Spencer D. Guthrie

First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction

PURPOSE Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). PATIENTS AND METHODS Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. RESULTS Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease. CONCLUSION Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.

Epidemiology of AL amyloidosis: a real-world study using US claims data

Amyloid light-chain (AL) amyloidosis is a rare disease caused by extracellular deposition of misfolded immunoglobulin light chains. This study aimed to provide an up-to-date estimate of prevalence and incidence of AL amyloidosis in the United States. Using claims databases from years 2007 to 2015, adults ≥18 years old with AL amyloidosis were included if they had (1) at least 1 inpatient or 2 outpatient claims consistent with AL amyloidosis and (2) received 1 AL-specific treatment. Prevalence was calculated as the number of AL patients divided by the number of enrollees on June 30th of each calendar year. Incidence was calculated as the number of patients with AL who were disease-free and enrolled with a health plan for 1 year prior, divided by the number of enrollees with enrollment from July 1st of the previous year to June 30th of each calendar year. The prevalence of AL amyloidosis increased significantly between 2007 and 2015, from 15.5 cases per million in 2007 to 40.5 in 2015, an annual percentage change (APC) of 12% (P < .001). The incidence ranged from 9.7 to 14.0 cases per million person-years (APC, 3%; P = .114) with no statistically significant increase. There was an increase in AL amyloidosis prevalence over a 9-year period coupled with stable incidence rates. Although there is no diagnosis code specific to AL amyloidosis and no validated method for identifying this condition using claims data, extrapolating from our data, there are at least 12 000 adults in the United States living with AL amyloidosis, and the number seems likely to rise.

The burden of amyloid light chain amyloidosis on health-related quality of life

BackgroundLight chain (AL) amyloidosis is a rare disease characterized by misfolded amyloid protein deposits in tissues and vital organs, and little is known about the burden of AL amyloidosis on health-related quality of life. This study aimed to quantify the burden of AL amyloidosis in terms of health-related quality of life in a diverse, community-based sample of AL amyloidosis patients.ResultsThe SF-36v2® Health Survey (SF-36v2), a widely used generic measure of health-related quality of life (using physical and mental summary scales and subscales assessing eight aspects of functioning and well-being), was administered as an online survey of AL amyloidosis patients with AL amyloidosis (ClinicalTrials.gov, NCT02574676; n = 341). Compared with adjusted general population sample norms, health-related quality of life of AL amyloidosis patients was significantly worse across all SF-36v2 scales and summary measures based on analysis of variance (p < 0.05 for all). The largest decrement in AL amyloidosis patients was related to General Health (Δ = 9.7; p < 0.001). With the exception of Bodily Pain and Mental Health, differences were also clinically meaningful based on established clinically minimal important differences. The burden of AL amyloidosis overall and in key subgroups tended to be greater on physical health than on mental health. Stratified analyses indicated additional burden among patients with recently diagnosed disease and those with cardiac involvement than among their respective counterparts.ConclusionUnderstanding the burden of AL amyloidosis highlights the unmet need for treatment, helps physicians identify ancillary treatments and services geared towards improving patients’ functioning, well-being, and overall health-related quality of life. These findings also help to support the use of health-related quality of life end points as important outcome measures in current and future treatment studies.Trial registrationClinicalTrials.gov, NCT02574676. Registered October 5, 2015.

Primary Amyloidosis With Renal Involvement: Outcomes in 77 Consecutive Patients at a Single Center

Background Outcomes in primary amyloid renal patients are of interest as the era of monoclonal antibody therapies begins. Patients and Methods We studied 77 consecutive primary amyloid renal patients (58% men) for renal progression (end stage renal disease [ESRD]), renal response (RR), and overall survival (OS). Results At diagnosis median age was 63 (range, 35‐81) years, estimated glomerular filtration rate 70 mL/min (range, 5‐114), difference between involved and uninvolved free light chains 127 mg/L (range, 1‐9957), ESRD 4%, renal stage 2 and 3 78%, and cardiac stage 2 and 3 56%. Ninety‐six percent received bortezomib and 44% stem cell transplantation as well as bortezomib, 68% achieved complete or very good partial hematologic response (CR/VGPR), 34% had ESRD, and 39% RR. Median times to ESRD and RR were 18 (range, 3‐81) and 12 (range, 2‐30) months, respectively. Median OS was not reached in this cohort and was not reached from onset of ESRD. More than two‐thirds of patients with ESRD also achieved CR/VGPR. In those without ESRD at diagnosis, baseline creatinine and absent RR predicted progression to ESRD in multivariate Cox regression analysis, whereas CR/VGPR predicted RR. In multivariate Cox regression analysis, cardiac stage and achievement of CR/VGPR predicted OS, enabling construction of a prognostic model. Conclusion Anti‐plasma cell therapies provide a definite albeit limited benefit and new approaches to amyloid‐related organ dysfunction are needed. Micro‐Abstract In primary amyloidosis toxic clonal immunoglobulins damage and deposit in the heart, kidneys and other organs. We report on 77 consecutive patients with primary amyloidosis and renal involvement treated and followed over a 7‐year period. Although two thirds achieved deep hematologic responses with chemotherapy, over a third progressed to ESRD, an outcome highlighting the hitherto unmet need for anti‐amyloid therapy.

