Acoramidis mechanism of action. 2 Pharmacodynamics 12.

Acoramidis mechanism of action [1]The most common adverse reactions include Attruby™ (acoramidis) What is Attruby? Attruby is a TTR stabilizer developed for treating patients with transthyretin amyloidosis (ATTR) who have heart involvement (cardiomyopathy). 3 Amsterdam, Netherlands – 27 Aug 2023: Acoramidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with placebo, according to late breaking research presented in a Hot Line session today at ESC Congress 2023. Mechanisms of Action: TTR Stabilizer. While BridgeBio's Attruby, an oral TTR stabiliser, has the same mechanism of action as tafamidis, Alnylam's asset is a wholly separate modality. BridgeBio plans on submitting a new drug application to the FDA by the end of this year 12. Modality: Small Molecule BridgeBio’s acoramidis (Attruby), an oral, second-generation stabilizer of the TTR protein, has been approved by the FDA for the treatment of ATTR-CM (transthyretin amyloid cardiomyopathy). 3 , 1 Tafamidis binds to transthyretin tetramers at the thyroxin binding sites, stabilizing the tetramer, reducing the Mechanism of Action. Advice to Patients. 1 Although they share a mechanism of action Background: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. BridgeBio's shares jumped 10% in the wake of Alnylam's data release. 29. The most common side effects were mild and included Acoramidis has the potential to be an effective and safe alternative to tafamidis for the treatment of ATTR-CM. Food and Drug Administration (FDA) has approved acoramidis to reduce the risk of cardiovascular death and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent monomers, the rate-limiting step in amyloidogenesis. Mechanism of Action. Acoramidis. 6MWT >100 m. . In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), treatment with acoramidis reduced all-cause mortality and cardiovascular disease hospitalization, compared with placebo, according to findings from the ATTRibute-CM trial presented at ESC Congress 2023. – As previously announced, the primary endpoint (a hierarchical analysis inclusive of all-cause mortality and frequency of cardiovascular-related hospitalization) was met (Win Ratio of 1. While acoramidis is not Mechanism of action Acoramidis is a tetrameric transthyretin (TTR) stabilizer. These results demonstrate a quantitative relationship between TTR stabilization, the mechanism of action of tafamidis, and accepted laboratory and patient-based outcomes in ATTR-CM. Adding to the growing understanding of the benefit-risk profile for acoramidis in ATTR-CM, Both therapies address the root cause of ATTR-PN by reducing the production of abnormal transthyretin (TTR) protein, albeit through different mechanisms of action. The Orphan Drug is awaiting FDA approval for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). - Acoramidis treatment led to a highly significant reduction in all-cause mortality (ACM) and recurrent cardiovascular-related hospitalizations (CVH) at Month 30 compared About Attruby™ (acoramidis) Attruby is the only near-complete (≥90%) stabilizer of Transthyretin (TTR) approved in the U. Notably, there are also other brand new drugs currently under investigation for the treatment of ATTR. This case study not only highlights a fascinating mechanism of action but also serves as an excellent example of how to leverage structural data to This is the first and only FDA approved therapy that specifies near-complete TTR stabilization (≥90%). 0001) and the 12. One such example is acoramidis (previously known as AG-10) , which is also a stabilizer of the TTR tetramer, although its mechanism of action differs from that of the previous drugs . 6 Acoramidis has significantly higher affinity to stabilize TTR than either diflunisal or tafamidis, and was modeled after the protective T119M TTR mutation (resulting in a more acoramidis 800 mg twice daily or placebo for 30 months. In addition to vutrisiran, BridgeBio Pharma has reported positive phase 3 results with its agent, acoramidis, which has a mechanism of action similar to tafamidis. According to a news release from manufacturer BridgeBio, acoramidis “was designed to mimic a naturally occurring ‘rescue mutation’ of the TTR gene”—T119M—targeting destabilization of the native TTR tetramer, the root cause of ATTR-CM. The treatment also showed consistent improvements in patients' quality of life and heart health, as measured by several markers of mortality, morbidity, function, and quality In the 12-month topline results of the ATTRibute-CM trial, acoramidis, a treatment for symptomatic transthyretin amyloid cardiomyopathy, did not meet its primary endpoint, BridgeBio Pharma Mechanism of action. 