快樂小藥師 Im pharmacist nichts glücklich

Transthyretin (TTR) is an amyloidogenic protein produced by the liver. It is a transport protein for thyroxine (form of thyroid hormone) and retinol (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 across the world, most of whom are in the EU. It can affect organs such as the nerves, heart and kidneys.

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

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

Vyndaqel (tafamidis)

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

It attaches to the TTR protein and prevents the mutation of the proteins and their deposition as amyloid fibrils, thus slowing the progression of the disease.

Clinical drug trials

A Phase I study was conducted to test the safety and efficacy of vyndaqel in 21 healthy Japanese and western subjects. The trial was started in July 2011 and completed in August 2011.

Two Phase II trials were conducted to assess the safety and efficacy of vyndaqel in patients with non-V30M TTR amyloidosis and V122I or wild-type TTR amyloid cardiomyopathy.

Approval of vyndaqel was based on two Phase II / III 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. The rate of change of NIS-LL was observed during the Fx-006 study.

In both the 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.

Three long-term Phase III open-label safety and efficacy trials are currently ongoing to collect additional data about the drug.

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 low availability of donors.

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

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