Updated Organ Response Results of an Open-Label Study to Evaluate the Safety and Tolerability of Cael-101 in Patients with AL Amyloidosis Receiving Anti-Plasma Cell Therapy

Background: CAEL-101 is an IgG1 monoclonal antibody intended to enable immune clearance of AL amyloid deposits. This study (NCT04304144) data allowed dose selection of CAEL-101 for the ongoing Phase 3 studies in patients with Mayo stage IIIa and IIIb AL amyloidosis cardiomyopathy newly diagnosed and treated with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) alone or in combination with daratumumab. Methods: 13 patients were treated with CAEL-101 and CyBorD and an additional 5 patients were treated with CAEL-101, daratumumab, and CyBorD. Organ response data on assessable patients were evaluated per consensus criteria as per institutional standard of care. Safety, pharmacokinetic and anti-drug antibody data will be reported separately. Results: The follow up for patients receiving CAEL-101 and CyBorD is 12 to 15 months and for the CAEL-101, Daratumumab, and CyBorD is 4 to 6 months. 16 of 18 patients remain on treatment. One discontinuation was due to death from E. coli sepsis and the other due to lack of hematologic response with deterioration of heart function requiring heart transplant after only 6 doses of CAEL-101. Organ response in cardiac patients by NT pro BNP criteria occurred in 4 of 8 evaluable patients treated with CAEL-101 and CyBorD (time to organ response range 2 - 12 months) and in 2 of 3 patients treated with CAEL-101, daratumumab, and CyBorD (time to organ response range 3 - 5 months). Four patients have had repeat echocardiogram 1 year from start of CAEL-101 based therapy with interpretable global peak longitudinal strain (GLS). The GLS improved in 2 patients by -5% (-6.4% to -11.4%) and -5.1% (-12.8% to -17.9%). GLS remained stable in the other 2 patients. All 9 patients with evaluable kidney involvement by 24 hour urine protein achieved an organ response. Responses occurred in as little as 2 months in 5 patients (range 2 - 7 months). The time to organ response were similar in the daratumumab and non-daratumumab treated patients. One patient with hematologic stable disease and persistent 71% improvement in 24 hour urine protein at 10 months from start of CAEL-101 based therapy is most notable. Conclusions: CAEL-101 with anti-plasma cell therapy remains reasonably well tolerated with no unanticipated adverse effects. Organ responses, most notably renal response, have occurred early in the course of therapy and appears to be durable. Organ responses in some patients have also improved over time with some significant improvement in patient GLS evaluations by echocardiogram. These results encourage clinical trial participation in the ongoing CAEL-101 clinical trials in Mayo stage IIIa and IIIb AL amyloidosis patients. Disclosures Valent: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Caelum Biosciences: Other: Clinical Trial Funding; Takeda Pharmaceuticals: Speakers Bureau. Silowsky: Caelum Biosciences: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Daniel: Caelum Biosciences: Current Employment. Jobes: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Anwer: GlaxoSmithKline: Research Funding; Allogene Therapeutics: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding. Zonder: BMS: Consultancy, Research Funding; Janssen: Consultancy; Caelum Biosciences: Consultancy; Intellia: Consultancy; Regeneron: Consultancy; Amgen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy. Liedtke: Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sobolov: Caelum Biosciences: Current Employment. OffLabel Disclosure: CAEL-101 is a monoclonal antibody directed at AL amyloid deposits. The purpose is to promote immune clearance of amyloid deposits.

Detection of Systemic AL Amyloidosis By 124I-p5+14 PET/CT Imaging - Providing the Complete Picture for Diagnosis

