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Accelerating Therapeutic Development for Huntington's Disease

2021 Conference

CHDI’s 16th Annual HD Therapeutics Conference was a virtual event that took place online April 27-29, 2021. This unique conference series focuses on drug discovery and development for Huntington’s disease, and draws participants and speakers from the biotech and pharmaceutical sectors as well as academia and research institutions. The conference is intended as a forum where all participants can share ideas, learn about new disciplines, network with colleagues and build new collaborative partnerships. We are indebted to all of the conference speakers, and especially grateful to those who are able to make their presentations available here for a wider audience.

A Ph1b/2a study of WVE-003, an investigational allele-selective, mHTT–lowering oligonucleotide for the treatment of early manifest Huntington’s disease, and review of PRECISION-HD results

Vissia Viglietta, MD, PhD, Wave Life Sciences

In July 2017, Wave Life Sciences initiated two Phase 1b/2a clinical trials (PRECISION-HD1 and PRECISION-HD2) of investigational stereopure oligonucleotides, WVE-120101 and WVE-120102, in patients with early manifest Huntington’s disease (HD). WVE-120101 and WVE-120102 target single nucleotide polymorphisms (SNPs) rs362307 (SNP1) and rs362331 (SNP2), respectively, that are associated with the mutant allele of the huntingtin gene (mHTT).

We will review results from these studies, which were designed to assess the safety and tolerability of single-ascending and multiple doses of WVE-120101 and WVE-120102, administered once monthly intrathecally (IT) by lumbar puncture, compared with placebo. We will also report results from available secondary and exploratory measures including biomarkers [e.g., mHTT and wild-type HTT (wtHTT) protein in CSF] and clinical effects. The PRECISION-HD trial results do not support further development of either WVE-120101 or WVE-120102.

Since the initiation of the PRECISION-HD trials, Wave has advanced new chemistries that have been shown to improve the pharmacological properties of oligonucleotides in preclinical studies. WVE-003, an investigational oligonucleotide that incorporates this new chemistry, has been developed to target SNP3, which is associated with mHTT. Wave is initiating an adaptive single- (SAD) and multiple-ascending dose (MAD) study to assess the safety and tolerability of WVE-003 in patients with early manifest HD. This phase 1b/2a study will also assess biomarkers for target engagement (mHTT and wtHTT in CSF) and neurodegeneration (neurofilament light chain), as well as clinical outcomes. The trial is designed to be adaptive, so that pharmacologic, safety and tolerability results from each cohort will inform the dosing strategy for subsequent cohorts in the SAD and MAD phases of the trial. The initial dose for this trial was informed by numerous preclinical studies in mice and non-human primates and is predicted to be pharmacologically active. This first-in-human study is designed to provide proof of concept of the safety, tolerability and pharmacodynamic effects of WVE-003 in early manifest HD.

This study was sponsored by Wave Life Sciences.

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Preliminary results from GENERATION HD1, a Phase III trial of tominersen in individuals with manifest Huntington’s disease

Scott A Schobel, F. Hoffmann-La Roche Ltd

Tominersen, an antisense oligonucleotide targeting huntingtin (HTT) mRNA, is the first investigational treatment to show a dose-dependent, reversible lowering of cerebrospinal fluid mutant HTT protein. Following a first-in-human, Phase I/IIa study (NCT02519036) in patients with early manifest Huntington’s disease (HD), tominersen is under investigation in a global Clinical Development Programme, including the ongoing Phase III study GENERATION HD1 (NCT03761849) in individuals with manifest HD.

On 22 March 2021, Roche announced the decision to discontinue dosing in GENERATION HD1, based on a recommendation from the independent data monitoring committee (iDMC). The iDMC made its recommendation based on the investigational therapy’s potential benefit–risk profile for study participants. No new or emerging safety signals were identified for tominersen in the review of the data from this study. Importantly, the iDMC recommended to continue the study to follow participants for safety and clinical outcomes, which will help significantly advance the understanding of tominersen and to inform research for other HTT-lowering therapies.

