*3.3.2.2 Tafamidis (Vyndaqel)*

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 population, tafamidis patients had significantly better outcomes with the primary endpoints. Furthermore, tafamidis group had more favorable outcomes in the secondary endpoints which included changes in neurologic function, nutritional status, and TTR stabilization. Tafamidis is generally well tolerated including in long term, post-marketing, extension studies, with the majority of adverse effects of mild to moderate severity [64, 65].

#### *3.3.3 Gene therapies*

Inhibiting the transcription of TTR mRNA by gene silencing technologies such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNA) constitute most promising approaches in the treatment of FAP. Inotersen and patisiran were approved by FDA in 2018.

#### *3.3.3.1 Inotersen*

Inotersen is a 2′-O-methoxyethyl-modified ASO, which selectively binds to the TTR complementary RNA and inhibits the liver synthesis of both wild-type and mutant TTR. In a double blinded 15 months study, NEURO-TTR, FAP patients in earlier neuropathy stages (ambulatory with or without assistance) received weekly subcutaneous injections of inotersen 300 mg after loading dose of 3 doses in the first week, versus placebo [66]. All of the patients also received daily Vitamin A supplementation 3000 IU. The serum TTR level in the inotersen group significantly dropped from its baseline with a median nadir of 79.0% from week 13 to 65. Inotersen recipients did significantly better in the primary endpoints: there was a difference in the least-square mean of 19.7 points in modified Neuropathy Impairment Score+7 (mNIS+7) and 11.7 points in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN), favoring inotersen group, after 66 weeks of treatment. Inotersen also slowed the weight loss with a statistical trend towards efficacy on decline of BMI. Improvement of the course of FAP and quality of life in the patients who received inotersen occurred regardless of the mutation type or the presence of cardiomyopathy. This study did not have sufficient power to assess efficacy of inotersen on cardiomyopathy. Significant side effects of inotersen included glomerulonephritis and thrombocytopenia. 23% of inotersen recipients developed a platelet count below 100 × 109 /L, and three patients had platelet counts to <25 × 109 /L, one of whom died of brain hemorrhage. Antiplatelet antibodies were positive in all of the 3 patients with severe thrombocytopenia pointing to the immune mediated nature of this complication. As thrombocytopenia associated with ASO treatment can be severe and fatal, platelet counts should be closely monitored in patients who receive inotersen. Patients who developed nephropathy had a crescentic glomerulonephritis on the background of amyloidosis, kidney function in one patients improved after treatment with prednisone and cyclophosphamide; therefore, monitoring of kidney function and urine protein are also necessary during treatment with inotersen. As a matter of fact, there was no additional cases of severe thrombocytopenia, and only a single patient developed a mild glomerulonephritis after the implementation of enhanced monitoring in the NEURO-TTR study. Local skin reactions were generally mild and did not result in discontinuation of the treatment in any patient.

#### *3.3.3.2 Patisiran*

Patisiran is a siRNA oligonucleotide wrapped in nanoparticles for specialized delivery to the liver, where it targets the 3′ untranslated region of TTR's messenger RNA, resulting its cleavage, and therefore lack of transcription of TTR mRNA to