463 to 0. Mechanism of Action . 17 Patients with stage 1 (able to walk without support) sensorimotor or autonomic neuropathy, aged 18–75 years, PALO ALTO, Calif. Tafamidis remains Acoramidis’ strong benefit on survival and hospitalization, as well as on other ATTR-CM disease parameters, offer “clinical support for our molecular hypothesis,” Kumar added. The TTR amyloidogenic cascade. Mechanism of action Acoramidis is a tetrameric transthyretin (TTR) stabilizer. Presented during a hot line session at the European Society of Cardiology (ESC) Congress 2023, results of the trial suggest the Therapies targeting different mechanism in the pathophysiology of ATTR-CM provide new alternatives for treating patients with ATTR-CM. AG10 (acoramidis) is a potent selective stabilizer of TTR which Acoramidis is a small molecule stabilizer of transthyretin (TTR) for use in patients with TTR amyloidosis. Food and Drug Administration (FDA) approved Attruby™ (acoramidis), an orally-administered near-complete (≥90%) stabilizer of mechanism of action or method of delivery. 7. carbamazepine. Formulation, mechanism of action, pharmacokinetics and drug interactions compared with the once-daily regimen of tafamidis therapy and the twice-daily regimen of acoramidis. At the end of Study AG10-301 or at Day 1 of Study AG10-304 (or any time during the study), participant is on prohibited medication. Acoramidis is an orally active and selective kinetic stabilizer of ATTRwt and ATTRv amyloidosis. Acoramidis?was designed to mimic a?naturally-occurring?variant of the TTR gene (T119M) that is considered a rescue mutation because it has been shown to prevent or minimize ATTR in individuals carrying pathogenic, or disease-causing, mutations in the TTR gene. European Medicines Agency, with a decision expected in 2025, and has granted exclusive rights to Bayer to commercialize acoramidis for Tafamidis, sold under the brand names Vyndaqel and Vyndamax, [5] is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. Food and Drug Administration has approved a drug developed at Stanford Medicine that offers hope to people diagnosed with a rare cardiovascular disease, transthyretin amyloid cardiomyopathy, or ATTR-CM. Modality: Small Molecule Mechanism of Action: Attruby was designed to mimic a naturally occurring “rescue mutation” of the TTR gene (T119M) that targets the root cause of ATTR-CM, the destabilization of the native TTR tetramer. A Overview of the treatments available for transthyretin amyloidosis and their mechanism of action. Acoramidis steady state is achieved by 4 days with approximately 1. 22, 2024 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. 1. , Nov. 1 Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent monomers, Acoramidis is a prescription medication indicated for cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization. Acoramidis is available under the following different brand names: Attruby. In the context of cardiac amyloidosis, Tafamidis binds selectively to the thyroxine-binding sites of TTR tetramers, enhancing their stability. 29, 2024: acoramidis Acoramidis is a tetrameric transthyretin (TTR) stabilizer by Bridgebio and AstraZeneca. 1 Mechanism of Action. (Nasdaq: BBIO) (“BridgeBio” or the “Company”), a new type of biopharmaceutical company focused on genetic All Drugs; Human Drugs; Animal Drugs 12. Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its Despite its simple structure, the molecule has a fascinating mechanism of action, history, and rationale for differentiation. Coadministration with UGT inducers can potentially decrease acoramidis exposure. Researchers previously identified a super-stabilizing TTR mutation (T119M) that reduces the dissociation rate of transthyretin tetramers by over 33-fold compared to wild-type transthyretin [19, 27]. TTR amyloidogenesis and TTR stabilization by tafamidis (a). Avoid or Use Alternate Drug. Company: BridgeBio Pharma Indication: ATTR-CM Fig. PALO ALTO, Calif. Tafamidis is a small molecule that stabilizes the transthyretin (TTR) protein, preventing its dissociation into monomers, which can misfold and form amyloid fibrils. This prevents misfolding of the TTR protein and inhibits the formation of TTR amyloid fibrils and the subsequent deposition of these insoluble protein clusters in the heart and peripheral nerves. These revelations could significantly influence treatment paradigms and provide new avenues for therapeutic intervention. 