Deep HTT Knockdown Without Clinical Proof Leaves Pivotal Leap Unfunded

Alnylam Reports Positive Phase Ib Brezosiran Data in Huntington's Disease

Alnylam Pharmaceuticals reported preliminary Phase Ib results for its investigational RNAi candidate, brezosiran (ALN-HTT02), in adults with Huntington’s disease (HD). The study, assessing single ascending intrathecal doses in 48 participants across five completed cohorts, demonstrated a dose-dependent reduction in mutant huntingtin protein levels. Patients in the highest dosage cohort achieved an average mutant protein drop of 60% to 64% from baseline at month 3, with an individual peak reduction of 83%. The therapy also showed an encouraging safety profile over monitoring periods up to 12 months, with no dose-dependent increases in ventricular brain volume, neurofilament light chain, or inflammatory markers. These findings support advancing brezosiran into a pivotal study, with plans for a placebo-controlled trial in 2027.

• Brezosiran achieved a deep and durable dose-dependent reduction in mutant huntingtin protein, with the highest dose cohort showing an average 60-64% drop from baseline at month 3 and an individual peak reduction of 83%. This key efficacy outcome was confirmed using two separate assays, indicating strong target engagement.
• The preliminary data indicated an encouraging safety profile, with no dose-dependent increases in ventricular brain volume, neurofilament light chain levels, or inflammatory markers in cerebrospinal fluid over monitoring periods up to 12 months. The longevity of the response suggests the potential for a convenient twice-yearly administration schedule in future development.
• Based on these positive Phase Ib results, Alnylam plans to advance brezosiran into a placebo-controlled pivotal study in 2027. Eligible participants from the primary phase can also join an open-label extension to assess long-term safety, sustained target engagement, and exploratory disease progression metrics with twice-yearly dosing for up to 36 months.

Addressing Key Challenges in Huntington's Disease Treatment

There is no specific treatment for Huntington's disease (HD). There is currently no therapy to modify the progressive course of the disease, and symptomatic treatment options are limited.

• Symptomatic-only management with limited options: Its many symptoms of motor, psychiatric, and cognitive deterioration are managed with symptomatic relief, rehabilitation, and support. Although many pharmacotherapies have been evaluated targeting dopamine, glutamate and GABA, few well conducted trials for symptomatic or neuroprotective interventions have yielded positive results, with a rate of success of only 3.5% approved molecules used as symptomatic treatment. Few treatment options are available for cognitive impairment in HD, which remains an important and largely unmet therapeutic need.

• Dependence on a single approved antichoreic with serious tolerability limits: The only drug approved by the US Food and Drug Administration (FDA) for the treatment of HD is an antichoreic agent, tetrabenazine, and tetrabenazine is the first drug approved by the Food and Drug Administration (FDA) for the management of HD-associated chorea. This drug is used sparingly because of uneasiness regarding its propensity to cause depression and suicidality in this population, which is already at risk for these complications. Tetrabenazine also has a black box warning for increasing the risk of depression and suicidality, and has been associated with parkinsonism, other extrapyramidal symptoms (particularly akathisia), neuroleptic malignant syndrome, sedation, drowsiness, corrected QT interval prolongation, orthostatic hypotension, and hyperprolactinemia. Clinical trials demonstrated that tetrabenazine reduces chorea, on average, by 5 units based upon the chorea score from the Unified Huntington's Disease Rating Scale, with duration of the antichorea effect reported to be approximately 5.5 hours.

• Complex pharmacology, metabolism and interactions: Tetrabenazine acts by depletion of the monoamines serotonin, norepinephrine, and dopamine in the central nervous system (CNS) by reversibly inhibiting vesicle monoamine transporter type 2 and thus preventing monoamine uptake into presynaptic neurons. Tetrabenazine is extensively metabolized hepatically by the CYP2D6 enzyme to its primary active metabolite, alpha-dihydrotetrabenazine, with half-life of alpha-dihydrotetrabenazine is 4-8 hours. It is subject to important drug-drug interactions with inhibitors and inducers of cytochrome P450 (CYP) 2D6, reserpine, and lithium, and is one of very few drugs whose dosing is based, in part, on the results of genotyping for CYP2D6 metabolizer status.

• Blood-brain barrier delivery barrier requiring invasive approaches: siRNA does not cross the blood-brain barrier and therefore delivery to the brain is limited to direct CNS delivery. Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics, and novel drug delivery techniques have been employed to overcome the blood brain barrier. The common feature of experimental therapies including deep brain stimulation, delivery of neurotrophic factors, cell transplantation, HTT gene silencing using RNA interference or antisense oligonucleotides, and delivery of intrabodies is that they all require a neurosurgical intervention, either for implantation of an electrode or for brain delivery of molecules, viruses or cells that do not cross the blood-brain barrier upon oral or intravenous administration.

• Unresolved questions for huntingtin-lowering strategies: It is unclear if the human CNS coverage with intrathecal or intraparenchymal delivery will be sufficient for efficacy. The extent that one must lower mutant huntingtin levels for it to be therapeutic is uncertain and the extent to which CNS lowering of wild-type huntingtin is safe is unclear. Cholesterol, which does not cross the blood-brain-barrier, is locally synthesized and renewed within the brain, complicating strategies to reinstate proper balance in HD.

