Durability of Initial Platelet Count Response in Patients Treated with Avatrombopag for Immune Thrombocytopenia (ITP): Post-Hoc Results from a Phase 3 Clinical Study

Blood â—½  
2020 â—½  
Vol 136 (Supplement 1) â—½  
pp. 22-23
Author(s):  
Shivi Jain â—½  
Matthew Wojdyla â—½  
Michael Vredenburg â—½  
Brian Jamieson â—½  
Terry B. Gernsheimer
Keyword(s):  
Research Funding â—½  
Rescue Medication â—½  
Rescue Therapy â—½  
Initial Response â—½  
Median Number â—½  
Boxed Warning â—½  
Phase 3 â—½  
Response Level â—½  
Loss Of Response â—½  
Post Hoc

Background: The clinical management of ITP has been evolving. Thrombopoietin receptor agonists (TPO-RAs) have become widely utilized as subsequent treatments, and the 2019 ASH guidelines recommend their use over rituximab to achieve a durable response. TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been FDA approved for over a decade with a well demonstrated efficacy profile. ELT, an oral medication, must be administered two hours prior to or four hours after meals containing polyvalent cations such as calcium or magnesium to mitigate clinically relevant effects on the pharmacokinetic profile (ELT prescribing information). Additionally, ELT carries a boxed warning for hepatoxicity that requires monitoring. ROMI, an injectable, is typically administered in a health care practitioner's office weekly which may be challenging for some patients (Pts). Avatrombopag (AVA) is an oral TPO-RA approved in 2019 for Pts with ITP. In clinical trials, AVA rapidly increased platelet count (PC) (5 days) and maintained it in the target range (50 to 150×109/L) with chronic dosing. Further, it has an exposure-adjusted safety profile generally comparable to placebo with no boxed warning for hepatotoxicity. AVA does not chelate polyvalent cations; therefore, it is administered with food and without restrictions regarding meal composition. A high proportion of Pts (~90%) respond to AVA; but limited information is available regarding the durability of response over time utilizing clinically relevant loss of response definitions. Aims: To understand the duration of initial response with AVA and the overall percent of treatment days a response level PC was achieved in responding Pts. Methods: A 6-month, multicenter, randomized, double-blind, Phase 3 study enrolled 32 AVA and 17 placebo-treated Pts with ITP. The study design included a 6-week study drug titration period, 12-week concomitant ITP medication reduction period, and an 8-week maintenance period. The primary endpoint was the median number of cumulative weeks of PC response (PC ≥50,000/µL) over the course of the study without rescue medication. Pts receiving rescue medication during the study were deemed to be non-responders for the remainder of the study. For this post-hoc analysis, we analyzed how many days it took for responding AVA Pts (n=29) to experience their first loss of response (LOR) or reach core study conclusion. After the initial PC ≥50,000/µL was noted, we also examined the percentage of remaining treatment time that initial response was maintained. Response was defined as the first time achieving a PC ≥50,000/µL. LOR was defined as a Pt experiencing a PC <30,000/µL for 4 consecutive weeks (LOR-4wk), or in a more conservative manner, Pts experiencing a PC <30,000/µL on 2 consecutive scheduled visits (LOR-2vis) [visits were weekly or biweekly depending on the phase of the study with 21 visits occurring over 26 weeks]. When a LOR was observed, the date of the first PC <30,000/µL was used for subsequent calculations with a return of response defined as a PC exceeding ≥30,000/µL again. Pts who required rescue therapy (n=6) were included in the analyses and the first date of administration was used for the LOR date. Pts requiring either corticosteroids (n=4) or IVIg (n=1) as rescue therapy were considered non-responders for a minimum of 8 weeks and Pts receiving a platelet transfusion (n=1) for a minimum of 1 week. Results: 72.4% (21/29) and 55.2% (16/29) of AVA responsive Pts never experienced a LOR-4wk or LOR-2vis, respectively. The median number of days until responding Pts experienced their first LOR-4wk, discontinued treatment, or completed the 6-month study was 170 (mean 134.7) and 146 (mean 119.1) for the LOR-2vis analysis. Pts maintained their initial response on average for 87.7% (median 100%) of their remaining time in the study for LOR-4wk and 84.5% (median 100%) for LOR-2vis analyses, with Pts often losing response only briefly when noted. Pts requiring rescue therapy often returned to a response level PC and remained in the 6-month study for approximately 5 months following their initial response. Conclusions: These data suggest that the initial response to AVA is stable and durable with up to 72.4% of Pts never experiencing a LOR, even with the planned objective of reducing the use of baseline concomitant ITP medications during the study. In those pts experiencing a LOR, many ended up achieving response level PCs again without a subsequent LOR. Disclosures Wojdyla: Dova Pharmaceuticals: Current Employment. Vredenburg:Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment. Gernsheimer:Amgen Corporation: Consultancy, Honoraria; Novartis: Consultancy; Cellphire: Consultancy; Rigel Corporation: Consultancy, Research Funding; Principia: Research Funding; Sanofi: Consultancy; Vertex: Consultancy; Dova Pharmaceuticals: Consultancy.

