Gene-based Therapies In Huntington's Disease Intrathecal Approaches in Huntington's Disease - Movement Disorder Society
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Gene-based Therapies
In Huntington’s Disease
Intrathecal Approaches
in Huntington’s Disease
Mark Guttman MD, FRCPC
University Of Toronto, Toronto, Canada
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Disclosures
• Advisory Boards: Roche, Novartis, PTC,
Triplet Therapeutics, Sunovion
• Research Funding: Roche, Wave Life
Sciences, Biogen, Triplet Therapeutics,
CHDI Foundation, Neurocrine
Biosciences, UCB
• Views and opinions expressed during my
presentation are mine alone
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Learning Objectives
• Describe the mechanisms of action of the
different gene-based therapies for
Huntington’s disease
• Illustrate the different approaches of these
therapies, their advantages and
challenges
• Evaluate the current state of development
of on-going clinical trials
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Outline
• Intrathecal Administration
• Ionis/Roche antisense oligonucleotide (ASO) program
– Phase 1 study completed
– Phase 3 study ongoing
– Open label data
• Wave Life Science ASO program
– Phase 1 study ongoing
– Open label study ongoing
• Triplet Therapeutics program
– Natural history study in preparation for Phase 1 study
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Centre for Movement Disorders :
Experience with Intrathecal (IT) drug
administration
• Intrathecal administration has not been a problem for most
patients
• Used spinal ultrasound to improve procedure
• Used Epidural positioning chair for patient comfort
• Chosen to have anesthetists assist in performing procedures
• Team of two neurologists, two nurses, three anesthetists,
three research assistants, pharmacist involved in IT
administration and procedures before and after
• Model has been to have high volume IT days with up to 10 IT
administration/LPs in one day
• Have not had a post-dural puncture headache with 24G
Whitacre needle
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Intrathecal Admimistration International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Pathophysiology of HD
Mutations in HTT disrupt cellular processes, resulting in progressive depletion of neurons
No HTT mutation
TRANSCRIPTION TRANSLATION Normal cellular function No clinical pathology
wtHTT gene HTT mRNA wtHTT protein
HTT mutation
Clinical HD symptoms
Cellular dysfunction
TRANSCRIPTION TRANSLATION Cognitive decline
Progressive neuron loss
Neuropsychiatric features
Motor dysfunction
mHTT gene* mHTT mRNA mHTT protein
*mHTT is recognised as HTT with ≥36 CAG repeats.
CAG, cytosine adenine guanine; HD, Huntington's disease; HTT, huntingtin gene; HTT, huntingtin protein; mHTT, mutant HTT; mHTT, mutant HTT; wtHTT, wild-type HTT; wtHTT, wild-type HTT.
Adapted from; 1. Bates GP, et al. Nat Rev Dis Primers. 2015; 1:15005; 2. Wild EJ, Tabrizi SJ. Lancet Neurol. 2017; 16:837–847.