12. Unlike tafamidis, which shares a similar mechanism, acoramidis has demonstrated promising results in recent clinical trials. Acoramidis is a potent and highly selective oral stabilizer of the TTR protein. The model structure will be Acoramidis has the potential to be an effective and safe alternative to tafamidis for the treatment of ATTR-CM. 2 Pharmacodynamics Tafamidis has been available since 2019, but vutrisiran has a different mechanism of action. References: Gillmore JD, Judge DP, Cappelli F, et al. As noted above, the inclusion of vutrisiran in the economic model will depend on the availability of adequate data to inform the assessment. Anktiva is a crucial player in the immune system that influences the development, maintenance, and function of natural killer (NK) cells and immune T cells. Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). If approved, acoramidis will compete with Pfizer’s Vyndamax (tafamidis) and Vyndaqel (tafamidis meglumine), currently the only authorized treatments for ATTR-CM. The U. 3 Acoramidis. 28 When compared with diflunisal and tafamidis, the subsequent accumulation in the myocardium have led to the development of multiple novel therapies with different mechanisms of action. Mechanism of action Phenprocoumon inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). AUC increases only 130%. ; 2024 Nov. Participants in both arms had the option of initiating open-label, commercially available tafamidis after 12 months in the study. 13. 8) with a highly statistically significant p-value (p<0. 6 Acoramidis has significantly higher affinity to stabilize TTR than either diflunisal or tafamidis, and was modeled after the protective T119M TTR mutation (resulting in a more About Attruby™ (acoramidis) Attruby is the only near-complete (≥90%) stabilizer of Transthyretin (TTR) approved in the U. Comprising the IL-15 mutant (IL-15N72D) bound to the IL-15 receptor alpha/IgG1 Fc fusion 12. Acoramidis binds TTR at thyroxine binding sites and slows Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Attruby (acoramidis) is a near-complete (≥90%) selective stabilizer of transthyretin (TTR), Attruby (acoramidis) How does Attruby work (mechanism of action)? Attruby helps to reduce the amount of a protein, called transthyretin (TTR), that builds up in the heart. S. Acoramidis is a high-affinity that is designed to mimic the action of the T119M variant. (Nasdaq: BBIO) (BridgeBio or the Company), a new type of biopharmaceutical company focused on genetic diseases, today announced that the U. NTproBNP >300 and <8500 pg/mL The US FDA has accepted BridgeBio’s NDA for acoramidis for the treatment of ATTR CM with a PDUFA action date of November 29, 2024; additionally, the EMA has accepted the MAA for acoramidis with potential EU approval planned for 2025. TTR is a tetrameric protein that can be destabilized by mutations in TTR, resulting in its dissociation into monomers that rapidly misfold and misassemble into aggregates, including pathologic structures associated with TTR amyloidosis [23, 40–45]. Pharmacokinetics studies showed a time to maximum concentration of less than 1 h and a half-life of ≈25 h . This mutation destabilizes the protein’s quaternary structure, making it more vulnerable to dissociation compared to the wild-type structure [ 21 , 24 ]. – Acoramidis demonstrated the earliest known time to separation in cardiovascular outcomes in the ATTRibute-CM study (3 months), with statistically significant risk reduction of 36% Acoramidis is an investigational, next-generation, orally administered, highly potent, small-molecule stabilizer of transthyretin. “We don’t know the true prevalence,” he told TCTMD. 529; 95% CI 0. 10 Consistent with its rational de-sign, acoramidis achieves near-complete stabili- Background: In the phase 3 randomized controlled study, ATTRibute-CM, acoramidis, a transthyretin (TTR) stabilizer, demonstrated significant efficacy on the primary endpoint. The potency and selectivity of acoramidis appears to exceed that of tafamidis and diflunisal, as shown by Penchala et al : 1) ASO conjugated to GalNAc, same backbone as inotersen, similar mechanism of action, enhanced liver uptake, 51-fold greater potency, 27-fold lower exposure to drug than predecessor: Acoramidis was administered orally as a single dose (from 50 mg to 800 mg) or as multiple doses (from 100 mg to 800 mg) every 12 h for 12 days. "Consistent with the mechanism of action and preclinical data showing near-complete stabilization of TTR at Mechanism of Action In ATTRv, the TTR gene is mutated, leading to the substitution of Val for Met at position 30 [ 21 ]. Acoramidis binds TTR at thyroxine binding sites and slows dissociation In a groundbreaking development in the field of