scholarly journals Durability of Platelet Response When Switching from Eltrombopag or Romiplostim to Avatrombopag in Immune Thrombocytopenia (ITP): A Multicenter Study

Blood â—½  
2021 â—½  
Vol 138 (Supplement 1) â—½  
pp. 1015-1015
Author(s):  
Hanny Al-Samkari â—½  
Debbie Jiang â—½  
Terry B. Gernsheimer â—½  
Howard A. Liebman â—½  
Susie Lee â—½  
...  
Keyword(s):  
Adverse Event â—½  
Platelet Count â—½  
Research Funding â—½  
Immune Thrombocytopenia â—½  
Rescue Therapy â—½  
Initial Response â—½  
Boxed Warning â—½  
Platelet Response â—½  
Platelet Counts â—½  
Loss Of Response

Abstract BACKGROUND : Thrombopoietin receptor agonists (TPO-RAs) are widely utilized second-line treatments for immune thrombocytopenia (ITP). The TPO-RAs eltrombopag and romiplostim have been FDA approved for over a decade with established efficacy and safety profiles. Avatrombopag is a newer oral TPO-RA approved in 2019 for ITP. Avatrombopag was efficacious in raising platelet counts in clinical trials, and it has an exposure-adjusted safety profile generally comparable to placebo with no boxed warning for hepatotoxicity as does eltrombopag. Also unlike eltrombopag, avatrombopag does not chelate polyvalent cations; therefore, it is administered with food and without restrictions regarding meal composition. A high proportion of patients (~90%) respond to avatrombopag; however, data describing the durability of platelet response on avatrombopag following treatment with other TPO-RAs is limited. AIMS : Understand the time until patients treated with avatrombopag experienced their first loss of response, if any, and their percent of time with a response following switch from eltrombopag or romiplostim. METHODS : We retrospectively evaluated all adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four U.S. tertiary ITP referral centers from July 2019 through December 2020. Reason for switching from eltrombopag or romiplostim (ineffectiveness, adverse event, convenience) was collected. Patients were treated with avatrombopag for at least two months to evaluate effectiveness. Response was defined as a platelet count ≥30,000/uL. Loss of response was defined as two consecutive platelet counts at least 7 days apart <30,000/uL. In these analyses, platelet counts were disqualified if <8 weeks from receipt of rescue corticosteroids or <4 weeks from intravenous immunoglobulin. RESULTS: 44 patients were included, with a median (range) age of 60 (21-87) years; 55% were female. At avatrombopag initiation, patients had an ITP diagnosis for a mean of 8.1 years with a mean of 4.8 unique prior ITP therapies. 42/44 (95%) of patients responded to avatrombopag at least once and 36/44 (81.8%) responded without the need for rescue therapy. 6/44 (13.6%) responded to avatrombopag and required at least one rescue therapy during exposure. 31/42 (73.8%) of patients never experienced a loss of response. All patients who responded to avatrombopag maintained response for 88.7% of their time on treatment. Patients who responded without the need for rescue therapy maintained their response for 93.6% of their time on avatrombopag. Patients who switched for convenience maintained a response for 96.5% of the time on avatrombopag. Patients who switched for adverse events maintained a response for 90.2% of the time. Patients who switched for efficacy maintained a response for 68.2% of the time. Overall, the median platelet count for all avatrombopag exposure was 107×10 9/L. The median platelet count for convenience switchers was 129×10 9/L, efficacy switchers was 60×10 9/L, and adverse event switchers was 93×10 9/L. CONCLUSION: In a heavily pretreated chronic ITP population who switched from another TPO-RA to avatrombopag, the initial response to avatrombopag was both durable (with up to 74% of patients never experiencing a loss of response) and stable (with patients maintaining a response on average for up to 89% of the time). Figure 1 Figure 1. Disclosures Al-Samkari: Argenx: Consultancy; Dova/Sobi: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Research Funding; Rigel: Consultancy; Agios: Consultancy, Research Funding; Moderna: Consultancy. Gernsheimer: Principia: Research Funding; Rigel: Research Funding; Amgen: Honoraria; Novartis: Honoraria; Cellphire: Consultancy; Dova: Consultancy; Sanofi: Consultancy. Liebman: Pfizer: Consultancy; Dova: Consultancy, Honoraria; Argenx: Research Funding; Amgen: Consultancy; Sanofi/Genzyme: Research Funding; Novartis: Consultancy, Research Funding. Lee: Dova: Honoraria. Bernheisel: Sobi, Inc.: Current Employment. Kolodny: Sobi, Inc.: Current Employment. Wojdyla: Sobi, Inc.: Current Employment. Vredenburg: Sobi, Inc.: Current Employment. Jamieson: Sobi, Inc.: Current Employment. Cuker: Takeda: Research Funding; Sanofi: Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy.

Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenia (ITP) Treated with Romiplostim in Two Phase 3 Placebo-Controlled Clinical Trials.

Blood â—½  
2009 â—½  
Vol 114 (22) â—½  
pp. 891-891 â—½  
Author(s):  
Ilene Ceil Weitz â—½  
Miguel A Sanz â—½  
David H. Henry â—½  
Martin Schipperus â—½  
Bertrand Godeau â—½  
...  
Keyword(s):  
Platelet Count â—½  
Board Of Directors â—½  
Research Funding â—½  
Rescue Medication â—½  
Bleeding Event â—½  
Bleeding Events â—½  
Phase 3 â—½  
Advisory Committees â—½  
Platelet Counts â—½  
Chronic Itp

Abstract Abstract 891 Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts and increased risk of bleeding. Rescue medications used to treat or prevent bleeding produce transient increases in platelet counts but may be associated with additional toxicities and costs. Romiplostim, approved for the treatment of adult chronic ITP, is a TPO mimetic peptibody protein that increases platelet production. Previously published data from phase 3 romiplostim trials showed that despite the increased use of rescue medication in the placebo arm, patient (pt) incidence of bleeding was reduced in the romiplostim arm vs placebo arm: 15% vs 34% (p = 0.02) for bleeding of grade ≥2 severity and 7% vs 12% (p=0.36) for grade ≥3 severity. Objective: To evaluate the effects of romiplostim treatment on bleeding outcomes in the phase 3 placebo controlled studies in chronic ITP pts with and without previous splenectomy. Bleeding events were captured as adverse events making it difficult to identify a single event reported multiple times versus persistent or recurrent bleeding. Further, we have developed a composite endpoint, termed bleeding-related episodes (BREs), which combines bleeding events and rescue medication administration to account for use of rescue medications to prevent bleeding. Methods: Adults with chronic ITP and a mean baseline platelet count <30 × 109/L were eligible. The previously published studies were conducted separately in splenectomized and nonsplenectomized populations. Pts were randomized (2:1) to receive romiplostim or placebo by subcutaneous injection once weekly for 24 weeks, with dose adjustments to maintain platelet counts between 50-200 × 109/L. Rescue medications were permitted to treat or prevent bleeding and included immunoglobulins, platelet transfusions, corticosteroids, or an increase in dose or frequency of a concurrent ITP medication. A BRE was defined as an actual bleeding event and/or the use of rescue medication. To collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single BRE. Bleeding events beginning 7 or more days after the start of the initial bleeding event were considered a new BRE. To account for differences in time spent on-study, rates of BRE per 100 pt-weeks were calculated. Results: A total of 125 pts (41 placebo, 84 romiplostim) were enrolled in the two studies. Baseline characteristics were well-balanced between the placebo and romiplostim-treated groups. During the treatment period, the rate of BREs was lower in the romiplostim group than in the placebo group, and results were consistent between splenectomized and nonsplenectomized pts (Table). Across both studies, the rate of BREs was reduced by 55% in pts receiving romiplostim compared to those receiving placebo (95% CI, 41% to 65%). BREs were more frequent at platelet counts <50 × 109/L (Table). BREs associated with hospitalizations were less common among romiplostim- than placebo-treated pts, and occurred at platelet counts <50 × 109/L in 10 of 11 cases. Corticosteroids (58 romiplostim, 38 placebo) and immunoglobulins (30 romiplostim, 73 placebo), were the most commonly used rescue medications and the rate of BREs including immunoglobulins was reduced by 88% in pts receiving romiplostim compared to placebo. Conclusions: In adults with chronic ITP, romiplostim was associated with a significant reduction in BREs compared to placebo. There was a marked reduction in BREs requiring immunoglobulins in the romiplostim arm compared to the placebo arm. Results were comparable in splenectomized and nonsplenectomized populations. The platelet count for a BRE starting ≥1 day after a platelet count measurement was calculated from the 2 proximal weekly measurements. Disclosures: Weitz: Amgen Inc.: Speakers Bureau. Sanz:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Henry:Amgen Inc.: Research Funding, Speakers Bureau; Orthobiotech: Research Funding, Speakers Bureau; Watson Pharma: Research Funding, Speakers Bureau. Schipperus:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Godeau:Amgen Inc.: Consultancy, Research Funding; Laboratoire Français de Fractionnement et de Biotechnologies (LFB): Consultancy; Roche: Research Funding. Gleeson:Amgen Inc.: Consultancy, Research Funding. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

