Tafimidis

Tafimidis is a substance from the substance group of transthyrethine stabilizers, which is used for the treatment of ATTR amyloidosis.

Significance: Tafimidis is the first substance to be approved in this substance group and, with the approval of Tafimidis 20mg in 2011, was the first and only drug therapy for the specific treatment of the pathophysiology of amyloidosis. The approval of Tafimidis 61mg for the treatment of cardiomyopathy in ATTR amyloidosis (ATTR-CM) in 2020 was another important milestone in the treatment of amyloidosis, which significantly improves the prognosis and quality of life of this slowly progressing, severely debilitating and life-shortening disease.

Tafimidis is a so-called orphan drug. Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a rare disease.

(For orphan drugs and approval of orphan drugs, see also: BfArM Orphan Drugs and BfArM Drugs for Rare Diseases).

Mechanism of action: Tafimidis is a selective stabilizer of TTR (transthyretin). Transthyretin, also known as prealbumin, is a protein that is produced in the liver and functions mainly as a transport protein for thyroxine (T4) and retinol (vitamin A). In amyloidosis, the tetramer structure of TTR becomes unstable and breaks down into monomers. Denaturation, misfolding and aggregation of the TTR monomers leads to the formation of insoluble amyloid fibrils, which are deposited in various organs and thus lead to different organ manifestations of amyloidosis.

The hereditary form of ATTR (hATTR) is caused by an autosomal-dominantly inherited genetic defect, while the wild-type form of ATTR (wtATTR) is caused by age-related instability and decay of TTR. ATTR amyloidosis is a progressive, severely debilitating and life-shortening disease that manifests in adulthood.

Tafimidis binds to the thyroxine binding sites of TTR, stabilizing the tetramer and slowing down the cleavage into monomers, the rate-determining step in the amyloidogenic process.

Tafimidis binds with negative cooperativity to the two thyroxine binding sites of the native tetrameric form of transthyretin and thus prevents cleavage into monomers. The inhibition of the cleavage of the TTR tetramer forms the basis for the use of Tafimidis in patients with ATTR amyloidosis. This slows down the progression of the disease.

Using a TTR stabilization assay, tafimidis was shown to stabilize both the wild-type TTR tetramer and the tetramers of 14 TTR variants, as well as stabilizing the TTR tetramer for 25 variants tested ex vivo, demonstrating TTR stabilization of 40 amyloidogenic TTR genotypes.

ATTR cardiomyopathy (ATTR-CM): The pivotal study for Tafimidis 61mg (30 months; RCT 61mg/20mg Tafimidis plus standard therapy HF versus placebo, 3-arm study; 441 patients in total) showed sustained TTR stabilization over 30 months. The biomarkers for heart failure (NT-proBNP and troponin I) improved. Overall mortality and hospital admissions due to cardiovascular morbidity were significantly improved. Functionality and quality of life were also significantly improved. Only in NYHA stage III was the reduction in the risk of hospitalization for cardiovascular morbidity no longer clearly demonstrable. Significant treatment effects are first detectable after 6 months (Maurer MS et al 2018).

ATTR polyneuropathy (stage I) ATTR-PN: The pivotal study for Tafimidis 20mg (18-month RCT 20 mg Tafimidis plus standard therapy versus placebo, 128 patients) shows that the progression of functional neurological symptoms and functional impairment in stage I ATTR-PN can be slowed and quality of life improved (Coelho T et al 2012).

Tafimidis is available in two differently concentrated preparations for the respective indications ATTR-CM and ATTR-PN:

Tafimidis 61mg for the treatment of ATTR cardiomyopathy (ATTR-CM).

Tafimidis 20mg for the treatment of ATTR polyneuropathy stage I (PN).

Absorption: Maximum concentration (_Cmax) after 4 hours (61mg);

high plasma protein binding (approx. 99%).

Metabolization and elimination: Probably mainly glucuronidation and excretion via the bile; approx. 59% of the total dose excreted via the intestine and approx. 22% detected in the urine; mean half-life approx. 49 hours (population-specific).

Tafamidis 61mg is indicated for the treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM).

Therapy should be administered under the supervision of a physician experienced in the treatment of patients with amyloidosis or cardiomyopathy.

Tafimidis 20mg is indicated for the treatment of transthyretin amyloidosis in adult patients with symptomatic stage 1 polyneuropathy to delay the decline in peripheral neurological function.

Therapy should be administered under the supervision of a physician experienced in the treatment of patients with transthyretin amyloidosis with polyneuropathy (ATTR-PN).

