Stock derivatives and seasoned equity offerings

PurposeThe article aims to explore if stock derivative types (stock options and stock warrants) are associated with stock returns for firms undergoing seasoned equity offerings (SEOs).Design/methodology/approachThe authors regress stock returns against stock derivatives for periods around SEO announcements with standard errors clustered at the month level.FindingsThe authors find that lower stock derivatives holdings for the fiscal year after the SEO are associated with superior pre-SEO returns. This can be explained by owners exercising their derivatives to capitalize on the pre-SEO price run-up. The authors find that greater stock option holdings by insiders for the fiscal year after the SEO are associated with superior post-SEO returns for up to ten years after the SEO announcement. This new finding does not hold for stock warrants.Research limitations/implicationsStock derivatives are supplied by Capital IQ. Given their description, the authors infer that stock options are owned largely by insiders. Thus, the insider conclusions for stock options depend on this implication.Practical implicationsStock options and stock warrants can be used strategically to reward stock derivative owners of strong performing firms for past performance. Stock options can be used to motivate insiders (primarily key executives) to achieve superior future performance.Originality/valueThis study is unique in comparing the influence of holdings for stock options and stock warrants on stock price performance around SEOs. The authors show that the sign of the association depends on whether the test includes pre-SEO periods.

Dealing With COVID-19 Through Employee Stock Ownership Plans

In this chapter, the authors argue that far from the shocking decision of firing employees to leverage their short-term liquidity, organizations may draw other innovative options such as giving company shares to their employees. Employee stock ownership (ESO) plans have the potential to secure financial liquidity for firms while simultaneously providing social inclusion as well as empowerment to people, relating their efforts directly to firms' performance and driving the economic system into a shared capitalism. However, while companies may be solving their financial constraints through ESO, the authors identified a trade-off related to the traditional position of hegemony of firms. They argue that the decision to share the risk through paying wages using firms' stock options derives in a progressive detriment of power and control that some organizations would not be willing to suffer.

Stock options: do they influence dividend payments?

Purpose This study aims to investigate whether there is any influence of the option plan to purchase shares protected from dividends to determine the distribution of dividends in Brazilian companies. Design/methodology/approach The authors used a Tobit dynamic and regressive regression model because their sample has an index higher than 30% of companies that do not pay dividends. The sample includes companies that pay dividends or not and pay their executives with executive stock option plans and is composed of 1,990 observations from 356 companies from 2010 to 2016. Findings The results indicated that the presence of a dividend protection clause has a positive association with the distribution of dividends. The authors sought to clarify that companies with a stock option plan protected by the distribution of dividends face fewer restrictions on the distribution of dividends. The authors found that most companies still use only stock options to benefit middle-ranking positions and fit the plan in their remuneration policy. The monitoring of these plans lasts an average of seven years, and specific acquisition conditions are not established with their beneficiaries, who must remain in the company and observe performance metrics. Originality/value This study is relevant because the relationship between dividends and stock options has not yet been analyzed in Brazil, especially concerning a dividend-protected option plan, which is a relatively recent modality, even unknown to some companies.

Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

A Phase II Trial of Anakinra for the Prevention of CAR-T Cell Mediated Neurotoxicity