Lack of Response of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) to Decitabine After Failure of Azacitidine

Blood â—½  
2012 â—½  
Vol 120 (21) â—½  
pp. 3858-3858 â—½  
Author(s):  
Bhavana Bhatnagar â—½  
Dan P. Zandberg â—½  
Emily J. Vannorsdall â—½  
Alison P. Duffy â—½  
Michael L. Tidwell â—½  
...  
Keyword(s):  
Research Funding â—½  
Disease Free Survival â—½  
Initial Response â—½  
Median Number â—½  
Initial Therapy â—½  
Cancer Center â—½  
Disease Response â—½  
University Of Maryland â—½  
Demethylating Agents â—½  
Demethylating Agent

Abstract Abstract 3858 Background: Standard therapy for high-risk MDS consists of one of two FDA-approved demethylating agents, azacitidine or decitabine. AML patients considered unfit for intensive chemotherapy are also frequently treated with one of these agents, both of which have activity in AML and an acceptable toxicity profile. These agents are not considered curative, and responses are of variable duration. When azacitidine or decitabine is not effective, or is no longer effective, few options are available. In view of differences in pharmacological properties between these two agents, it is not uncommon to switch demethylating agents after failure of initial demethylating agent therapy. To date, only two small studies have addressed the outcome of this intervention, with conflicting results. In a study of 14 MDS patients treated with decitabine following failure of, or progression on, azacitidine, 4 patients (28%) responded (Borthakur et al, Leuk Lymph 2008), while a subgroup analysis of 10 evaluable patients treated with decitabine following azacitidine failure demonstrated no complete or partial responses (Prebet et al, J Clin Oncol 2011). Here we report outcomes in a retrospective analysis of 22 MDS and AML patients who received decitabine after azacitidine. Methods: Charts of 22 MDS or AML patients who were evaluated at the University of Maryland Greenebaum Cancer Center between January 1, 2008 and March 31, 2012 and who received decitabine after azacitidine were reviewed. Results: Patient and disease characteristics for 13 MDS patients and 9 AML patients are shown in Table 1. All patients were initially treated with azacitidine before being switched to decitabine following lack of response to initial therapy or disease progression after initial response. Five of 9 AML patients received azacitidine as frontline therapy, while four received it after other induction chemotherapy regimens. Disease responses following azacitidine 75mg/m2 for 5–7 days in 28-day cycles were variable as shown in Table 1. The median number of courses of azacitidine to disease response for MDS and AML patients who responded was 5 (range, 2–10), median disease-free survival (DFS) was 6.1 months (range, 2.3–16), and median number of courses of azacitidine received was 9 (range, 1 to 17). All 22 MDS and AML patients were refractory to, or progressed after, subsequent decitabine therapy after receiving a median of 2 courses (range, 1–6). Conclusions: Our study population represents the largest to date and the first in which AML disease responses to decitabine after failure of azacitidine have been studied. All MDS and AML patients were refractory to decitabine therapy following initial treatment with azacitidine. Thus this approach should generally not be employed. New therapies are needed for patients for whom demethylating agent therapy is, or becomes, ineffective, and these patients should be enrolled on clinical trials whenever possible. Disclosures: Baer: Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding.

