Advancing Transthyretin Amyloidosis Drug Development in an Evolving Treatment Landscape: Amyloidosis Forum Meeting Proceedings.

INTRODUCTION: Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data. MAIN BODY: The Amyloidosis Forum is a public-private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium ( www.arci.org ). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities). CONCLUSION: Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies.

Pathway for Development and Validation of Multi-domain Endpoints for Amyloid Light Chain (AL) Amyloidosis.

Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease.

Moving towards establishing centres of excellence in cardiac amyloidosis: an International Cardio-Oncology Society statement.

The prevalence of amyloidosis has been increasing, driven by a combination of improved awareness, evolution of diagnostic pathways, and effective treatment options for both transthyretin and light chain amyloidosis. Due to the complexity of amyloidosis, centralised expert providers with experience in delineating the nuances of confirmatory diagnosis and management may be beneficial. There are many potential benefits of a centre of excellence designation for the treatment of amyloidosis including recognition of institutions that have been leading the way for the optimal treatment of this condition, establishing the expectations for any centre who is engaging in the treatment of amyloidosis and developing cooperative groups to allow more effective research in this disease space. Standardising the expectations and criteria for these centres is essential for ensuring the highest quality of clinical care and community education. In order to define what components are necessary for an effective centre of excellence for the treatment of amyloidosis, we prepared a survey in cooperation with a multidisciplinary panel of amyloidosis experts representing an international consortium. The purpose of this position statement is to identify the essential elements necessary for highly effective clinical care and to develop a general standard with which practices or institutions could be recognised as a centre of excellence.

Peripheral Nervous, Hepatic, and Gastrointestinal Endpoints for AL Amyloidosis Clinical Trials: Report from the Amyloidosis Forum Multi-organ System Working Group.

Systemic immunoglobulin light chain (AL) amyloidosis is a heterogeneous rare disease driven by a destructive monoclonal gammopathy and typified by misfolded immunoglobulin light and/or heavy chains which aggregate and deposit in organs as insoluble amyloid fibrils. Disease heterogeneity is driven by the degree of multi-systemic involvement; cardiac, renal, neurological, and gastrointestinal (GI) systems are affected to varying degrees in different patients. While prognosis is primarily driven by hematologic response to treatment and outcomes associated with cardiac events and overall survival, the involvement of the peripheral nervous, hepatic, and GI systems can also have a significant impact on patients. The Amyloidosis Forum ( https://amyloidosisforum.org ) is a public-private partnership between the nonprofit Amyloidosis Research Consortium ( www.arci.org ) and the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research formed to advance drug development for the treatment of systemic amyloid disorders. A series of virtual workshops focused on the development of novel, patient-relevant endpoint components and analytical strategies for clinical trials in AL amyloidosis. This review summarizes the proceedings and recommendations of the Multi-Systemic Working Group which identified, reviewed, and prioritized endpoints relevant to the impacts of AL amyloidosis on the peripheral nervous, hepatic, and GI systems. The Working Group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the FDA, Medicines and Healthcare products Regulatory Agency (MHRA), and pharmaceutical companies. Prioritized neuropathy/autonomic endpoints included a modified form of the Neuropathy Impairment Score (NIS + 7) and the Composite Autonomic Symptom Score (COMPASS-31), respectively. Alkaline phosphatase was identified as the most relevant indicator of liver involvement and disease progression. Following extensive review of potential GI endpoints, the Working Group identified multiple exploratory endpoints. These recommended components will be further explored through evaluation of clinical trial datasets and possible integration into composite endpoint analysis.

The Transthyretin Amyloidosis - Quality of Life (ATTR-QOL) Questionnaire: Development of a Conceptual Model and Disease-Specific Patient-Reported Outcome Measure.