Here, we report preliminary results of GENERATION HD1 that led to the iDMC recommendation. Once full data from the study are available and analysed, Roche will share learnings and future plans with the HD community.

GENERATION HD1 is the largest Phase III clinical trial to date of an HTT-lowering investigational therapy for the treatment of HD. The data generated across all tominersen studies will significantly advance our understanding of HTT lowering as a potential treatment approach.

We would like to thank all of the individuals and families participating in the study for their contribution, as well as the broader HD community for their commitment and collaboration.

GENERATION HD1 is sponsored by F. Hoffmann-La Roche Ltd.

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The case for continued human genetic analysis

James Gusella, PhD, Massachusetts General Hospital/Harvard Medical School

Discovery of an expanded, unstable CAG repeat as the cause of Huntington’s disease (HD) refocused the quest for understanding pathogenesis and developing treatments on the polyglutamine in huntingtin and genetically-engineered animal models, but genetic analysis of human HD has continued to inform both of these goals. It has established that HD shows true phenotypic dominance (i.e., no impact of a shorter normal or expanded allele on onset), arguing against continuous dose-dependent neuronal toxicity. Aided by the thousands of participants in large natural history studies, five genome-wide association studies (GWAS) from the Genetic Modifiers of HD Consortium (GeM-HD) have revealed that a property of the uninterrupted CAG repeat, not the polyglutamine segment, determines the timing of onset and have identified multiple HD modifiers, many affecting the sequence or regulation of genes involved in DNA repair and associated with instability of long DNA repeats. These modifiers provide new inhuman validated targets for therapeutic intervention to delay or prevent HD onset. Together, the human genetic findings indicate that HD pathogenesis involves two sequential components: 1) somatic expansion of the inherited expanded HTT CAG repeat in vulnerable cells proceeds at a rate influenced by the DNA maintenance gene modifiers and 2) when a critical threshold CAG repeat length is reached, an as yet uncertain toxicity mechanism is triggered, causing damage, dysfunction and ultimately cell death. Recently, GWAS has been extended to other disease landmarks and phenotypes, revealing that these can provide increased power and discriminate between modifier alleles, pointing to differential effects of particular modifier haplotypes in different cell types. GeM-HD is currently analyzing a sixth GWAS that will greatly increase the overall sample size and further increase power, with the expectation that new modifiers of both components of HD will emerge as additional therapeutic targets and eventually contribute to more precise assessment of clinical trial outcomes.

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Dissecting genetic modifiers of HD: towards understanding mechanism

Vanessa Wheeler, PhD, Massachusetts General Hospital/Harvard Medical School

Genome-wide association studies (GWAS) in Huntington’s disease (HD) individuals support a twostep model of HD pathogenesis in which (1) the timing of phenotypic onset is determined by the rate of somatic CAG expansion, and (2) somatically expanded repeats trigger a toxic process(es) in vulnerable cells, resulting ultimately in clinical disease. To test roles of candidate onset modifier genes identified in the GWAS in somatic CAG expansion we have used in vivo somatic CRISPR-Cas9 genome editing to inactivate genes in the liver of HttQ111 knock-in mice. The liver is efficiently transduced by adeno-associated virus (AAV) expressing guide RNAs targeting genes of interest, and exhibits high levels of CAG expansion, providing a sensitive readout of instability in a relatively short timeframe. Our observations provide support for the idea that some onset modifier genes are likely to alter disease via effects on somatic CAG expansion, while others are more likely to modify cellular toxicity processes. Extending this, we also tested interactions between instability modifying genes in the mismatch repair (MMR) pathway and with Fan1. The data reveal multiple genetic interactions indicating that these genes act in a common pathway to modulate repeat expansion. The data also suggest that the roles of DNA repair genes in CAG expansion may differ from those in the canonical pathways in which they are classically described. To gain insight into the contribution of a specific DNA repair gene function in CAG instability we crossed HttQ111 mice onto an “endonuclease dead” Mlh3 genetic background. This resulted in the suppression of CAG expansion, providing support for a critical role of MLH3’s endonuclease activity. Together, these genetic studies begin to unravel the pathways underlying CAG instability, prompting further dissection of mechanism particularly in the context of human modifier alleles. A comprehensive understanding of this mechanism will provide opportunities for therapeutic intervention, targeting the first step in the HD pathogenic process.