scholarly journals Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Blood â—½  
2020 â—½  
Vol 136 (Supplement 1) â—½  
pp. 44-45
Author(s):  
Antonio Risitano â—½  
Ilene C. Weitz â—½  
Carlos M. de Castro â—½  
Jean-Jacques Kiladjian â—½  
Morag Griffin â—½  
...  
Keyword(s):  
Board Of Directors â—½  
Research Funding â—½  
Paroxysmal Nocturnal Hemoglobinuria â—½  
Response To Treatment â—½  
Publicly Traded â—½  
Phase 3 â—½  
Advisory Committees â—½  
Post Hoc Analysis â—½  
Hematologic Response â—½  
Post Hoc

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin &lt;10.5 g/dL (despite stable ECU for ≥3 months). METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH &gt;1.5× upper limit of normal and/or ARC &gt;150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (&lt;3 units/6 months). Minor response: regular transfusions required (3-6 units/6 months). No response: regular and frequent transfusions required (&gt;6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study

Blood â—½  
2020 â—½  
Vol 136 (Supplement 1) â—½  
pp. 1-3
Author(s):  
Nichola Cooper â—½  
Robert P. Numerof â—½  
Sandra Tong â—½  
David J. Kuter
Keyword(s):  
Research Funding â—½  
Rescue Therapy â—½  
Phase 2 â—½  
Publicly Traded â—½  
Open Label â—½  
Phase 3 â—½  
Double Blind â—½  
Double Blind Placebo â—½  
Phase 2 Study â—½  
Syk Inhibitor

Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of &gt;4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: Age ≥18;Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);failure of ≥1 prior treatment for wAIHA;Haptoglobin &lt;LLN (lower limit of normal) or total bilirubin &gt;ULN (upper limit of normal) or lactate dehydrogenase (LDH) &gt;ULN;Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is &gt;9 g/dL to &lt;10 g/dL, subject must be on a permitted wAIHA treatment AND have symptoms associated with anemia. Exclusion Criteria include: Presence of other forms of AIHA;Uncontrolled or insufficiently controlled hypertension;Neutrophil count &lt;1,000/µL,Platelet count &lt;30,000/μL (unless patient has Evans syndrome);Transaminase levels &gt;1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy; duration of hemoglobin response; and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patients have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. Figure Disclosures Cooper: Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Numerof:Rigel: Current Employment, Current equity holder in publicly-traded company. Tong:Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter:Incyte: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Shionogi: Consultancy; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria.

scholarly journals Association of High Body Mass Index with Response Outcomes in Patients with CML-CP Treated with Dasatinib Versus Imatinib in the First Line: Exploratory Post Hoc Analysis of the Phase 3 DASISION Trial

Blood â—½  
2019 â—½  
Vol 134 (Supplement_1) â—½  
pp. 4155-4155
Author(s):  
Massimo Breccia â—½  
Jorge E. Cortes â—½  
Neil P Shah â—½  
Giuseppe Saglio â—½  
Antonio Jiménez-Velasco â—½  
...  
Keyword(s):  
Median Time â—½  
Research Funding â—½  
High Body Mass Index â—½  
Molecular Response â—½  
Phase 3 â—½  
Post Hoc Analysis â—½  
Post Hoc â—½  
High Bmi

