investigator initiated trial Safety and efficacy of lithium carbonate in patients with ALS and UNC13A C-allele homozygosity

46 PRELUDE

47

48 EVENTUALLY, ALS WILL BE SEGREGATED BY SPECIFIC CHARACTERISTICS

49 WHAT IT WILL LOOK LIKE

50 CONCLUSIONS New treatments in ALS will be driven by a precision medicine approach Better patient selection, trial design and improved outcome measures will move the field forward

51 Clinical Bernie Corr Sara Colla Dr.Deirdre Murray Lesley Doyle Kitty McElligott Imaging & EEG Dr.Peter Bede Dr.Bahman Nasseroleslami Dr.Parames Iyer Dr.Eoghan Finnegan Dr.Amina Coffey Dr.Christina Schuster Stefan Dukic Roisin McMackin Team Neuropsychology Dr.Niall Pender Dr.Tom Burke Marta Pinto Epidemiology Dr.Marie Ryan Dr. James Rooney Mark Heverin (Register) Dr.Katy Tobin Genetics Prof Dan Bradley Dr.Russell McLaughlin Dr. Kevin Kenna Ross Byrne Mark Doherty Academic Neurology Dominique Plant Health Services Dr. Miriam Galvin Dr.Katy Tobin Dr.Sinead Maguire EMG & Biomarkers Dr.Taha Omar Dr.Amina Coffey Clinical Trials Liz Fogarty Research Manager Mark Heverin Laboratory/Neuropharm Dr. Julie Kelly Gill Slator

52 RESEARCH FUNDING