**3.3 Treatment of familial ATTR**

Disease modifying treatments have become available for FAP since 1990s, starting with liver transplantation (**Figure 3**). Treatment strategies include: (1), depleting the source of mutant TTR (liver transplantation); (2), inhibition of formation of TTR (wild type and mutant), by preventing translation of mRNA with antisense oligonucleotide (ASO) or with small interfering RNA (siRNA) technologies; (3), stabilization of TTR tetramere by small molecules (diflunisal and tafamidis); and (4), therapy directed to remove the amyloid deposits [19]. Currently approved disease modifying treatments by US food and drug administration (FDA) include inotersen and patisiran; with tafamidis approval under FDA review.

#### *3.3.1 Liver transplantation*

Removing the source of mutant TTR (liver) was the first disease modifying treatment for FAP. Liver transplantation, however, involves a major surgery, which is not tolerated with patients with significant underlying cardiovascular disease, and necessitates lifelong immunosuppression. Overall 5 year survival after liver transplantation is ~80% [50]. The 5 and 10 years survival rates post- transplantation were significantly better after Val30Met cases (82 and 74%) than the other mutations [50, 51]. Cardiomyopathy is a major determinant of prognosis with 10-year survival rates of 92 and 64% post-transplantation for patients without and with cardiomyopathy in a previous study [52]. Furthermore, liver transplant is more effective in changing the natural course of the disease in early onset Val30Met than the late onset cases, which could be due to more severe cardiomyopathy in the latter subtype [53]. Liver transplant is not an effective treatment for ATTRwt, leptomeningeal and ocular amyloidosis. Although ~90% of patients with early sensory neuropathy demonstrate disease stability after a liver transplant, organ involvement is not usually reversed, furthermore, FAP, and specially cardiomyopathy often deteriorate gradually post-transplant due to the deposition of ATTRwt [54, 55]. Advanced age and malnutrition are also risk factors for poor outcome/survival after liver transplantation [53, 56], partly because there is more predisposition to deposition of wild-type TTR in older age.

**97**

*Neurological Manifestations of Transthyretin-Related Amyloidosis*

Combined liver-kidney or liver-heart, and rarely liver-heart-kidney transplantation

Nonsteroidal anti-inflammatory drugs (NSAIDs) and tafamidis meglumine inhibit TTR tetramere degradation and therefore formation of amyloidogenic monomers. NSAIDs have structural resemblance to thyroxine, a natural tetramere stabilizer. Diflunisal and tafamidis are disease modifying treatments for fATTR.

In a randomized, double blinded, placebo controlled trial on 130 patients with FAP, diflunisal 250 mg twice a day was well tolerated and slowed the progression of neuropathy over a period of 2 years [57]. In that study, the Neuropathy Impairment +7 (NIS + 7) score increased by an average of 25.0 points in the placebo group versus 8.7 points in the diflunisal group (increase indicates deterioration of neuropathy). On the other hand, diflunisal also had a favorable effect on the quality of life; average of 36-Item Short-Form Health Survey (SF-36) physical scores decreased by 4.9 points in the placebo group and increased by 1.5 points in the diflunisal group. Modified body mass index (BMI), the product of serum albumin concentration (measured in grams per liter) and BMI (calculated as weight in kilograms divided by height in meters squared), which is an indicator of malnutrition and correlates with survival in FAP [58, 59], was the only endpoint which did not show improvement with diflunisal. In another study on 40 Japanese patients with fATTR, diflunisal was effective on neurological and cardiological manifestations after a period of 24 months, 3 patients could not tolerate diflunisal because of declining renal function or thrombocytopenia [60]. Diflunisal is inexpensive and widely available, but some of the potential problems associated with NSAIDs in general, such as gastrointestinal adverse effects including bleeding, limit its use, and caution is to be

exercised in its use in the setting of underlying heart or kidney disease [61].

Tafamidis was the approved in European Union in 2011, for adult patients with early FAP regardless of the type of mutation [12]. It has since also been approved in Argentina, Japan and Mexico, for delaying the neurological disabilities of FAP [62]. Tafamidis binds selectively to the two normally unoccupied thyroxinebinding sites of the tetramer, and kinetically stabilizes TTR, including the less stable mutant TTR tetramers, preventing the tetramer dissociation, which is the rate-limiting step in the generation of amyloidogenic monomers [63] (**Figure 1**). In a previous study, 98% of the patients had TTR stabilization after 18 months of tafamidis [64]. Tafamidis is more effective in early onset Val30Met cases than late onset Val30Met and non-Val3 Met mutations, there was progression of disability score in 55% and deterioration of neuropathy score of most of patients with lateonset ATTR V30 M involved in a nonrandomized controlled trial [13]. In a double blinded multicenter study, tafamidis 20 mg per day, was compared to placebo in an 18-month study in adult patients with early-stage Val30Met TTR-FAP [64]. There were no statistically significant differences between tafamidis and placebo for the coprimary endpoints (changes of the Neuropathy Impairment Score-Lower Limb (NIS-LL) and Norfolk Quality-of- Life (QOL) Diabetic-Neuropathy Questionnaire) in the intent to treat population, which included patients who dropped out for liver transplantation. On the other hand, in the efficacy evaluable

has been used for FAP patients with advanced renal or heart disease [55].

*DOI: http://dx.doi.org/10.5772/intechopen.84470*

*3.3.2 Stabilizers of TTR tetramere*

*3.3.2.1 Diflunisal*

*3.3.2.2 Tafamidis (Vyndaqel)*

#### **Figure 3.**

*Treatment strategies for fATTR (modified, from [92], with permission).*

Combined liver-kidney or liver-heart, and rarely liver-heart-kidney transplantation has been used for FAP patients with advanced renal or heart disease [55].
