Donidalorsen

Approved by the U.S. FDA on August 21, 2025 as Dawnzera (donidalorsen) for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older. Donidalorsen is the first and only RNA-targeted (antisense oligonucleotide) medicine approved for HAE. It is self-administered as an 80 mg subcutaneous injection by autoinjector once every 4 weeks, with the option to extend to once every 8 weeks in patients who are well controlled. Donidalorsen received Orphan Drug Designation (2023) and has also been approved in the European Union for HAE prophylaxis. Developed and commercialized by Ionis Pharmaceuticals. It is a prescription biologic given under specialist care - not a supplement or research chemical.

Effective: 2025-08-21

An approved, once-monthly, self-administered subcutaneous GalNAc-conjugated antisense oligonucleotide (ASO) from Ionis and AstraZeneca that treats transthyretin-mediated (ATTR) amyloidosis by lowering the liver's production of transthyretin (TTR). Transthyretin is a liver-made transport protein that can misfold and deposit as amyloid in nerves and the heart; eplontersen is a short synthetic strand of chemically modified DNA/RNA that binds TTR messenger RNA and directs its enzymatic (RNase H1) degradation before the protein is made, cutting circulating TTR by roughly 80%. A triantennary N-acetylgalactosamine (GalNAc) tag delivers it to liver cells, allowing a low-dose 45 mg injection just once a month via autoinjector or pre-filled syringe. Marketed as Wainua (US) and Wainzua (EU), it was FDA-approved in December 2023 for the polyneuropathy of hereditary ATTR amyloidosis (ATTRv-PN) on the strength of the NEURO-TTRansform trial, and is now approved in more than 20 countries. Eplontersen is the antisense (ASO) counterpart to the siRNA drug vutrisiran (Amvuttra): both silence TTR, and both were tested in ATTR cardiomyopathy - but where vutrisiran's HELIOS-B trial succeeded on top of a stabilizer background, eplontersen's much larger CARDIO-TTRansform cardiomyopathy trial missed its primary endpoint in July 2026, with a benefit seen only in the prespecified monotherapy subgroup. It is a GalNAc-ASO sibling of Ionis's olezarsen and pelacarsen and the second-generation successor to the earlier, non-GalNAc TTR antisense drug inotersen (Tegsedi).

An approved, twice-yearly subcutaneous GalNAc-conjugated small interfering RNA (siRNA) from Novartis (originally discovered by Alnylam) that lowers LDL cholesterol by silencing PCSK9 (proprotein convertase subtilisin/kexin type 9), the liver protein that destroys LDL receptors. By switching off PCSK9 production inside hepatocytes, inclisiran leaves more LDL receptors on the liver surface to pull LDL cholesterol out of the blood - achieving roughly a 50% LDL reduction with an injection given only twice a year after a loading dose. Marketed as Leqvio, it was the first siRNA medicine approved for a chronic cardiovascular condition: the EU cleared it in December 2020 and the FDA in December 2021, and in July 2025 the FDA expanded the U.S. label to first-line monotherapy, dropping the requirement that it be added on top of a statin. Its Phase 3 ORION-9, ORION-10 and ORION-11 trials established the LDL benefit; a large cardiovascular outcomes program (VICTORION-2-PREVENT and others) is still running to test whether that LDL lowering prevents heart attacks and strokes. Inclisiran is the approved, real-world proof-of-concept for the GalNAc-siRNA cardiometabolic platform that newer investigational agents like zodasiran, solbinsiran, olpasiran and plozasiran build on.

An FDA-approved subcutaneous antisense oligonucleotide (ASO) from Ionis Pharmaceuticals, branded Tryngolza, that lowers triglycerides by silencing the messenger RNA for apolipoprotein C-III (apoC-III). Self-injected once a month, it was the first-ever therapy approved for familial chylomicronemia syndrome (FCS) on December 19, 2024, and on June 24, 2026 it became the first and only treatment approved to reduce both triglycerides and the risk of acute pancreatitis in the far larger severe hypertriglyceridemia (sHTG) population.

A first-in-class, once-monthly injectable antisense oligonucleotide (ASO) from Ionis and Novartis that lowers lipoprotein(a) [Lp(a)] by shutting down apolipoprotein(a) production in the liver. Its pivotal Lp(a)HORIZON trial (8,323 patients) is the first-ever cardiovascular outcomes trial for any Lp(a)-lowering drug, with a landmark topline readout due in 2026.

