Doxycycline and tauroursodeoxycholic acid for FAP

Last updated March 26, 2024, by Marisa Wexler, MS
Fact-checked by Marta Figueiredo, PhD

What was doxycycline and TUDCA for FAP?

The combination of doxycycline and tauroursodeoxycholic acid — better known as TUDCA — is a potential oral treatment for transthyretin amyloidosis (ATTR), a group of conditions that includes familial amyloid polyneuropathy (FAP), that’s been investigated for slowing disease progression.

Doxycycline is a long-established antibiotic, while TUDCA has been used to treat certain liver and neurodegenerative diseases.

A combination of the two has been tested in people with transthyretin amyloidosis, including FAP, in a single clinical trial. Now, however, the combo’s clinical development seems to be focused on transthyretin amyloid cardiomyopathy (ATTR-CM), a FAP-related disease marked mostly by damage in the heart instead of the nerves.

Therapy snapshot

How do doxycycline and TUDCA work in FAP?

Transthyretin amyloidosis comprises a group of rare diseases marked by the accumulation of toxic clumps of a protein called transthyretin, which causes damage to certain organs and tissues.

Inherited forms of ATTR such as FAP are caused by mutations in the TTR gene that result in the production of an abnormal transthyretin protein that is prone to forming toxic aggregates, or clumps.

In FAP, also known as hereditary transthyretin amyloidosis with polyneuropathy, these clumps mainly accumulate in the nerves outside the brain and spinal cord, causing nerve damage and the disease’s variety of symptoms.

Doxycycline is an antibiotic that’s been used for decades to help treat certain types of infections. TUDCA, also known as ursodoxicoltaurine and taurursodiol, is a bile acid, a type of substance made naturally in the liver to help with digestion.

TUDCA has been used for treating a number of liver diseases, and also is part of a combination therapy approved as Relyvrio for the treatment of a neurodegenerative disease called amyotrophic lateral sclerosis. As both doxycycline and TUDCA have been in use for many years, their safety profiles are quite well established.

Studies in mouse models of FAP have shown that treatment with TUDCA reduces toxic transthyretin deposits, while doxycycline can break up the toxic aggregates. However, treatment with both was found to be more effective at lowering toxic transthyretin clumps and FAP biomarkers than either medication individually.

It’s thought that, by reducing toxic protein clumps, the combination of doxycycline and TUDCA may help slow the progression of FAP and other forms of ATTR.

How were doxycycline and TUDCA administered in FAP?

Doxycycline and TUDCA are both taken orally. In the single trial that tested the combination therapy in people with FAP, the dosage used was 100 mg of doxycycline, taken twice a day, and 250 mg of TUDCA, taken three times a day.

Doxycycline and TUDCA in FAP clinical trials

The safety and effectiveness of a combination treatment with doxycycline and TUDCA were evaluated in FAP patients in a single Phase 2 trial called DOXYTUDCA2010 (NCT01171859). 

The study was sponsored by Italy’s Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Policlinico S. Matteo and launched in 2010 at a single Italian site.

It tested the effects of the combination therapy in 40 adults with FAP and other forms of ATTR. In the study’s first part, all participants were given 100 mg of doxycycline twice daily and 250 mg of TUDCA three times daily for up to one year. The second part consisted of a withdrawal period in which disease progression was monitored for six months after stopping treatment.

The trial’s main goal was to assess response rates. For participants with polyneuropathy, or damage to several nerves — which typifies FAP — a response to treatment was mainly defined as less than a two-point increase in the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), which assesses neuropathy-related disability in the lower limbs.

Data from the first 20 patients was published in 2012. Of them, 15 had signs of polyneuropathy, or FAP, and six FAP patients completed a full year of treatment.

The NIS-LL scores remained stable over the year of treatment in four of these six patients, and was reduced in another patient, indicating less severe polyneuropathy — a notable difference from the disease’s typical trajectory, in which symptoms worsen over time.

One of the six FAP patients who completed the trial’s first part experienced a greater than two-point NIS-LL score increase, indicating significant disease worsening after a year of treatment.

The results also suggested the combination treatment stabilized or eased cardiomyopathy, or heart damage, in all seven patients — six with FAP, one without — who finished the trial and had signs of such damage at the study’s start.

Quality of life measures tended to improve throughout the study for all 20 patients, though the changes were not statistically significant.

While the trial ended in 2015, no data from the remaining 20 enrolled patients, or from the withdrawal period, have been published to date. Following results from the first group of participants, the IRCCS also launched a Phase 3 trial (NCT03481972) to test doxycycline plus TUDCA as an add-on to standard treatment in people with ATTR-CM. However, no further studies have been conducted that involved FAP patients, and it’s unclear if that indication will be pursued in the future.

Common side effects of doxycycline and TUDCA

In the single trial that tested the combination treatment in FAP patients, which also included people with other forms of ATTR, the only reported side effects were stomach pain, nausea, and loss of appetite. These led two patients to stop the combination therapy within the first month of treatment.

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