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Mechanism of FAN1 stabilisation of the HTT CAG repeat

Michael Flower, MA, MB BChir PhD, University College London

Human genetic studies have shown that, after CAG repeat length, DNA maintenance is the main process that influences disease onset and the rate of progression. It likely acts through somatic repeat expansion, a process in which the pathogenic CAG repeat expands throughout life. Those with more repeat expansion have earlier onset and faster progression. The DNA damage response genetic modifiers include the interstrand crosslink repair nuclease FAN1 and numerous mismatch repair factors, including MLH1, PMS2 and MSH3. We showed that FAN1 depletion in human cells, including patient-derived medium spiny neurons, accelerates CAG repeat expansion, demonstrating its protective repeat stabilising activity. Depletion of mismatch repair factors, including MLH1 and MSH3, prevented this expansion, showing they act downstream to promote repeat instability. Our new results elucidate FAN1’s protective function at the CAG repeat and the molecular nature of its interaction with mismatch repair. These findings open novel therapeutic opportunities for Huntington’s and related repeat expansion diseases.

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RNAi-based modulation of MSH3 blocks somatic expansion in a Huntington’s disease model

Daniel O’Reilly, PhD, University of Massachusetts Medical School

Huntington’s disease (HD) is a rare autosomal dominant genetic disease caused by the expansion of a CAG trinucleotide repeat in exon 1 of the  huntingtin gene (HTT). CAG repeat expansion results in the production of a mutant huntingtin (mHTT) protein that is prone to forming aggregates or “inclusions” in the nucleus and cytoplasm of neurons. mHTT inclusions cause neurodegeneration throughout the brain, particularly the striatum, leading to cognitive loss, mood swings, and chorea in patients. CAG repeat length is strongly associated with age of HD onset – individuals with 30-60 CAG repeats will experience later onset (30-40 years old), whereas those with >70 CAG repeats will have juvenile onset. Moreover, the CAG repeat expansion, which is somatically unstable, undergoes length increases over time. For adult-onset HD, somatic expansion is required for disease progression. Identifying factors underlying the link between repeat expansion and HD progression may open new avenues for HD treatment. Transcriptome wide association studies have already identified potential modifiers of somatic expansion and HD progression, one of which is MSH3. MSH3 has the potential to be a new therapeutic target for treating HD as genetic knockout of MSH3 has been shown to block somatic expansion and it is not associated with any brain cancers.

The Khvorova lab has recently published their di-valent siRNA architecture which has enhanced delivery to the brain and CNS. They have shown that this architecture potently silences mHTT up to six months in mice brains. This work, will develop potent siRNA for targeting MSH3. We will then apply our labs di-valent architecture and show that in the Q111 mouse model, we have 90% silencing of the Msh3 protein. We will also show how this silencing results in complete blockage of somatic expansion. Our work will highlight silencing of MSH3, with clinical grade siRNA, could be another paradigm for treating HD.

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Development of TTX-3360 to treat/prevent HD and other repeat expansion disorders by halting somatic expansion

Irina Antonijevic, MD, PhD, Triplet Therapeutics, Inc.