Introduction: Early responses to tyrosine kinase inhibitors (TKIs) are associated with improved long-term outcomes in patients with chronic myeloid leukemia in chronic phase (CML-CP), and guideline recommendations support the achievement of major molecular response (MMR) at 18 months as a therapeutic goal in CML treatment. Dasatinib is a first-line (1L) treatment option for patients with CML-CP, and long-term results from the DASISION study have demonstrated that patients on dasatinib achieved faster, deeper, and more durable molecular responses than patients on imatinib (Cortes J et al. J Clin Oncol 2016). Earlier reports have shown that obesity may increase the risk of developing CML (Strom SS et al. Cancer Epidemiol Biomarkers Prev 2009) and that patients with a high body mass index (BMI; > 25 kg/m2) at diagnosis who receive 1L imatinib have a significantly longer median time to response and a reduced rate of MMR compared with patients with a normal BMI (< 18.5-25 kg/m2; Breccia M et al. Cancer Lett 2013). In this exploratory post hoc analysis of the phase 3 DASISION trial (NCT00481247), we further investigated the association of high BMI with treatment responses with 1L TKIs. Methods: DASISION was a multinational, open-label, phase 3 trial of dasatinib versus imatinib for newly diagnosed CML-CP. Patients were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. Response outcomes were retrospectively stratified on the basis of two BMI categories: high (≥ 25 kg/m2) and normal (< 25 kg/m2). Median time to response was estimated using Kaplan-Meier analysis; Cox proportional hazard models and log-rank tests were stratified by Hasford scores. Molecular response rates were compared using Cochran-Mantel-Haenszel tests (stratified by Hasford scores). P values are descriptive and unadjusted for multiple comparisons. Results: In total, 109 patients with a high BMI and 147 patients with a normal BMI were treated with dasatinib, and 107 patients with a high BMI and 147 patients with a normal BMI were treated with imatinib. Baseline characteristics were balanced within BMI subgroups and are listed in the table below (Table). Median time to complete cytogenetic response (CCyR) was significantly shorter with dasatinib versus imatinib in patients with a high BMI (3.1 vs 6.1 months; P < 0.0001). MMR was also achieved faster in patients with a high BMI who were treated with dasatinib versus imatinib (median time 9.2 vs 27.6 months; P < 0.0001; Figure). More patients with a high BMI treated with dasatinib achieved MMR compared with those treated with imatinib (79.8% vs 59.8%; P = 0.0004). Likewise, 54.1% of patients with a high BMI achieved MR4.5 with dasatinib, compared with 34.6% with imatinib (P = 0.0013). In the normal BMI group, median time to CCyR (5.6 vs 6.0 months; P = 0.1055) and MMR (18.0 vs 21.5 months; P = 0.4095) was faster for dasatinib versus imatinib, and more patients on dasatinib versus imatinib achieved MMR (73.5% vs 67.3%; P = 0.3335) and MR4.5 (36.7% vs 33.3%; P = 0.6344). Although these results were numerically better with dasatinib, the differences were not statistically different. A graphical exploratory analysis suggested that there was no difference in exposures across BMI subgroups with respect to dasatinib. However, imatinib exposure data were not available to make comparisons across the BMI subgroups. There was no major difference in the previously reported adverse event profiles between treatment groups when assessed based on BMI. Any-cause pleural effusion occurred more frequently with dasatinib (34.3% [high BMI] and 24.5% [normal BMI]) compared with imatinib (0% [high BMI] and 2.0% [normal BMI]). Additional analyses are being planned to address the role of any potential confounders (eg, Hasford risk scores). Conclusions: In this exploratory post hoc analysis, patients with a high BMI treated with dasatinib demonstrated a significantly faster time to response compared with imatinib, with an increased percentage of patients also achieving MMR and MR4.5 at 5 years. However, these differences were not apparent in patients with a normal BMI. Although these findings highlight the potential role of BMI in affecting treatment responses to TKIs, additional validation of these findings is necessary to define the overall impact of BMI as a prognostic factor for patients with CML-CP. Study support: BMS. Writing support: Jane Cheung, Caudex, funded by BMS. Disclosures Breccia: Bristol-Myers Squibb, Celgene, Incyte, Novartis, Pfizer: Honoraria. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Saglio:Celgene: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy. Le Coutre:Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Brun:Bristol-Myers Squibb: Employment. DeGutis:Bristol-Myers Squibb: Employment, Other: Stock options. Sy:Bristol-Myers Squibb: Employment, Equity Ownership. Jabbour:AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding.

scholarly journals Modelling FVIII Levels for Prediction of Zero Spontaneous-Joint Bleeding in a Cohort of Severe Hemophilia a Subjects with Target Joints Initiated on Tertiary Prophylaxis

Blood â—½  
2016 â—½  
Vol 128 (22) â—½  
pp. 2576-2576 â—½  
Author(s):  
Kathelijn Fischer â—½  
Pratima Chowdary â—½  
Peter Collins â—½  
Amy Cotterill â—½  
Barbara Konkle â—½  
...  
Keyword(s):  
Research Funding â—½  
Median Number â—½  
Activity Level â—½  
Severe Hemophilia â—½  
On Demand â—½  
Kaplan Meier â—½  
Fviii Activity â—½  
Equity Ownership â—½  
Post Hoc â—½  
Trough Levels