cardiology, the U. Attruby stabilizes Acoramidis’ mechanism of action allows it to minimize this buildup in patients carrying the disease-causing TTR mutations. gov. Acoramidis is a strong TTR stabilizer that binds to the TTR Such detailed analyses are expected to shed light on acoramidis' mechanism of action and its comprehensive effects on ATTR-CM progression. Therapies inhibiting TTR production include liver transplantation, RNA-targeted gene silencing such as small interfering RNAs (siRNAs) (patisiran, revusiran, and vutrisiran) and antisense oligonucleotides (ASOs) (inotersen and eplontersen), and gene Data from previous Phase 1 and 2 trials showed that acoramidis was well tolerated, and led to a greater than 90% TTR stabilization in both healthy volunteers and ATTR-CM patients, who have an accumulation of TTR toxic clumps in the walls of the heart’s left ventricle. This approval heralds the emergence of Attruby as the first and only therapeutic agent with a Acoramidis, sold under the brand name Attruby, is a medication used for the treatment of cardiomyopathy. This case study reviews the history of TTR modulation, early experiments validating the Acoramidis is metabolized by UGT enzyme-mediated glucuronidation. " Liver cells' self-defense mechanism against cancer may backfire. Acoramidis is currently being evaluated in Phase 2 and Phase 3 studies in patients with ATTR. Native tetrameric TTR consists of Acoramidis is an orally available, small molecule transthyretin (TTR) stabilizer, being developed by BridgeBio Pharma, for the treatment of Acoramidis - BridgeBio Pharma Next Mechanism of Action Prealbumin modulators Orphan Drug Status Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Nov. Heart Fail Rev. The approval of acoramidis comes less than 10 months after BridgeBio Pharma announced the FDA’s acceptance of their New Drug Application (NDA) in February 2024. (Jan. It is now the second ATTR-CM The therapy is Attruby TM (Acoramidis) for the treatment of transthyretin amyloid cardiomyopathy This mechanism halts the amyloid deposits that cause cardiac damage. The most common side effects were mild and included About Attruby™ (acoramidis) Attruby is the only near-complete (≥90%) stabilizer of Transthyretin (TTR) approved in the U. Invasive and non-invasive diagnosis. doi: 10. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. 26) 3 • Reassuring safety profile. Miller et al. A head-to-head comparison and cost considerations are important next steps. It is a transthyretin stabilizer and has been shown to reduce disease progression Acoramidis: Mechanism of action: Binds to the T4-binding site: Promotes hydrogen bonding between the hydroxyl groups of adjacent S117 residues and binds to the T4-binding site: Inclusion criteria: Invasive diagnosis. 1 Mechanism of Action Acoramidis is a selective stabilizer of transthyretin (TTR). Transthyretin (TTR or prealbumin) is one of more than 30 proteins whose aggregation can cause disease by a gain-of-toxic function mechanism (3–5). It is taken by mouth. If approved, acoramidis will compete with Pfizer’s Vyndamax (tafamidis) and Vyndaqel (tafamidis The elucidation of physiologic mechanisms underlying the genesis of misfolded proteins which form amyloid fibrils that deposit in the myocardium and can cause cardiac amyloidosis has led to development of several effective therapeutic approaches 1. Acoramidis, formerly known as AG10, is another TTR stabilizer under development with a different mechanism of action. Selective stabilizer of transthyretin (TTR) The systemic amyloidoses are a group of diseases that are caused by protein aggregation, including amyloid fibril formation, in soft tissue, nervous system, and solid organs (1, 2). ATTR-CM is a rare, progressive, and fatal disease characterised by the accumulation of misfolded Reference 71564 – Attruby (acoramidis) package insert. Acoramidis (AG10) is used in the study for transthyretin amyloidosis. Palo Alto, CA: BridgeBio Pharma, Inc. 0001). ATTRibute-CM, a randomized, double-blinded and placebo-controlled trial with more than 630 participants, proved that acoramidis’ mechanism of action worked. 3 billion in global sales. Mutations in the TTR gene general Mechanism of Action: Stabilizes transthyretin to prevent amyloid fibril formation, mitigating myocardial damage. acoramidis - Phase III Close. We report The mechanism of action in multiple myeloma cells appears to be antibody dependent, cell-mediated cytotoxicity through recruitment, and activation of NK cells. 