Emerging Therapies to Slow the Progression of Huntington Disease

Huntington disease (HD) is a rare neurodegenerative disorder with an estimated worldwide prevalence of 2.7 per 100,000.¹ HD is associated with an expanded CAG repeat in exon 1 of the huntingtin (HTT) gene,² and the clinical presentation is complex, with variable combinations of motor and nonmotor features. Chorea is the paradigmatic motor feature, and progressive parkinsonism tends to be more significant later in adult-onset HD.² Nonmotor symptoms include cognitive decline with dementia and various behavioral changes, including apathy, depression, irritability, anxiety, obsessive/compulsive behaviors, and, more rarely, psychosis.³ Treatment options with a formal indication for HD are limited to chorea. HD remains a fatal disease with time from symptom onset to death ranging between 10 and 15 years.²

The panorama of drug development in HD is very dynamic, and multiple drug development programs are underway focused on slowing disease progression. This review covers clinical trials of potential disease-modifying therapies (DMTs) with a focus on interventions collectively known as HTT-lowering therapies. The development of an HD staging system that allows focused DMT development with immediate application in clinical research and well-defined indications for future therapies is also covered.

Mapping Natural History of HD

Comprehensive knowledge of HD natural history is based on long-term observational studies that robustly document subtle cognitive and behavioral changes and structural brain abnormalities many years before classic motor features that support a clinical diagnosis appear.^4,5 Applying knowledge of biomarkers and clinical progression markers has allowed the development of an HD staging system. In 2019, the HD Task Force of the International Parkinson’s and Movement Disorder Society proposed a 3-stage diagnostic category system consisting of presymptomatic HD, prodromal HD, and manifest HD, according to the presence and severity of motor and cognitive changes based on expert informal consensus.⁶ In 2022, the HD Integrative Staging System (HD-ISS) was proposed based on an evidence-based, data-driven process and a formal consensus methodology.⁷ The HD-ISS provides a biologic definition of HD and divides the natural history into 4 stages defined by landmark assessments (Figure). In stage 0, an HD-related genetic variant is present, but there are no clinical symptoms or other measures of HD pathophysiology present. In stage 1, there are measurable indicators of HD pathophysiology, and in stage 2, there is a detectable clinical phenotype. In stage 3, functional impairment is present. Each stage is anchored on well-defined landmark assessments with cut-off scores for clinical and/or neuroimaging markers.

Emerging HTT-Lowering DMTs for HD

In the last 3 decades, many trials aimed to document a disease-modifying effect on HD, without success.⁸ Various interventions targeted cell processes including oxidative stress, transcriptional dysregulation, mitochondrial dysfunction, and excitotoxicity.⁸ More recently, the field of HD therapeutics steered towards more disease-specific targeted approaches focused on proximal pathways in HD pathogenesis, namely, the trajectory of mutant HTT (mHTT) in human cells from the gene to a pathologically long pre-mRNA encoding the unstable mHTT protein.⁸ In the last decade, HTT biology started to shape multiple therapeutic development programs, and some are in clinical trials (Table).⁸ Broadly, HTT-lowering therapies encompass DNA-, RNA-, or protein-based interventions. DNA-based interventions to inhibit gene transcription are in preclinical stages of development. In the future, CRISPR-Cas9 gene-editing systems may be one of those DNA-based interventions. RNA-based interventions inhibit the translation of mHTT RNA into protein. Protein-based interventions aim to modulate protein homeostasis. Programs that have advanced the furthest to date for HTT lowering are RNA-based and include antisense oligonucleotides (ASOs) that bind to pre-mRNA, RNA interference (RNAi) strategies to inhibit the direct coupling of mRNA to the ribosome, and small molecule splicing modifiers that modulate the splicing process before mRNA exits the nucleus.⁹

ASO Therapies

ASOs are synthetic single-stranded oligonucleotide analogues ranging from 16 to 22 nucleotides that hybridize with complementary native RNA sequences leading to an early degradation via ribonuclease H-mediated hydrolysis.¹⁰ ASOs can be allele-specific with affinity binding to the mHTT mRNA or nonallele-specific, targeting both HTT mRNA species. ASOs were the first HTT-lowering therapies to enter a clinical development phase.

Tominersen. The nonallele-specific ASO tominersen, was the first ASO for HD tested in humans and was reported to provide a persistent dose-dependent (10-20 mg tominersen) mean 40% reduction in mHTT cerebrospinal fluid (CSF) levels in people with early manifest HD. In a subsequent confirmatory phase 3 trial, over 800 participants with early manifest HD were assigned to receive 120 mg tominersen every 8 or 16 weeks or placebo. This trial was stopped prematurely owing to increased progression as assessed by the composite Unified Huntington’s Disease Rating Scale (cUHDRS) and total functional capacity (TFC) scores of the UHDRS in the group receiving 120 mg tominersen every 8 weeks compared with those receiving tominersin every 16 weeks or placebo. Recently, the study sponsor announced a new phase 2 study based on an unplanned post hoc subgroup analysis that was motivated by statistically insignificant favorable primary and secondary outcomes in a group of participants under age 48, who had lower CAG-age-product (CAP) scores at enrollment and received 120 mg tominersen every 16 weeks.¹¹

