Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States

Abstract Introduction: Peripheral leukocyte deficiency is a common feature of multiple diseases and may render affected individuals susceptible to infections, both common and opportunistic. The CXCR4 chemokine receptor regulates the trafficking of leukocytes among the bone marrow, blood, and lymphatic system (Al Ustwani O, et al. Br J Haematol. 2014;164:15-23). Mavorixafor is an orally available investigational, small-molecule, selective antagonist of the CXCR4 receptor with potential to restore physiological trafficking and maturation of white blood cells (WBCs). Mavorixafor was previously shown to increase totals and subsets of WBCs in healthy volunteers and in a phase 2 clinical trial in adults with WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome (Stone N, et al. Antimicrob Agents Chemother. 2007;51(7):2351-2358; Dale D, et al. Blood. 2020;136(26):2994-3003). Here, we report the effect of daily oral administration of mavorixafor on peripheral WBC counts and subsets in patients with clear cell renal cell carcinoma (ccRCC), WHIM syndrome, and Waldenström's macroglobulinemia (WM). Methods: Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations. Results: In the study evaluating combination mavorixafor (400 mg QD) and axitinib in ccRCC, total WBC count, ANC, ALC, and AMC increased to 153%, 158%, 143%, and 182% of baseline after 4 weeks (n=49), and with increases sustained at 159%, 171%, 139% and 166% of baseline after 6 months' treatment (n=20). In the study evaluating mavorixafor in combination with nivolumab in ccRCC, total WBC count, ANC, ALC, and AMC increased to 146%, 143%, 141%, and 179% of baseline after 4 weeks (n=9), and with increases sustained at 147%, 136%, 152%, and 191% of baseline after 6 months (n=2). In an interim analysis of the phase 1b trial in WM, compared to screening values, total WBC count, ANC, ALC, and AMC increased to 192%, 170%, 219%, and 186% of baseline after 4 weeks (n=8), and with increases sustained at 163%, 192%, 106%, 172% of baseline after 6 months' (n=5) treatment. In the WHIM syndrome phase 2 extension, total WBC count, ANC, ALC, and AMC increased to 339%, 652%, 239%, and 486% of baseline after 6 months' (n=5) treatment, with annualized infection rate decreasing from 5.6 (SD ± 3.13) events at baseline to 2.2 (SD ± 0.93) events after 40 months. Mavorixafor was generally well tolerated, with manageable safety profile across all indications either alone or in combination with other drugs. Conclusions: Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome. Assessment of the beneficial effects of mavorixafor on total and WBC subsets is ongoing in a phase 3 trial of WHIM syndrome and a phase 1 trial of severe chronic neutropenia (SCN) that will assess the potential to correct cytopenias by elevating total WBC counts. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Treon: AbbVie: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; X4: Research Funding. McDermott: Johnson and Johnson: Consultancy, Honoraria; Genentech: Research Funding; Eisia Inc.: Consultancy, Honoraria; Werewolf Therapeutics: Consultancy, Honoraria; Calithera Biosciences: Consultancy, Honoraria; X4 Pharmaceuticals: Research Funding; Iovance: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Exelixis: Research Funding; Alkermes, Inc.: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luo: X4 Pharmaceuticals: Consultancy. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bhandari: X4 Pharmaceuticals: Current Employment.

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A Phase 1/1b Open-Label, Multicenter, Two-Part Study of SETD2 Inhibitor EZM0414 in Patients with Relapsed/Refractory Multiple Myeloma or Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-147967 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1679-1679

Author(s):

Paul G. Richardson ◽

Ruben Niesvizky ◽

Jay Yang ◽

Neelu Yadav ◽

Helen Hsu ◽

...