DNA damage response (DDR) genes are potent modifiers of onset and severity of diseases caused by expansion of short DNA repeats (i.e. repeat expansion disorders, REDs), including Huntington’s disease (HD), myotonic dystrophy, and spinocerebellar ataxias. DDR genes act via modulation of somatic repeat expansion at disease causing loci (e.g. HTT, DMPK, ATXN1/2/3/7). Triplet is developing ASOs and siRNAs to knockdown (KD) specific DDR genes selected for somatic instability phenotypes and loss of function tolerance. This approach operates upstream of respective disease genes and addresses a fundamental unifying pathway driving multiple REDs. Data by Triplet and others have shown that lowering expression of certain DDR genes by about 50% halts repeat expansion over time in both HD patient-derived cell lines and HD model mice. Based on safety and KD efficacy (e.g. selectivity, distribution, durability) assessed in silico, in vitro and in vivo in rodents and non-human-primates (NHPs), TTX-3360, an ASO, was selected as Triplet’s first clinical candidate. Single and repeat doses, at different dose levels, of TTX-3360 administered via multiple routes to NHPs were well tolerated and drove significant target KD. Specifically, a single injection of TTX-3360 at a well-tolerated dose level in NHPs lowered target mRNA by >50% in HD-relevant brain regions such as caudate and putamen. IND-enabling studies with TTX-3360 are underway to support initiation of the Phase 1/2a trial in HD in the 2nd half of 2021.

To inform its Phase 1/2a, Triplet is conducting SHIELD HD, a multinational natural history study in premanifest and early manifest HD patients, to assess DDR gene expression, somatic expansion, and various outcomes of disease progression over time. SHIELD HD completed enrollment ahead of schedule in 2020 and interim data will inform the Phase 1/2a design. Dose escalation data from this trial will support initiation of trials with TTX-3360 in other CNS REDs, seeking to stop disease manifestation and progression by halting somatic DNA repeat expansion in multiple indications.

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Restoring autophagy, reversing disease

Peter Hamley, PhD, Samsara Therapeutics Inc.

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Small molecules that lower mutant huntingtin

Beth J. Hoffman, PhD, Origami Therapeutics, Inc.

The CAG repeat expansion in the HTT gene results in an expanded stretch of glutamines in the huntingtin protein (HTT). Observations of mHTT aggregation in human HD post-mortem brains suggest that mutant HTT (mHTT) has a protein folding defect. Cryo-electron microscopy studies demonstrate that wildtype (WT) HTT and mHTT have distinctly different shapes. N-terminal exon 1 structure is dynamic with mHTT showing greater conformational variety than WT HTT. This may explain why mHTT is more likely to undergo proteolysis to generate toxic fragments compared to the WT HTT protein. Decreases in mHTT protein by multiple modalities leads to reversal of disease in various animal models of HD. If toxic mHTT can be safely reduced or eliminated in patients, this approach holds promise as a disease-modifying treatment for HD. Origami Therapeutics, Inc. proposes to treat HD using small molecules to lower mHTT through degradation of toxic mHTT protein. The ideal treatment would selectively reduce the misfolded toxic mHTT protein while maximizing the residual total HTT function. This should maintain normal cellular function and physiology, increasing the potential to treat early in disease, before symptoms appear. Origami designed and verified a high content cell-based screening assay, using mHTT aggregation as a surrogate for protein misfolding, that is differentiated from others in the literature. From a library of 91,000 compounds, 73 structural clusters were initially identified. Hit expansion revealed 60 structural clusters with emerging SAR. Compounds that lower mHTT protein levels are being tested for their ability to suppress mHTT toxicity in HD patient iPSC-derived medium spiny neurons (MSNs). A panel of measures that are significantly different between WT and HD MSNs have been identified. Multiple compounds have demonstrated suppression of mHTT toxicity in HD MSNs. These data suggest that we have identified multiple chemical scaffolds with potential to suppress mHTT toxicity by lowering mHTT levels. Further plans to select and optimize lead series will be discussed.

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Glial replacement as a treatment strategy in Huntington disease