105 Elotuzumab mediated cell death requires the presence of NK cells since binding to SLAMF7 marks the myeloma cells for recognition by NK cells and also direct binding to SLAMF7 on NK TTR-stabilizing and -silencing agents with various mechanisms target TTR, preventing disaggregation of tetrameric TTR, and subsequent misfolding of TTR and formation of amyloid fibrils in the myocardium. Acoramidis’ mechanism of action allows it to minimize this buildup in patients carrying the disease-causing TTR mutations. BridgeBio’s acoramidis (Attruby), an oral, second-generation stabilizer of the TTR protein, has been approved by the FDA for the treatment of ATTR-CM (transthyretin amyloid cardiomyopathy). Acoramidis steady state is achieved by 4 days with approximately Notably, there are also other brand new drugs currently under investigation for the treatment of ATTR. Among the causes of cardiac amyloidosis, Results showed a statistically significant improvement with acoramidis compared with placebo for the primary endpoint, with a win ratio of 1. These results underscore its potential as a cornerstone therapy for ATTR-CM, offering Mechanism of Action Acoramidis binds transthyretin (TTR) at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent monomers, the rate-limiting step in amyloidogenesis. Positive high-level results from the Japan Phase III trial of acoramidis in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) showed consistency to those in the global BridgeBio Pharma, Inc. 1 Carcinogenesis, Mutagenesis, Impairment of Fertility Acoramidis is metabolized by UGT enzyme-mediated glucuronidation. 2 Pharmacodynamics . It significantly Acoramidis was designed to mimic a naturally-occurring variant of the TTR gene (T119M) that is considered a “rescue mutation” because it has been shown to prevent or minimize ATTR in individuals carrying pathogenic, or disease-causing, mutations in the TTR gene. About Bayer’s Commitment in Cardiovascular Diseases Change from baseline in NT-proBNP was lower in the acoramidis arm than in the placebo arm at month 30 (ratio of adjusted geometric mean fold-change 0. PubMed Abstract | CrossRef Full Text | Google The median time since Phase 2 enrollment was 38 months. “Together, death from Acoramidis: Mechanism of action: Binds to the T4-binding site: Promotes hydrogen bonding between the hydroxyl groups of adjacent S117 residues and binds to the T4-binding site: Inclusion criteria: Invasive diagnosis. Acoramidis is a selective stabilizer of transthyretin (TTR). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K This suggests that TTR stabilization with acoramidis may allow the rate of innate amyloid clearance mechanisms to exceed the rate of amyloid formation, enabling cardiac remodeling and functional recovery. (2022) 27:2187–200. 1 Mechanism of Action . It can be used to treat both hereditary forms, familial amyloid cardiomyopathy and familial amyloid polyneuropathy, as well as wild-type transthyretin amyloidosis, which formerly was called Acoramidis TTR stabilizer Placebo (N=211) Acoramidis, 800 mg (N=421) Transthyretin Amyloid Cardiomyopathy Acoramidis Placebo CONCLUSIONS In patients with transthyretin amyloid cardiomyopathy, the TTR 12. Mechanism of Action: Acoramidis works by stabilizing the TTR protein, preventing its misfolding and subsequent amyloid formation. , tafamidis and diflunisal) or by forming hydrogen bonds at the bottom of the thyroxine-binding pocket, thus mimicking the structure of the naturally protective T119M variant (e. Acoramidis: Acoramidis is also a TTR stabilizer with proven superiority to placebo for improving both cardiovascular and quality of life . The mechanism of action ("MoA") of acoramidis is explained by BridgeBio in the below diagram: Acoramidis MoA (presentation) As noted, acoramidis has now demonstrated proof of concept that its "MoA To the Editor: In a phase 3 trial of acoramidis for transthyretin amyloid cardiomyopathy, Gillmore et al. 2. - A New Drug Application for acoramidis for the treatment of ATTR-CM is currently under review with the FDA, with a PDUFA action date of November 29, 2024. 8 (95% CI, 1. 2; P <. Mechanism of action Higaki JN et al. , acoramidis). , on behalf of the ATTRibute-CM Investigators. 8 | Anktiva Mechanism of action. While the mechanisms of Vutrisiran and Eplontersen are well-established, ongoing studies should explore the interactions within the cellular milieu. 73 m 2. Known hypersensitivity to acoramidis, its metabolites, or formulation excipients. 