Keyword(s):

Stock Options ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Phase 2 ◽

Open Label ◽

Large B Cell Lymphoma ◽

Phase 1B

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease of monoclonal plasma cells. More than 40% of patients with MM harbor translocations of the immunoglobulin heavy chain (IGH) gene on chromosome 14, leading to overexpression of putative oncogenes which can ultimately lead to plasma cell-derived, post-malignancy MM. One such translocation, t(4;14), is seen in 15% of patients and juxtaposes IGH control elements with two genes on chromosome 4, FGFR3 and MMSET. Patients harboring the (4;14) translocation have a poor response to standard of care therapies and an overall poor prognosis. MMSET expression has been confirmed as a driver in t(4;14) MM pathogenesis, but MMSET inhibitors have not yet been successfully developed in the clinic. Since MMSET generates the substrate for Su(var)3-9, enhancer of zeste, trithorax domain-containing 2 (SETD2) activity, SETD2 inhibition offers promise for targeting the underlying oncogenic mechanism in t(4;14) MM. Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in the United States, with a 5-year relative survival rate of 53% in patients diagnosed with stage IV DLBCL. Given the poor survival outcomes and low remission rates for patients with relapsed or refractory (R/R) DLBCL, there is a need for better treatment options. Although SETD2 mutations are described in DLBCL, the mechanism of action of SETD2 inhibitors remains unclear. EZM0414 is a potent and selective, orally bioavailable small-molecule inhibitor of SETD2. Preclinical data have demonstrated antitumor activity of EZM0414 in both t(4;14) and non-t(4;14) MM and DLBCL models. This study (enrollment scheduled to begin Q3 2021) will evaluate the safety and efficacy of EZM0414 when administered as monotherapy in patients with R/R MM with or without t(4;14), or with R/R DLBCL. Study Design and Methods: This first-in-human, 2-part, multicenter, open-label study will enroll patients aged ≥18 years with R/R MM who have received prior treatment with immune modulators, proteasome inhibitors, and anti-CD38 therapy, or who are intolerant to established therapies known to provide clinical benefit in MM, or with R/R DLBCL who have received at least 2 prior lines of therapy, including treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH); rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper CVAD); or other standard of care therapies. Patients eligible for autologous stem cell transplantation will be excluded from this study. The first part of the study will be a phase 1 dose escalation study using a Bayesian optimal interval design to evaluate the safety and tolerability of EZM0414 in patients with R/R MM with or without t(4;14), or with R/R DLBCL. Six dose levels of 100, 200, 300, 400, 600, and 900 mg administered once daily will be tested. Patients will be enrolled and treated in a cohort size of 3, and up to 36 patients will be enrolled to evaluate at least 10 patients at the maximum tolerated dose (MTD). The MTD will be selected at the dose level with a target dose-limiting toxicity rate ≤25%. The second part of the study (phase 1b) will be a dose expansion at the MTD in patients with R/R MM with or without t(4;14), or with R/R DLBCL using the Bayesian optimal phase 2 design. Dose expansion will include 3 cohorts of up to 20 patients each. Cohort 1 will enroll patients with t(4;14)-positive R/R MM, cohort 2 will enroll patients with t(4;14)-negative R/R MM, and cohort 3 will enroll patients with R/R DLBCL. The primary endpoints will be determining safety, dose-limiting toxicities, the MTD, and a recommended phase 2 dose. Secondary endpoints include the objective response rate, progression-free survival, and duration of response. Exploratory endpoints include a pharmacokinetic/pharmacodynamic profile analysis and the determination of mechanism of action biomarkers, such as histones and histone methylation. The study design will include a futility assessment in the phase 1b part of the study, which will be initiated when clinical data from the first 10, 15, and 20 enrolled patients in the expansion cohort are available. Disclosures Richardson: Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Secura Bio: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Oncopeptides: Consultancy, Research Funding. Niesvizky: BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Yang: Epizyme, Inc.: Current Employment, Other: May own stock/options. Yadav: Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Hsu: Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Flowers: Iovance: Research Funding; Adaptimmune: Research Funding; Guardant: Research Funding; Denovo: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Kite: Research Funding; Spectrum: Consultancy; Biopharma: Consultancy; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Epizyme, Inc.: Consultancy; Acerta: Research Funding; 4D: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Nektar: Research Funding; Sanofi: Research Funding; Morphosys: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; National Cancer Institute: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Cellectis: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; BeiGene: Consultancy; Xencor: Research Funding; TG Therapeutics: Research Funding; EMD: Research Funding; Burroughs Wellcome Fund: Research Funding; Ziopharm: Research Funding; Pharmacyclics: Research Funding.