Background: Immunoglobulin light chain-associated (AL) amyloidosis is associated with the deposition of fibrils in abdominothoracic organs, notably the heart, liver, spleen and kidneys, resulting in organ dysfunction and significant morbidity. The heterogeneous organ presentation of amyloid and the variable amounts of amyloid burden make accurate and rapid diagnosis challenging. At present, organ biopsy and inferences based on anatomic imaging or changes in serum and urine biomarkers are commonly used to assess organ involvement. Currently, there are no approved radiotracers in the US for the non-invasive detection of AL amyloid load in major organs. To address this, we have developed a synthetic peptide radiotracer, designated 124I-p5+14 (AT-01), suitable for PET/CT imaging. This peptide binds many forms of amyloid through multivalent electrostatic interactions with the amyloid-associated glycosaminoglycans and fibrils. Preclinical studies demonstrated the specific reactivity of the peptide with diverse forms of amyloid (Wall, J.S. et al. (2015) Molecules, 20, 7657). Based on these observations, peptide p5+14 was labeled with iodine-124 and evaluated in a Phase 1/2 PET/CT imaging trial of patients with systemic amyloidosis (NCT 03678259). Herein we describe 23 patients with systemic AL amyloidosis and 5 healthy subjects that have completed the study. Efficacy endpoints include patient- and organ-based sensitivity of 124I-p5+14 uptake in the heart, liver, spleen and kidney. Methods: Subjects, >18 years of age, with a confirmed diagnosis of AL amyloidosis based on organ or abdominal fat pad biopsy findings, with organ-related biomarker changes. Patients taking heparin therapy were excluded. Subjects received an IV infusion of <2 mg of 124I-p5+14 (<2 mCi) and images were acquired at 5-6 h post injection using a Biograph PET/CT with a low dose CT. Prior to imaging, the organ-based distribution of amyloid was determined based on review of the medical record. PET/CT images were evaluated for visual uptake of radiotracer by a reader blinded to patient-related clinical data. Patient and organ-specific sensitivity were determined based on comparison of visual interpretation of the images by a reader blinded to organ involvement and the organ involvement based on the clinical record. Results: Twenty-three patients with systemic amyloidosis and five healthy subjects completed the study. No subjects discontinued or were lost to follow-up. In healthy subjects, radioactivity was observed in the parotid, salivary and thyroid glands, saliva, stomach lumen and urine in the ureters and bladder, consistent with the biodistribution of free radioiodide. No uptake in abdominothoracic organs was observed. In contrast, patients with AL amyloidosis exhibited uptake in the heart (71% of patients), kidneys (61%), spleen (43%), liver (30%), pancreas, lung, bone marrow and other sites. The patient-based sensitivity (patients with visual uptake in at least one anatomic site) was 96% (22/23). The organ-based sensitivity (i.e., clinically positive heart, liver, spleen or kidney that exhibited visual uptake of 124I-p5+14) was 86% (13/14 heart; 3/3 liver; 1/1 spleen; 7/10 kidney). Of note, the one patient without cardiac uptake was 8 years post diagnosis and 7 years post successful stem cell transplant therapy. The percent of abdominothoracic organs detected by PET/CT imaging was 68% higher (47 vs 28) than was noted clinically (16/14 heart; 7/3 liver; 10/1 spleen; 14/10 kidney) Conclusion: PET/CT imaging of amyloidosis using 124I-p5+14 provides accurate detection of AL amyloid deposits in multiple organ systems. Clinically undetected amyloid was observed in numerous anatomic sites with amyloid visualized by 124I-p5+14 in 68% more abdominothoracic organs as compared to that documented in the clinical record. Non-invasive PET/CT imaging with 124I-p5+14 can improve detection of amyloid throughout the body providing a more comprehensive picture of the disease and may provide a method to monitor changes in disease progression. Acknowledgments: This study was supported in part by the National Heart Lung and Blood Institute, National Institutes of Health, through the Science Moving Towards Research Translation and Therapy (SMARTT) program and by contributions to the ACTP Gift Fund at the UTGSM. Disclosures Wall: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder, Research Funding. Martin: Attrlaus Inc: Current holder of stock options in a privately-held company. Stuckey: Attralus Inc: Current holder of stock options in a privately-held company. Guthrie: Attralus Inc: Current Employment, Current holder of stock options in a privately-held company. Kennel: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder.

Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM

Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo λ1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body.

Small Fiber Neuropathy Incidence, Prevalence, Longitudinal Impairments, and Disability

Background and Objectives:There is limited population-based data on small fiber neuropathy (SFN). We wished to determine SFN incidence, prevalence, comorbidities, longitudinal impairments, and disabilities.Methods:Test-confirmed patients with SFN in Olmsted, Minnesota and adjacent counties were compared 3:1 to matched controls (January 1st, 1998-December 31st, 2017).Results:Ninety-four patients with SFN were identified, incidence 1.3/100,000/year increasing over the study period, prevalence 13.3/100,000. Average follow-up was 6.1 years (0.7-43 years), mean onset age 54 years (range 14–83). Female (67%), obesity (BMI mean 30.4 versus 28.5), insomnia (86% versus 54%), analgesic-opioid prescriptions (72% versus 46%), hypertriglyceridemia (180 mg/dl mean versus 147 mg/dl) and diabetes mellitus (DM) (51% versus 22%, p<0.001) were more common (OR 3.8-9.0, all p<0.03). Patients with SFN did not self-identify as disabled with median mRS of 1.0 (range 0-6) versus controls 0.0 (0-6), p=0.04. Higher Charlson comorbidities (median 6, range 3-9) occurred versus controls (median 3, range 1-9) p<0.001. Myocardial infarctions occurred in 46% versus 27% of controls (p<0.0001). Classifications included: idiopathic (70%); DM (15%); Sjögrens (2%); AL-amyloid (1%); transthyretin-amyloid (1%); Fabry (1%); lupus (1%); post viral (1%); Lewy body (1%) and multifactorial (5%). Foot ulcers occurred in 17, with 71% having DM. Large fiber neuropathy developed in 36%, on average 5.3 years (range 0.2-14.3 years) from SFN onset. Median onset Composite Autonomic Severity Score (CASS) was 3, change/year 0.08 (range 0-2.0). Median Neuropathy Impairment Score (NIS) was 2 at onset (range 0 to 8), change/year +1.0 (range -7.9 to +23.3). NIS and CASS change >+1 point/year occurred in only AL-amyloid, hereditary transthyretin-amyloid, Fabry, uncontrolled DM, and Lewy body. Death from symptom onset was higher in patients with SFN 19% versus controls 12%, p<0.001, 50% secondary to DM complications.Discussion:Isolated SFN is uncommon but increasing in incidence. Most patients do not develop major neurological impairments and disability but have multiple comorbidities, including cardiovascular ischemic events, and increased mortality from SFN onsets. Development of large fiber involvements and DM are common over time. Targeted testing facilitates interventional therapies for DM but also rheumatologic and rare genetic forms.