Introduction: Chimeric antigen receptor (CAR)-T cell therapy is limited in most cases to inpatient use due to risk of severe treatment-related toxicities. The two primary toxicities observed with CAR-T therapy, cytokine release syndrome (CRS) and neurotoxicity, are associated with increased circulating inflammatory cytokines such as IL-6 and IL-1. Targeting IL-6 with tocilizumab is effective for treating CRS but not neurotoxicity. Anakinra is an FDA-approved recombinant IL-1 receptor antagonist that competitively inhibits IL-1 receptor signaling and therefore blocks downstream production of inflammatory cytokines including IL-6. Leveraging support from Kite Pharma, we opened an investigator-initiated clinical trial (NCT04150913) with the hypothesis that anakinra could be administered prophylactically to prevent severe CRS and neurologic events (NE) in patients receiving axicabtagene ciloleucel (axi-cel). Here we report preliminary outcomes of this study. Study Design and Methods: This is a phase II single center, open-label study for patients ≥18 years old with relapsed or refractory large cell lymphoma. Patients must have progressed after ≥2 lines of systemic therapy but could not have CNS disease or have been previously treated with CAR-T therapy. Following leukapheresis and manufacturing, patients received 3 days of lymphodepleting chemotherapy (LDC, cyclophosphamide 500mg/m 2 and fludarabine 30 mg/m 2) and 200 mg of subcutaneously administered anakinra starting 4 hours prior to axi-cel infusion and daily thereafter for a total of 7 days. CRS and NE were graded based on the Lee 2013 criteria and the CTCAE 4.03 criteria, respectively, to enable direct comparison to the pivotal Zuma-1 cohorts. The primary endpoint is the rate and severity of NE within the first 30 days of infusion; secondary endpoints include the incidence and severity of CRS and disease response. CAR-T cell expansion, serum cytokines, and circulating biomarkers of toxicity were measured at baseline, day 3, 7, 14, 21, and 28 post CAR-T cell infusion. Results: Interim analysis of the first 6 patients demonstrated a median age of 68 (range 59-72). Patients included a diverse group of histologies including double-hit lymphoma (n=2), transformed indolent NHL (n=3), and DLBCL NOS (n=1). Two patients were considered primary refractory at time of enrollment. Pre-LDC baseline characteristics included a median SPD of 2819 mm 2 (range 1063-5802), median LDH of 415 (range 147-497) which were comparable to the pivotal ZUMA-1 cohorts. Baseline ferritin, CRP, SAA and IL-15 were similar to the pivotal ZUMA-1 cohorts. While low-grade CRS was observed in 5/6 patients, no patients experienced severe CRS and median onset occurred on day +8 (range 1-8). Four patients did not experience any NE, while two patients experienced grade 3 NE on days +6 till +9 (somnolence) and +12 (global aphasia only, for one day) respectively. With a median follow-up of 4 months, the day +28 overall response rate was 100% (4 CRs, 2 PRs), with 4/6 patients having an ongoing complete response at last disease assessment. One patient was re-infused at progression and remains in a CR 3 months from re-infusion. Responses were seen despite varying CAR-T peak level with most patients demonstrating expansion in the lower quartile of the historic ZUMA-1 cohort. Median post-infusion peak of CRP, ferritin, IL-2, GM-CSF, IFNγ, IL-10, IL-6 and SAA were lower than that observed in the pivotal ZUMA-1 cohorts. All patients remain alive at time of data analysis. Conclusions: With a limited number of patients analyzed thus far, anakinra appears to provide benefit to the toxicity profile of axi-cel, presenting reduced and/or delayed CRS and NE and a decrease in post-infusion inflammatory analytes, when compared to ZUMA-1 pivotal cohorts. No severe CRS was observed in this initial analysis and 2/6 patients experienced grade 3 NE (somnolence and global aphasia) after day 6. Despite CAR-T expansion in the lower quartile of that of ZUMA-1, we observed a 100% ORR with 4 patients remaining in CR at a median follow-up of 4 months. Additional subjects will be assessed to investigate the role of prophylactic anakinra in the management of CRS and NE, which has potential for making axi-cel treatment an outpatient therapy. Disclosures Frigault: BMS: Consultancy; Editas: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Takeda: Consultancy; Kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Wehrli: CSL Behring: Patents & Royalties; Nestle: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Chou: Kite Pharma: Current Employment. Shen: Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties; Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties. Filosto: Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership ; Tusk Therapeutics: Patents & Royalties: or other intellecular property. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Maus: Agenus: Consultancy; Arcellx: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Atara: Consultancy; Bayer: Consultancy; BMS: Consultancy; Cabaletta Bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; In8bio (SAB): Consultancy; Intellia: Consultancy; GSK: Consultancy; Kite Pharma: Consultancy, Research Funding; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Novartis: Consultancy; Tmunity: Consultancy; Torque: Consultancy, Current holder of stock options in a privately-held company; WindMIL: Consultancy; Adaptimmune: Consultancy; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company.

Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry

Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding . Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years; incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p<0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality; the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. Figure 1 Figure 1. Disclosures Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Tempus: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tempus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dendreon: Consultancy; Caris: Other: Serves as a molecular tumor board ; Vividion: Consultancy; Sorrento Therapeutics: Consultancy; Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria; CSL Behring: Research Funding; Alnylam: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Whole Blood Adhesion to VCAM-1 and P-Selectin and RBC Mechanical Fragility Can be Compromised in Long COVID-19 Patients with Sickle Cell Disease

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause severe vascular complications associated with endothelial dysfunction and systemic inflammation. COVID19-specific IgG are detectable within a week of infection. Long COVID-19 has been described in patients continuing to exhibit symptoms after the virus is no longer detectable in the respiratory secretions, including fatigue, dyspnea, headache, and brain fog. The recent FAIR Health study reviewed a total of 1,959,982 COVID-19 patients for the prevalence of long COVID symptoms and reported that 23.2% had at least one post-COVID symptom [1]. The underlying biologic mechanisms of long COVID remain unclear, thus treatments are limited to symptomatic relief and supportive care. Many long COVID symptoms are consistent with systemic inflammation and impaired oxygen delivery observed in individuals with sickle cell disease (SCD), in turn associated with elevated blood cell adhesion and decreased red blood cell (RBC) stability. The aim of this study was to determine if deleterious changes in in blood cell properties related to adhesion and membrane stability under stress can be associated with the symptoms of long COVID-19. In this work we evaluated 7 SCD patients that were diagnosed with SARS-Cov-2 and tracked their recovery using semiquantitative IgG and blood cell function assays. Methods: Blood samples were collected by the Foundation for Sickle Cell Disease (SCD) Research from SCD (homozygous SS, n=6) patients coming for regular or urgent clinic visit with SARS-CoV-2 serological and blood cell functions tests performed per the standard of care. Semiquantitative IgG assay was performed using DXi-80 (Beckman Coulter). Flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM)and P-Selectin (FA-WB-Psel) substrates were determined by counting the cells that remain adherent in a microfluidics channel after perfusion with whole blood 1:1 diluted with HBSS buffer and washed by reversed flow at 1 dyne/cm 2. Red blood cell mechanical fragility (RBC MF) was measured as hemolysis induced by an oscillating cylindrical magnet with periodic non-invasive probing of cell-free hemoglobin fraction. Six individuals with SCD recovering from SARS-Cov-2 with biomarker data available both before and for more than 3 months after the infection (179±62 days) were included in the study. Results: IgG levels varied from less than 0.1 to 37, with positive values being defined as IgG > 1. The median estimated half-life of IgG decline was 53 days ranging from 25 to 90 days (the last, for the hospitalized patient). Averaged for IgG positive (IgG+) and IgG negative (IgG-) conditions, combining pre- and post-infection IgG- conditions, values of patient hemoglobin (Hb), FA-WB-VCAM, FA-WB-Psel, and RBC MF cell properties lacked statistical significance (under both a paired t-test and population statistics). Hb levels remained essentially unchanged regardless of the time from infection or IgG status. However, FA-WB-VCAM, FA-WB-Psel, and RBC MF were all significantly elevated after SARS-Cov-2 seroconversion and remained elevated despite declining IgG levels (e.g., Fig. 1). These increases in biomarker values were statistically significant for both FA-WB-VCAM and RBC MF, and were approaching significance for FA-WB-Psel (p<0065). These increases were highly patient-specific with potential return to pe-infection values observed in some cases at about 5-6 months after the infection. A qualitative review of the medical records indicated a new subjective report of fatigue in 5 of 6 patients. Longer observations are required to determine if abnormal blood cell adhesive properties and RBC membrane instability are mechanisms of long-COVID-19 pathophysiology. Conclusions: Whole blood adhesion to both p-selectin and VCAM-1 as well as RBC membrane stability can be significantly impaired in convalescent SARS-Cov-2 patients suggesting an association with long COVID-19. New and emerging treatments that modify whole blood adhesive properties and RBC membrane stability should be investigated for their potential to accelerated recovery from long COVID-19. Health F. A Detailed Study of Patients with Long-Haul COVID: An Analysis of Private Healthcare Claims; White Paper. June 15, 2021 Disclosures Tarasev: Functional Fluidics: Current holder of stock options in a privately-held company. Ferranti: Functional Fluidics: Current holder of stock options in a privately-held company. Allen: Functional Fluidics: Current Employment. Gao: Functional Fluidics: Current Employment. Topping: Functional Fluidics: Current Employment. Ferranti: Functional Fluidics: Current Employment. Makinde-Odesola: Functional Fluidics: Other: conduct research for academic program. Hines: Functional Fluidics: Current holder of stock options in a privately-held company.

