In this randomized trial involving patients with multiple sclerosis, BG-12 (dimethyl fumarate) reduced clinical relapses, disability progression, and MRI lesions. BG-12 treatment resulted in reduced ...lymphocyte counts and elevated liver aminotransferase levels.
Oral BG-12 (dimethyl fumarate) is being investigated for the treatment of multiple sclerosis. Inflammation and oxidative stress are central pathologic factors in multiple sclerosis.
1
,
2
Immune cell activation and infiltration into the central nervous system are thought to result in widespread cellular damage, potentially owing to the dysregulated production and release of reactive oxygen and nitrogen species, such as hydrogen peroxide and peroxynitrite, and proinflammatory stimuli.
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This combination of toxic factors ultimately results in demyelination and neurodegeneration, causing disease activity and progression of disability.
BG-12 has been shown to have beneficial effects in preclinical models of neuroinflammation, neurodegeneration, and toxic . . .
Vutrisiran (ALN‐TTRsc02) is a liver‐directed, investigational, small interfering ribonucleic acid drug for the treatment of transthyretin (TTR)‐mediated amyloidosis. This phase I, randomized, ...single‐blind, placebo‐controlled, single ascending dose study evaluated the pharmacodynamics, pharmacokinetics, and safety profile of subcutaneously administered vutrisiran (5–300 mg) in healthy subjects (n = 80). Vutrisiran treatment achieved potent and sustained TTR reduction in a dose‐dependent manner, with mean maximum TTR reduction of 57–97%, maintained for ≥ 90 days post dose. Vutrisiran was rapidly absorbed (peak plasma concentration 3–5 hours post dose), had a short plasma half‐life (4.2–7.5 hours), and plasma concentrations increased in a dose‐proportional manner. Pharmacodynamic and pharmacokinetic results were similar in Japanese and non‐Japanese subjects. Vutrisiran had an acceptable safety profile; the most common treatment‐related adverse event was mild, transient injection site reactions in four (6.7%) vutrisiran‐treated subjects. The favorable pharmacokinetic, pharmacodynamic, and safety results observed here support vutrisiran's continued clinical development.
In this trial involving patients with relapsing–remitting multiple sclerosis, BG-12 (dimethyl fumarate) reduced the annualized relapse rate and number of MRI lesions but not disability progression. ...BG-12 was associated with flushing, diarrhea, and decreased lymphocyte counts.
Multiple sclerosis is a chronic demyelinating and neurodegenerative disease of the central nervous system, which is commonly treated with parenteral agents (interferon beta and glatiramer acetate). Oxidative stress and proinflammatory stimuli are important pathologic factors in multiple sclerosis.
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Experimental data suggest that BG-12, an oral formulation of dimethyl fumarate, has antiinflammatory and cytoprotective properties that are mediated through activation of the nuclear factor (erythroid-derived 2)–like 2 transcriptional pathway, among others.
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Here, we report the results of the Comparator and an Oral Fumarate in Relapsing–Remitting Multiple Sclerosis (CONFIRM) trial, a randomized, multicenter, double-blind, 2-year study evaluating the efficacy and . . .
Hereditary transthyretin‐mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life‐threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA ...interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN‐18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin‐MC3‐DMA and PEG2000‐C‐DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure‐response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran‐treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine‐to‐methionine mutation at position 30 V30M and non‐V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN‐18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.
In this phase 1 study involving persons with hypertension, zilebesiran (an RNA interference therapeutic agent) was associated with decreases in angiotensin levels and systolic and diastolic blood ...pressure.
Primary hyperoxaluria type 1 is caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. This trial tested whether an ...oligonucleotide drug can reduce the production of hepatic oxalate.
Manufacturer's Response to Case Reports of PML Sweetser, Marianne T; Dawson, Katherine T; Bozic, Carmen
The New England journal of medicine,
04/2013, Letnik:
368, Številka:
17
Journal Article
Recenzirano
Odprti dostop
To the Editor:
In the letters from Ermis et al.
1
and van Oosten et al.
2
published in this issue of the
Journal,
progressive multifocal leukoencephalopathy (PML) is reported in two patients with ...psoriasis who were being treated with Fumaderm (Biogen Idec) or a compounded version of fumaric acid esters (FAEs) referred to as Psorinovo (compounding pharmacy, Mierlo-Hout). Compounded FAEs and other compounded products are not approved by regulatory authorities and may be associated with risks.
3
Fumaderm, an approved, fixed-combination product, contains four active ingredients: dimethyl fumarate and three monoethyl hydrogen fumarates (calcium, magnesium, and zinc salts). The compounded product Psorinovo . . .
Background & Aims
Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to ...the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria.
Methods
Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events.
Results
Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double‐blind period, 0.0 in open‐label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period.
Conclusions
Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.
Zilebesiran for Hypertension. Reply Desai, Akshay S; Sweetser, Marianne T; Bakris, George L
The New England journal of medicine,
10/2023, Letnik:
389, Številka:
15
Journal Article
Background and purpose
Hereditary transthyretin‐mediated amyloidosis with polyneuropathy (ATTRv‐PN v for variant) is a rare, progressive disease associated with multisystemic impairments. This study ...assessed the real‐world outcomes of patients with ATTRv‐PN who switched from tafamidis to patisiran, as well as the reasons for the treatment switch.
Methods
This was a retrospective chart review study at a large expert referral center. Data were extracted from medical charts of patients with ATTRv‐PN who switched from tafamidis to patisiran on or before 30 August 2019. Data elements included demographic and clinical characteristics, rationale for switch, and disease measures evaluated from tafamidis initiation through the 12‐month patisiran treatment period.
Results
Among the 24 patients with ATTRv‐PN included in the study, 50.0% had a V30M variant, and the mean (SD) age was 67.3 (8.0) years. During tafamidis treatment (mean SD = 30.1 17.5 months) before switching to patisiran, patients worsened across multiple polyneuropathy measures, including walking ability, Neuropathy Impairment Score, and autonomic function. Neuropathic disease progression on tafamidis was the principal reason for switching to patisiran. After 12 months on patisiran (mean SD = 11.7 1.4 months), patients experienced attenuated disease progression or improvement in the aforementioned measures of polyneuropathy.
Conclusions
Switching from tafamidis to patisiran attenuated the rate of functional decline, and most patients experienced stabilization or improvement of at least one polyneuropathy measure within 12 months of patisiran treatment. Timely switch from tafamidis to patisiran can be beneficial to avoid rapid disease progression in patients with ATTRv‐PN.
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