Slide provided by Roche
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Pathophysiology of HD
Mutations in HTT disrupt cellular processes, resulting in progressive depletion of neurons
MoA SCHEMA ADAPTED FROM WILD AND TABRIZI, LANCET NEUROLOGY, 2017
Nucleus DNA
pre-mRNA
mRNA
Cause
Toxic mHTT*
of disease
Impaired axonal Proteasome Neuronal dysfunction Excitotoxicity
Cellular transport inhibition and death
dysfunction Caspase/protease Synaptic Transcriptional Mitochondrial
activation dysfunction deregulation dysfunction
Atrophy Cognitive and functional Motor
Clinical ▪ Brain tissue loss ▪ Coordination
pathological ▪ Psychomotor
▪ Muscle wasting ▪ Balance/gait
domains ▪ Inattention
▪ Weight loss ▪ Chorea
Speech and swallowing ▪ Apathy/behavior ▪ Progressive akinesia
Slide provided by Roche
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org
Levels of CSF mHTT as a biomarker in HD
Clinical evidence
Levels of mHTT in CSF correlated with disease stage, symptom severity and markers
of neuronal damage in people with HD1
CSF mHTT levels increase as HD progresses, and CSF mHTT, CSF NfL and plasma NfL correlate with disease stage2
are two to three times higher in people with manifest HD1
CSF mHTT CSF NfL Plasma NfL
p=7.79 x 10-8 p
Tominersen Mechanism of action
Tominersen results in partial and reversible lowering of HTT protein
Tominersen, a DNA strand with sequence complementary to HTT mRNA, binds both HTT pre-mRNA (in the
nucleus) and HTT mRNA (in the cytoplasm), resulting in a complex that is recognised as foreign by the cell,
thereby recruiting RNase H1 to mediate degradation of the hybrid ASO-HTT mRNA1–4
TRANSCRIPTION + COMPLEMENTARY
BASE PAIRING
mRNA
DEGRADATION
+ REDUCED
TRANSLATION
wtHTT mHTT wtHTT mHTT ASO HTT mRNA–ASO Degraded ASO Reduced production
gene gene mRNA mRNA hybrids wtHTT and mHTT of wtHTT and mHTT
mRNA proteins
Tominersen is investigational and has not been authorized for sale by Health
Canada, and that efficacy and safety have not been established
Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgHuntington Lowering Therapy
Approach
ASO design considerations
Ability to target the entire HTT gene to
identify a potent ASO
Potential to treat all HD patients
regardless of individual genetic
background
Partial, dose-dependent and reversible
lowering of HTT protein
Available safety and tolerability data from
animals and human studies support
further clinical development
Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgPhase I/IIa study: Tominersen in
patients with early HD (Stage I)
Multiple ascending dose study design: Five dose levels versus placebo; 3:1 active to placebo
Study Population
Placebo Q4W (n=12)
• Aged 25–65
• Diagnosed with early 10mg tominersen Q4W (n=3)
manifest HD, defined as:
– ≥36 CAG repeats in HTT 30mg tominersen Q4W (n=6)
Open-Label Extension
– Clinical Stage 1 disease R tominersen 120mg IT
(TFC 11–13; little to no
functional impairment) 60mg tominersen Q4W (n=6) Q4W or Q8W
• Able to tolerate MRI scans,
blood draws and LPs 90mg tominersen Q4W (n=9)
(n=46) 120mg tominersen Q4W (n=10)
Primary Endpoint: Exploratory Endpoint: Exclusion
• Evaluate safety and tolerability •CSF mHTT • Recent treatment with an ASO
of tominersen • Fluid biomarkers, MRI, EEG • History of post-LP headache of moderate or severe
Secondary Endpoint: •PK in plasma • Patients unable to participate or completion study
• PK in CSF • Clinical outcomes (e.g. UHDRS)
Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgPhase I/IIa study: Tominersen in patients with early HD
(Stage I) - Safety summary
Events observed in >5 patients who received tominersen
Placebo Tominersen
(n=12) (n=34)
• No participants discontinued tominersen Patients Events Patients (%) Events
treatment (%)
– Most AEs were mild and considered Patients reporting at
12 (100.00) 78 33 (97.1) 216
unrelated to study drug least one AE
– Post-LP headaches occurred after Injury, poisoning and procedural complications
about 10% of LPs; epidural blood patch
Procedural pain 6 (50.0) 12 19 (55.9) 45
treatment was not required
• No SAEs in active treatment groups Post-LP syndrome 5 (41.7) 11 12 (35.3) 24
– One SAE in a placebo-treated patient; Fall 3 (25.0) 5 7 (20.6) 8
mild post-LP headache, hospitalised for
observation, no sequelae Infections
• No clinically meaningful changes in safety Nasopharyngitis 2 (16.7) 3 7 (20.6) 7
laboratory parameters
Nervous system disorders
Headache 6 (50.0) 13 6 (17.6) 15
AE, adverse events; LP, lumbar puncture; SAE, severe adverse event.
