Safety And Efficacy Evaluation Of Fx-1006a In Patients With V122i Or Wild-Type Transthyretin (TTR) Amyloid Cardiomyopathy

Safety And Efficacy Evaluation Of Fx-1006a In Patients With V122i Or Wild-Type Transthyretin (TTR) Amyloid Cardiomyopathy

Open-Label Safety And Efficacy Evaluation Of Fx-1006a In Patients With V122i Or Wild-Type Transthyretin (TTR) Amyloid Cardiomyopathy

Open-label Safety and Efficacy Evaluation of Fx-1006a in Patients with V122i Or Wild-type Transthyretin (ttr) Amyloid Cardiomyopathy. Patients who successfully complete Fx1B-201 will report to the clinical unit on Day 0 to sign the informed consent form and determine eligibility for Protocol Fx1B-303. In addition, on Day 0, patients will have their entrance criteria reviewed, and medical histories and demographic characteristics obtained. The physical examination (including weight and vital signs) and the relevant end of study clinical laboratory tests (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, gamma glutamyl transferase, creatinine, total bilirubin, international normalized ratio, troponin I, troponin T, and amino-terminal B-type natriuretic peptide) from Protocol Fx1B-201 will be used for Protocol Fx1B-303. If more than 30 days has elapsed between the final study visit of Protocol Fx1B-201 and Day 0 of Protocol Fx1B-303, an abbreviated physical examination (including weight and vital signs) and clinical laboratory assessments must be performed on Day 0. Eligible patients will begin once-daily dosing with 20 mg Fx-1006A at home on Day 1 (i.e., first dose) and will return to the clinical unit for study visits every 6 months. Adverse events (AEs) and concomitant medication use will be collected at each 6-month visit to the clinical unit. Blood draws for clinical safety laboratory tests and abbreviated physical examinations (including weight and vital signs) will also be performed at each 6-month clinic visit. ECGs will be performed every 12 months on an annual basis. A telephone call will be made at 3-month intervals between clinic visits to assess safety and use of concomitant medications. For the evaluation of efficacy, the Patient Global Assessment, NYHA classification, KCCQ, 6-minute walk test, and efficacy-related clinical laboratory tests (serum levels of troponin T, troponin I, and NT-pro-BNP) will be determined every 6 months. In addition, echocardiograms will be performed every 12 months on an annual basis. An end of study visit including all safety and efficacy assessments will occur upon patient completion of the study, premature withdrawal (for any reason), or in the event of program discontinuation by the Sponsor.

Percentage of Participants With Categories of Patient Global Assessment (PGA) for Follow-up Visit: Month 12

Participants overall quality of life was measured by PGA. At follow-up visit, participants were asked, "How do you feel today as compared to when we talked with you at your last clinic visit for this study?" and participants responded to any of the following: markedly improved, moderately improved, mildly improved, unchanged, mildly worsened, moderately worsened or markedly worsened.

Percentage of Participants With Categories of Patient Global Assessment (PGA) for Follow-up Visit: Month 60

Participants overall quality of life was measured by PGA. At follow-up visit, participants were asked, "How do you feel today as compared to when we talked with you at your last clinic visit for this study?" and participants responded to any of the following: markedly improved, moderately improved, mildly improved, unchanged, mildly worsened, moderately worsened or markedly worsened.

Number of Participants Classified on the Basis of New York Heart Association (NYHA) Classification at Baseline

NYHA classified participants in 4 classes. Class I included participants with cardiac disease without limitations of physical activity. Ordinary physical activity did not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II included participants with cardiac disease with slight limitation of physical activity. They were comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea, or anginal pain. Class III included participants with cardiac disease with marked limitation of physical activity. They were comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea, or anginal pain. Class IV included participants with cardiac disease with the inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome might be present even at rest. If any physical activity was undertaken, discomfort was increased.

Number of Participants With Change From Baseline in New York Heart Association (NYHA) Classification at Month 12

NYHA classified participants in 4 classes: Class I: cardiac disease without limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or angina pain. Class II: cardiac disease with slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or angina pain. Class III: cardiac disease with marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or angina pain. Class IV: cardiac disease with inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or angina syndrome might be present even at rest. If any physical activity was undertaken, discomfort was increased. Participants with change from baseline were classified as improved (shifted from higher to lower class), unchanged (no change in class) or worsened (shifted from lower to higher class).

