Vyndaqel Fails to Prevent Progression of Rare FAP Variant, Case Report Shows

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by Alice Melao |

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Vyndaqel (tafamidis) failed to prevent the progressive accumulation of abnormal transthyretin protein in a patient with a rare variant of familial amyloid polineuropahy (FAP), also known as transthyretin amyloidosis, according to a case report.

The case was reported in the study, “Failure of Tafamidis to Halt Progression of Ala36Pro TTR Oculomeningovascular Amyloidosis,” published in the Journal of Stroke and Cerebrovascular Diseases.

Genetic mutations in the TTR gene are associated with transthyretin amyloidosis, which is characterized by the accumulation of transthyretin protein in the liver, eye, and nerve cells, among other tissues.

Some patients may experience a particular form of this disease — an oculomeningovascular variant — that is associated with protein deposition in the eyeball, in the layers that protect the brain and spinal cord (meninges), and its blood vessels (leptomeningeal vessels).

This particular pattern of protein accumulation can result in blindness, reduced brain oxygenation, small hemorrhages and accumulation of iron in the meninges. In severe cases, oculomeningovascular amyloidosis can cause damaging accumulation of cerebrospinal fluid in the brain and spinal cord.

Vyndaqel is a therapy developed by Pfizer that can stabilize the transthyretin protein, preventing it from forming aggregates and deposits in tissues. This oral treatment has been shown to effectively halt protein accumulation in the heart and peripheral nerve cells. However, a previous report revealed that Vyndaqel had limited effectiveness in preventing the ocular manifestations of transthyretin amyloidosis caused by the Val30Met mutation in the TTR gene.

In the current study, Italian researchers presented the case of a patient with oculomeningovascular amyloidosis caused by an Ala36Pro TTR mutation who did not respond to Vyndaqel treatment.

The patient was diagnosed when she was 24 years old, and started to experience abnormal sensation of the lower limbs and bowel dysfunction at age 26. She was the daughter of a patient with an Ala36Pro TTR mutation, who died at 43 years old due to a stroke caused by leptomeningeal vascular amyloidosis.

Evaluation of the patient’s sensory and motor skills revealed that she had mild peripheral nerve damage (neuropathy). She had no visual symptoms, but a more detailed assessment showed she had some protein deposits in the jelly structure behind the lens of the eye (corpus vitreum). She started taking 20 mg of Vindaqel per day.

Sixteen months later, she complained of severe headaches followed by abnormal numbness and impaired sensation affecting just one side of the body, events that lasted for about 20 minutes. A magnetic resonance imaging (MRI) scan revealed multiple iron deposits in her brain.

A new evaluation showed increased accumulation of protein aggregates in her eyes and progression of peripheral nerve disease. At this point, her heart also showed signs compatible with cardiac amyloidosis.

These findings further confirmed that Vyndaqel is ineffective for the treatment of eye manifestations in the disease. But it also suggests that Vyndaqel fails to prevent the clinical onset of vessel damage in the meninges.

“Incapability of tafamidis to cross the blood-retina and blood-brain barriers can be hypothesized to explain progression of vitreal and meningovascular deposition,” the researchers wrote.

This case highlights the need for improved, targeted therapies that may halt progression of this particular type of transthyretin amyloidosis.