Tabrizi SJ, et al. Presented at CHDI 2018.
Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgPhase I/IIa study: Tominersen treatment effects on CSF mHTT
Maximum reduction of CSF mHTT was 63% and mean reduction was ~40% in 90 mg and 120 mg dosing groups
Steady state maximum reduction of CSF mHTT was not reached during the 3-month dosing period1,2
mHTT percentage change from baseline mHTT percentage change over time
to trough after 3 or 4 monthly doses*
80
NS p=0.01 p=0.02 pPhase I/IIa study: Results
summary
• No participants discontinued treatment
– AEs were mild and considered unrelated to study drug
– Placebo or tominersen was administered monthly; post-LP headaches occurred after about 10% of LPs
• Significant, dose-dependent reduction of mHTT in CSF
– Magnitude of reduction exceeds amount that was effective in HD animal models
– As of last CSF measurement mHTT levels were still decreasing
• There were no significant group-wise findings on exploratory clinical measures
– Degree of mHTT lowering was associated with positive signals in post hoc analyses of several exploratory clinical
measures but confirmation is required with a larger sample size
Tominersen open-label extension study is underway and will investigate effects of sustained mHTT lowering
The efficacy and safety of tominersen will be assessed in the pivotal Phase III study
Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgOLE of Phase I/IIa Study: CSF mHTT percentage change from
baseline at 15 months (preliminary analysis)
Q4W (N=23)1 Q8W (N=23)1
70% mean trough lowering at 15 months 44% mean trough lowering at 15 months
0 0 Target range
Phase I/IIa tominersen 120 mg Q4W 2
CSF mHTT change
from baseline (%)
CSF mHTT change
-20 -20
from baseline (%)
-40 -40
-60 -60
-80 -80
-100 -100
BL 85 169 253 337 421 BL 85 169 253 337 421
Visit day Visit day
n= 23 23 23 23 23 22 23 22 22 21 19 19 16 19 17 18 n= 23 23 2 23 23 22 22 23 22 21
• Pharmacologically relevant CSF mHTT lowering was observed in both treatment arms
• Data show that Q8W dosing is sufficient to reach target CSF mHTT reductions
Data points represent mean values and error bars represent ±1 standard deviation of the full intent-to-treat population.
At the time of the data cut-off (18 July 2019) 43 out of the 46 patients had reached the 15-month visit time point (Q4W: n=22, Q8W: n=21), three patients were enrolled in the study 3 months after all other study participants and the 15-month visit
had not been conducted at time of data cut-off. BL, baseline; CSF, cerebrospinal fluid; mHTT, mutant huntingtin protein; Q4W, every month; Q8W, every 2 months.
1. Schobel SA. Presented at the 15th Annual HD Therapeutics Conference 2020; 2. Tabrizi SJ, et al. N Engl J Med. 2019; 380:2307–2316.
Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgGENERATION HD1 (NCT03761849) revised protocol:
Phase III study of intrathecally administered tominersen in
manifest Huntington’s disease
Randomised, multicentre, double-blind, placebo-controlled study1‒3
Key inclusion criteria: Tominersen 120 mg Q8W
• clinically diagnosed (Q4W tominersen 120 mg for Doses 1–2, thereafter,
tominersen 120 mg Q8W IT bolus)
manifest HD (DCL=4)
• aged 25–65 years GEN-EXTEND4
R 1:1:1
Tominersen 120 mg Q16W
• CAP>400* (Q4W tominersen 120 mg for Doses 1–2, thereafter, (OLE)
tominersen 120 mg alternating with placebo Q8W IT bolus) (optional)†
• Independence Scale ≥70
• ambulatory, verbal
Placebo Q8W
Tominersen
Q8W or Q16W
N=791 (Q4W for Doses 1–2, thereafter, placebo Q8W IT bolus)
25 months (plus follow-up)
Objective: Evaluate efficacy and safety of intrathecally administered tominersen in adult patients with manifest HD
* CAP >400.01. † Provided participants meet eligibility criteria, the data for tominersen support continued development and the study is approved by Authorities and Ethics Committees/Investigational Review Boards.CAP, CAG-age product;
cUHDRS, composite Unified HD Rating Scale; DCL, diagnostic confidence level; HD, Huntington's disease; IT, intrathecal; OLE, open-label extension; Q4W, every month; Q8W, every 2 months; Q16W, every 4 months; R, randomised.