Brezosiran's Phase Ib: Deep Mutant Huntingtin Lowering

A randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease (ClinicalTrials.gov number, NCT02519036) evaluated HTT, also described as IONIS-HTT, an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. Patients were randomly assigned in a 3:1 ratio to receive HTT or placebo as a bolus intrathecal administration every 4 weeks for four doses, with 34 randomly assigned to receive HTT at ascending dose levels of 10 to 120 mg and 12 to receive placebo. Adverse events, all of grade 1 or 2, were reported in 98% of the patients, no serious adverse events were seen in HTT-treated patients, and there were no clinically relevant adverse changes in laboratory variables. The prespecified exploratory end point of concentration of mutant huntingtin in CSF showed a dose-dependent reduction, with mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTT 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively.

A 26-week, randomised, double-blind, placebo-controlled trial (ClinicalTrials.gov, NCT01590888) evaluated once daily PBT2 250 mg, PBT2 100 mg, or placebo in adults (≥25 years old) with early-stage to mid-stage Huntington's disease, with 109 participants randomly assigned to PBT2 250 mg (n=36), PBT2 100 mg (n=38), or placebo (n=35). For safety and tolerability, 32 (89%) individuals on PBT2 250 mg, 38 (100%) on PBT2 100 mg, and 34 (97%) on placebo completed the study, while six serious adverse events (acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease) occurred in five participants in the PBT2 250 mg group, three (fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease) occurred in two participants in the PBT2 100 mg group, and one (increasing aggression) occurred in a participant in the placebo group. For efficacy, compared with placebo, neither PBT2 100 mg (least-squares mean 0·02, 95% CI -0·10 to 0·14; p=0·772) nor PBT2 250 mg (0·07, -0·05 to 0·20; p=0·240) significantly improved the main composite cognition Z score between baseline and 26 weeks, while the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group (17·65 s, 0·65-34·65; p=0·042) but not in the 100 mg group (0·79 s improvement, -15·75 to 17·32; p=0·925).

An open label extension study for up to 80 weeks assessed long-term safety and effectiveness of tetrabenazine (TBZ), which selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter, for chorea in Huntington disease in subjects who completed a 13-week, double blind protocol (Clinicaltrials.gov registration number (initial study): NCT00219804). Of the 75 participants, 45 subjects completed 80 weeks, with three participants terminating due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics, and the most commonly reported AEs when mild and unrelated AEs were excluded were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Chorea assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale had significantly improved from baseline at week 80 with a mean reduction in the TMC score of 4.6 (SD 5.5) units, at a mean dosage at week 80 of 63.4 mg (range 12.5-175 mg), while parkinsonism and dysarthria scores were significantly increased at week 80 compared to baseline.

Paving the Way for Durable, Less Frequent Dosing

Long-term tetrabenazine data show sustained chorea suppression with substantial discontinuation. In the open-label continuation study, of 75 participants, 45 subjects completed 80 weeks, with chorea significantly improved from baseline at week 80 with a mean reduction in the Total Maximal Chorea (TMC) score of 4.6 (SD 5.5) units on a mean dosage at week 80 of 63.4 mg (range 12.5-175 mg). When mild and unrelated adverse events were excluded, the most commonly reported adverse events (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9), and parkinsonism and dysarthria [corrected] scores were significantly increased at week 80 compared to baseline. In real-world claims, 1644 patients met selection criteria (mean age ± standard deviation: 54.5 ± 15.5), of which 151 (9.2%) were treated with tetrabenazine, with average (median) daily dose of 45.5 (42.3) mg/day, and a total of 41.8% (59/141) who initiated tetrabenazine experienced a ≥60-day gap in therapy, with a median time to discontinuation of 293.5 days and a median time to discontinuation of 9 months. A retrospective study of 63 patients under tetrabenazine therapy for an average period of 34 months showed a stable effect on chorea, despite a slight reduction of effect over time, while in the one-year French randomized multicenter study (Neuro-HD) enrolling 179 patients, Independence Scale declined similarly across all treatment arms from baseline to week 52, chorea improved significantly with both tetrabenazine and olanzapine, whereas rigidity increased only with olanzapine, irritability improved with olanzapine and tiapride, and the total behavioral score improved only with olanzapine.

