Alnylam Pharmaceuticals (United States)

Predicting the effects of genetic variants and assessing prediction performance are key computational tasks in genomic medicine. It has been shown that well-calibrated variant effect predictors can be reliably used as evidence towards establishing pathogenicity (or benignity) of missense variants, thereby rendering these variants suitable for use in (or exclusion from) the genetic diagnosis of rare Mendelian conditions. However, most predictors have been trained or calibrated on data that may not be sufficiently representative to lead to similar performance across all genetic ancestries. This raises questions about the responsible deployment of these tools to improve human health. To better understand the utility of computational predictors, we set out to assess their ancestry-specific performance in terms of accuracy and evidence strength according to the ACMG/AMP guidelines. First, we determined that the expected count of rare variants in an individual’s genome and the allele frequency distribution of these variants are the key confounders when evaluating a predictor’s performance across different genetic ancestries. Second, we found that a predictor’s accuracy itself inversely correlates with the allele frequency of the rare variant. After stratifying according to allele frequency, we show that established methods for predicting the pathogenicity of missense variants have comparable performance levels across major ancestry groups. Our results therefore support the wide deployment of such models in the context of genetic diagnosis and related applications.

Background This study assessed the effectiveness and safety of patisiran in patients with V122I/T60A variant transthyretin (ATTRv) amyloidosis with polyneuropathy. These variants have been under-represented in previous trials of gene-silencing agents. Methods This was a multicenter, phase IV study conducted at 27 sites in the USA. Patients were ≥ 18 years, diagnosed with ATTRv amyloidosis with polyneuropathy and a documented V122I or T60A variant. Patisiran-treated patients were enrolled prospectively, ambispectively, and retrospectively. The primary endpoint was the proportion of patients with a stable or improved polyneuropathy disability (PND) score at 12 months vs. baseline. Safety was monitored throughout the trial. Results Sixty-seven patients were enrolled, of whom 58 received ≥ 1 dose of patisiran. In the efficacy population, 42/45 (93.3%) patients demonstrated stable or improved PND scores from baseline to Month 12. Patients also showed stable or improved quality of life, health status, autonomic symptoms, and cardiac function vs. baseline. Adverse events occurred in 13/42 (31.0%) patients in the prospective and ambispective cohorts; most were mild or moderate. No deaths or cardiac hospitalizations were considered related to patisiran. Conclusions Patisiran demonstrated a consistent positive effect across multiple endpoints in patients with V122I/T60A ATTRv amyloidosis, including polyneuropathy manifestations.

BackgroundSingle doses of mivelsiran, an investigational RNA interference (RNAi) therapeutic, have demonstrated robust amyloid‐beta precursor protein (APP) lowering in the CNS. We report additional interim safety and pharmacodynamic data in patients with early‐onset Alzheimer’s disease (EOAD) who received single ascending doses (SAD) and, for the first time, multiple doses of mivelsiran in the ongoing Phase 1 study (NCT05231785).MethodsPatients with EOAD (symptom onset <65 years of age, Clinical Dementia Rating global score 0.5 or 1.0, Mini‐Mental State Examination score >20) were randomized to a single intrathecal dose of mivelsiran 25–100mg or placebo for 6 months (plus up to 6 months follow‐up if needed for washout). After washout, patients could enter a separate multiple ascending dose (MAD) portion and receive open‐label mivelsiran. Presented here are data from a SAD cohort of mivelsiran 100mg and a MAD cohort of mivelsiran 50mg every 6 months (Q6M). Frequency of adverse events (AEs) and pharmacodynamics were primary and secondary endpoints, respectively.ResultsForty‐five patients were enrolled in SAD cohorts (as of 11/20/2024). Of those, 9 patients were randomized to mivelsiran 100mg or placebo (mean [SD] age, 64.1 [3.7] years; 33.3% male; 100% white). Most AEs were mild or moderate. Peak mean (SE) change from baseline in cerebrospinal fluid (CSF) soluble APP beta (sAPPβ) at Month 1 (─84.5% [1.3]) was largely sustained through Month 10 (─61.1% [2.8]).After meeting washout criteria, 10 patients from SAD cohorts received mivelsiran 50mg Q6M (mean [SD] age, 59.9 [4.4] years; 70.0% male; 70.0% white). No serious or severe AEs were reported. At Day 15 after the first dose, mean (SE) change from baseline in CSF sAPPβ was ─63.7% (5.0); at Month 1 after the second dose, change was ─83.8% (2.3). Additional data will be presented.ConclusionsIn this first report of multiple‐dose clinical data for a CNS‐targeting RNAi therapeutic, single and multiple doses of mivelsiran were generally well tolerated and continued to demonstrate robust, durable, dose‐dependent CSF sAPPβ reductions. Further sAPPβ lowering was observed after a second dose of mivelsiran 50mg. These results support further evaluation of mivelsiran in patients with Alzheimer’s disease or cerebral amyloid angiopathy.