1. Clinicaltrials.gov/show/NCT03761849 (Accessed September 2020); 2. Schobel S, et al. J Neurol Neurosurg Psychiatry. 2018; 89(Supp 1):A98; 3. Boak L. HDSA Annual Convention 2020. 4–7 June 2020;
4. Clinicaltrials.gov/show/NCT03842969 (Accessed September 2020).
2. Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgGEN-EXTEND (OLE)
Objective: Evaluate the long-term safety, tolerability and efficacy
of tominersen treatment in patients who have previously participated in the GDP
GEN-EXTEND is a tominersen OLE study for patients who have completed another
Roche-Genentech-sponsored study in the tominersen GDP*
• Patients who have:
– received 120 mg tominersen Q8W in a previous study
or are currently receiving this will continue on this arm Tominersen 120 mg Q8W (n=~500)
– not previously received tominersen will be randomised (Q8W IT bolus)
to either treatment arm following a loading dose
– previously received 120 mg tominersen Q4W will be Tominersen 120 mg Q16W (n=~500)
randomised to either treatment arm
(Q16W IT bolus)
• If a single treatment regimen is selected during the Clinical
Development Programme, all GEN-EXTEND patients will
receive that regimen ~5 years
Primary outcome measures: Exploratory outcome measures: • safety and tolerability
• percentage of participants with AEs • change from baseline in: • immunogenicity
• change from baseline in: – cUHDRS, TFC, TMS, SDMT • PK/PD measures
– behavioural findings as assessed by C-SSRS SWR and CGI scores • sensor-based measures
– cognition as assessed by MoCA – plasma and CSF collected by digital
biomarkers monitoring platform
* Provided participants meet eligibility criteria, the data for tominersen support continued development and the study is approved by Authorities and Ethics
Committees/Investigational Review Boards.
AE, adverse events; C-SSRS, Columbia-Suicide Severity Rating Scale; CGI, Clinician Global Impression; CSF, cerebrospinal fluid; cUHDRS, composite Unified Huntington’s Disease
Rating Scale; GDP, Global Development Programme; HD, Huntington’s disease; IT, intrathecal; MoCA, Montreal Cognitive Assessment; OLE, open-label extension; PD, pharmacodynamic; PK,
pharmacokinetic; Q8W, every 2 months; Q16W, every 4 months; SDMT, Symbol Digital Modalities Test; SWR, Stroop Word Reading; TFC, Total Functional Capacity; TMS, Total Motor Score.
Clinicaltrials.gov/show/NCT03842969 (Accessed October 2019).