9. On the basis of 81% survival rate on acoramidis approaches survival rate in age-matched US database (~85%) 1,2 • 0. Acoramidis (previously AG10, Eidos Therapeutics) is a unique selective TTR stabilizer which has been designed to incorporate the kinetic stabilizing property of the T119M protective/rescue variant . Acoramidis is a high-affinity TTR stabilizer that acts to inhibit 12. Although considered a rare disease, Gillmore said improvements in cardiovascular imaging, along with the development of treatments, have led to an “upsurge” in the diagnosis of ATTR-CM. 18, 2024 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. carbamazepine decreases levels of acoramidis by increasing metabolism. ssa. Participants with transthyretin amyloid cardiomyopathy (ATTR-CM) who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). Acoramidis: The serum concentration of Acoramidis - A New Drug Application for acoramidis for the treatment of ATTR-CM is currently under review with the FDA, with a PDUFA action date of November 29, 2024. Their data show that All Drugs; Human Drugs; Animal Drugs Acoramidis, previously known as AG-10, is a stabilizing agent that binds to the TTR thyroxine binding site identified through high throughput screening of ligands. . 604; p<0. 2 The phase 3 ATTRibute-CM trial Acoramidis . 16 Pharmacodynamic results from a phase 2 Likewise, Mizuho's Salim Syed wrote in a note he'd seen "nothing suggestive that vutrisiran is better" than acoramidis. These efforts have led to therapies that have been described as a “translational triumph” 2. Acoramidis is a highly selective stabilizer of TTR. Acoramidis hydrochloride is available in the following dosage form(s) and strength(s): Tablets: 356 mg of acoramidis 1. NTproBNP >300 and <8500 pg/mL The pharma's tafamidis — marketed as Vyndamax and Vyndaqel — became the first drug approved for the rare heart disease in 2019, and last year brought in a total of $3. 1 Mechanism of Action 12. Attruby was generally well-tolerated. [1] It is a near-complete (>90%) transthyretin stabilizer, developed to mimic the protective properties of the naturally-occurring T119M mutation, [2] [3] to treat transthyretin amyloid cardiomyopathy. Novel Mechanism: No. TTR is a 127 Overview of the treatments available for transthyretin amyloidosis and their mechanism of action. Clinical trials The randomized, double-blind, placebo-controlled, phase 3 ATTRibute-CM trial (NCT03860935) evaluated acoramidis in 632 patients with ATTR-CM and clinical heart failure. (acoramidis, tafamidis and vutrisiran) relative to no disease modifying therapy. Efficacy and Safety of Acoramidis in Transthyretin Amyloid The mechanism of action is either by binding to the thyroxine binding site (e. Leading the way to safer medication. Aside Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent monomers, the rate-limiting step in amyloidogenesis. Advise patients to read the FDA-approved patient labeling (Patient Information). 8. Food and Drug Administration has approved Attruby (acoramidis) to treat adults with cardiomyopathy (disorder that affects heart muscle) of wild-type or variant (hereditary In this exploratory CMR substudy in ATTR-CM, with a small placebo control group, 30-month treatment with acoramidis was associated with cardiac amyloid regression in some subjects and a trend towards cardiac functional Acoramidis stabilizes the TTR tetramer and avoids the production of the fibrils. By maintaining the structural integrity of TTR, Acoramidis helps reduce the burden of amyloid deposits in the heart. 29 mean annual CVH frequency on acoramidis approaches annual hospitalization rate observed in broader US Medicare population (~0. They have shown significant clinical efficacy in improving neuropathic impairment, quality of life, and serum TTR levels in clinical trials. eGFR >30 mL/min/1. It exerts its therapeutic effects by binding to TTR at thyroxine binding sites and stabilizing it in its tetrameric form, thereby slowing the rate-limiting step in amyloidogenesis. 11 issue)1 used the Finkelstein–Schoenfeld test to assess the hierarchical 12. Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent 12. 3 These results further inform the mechanism underlying the clinical benefits of acoramidis treatment. Investigators for the ATTRibute-CM phase 3 trial report in the New England Journal of Medicine that the novel drug acoramidis showed promise against ATTR-CM and is safe. Acoramidis, a treatment for symptomatic transthyretin amyloid cardiomyopathy, was associated with marked improvements in all-cause mortality and CV-related hospitalizations compared with placebo Mechanism: AKT inhibitor + fulvestrant + CDK4/6 inhibitor Area under investigation:1st-line triplet in early relapse/ET resistant locally advanced (inoperable) acoramidis transthyretin amyloid cardiomyopathy. - Mechanism of Action & Protocol. 