Steve Goldman, MD, PhD, University of Copenhagen/University of Rochester

Huntington’s disease (HD) involves cell-intrinsic glial as well as neuronal dysfunction. By generating glial chimeric mice using glial progenitor cells (hGPCs) derived from either fetal tissue or mutant HTT (mHTT)-expressing human embryonic stem cells (hESCs), we investigated the contributions of glial progenitor cells and their derived astrocytes to HD. We found that mice chimeric for mHTT glia manifested delayed motor learning and poor coordination, as well as hyperexcitable medium spiny striatal neurons. Investigating the gene expression of these cells, we noted that mHTT-expressing glial progenitors and astrocytes were deficient in their expression of a co-regulated set of K+ channels and transporters, as well as of glutamate transporters, yielding a hyperexcitable synaptic environment (PMID: 30554964). On that basis, we transplanted normal hGPCs into first neonatal, and then adult, R6/2 mice, and in each case found that striatal engraftment with wild-type human glia was sufficient to rescue aspects of both anatomic and behavioral pathology in the transplanted mice, in tandem with a rescue of striatal interstitial K+ levels (PMID: 27273432). To capitalize upon these observations, we then established GMP-compliant manufacture of hGPCs from hESCs, and verified the capability of these cells to replace diseased host cells in vivo, in both neonatal and adult R6/2 mice. Importantly, we also noted the replacement of mHTT-expressing human glia by normal human glia, in adult mice that were neonatally rendered chimeric for mHTT-expressing glia at birth, and then transplanted again as adults with normal human glia. This human-on-human transplant model provides additional evidence that the replacement of diseased glia by healthy cells may be both feasible and clinically beneficial in HD.

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From spinal muscular atrophy to Huntington’s disease therapeutics

Rajeev Sivasankaran, PhD, Novartis Institutes for Biomedical Research

Huntington’s disease (HD) is caused by the abnormal and pathogenic expansion of CAG trinucleotide in exon 1 of the HTT gene. Although multiple downstream mechanisms have been implicated in HD, approaches that lower mutant HTT transcript and protein have emerged as the most promising therapeutic strategy based, in part, on compelling pre-clinical data. To date, no disease modifying therapies are available for HD although RNA interference, gene therapy and anti-sense oligonucleotide approaches to lower HTT are currently being tested in the clinic. We will show that branaplam, an orally available small molecule splicing modulator currently in a clinical trial for spinal muscular atrophy lowers HTT levels in animals and humans. We will present in vitro and in vivo data demonstrating the lowering of mutant HTT in cells as well as in key regions of the brain and peripheral tissues in a mouse model of HD and share plans for clinical evaluation of the molecule.

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A novel mutant huntingtin imaging ligand for assessment of mHTT lowering strategies

Daniele Bertoglio, PhD, University of Antwerp

Several (m)HTT-lowering therapeutic strategies are currently being explored for the treatment of Huntington’s disease (HD). In this context, measuring mHTT levels is a primary need to assess the extent of mHTT lowering and the efficacy of these therapies. Recent clinical studies have quantified mHTT in cerebrospinal fluid (CSF) and observed a reduction of its levels following administration of HTT-lowering antisense oligonucleotide (ASO). However, the indirect nature of the CSF readout and the presence of mHTT in the spinal cord limit the reliability of this approach. Targeting mHTT with a non-invasive imaging tool has the potential to better evaluate at the cerebral level the pharmacological effects of drugs lowering mHTT. Using the novel clinical candidate mHTT radioligand [11C]CHDI-180R and positron emission tomography (PET) imaging, we imaged and quantified mHTT accumulation in rodent models of HD. Next, we assessed whether this imaging tool could be employed to evaluate regional mHTT-lowering therapeutic effects. Specifically, we exploited a virally expressed zinc-finger transcription factor repressor to achieve local and extensive mHTT reduction as well as an inducible HD mouse model characterized by systemic but moderate mHTT suppression. Additionally, we investigated the relevance of time of intervention as well as the extent of mHTT lowering required to achieve a significant reduction in mHTT cerebral levels as well as preservation of striatal markers in preclinical models of HD.

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Clinical development of novel PET radioligands for quantification of aggregated mutant huntingtin