**99**

*Neurological Manifestations of Transthyretin-Related Amyloidosis*

a protein product. Treatment with patisiran therefore results in reduction in the production of both wild-type and mutant TTR. After preliminary studies showed dose dependent reduction of serum TTR in normal subjects and patients with FAP who received patisiran, and possible favorable effect on the course of neuropathy in a phase 2 study [67, 68], a recent phase 3 double blinded (APOLLO) study compared patisiran 0.3 mg/kg every 3 weeks intravenously to placebo in patients with FAP [69]. Patients who had undergone liver transplantation or those with advanced heart failure were excluded. Treatment with patisiran resulted in sustained reduction of serum TTR over a period of 18 months (median 81%, range − 38–95). Patisiran recipients did significantly did better in all primary endpoints: the least-squares mean mNIS+7 change from baseline was −6.0 in the patisiran versus + 28.0 in the placebo group (difference of 34.0 points favoring the patisiran group; P < 0.001) and the effect could be seen as early as 9 months; The least-squares mean change from baseline in Norfolk QOL-DN was −6.7 in patisiran versus 14.4 in the placebo group (difference, −21.1 points, P < 0.001); patisiran recipients also did better with the modified BMI and gait speed. Fifty one percent of patients who received patisiran versus 10% of those on placebo had improvement in the Norfolk QOL-DN score after 18 months. Treatment efficacy included patients with Val30Met as well as other mutations, and included sensory, motor and autonomic aspects of neuropathy. Patients in the patisiran group also had better cardiac outcomes, i.e. changes in NT-proBNP, left ventricular wall thickness and longitudinal stress, than those on placebo. The side effects that were more common in the patisiran than the placebo included infusion-related reactions (19%) and peripheral edema (30%). Infusion reactions (back pain, flushing, abdominal pain, and nausea) were mild to moderate and only one patient dropped from the study as their result. Thrombocytopenia and nephropathy were not among the

A combination of doxycycline, which is proposed to disrupt deposited fibrillar TTR amyloid fibrils [19, 55, 70] and tauroursodeoxycholic acid (a biliary acid, and also a disrupter of nonfibrillar TTR) has been effective in removal of amyloid deposits in a mouse model [71]. Another promising approach to resolve existing amyloid deposits is targeting serum amyloid P (SAP) component, which has an avid binding to all amyloid fibril types, resulting in stabilization of the amyloid fibrils and preventing their proteolysis [72]; antibodies to SAP have been promising in animal models of amyloidosis [73], and are being investigated in different forms of

**4. Wild-type ATTR (ATTRwt), aka. senile systemic amyloidosis**

Systemic Deposition of ATTRwt is a rather common process associated with aging. Previous studies have reported a prevalence of 12–25% for tissue deposition of ATTRwt in people older than 80 year old [74, 75]. Despite very common prevalence in postmortem and tissue studies, ATTRwt is not a very recognized entity among the community physicians and therefore it is rather underdiagnosed. Patients with ATTRwt typically present with cardiac manifestations, including congestive heart failure, atrial fibrillation and other arrhythmias. ATTRwt is increasingly diagnosed as a cause of heart failure with preserved ejection fraction (HFpEF) [76]. Embolic evens are frequently encountered, mean survival period from the onset of congestive heart failure symptoms is ~75 months [19]. There are differences between fATTR and ATTRwt in the pattern and shape of tissue amyloid

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

patisiran related side effects in that study.

*3.3.4 Other potential treatments*

human amyloidosis.

#### *Neurological Manifestations of Transthyretin-Related Amyloidosis DOI: http://dx.doi.org/10.5772/intechopen.84470*

*Amyloid Diseases*

*3.3.3 Gene therapies*

*3.3.3.1 Inotersen*

approved by FDA in 2018.

count below 100 × 109

of mild to moderate severity [64, 65].

population, tafamidis patients had significantly better outcomes with the primary endpoints. Furthermore, tafamidis group had more favorable outcomes in the secondary endpoints which included changes in neurologic function, nutritional status, and TTR stabilization. Tafamidis is generally well tolerated including in long term, post-marketing, extension studies, with the majority of adverse effects

Inhibiting the transcription of TTR mRNA by gene silencing technologies such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNA) constitute most promising approaches in the treatment of FAP. Inotersen and patisiran were