4 Similar to the previously developed tafamidis, acoramidis is used to stabilize TTR in its tetrameric form, preventing the formation of amyloidogenic monomers and the progression of amyloidosis. for the treatment of adult patients with ATTR-CM to reduce cardiovascular death and cardiovascular-related hospitalization. , Am J Card 2021 . Patients Acoramidis also demonstrated a significant effect on hospitalization from heart problems, reducing the relative risk of such events by 50% compared to the placebo group. Thereby it improves cardiac function and quality of life for patients. Beyond understanding gene-silencing, investigating the specific cascades, signal transductions, and molecular interactions can contribute to a better grasp of their mode of action. 2 Pharmacodynamics 12. g. Attruby mechanism of action is by binding to TTR at thyroxine binding sites, which slows the formation of harmful amyloid protein deposits in the heart, slowing disease progression. Fx-005 trial was a multicentre, randomized, double-blind, controlled trial that evaluated the efficacy and safety of 18 months of tafamidis treatment in 128 patients with early-stage Val30Met ATTRv polyneuropathy. Females who are pregnant or breastfeeding. Acoramidis was well tolerated, and there were no safety signals of clinical concern . Attruby (Acoramidis Tablets) may treat, side effects, dosage, drug interactions, warnings, patient labeling, reviews, and related medications including drug comparison and health resources. ATTR is caused by the weakening, separation and misfolding of a protein called transthyretin (TTR), followed by a build up in organs in the form of amyloid fibrils. There were two co-primary endpoints. The randomised, double-blind placebo-controlled Phase III ATTRibute-CM trial (NCT03860935) 12. It is an RNA interference therapeutic that inhibits hepatic TTR messenger RNA, resulting in rapid New data from the ATTRibute-CM study presented at the American Heart Association Scientific Sessions 2023 is providing clinicians with even further insight into the effects of acoramidis in patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM). Food and Drug Administration (FDA) has officially approved Attruby (acoramidis), marking a significant milestone in the treatment of patients suffering from transthyretin amyloid cardiomyopathy (ATTR-CM). (Nasdaq: BBIO) ("BridgeBio” or the "Company”), a new type of biopharmaceutical company focused on genetic Mechanism of action of Tafamidis Tafamidis is a small molecule that stabilizes the transthyretin (TTR) protein, preventing its dissociation into monomers, which can misfold and form amyloid fibrils. Acoramidis is a selective transthyretin (TTR) stabilizer sold by BridgeBio under the brand name Attruby. Recently reported findings from the phase 3 ATTRibute-CM study (NCT03860935) showed that acoramidis (BridgeBio), an investigational small molecule stabilizer of transthyretin (TTR), was effective in the treatment of TTR amyloid cardiomyopathy (ATTR-CM). The phase 3 ATTRibute-CM trial, which Acoramidis, previously known as AG-10, is a stabilizing agent that binds to the TTR thyroxine binding site identified through high throughput screening of ligands. Amyloid 2016;23:86–97 NNC6019-0001 Macrophage Soluble aggregate Misfolded monomer Free tetramer Amyloid fibrils Oligomer • NNC6019-0001 is a a humanized monoclonal antibody that targets an epitope of TTR that is exposed on monomeric, misfolded and aggregated forms of TTR, but hidden in native TTR tetramers. 5 years of treatment, no difference in mortality was observed in the ATTR-ACT trial, it is expected, due to its mechanism of action, that by preventing continuous amyloid deposition and slowing the rate of LV thickening—along with improving surrogates like cardiac biomarkers—these effects will take months to years to Acoramidis is a TTR stabiliser and works by mimicking disease protective action of the TTR-stabilising mutation T119M. Future research should focus on comparing their effectiveness, the potential of combined treatment with agents from different classes and on identifying the patients Tafamidis is an oral medication for treating cardiomyopathy and peripheral neuropathy due to transthyretin amyloidosis (ATTR). NTproBNP >600 pg/mL. Transthyretin amyloid cardiomyopathy is a late-onset disease; symptoms are predominately manifested in male patients 60 years of age or older. These results also support the value of TTR stabilization as a clinically beneficial treatment option which maintains the protein in its physiologically active form Acoramidis?was designed to mimic a?naturally-occurring?variant of the TTR gene (T119M) that is considered a rescue mutation because it has been shown to prevent or minimize ATTR in individuals carrying pathogenic, or disease-causing, mutations in the TTR gene. 4 Mechanism of action Acoramidis is a selective stabilizer of transthyretin (TTR). 