Long-term deutetrabenazine exposure demonstrated durable chorea control with stable dosing. Of 119 patients (Rollover, n = 82; Switch, n = 37), 100 (84%) completed ≥ 1 year of treatment, with end-of-study exposure-adjusted incidence rates for adverse events in Rollover and Switch, respectively, of: any, 2.57 and 4.02; serious, 0.11 and 0.14; leading to dose suspension, 0.05 and 0.04. Common adverse events (≥ 4% either cohort) included somnolence (Rollover, 20%; Switch, 30%), depression (32%; 22%), anxiety (27%; 35%), insomnia (23%; 16%), and akathisia (6%; 11%), with suicidality (9%; 5%) and parkinsonism (4%; 8%). Mean dose at week 8 was 38.1 mg (Rollover) and 36.5 mg (Switch), mean dose across cohorts after titration was 37.6 mg, and at the final visit mean dose across cohorts was 45.7 mg. Patients showed minimal change in the Unified Huntington's Disease Rating Scale total maximal chorea scores with stable dosing from weeks 8-145 or at the end of treatment, but total motor score increased versus week 8 (mean change [standard deviation]: 8.2 [11.9]), there were no unexpected adverse events upon drug withdrawal, and mean (standard deviation) total maximal chorea scores increased 4.7 (4.6) units from week 8 to 1-week follow-up. In ARC-HD, 116 of the 119 participants enrolled entered the stable-dose period, where no apparent differences were seen in exposure-adjusted incidence rates (EAIRs) when receiving deutetrabenazine dosages ≤ 48 mg/d (exposure = 177.7 person-years) compared with > 48 mg/d (exposure = 74.1 person-years), and among the subset who received dosages > 48 mg/d at least once (n = 49, 42%), comparison of ≤ 48 mg/d (exposure = 37.9 person-years) versus > 48 mg/d (74.1 person-years) showed similar results. For most participants, the lowest deutetrabenazine dosage needed to achieve a TMC response (≥ 30% improvement from baseline) was between 24 and 48 mg/d in both the rollover (n = 57, 74.0%) and switch (n = 16, 46.0%) cohorts.

Persistence, adherence, and psychiatric safety over extended follow-up further characterize durability. In claims analysis, of HD patients on deutetrabenazine, 62.5% were adherent at 6 months, with use of anticonvulsants (HR = 2.00 [95% CI = 1.03, 3.85]), lipid-lowering agents (2.22 [1.03, 4.76]), and Medicaid versus Medicare insurance (2.27 [1.03, 5.00]) predicting persistence, whereas only comorbid anxiety disorders predicted discontinuation (0.46 [0.23, 0.93]). In a dual-site cohort of 30 patients titrated to >48 mg/day (47% female, 93% White, median age 56 years), the rate of adverse events reported before and after transitioning to doses >48 mg/day was the same, psychiatric changes were less commonly reported at doses >48 mg/day but extrapyramidal symptoms were more common, median total maximum chorea score was 13 (IQR 9-19) and 13 (IQR 7-18) at baseline and follow-up, respectively, median proportion of days covered [PDC] was 0.99 (IQR 0.94-1.00), and two patients discontinued therapy due to adverse events. In a longitudinal prospective study of 1360 individuals with HD at 48 research centers, 77 individuals were on tetrabenazine at enrollment, 64 were exposed during the course, and 1219 had no exposure; the hazard ratio for depressed mood among those with prior exposure versus no exposure was 0.9 (95% CI, 0.5-1.6) and for new exposure versus no exposure was 1.2 (95% CI, 0.8-1.9), one individual (1.3%) with prior exposure, one (1.6%) with new exposure, and 35 (2.9%) with no exposure reported suicidal thoughts, with hazard ratio for suicidal ideation of 0.5 (95% CI, 0.1-3.8) for prior exposure and 0.6 (95% CI, 0.1-4.4) for new exposure, and among those with prior or new exposure no suicide attempts or suicides occurred compared with 17 suicide attempts (1.4%) and four suicides (0.3%) among those with no exposure.

RNAi in HD: A Look at the Competitive Landscape

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Brezosiran's Dual Promise: Potent HTT Reduction, Favorable Safety Profile

The recent preliminary Phase Ib results for brezosiran (ALN-HTT02) in Huntington's disease mark a significant moment for the neurodegenerative pipeline. The investigational RNAi candidate demonstrated a compelling dose-dependent reduction in mutant huntingtin protein, the genetic driver of HD, with an impressive average drop of 60% to 64% and a peak individual reduction of 83% in the highest dose cohort. This level of target engagement is a strong indicator of the therapy's potential to address the root cause of the disease.

Equally important is the encouraging safety profile observed. The absence of dose-dependent increases in ventricular brain volume, neurofilament light chain, or inflammatory markers in the cerebrospinal fluid addresses critical safety concerns that have emerged in the development of other huntingtin-lowering therapies. This favorable safety signal, combined with potent target reduction, significantly de-risks the program as it moves towards pivotal studies.

However, several considerations remain paramount. While biomarker reduction is promising, the ultimate success of brezosiran hinges on its ability to translate these biochemical changes into meaningful clinical benefits for patients, impacting motor, cognitive, and psychiatric symptoms. This clinical efficacy is yet to be demonstrated and will be the focus of the planned placebo-controlled pivotal trial in 2027. Furthermore, the long-term safety and durability of effect, particularly with chronic intrathecal administration, require continued monitoring. The invasive nature of this delivery method also presents practical challenges for patient adherence and broad accessibility, which could influence its real-world adoption. Despite these considerations, the early data position brezosiran as a leading candidate in the pursuit of effective disease-modifying treatments for Huntington's disease, offering a renewed sense of optimism for patients and clinicians alike.