BackgroundAmyloid‐beta precursor protein (APP) is the source of all amyloid‐beta (Aβ), the amyloidogenic peptide that aggregates in Alzheimer’s disease (AD). Lowering APP mRNA expression with RNA interference (RNAi) is a novel treatment strategy under investigation for AD. The 5xFAD mouse model of AD overexpresses APP and PSEN1 with five familial AD mutations, resulting in robust pathology, including amyloid plaques, microgliosis, inflammation, synaptic loss, neuronal loss, and behavioral changes. This work evaluates the effects of early and late intervention with an APP‐lowering small interfering RNA (siRNA) in this established AD model.MethodAPP‐targeting siRNAor artificial CSF (aCSF; control) was administered by intracerebroventricular injection in 5xFAD mice at late (8‐months‐old) and early (12‐weeks‐old) disease stages, and in age‐matched wild‐type mice. Late intervention mice received either aCSF or 300µg single dose. Early intervention mice received one of four dose regimens: control (aCSF:aCSF), transient lowering (75µg APP siRNA:aCSF), moderate sustained lowering (75µg APP siRNA:75µg APP siRNA), or robust sustained lowering (300µg APP siRNA:300µg APP siRNA). The impact of late and early siRNA intervention on molecular, biochemical, histological, and disease‐related behavioral outcomes (assessed using the elevated plus‐maze and open‐field assay) were assessed in 12‐month‐old mice (Figure 1).ResultTreatment in the late intervention group lowered amyloid burden to levels below the 8‐month baseline (Figure 2A, 2B). Compared with age‐matched aCSF mice, late treatment decreased pathogenic amyloid species, Aβ40 and Aβ42, in CSF and tissue, reduced markers of glial inflammation, and reduced plasma neurofilament light chain (NfL). No significant behavioral changes were noted (Figure 3A).Treatment in early intervention groups lowered amyloid burden in tissue (Figure 2C, 2D), reduced markers of glial inflammation, reduced plasma NfL, and decreased anxiety‐like behavior, all in a dose‐dependent manner. Notably, robust, sustained lowering of APP completely prevented the emergence of disease‐associated anxiety‐like behavior (Figure 3B).ConclusionTreatment with APP‐lowering siRNA reduced AD pathology in the 5xFAD mouse model. Early intervention with the highest dose regimen prevented the emergence of behavioral deficits and substantially improved many aspects of disease phenotype. These results support the continued development of mivelsiran, an investigational, first‐in‐class APP‐lowering RNAi therapeutic, in patients with AD (NCT05231785).