Roche slide
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgObjectives of selective mutant huntingtin
lowering approach to Huntington’s disease
Slow the progression of HD
Selectively lower mutant huntingtin protein
while potentially preserving healthy
huntingtin
Potentially enable treatment earlier in the
course of HD
Utilize antisense oligonucleotides (ASOs)
enabling reversible targeting of mHTT ASO
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgSNPs enable selective targeting of
mutant huntingtin protein
Wave’s HD approach utilizes SNPs to target mutant HTT while preserving healthy HTT
• SNPs are variations in DNA where ONE letter SNP
at a specific location is different
– Located in specific spots in our DNA—
like a pin on a map GC A ACG T T A G A
• Certain SNPs are more frequently found on SNP
the mutant HTT copy (or allele) than the
healthy copy
GC A GCG T T A G A
• The association between SNPs and mutant HTT
makes it possible to selectively target mutant HTT SNP
in order to preserve healthy HTT
GC A T CG T T A G A
*SNP: single nucleotide polymorphism
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgStereopure ASOs designed to target different
SNPs on the mHTT gene
Up to 80% of people living with HD estimated to carry SNP1, SNP2, and/or SNP3
Healthy huntingtin RNA
Mutant huntingtin RNA
WVE-120102
targets mHTT “SNP2”
WVE-120102 targets WVE-120101 targets
“SNP2” “SNP1”
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgPRECISION-HD clinical trials
Investigational assay confirms SNP is present
and located on the mutant RNA Key inclusion criteria
• Prescreened with targeted SNP on the same allele
Patient with HD consented for as the pathogenic CAG expansion
Pre-Screening
• Documented CAG triplet repeats ≥36 in the
Huntingtin gene
Blood sample • Aged 25 to 65 years
• Clinical diagnostic motor features of HD
• Early manifest HD, Stage I or Stage II based on
PCR & Sanger sequencing UHDRS Total Functional Capacity Scores ≥7 and
≤13
CAG repeats and heterozygosity No Patient not
confirmed? eligible
Yes
Confirm SNP presence on same allele No Patient not
as CAG expansion (phasing) eligible
Yes
Continue to full screening
Claassen DO, et al. Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease. Neurol Genet. 2020 May 14;6(3):e430.
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.org&
Primary endpoint
• Safety and tolerability of treatment, compared with
placebo, as assessed by
– Number (%) of patients with AEs
– Severity of AEs
– Number (%) of patients with SAEs
– Number (%) of patients who withdrew due to AEs
Secondary endpoints
• Pharmacokinetics, pharmacodynamics, Total
Functional Capacity
Exploratory endpoints
• UHDRS, behavior assessment, MRI
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgPRECISION-HD clinical trials
Two Phase 1b/2a clinical trials for investigational WVE-120101 and WVE-120102
Single Dose Washout Multidose OLE
Study Day* 1 28 56 84 112 140 196
Dose
CSF sample
• In an interim analysis† comparing all patients treated with multiple intrathecal doses (2, 4, 8, 16
mg) of WVE-120102 to placebo, a statistically significant reduction of 12.4%1 (pPRECISION-HD clinical trials and
Open Label Extension (OLE)
Multidose Cohorts
(N = 12 per cohort)
2 mg
4 mg
OLE Study:
Patients are migrated to
8 mg highest dose tested
16 mg
32 mg
• The majority of patients in the PRECISION-HD clinical trials have received multiple, monthly doses
of study drug up to and including 16 mg in the OLE
• An independent Safety Monitoring Committee (SMC) routinely reviews all safety data
PRECISION-HD results, including complete 32 mg cohorts and
available OLE data, expected in 1Q 2021
OLE: Open label extension
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgPatient data not consistent with expanded
genes being sole drivers of disease
1. Mutant Gene Dose 2. Number Of DNA 3. Somatic Instability is
Does Not Influence Repeats is Not Observed in Multiple
Disease Severity Fixed at Birth REDs
Patient A Patient B HD Patient 1 HD Patient 2
(single mutant allele) (two mutant alleles) ~13 years before ~10 years after
predicted onset disease onset DM1 SCA1 ALS
Repeat Expansion
Repeat Expansion
Expanded Expanded
DNA repeat DNA repeat
Inherited Inherited
Mutant Mutant
allele allele
Striatum Cortex Striatum Cortex Inherited Inherited