Andrew Wood, PhD, CHDI

ImagemHTT is a FIH adaptive PET imaging study that is exploring the binding and kinetic properties of novel PET radioligands for mutant huntingtin. Presently, there is no way to measure the mutant form of huntingtin protein in the brain, thus development of a radioligand with ability to reliably detect mutant huntingtin would be a significant advance in the field of Huntington’s disease research. The PET radioligands that are being used in the imagemHTT study have been shown to detect the mutant form, but not the normal form of huntingtin protein in HD mouse models and have been tested for safety in animals. This study will be the first time these PET radioligands are used for mutant huntingtin imaging in humans. The study will consist of two phases; Phase 1 will determine if the radioligands have suitable properties for PET imaging in humans and will detect mutant huntingtin in the brain by evaluating binding and kinetics in young control and in Stage 2 HD participants. Phase 2 will focus on quantification of mutant huntingtin and test-retest variability of the radioligands in Pre-manifest, Stage 1 and Stage 2 HD participants compared to age matched control participants. The talk will describe progress of the imagemHTT study and introduce a series of backup candidates seeking to develop improved properties and characteristics suitable for adoption in multisite clinical studies. The results of this study may lead to the development of a PET radioligand to quantify mutant huntingtin protein in the brain of HD patients providing an avenue to follow and track the progression of HD and to support biomarker development for a mutant huntingtin lowering therapeutic.

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Assessment of translational biomarkers in a rhesus macaque model of HD

Jodi McBride, PhD, Oregon National Primate Research Center / Oregon Health & Science University

Our laboratory has created a novel adeno-associated viral vector (AAV)-mediated macaque model of Huntington’s disease (HD). Delivery of AAV2.retro expressing the N171 fragment of human mutant HTT bearing 85 CAG repeats (N171-HTT85Q) to the adult macaque caudate and putamen results in widespread expression of soluble and aggregated mHTT throughout the cortico-basal ganglia circuit, including brain regions that comprise cognitive, motor and limbic circuitry (Weiss et al, 2020). This talk will focus on our efforts over the past 24 months to identify translational biomarkers of disease progression in this new model using a variety of motor and cognitive behavioral assays as well as multimodal imaging including MRI, DTI and PET. In addition, analysis of biofluid biomarker candidates from cerebral spinal fluid and plasma collected longitudinally from this same cohort of animals is ongoing.

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Innovative MRI technologies in the context of HD progression and biomarker development

Derek Jones, PhD, Cardiff University

In this presentation, I will address the question “Where are we now, and where might we be going with advanced MRI techniques to understand and monitor disease progression?”. I will focus on the characterisation of brain macrostructure (measuring tissue on the length scale of mm) and microstructure (measuring on the length scale of mm).

In addition to Huntington’s disease, I will draw on examples from neurodevelopment and other diseases to demonstrate the shortcomings of current widely used approaches (brain volumetrics and diffusion tensor MRI) for understanding tissue change in the brain. This includes highlighting the problem of ‘degeneracy’ in the signals which is when two or more completed different changes in tissue can give rise to exactly the same change in commonly used neuroimaging metrics. I will then highlight promising new and emerging quantitative imaging techniques that have yet to be widely deployed in HD research, and which may well hold promise for a deeper in vivo microstructural phenotype of the brain. I will try and highlight their sensitivity and specificity to the subcomponent they purport to measure. Many of these will be used in the forthcoming CHDI ImageClarity project.

Some additional approaches require advanced MR hardware, such as ultra-strong magnetic field gradients and/or ultra-high field, which are not currently widely available, but I predict that they will be in the near future. I will argue for their utility in isolating distinct changes in the brain tissue sub-compartments (myelin, axon density/diameter, soma density/diameter), but also in their combination for sensitive triangulation of tissue change in neurodegenerative diseases.

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Identification of protein changes in cerebrospinal fluid from patients with Huntington’s disease

Niels Skotte, PhD, University of Copenhagen

The overall goal is to identify proteins that may track disease progression in Huntington’s disease patients to help facilitate the development and evaluation of potential therapies.

We have analyzed 120 cerebrospinal fluid (CSF) samples from 27 healthy individuals, 39 premanifest and 55 manifest HD gene-expansion carriers using unbiased state-of the art mass spectrometry (Thermo Scientific Orbitrap Exploris Mass Spectrometers connected to the EASY-nLC 1200 System). MS raw data was analysed in Spectronaut software (Biognosis) and transferred to our in-house software ‘Clinical Knowledge Graph’ for data processing, analysis, and visualization.