Birtamimab in Patients with Mayo Stage IV AL Amyloidosis: Rationale for Confirmatory Affirm-AL Phase 3 Study Design

Background: Light chain (AL) amyloidosis is a rare, progressive, and typically fatal hematologic disorder caused by plasma cells that produce misfolded AL protein, resulting in deposits of amyloid in tissues and organs that cause organ dysfunction and failure. Birtamimab is an investigational monoclonal antibody designed to neutralize circulating soluble amyloid and deposited insoluble amyloid, thus promoting the phagocytic clearance of amyloid deposits. In 2018, the global phase 3 VITAL study in newly diagnosed, treatment-naïve patients was terminated based on a futility analysis of the composite primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization >90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835, 95% CI 0.5799, 1.2011; p=0.330). Post hoc analysis of ACM over 9 months revealed a pronounced survival benefit (HR=0.413, 95% CI 0.191, 0.895; p=0.025; Figure) in a subgroup of patients at high risk for early mortality (Mayo stage IV). At 9 months, the proportions of surviving patients were 74% and 49% in the birtamimab + SOC and placebo + SOC groups, respectively. Post hoc analyses of secondary endpoints in this subgroup also supported clinical and functional benefits of birtamimab + SOC, with clinically meaningful improvements observed in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance (both nominal p<0.05) at 9 months. Across all birtamimab clinical trials, no drug-related deaths, dose-limiting toxicities, or major risks were identified. Aims: To evaluate the efficacy and safety of birtamimab + SOC versus placebo + SOC in Mayo stage IV patients with AL amyloidosis by assessing time to ACM over 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study will enroll up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will receive either 24 mg/kg intravenous birtamimab or placebo every 28 days (both arms will also receive SOC, defined as concomitant chemotherapy with a first-line bortezomib-containing regimen). Patients will be randomly assigned 2:1 to birtamimab or placebo and will be stratified at randomization based on their 6MWT distance (<300 meters vs ≥300 meters). The primary efficacy endpoint of AFFIRM-AL is time to ACM using a log-rank test. Secondary endpoints are change from baseline to month 9 in SF-36v2 and 6MWT distance. Safety endpoints include adverse events, clinical laboratory observations, and immunogenicity analyses. An interim efficacy analysis is planned when ~50% of the events have occurred. Results: Given the >50% relative risk reduction for ACM observed in the post hoc analysis of VITAL for the AL amyloidosis subpopulation of patients with Mayo stage IV disease, the phase 3 AFFIRM-AL study is designed to confirm this effect of birtamimab under a Special Protocol Assessment agreement with the US FDA. Conclusion/Summary: Effective treatments to improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo stage IV disease is approximately 6-9 months. Birtamimab is the only investigational therapeutic in which a survival benefit has been observed, in a post hoc subgroup analysis of VITAL in patients with AL amyloidosis with advanced cardiac involvement. AFFIRM-AL is expected to initiate in mid-2021. (NCT04973137) Figure 1 Figure 1. Disclosures Gertz: Alnylam, Amgen, Annexon, Appellis, Celgene, Ionis/Akcea, Janssen, Medscape, Physicians Education Resource, Prothena, Research to Practice: Other: personal fees; Spectrum: Other: personal fees, Research Funding; AbbVie: Other: personal fees for Data Safety Monitoring board; Teva, Johnson and Johnson, Medscape, DAVA oncology: Other: speaker fees; Pharmacyclics, Proclara: Other: Advisory Board; i3Health: Other: development of educational materials; Springer Publishing: Patents & Royalties. Tripuraneni: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001). Kinney: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001).