Bone marrow involvement by ATTR amyloid is common in cardiac amyloidosis patients and may signal advanced-stage disease

Introduction/Objective Amyloidosis encompasses a heterogeneous group of disorders characterized by abnormal deposition of misfolded proteins leading to progressive organ failure. Accurate amyloid typing is essential for proper patient management, as treatment regimens vary dramatically across different types. Bone marrow (BM) biopsy, in conjunction with fat pad aspiration/biopsy, is often the first step in patients with suspected amyloidosis. Although BM involvement by AL amyloid has been previously characterized, little is known about the incidence, morphology and clinical phenotype of non-AL amyloid in BM. Methods/Case Report We retrospectively identified 1469 BM biopsies by querying our reference laboratory database of 19,298 specimens from myriad anatomic sites typed by mass spectrometry-based proteomics (LC-MS/MS). These were reviewed for frequency of amyloid types (N=1469), distribution of amyloid deposits (N=139), and clinical phenotypes (N=345), with particular emphases on cardiac involvement. Results (if a Case Study enter NA) We identified the following amyloid types: AL (N=1172; 79.8%), ATTR (transthyretin) (N=240; 16.3%), AH (immunoglobulin heavy chain) (N=38; 2.6%), AA (serum amyloid A) (N=17; 1.2%), and Aβ2M (β2-microglobulin) (N=2; 0.1%). ATTR deposits showed striking predilection for periosteal soft tissue and/or periosteal vessels, and rarely involved BM stroma and/or interstitial vessels, while AL variably involved these compartments. AA primarily involved interstitial vessels. Both AL and ATTR cases commonly had a monoclonal gammopathy (AL: 92.9%; ATTR: 62.5%) with concomitant cardiac amyloidosis (AL: 91.6%; ATTR: 100%). Compared to AL, ATTR patients had higher stage cardiac amyloidosis and lower overall survival. Conclusion ATTR is common in BM, constituting16.3% of cases in our cohort. Rarer amyloid types, such as AA, AH and AB2M can also occur in BM. ATTR was frequently identified in patients with concomitant monoclonal gammopathy, in whom AL may have been suspected. Although ATTR deposits have distinctive morphologic distribution, primarily involving periosteal soft tissue and/or periosteal vessels and rarely involving BM stroma and/or interstitial vessels, there is considerable morphologic overlap with AL. Therefore, it is imperative to type BM amyloidosis, preferably by LC-MS/MS, to ensure proper patient management. Furthermore, BM involvement by ATTR may be a marker for advanced stage of disease.

The AL Amyloid Fibril: Looking for a Link between Fibril Formation and Structure

The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, as virtually every patient has a variety of mutations resulting in their own unique AL protein and thus a unique fibril deposited in the body. Here, I review recent biochemical and biophysical studies that have expanded our knowledge on how versatile the structure of AL fibrils in patients is and highlight their implications for the molecular mechanism of fibril formation in AL amyloidosis.

Nephrotic Syndrome Following Resection of an Adrenal Incidentaloma:A Case Report

A 69 year old man had a 5 cm right adrenal lesion discovered incidentally while being investigated for a deterioration in previously well-controlled hypertension. Routine investigations including serum albumin were normal. Further investigation confirmed a non-functioning adrenal lesion. MRI revealed a ‘non-fat-containing T1 hyperintense indeterminate adrenal lesion with speckling of T2 hyperintensity, not typical for adenoma, hyperplasia, myelolipoma, haemangioma or pheochromocytoma’. An uncomplicated laparoscopic adrenalectomy was performed. Histology revealed a 118 g adrenal neoplasm, modified Weiss score 0, with abundant hyaline deposits.3 months later the patient complained of peripheral oedema. Investigations revealed a serum albumin of 24 g/L and 14 g of proteinuria in 24 hours. Serum protein electrophoresis revealed a monoclonal IgA type lambda band. Renal biopsy revealed amorphous material displaying apple green birefringence on staining with Congo Red, which stained with antibodies to lambda light chains, confirming AL amyloid. Therefore the patient’s resected adrenal specimen was retrieved and stained with Congo Red, revealing apple green birefringence in the walls of the blood vessels, confirming the presence of amyloidosis. Although adrenal gland involvement in secondary amyloidosis is common, adrenal involvement in primary amyloidosis is less well described. This case illustrates the indolent nature of primary amyloidosis, prior to the development of often catastrophic symptoms. Consideration should be given to Congo Red staining of resected pathologic specimens containing hyaline deposition, to potentially allow for earlier recognition of this devastating disease. A pathophysiologic link between the patient’s incidentaloma, adrenalectomy, and onset of nephrotic syndrome remains a matter for conjecture.