Allele-specific ASOs. There were 2 allele-specific ASOs evaluated in 2 proof-of-concept phase 1b/2a clinical trials using single and multiple ascending doses, but as reported in a press release from the sponsor, median reductions of CSF mHTT across all intervention arms were not different from placebo,¹² and development was discontinued. Allele-specificity is obtained by targeting individual single nucleotide polymorphisms (SNPs) that are found in some HTT gene carriers.¹³ For example, it is estimated that approximately two-thirds of people with HD were eligible to participate in the trials of allele-specific ASOs described, based on the presence of SNP1 or SNP2.¹⁴ A third allele-specific ASO has been developed based on a third SNP that may be found in 40% of people with HD¹⁵ and is being evaluated in the SELECT-HD^a phase 1b/2a clinical trial. This third allele-specific ASO has a newly developed phosphoryl-guanidine-containing backbone reported to be more stable and durable,¹⁵ which—in preclinical studies—reduced mHTT in mice models of HD by 50% but did not affect mHTT levels in mice that were wild-type for HTT.¹⁵ These preclinical studies represent a more complete assessment than was done for the first 2 allele-specific ASOs because for those, target engagement data was obtained exclusively from in-vitro assays. The SELECT-HD trial uses an adaptive design that allows dose and frequency of administration changes driven by data collected in single-dose cohorts of a multiple ascending-dose protocol with multiple dosing cohorts to follow. The main outcomes being evaluated are safety and pharmacokinetics. If target engagement is documented successfully, there will likely be better insight into the relevance of allele-specificity for HTT-lowering strategies.¹⁵

The studies described are landmarks for HTT-lowering therapies and have raised questions that must be addressed for any drug development program in this area. Allele specificity or lack thereof, possible off-target effects, and proinflammatory activity of compounds can be a source of safety issues and potentially jeopardize a program. Finally, the route of administration may determine the outcome. For example, animal studies have suggested that the intrathecal administration of tominersen was associated with an approximate 50% reduction of mHTT in the cortex and about 15% to 20% in the caudate nucleus,¹⁶ which may lead to regional differences in therapeutic benefit or harm. It is conceivable that a greater rescue of cortical function from neurodegeneration may lead to a different HD phenotype, with more motor symptoms and fewer behavioral/cognitive symptoms.¹⁷ In addition, the repeated intrathecal administration of ASOs may raise logistic issues for clinical use. Peptide conjugates of ASOs are being evaluated for potentially more convenient intravenous administration and possibly a wider CNS distribution.¹⁸

RNA Interference Therapies

Small noncoding RNAs promote mRNA degradation at the level of spliced mRNA, which leads to translational suppression and reduced levels of the coded protein. RNAi strategies include small-interfering RNA (siRNA), short-hairpin RNA (shRNA), and cloned artificial microRNA (miRNA).¹⁹ RNAi strategies require more invasive administration owing to reduced CNS permeability and cell transduction.

Nonallele-specific miRNA. A nonallele-specific miRNA coupled to an adeno-associated viral 5 (AAV5) vector is being tested in the HD-Gene TRX1^b phase 1a/2 randomized, sham-controlled trial in early HD, with low-dose (6x10¹² vector genomes; n=12) and high-dose (6x10¹³ vector genomes; n=14) intervention arms. Administration of the nonallele-specific miRNA is achieved with an MRI-guided convection-enhanced delivery system for a single bilateral caudate and putaminal intracranial administration. HD-Gene TRX1 is a 5-year study, with an initial 18-month blinded period followed by an open-label extension to assess safety and efficacy signals through clinical and laboratory biomarkers and imaging outcomes. The potential advantages of miRNA therapy are 1-time treatment and direct targeting of core brain structures involved in HD. Safety concerns regarding an irreversible intervention associated with long-term mHTT silencing and possible off-target effects remain, however. In addition, the potential limited effect, owing to inability to target other brain regions (eg, cortex) affected by HD neurodegeneration may influence outcomes. A press release from the study sponsor announced complete enrollment (n=26) as of July 2022 and provided data from 12-month follow-up visits suggesting no safety concerns and robust target engagement with a mean reduction of 53.8% of CSF mHTT in 4 of 6 participants who received the lower dose vs a 16.8% reduction in those who received sham treatment.²⁰ Dosing of the high-dose treatment arm, however, was discontinued (as announced in an August press release)²¹ because 3 of 14 participants had suspected unexpected serious adverse reactions. Further analysis including data from longer follow-up periods is expected to aid understanding of the temporal evolution of these outcomes. The complementary open-label phase 1b/2 HD-Gene TRX2^c trial in 15 participants is ongoing in Europe to explore safety, tolerability, and efficacy.