wild-type wild-type
allele allele
• Patient B does not exhibit increased • DNA repeats in the brain are significantly • Somatic tissues with disease pathology
disease severity longer than inherited repeats and not historically analyzed for expansion
continue to increase as disease
• Longer inherited allele influences progresses • Dozens of REDs may exhibit somatic
disease onset expansion
• DNA repeats expand at varying rates
across tissues
Mutant RNA & Protein Repeats Continue to Common Pathway
Are Not the Sole Expand Over the May Drive Disease in
Drivers Of Toxicity Lifetime of a Patient Multiple REDs
HD: Kennedy et al. (2003); Telenius et al. (1994); Cubo et al. (2019); DM1: Cumming et al. (2019); SCA1: Zühlke et al. (1997); ALS: Buchman et al. (2013)
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgSomatic expansion of the mHTT gene in
the brain associated with age at onset
• Same inherited repeat length but different age at Post-mortem brain analysis shows
onset somatic expansion of the mutant HTT gene
• Later onset associated with less somatic expansion before predicted age of onset
Increasing somatic expansion
• CAG 47 / 18
Grey bars: Unchanged 13 years before ~6 years before
alleles
• Age at onset: 25 (i.e. inherited
alleles)
Increasing somatic expansion
Red bar: All somatic
expansions
Purple bars: Somatic
expansions
beyond
specific
thresholds
Blue bars: Somatic
• CAG 47 / 19 contractions
• Age at onset: 41
Striatum Cortex Striatum Cortex
Swami et al. Human Mol Genetics 2009; Kennedy et al. Human Mol Genetics 2003
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgPatient data reveal DNA Damage Response (DDR) genes
as drivers for repeat expansion and pathology
Same Number of Inherited Repeats can Genetic Studies Point to DDR Pathway Naturally Lower Levels of DDR Protein
Yield Different Outcomes Genes as Modifiers in REDs Confer Less Severe Symptoms
FAN1
DDR Disease trajectory in patients
Age of Disease Onset
HTT
Genomic Analysis SNP Variant expression with DDR variants
Two patients born with to Explain Variance Analysis
same # of CAG repeats MLH1 MSH3 MLH3 LIG1 Expansion Age at onset Progression
is lower is higher is slower
G
~40 years difference
N/A
in disease onset
PMS1
Select DDR genes found to
impact HD age of onset − HD DM1
Genes with variants outside of orange
Number of Inherited Repeats
bands significantly impact disease onset
Difference in age of onset despite same Genetic studies in multiple REDs identified Reduced levels of select DDR modifiers
number of inherited repeats suggests select DDR genes as powerful disease can slow repeat expansion, resulting in
existence of modifiers modifiers later disease onset & slower progression
Ranen et al. (1995); Trottier et al. (1994); Vital et al. (2016); Dichotomous phenotype analysis; modified from Genetic Flower et al. (2019); Bettencourt et al. (2016)
Andrew et al. (1993) Modifiers of Huntington’s Disease Consortium (2015 & 2019)
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
Tel: +1 414-276-2145 | www.movementdisorders.org | info@movementdisorders.orgClinical development plans and key
endpoints
Triplet’s Natural History Studies will inform clinical trial
design and
examine novel outcomes to monitor disease
• DDR levels in biofluids and
progression Cognitive, motor, and
clinical measures / biomarkers
behavioral assessments
will be monitored to establish
Target Patient Segment disease trajectories
Blood and CSF
• Triplet sponsored a natural
Natural History MRI
history study to support clinical
development in DM1 (END-DM1)
Study
First-in-human trial First-in-Human trial for TTX-3360 in HD: Proof-of-Principle
Anticipated Endpoints
in HD in H2 2021 & Proof-of-Concept
Primary measure for dose escalation
• Safety and tolerability
• Triplet will leverage precedents set
• Target engagement by others in addition to new clinical
Phase 1 extension study endpoints and biomarkers that
• cUHDRS Triplet is optimizing in its natural
• HD-CAB* history study
• Patient reported outcome (FuRST)*
• Change in NfL protein level in CSF and plasma
• Change in brain region volumes (MRI)
* Developed specifically for premanifest HD with FDA input through the HD C-path consortium
International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA
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