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ZUMA-4: A Phase 1/2 Multicenter Study of KTE-X19 in Pediatric and Adolescent Patients With Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-137233 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-42

Author(s):

Alan S. Wayne ◽

Gerard Michel ◽

Daniel W. Lee ◽

André Baruchel ◽

Sonali Chaudhury ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Lymphoblastic Leukemia ◽

Phase 1 ◽

B Cell Lymphoma ◽

Primary Phase ◽

Phase 2 ◽

Publicly Traded

Background: Although approximately 80% - 85% of patients with acute lymphoblastic leukemia (ALL), the most common childhood malignancy, achieve durable complete remissions (CRs) after initial treatment, the remaining 15% - 20% of patients with relapsed or refractory (R/R) ALL have unfavorable outcomes (Leukemia2018;32:2316-25; N Engl J Med 2015;373:1541-52) and could benefit from effective new therapies. KTE-X19 is an autologous, anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of R/R mantle cell lymphoma and under investigation for additional R/R hematologic malignancies including chronic lymphocytic leukemia, adult ALL, and pediatric B cell ALL and non-Hodgkin lymphoma (NHL). KTE-X19 treatment has shown high rates of CRs, with a manageable safety profile for adult patients with R/R B cell ALL in the Phase 1 portion of ZUMA-3, including those with poor risk factors (J Clin Oncol 2019;37[suppl, abstr]:7006). ZUMA-4 is an ongoing Phase 1/2 study evaluating KTE-X19 in pediatric and adolescent patients with R/R B cell ALL or NHL (NCT02625480). End-of-Phase 1 interim analysis of ZUMA-4 showed the feasibility of KTE-X19 therapy with optimized dosing and adverse event (AE) management strategies for the treatment of pediatric patients with R/R ALL (Pediatr Blood Cancer 2019;66[suppl]:S24). The protocol for Phase 2 of ZUMA-4 has been amended to include broader B cell ALL enrollment criteria with a focus on patients with early relapse associated with poorer outcomes, and an NHL cohort was added. Methods: Key B cell ALL enrollment criteria include age ≤ 21 years, weight ≥ 10 kg, and B cell ALL that is primary refractory, relapsed within 18 months of first diagnosis, R/R after ≥ 2 lines of systemic therapy, or R/R after allogeneic stem cell transplantation at least 100 days prior to enrollment. Criteria for disease burden have been amended to also include patients with minimal residual disease-positive disease at enrollment. Patients with Philadelphia chromosome-positive ALL are eligible if intolerant to tyrosine kinase inhibitor therapy or if R/R after ≥ 2 tyrosine kinase inhibitor therapies. Patients with chronic myelogenous leukemia lymphoid blast crisis or clinically significant infections are not eligible. For B cell NHL, key enrollment criteria include age < 18 years, weight ≥ 10 kg, histologically confirmed diffuse large B cell lymphoma not otherwise specified (DLBCL NOS), primary mediastinal large B cell lymphoma, Burkitt lymphoma (BL), Burkitt-like lymphoma or unclassified B cell lymphomas intermediate between DLBCL and BL, with ≥ 1 measurable lesion. For NHL, disease must be primary refractory, R/R after ≥ 2 lines of systemic therapy, or R/R after autologous or allogeneic stem cell transplantation ≥ 100 days prior to enrollment. Patients with acute graft-versus-host disease or chronic graft-versus-host disease requiring treatment within 4 weeks of enrollment are not eligible. Patients with central nervous system-1 disease (no detectable lymphoblasts in cerebrospinal fluid), with central nervous system-2 disease (detectable disease, but white blood cell count < 5/μL in cerebrospinal fluid) without clinically evident neurologic changes, or who had prior blinatumomab treatment can be included in the ALL and NHL cohorts. Patients with prior CD19-directed therapy, except for blinatumomab, are excluded. Patients receive conditioning chemotherapy with fludarabine 25 mg/m2 on Days −4, −3, and −2 and cyclophosphamide 900 mg/m2 on Day −2 followed by a single infusion of KTE-X19 at a target dose of 1 × 106 anti-CD19 CAR T cells/kg on Day 0. The study has completed the Phase 1 portion and is currently enrolling in Phase 2, with a target accrual of approximately 50 additional patients with ALL and 16 with NHL. For ALL, the primary Phase 2 objective is to evaluate KTE-X19 efficacy as assessed by overall CR rate (CR + CR with incomplete hematologic recovery). For NHL, the primary Phase 2 objective is KTE-X19 efficacy assessment by objective response rate (complete response + partial response). Secondary Phase 2 objectives for ALL and NHL cohorts include safety and tolerability, additional efficacy endpoints, and changes in patient-reported outcome scores. ZUMA-4 is currently recruiting at 23 sites in the United States, Canada, France, and the Netherlands. Disclosures Wayne: Servier: Research Funding; Kite, a Gilead Company: Research Funding. Lee:Amgen Oncology: Consultancy; Kite, a Gilead Company: Research Funding; Juno: Consultancy; Harpoon Therapeutics: Consultancy. Baruchel:Bristol-Myers Squibb: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bellicum: Consultancy. Brown:Novartis: Consultancy; Janssen: Consultancy; Servier: Honoraria; Jazz: Honoraria. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Krueger:Atara: Other: Travel support; Kite, a Gilead Company: Other: Travel support; Novartis: Consultancy, Other: Travel support; no honoraria, Speakers Bureau. Shen:Gilead: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Travel support. Tailford:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Masouleh:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company.