Abstract Background Prophylaxis is increasingly the standard of care for adults with severe hemophilia A (SHA), however the optimal dose and treatment regimen when initiating tertiary prophylaxis is unknown. The relationship between factor level and risk of bleeding is not established, particularly in patients with joint disease. A post hoc analysis was conducted on a cohort of adult SHA patients who switched to prophylaxis from on demand therapy. Methods The cohort included 63 subjects with measured factor VIII (FVIII) levels of <1 IU/dL, aged 7 to 59 years, receiving on-demand treatment and with a minimum of eight joint hemorrhages in the 12 months prior to enrollment. After 6 months observation of on demand treatment and a full pharmacokinetic (PK) analysis, subjects were randomized to 12 months of either standard prophylaxis (20-40 IU kg−1 every 2nd day) or PK-tailored prophylaxis (20-80 IU kg−1 every 3rd day) targeting FVIII trough levels ≥1 IU/dL. Subjects had a median age of 28 years, and median weight of 71Kg. At study start, 95.2% of subjects had ≥1 target joints (median 3). During on demand treatment before randomization, the median number of spontaneous-joint bleeds was 29.9/year (range: 0 to 91.3). During prophylaxis, the median number of spontaneous-joint bleeds was 0/year (range: 0 to 10.2) in the combined prophylaxis groups. A PK model was fitted to the FVIII activity levels collected during the PK analysis for each subject independently. These individual models were used to predict the FVIII activity level at the time of bleed on the assumption of linear pharmacokinetics and no inter-occasion variability. For each subject the highest FVIII activity level associated with a spontaneous-joint bleeding event was considered as the minimally effective level to prevent spontaneous-joint bleeds. A Kaplan-Meier estimate for the proportion of subjects with no spontaneous-joint bleeds above FVIII activity level was carried out. For subjects who had no spontaneous-joint bleeding events an assumption was made that they would have bled only at 0 IU/dL, even in situations where the trough levels may have been higher. Results The Kaplan-Meier curve for proportion of the cohort without spontaneous-joint bleeds as function of predicted FVIII level is presented in Figure 1. The corresponding estimates are presented in Table 1. Based on this analysis in this cohort, the majority of patients (63%) would not be expected to have spontaneous-joint bleeds while maintaining a trough level of 1 IU/dL with more marginal improvements in response to higher FVIII levels. These results indicate that, in subjects with multiple target joints starting tertiary prophylaxis, most experience no spontaneous-joint bleeds for a predicted FVIII level ≥1 IU/dL, however, bleeds occurred at much higher predicted FVIII levels in some subjects. This is within the range of FVIII levels associated with hemophilia (0-40%) (White GC, et al. Thromb Haemost. 2001 Mar; 85(3):560). Conclusion The results of the model and the present post-hoc analysis support current trends to personalize prophylaxis based on individual variations in bleeding phenotypes, despite similar FVIII levels. To prevent all spontaneous-joint bleeds, some patients may require higher levels, findings which are congruent with those published on the natural history of joint bleeding in mild, moderate, and severe hemophilia patients (Den Uijl IE et al. Haemophilia. 2011;17(6):849-853). Disclosures Fischer: Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Chowdary:Sobi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria; Bayer: Honoraria. Collins:NovoNordisk: Consultancy; Sobi: Consultancy; CSL Behring: Consultancy, Research Funding; Shire: Consultancy, Speakers Bureau. Cotterill:Shire: Employment. Pipe:UniQure: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; Biogen: Consultancy; CSL Behring: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy, Other: Grant funding. Wolfsegger:Shire: Employment, Equity Ownership. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Goldstine:Shire: Employment. Valentino:Shire: Employment. Spotts:Shire: Employment.

scholarly journals LB001EFFICACY AND SAFETY OF BELIMUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS: A PHASE 3, RANDOMISED, PLACEBO-CONTROLLED TRIAL

2020 â—½  
Vol 35 (Supplement_3) â—½  
Author(s):  
Brad Rovin â—½  
Frédéric A Houssiau â—½  
Richard Furie â—½  
Ana Malvar â—½  
Y K O Teng â—½  
...  
Keyword(s):  
Treatment Group â—½  
Lupus Nephritis â—½  
Renal Disease â—½  
Rescue Therapy â—½  
High Dose â—½  
Related Event â—½  
Phase 3 â—½  
Renal Response â—½  
Induction Regimen â—½  
Post Hoc

