Transcript AAN Kickoff Seminar Treatment of ALS PHARMACOTHERAPY IN ALS

Clinical Trials in ALS
December, 2005
Robert G. Miller MD
Director, Forbes Norris MDA/ALS Research Center
California Pacific Medical Center
San Francisco, CA
Conflict of Interest Disclosure
(Robert G. Miller, M.D.)
Since 2004
 Research Grants: Novartis, Aeolus
 Educational Grants: Aventis
 Honoraria for consultation: Novartis,
Pharmacyclics, Jazz Pharmaceuticals,
Teva
 No other financial relationship
Summary
 To discuss ALS disease mechanisms
targeted in current treatment trials
 To review recent clinical trial results
 Upcoming clinical trials
 New treatment strategies
Cell Death Process in ALS Motoneurons
SOD Mutations
Glutamate
Excitotoxicity
Astrocyte
Dysfunction
Virus
Mitochondrial dysfunction
Oxidative injury
Nitration, glycation
Neurofilament abnormality
Apoptosis
Neurotrophic factor impairment
DNA injury
Aging
Trace Metals
Excessive
Physical Activity
Environmental Factors
Autoimmunity
Inflammation
Treatment Strategies
Anti-glutamate
 Riluzole
 Gabapentin
 Topiramate
 Ceftriaxone
Evidence for Glutamate
Excitotoxicity in ALS
1. Abnormal glutamate metabolism
2. Loss of glutamate transport protein
3. Motor neuron susceptibility to glutamate
toxicity
4. Clinical efficacy of anti-glutamate agents
Riluzole
 AAN Practice Advisory - Neurology 1997
 Approved in Canada 2000 (U.S., Europe 1996)
 National Institute for Clinical Effectiveness (NICE)
 systematic review 4 trials
 approved in U.K. (2001)
 Cochrane Review 2003
 Registry Data (UK, IR, UW) - 8-16m increased
survival
Implications for Practice
 Proven efficacy - modest effect size
 Generally safe and well tolerated
 Expensive ($10,000 US/yr)
 Provides hope - none before
 Education - adjustment/perception
Treatment Strategies
 Anti-oxidants
– Vitamin E - 2 large trials negative
– Creatine - 2 negative trials, 2003,4
– Edaravone (small phase 2)
– Manganese-porphyrin (phase I)
– CoQ10
High dose vitamin E therapy in amyotrophic
lateral sclerosis as add-on therapy to riluzole
Graf M, et al 2004
 A double blind, placebo-controlled, randomized,
stratified, and parallel-group clinical trial.
 160 patients, all treated with riluzole, were randomly
assigned to receive either Vitamin E (5000 mg per day) or
placebo for 18 months.
 The primary outcome: survival.
 No significant difference between placebo and vitamin E.
 Megadose vitamin E caused no significant side effects in
this patient population.
Neurotrophic Factors
 Spectacular survival- promoting
effects on motor neurons
 Requiring a minute amount of
protein
 Mostly target-derived
 Neuronal growth, differentiation,
maturation, and regeneration/
repair
Treatment Strategies
 Neurotrophic factors (subcutaneous)
–
–
–
–
CNTF
BDNF
GDNF
IGF-1 (Repeat study is on-going)
 Novel delivery techniques
INFLAMMATION
MICROGLIA
COX2
Prostaglandin E2
COX2
M
N
CASPASE
Bax
ROS
Cell Deassembly
N
N
ASTROCYTE
IL-6, IL-1ß
ICAM
TNF-α
Chemokines
MOTONEURON
N
T-LYMPHOCYTE
Anti-inflammatory
 Immunosuppressive agents - negative trials
(cytoxan, XRT, PE)
 COX-2 inhibitors
– Celecoxib - large trial negative in 2004
 Anti-microglial agents
– Minocycline - enrolling
Minocycline
 Inhibits MAP Kinase (Caspase 1 and 3)
 Neuroprotection in SOD mouse
 High penetration into brain/cord
 Well tolerated orally
 Pilot trial UNM, CPMC