Number of Participants With Change From Baseline in New York Heart Association (NYHA) Classification at Month 60

NYHA classified participants in 4 classes: Class I: cardiac disease without limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or angina pain. Class II: cardiac disease with slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or angina pain. Class III: cardiac disease with marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or angina pain. Class IV: cardiac disease with inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or angina syndrome might be present even at rest. If any physical activity was undertaken, discomfort was increased. Participants with change from baseline were classified as improved (shifted from higher to lower class), unchanged (no change in class) or worsened (shifted from lower to higher class).

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, the total distance that a participant could walk in 6 minutes was evaluated.

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, the total distance that a participant could walk in 6 minutes was evaluated.

Number of Participants Categorized Based on Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 12

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, participants were categorized based on the total distance walked as Level 1 = total distance walked less than (<) 300 meter; Level 2 = total distance walked between 300 to 374.9 meter; Level 3 = total distance walked between 375 to 449.9 meter; Level 4 = total distance walked greater than or equal to (>=) 450 meter.

Number of Participants Categorized Based on Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 60

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, participants were categorized based on the total distance walked as Level 1 = total distance walked < 300 meter; Level 2 = total distance walked between 300 to 374.9 meter; Level 3 = total distance walked between 375 to 449.9 meter; Level 4 = total distance walked >=450 meter.

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. Dyspnea: participants were asked to rate the difficulty of their breathing, pre-walk and post-walk at each visit, on a scale of range 0 (no breathlessness at all) to 10 (maximum breathlessness). Higher scores indicated more severity. Fatigue: participants were asked to rate the how tired they felt, pre-walk and post-walk at each visit, on a scale of range 0 (not at all) to 10 (maximal) Higher scores indicated more fatigue. At each visit, scores for pre-walk test, post-walk test and within visit difference (difference from post-walk to pre-walk) were evaluated. Change from baseline was calculated for each pre-walk test, post-walk test and within visit difference at Month 12.

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. Dyspnea: participants were asked to rate the difficulty of their breathing, pre-walk and post-walk at each visit, on a scale of range 0 (no breathlessness at all) to 10 (maximum breathlessness). Higher scores indicated more severity. Fatigue: participants were asked to rate the how tired they felt, pre-walk and post-walk at each visit, on a scale of range 0 (not at all) to 10 (maximal) Higher scores indicated more fatigue. At each visit, scores for pre-walk test, post-walk test and within visit difference (difference from post-walk to pre-walk) were evaluated. Change from baseline was calculated for each pre-walk test, post-walk test and within visit difference at Month 60.

Number of Participants Categorized on Basis of Change From Baseline in Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 12

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, participants on basis of change from baseline in total distance walked were categorized as worsened, unchanged or improved. If distance walked at a visit was greater than distance walked at baseline, then categorized as 'improved'. If distance walked at a visit was equal to distance walked at baseline, then categorized as 'unchanged'. If distance walked at a visit was less than distance walked at baseline, then categorized as 'worsened'.

Number of Participants Categorized on Basis of Change From Baseline in Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 60

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, participants on basis of change from baseline in total distance walked were categorized as worsened, unchanged or improved. If distance walked at a visit was greater than distance walked at baseline, then categorized as 'improved'. If distance walked at a visit was equal to distance walked at baseline, then categorized as 'unchanged'. If distance walked at a visit was less than distance walked at baseline, then categorized as 'worsened'.

KCCQ is a 23-item participant-completed questionnaire that assesses health status and health-related quality of life in participants with heart failure. Eight domain scores were calculated for the KCCQ: physical limitation, social limitation, quality of life, self-efficacy, symptom stability, symptom frequency, symptom burden, and total symptoms (calculated as the mean of symptom frequency and symptom burden scores). Two summary scores were calculated: clinical summary (calculated as mean of physical limitation and total symptom scores) and overall summary (calculated as mean of physical limitation, social limitation, total symptoms, and quality of life scores). Each domain and both summary scores were scaled to range from 0 (worse health status) to 100 (best health status); higher scores represented better health status.