An approved, quarterly (once-every-three-months) subcutaneous GalNAc-conjugated small interfering RNA (siRNA) from Alnylam that treats transthyretin-mediated (ATTR) amyloidosis by silencing the TTR gene in the liver. Transthyretin is a liver-made transport protein that can misfold and pile up as amyloid deposits in nerves and, critically, the heart; vutrisiran uses RNA interference (RNAi) to degrade both mutant and wild-type TTR messenger RNA before the protein is made, lowering circulating TTR by roughly 80% and starving the amyloid of its raw material. Marketed as Amvuttra, it was first FDA-approved in June 2022 for the polyneuropathy of hereditary ATTR amyloidosis (HELIOS-A), and in March 2025 the FDA expanded the label to ATTR cardiomyopathy (ATTR-CM) of wild-type or hereditary disease - making vutrisiran the first RNAi therapeutic shown to reduce cardiovascular death and cardiovascular events, on the strength of the HELIOS-B outcomes trial. It shares the exact GalNAc-siRNA delivery platform that underlies the cardiometabolic RNAi medicine inclisiran and the investigational agents olpasiran, lepodisiran, zerlasiran, zilebesiran, zodasiran, solbinsiran and plozasiran, and it is the direct successor to Alnylam's earlier intravenous TTR siRNA patisiran (Onpattro).

An FDA-approved RNA-interference (RNAi) therapy for hemophilia that works by lowering a natural blood-thinning protein rather than replacing a missing clotting factor. Fitusiran (brand name Qfitlia) is a GalNAc-conjugated small interfering RNA (siRNA) that is taken up by liver cells and silences the gene for antithrombin, the body's main brake on clotting. By reducing antithrombin, fitusiran 'rebalances' hemostasis so that people with hemophilia A or B can generate enough thrombin to form stable clots and bleed less often. It was approved by the U.S. FDA on March 28, 2025 - the first siRNA (RNAi) therapy for hemophilia and the first medicine that treats hemophilia by lowering antithrombin - for routine prophylaxis in adults and children aged 12 and older with hemophilia A or B, with or without factor VIII or IX inhibitors. A key practical advantage is that it is given as an infrequent subcutaneous injection (starting once every two months, as few as about six injections per year) and works regardless of hemophilia type or inhibitor status. In the pivotal Phase 3 ATLAS trials, fitusiran reduced the annualized bleeding rate by about 90% versus on-demand treatment. Because lowering antithrombin shifts the clotting balance, fitusiran carries a boxed warning for thrombotic (clotting) events and gallbladder disease, and it is now dosed to a target antithrombin level (15-35%) to reduce clot risk. Fitusiran is a prescription biologic administered under medical supervision - not a supplement or research chemical.

An investigational next-generation RNA interference (RNAi) therapeutic from Alnylam Pharmaceuticals designed to silence the transthyretin (TTR) gene and treat transthyretin amyloidosis (ATTR) - the same disease targeted by Alnylam's approved drugs patisiran and vutrisiran (Amvuttra) and by Ionis/AstraZeneca's eplontersen (Wainua/Wainzua). Nucresiran (formerly ALN-TTRsc04) is a subcutaneous GalNAc-conjugated small interfering RNA (siRNA) built on Alnylam's newer IKARIA platform, engineered for deeper, more durable knockdown of both mutant and wild-type TTR with the potential for once- or twice-yearly dosing - a substantial step beyond the current quarterly (vutrisiran) or monthly (eplontersen) schedules. In an interim Phase 1 single-ascending-dose study in 48 healthy volunteers (presented at AHA 2024), a single dose of 300 mg or higher rapidly lowered serum TTR by more than 90% by Day 15 and by more than 96% at peak (Day 29), with more than 70% reduction still present at one year after a single 300 mg dose and low patient-to-patient variability; all doses were well tolerated with no injection-site reactions and no liver safety signals. Alnylam has moved nucresiran into a Phase 3 TRITON program: TRITON-PN (NCT07223203) in hereditary ATTR with polyneuropathy, an open-label study using vutrisiran as an active comparator, and TRITON-CM (NCT07052903), a large event-driven cardiovascular outcomes trial in ATTR cardiomyopathy dosing nucresiran 300 mg subcutaneously once every six months. Nucresiran is investigational and not approved by the FDA, EMA or any regulator; it is studied only in clinical trials and is not a supplement or research chemical.

