An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy

An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy

An Open-Label Extension Of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy

This study is designed to determine the long-term safety and tolerability of Fx-1006A as well as the effects of Fx-1006A on clinical outcomes in patients with ATTR-PN. All patients who enroll in this extension study will receive once-daily oral 20 mg Fx-1006A for 12 months; therefore, patients randomized to placebo in Study Fx-005 will cross over to active drug (Fx-1006A 20 mg) during this study. However, patients and their families as well as clinical Investigators and their clinical site staff will remain blinded to the original Fx-005 treatment assignment. It is intended that there will be no interruption in study medication administration between the two studies. The majority of safety and clinical outcomes assessments will be identical to those evaluated in Study Fx-005. Additional assessments for this open-label extension study include 24-hour Holter monitoring and skin biopsy for IENF; patients will be required to provide written informed consent to participate in this open-label extension study prior to having these additional procedures performed. The values obtained from procedures and evaluations conducted during the Month 18 visit of Study Fx-005 will be used as the Baseline values for this open-label extension study. The Baseline assessments of IENF and Holter monitoring may be conducted at either day of the Month 18 visit days of Study Fx-005, but prior to the first Fx-1006A dose in this open-label extension study. Clinic Visits will be conducted at Week 6 (± 2 days), and Month 3 (± 1 week), Month 6 (± 2 weeks), and Month 12 (± 2 weeks). Monthly telephone contacts (± 1 week of the scheduled date) will be made during months in which no investigative site visits are scheduled (Months 2, 4, 5, 7, 8, 9, 10, and 11) for assessment of adverse events and concomitant medications. Neurological evaluation by NIS-LL will be performed at Months 6 and 12. The NIS-LL will be assessed by utilizing the average of two successive NIS-LL clinical assessment scores obtained at least 24 hours apart within a one week period for each study visit. A dedicated neurologist will be required to perform NIS-LL scoring across all time-points for each individual patient enrolled in the study. Quality of life utilizing the Norfolk QOL-DN will be assessed at Months 6 and 12 (based on the total score as well as the five individual domains of the questionnaire). QST (utilizing CASE IV), NCS, HRDB, mBMI, and echocardiography will be conducted at Months 6 and 12. Holter monitoring will be conducted at Baseline and Months 6 and 12. Biopsies for IENF will be obtained at Baseline only. Assessments of troponin I and NT-pro-BNP levels will be made at each study visit. Blood samples for pharmacokinetic assessments (Fx-1006A concentrations as well as calculated steady-state parameters) and pharmacodynamic assessments (TTR stabilization) will be collected at Week 6 and Months 6 and 12. Safety and tolerability will be assessed throughout the study. Vital signs, 12-lead ECG, blood and urine samples for clinical laboratory tests (serum chemistry, hematology, coagulation panel, urinalysis, and urine pregnancy testing), adverse events, and concomitant medications will be assessed at each study visit. Eye examinations (including fundal photography) will be conducted at Months 6 and 12. Abbreviated physical examinations will be conducted at Week 6, and Months 3 and 6, and a complete physical examination will be conducted at Month 12. All patients will be contacted by telephone 30 days (± 1 week) after the last dose of study medication for assessment of adverse events and concomitant medications. Patients who complete the Month 12 visit of this open-label study may be allowed to continue receiving Fx-1006A under a compassionate use program. Patients who discontinue from the study at any time after enrollment (i.e., early termination) will have final safety assessments performed at the time of discontinuation. Any patient discontinuing after the Month 6 visit will have all safety and clinical outcomes assessments scheduled for the Month 12 visit performed.

FAP, Familial Amyloid Polyneuropathy, ATTR-PN, transthyretin, TTR, amyloid, polyneuropathy, familial, hereditary, amyloidosis, FoldRx

Fx-1006A 20mg soft gelatin capsule administered orally once daily (at the same time each day) for 12 months.

Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6

Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than[<] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.

Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12

Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than[<] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.

Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6

Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.

Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12

Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.

NIS-LL: assessed muscle weakness, reflexes and sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) are scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) were scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS-LL score range 0-88, higher score=greater impairment.

Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12

Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7:scored as 1=symptoms present, 0=symptoms absent. Item 8-35:scored on 5-point Likert scale: 0=no problem,4=severe problem (except item 32: -2=much better, 0=about same, 2=much worse). Norfolk QOL-DN summarized in 5 domains(score range):physical functioning/large fiber neuropathy(-2 to 58), activities of daily living(ADLs) (0 to 20), symptoms(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12); higher score=greater impairment,for each. Total score=-2 to138(higher score=worse QOL).

Summated 7 score: composite score included five Nerve Conduction Studies (NCS) attributes (peroneal nerve distal motor latency, peroneal nerve compound muscle action potential, peroneal nerve motor conduction velocity, tibial nerve distal motor latency, and sural nerve sensory nerve action potential amplitude) along with Vibration Detection Threshold (VDT) obtained in great toes, and Heart Rate Response to Deep Breathing (HRDB) value. Score was determined through reference to normal values for age, sex and height. Total score range= -26 to 26, where higher score=worse nerve function.