Abstract Background and Aims Belimumab (BEL), an anti-B-cell-activating factor (BAFF) monoclonal antibody, is approved in patients (pts) ≥5 years of age with active systemic lupus erythematosus (SLE). Post hoc analyses of pooled renal outcomes data from two Phase 3 SLE studies showed favourable trends of greater reduction in proteinuria, haematuria, pyuria and lower renal flare rates in BEL-treated pts vs placebo (PBO).1 This is the largest study in acute lupus nephritis (LN) to date that evaluated efficacy and safety of intravenous (IV) BEL plus standard therapy (ST) in pts with active LN. Method BLISS-LN is a Phase 3, randomised, double-blind, placebo-controlled, 104-week study (GSK study BEL114054, NCT01639339); eligible pts (≥18 years) with autoantibody-positive SLE and active, biopsy-proven LN (classes III, IV and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Randomisation was stratified by induction regimen: high dose corticosteroids [HDCS] plus either cyclophosphamide (CyC), followed by azathioprine + low dose corticosteroids (LDCS), or mycophenolate mofetil (MMF), followed by MMF + LDCS. Primary endpoint: primary efficacy renal response (PERR; defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] no more than 20% below pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: complete renal response (CRR; defined as uPCR &lt;0.5; eGFR no more than 10% below pre-flare value or ≥90 ml/min/1.73m2; no rescue therapy) at Wk 104; PERR at Wk 52; risk of renal-related event (defined as end-stage renal disease/doubling of serum creatinine/renal worsening/renal disease-related treatment failure) or death at any time up to Wk 104. Other endpoints: PERR and CRR at Wk 104 by induction regimen; proportions of pts with baseline uPCR ≥0.5 with uPCR shift to &lt;0.5 while on study. Results Overall, 448 pts were randomised (efficacy: 223/treatment group; safety: 224/treatment group); 118 pts received CyC induction and 328 MMF induction; 278 (62.3%) completed the treatment. At Wk 104, 43.0% BEL and 32.3% PBO pts achieved PERR (OR [95% CI] vs PBO 1.55 [1.04, 2.32], p=0.0311); 30.0% BEL and 19.7% PBO pts achieved CRR (OR [95% CI] vs PBO 1.74 [1.11, 2.74], p=0.0167). Over 104 weeks, more BEL than PBO pts achieved CRR at each visit (Figure 1A). PERR at Wk 52 was achieved by 46.6% BEL and 35.4% PBO pts (OR [95% CI] vs PBO 1.59 [1.06, 2.38], p=0.0245). The risk of a renal-related event or death was 49% lower with BEL than PBO (HR [95%CI] 0.51 [0.34, 0.77]; p=0.0014) at any time point during the study. Overall, 15.7% of BEL and 28.3% of PBO pts experienced a renal-related event or death. When analysed by induction regimen, PERR at Wk 104 was achieved by 33.9% BEL and 27.1% PBO CyC-induced pts (OR [95% CI] vs PBO 1.52 [0.66, 3.49], p=0.3272), and by 46.3% BEL and 34.1% PBO MMF-induced pts (OR [95% CI] vs PBO 1.58 [1.00, 2.51], p=0.0501). CRR at Wk 104 was achieved by 18.6% BEL and 18.6% PBO CyC-induced pts (OR [95% CI] vs PBO 1.07 [0.41, 2.78], p=0.8843), and by 34.1% BEL and 20.1% PBO MMF-induced pts (OR [95% CI] vs PBO 2.01 [1.19, 3.38], p=0.0085). Proportions of pts with uPCR shift from ≥0.5 at baseline to &lt;0.5 while on study (calculated post hoc) are presented in the Figure 1B. Overall, 95.5% BEL and 94.2% PBO pts had ≥1 adverse event (AE); 25.9% BEL and 29.9% PBO pts had ≥1 serious AE; 13.8% BEL and 17.0% PBO pts had serious infections; 12.9% pts in each group had ≥1 AE resulting in study treatment discontinuation; on-treatment fatal AEs were reported in 1.8% BEL and 1.3% PBO pts. Conclusion BEL demonstrated improved renal responses vs PBO in pts with active LN, with a safety profile consistent with previous BEL trials.

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