Familial Amyloid Polyneuropathy (FAP) is an inherited progressive disorder caused by an abnormal build-up of proteins called amyloid deposits in various body tissues. This is commonly due to a mutation in a gene called transthyretin (TTR), which encodes for a protein normally produced by the liver (and to a lesser degree, the eyes and the brain). The role of this protein is to transport thyroid hormone and vitamin A around the body. Due to this FAP can also be referred to as TTR amyloidosis.

While there are FAP-specific medications now available, such as Vyndaqel (tafamidis), there is still no cure for the disease. Research is ongoing to identify more effective medications and potential cures for FAP. Some therapies that are currently in clinical trials are described below.

Small molecule drugs

SOM0226 (tolcapone)

SOM0226 acts as a stabilizer for the TTR protein and a disruptor of TTR fibrils.

The small molecule drug has been successfully tested in a Phase 1/2 clinical trial (NCT02191826), carried out by SOM Biotech SL.

Results of a Phase 2a clinical trial, published in Orphanet Journal of Rare Diseases, demonstrated that SOM0226 can successfully stabilize TTR, supporting it as a potential therapy for FAP.

In May 2017, SOM Biotech licensed out the right to SOM0226 to Corino Therapeutics for further investigation.

Dolobid (diflunisal)

Dolobid is a nonsteroidal anti-inflammatory drug (NSAID) that suppresses the formation of amyloid fibrils. By doing this, it is thought that the small molecule drug may slow the progression of FAP.

The effect of Dolobid on FAP has been investigated in two clinical trials (NCT01432587) and (NCT00294671). The results of the second trial reported in the scientific journal, JAMA, showed that Dolobid reduced the rate of progression of the disorder and also preserved quality of life of patients for longer, compared to a placebo.

Doxycycline and taurodesoxycholic acid

A combination of doxycycline and taurodesoxycholic acid (TUDCA) has been shown to suppress TTR deposits in mice. Results of a small Phase 2 study, published in the scientific journal Amyloid, evaluating doxycycline plus TUDCA compared to a placebo in 20 patients, suggested that the therapy was well tolerated and could prevent progression of the disorder for at least one year.

Gene silencing therapies

Inotersen (IONIS-TTRRX)

Inotersen, developed by Ionis Pharmaceuticals, is an antisense drug that aims to reduce the levels of TTR protein produced by the body. It is hoped that this would reduce the amyloid deposits that cause the progression of FAP.

Inotersen has been granted orphan drug designation and fast track status by the U.S. Food and Drug Administration (FDA).

Ionis recently announced that the Phase 3 study called NEURO-TTR (NCT01737398) testing the safety and efficacy of Inotersen in FAP was producing positive results. According to this, patients treated with Inotersen had a significantly improved quality of life compared to those treated with placebo. Patients who complete this trial are invited to participant in an open-label extension study (NCT02175004) to assess the long-term safety and efficacy of Inotersen.

Patisiran (ALN-TTR01)

Patisiran is a potential drug being developed by Alnylam Pharmaceuticals. It uses a mechanism called RNA interference (RNAi), to block the messenger RNA (mRNA), which is the instructions sent to the protein-making machinery of the cell used to make a protein. This aims to reduce the levels of TTR protein made, in order to slow or stop the progression of FAP.

Patisiran is currently being tested in a Phase 3 clinical trial (NCT01960348) called APOLLO. Participants completing the APOLLO study can take part in an open label extension study (NCT02510261) to test the long-term safety of Patisiran.

ALN-TTRsc02

Alnylam is also developing another RNAi-based therapy, ALN-TTRsc0. This potential drug, which is administered as an injection under the skin also targets the mRNA that codes for transthyretin (TTR). The safety and tolerability of ALN-TTRsc0 are currently being tested in a Phase 1 clinical trial (NCT02797847) in healthy volunteers.

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