Nonallele-specific RNAi. In a preclinical trial in nonhuman primates, an nonallele-specific RNAi coupled to the AAV1 vector resulted in a dose-dependent, robust, and durable suppression of HTT mRNA and protein after MRI-guided delivery.²² A phase 1/2 clinical trial^d was suspended before recruitment started, and the program is searching for a novel vector that may enable intravenous administration with a proprietary screening platform. Preclinical data from other programs show the promise of intravenous administration of RNAi utilizing an mHTT-specific RNAi-AAV9 system able to reduce mHTT expression in multiple brain regions and peripheral tissues.²²

Small Molecules Targeting RNA

Splicing modifiers promote inclusion of a pseudoexon containing a premature stop codon that leads to earlier metabolism of HTT mRNA. Splicing modifiers are small molecules with the attractive characteristic of oral bioavailability owing to the ability to cross the blood-brain barrier without significant efflux. An oral DMT for HD would be a very convenient and attractive scenario in the future. In addition, systemic exposure with an orally administered drug could address regional asymmetric target engagement in specific brain regions seen with other mHTT lowering therapies, which may have importance for a disease-modifying effect. Peripheral effects, however, may raise safety concerns. There are 2 clinical trials ongoing for splicing modifiers developed by independent programs (Table).

Branaplam is an oral liquid initially studied for spinal muscular atrophy type 1 and repurposed for HD after observation of an off-target effect on the HTT gene. An initial phase 1 study in adults informed the branaplam dose range (56-154 mg) and weekly administration in the phase 2b double-blind, placebo-controlled, dose-finding Vibrant-HD trial^e to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in early HD. In August 2022, the sponsor of Vibrant-HD announced drug administration was paused because of safety concerns related to development of peripheral neuropathy.²³

PTC518-HD is a splicing modifier specifically developed for HD. In a phase 1 multiple ascending-dose trial in healthy volunteers, PTC518-HD demonstrated safety and tolerability. There was also a 40% to 60% dose-dependent lowering of HTT mRNA with a multiple dosing regimen (15-30 mg) that was reversible after drug discontinuation. A reduction in HTT protein levels paralleled the reduction in mRNA. The phase 2a placebo-controlled Pivot-HD trial^f to evaluate the safety and pharmacodynamic effects of PTC518 is underway. A range reduction of mHTT between 30% and 50% was defined as a proof-of-concept benchmark; the dose required to reach this will determine use of 5 or 10 mg/day or higher doses. Participants will be followed for 1 year using safety, pharmacokinetic, imaging, laboratory biomarkers and exploratory clinical outcomes.²⁴ Of note, Pivot-HD is recruiting participants who are HTT-gene carriers with normal function (HD-ISS stage 2) using an enrichment strategy for a time closer to phenoconversion based on the HD prognostic index score (PINHD).²⁵

DMTs Targeting Neurodegeneration and Neuroinflammation

Another approach to disease-modification in HD is targeting gene modifiers (eg, mismatch repair genes associated with CAG repeat expansion in somatic cells) that affect gene expression over the lifespan of people who are HTT-gene carriers. These changes in gene expression, or somatic instability, may lead to different disease trajectories (phenotypes) for individuals with the same genetic test result (genotype). The 2-year observational SHIELD-HD^g study is evaluating how expression of DNA damage-repair gene expression relates to clinical and biomarker-related (eg, neurofilament light [NfL]) outcomes in HD to prepare for future clinical trials. A new ASO targets the mismatch repair gene MSH3, which is associated with worsening motor and cognitive outcomes and is presently being considered for a clinical trial in HD.^26,27

Other programs for potential DMTs for HD exist, including immunomodulatory compounds.⁸ Pepinemab is a monoclonal antibody to semaphorin 4D (SEMA4D) that did not improve cognition or other clinical outcomes (eg, UHDRS-TFC, UHDRS-TMS, and Q-motor scores) in late prodromal and early manifest HD. Favorable imaging outcomes (eg, volumetric brain MRI)²⁸ in early manifest HD, however, may lead to a new trial.

An icompound that blocks complement C1q, the initiating molecule of the classical complement pathway is also being evaluated, and a press release²⁹ from the sponsor recently announced target engagement was seen and clinical progression halted, as measured with the cUHDRS and TFC over a 9-month period in a phase 2 multicenter, open-label clinical trial.^h Although this announcement is encouraging, these preliminary results of a small open-label noncontrolled study warrant replication in a larger, placebo-controlled, blinded study.

Concluding Remarks

The field of HD therapeutics is experiencing a new phase with experimental therapies targeting the pathogenic mHTT protein to slow disease progression. The first results of human clinical trials have been disappointingly negative but carry forward knowledge to present and future clinical trials of other HTT-lowering therapies. The development of evidence-based staging systems such as the HD-ISS set the stage for recruiting prodromal HD subjects. In this setting, more robust biomarkers and more sensitive clinical scales are a priority.