Ionis Pharmaceuticals

Severe and extreme hypertriglyceridemia (sHTG [TG 500–879 mg/dL; 5.65–9.93 mmol/L]; eHTG [TG ≥ 880 mg/dL; ≥ 9.94 mmol/L]) are important risk factors for acute pancreatitis (AP) and cardiovascular (CV) events. The objective of this study was to estimate rates of AP and CV events for adults with (and without) sHTG/eHTG in US clinical practice. A retrospective design and data from the MarketScan Research Databases were employed. Study population comprised adults with ≥ 1 TG value and was stratified by index TG (< 150, 150–499, 500–879, ≥ 880 mg/dL; < 1.69, 1.69–5.64, 5.65–9.93, ≥ 9.94 mmol/L). AP/CV events (per 1,000 person-years [PY]) were ascertained from index TG through end of study period, and were estimated for TG-specific subgroups and selected subsets defined therein. Study population totaled 1.8 M adults (TG < 150 mg/dL [< 1.69 mmol/L]: N = 1.3 M; TG 150–499 mg/dL [1.69–5.64 mmol/L]: N = 449 K; TG 500–879 mg/dL [5.65–9.93 mmol/L]: N = 12,050; TG ≥ 880 mg/dL [≥ 9.94 mmol/L]: N = 3,944). AP rates (per 1,000 PY) increased from lowest to highest TG value (0.6 [< 150 mg/dL; < 1.69 mmol/L]) to 9.9 [≥ 880 mg/dL; ≥ 9.94 mmol/L]); rates were highest for adults with TG ≥ 880 mg/dL (≥ 9.94 mmol/L) and history of AP (193.0), pre-existing diabetes (13.9), or history of LLT (13.9). CV event rates (per 1,000 PY) also increased from lowest to highest TG value (3.3 [< 150 mg/dL; < 1.69 mmol/L]) to 10.3 [≥ 880 mg/dL; ≥ 9.94 mmol/L]); rates were highest for adults with TG ≥ 880 mg/dL (≥ 9.94 mmol/L) and history of CV events (116.5), pre-existing diabetes (18.1), or history of LLT (14.5). Rates of AP/CV events are substantially higher among adults with elevated TG values, and are especially high among adults with sHTG or eHTG, in particular those with these conditions and other risk factors. Understanding the magnitude of disease risk among sHTG/eHTG patients, with increasing TG levels as well as within important subgroups, is critical to improving patient care and outcomes.

BACKGROUND:Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS:We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS:Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197-331), and remnant cholesterol was 53 mg/dL (interquartile range, 38-76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2-213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, -3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS:Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05610280.

Although there are many long-term prophylactic treatments available for hereditary angioedema, few studies have assessed patient preferences for these treatments. We aimed to assess patient preferences for long-term prophylactic treatment attributes, including treatment trade-offs and the likelihood of starting or switching to a new treatment. An online discrete-choice experiment survey instrument was developed and administered to adults in the USA with a self-reported diagnosis of hereditary angioedema. Respondents evaluated a series of choices between pairs of hypothetical long-term prophylactic hereditary angioedema treatment alternatives. A total of 250 respondents (81.6

Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that, in mice, changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell type-specific profiling revealed that spinal inhibitory and excitatory neurons exhibited substantial changes in translation after peripheral nerve injury. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV+) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV+ neurons decreased their intrinsic excitability and spiking activity. Conversely, reducing translation in spinal PV+ neurons prevented the nerve injury-induced decrease in excitability but did not alleviate mechanical hypersensitivity. Together, these findings advance our understanding of translational control mechanisms in the spinal cord during neuropathic pain and highlight their cell type- and phase-specific contributions to gene expression and pain hypersensitivity.

Antisense oligonucleotides (ASOs) are an important therapeutic modality across several therapeutic areas, offering currently available and potential future treatment options for patients. ASO pharmacokinetics, biodistribution, and regional brain uptake are not fully characterized, particularly in humans. Here, we report preclinical studies and the first-in-human imaging trial measuring the biodistribution of [99mTc]Tc-MAG3-tofersen. The tracer was designed to be a proxy for tofersen (Qalsody; Biogen), an ASO approved for the treatment of amyotrophic lateral sclerosis in adults who have a variant in the SOD1 gene (SOD1-ALS). Methods: Tofersen was conjugated to a MAG3 moiety, which chelates 99mTc to yield [99mTc]Tc-MAG3-tofersen. [99mTc]Tc-MAG3-tofersen and unlabeled tofersen were intrathecally injected in rats, nonhuman primates (NHPs), and healthy human volunteers (n = 3) via lumbar puncture, followed by SPECT/CT imaging. Tofersen was coadministered at a therapeutic dose. The tracer [99mTc]Tc-MAG3-tofersen was prepared with greater than 99% purity. Results: Findings in rats demonstrated that [99mTc]Tc-MAG3-tofersen was a proxy measure of unlabeled tofersen, and dosimetry was calculated from NHP imaging data. In a clinical study, unlabeled tofersen coadministered with a microdose of [99mTc]Tc-MAG3-tofersen (≤129.5 MBq [3.5 mCi]) was well-tolerated. Human dosimetry estimates were within safe radiation dose levels. Imaging showed consistent distribution of radiolabeled ASO throughout the spinal cord and brain across species, with clearance patterns diverging in humans. Although rats and NHPs demonstrated declining brain concentrations over the study duration, human brain uptake increased during the first 4 h after injection. Additionally, tracer clearance from the spine in rodents and NHPs plateaued after 6 h but continued to decrease in humans. Radiolabeled ASO clearance from the lumbar spine was observed across all species, with peripheral clearance mediated primarily through the liver and kidneys. Broad uptake of the ASO in the brain and spinal cord is consistent with the clinical effects of tofersen observed in individuals with the SOD1-ALS variation. Conclusion: In preclinical and human SPECT/CT studies, [99mTc]Tc-MAG3-tofersen mirrored unlabeled drug distribution, showing broad spinal cord and brain uptake, with some differences in kinetics among species.