Tikka et al, Brain 2002; 125:722
Minocycline
 Positive results in SOD1 mouse – 4 labs
 Two Phase I/II trials complete; some toxicity with
doses up to 400mg/day (esp GI)
 Tolerability of higher doses, long dosing
 NIH/MDA funding
 Enrollment – widely available drug
Gordon 2003
CELL APOPTOSIS
Death Signals
Mitochondria
Mitochondria
Other
pathways
Endoplasmic
reticulum
A Family of
Caspase Proteins
Treatment Strategies
 Anti-apoptotic agents
–
–
–
–
Indinavir (small phase II) - negative
TCH 346 (Novartis)
Minocycline
Methyl-cobalamin
 Preserve cAMP and cGMP
– Pentoxyfilline (ExonHit)
 Astrocyte modulator
– Ono-2506 (Ono)
 Protein kinase C inhibitor
– Tamoxifen
 Hyperbaric oxygen therapy (small phase I)
TCH-346 (Novartis)
 16 week lead-in phase (before randomize)
 52 week treatment phase
 5 groups (4 dose groups and placebo)
 Over 500 patients (International)
 Primary outcome: slope of the ALSFRSR
 Secondary outcomes: time to event (death and
tracheostomy), MMT, FVC, and Neuro-cognitive
evaluation (selected sites)
 There were no differences in groups
Pentoxifylline: A phase II trial
V. Meininger, et al. Reported at the 15th International
ALS/MND Symposium, Nov 2004, Philadelphia
 Increases intracellular cAMP
 RCT to assess the efficacy (15% difference) of
pentoxifylline 400 mg t.i.d. (or placebo)
 400 patients
 The primary endpoint was 18-month survival rate
 The secondary endpoints: ALSFRS, MMT
 No benefit with drug treatment
Tamoxifen, phase I/II study
Ben R. Brooks, M.D. Univ of Wisconsin,
reported at 2005 AAN meeting
 Tamoxifen, anti-breast cancer agent, protein kinase C inhibitor
 A patient with breast cancer and ALS who was treated with
tamoxifen experienced marked slowing in progression of ALS
 Abnormally activated protein kinase C in degenerating motor
neurons
 The drug was well tolerated but both sexes experienced hot
flashes
 Patients receiving 20 to 40 mg per day may have longer survival
compared to patients receiving only 10 mg per day
 A Phase III trial is required
Symptomatic Treatment
Treatment of Pseudobulbar Affect in
ALS With DM/Q
n=70
DM/Q bid
(DM 30 mg/Q 30 mg)
 Probable or definite
ALS (≥2 months)
 History of PBA
 CNS-LS score ≥13
Randomize
n=33
DM 30 mg bid
N=140
 HAM-D score ≤16
n=37
Q 30 mg bid
Primary outcome measure: Change from baseline in CNS-LS
ALS=amyotrophic lateral sclerosis. CNS-LS=Center for Neurologic Study-Lability Scale. HAM-D=Hamilton Depression
Rating Scale. Brooks BR, et al. Neurology. 2004;63:1364–1370.
Plasma Concentration of DM
150
P < .0001
ng/mL
100
n=35
50
n=23
0
DM/Q
DM
Brooks BR, et al. Neurology. 2004;63:1364–1370
Improvement of CNS-LS Score
in ALS Patients
Reduction in CNS-LS Score
0
DM/Q
DM
Q
2.5
5.0
7.5
P< .001
Brooks BR, et al. Neurology. 2004;63:1364–1370
Quality of Life Scores
(Visual scale)
30
Change in QoL (VAS)
P< .002
20
10
0
DM/Q
DM
Q
Brooks BR, et al. Neurology. 2004;63:1364–1370
Adverse Events (AEs)
 Adverse events reported in 89% of DM/Q, 70% of
DM, and 65% of Q patients
 Events occurring at a significantly higher incidence
in the DM/Q group compared to the DM- and Qalone groups:
 Nausea (33%)
 Dizziness (20%)
 Somnolence (13%)
Brooks BR, et al. Neurology. 2004;63:1364–1370
Bourke et al studied the benefits of non-invasive
positive pressure ventilation (NIPPV) to 40
patients with ALS.