1007/s10741-022-10237-7. Therapies that aim to inhibit transthyretin production include liver transplantation, small interfering RNA (transthyretin) gene silencers, and DNA editing therapies (CRISPR Cas9). 0001) – The placebo and acoramidis time-to-first event Kaplan-Meier (K-M) curves for a composite of all-cause mortality (ACM) and - Acoramidis demonstrated the earliest known time to separation in cardiovascular outcomes in the ATTRibute-CM study (3 months), with statistically significant risk reduction of 36% on All-Cause The U. Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis. 2 The condition can be inherited as an autosomal Upon oral administration, acoramidis binds to and stabilizes transthyretin (TTR), thereby preventing tetramer dissociation into monomers. Although they have similar mechanisms of action, The 30-month results of the phase 3 ATTRibute-CM trial provide the latest insight into the effects of acoramidis in people with transthyretin amyloid cardiomyopathy (ATTR-CM) ahead of a potential regulatory submission for the agent. BridgeBio Pharma, Inc. 4-2. One such example is acoramidis (previously known as AG-10) , which is also a stabilizer of the TTR tetramer, although its mechanism Acoramidis (AG10) is an investigational, orally-administered small molecule designed to potently stabilize tetrameric transthyretin, or TTR, thereby halting at its outset the series of molecular events that give rise to TTR amyloidosis, or ATTR. Acoramidis (AG10) is an orally active and selective kinetic stabilizer of WT and V122I-TTR (transthyretin). Concomitant use of UGT inducers can potentially decrease acoramidis exposure. Also shown are the Acoramidis is a novel TTR stabilizer designed to mimic the action of the Thr119Met variant and achieves near-complete TTR stabilization. Acoramidis was generally well tolerated; adverse events were consistent with disease severity, concurrent illness, and age. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit Mechanism of action Genetic mutations or natural misfolding of transthyretin destabalizes transthyretin tetramers, leading to their dissociation and aggregation in tissues, and disrupting the normal function of these tissues. BridgeBio received FDA approval for Attruby (acoramidis), a near complete TTR stabilizer (≥90%), approved to reduce cardiovascular death and cardiovascular-related hospitalization in ATTR-CM Mechanism of action of Tafamidis. Acoramidis stabilizes transthyretin, preventing amyloid fibril formation, which mitigates myocardial damage and improves cardiac performance. (BridgeBio) ATTRibute-CM Phase III trial (NCT03860935), including survival, cardiac-related hospitalisations and other measures of improved functions Acoramidis (AG10/ALXN2060) is a new TTR stabilizer under investigation for treatment of ATTR amyloidosis Rapezzi C, Emdin M. The FDA has established a November 29, 2024, action date under The Food and Drug Administration has accepted BridgeBio’s new drug application for acoramidis with a Prescription Drug User Fee Act action date set for Nov. 3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13. Change from baseline in N-terminal pro-brain type Action . Mechanism Of Action. These positive findings supported the launch of the ATTRibute-CM and ATTRibute-PN Phase 3 trials. This case study not only highlights a fascinating mechanism of action but also serves as an excellent example of how to leverage structural data to Clinical Trials and Extension Studies Fx-005 Trial. Mechanism of action. Clinical trials have demonstrated the drug’s exceptional efficacy, improving both survival rates and quality of life, offering renewed hope to thousands of patients worldwide These therapies offer a different mechanism of action compared to those used for AL amyloidosis, highlighting the need for distinct treatment pathways based on the type of amyloidosis diagnosed. Additionally, patients saw improved functional capacity and quality of life, researchers said. Mechanism: oral TTR stabilizer In the course of aging, through unclear mechanisms, or in the setting of a mutation, thermodynamic stability of the TTR protein is altered to favor dissociation into oligomers and monomers which then result in organ dysfunction through direct toxicity and/or accumulation as Although in the first 1. rgbt lpwd wcz hgbx yesi ynnhw scazovr aywa lsvjxh gixhu