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Vyndamax (free acid) and Vyndaqel (meglumine salt)48,49
Transthyretin stabilizer (pharmacological chaperone)
Cardiomyopathy of transthyretin-mediated amyloidosis$†
Tafamidis (the free acid form) and tafamidis megulumine (a salt form) represent first-in-class TTR stabilizers and the first drug products to be approved by the FDA for the treatment of ATTR-CM. Tafamidis has been used as an orphan drug for hATTR-PM since 2006.22 It was first licensed in the European Union for this indication in 2011, but it failed to clear the bar for FDA approval because the comparative measure of neurological benefit versus placebo did not reach the level for statistical significance.187,188 Tafamidis has been used as an orphan drug for ATTR-CM in the U.S. since 2012, and its approval for this indication is heralded as a therapy breakthrough for wild-type or hereditary ATTR-CM in adults to reduce cardiovascular mortality and cardiovascular-related hospitalizations.187
TTR is a tetrameric serum and cerebrospinal fluid transport protein for thyroxine and vitamin A (retinol). Monomeric TTR strands are unstable and have an intrinsic propensity to polymerize to form insoluble amyloid fibrils by triggering an aberrant degradation cascade.188–190 ATTR is a rare, progressive, and fatal disease that is caused by the accumulation of amyloid fibrils that aggregate into deposits in the heart, peripheral and central nervous systems, kidneys, eyes, and other tissues.189–192 ATTR can be caused through the inheritance of gene mutations that produce misfolded and unstable TTR proteins (more than 120 gene mutations are implicated) or through an acquired age-related decline in the stability of wild-type tetrameric TTR proteins.188–190,193 ATTR-CM can affect the heart in isolation or as part of a systemic disorder, making it difficult to diagnose.189,190,193 Cardiac manifestations of AATR-CM occur mainly as a result of amyloid deposits in the interstitial spaces of the heart muscle, leading to increased wall thickness, diastolic dysfunction, shortness of breath, fatigue, heart failure, arrhythmias, and death, usually within 5 or 6 years after diagnosis.49,189,190,193 Traditional treatment of AATR-CM has been symptomatic with heart or heart/lung transplants offering only limited benefits.189,193 A protocol for ATTR-CM screening has recently been proposed.191
Tafamidis (Figure P1–4) is a chemically modified benzoxazole form of the nonsteroidal anti-inflammatory drug, diflusinal (Figure P1–5). Diflusinal is also used off label for ATTR-CM.187,192–194 Diflusinal and tafamidis both act as pharmacological chaperones.195–199 By binding to unoccupied thyroxine binding pockets on mutated and wild-type TTR proteins, they slow tetrameric dissociation and protect their degradation products from triggering the amyloidogenic cascade.188,190,193 No adverse consequences related to reduced thyroxine or retinol binding have been detected.200 Tafamidis was preceded to market by two TTR gene knockdown therapies indicated for hATTR-PM: inotersen, an antisense oligonucleotide (ASO), and patisiran, a small interfering double-stranded ribonucleic acid (siRNA) agent.201 Inotersen, patisiran, and other treatment strategies are being investigated for ATTR-CM, including options that inhibit hepatic synthesis of TTR, disrupt serum amyloid fibrils, stabilize the tetramer, or otherwise target TTR.192,202 Some of these include epigallocatechin‐3‐gallate (a catechin isolated from green tea), AG‐10 (a novel selective stabilizer modeled after a TTR-stabilizing mutation),203 CHF5074 (an NSAID derivative devoid of cyclooxygenase inhibitory properties), PRX004 (a monoclonal antibody directed at misfolded TTR), AKCEA‐TTR‐LRx (an ASO), and vutrisiran (an siRNA).188,189
Tafamidis is taken once daily at a dose of either four 20-mg tafamidis meglumine capsules (80 mg), or one 61-mg tafamidis (free acid) “convenience capsule.” Due to better bioavailability of tafamidis from capsules containing the meglumine salt compared with capsules containing the free acid, four 20-mg tafamidis meglumine capsules (containing the equivalent of 12.2 mg of free acid/capsule) are bioequivalent to one 61-mg (free acid) capsule.187 Under- or overdosing pharmacy dispensing errors would result from wrong (“per mg”) substitutions of the two. For example, (1) substituting three 20-mg capsules for one 61-mg convenience capsule (60 mg of salt containing the equivalent of only 36.6 mg of free acid) would result in underdosing, and (2) substituting five 20-mg capsules for one 61-mg capsule (containing the equivalent of 61 mg of free acid in 100 mg of salt) would result in overdosing.
The mean half-life of tafamidis is ∼49 hours.48 Clearance is through unchanged drug in feces and as the glucuronide metabolite in urine.48 Tafamidis induces CYP2B6 and CYP3A4, inhibits intestinal activities of UGT1A1, and inhibits BCRP.48 Tafamidis therapy is expected to cost $250,000/year,204 and recommended criteria for selection of appropriate patients for therapy have been published.205 FDA approval of tafamidis was based on a single multicenter, international, randomized, double-blind, placebo-controlled study (ATTR cardiomyopathy clinical trial [ATTR-ACT; NCT01994889)206 in which patients were randomized to receive either 20 mg (the dose studied for ATTR-PM) or 80 mg of tafamidis megulmine daily for 30 months.207 The pooled results demonstrated that in addition to being associated with the highly statistically significant benefits of slower rate of decline in walking and quality of life scores, tafamidis is better than placebo in lowering the combination of all‐cause mortality and cardiovascular-related hospitalizations in patients with ATTR-CM (p<0.001). In terms of survival, 186 of 264 (70.5%) and 101 of 177 (57.1%) patients treated with tafamidis and placebo, respectively, were still alive after 30 months of study (p=0.0006).
2018 Goodman & Gillman Year in Review New and Noteworthy FDA Approvals. First-In-Class and Pharmacological Similars
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals