Vyndaqel (Tafamidis) – Treatment for Transthyretin Familial Amyloid Polyneuropathy

Vyndaqel works by preventing the mutation of TTR proteins and the formation of amyloid deposits. Image courtesy of Pfizer.

FAP is a hereditary disease caused by the mutation of a TTR gene, located on human chromosome 18q12.1-11.2. Image courtesy of Pfizer.

Vyndaqel is approved by the European Commission and also awarded orphan drug designation in the US. Image courtesy of Pfizer.

Vyndaqel (tafamidis meglumine) is a first-in-class transthyretin stabiliser indicated for the treatment of Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP).

The drug was developed by FoldRx Pharmaceuticals, which was acquired by Pfizer in September 2010.

Vyndaqel was awarded orphan drug designation in the US and the European Union (EU). Pfizer announced the approval of Vyndaqel by the European Commission for the treatment of stage one TTR-FAP in adult patients in November 2011.

Pfizer filed a new drug application (NDA) with the US Food and Drug Administration (FDA) in April 2011. Following a preliminary review, the FDA issued a ‘refusal to accept’ letter to Pfizer. The letter stated the application was incomplete to carry out a substantive review of the drug.

In November 2018, Pfizer resubmitted the NDA to the FDA, which was reviewed under priority review status. The drug received approval from the Ministry of Labour Health and Welfare in Japan under Sakigake designation in March 2019. The FDA finally approved Vyndaqel in May 2019.

The drug is available as yellow, opaque, oblong oral capsules in 20mg strength.

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP)

Transthyretin (TTR) is an amyloidogenic protein produced by the liver. It is a transport protein for thyroxine (a type of thyroid hormone) and retinol (a form of vitamin A). Mutation of the TTR gene is the main cause of TTR-FAP, a rare and terminal neurodegenerative disease.

The TTR gene mutates and leads to the development of unstable TTR proteins. These proteins accumulate as amyloid fibrils and get deposited in various organs of the body, affecting the normal function of the organs.

TTR-FAP affects nearly 8,000 people worldwide, most of whom are in the EU. It can affect organs such as the nerves, heart and kidneys.

Patients suffering from the disease may experience loss of sensation, pain and weakness in the lower limbs, as well as severe impairment of the nervous system, which leads to erectile dysfunction, weight loss and urinary incontinence.

The disease is progressive and patients can lose their ability to walk, become bedridden and unable to take care of themselves. It usually manifests in adults in their early 30s and reaches a terminal stage in approximately ten years.

Vyndaqel’s mechanism of action

Development of Vyndaqel was based on research carried out at the Scripps Research Institute. The active substance in Vyndaqel is tafamidis meglumine.

Vyndaqel selectively stabilises TTR by binding to the TTR protein at thyroxine-binding sites and prevents the mutation of the proteins and their deposition as amyloid fibrils, slowing the progression of the disease.

Clinical trials on Vyndaqel

The FDA’s approval of Vyndaqel came from a pivotal phase three clinical trial named Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT).

ATTR-ACT was a global, double-blind, randomised, placebo-controlled clinical study, which enrolled 441 patients. Patients were administered with either Vyndaqel or placebo once daily for 30 months.

The patients receiving Vyndaqel demonstrated a 30% reduction in risk of mortality due to all causes and a 32% reduction in the risk of hospitalisation due to cardiovascular problems.

The European Commission’s (EC) approval of Vyndaqel was based on two phase two / three clinical trials, Fx-005 and Fx-006. Fx-005 was an 18-month randomised double-blind study carried out across eight international sites. The study tested the effect of the drug in 128 patients with TTR-FAP. The primary endpoint of the study was a measure of the Neuropathy Impairment Score-Lower Limb (NIS-LL), which is a neurologic exam of the lower limbs.

The second trial, Fx-006, was a 12-month long open-label extension study of Fx-005. Out of the 128 patients recruited for the Fx-005 study, 86 participated in the Fx-006 study. Researchers observed the rate of change of NIS-LL during the Fx-006 study.

In both studies, Vyndaqel demonstrated its ability to delay peripheral neurologic impairment when compared to placebo. In patients treated with Vyndaqel, 51% to 81% less deterioration was observed in neurologic function. Vyndaqel was also effective in improving the modified body mass index of the patients. The most adverse reactions during the studies were diarrhoea, abdominal pain and urinary tract infection.

Marketing commentary

Treatment for rare diseases such as TTR-FAP is a fast-growing sector. The only treatment available for the disease is a liver transplant, which is limited by the low availability of donors.

The procedure for a liver transplant is expensive and invasive and does not always guarantee success.

Vyndaqel is the first approved drug in its class where the number of people affected by TTR-FAP is high. Orphan drug designation in both the EU and the US will strengthen Vyndaqel’s market position.