– In RCT, 22 patients received NIPPV and 19 had
standard care.
– Patients with NIPPV survived significantly longer
and had a better quality of life.
12/04 Phila.
CURRENT and UPCOMING
MAJOR TRIALS





IGF-I (NIH– GLALS, USA) -- enrolled
Minocycline (NIH– WALS/Columbia, USA) -- enrolling
CoQ10 (NIH– Columbia, USA) – enrolling
Manganese-porphyrin (Aeolus, USA) – phase I, in progress
Ceftriaxone (NIH funded) – phase II study (high throughput
screening)--planned fall 2005
 Respiratory and nutritional treatment in ALS (NIH– Univ
of Kentucky, USA) --- phase II study (early 2005)
 Methyl-cobalamin (Aisai, in Europe) – phase I study
Ceftriaxone treatment at disease onset increases survival
of G93A SOD1 mice
(preliminary analysis)
1.0
Ceftriaxone (200mg/kg/day
0.9
% Surviving
0.8
0.7
0.6
Start
Therapy
0.5
0.4
0.3
Saline control
0.2
0.1
0.0
80
85
90
95
100
105
110
115
120
Survival (Days)
125
130
135
140
Ceftriaxone clinical trial in patients with
ALS
NINDS funded
Phase I- III
– 60 subjects – PK and safety study
– 600 subjects – efficacy study
– Efficient study design – to expedite drug development
FDA Requirement for additional animal toxicology
Enrollment planned for early 2006
Northeast ALS Consortium (NEALS)
– 46 centers US and Canada
Sodium phenylbutrate is a HDAC inhibitor
that may be promising for ALS and other
neurodegenerative disorders
Currently used for management of urea cycle disorders
In testing phase for Huntington’s Disease and spinal
muscular atrophy
Efficacy in ALS mouse model (Ferrante et al)
VA – Northeast ALS Collaboration
Phase 1 safety and dose finding study started 04/05
A safety and dose finding study of sodium
phenylbutrate, a HDAC inhibitor began in
April 2005.
• Currently used for
management of urea cycle
disorders
• In testing phase for
Huntington’s Disease and
spinal muscular atrophy
• Funded by VA (primary) and
MDA
• Phase 1 safety and dose
finding study at 8 sites in
Ryu H, Camelo SI, Carreras I, Lee I, Iglesias AH, Kubilus JK, Smith K, Cudkowicz ME, Brown Jr. RH Jr, Dangond F,
Ferrante RJ
April 05
Arimoclomol
Treatment with a co-inducer of heat shock proteins delays disease
progression in a murine model of ALS
• At 120 days Arimoclomol
treatment
• Phase IIA Clinical trial in
ALS start October 2005
(NEALS)
100
% Survival
increases motor unit survival
increases motoneuron
survival
rescues large motoneurons
Increases heat shock protein
expression
120
80
60
40
20
0
11 12 13 14 15 16 17 18 19 20 21 22 23 24
Age (weeks)
Dairin Kieran, Bernadett Kalmar, James Dick, Joanna
Riddoch-Contreras, Geoffrey Burnstock & Linda
Greensmith
Coenzyme Q10
Encouraging results in Parkinsonism
Stage 1 – compare 1000 & 2000mg/day
Stage 2 – compare best dose to placebo
Phase II, 20 sites, 10 months
NIH funding, PI-Petra Kaufman, Columbia Univ.
Manganoporphyrin
Novel antioxidant (AEOLUS)
38% increase survival in SOD1 mouse
Phase I, subcutaneous injections
Single doses well tolerated
Multi-dose study underway
IGF-1
Growth factor nourishing muscle, nerve
Positive study in US, 1997
Negative study in Europe (Mayo, Eric Sorensen,
M.D.)