A longitudinal evaluation of health‐related quality of life in patients with AL amyloidosis: associations with health outcomes over time

Light chain (AL) amyloidosis is a rare disease associated with significant, irreversible organ dysfunction and high case fatality. An observational study was conducted to assess health‐related quality of life (HRQoL) in patients treated for AL amyloidosis between 1994 and 2014 with both high dose melphalan and stem cell transplantation (HDM/SCT) or non‐SCT chemotherapy regimens. The SF‐36v1® Health Survey (SF‐36) was administered to assess HRQoL during clinic visits. Analysis of variance was used to compare pre‐ and post‐treatment HRQoL within each treatment group to an age‐ and gender‐adjusted general population (GP) normative sample. Cox proportional hazard models were fit to examine associations between pre‐treatment levels of HRQoL and mortality within 1 and 5 years after initiating specific treatment regimens (HDM/SCT: n = 402; non‐SCT chemotherapy regimens: n = 172). Among patients who received HDM/SCT, there were significant improvements following treatment in vitality, social functioning, role‐emotional and mental health. Worse pre‐treatment SF‐36 physical component scores were associated with a greater risk of mortality in both treatment groups and follow‐up periods (P ≤ 0·005 for both). [Correction added on 20 October 2017, after first online publication: This P value has been corrected]. Using HRQoL assessments in every physician visit or treatment may provide valuable insights for treating rare conditions like AL amyloidosis.

Psychometric validation of the SF-36 Health Survey in light chain amyloidosis: results from community-based and clinic-based samples

Background Light chain (AL) amyloidosis, a rare and life-threatening protein misfolding disorder, causes organ damage and severely impacts health-related quality of life (HRQoL). No patient-reported outcome (PRO) HRQoL measure has been validated for use in an AL amyloidosis patient population, leaving a gap for researchers conducting observational studies and clinical trials for drug development. The SF-36 Health Survey (SF-36) has been the most frequently used PRO in AL amyloidosis studies to date, and early qualitative validation studies support its use in this population. The aim of this study was to assess the psychometric properties of the SF-36 among patients with AL amyloidosis. Methods Data from community-based (n=341) and clinic-based (n=1,438) observational studies were used to document the psychometric properties of the SF-36 in this disease population. Reliability was estimated using internal consistency (Cronbach’s alpha) and test–retest reliability (intraclass correlation). Convergent validity, known-groups validity, and the ability to detect change were assessed with available criterion variables. Results Scale reliability (Cronbach’s alpha ≥0.780 for all scores) and test–retest reliability (intraclass correlation coefficients ≥0.731 for all) were acceptable. Scale convergent validity was supported by strong correlations with conceptually related measures. Mean SF-36 scores varied by response to treatment (P<0.05 for all scores) and a self-reported measure of disease severity (P<0.001 for all scores). Data indicate that the SF-36 is sensitive to changes in other measures over time. Conclusion This study provided clear and consistent evidence of the psychometric properties of the SF-36 in both community-based and clinic-based samples of patients with AL amyloidosis.

INOTERSEN IMPROVES QUALITY OF LIFE IN PATIENTS WITH HEREDITARY TRANSTHYRETIN AMYLOIDOSIS WITH POLYNEUROPATHY AND CARDIOMYOPATHY: RESULTS OF THE PHASE 3 STUDY NEURO-TTR

Hereditary transthyretin amyloid (hATTR) is a severe, progressive, disabling, and often fatal disease caused by deposition of amyloid in nerves and cardiac tissue that leads to multiorgan failure. Inotersen, a generation 2+ antisense oligonucleotide inhibitor of TTR protein production, was evaluated

NEOD001 DEMONSTRATES CARDIAC BIOMARKER RESPONSES IN PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS: RESULTS FROM THE PHASE 1/2 STUDY

Background: Current therapies used to treat AL amyloidosis limit light chain (LC) production but do not directly target deposits underlying multiorgan failure. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits

Content validation of the SF-36v2® health survey with AL amyloidosis patients

BackgroundThis study examined the content validity of the SF-36v2® Health Survey (SF-36v2) in patients with AL amyloidosis using qualitative interviews with physicians and patients. The study included three distinct phases of qualitative research: concept elicitation interviews among physicians, concept elicitation interviews among patients, and cognitive debriefing interviews among patients. The concept elicitation interviews focused on areas of health-related quality of life that are affected by AL amyloidosis and may be affected by treatment, while patient cognitive debriefings aimed to confirm whether the SF-36v2 instructions, recall period, items, and response choices were comprehensive and understandable to AL amyloidosis patients.ResultsPhysicians discussed the importance of measuring physical functioning, general health, mental/emotional health, sleep, fatigue, and work impact; though they also reported that they do not routinely use a standard Patient-Reported Outcome (PRO) measure of health-related quality of life. Patients described social, physical, role, and emotional impacts of AL amyloidosis and various treatments. Cognitive debriefing interviews confirmed the relevance of the concepts measured by the SF-36v2 and indicated that patients found the SF-36v2 both easy to understand and complete, that the SF-36v2 instructions and items were comprehensive and understandable without change, and the response choices and recall period were appropriate for use with patients with AL amyloidosis.ConclusionsThe findings support the content validity of the SF-36v2 as an appropriate measure of health-related quality of life in patients with AL amyloidosis.

Patient experience with hereditary and senile systemic amyloidoses: a survey from the Amyloidosis Research Consortium

Background Amyloidosis is caused by the accumulation of misfolded proteins, resulting in dysfunction of vital organs (eg, heart, kidneys, nervous system). Diagnosis and access to appropriate therapy pose significant challenges, and there is a paucity of literature depicting the patient (pt) experience. We conducted a survey to identify the challenges in establishing a diagnosis of amyloidosis and to gain insight into the pt experience.