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Gene Therapy for Fanconi Anemia, Complementation Group a: Updated Results from Ongoing Global Clinical Studies of RP-L102

Blood ◽

10.1182/blood-2020-137106 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-14

Author(s):

Agnieszka Czechowicz ◽

Rajni Agarwal ◽

Julián Sevilla ◽

Paula Río ◽

Susana Navarro ◽

...

Keyword(s):

Gene Therapy ◽

Bone Marrow ◽

Fanconi Anemia ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Medicinal Products ◽

Publicly Traded ◽

Hematopoietic Stem

Background: Fanconi anemia (FA) is a rare inherited disorder of defective cellular deoxyribonucleic acid (DNA) repair, associated with developmental abnormalities and characterized by progressive bone marrow failure (BMF) and a predisposition to hematologic malignancies and solid tumors. Approximately 60-70% of all cases result from mutations in the Fanconi Anemia Complementation Group A (FANCA) gene (FA-A). 80% of FA patients develop BMF within the first decade of life. Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potentially curative treatment for BMF, its utilization and efficacy are limited by availability of suitable human leukocyte antigen (HLA)-matched donors, risk of graft-versus-host disease (GVHD) and transplant-related toxicities. Ex-vivo lentiviral mediated gene therapy of autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) has been shown to confer a survival advantage to gene-modified HSPCs in preclinical studies and, most recently, in the investigator initiated Phase 1/2 FANCOLEN-I clinical trial conducted in Madrid, Spain. Based on the highly favorable safety profile and promising preliminary efficacy data, global studies using "Process B" optimization including transduction enhancers, commercial-grade vector, and modified cell processing are underway. Herein, we report updated results from the US Phase 1 clinical trial and preliminary data from the global Phase 2 study in US and EU. Design and Methods: Subjects with a confirmed FANCA gene mutation aged 1 year or older, with no HLA-matched sibling donor and at least 30 CD34+ cells/µL in bone marrow (BM) were eligible for enrollment. Peripheral blood (PB) mononuclear cells were collected via leucocytapheresis on two consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. CD34+ HSPCs were enriched, transduced with a lentiviral vector (PGK-FANCA-WPRE) and infused fresh (not cryopreserved) without any antecedent conditioning. Patients are being followed for 3 years post-infusion for safety assessments (replication competent lentivirus (RCL), insertion site analysis (ISA)) and to ascertain evidence of efficacy (increasing PB vector copy number (VCN) and BM mitomycin-C (MMC) resistance), along with stabilization/correction of cytopenias. Results: As of August 2020, 2 subjects (aged 5 and 6 years) have received RP-L102 infusion on the Phase 1 study with over 12 months of follow up. Preliminary evidence of gene marking in PB post-RP-L102 infusion at various timepoints has been observed in both subjects. Increased bone marrow (BM) mitomycin-C (MMC) resistance post treatment has also been identified in at least 1 subject. Subject L102-001-1001 has had blood count stabilization over the 12 months following gene therapy administration. Subject L102-001-1002's course has been complicated by influenza B infection with concomitant decreases in blood counts requiring red blood cell transfusions. Transfusion requirements have decreased following resolution of infection. Since November 2019, 5 additional subjects have been enrolled onto the global Phase 2 study and received investigational infusion. Updated preliminary safety and efficacy data including PB VCN, blood counts and BM MMC resistance will be available at the time of presentation for subjects with over 12 months of follow up; drug product (DP) information (VCN and CD34+ cell dose) will be available for all treated subjects. Conclusions: DP has been successfully manufactured in the Phase I (N=2) and Phase 2 (N=5) to meet the required specificationsSafety profile of RP-L102 continues to be highly favorable.Evidence of engraftment has been seen in at least 1 subject with follow up of at least 12 months as indicated by PB genetic markings and increasing BM CFC MMC resistance; 12+ months of follow-up may be required to observe the proliferative advantage of transduced HSPCs. Disclosures Czechowicz: Rocket Pharmaceuticals, Inc.: Research Funding. Sevilla:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Río:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: PR has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Navarro:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: SN has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Beard:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Wagner:BlueRock: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from this company., Patents & Royalties, Research Funding.