BackgroundCerebral amyloid angiopathy (CAA) is characterized by progressive cerebrovascular amyloid‐beta deposition associated with hemorrhagic and nonhemorrhagic manifestations. Evidence of prior cerebral hemorrhage and CAA can have significant implications for treatment with some approved therapies. This study sought to estimate the proportion of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who have probable CAA by systematically applying Boston Criteria version 2.0. In addition, we sought to evaluate characteristics associated with probable CAA in this population.MethodParticipants in ADNI with cognitive symptoms or deficits (at least one Clinical Dementia Rating‐Sum of Boxes [CDR‐SB] score of >0) with relevant imaging for CAA adjudication were included. 3D T1‐weighted, fluid‐attenuated inversion recovery (FLAIR) and T2* Gradient Echo magnetic resonance imaging (MRI) sequences were downloaded from the ADNI database. Blinded neuroradiologists evaluated brain MRIs to categorize participants as having no CAA, possible CAA, or probable CAA using the Boston Criteria version 2.0. A 10% sample was randomly selected to evaluate inter‐reader variability. Baseline characteristics associated with probable CAA were assessed using univariate and multiple regression analyses.Result828 participants met inclusion criteria (Figure 1): 30.8% had no CAA, 43.5% had possible CAA, and 25.7% had probable CAA. Among those with probable CAA, 46.9% had mild cognitive impairment and 44.6% had dementia; median CDR‐SB score was 3 (IQR 1‐5). Among age, sex, CDR‐SB score, apolipoprotein E4 (APOE4) homozygosity, hypertension, and antithrombotic medication use, an exploratory multiple logistic regression identified older age, higher CDR‐SB score, and APOE4 homozygosity as independently and significantly associated with probable CAA (p <0.05). High interobserver agreement was observed (inter‐reader correlation >90%). Additional results will be presented.ConclusionSystematic application of Boston Criteria version 2.0 using the ADNI database identified probable CAA in approximately 26% of participants with cognitive symptoms or deficits. Age, dementia severity, and APOE4 genotype may inform the likelihood of having CAA; however, probable CAA was identified in patients across the spectrum of cognitive impairment severity. These data underscore the value of rigorous assessment of CAA in patients with cognitive complaints broadly, and the need for research and clinical paradigms to meet the needs of such patients.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by extracellular deposition of amyloid in the heart. Vutrisiran, an RNA interference agent, rapidly suppresses hepatic production of TTR. The present analyses evaluate the impact of vutrisiran on cardiac structure, function and amyloid load measured by cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping. Purpose: To analyze the impact of vutrisiran vs placebo on cardiac structure, function and amyloid burden in HELIOS-B participants. Methods: In HELIOS-B ATTR-CM patients were randomized 1:1 to vutrisiran or placebo. The study population comprised HELIOS-B participants who underwent serial CMR assessments at the National Amyloidosis Centre as part of routine clinical care. CMRs were conducted at baseline, 1, 2, and 3-year timepoints during the HELIOS-B study. Image analysis was blinded to treatment allocation. Amyloid regression and progression were defined as an absolute reduction and increase in ECV of &gt; 5%, respectively. Changes in CMR parameters between baseline and follow-up were evaluated, and linear regression modelling was used to determine treatment effects. Results: Forty-three patients (mean (SD) age 75.0(5.67) years, 41/43male) underwent baseline CMR (21vutrisiran, 22placebo). Thirty-nine (21 vutrisiran, 18 placebo), 26 (14 vutrisiran, 12 placebo) and 17 (9 vutrisiran, 8 placebo) patients underwent 1, 2 and 3-year CMR, respectively. No patients received background tafamidis treatment. Baseline CMR characteristics were comparable between the treatment groups. At 3 years, vutrisiran led to significant increases in left and right ventricular ejection fractions (least square mean difference LVEF+20.5%, RVEF+21.1%; both p &lt; 0.001), stroke volumes (LVSV+27.4 mL, RVSV+25.7 mL; p = 0.005 and p = 0.026, respectively), significant reductions in LVmass (–30.8 g; p = 0.014), and cardiac amyloid load (ECV –6.7%; p = 0.009) compared to placebo. For all parameters noted above, vutrisiran led to improvements while placebo led to deterioration. Amyloid regression was observed in 22% of vutrisiran patients; no placebo patients regressed. Conversely, 63% of placebo patients demonstrated progression vs 11% for vutrisiran. Significant changes in cardiac structure and function were emergent as early as year two. Conclusion: In patients with ATTR-CM, treatment with vutrisiran was associated with improvements in cardiac structure, function and amyloid burden compared to placebo.

Background/Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a progressive and fatal disease with >130 known underlying variants in the TTR gene. We describe the utility of two no-charge genetic testing programs in identifying TTR variants in participants across Europe/Middle East and North America, respectively. Methods: Eligible adult participants in GeneAct® and Alnylam Act® had a family history or clinical suspicion of ATTRv. Testing was performed using gene panels for neuropathies or cardiomyopathy, or a single-gene TTR test. Diagnostic yield was defined as one pathogenic/likely pathogenic variant in TTR. Results: Overall, 2713 and 89,760 participants were tested in GeneAct® and Alnylam Act®. Genetic diagnosis was established in 95 and 4297 participants, respectively, resulting in a diagnostic yield of 3.5% and 4.8%. V122I (p.V142I) was the most common variant, identified in 34 of these participants in GeneAct® and 3299 in Alnylam Act®. Cardiac and neurologic signs/symptoms were the most common manifestations across both programs, as reflected in the specialties ordering tests in Alnylam Act® (cardiology, 29.1%; neurology, 31.5%). Conclusions: These data highlight the importance of genetic testing for early identification of ATTRv, especially among patients with cardiac and neuropathy symptoms. Genetic testing has the potential to improve diagnostic timeframes and outcomes in ATTRv.