NIH funding
24 months, muscle strength
Arimoclomol





80 patients, 10 sites
12 weeks treatment
4 weeks wash out
Tolerability, toxicity
Pharmacodynamics
New Treatment Strategies
Stem Cell Therapy
 Appel S, et al. A small clinical trial with allogeneic
hematopoietic stem cell (from HLA-matched siblings)
transplantation in 6 patients. (Reported at the 15th
International ALS/MND Symposium, Philadelphia, Nov 2004)
– 2 died, 1 progressed, 1 experienced a slowing of
progression, and 1 had an unexpectedly stable course.
– 17% to 25% of total DNA in CNS was donor-derived,
although only 1% was donor-derived DNA in the motor
cortex.
– Unusually high numbers of CD68+ cells were found in the
CNS, suggesting a neuroinflammation induced by
chemokine signaling.
Stem Cell Therapy (cont'd)
 Mazzini L, et al. Stem cell therapy in amyotrophic
lateral sclerosis: a methodological approach in
humans. (Amyotroph Lateral Scler Other Motor Neuron
Disord. 2003;4:158-61)
– No preliminary studies in rodents or primates.
– 9 patients direct injections of their own BM mesenchymal
cells into the spinal cord. Claimed to note“stabilization”
but eventually a few patients died without autopsy.
Gene Therapy
Retrograde Viral Delivery of IGF-1 Prolongs
Survival in a Mouse ALS Model
(Brian K. et al. Science 2003; 301: 839-842.)
Exercise in ALS
 Little evidence, conflicting advice
 RCT (n=25) - slower decline ALSFRS,
Ashworth at 3 mos, trend at 6 mos
 Transgenic SOD1 mice treadmill 10 wks vs no
exercise - prolonged survival
 Worse high intensity exercise
Drory 2001, Kirkinezos 2003, Mahoney, 2004
Exercise and Insulin-like Growth
Factor-1
 Comparison of exercise (0,2,6,12hr/day) and gene
therapy (AAV-IGF-1) in ALS mouse
 Prolonged survival (30-40d) and functionality with
exercise (6,12h) and also with IGF-1
 Remarkable synergistic effect with both exercise
and IGF-1 on survival (83 days!) and functionality
 Emerging evidence about exercise in ALS
Kaspar, May 2005
Drug Trials:
Potential treatments for ALS
Indinavir
Celebrex
Pentoxyfilline
ONO 2506
TCH346 (Novartis)
Ritonavir/hydroxyurea
IGF-1
Minocycline
Coenzyme Q10
Neotrofin AIT-082
NAADALase
Talampanel
Tamoxifen
IV Ceftriaxone
Phenyl butyrate
AVP-923-Neurodex
Aeolus/Incara 10150
Arimoclomol? Thalidomide?
Myogane?
Cell Therapy
Bone Marrow
Human Cord Blood
Embryonic derived and fetal
stem cells
Gene Therapy
AAV-IGF1
Equine IA Virus – VEGF
Gene Shut-down
RNAi for mutant SOD1
Anti-sense for mutant SOD1
Multiple therapeutic studies are underway or planned in ALS
Drug Trials (14)
Celebrex
Pentoxyfilline
ONO 2506
TCH (Novartis)
Topiramate
Negative
IGF-1
Minocycline
Coenzyme Q10
Talampanel
Tamoxifen
IV ceftriaxone
Phenyl butyrate
Gene Therapy
AAV1-IGF1
EIAV-VEGF
Cell Therapy
Bone marrow
Embryonic stem cells
Allele Inactivation
siRNA
Anti-sense
10/04
1/05
1/06
1/07
Clinical Trials – The Future
 Dose finding (Gaba 2400/3600)
 Patient selection (early pts) 75% VC, 2yr, poss
vs. lab support prob
 Markers (MUNE, NI, PGE2, NFL etc)
 Innovation (stem cells, gene therapy, new trial
designs)
Summary and Conclusions
 Unprecedented number of clinical trials in ALS at
one time
 Marked diversity in technology and targeting
different disease mechanisms.
 We will have more clinical trials in ALS in the next
few years.
 Partnerships between NIH, ALSA, MDA and
corporate sector are forming
 New national ALS research group formed
 We need to improve patient access issues and the
efficiency of clinical trials.