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Hepcidin Mimetic (PTG-300) Reverses Iron Deficiency While Controlling Hematocrit in Polycythemia Vera Patients

Blood ◽

10.1182/blood-2020-137304 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-41

Author(s):

Yelena Ginzburg ◽

Marina Kremyanskaya ◽

Andrew T. Kuykendall ◽

Abdulraheem Yacoub ◽

Jay Yang ◽

...

Keyword(s):

Iron Deficiency ◽

Serum Ferritin ◽

Research Funding ◽

Serum Iron ◽

Iron Status ◽

Transferrin Saturation ◽

Phase 2 ◽

Publicly Traded ◽

Advisory Committees ◽

Phase 2 Trial

Background. The majority of PV patients are iron deficient at diagnosis [Ginzburg Leukemia 2018]. PV patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels <45% in an effort to reduce the incidence of thrombotic events [Marchioli NEJM 2013]. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis and TP worsens iron deficiency and PV patients can be severely symptomatic from their iron deficiency [Krayenbuehl Blood 2011]. Iron deficiency is defined as insufficient iron stores to meet the needs of cellular homeostasis. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and iron availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in pre-clinical studies. In healthy volunteers PTG-300 decreases serum iron and transferrin saturation (TSAT) by >70% within 12 hours and the effect persists for 3-7 days. In a phase 2 trial in β-thalassemia, PTG-300 also decreased serum iron and TSAT but did not demonstrate off-target effects. The current study aims to compare the iron status in frequent TP-requiring PV patients before, during, and after treatment with PTG-300. Methods. Polycythemia patients who met 2016 WHO criteria for diagnosis were enrolled in the 28-week dose finding part of a Phase 2 trial. All patients required ≥3 phlebotomies with or without concurrent cytoreductive therapy over 6 months prior to enrollment. Patients were given PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly in individualized adjustment to maintain hematocrit <45%. Body iron status was quantified by monitoring serum ferritin, serum iron, transferrin saturation (TSAT), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 on concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. All subjects-maintained hematocrit <45% after appropriate dose adjustment. Mean baseline values were serum ferritin = 14.2 ng/mL (5, 37); serum iron = 33.0 ug/dL (16.8, 107.8); and TSAT = 7.6% (4, 30). During treatment with PTG-300, serum ferritin levels increased progressively toward normal (Figure 1a) reflecting increase in iron stores. TSAT (Figure 1b) and serum iron values increased modestly but remained below normal ranges, reflecting PTG-300's pharmacodynamic effect of inhibiting iron release from intracellular stores. This was associated with increased MCV (Figure 1c) and MCH (Figure 1d) and decreased hematocrit and erythrocyte counts, together suggesting a normalization of iron distribution. Conclusions. The current results indicate that PTG-300 is an effective agent for the controlling hematocrit and reversing iron deficiency. The effect of PTG-300 on PV-related symptoms and those of iron deficiency, are also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Kuykendall:Novartis: Research Funding; Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding. Yacoub:Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Hoffman:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Forbius: Consultancy; Protagonist: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; CTI Biopharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding.