Purpose: Patients with transthyretin amyloidosis (ATTR) experience a wide variety of symptoms and impacts on health-related quality of life (HRQoL). However, the lack of an ATTR-specific patient-reported outcome (PRO) measure has made consistent measurement of HRQoL in ATTR challenging. This paper describes the development of a conceptual model and subsequent content for the Transthyretin Amyloidosis - Quality of Life Questionnaire (ATTR-QOL), an ATTR-specific PRO measure. Methods: This was a cross-sectional, non-interventional, US-based study. The study design included three stages: 1) a targeted literature review followed by qualitative data collection with patients and experts; 2) development of a conceptual model and PRO measure; and 3) review of the PRO measure using a modified Delphi method, translatability assessment, and interviews with patients and experts. Revisions were made to the measure after each round of review. Results: Forty-four patients and 29 experts participated in this study. The conceptual model included two primary concepts of interest: symptoms (cardiac, neuropathic-peripheral, neuropathic-autonomic, and other) and impacts (eg, physical, role, and mental/emotional functioning). Seventy-two items were created (32 symptoms; 40 impacts) to align with the model. A recall period of one month was selected based on participant input. Conclusion: The ATTR-QOL was created with significant patient involvement and guidance from a multidisciplinary group of experts. The mix of patient and clinical perspectives helped to ensure a balanced representation of all relevant disease experiences and clinical specialties. With further refinement from psychometric testing, the ATTR-QOL will provide a standard, comprehensive measure for all ATTR-specific research including both clinical trials and clinical practice.

Health-Related Quality of Life Instruments for Clinical Trials in AL Amyloidosis: Report from the Amyloidosis Forum HRQOL Working Group.

Systemic AL (light chain) amyloidosis is a rare protein misfolding disorder associated with plasma cell dyscrasia affecting various organs leading to organ dysfunction and failure. The Amyloidosis Forum is a public-private partnership between the Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research with the goal of accelerating the development of effective treatments for AL amyloidosis. In recognition of this goal, 6 individual working groups were formed to identify and/or provide recommendations related to various aspects of patient-relevant clinical trial endpoints. This review summarizes the methods, findings, and recommendations of the Health-Related Quality of Life (HRQOL) Working Group. The HRQOL Working Group sought to identify existing patient-reported outcome (PRO) assessments of HRQOL for use in clinical trials and practice deemed relevant across a broad spectrum of patients with AL amyloidosis. A systematic review of the AL amyloidosis literature identified 1) additional signs/symptoms not currently part of an existing conceptual model, and 2) relevant PRO instruments used to measure HRQOL. The Working Group mapped content from each identified instrument to areas of impact in the conceptual model to determine which instrument(s) provide coverage of relevant concepts. The SF-36v2® Health Survey (SF-36v2; QualityMetric Incorporated, LLC) and Patient-Reported Outcomes Measurement Information System-29 Profile (PROMIS-29; HealthMeasures) were identified as instruments relevant to patients with AL amyloidosis. Existing evidence of reliability and validity was evaluated with a recommendation for future work focused on estimating clinically meaningful within-patient change thresholds for these instruments. For sponsors, the context of use-including specific research objectives, trial population, and investigational product under study-should inherently drive selection of the appropriate PRO instrument and endpoint definitions to detect meaningful change and enable patient-focused drug development.

Proposed Cardiac End Points for Clinical Trials in Immunoglobulin Light Chain Amyloidosis: Report From the Amyloidosis Forum Cardiac Working Group.

Immunoglobulin light chain amyloidosis is a rare, multisystemic, phenotypically heterogenous disease affecting cardiovascular, renal, neurological, and gastrointestinal systems to varying degrees. Its underlying cause is a plasma cell dyscrasia characterized by misfolding of monoclonal immunoglobulin light chains which leads to aggregation and deposition of insoluble amyloid fibrils in target organs. Prognosis is primarily dependent on extent of cardiac involvement and depth of hematologic response to treatment. To facilitate development of new therapies, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify novel/composite end points and analytic strategies to expedite clinical trials for development of new therapies for the primary hematologic disorder and organ system manifestations. Specialized working groups identified organ-specific end points; additional working groups reviewed health-related quality of life measures and statistical approaches to data analysis. Each working group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the Food and Drug Administration, the UK Medicines and Healthcare Products Regulatory Agency, and pharmaceutical companies. This review summarizes the proceedings and recommendations of the Cardiac Working Group. Using a modified Delphi method, the group identified, reviewed, and prioritized cardiac end points relevant to immunoglobulin light chain amyloidosis in the context of an antiplasma cell therapy. Prioritized cardiovascular end points included overall survival, hospitalization, N-terminal pro-B-type natriuretic peptide level, 6-minute walk test, Kansas City Cardiac Questionnaire, and cardiac deterioration progression-free survival. These recommended components will be further explored through evaluation of clinical trial datasets and formal guidance from regulatory authorities.

Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy.

Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.

The diagnostic challenges of cardiac amyloidosis: A practical approach to the two main types.

Systemic amyloidosis of the immunoglobulin light-chain (AL) or transthyretin type (ATTR) is a multisystem protein deposition disease that often involves the heart. Delays in diagnosis are very common and can have detrimental consequences on patient outcomes. Because both major types can now be distinguished quickly and treated effectively, clear approaches are required. There have been advances in radioisotope scintigraphy, monoclonal protein testing and mass spectrometry for typing that need coordinated application. We have entered an era in which rapid diagnosis and ready therapy will save lives, therefore we must develop coherent approaches to this multisystem disease. The prognosis for AL has improved significantly with the incorporation of novel agents such as proteasome inhibitors, immunomodulators and monoclonal antibodies against plasma cells. Multiple independent studies have demonstrated the efficacy of these agents in AL, though tolerability can become an issue with dose reductions required in many cases. Median overall survival for patients achieving complete responses after stem cell transplant and consolidation exceeds a decade. The prognosis for ATTR, both age-related wild-type (ATTRwt) and hereditary due to variants of transthyretin (ATTRv), has improved as well due to the availability of the stabilizer tafamidis and the RNA-interference agents patisiran and inotersen. In both AL and ATTR, with elimination or suppression of the pathologic amyloid-forming protein, symptomatic involvement of the heart, kidneys and peripheral nervous system can improve as well. In this review, we present the current state of diagnosing and treating the two major types of systemic amyloidosis, emphasizing the coherent clinical application of the new tools and treatments. Implementation of the approaches we provide will enable rapid identification of amyloid type and rational selection of therapy.

The Impact of AL Amyloidosis: The Patient Experience.

This article focuses on the patient experience of AL amyloidosis; the unique challenges that patients face from the journey to diagnosis through treatment; and management of this complex multisystemic disease. Included are descriptions of the most significant AL amyloidosis symptoms as well as addressing burden of disease, including financial concerns, and psychological impact. In 2015 a Patient Focused Drug Development meeting held at the Food and Drug Administration provided valuable data that is shaping the drug development landscape and are reviewed here. The article concludes with a list of useful resources and organizations for patients and caregivers.

Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner.

BACKGROUND: Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. METHODS: These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. RESULTS: The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. CONCLUSIONS: A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.

The Amyloidosis Forum: a public private partnership to advance drug development in AL amyloidosis.

BACKGROUND: Immunoglobulin light chain (AL) amyloidosis is a rare, multi-systemic disorder characterized by two disease processes: an underlying plasma cell dyscrasia that provides the source of pathologic light chains, and the resulting organ dysfunction caused by deposition of amyloid light chain fibrils. There are no FDA approved treatments for AL amyloidosis; regimens developed for multiple myeloma are used off-label to treat the plasma cell disorder and no therapies are directed at organ deposition. Thus, an unmet medical need persists despite advances in disease management. A public-private partnership was recently formed between the Amyloidosis Research Consortium (ARC) and the US Food and Drug Administration (FDA) to bridge scientific gaps in drug development for the treatment of AL amyloidosis. MAIN BODY: The inaugural Amyloidosis Forum was convened at FDA on 12 November 2019 and led by a multidisciplinary panel of physicians, health outcomes professionals, and representatives from the FDA, ARC, and pharmaceutical companies. Patients provided important perspectives on the pathway to diagnosis, challenges of rigorous treatment, and the burden of disease. The panel reviewed the epidemiology, pathobiology, and clinical features of AL amyloidosis. Hematologic characteristics, staging systems, and response criteria were examined with clear consensus that a "deep response" to plasma cell-directed treatments was critical to overall survival. Emphasis was placed on the heterogeneous clinical phenotypes of AL amyloidosis, including cardiovascular, renal, neurological, and gastrointestinal system manifestations that contribute to morbidity and/or mortality, but render challenges to clinical trial endpoint selection. FDA representatives discussed regulatory perspectives regarding demonstration of clinical benefits of investigational therapies in the context of a rare disease with multi-systemic manifestations. The panel also highlighted the potential importance of well-designed health-related quality of life instruments, quantification of system organ effects, the potential of advanced imaging technologies, and survival prediction models. CONCLUSIONS: The Amyloidosis Forum identified a clear need for novel trial designs that are scientifically rigorous, feasible, and incorporate clinically meaningful endpoints based on an understanding of the natural history of the disease in an evolving therapeutic landscape. Future forums will delve into these issues and seek to include participation from additional stakeholders.

Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis.

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.

Light Chain (AL) Amyloidosis: The Journey to Diagnosis.

BACKGROUND: Light chain (AL) amyloidosis is a rare, complex disease associated with significant morbidity and mortality. Delays in diagnosis are common and may have detrimental consequences on patients' prognosis. Too little is known regarding the patient journey to diagnosis. OBJECTIVE: The objective of this study was to describe the patient-reported journey to a correct diagnosis for AL amyloidosis. METHODS: Using a mixed-methods approach, data were collected from clinician (n = 4) and patient (n = 10) interviews and a survey of community-based patients with AL amyloidosis (n = 341). Data were used to document the patient experience between the onset of symptoms and the receipt of a diagnosis. RESULTS: Delays in diagnosis were common. Qualitative and quantitative data indicated that initial symptoms were varied and similar to other more prevalent diseases. Two themes regarding the journey to diagnosis emerged: (1) barriers to an early diagnosis; and (2) the emotional toll of the journey. Time to diagnosis was heavily influenced by how patients interpreted their initial symptoms, whether they sought early medical help, and challenges associated with making differential diagnoses. Survey results indicate that patients with primary cardiac involvement were more likely to receive a delayed diagnosis than those with primary kidney involvement. Patients described mixed emotions associated with the eventual diagnosis of AL amyloidosis. CONCLUSIONS: These data support a need for better early identification and support for patients seeking a diagnosis. Increasing clinician awareness may reduce the time to diagnosis. Additional research is needed to identify optimal diagnostic testing to reduce delays in treatment initiation and subsequent severe impacts on health.

Light Chain Amyloidosis: Patient Experience Survey from the Amyloidosis Research Consortium.

INTRODUCTION: Information detailing the experience of patients with light chain (AL) amyloidosis is lacking. The primary aim of this study was to gather data on the patient experience to understand the challenges in diagnosis and to gain insight into barriers to accessing appropriate care. METHODS: Patients with amyloidosis, family members, and caregivers were invited to participate in an online 16-question survey (available from January 29 to February 5, 2015). Participants with AL amyloidosis were sent an eight-question follow-up survey. RESULTS: The initial survey was completed by 533 participants (follow-up survey completed by 201 participants). AL amyloidosis was the most common diagnosis. For 37.1% of respondents, the diagnosis of amyloidosis was not established until ≥ 1 year after the onset of initial symptoms. Diagnosis was received after visits to 1, 2, 3, 4, or ≥ 5 physicians by 7.6%, 23.5%, 20.3%, 16.8%, and 31.8% of respondents, respectively. Correct diagnosis was most often made by hematologists/oncologists (34.1%). Treatments included chemotherapy (63.1%) and stem cell transplantation (38.9%) and were difficult to tolerate for 54.1% of respondents. A significant number of respondents felt uninformed about clinical trials. Nevertheless, approximately half (46.1%) believed that enrolling in a trial would enhance their care. CONCLUSIONS: Establishing a diagnosis of amyloidosis is difficult. Current treatments are difficult to tolerate and do not substantially improve quality of life for most patients. There is an urgent need for well-tolerated therapies with clear treatment benefit. Patient awareness of clinical trials can be improved, especially given that respondents indicated high willingness to participate.