In CSF, we found 282 significant protein changes with 64, 145, and 73 protein changes between control and premotor, control and motor, and premotor and control, respectively. Several proteins previously observed altered in HD including NEFL, BDNF, PENK, and YKL-40 demonstrated correlation with disease progression, confirming our experimental approach.

In conclusion, we have identified several new biomarker candidates that require further exploration and validation.

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The new Huntington’s disease Integrated Staging System (HD-ISS)

Sarah Tabrizi, MD, FRCP, PhD, University College London
Jeffrey D Long, PhD, University of Iowa

Objective: To propose a new HD framework, referred to as the HD-ISS, that comprises an HD biological research definition and evidence-based staging centered on prognostic biological, clinical, and functional landmarks.

Background: HD is an inherited autosomal dominant neurodegenerative disease. While there is biological certainty that individuals with a pathogenic expansion in the huntingtin gene (HTT) will develop the signs and symptoms of HD within a normal lifespan, this is not reflected in presently-used terminology. Current staging methods do not address disease progression before an overt clinical phenotype, despite wellaccepted biomarkers of neurodegeneration predating clinical diagnosis.

Methods: This framework is the result of a formal consensus process by the HDRSC’s Regulatory Science Forum (RSF), a working group of expert representatives from industry and academia. The RSF considered biomarkers as well as signs and symptoms of the disease to formulate the HD-ISS. Observational data was employed to calculate “cut-offs” using the extreme values in models of the control population to define the HD-ISS Stages and to evaluate the framework.

Results: The HD-ISS characterizes individuals from birth and allows for common terminology to enable cohesive clinical research and the development of interventional studies on the early phases of HD. The HD-ISS incorporates landmarks demonstrating robust prognostic value to classify individuals into each Stage and data-driven landmark thresholds to define Stage boundaries that are not CAG-dependent. Individual study visits, participant Stage progression, and longitudinal models of Stage progression align with the natural history of HD and with increased CAG predicting accelerated transitions.

Conclusions: The RSF has developed a biological definition of HD and an evidencebased staging system that encompass the full course of the disease and are unconstrained by concepts such as “manifest,” “pre-manifest,” or “prodromal.” The HD-ISS is primarily intended for research settings and provides a new structure to anchor and harmonize clinical study populations and will facilitate assessment of interventions that prevent or delay the onset of HD symptoms. The immediate research use of the HD-ISS will allow for further validation. We hope that the HD-ISS will enable the HD community to work together to change the future of HD.

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HD-GeneTRX-1: A phase I/II clinical trial of CNS-administered gene therapy (AMT-130) for earlystage HD

David L. Cooper, MD, MBA, uniQure Inc.

AMT-130 is a one-time administered, investigational gene therapy comprising a recombinant adenoassociated virus serotype 5 (AAV5) vector carrying a DNA cassette encoding a microRNA targeting exon 1 of the Huntington mRNA (AAV5-miHTT) that lowers HTT protein in Huntington’s disease (HD) patients. Proof-of-concept of AMT-130 gene therapy has been demonstrated by efficacy and safety in preclinical studies with no off-target effects. The CT-AMT-130-01 (HD-GeneTRX-1) study is the first FDA-approved clinical study for gene therapy for patients with early manifest HD (NCT04120493). HD-GeneTRX-1is a Phase 1/2 double-blind, randomized, imitation-surgery (sham) controlled study conducted at ~12 centers in the US. Twenty-six planned patients will be randomized to receive AMT-130 (6×1012 [low-dose; n=6]) or 6×1013 [high-dose; n=10] genome copies/patient) by one-time intracranial injection into striatum (caudate nucleus and putamen) or to receive imitation-surgery (n=10). The first dose cohort completed enrolment in April 2021 and includes 10 patients (AMT-130, n=6; imitation surgery, n=4). The second dose cohort is ongoing and plans to include 16 patients (AMT-130, n=10; imitation surgery, n=6). The trial consists of a 12-month blinded post-treatment follow-up period followed by unblinded long-term follow-up for 5 years. Crossover will be implemented after review of preliminary data by the data safety monitoring board and the FDA. The primary objective is to demonstrate safety of AMT-130 with associated endpoints around adverse events, structural MRI, and immunological lab assays. Secondary/exploratory objectives and endpoints consider AMT-130 expression, HTT protein knockdown, and HD progression using a combination of clinical measures (UHDRS, HD-CAB, Q-Motor) bioimaging and biofluid biomarkers. The ongoing assessment of screening striatal volumes enabled evolution of the study inclusion criteria for this study, and a parallel open-label European study, CT-AMT-130-02 (HD-GeneTRX-2), being initiated in 2H2021.