Summated 3 Nerve Tests Small Fiber Normal Deviates Score (NTSFnds) included cooling threshold for the lower limbs, heat pain threshold for the lower limbs and HRDB. Total score range= -11.2 to 11.2, where higher score=worse nerve function.

BMI was calculated by weight divided by height squared. mBMI was calculated by multiplying BMI by serum albumin levels to compensate for edema formation. A progressive decline in mBMI indicated worsening of disease severity.

Troponin I was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ left ventricular [LV] wall stress).

Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12

NT-proBNP was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ LV wall stress).

IENF density was quantified in 3 millimeter (mm) immunostained skin punch biopsies containing epidermis and superficial dermis to evaluate the amount and morphological appearance of small diameter nerve fibers, both somatic and autonomic, in sensory neuropathies. It is used in diagnosing various neuropathic conditions.

TTR tetramer was assessed using a validated immunoturbidimetric assay. The Fraction of Initial (FOI) is the ratio of the measured TTR tetramer concentration after denaturation to the measured TTR tetramer concentration before denaturation. TTR tetramer stabilization is based on the difference between the on-treatment FOI and the baseline FOI expressed as a percentage of the baseline FOI.

An Adverse Event (AE) was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent/significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug, up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

AE=any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events=death related to an AE. Treatment-emergent events=between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings

Clinically significant ECHO findings included: LV posterior wall thickness greater than or equal to (>=)13 mm, LV septal thickness >= 13 mm, right ventricular thickness >= 7 mm, ratio of peak mitral early diastolic and atrial contraction velocity (E/A ratio) >= 2, prime septal (E/E) >15, ejection fraction < 50 percent (%), E deceleration time <= 150 millisecond (ms), isovolumic relaxation time (IVRT) <= 70 ms, any valve thickening (> trace regurgitation in mitral, aortic, pulmonary, or tricuspid valves), abnormal respiratory variation of inferior vena cava, pericardial effusion.

Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings

Clinically significant ECG findings included: corrected QT (QTc) > 450 ms, QTc >500 ms, change in QTc between 30 and 60 ms, change in QTc greater than or equal to 60 ms.

Clinically significant Holter monitor findings included: atrial fibrillation/flutter, atrial tachycardia, non-sustained ventricular tachycardia (<30 beats), sustained ventricular tachycardia (>= 30 beats), sinus pause (RR >2.0 second, where RR=60/heart rate), ventricular premature contractions.

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Inclusion Criteria: Male and non-pregnant female patients meeting all of the following criteria are eligible for enrollment in this study: Patient has completed the Month 18 visit of Study Fx-005. If female, patient is post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide) throughout the study. (A condom alone is not considered an acceptable method of birth control.) If male with a female partner of childbearing potential, willing to use an acceptable method of birth control for the duration of the study. For both females and males, acceptable birth control must be used for at least 3 months after the last dose of study medication. Patient is, in the opinion of the investigator, willing and able to comply with the study medication regimen and all other study requirements. Patient agrees not to participate in another investigational drug or device study while participating in this open-label extension study. Exclusion Criteria: Patients meeting any of the exclusion criteria will not be enrolled in the study: Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), defined as greater than 3-4 times/month (ibuprofen and nimesulide will be permitted). If female, patient is pregnant or breast feeding. Patient has liver function test abnormalities: alanine transaminases (ALT) and/or aspartate transaminases (AST) >2 times upper limit of normal (ULN) that in the medical judgment of the investigator are due to reduced liver function or active liver disease.

Merlini G, Coelho T, Waddington Cruz M, Li H, Stewart M, Ebede B. Evaluation of Mortality During Long-Term Treatment with Tafamidis for Transthyretin Amyloidosis with Polyneuropathy: Clinical Trial Results up to 8.5 Years. Neurol Ther. 2020 Jun;9(1):105-115. doi: 10.1007/s40120-020-00180-w. Epub 2020 Feb 27.

Huber P, Flynn A, Sultan MB, Li H, Rill D, Ebede B, Gundapaneni B, Schwartz JH. A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy. Amyloid. 2019 Dec;26(4):203-209. doi: 10.1080/13506129.2019.1643714. Epub 2019 Jul 27.

Amass L, Li H, Gundapaneni BK, Schwartz JH, Keohane DJ. Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy. Orphanet J Rare Dis. 2018 Dec 17;13(1):225. doi: 10.1186/s13023-018-0947-7.

Waddington Cruz M, Amass L, Keohane D, Schwartz J, Li H, Gundapaneni B. Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid. 2016 Sep;23(3):178-183. doi: 10.1080/13506129.2016.1207163. Epub 2016 Aug 5.

Coelho T, Maia LF, da Silva AM, Cruz MW, Plante-Bordeneuve V, Suhr OB, Conceicao I, Schmidt HH, Trigo P, Kelly JW, Labaudiniere R, Chan J, Packman J, Grogan DR. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013 Nov;260(11):2802-14. doi: 10.1007/s00415-013-7051-7. Epub 2013 Aug 22.