The combination of doxycycline and taurodesoxycholic acid (TUDCA) is currently being investigated as a potential treatment for familial amyloid polyneuropathy (FAP), a disorder characterized by the unusual deposits of transthyretin (TTR) amyloid in one or more organs, with a particular involvement in peripheral nerves.

How the combination therapy works

Doxycycline is an antibiotic and TUDCA is a bile acid. They are both amyloid matrix solvents that work by disrupting or dissolving the deposited amyloid fibrils. The two drugs overcome the limitations of each, and work as a cascade that lower inflammatory stress. The activity of the drugs results not only in the removal of TTR deposits, but also leads to tissue repair.

Studies involving doxycycline and TUDCA

The combined doxycycline and TUDCA treatment in lowering TTR deposits was tested in different animal models of FAP. In one study, it was found that the two drugs have a synergistic effect and work by lowering both fibrillar and non-fibrillar deposits. The results of this study, published in the Journal of Translational Medicine, indicate that doxycycline acts as a fibril disruptor in vitro and works by removing TTR amyloid deposits. TUDCA works by lowering the amount of deposited non-fibrillar TTR.

These positive results led to the investigation of the effect of doxycycline plus TUDCA in patients with transthyretin amyloidosis, or ATTR amyloidosis, of which FAP is a subtype.

The results of a Phase 2, open-label study of doxycycline (100 mg twice daily) plus TUDCA (250 mg three times a day), published in the journal Amyloid, indicated that the combination of the two compounds stabilized the disease in patients. The treatment was well tolerated and halted the progression of heart disease as well as neuropathy in patients for at least one year.

Other information

The tolerability and efficacy of the combination of doxycycline and TUDCA are also being investigated in patients with other types of ATTR amyloidosis. An open-label, single-arm, Phase 1/2 study (NCT01855360) in transthyretin amyloid cardiomyopathy, which can overlap with FAP, has recently been completed.

The study involved 38 patients and was conducted to determine whether the combination of TUDCA (250 mg three times daily) and doxycycline (100 mg twice daily) can help to slow the progression of both familial and senile cardiac amyloidosis. The results of the study are due to be released shortly.

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