Garadacimab (brand name Andembry; garadacimab-gxii) is a first-in-class, fully human monoclonal antibody that inhibits activated Factor XII (FXIIa), used once monthly to prevent attacks of hereditary angioedema (HAE). HAE is a rare, potentially life-threatening genetic disease in which unchecked activation of the plasma contact system floods the body with bradykinin, causing sudden, recurrent swelling of the skin, gut and airway. FXIIa is the very first enzyme in that contact-system cascade, so garadacimab shuts the pathway off at its source - blocking FXIIa before it can activate plasma kallikrein and generate the bradykinin that drives swelling. It is given as a 400 mg subcutaneous loading dose followed by 200 mg once-monthly subcutaneous self-injection with an autoinjector (an injection that takes about 15 seconds), making it the only HAE prophylaxis that targets FXIIa and offers once-monthly dosing for all eligible patients from the start. Approval rests on the pivotal Phase 3 VANGUARD trial (NCT04656418), a global, randomized, double-blind, placebo-controlled study of 64 patients aged 12 and older, in which garadacimab cut the monthly HAE attack rate by a least-squares mean of 89.2% versus placebo (median reduction greater than 99%) over the 6-month treatment period, with 62% of treated patients attack-free; the results were published in The Lancet in 2023. The FDA approved Andembry on June 16, 2025 to prevent HAE attacks in people aged 12 and older, following European (February 2025), Australian and Canadian approvals. On July 27, 2026 CSL reported positive top-line Phase 3b results in children aged 2 to 11, with most young participants remaining attack-free over a 12-month treatment period, supporting a planned expanded pediatric filing. Discovered and optimized at CSL's Bio21 research site and developed by CSL Behring, garadacimab sits alongside the antisense prekallikrein-lowering drug donidalorsen, the anti-plasma-kallikrein antibody lanadelumab, the oral kallikrein inhibitor berotralstat and C1-esterase-inhibitor concentrates in the modern HAE prevention toolkit.

Sebetralstat (brand name Ekterly) is a first-in-class, orally administered small-molecule inhibitor of plasma kallikrein and the first and only oral on-demand treatment approved for acute attacks of hereditary angioedema (HAE). HAE is a rare, sometimes life-threatening genetic disease in which unchecked activation of the plasma contact system floods the body with bradykinin, causing sudden, recurrent swelling of the skin, gut and airway. Plasma kallikrein is the enzyme that liberates bradykinin, so sebetralstat stops an attack by blocking kallikrein the moment symptoms begin - delivered as a tablet that can be taken at home rather than as an injection or infusion. The approved dose is 600 mg (two 300 mg tablets) at the earliest recognition of an attack, with a second 600 mg dose allowed at least 3 hours later if the response is inadequate or symptoms recur, up to a maximum of 1200 mg in 24 hours. Approval rests on the pivotal Phase 3 KONFIDENT trial (NCT05259917) - the largest HAE trial ever conducted, with 136 patients at 66 sites across 20 countries - a randomized, double-blind, placebo-controlled, event-driven crossover study in which sebetralstat cut the median time to the beginning of symptom relief to 1.61 hours (300 mg) and 1.79 hours (600 mg) versus 6.72 hours for placebo (p<0.0001 and p=0.0013), and also shortened the time to reduced attack severity and to complete resolution; results were published in the New England Journal of Medicine in 2024. The FDA approved Ekterly on July 7, 2025 for patients aged 12 and older, followed by European Commission and Swissmedic approvals on September 19, 2025 and UK MHRA approval. In 2026 the program widened further: an international pediatric HAE guideline named sebetralstat a first-line on-demand option for adolescents aged 12 and older, and in March 2026 KalVista reported positive interim Phase 3 results from the KONFIDENT-KID study in children aged 2 to 11 using an orally disintegrating tablet, with a US filing planned for late 2026. Developed by KalVista Pharmaceuticals, sebetralstat is a rescue (on-demand) therapy that complements the prophylactic HAE drugs garadacimab, donidalorsen, lanadelumab and berotralstat rather than replacing them.