Inotersen is a 2′-O-methoxyethyl-modified ASO, which selectively binds to the TTR complementary RNA and inhibits the liver synthesis of both wild-type and mutant TTR. In a double blinded 15 months study, NEURO-TTR, FAP patients in earlier neuropathy stages (ambulatory with or without assistance) received weekly subcutaneous injections of inotersen 300 mg after loading dose of 3 doses in the first week, versus placebo [66]. All of the patients also received daily Vitamin A supplementation 3000 IU. The serum TTR level in the inotersen group significantly dropped from its baseline with a median nadir of 79.0% from week 13 to 65. Inotersen recipients did significantly better in the primary endpoints: there was a difference in the least-square mean of 19.7 points in modified Neuropathy Impairment Score+7 (mNIS+7) and 11.7 points in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN), favoring inotersen group, after 66 weeks of treatment. Inotersen also slowed the weight loss with a statistical trend towards efficacy on decline of BMI. Improvement of the course of FAP and quality of life in the patients who received inotersen occurred regardless of the mutation type or the presence of cardiomyopathy. This study did not have sufficient power to assess efficacy of inotersen on cardiomyopathy. Significant side effects of inotersen included glomerulonephritis and thrombocytopenia. 23% of inotersen recipients developed a platelet

/L, and three patients had platelet counts to <25 × 109

of whom died of brain hemorrhage. Antiplatelet antibodies were positive in all of the 3 patients with severe thrombocytopenia pointing to the immune mediated nature of this complication. As thrombocytopenia associated with ASO treatment can be severe and fatal, platelet counts should be closely monitored in patients who receive inotersen. Patients who developed nephropathy had a crescentic glomerulonephritis on the background of amyloidosis, kidney function in one patients improved after treatment with prednisone and cyclophosphamide; therefore, monitoring of kidney function and urine protein are also necessary during treatment with inotersen. As a matter of fact, there was no additional cases of severe thrombocytopenia, and only a single patient developed a mild glomerulonephritis after the implementation of enhanced monitoring in the NEURO-TTR study. Local skin reactions were generally

mild and did not result in discontinuation of the treatment in any patient.

Patisiran is a siRNA oligonucleotide wrapped in nanoparticles for specialized delivery to the liver, where it targets the 3′ untranslated region of TTR's messenger RNA, resulting its cleavage, and therefore lack of transcription of TTR mRNA to

/L, one

**98**

*3.3.3.2 Patisiran*

a protein product. Treatment with patisiran therefore results in reduction in the production of both wild-type and mutant TTR. After preliminary studies showed dose dependent reduction of serum TTR in normal subjects and patients with FAP who received patisiran, and possible favorable effect on the course of neuropathy in a phase 2 study [67, 68], a recent phase 3 double blinded (APOLLO) study compared patisiran 0.3 mg/kg every 3 weeks intravenously to placebo in patients with FAP [69]. Patients who had undergone liver transplantation or those with advanced heart failure were excluded. Treatment with patisiran resulted in sustained reduction of serum TTR over a period of 18 months (median 81%, range − 38–95). Patisiran recipients did significantly did better in all primary endpoints: the least-squares mean mNIS+7 change from baseline was −6.0 in the patisiran versus + 28.0 in the placebo group (difference of 34.0 points favoring the patisiran group; P < 0.001) and the effect could be seen as early as 9 months; The least-squares mean change from baseline in Norfolk QOL-DN was −6.7 in patisiran versus 14.4 in the placebo group (difference, −21.1 points, P < 0.001); patisiran recipients also did better with the modified BMI and gait speed. Fifty one percent of patients who received patisiran versus 10% of those on placebo had improvement in the Norfolk QOL-DN score after 18 months. Treatment efficacy included patients with Val30Met as well as other mutations, and included sensory, motor and autonomic aspects of neuropathy. Patients in the patisiran group also had better cardiac outcomes, i.e. changes in NT-proBNP, left ventricular wall thickness and longitudinal stress, than those on placebo. The side effects that were more common in the patisiran than the placebo included infusion-related reactions (19%) and peripheral edema (30%). Infusion reactions (back pain, flushing, abdominal pain, and nausea) were mild to moderate and only one patient dropped from the study as their result. Thrombocytopenia and nephropathy were not among the patisiran related side effects in that study.