In principle, the diagnosis of ATTR-CM (wild type or hereditary form) or ATTR-PN must be confirmed and AL amyloidosis ruled out before initiating therapy with Tafimidis.

The earlier therapy with Tafimidis is initiated in the course of the disease, the more effective the effect in terms of clinical benefit.

Treatment should therefore be initiated as early as possible in the course of the disease.

Treatment with Tafimidis 61mg in advanced ATTR-CM (e.g. NYHA stage III) should only be initiated or continued by a physician experienced in ATTR-CM. Only limited data are available for NYHA stage IV.

There are no data on use after organ transplantation. Therapy with Tafimidis is not recommended and should be discontinued after organ transplantation.

There is no relevant benefit for use in children and adolescents.

Tafimidis is contraindicated during pregnancy and breastfeeding.

Women of childbearing age require reliable contraception. This must be continued until 1 month after the end of treatment due to the long half-life of Tafimidis.

Animal studies have shown developmental toxicity.

Data from animal experiments show that Tafimidis passes into breast milk.

Impairment of fertility has not been demonstrated in preclinical studies.

In case of unforeseen pregnancy information and advice from Embryotox Charité.

Tafimidis is available in two different concentrations:

Tafimidis 61mg for the treatment of ATTR cardiomyopathy (ATTR-CM).

Tafimidis 20mg for the treatment of ATTR polyneuropathy stage I (PN).

Tafimidis is administered orally as a capsule; the recommended daily dose is 1x1 capsule according to the indication for ATTR-CM 1x61mg or for ATTR-PN stage I 1x20mg; independent of food.

1capsule 61mg micronized tafimidis corresponds to 80mg tafimidis meglumine.

1capsule 20mg contains 20mg micronized tafimidis meglumine equivalent to 12.2mg tafimidis.

(Dosages for tafimidis and tafimidis-meglumine are not equivalent and not interchangeable).

Capsules additionally contain approx. 44mg sorbitol.

The capsule must be swallowed whole and should not be divided or crushed.

Dose adjustment not necessary for patients ≥65 years.

No dose adjustment required for mild renal impairment and mild to moderate hepatic impairment; only limited data for severe renal impairment (creatinine clearance ≤ 30 ml/min); no data on severe hepatic impairment; use with caution in these patients!

Tafimidis is generally well tolerated.

Gastrointestinal complaints, skin rash and pruritus are common.

An increase in serum transaminases is possible.

The serum concentration of total thyroxine may decrease with Tafimidis, without any change in free thyroxine (T4) or TSH. This is presumably due to the strong binding affinity of Tafimidis to the TTR thyroxine receptor.

The substance is subject to increased pharmacovigilance. Reports of suspected adverse effects in connection with the treatment to Nebenwirkungen.bund.de

Tafamidis inhibits the efflux transporter BCRP (Breast Cancer Resistant Protein) in vitro and can therefore potentially lead to WW with substrates of this transporter. WW are possible with e.g. methotrexate, rosuvastatin, imatinib (selection only).

In addition, tafamidis inhibits the uptake transporters OAT1 and OAT3 (organic anion transporters) and could, in clinically relevant concentrations, lead to AD with substrates of these transporters, e.g. non-steroidal anti-inflammatory drugs, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir, cidofovir, zidovudine, zalcitabine (selection only).

Tafimidis contains sorbitol. The sorbitol content can influence the bioavailability of other drugs administered orally at the same time.

This is only a selection; other possible side effects may need to be clarified in individual cases.

Interaction studies investigating the effect of other medicinal products on tafamidis have not been carried out.

For further information, see the Information for healthcare professionals.

Hypersensitivity to the active substance or any of the other ingredients (see Information for healthcare professionals).

Caution in case of severe renal impairment and severe impairment of liver function! There are no data available on this!

1. Specialist information Vyndaqel® 20mg
2. Specialist information Vyndaqel® 61mg
3. Coelho T, Maia LF, Martins da Silva A et. al. (2012). Tafamidis for transthyretin familial amyloid polyneuropathy. A randomized, controlled trial. Neurology 79 (8) 785-792 doi.org/10.1212/WNL.0b013e3182661eb1
4. Maurer MS, Schwartz JH, Gundapaneni B, et. al. for the ATTR-ACT Study Investigators (2018). Tafimidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med 379:1007-1016 DOI 10.1056/NEJMoa1805689 VOL. 379 NO. 11.