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Results of phase 2 SIGNAL trial of SEMA4D blocking pepinemab antibody support a novel potential treatment for Huntington’s disease

Maurice Zauderer, PhD, Vaccinex, Inc.

SIGNAL is a completed double-blind, randomized, placebo-controlled, phase 2 study of pepinemab antibody in HD. Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons in response to stress and triggers reactive transformation of astrocytes that express its cognate plexin-B1 receptor.

Cohort B of SIGNAL enrolled 179 patients with early manifest disease (TFC 11-13, CAG repeat ≥36 (avg 43.8) and, 86 prodromal subjects (DCL 2 or 3, CAG rpeat ≥36 (avg 42.6). Co-primary endpoints included measures of cognition and Clinical Global Impression of Change (CGIC). A prespecified family of two cognitive measures, One Touch Stocking (OTS) and Paced Tapping (PTAP) was selected from the 6 HD-CAB assessments based on relative effect sizes in a small pilot study (Cohort A). Results showed a favorable trend of benefit, OTS, p=0.028 and PTAP, p=0.06 (1-sided) but missed statistical significance. In contrast, the pre-specified exploratory HD-CAB Composite score was highly significant at p=0.007. Sensitivity analysis indicated that the Composite score did not have undue dependence on a particularly favorable individual assessment. CGIC did not meet statistical significance for the total TFC 11-13 population, however, stratified post-hoc analysis of the subpopulations with TFC 11 and TFC 12-13 at baseline, indicated a stronger signal in patients with somewhat more advanced disease progression. We attribute this to the sigmoidal shape of UHDRS rating scales that change slowly at the top of their range (TFC 12-13), and then accelerate with progression (TFC ≤11).

A phase 3 trial of pepinemab in HD is warranted. Based on the phase 2 data, we favor coprimary endpoints of the full HD-CAB Composite score and CGIS enrolling patients with TFC 8-12 at baseline. The expanded TFC range may allow changes to be detected in not only CGIS but also in standard UHDRS scales, e.g. TFC and TMS. In view of the broad relevance of the pepinemab mechanism of action to other slowly progressive neurodegenerative diseases, we plan to initiate a phase 1b/2a study in Alzheimer’s disease (SIGNAL-AD) in June, 2021 (NCT04381468).

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HD drug discovery in the public domain – a model for CHDI

Aled Edwards, PhD, Structural Genomics Consortium

Drug discovery is widely considered the responsibility of the private sector, and as a result market forces often drive many of the decisions made in the discovery and development processes. Companies shy away from diseases for which they cannot generate sufficient returns. Companies keep data confidential to maintain their competitive advantages. Companies patent results to exclude others from using the invention. Companies price any successful medicine at the highest price the market will bear. In the current system, these business decisions are entirely rational. However, for many diseases, including HD, these decisions may not be in the public interest. The SGC has been pioneering a different approach. Our charity has committed to place all of our research into the public domain without restriction, including research that has direct implications for drug discovery, such as medicinal chemistry. So far, for HD, our team has developed expression constructs for HTT, purified the HTT protein to homogeneity, determined its structure at 2.6Å resolution (a resolution that can enable structure-guided drug discovery), and shared both the protein and its structure with dozens of scientists, without restriction. Our aim over the next 5 years is to launch formal HD drug discovery programs in the public domain, using an alternative business model that builds off open science, that exploits alternative legal mechanisms to protect marketing rights, and that prioritizes fair pricing for all.

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