KCCQ is a 23-item participant-completed questionnaire that assesses health status and health-related quality of life in participants with heart failure. Eight domain scores were calculated for the KCCQ: physical limitation, social limitation, quality of life, self-efficacy, symptom stability, symptom frequency, symptom burden, and total symptoms (calculated as the mean of symptom frequency and symptom burden scores). Two summary scores were calculated: clinical summary (calculated as mean of physical limitation and total symptom scores) and overall summary (calculated as mean of physical limitation, social limitation, total symptoms, and quality of life scores). Each domain and both summary scores were scaled to range from 0 (worse health status) to 100 (best health status); higher scores represented better health status.

Troponin I and troponin T are the cardiac markers. Troponin I and troponin T are part of the troponin complex, where troponin I is bound to actin in thin myofilaments and troponin T is bound to tropomyosin. Higher level of these markers is indicative of heart damage.

Troponin I and troponin T are the cardiac markers. Troponin I and troponin T are part of the troponin complex, where troponin I is bound to actin in thin myofilaments and troponin T is bound to tropomyosin. Higher level of these markers is indicative of heart damage.

Change From Baseline in Amino-Terminal B-type Natriuretic Peptide (NT-proBNP) Serum Level at Month 12

NT-proBNP is biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ left ventricular [LV] wall stress).

Change From Baseline in Serum Levels of Amino-Terminal B-type Natriuretic Peptide (NT-proBNP) at Month 60

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

Percentage of Participants With Categories of Patient Global Assessment (PGA) for Follow-up Visit: Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126 and 132

Participants overall quality of life was measured by PGA. At each follow-up visit, participants were asked, "How do you feel today as compared to when we talked with you at your last clinic visit for this study?" and participants responded to any of the following: markedly improved, moderately improved, mildly improved, unchanged, mildly worsened, moderately worsened or markedly worsened.

Number of Participants With Change From Baseline in New York Heart Association (NYHA) Classification at Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126 and 132

NYHA classified participants in 4 classes: Class I: cardiac disease without limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or angina pain. Class II: cardiac disease with slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or angina pain. Class III: cardiac disease with marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or angina pain. Class IV: cardiac disease with inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or angina syndrome might be present even at rest. If any physical activity was undertaken, discomfort was increased. Participants with change from baseline were classified as improved (shifted from higher to lower class), unchanged (no change in class) or worsened (shifted from lower to higher class).

Change From Baseline in Total Distance Walked During 6 Minute Walk Test (6MWT) at Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120 and 132

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, the total distance that a participant could walk in 6 minutes was evaluated.

Number of Participants Categorized Based on Total Distance Walked During 6 Minute Walk Test (6MWT) at Baseline, Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126 and 132

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, participants were categorized based on the total distance walked as Level 1 = total distance walked < 300 meter; Level 2 = total distance walked between 300 to 374.9 meter; Level 3 = total distance walked between 375 to 449.9 meter; Level 4 = total distance walked >=450 meter.

Change From Baseline in Dyspnea and Fatigue Scores During 6 Minute Walk Test (6MWT) at Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120 and 132

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. Dyspnea: participants were asked to rate the difficulty of their breathing, pre-walk and post-walk at each visit, on a scale of range 0 (no breathlessness at all) to 10 (maximum breathlessness). Higher scores indicated more severity. Fatigue: participants were asked to rate the how tired they felt, pre-walk and post-walk at each visit, on a scale of range 0 (not at all) to 10 (maximal) Higher scores indicated more fatigue. At each visit, scores for pre-walk test, post-walk test and within visit difference (difference from post-walk to pre-walk) were evaluated. Change from baseline was calculated for each pre-walk test, post-walk test and within visit difference at specified visits.

Number of Participants Categorized on Basis of Change From Baseline in Total Distance Walked During 6 Minute Walk Test (6MWT) at Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120 and 132

6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance. Participants were asked to walk as far as possible for 6 minutes at a pace that was comfortable to them, and were permitted to slow down, to stop, and to rest as necessary. In this outcome measure, participants on basis of change from baseline in total distance walked were categorized as worsened, unchanged or improved. If distance walked at a visit was greater than distance walked at baseline, then categorized as 'improved'. If distance walked at a visit was equal to distance walked at baseline, then categorized as 'unchanged'. If distance walked at a visit was less than distance walked at baseline, then categorized as 'worsened'.

Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Summary Score at Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126 and 132

KCCQ is a 23-item participant-completed questionnaire that assesses health status and health-related quality of life in participants with heart failure. Eight domain scores were calculated for the KCCQ: physical limitation, social limitation, quality of life, self-efficacy, symptom stability, symptom frequency, symptom burden, and total symptoms (calculated as the mean of symptom frequency and symptom burden scores). Two summary scores were calculated: clinical summary (calculated as mean of physical limitation and total symptom scores) and overall summary (calculated as mean of physical limitation, social limitation, total symptoms, and quality of life scores). Each domain and both summary scores were scaled to range from 0 (worse health status) to 100 (best health status); higher scores represented better health status.

Echocardiography abnormalities included: absent respiratory variation of inferior vena cava, any valve thickening, aortic valve thickening, decreased respiratory variation of inferior vena cava, dilated inferior vena cava, E deceleration time less than or equal to (<=) 150 millisecond, E wave/A Wave (E/A) ratio >=2, ejection fraction < 50%, isovolumic relaxation time (IVRT) <=70 millisecond, left ventricular posterior wall thickness >=13 millimeter (mm), left ventricular septal thickness >= 13 mm, mitral valve thickening, pericardial effusion, pulmonary valve thickening, right ventricular thickness >=7 mm, tricuspid valve thickening, ratio between early mitral inflow velocity and mitral annular early diastolic velocity (e/e') Lateral greater than (>) 15, e/e' Septal >15.

Change From Baseline in Troponin I and Troponin T Serum Levels at Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120 and 126

Troponin I and troponin T are the cardiac markers. Troponin I and troponin T are part of the troponin complex, where troponin I is bound to actin in thin myofilaments and troponin T is bound to tropomyosin. Higher level of these markers is indicative of heart damage.

Change From Baseline in Amino-Terminal B-type Natriuretic Peptide (NT-proBNP) Serum Level at Months 6, 18, 24, 30, 36, 42, 48, 54, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120 and 126

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

All cause hospitalization was defined as any serious adverse event, which resulted in hospitalization. Cardiac-related hospitalization was any hospitalization meeting the following criteria: cardiac disorders or AE preferred term as chest discomfort, chest pain, death, cerebrovascular accident, embolic stroke, disease progression.

Time to death for all participants with a death date in Clinical Database, or censored at the last dose date + 28 days for those participants who were alive at the end of the study is reported.

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. 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; medically important events. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and all non-serious adverse events.

Number of Participants With Treatment-Related Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and all non-serious adverse events. Relatedness to study drug was assessed by the investigator as (Yes/No).

Physical examination included examination of general appearance, endocrine, head and neck, cardiovascular, eyes, abdomen, ears, skin, nose, musculoskeletal, throat, neurological, respiratory, immunologic/allergies, genitourinary, hematologic/lymphatic. Clinical significance of any physical examination finding was judged by investigator.

ECG parameters included PR interval (millisecond), RR interval (millisecond), QRS interval (millisecond), QT and QTc interval (millisecond) and heart rate (beats per minute). Clinical significance of any ECG finding was judged by investigator.

Laboratory parameters included hematology and biochemistry: alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, gamma glutamyl transferase (GGT), creatinine, total bilirubin, international normalized ratio (INR), troponin I, troponin T, prothrombin time, sodium, globulin potassium, chloride, bicarbonate, cholesterol, calcium, uric acid, inorganic phosphorous, thyroid-stimulating hormone, glucose, total thyroxine (T4), free T4, total proteins, prealbumin (transthyretin), albumin, hemoglobin, platelets, hematocrit, white blood cell count, red blood cell count, neutrophils, packed cell volume, lymphocytes, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, eosinophils, mean corpuscular hemoglobin concentration, basophils, retinol-binding protein, Urinalysis: bilirubin, pH, blood (free Hb), protein, nitrite, glucose, urobilinogen, ketones, specific gravity.

Inclusion Criteria: Patient successfully completed Protocol Fx1B-201. If female; patient is post menopausal. If male, female partner is post-menopausal. If female is of child bearing potential, willing to use acceptable method of birth control up to 3 months after last dose (included female partners of male participants). Patient is willing to comply with protocol. Exclusion Criteria: Patient did not successfully complete Fx1B-201. Chronic use of NSAIDS. Patient has a clinically significant medication condition that increases risk of study participation. Patient has received heart or liver transplant.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=FX1B-303&StudyName=Safety%20And%20Efficacy%20Evaluation%20Of%20Fx-1006a%20In%20Patients%20With%20V122i%20Or%20Wild-Type%20Transthyretin%20%28TTR%29%20Amyloid%20Cardiomyopathy%20