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Final Results From the Phase 2 Continuation Study of the Lenalidomide and Azacitidine Combination in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v118.21.607.607 ◽

2011 ◽

Vol 118 (21) ◽

pp. 607-607 ◽

Cited By ~ 1

Author(s):

Mikkael A. Sekeres ◽

Rami S. Komrokji ◽

Jeffrey E. Lancet ◽

Ramon V. Tiu ◽

Anjali S. Advani ◽

...

Keyword(s):

Bone Marrow ◽

Neutrophil Count ◽

Research Funding ◽

Phase 1 ◽

Injection Site Reaction ◽

World Health ◽

Phase 2 ◽

Phase 1 Study ◽

Bone Marrow Biopsies ◽

Phase 2 Trial

Abstract Abstract 607 Background: Lenalidomide (LEN) and azacitidine (AZA) have activity in lower- and higher-risk MDS patients (pts), where both microenvironment and cell regulatory mechanisms play a role. The LEN/AZA combination was well-tolerated in the Phase 1 study (Sekeres JCO 2010) that established Phase 2 dosing, with an overall response rate (ORR) of 67%. Methods: The primary objectives for this multicenter, Phase 2 trial were to determine the efficacy and safety of combination therapy, with AZA 75mg/m2 daily × 5 days, and LEN 10mg daily × 21 days of a 28-day cycle (maximum of 7 cycles), in pts with higher-risk MDS (IPSS score ≥1.5, or World Health Organization (WHO) classification with ≥5% myeloblasts) not previously treated with AZA or LEN. Adverse Events (AEs) were assessed per NCI CTC v.3.0, with median decrease in absolute neutrophil count (ANC) or platelets (plt) calculated for the first 8 weeks of therapy. Subjects were enrolled to the Phase 1 study from 5/05 through 5/08, and to the Phase 2 continuation from 3/09 through 4/11, with results reported through 7/11. Bone marrow biopsies were performed after the 4th and 7th cycles, and pts could continue on AZA monotherapy off-study. Responses were assessed per modified International Working Group criteria as complete or partial response (CR, PR), or hematologic improvement (HI), and validated centrally. Time to progression was from date of CR, and overall survival (OS) from date of study enrollment. Results: A total of 36 pts were enrolled at 3 centers (18 Phase 1, 18 Phase 2); median age was 68 years (range 47–78), 13 pts (36%) were female, median interval from diagnosis was 8 weeks (range, 2–106), and median follow-up was 15 months (range 2–60). Prior MDS therapies included growth factors (19%), immunosuppressants (14%), and chemotherapy (17%). Median baseline hemoglobin was 9.7 g/dL, platelet count 65 k/uL, neutrophil count 840 k/uL, erythropoietin level 108 MIU/mL, and bone marrow blast percentage was 11%. IPSS categories were Int-1 (5 pts), Int-2 (20 pts), and High (11 pts); 8 pts had RAEB-1, 21 had RAEB-2, and 3 had CMML. Only 1 pt had a chromosome 5q deletion. Pts received a median of 5 cycles of therapy on-study. Grade 3/4 non-hematologic AEs (related or unrelated) included cardiac (11%), febrile neutropenia (31%), other infection (8%), pulmonary (11%), vascular access-related thrombosis (6%), CNS hemorrhage (6%), or other (11%). Three pts (8%) died while on-study. The most common grade ≤2, non-hematologic AEs related to treatment included constipation (47%), dermatologic (rash or injection site reaction) (44%), fatigue (39%), diarrhea (39%), nausea (19%), dizziness (19%), and dyspnea (19%). Median decrease from baseline in ANC was 35% and in plts was 18%. Of 35 patients evaluable, the ORR was 71%: 14 pts (40%) had a CR and 11 (31%) had HI, of whom 3 had bi- or tri-lineage HI. Median time to response was 3 months (range, 1–7). Three patients had progressive disease while on-study. Among pts achieving a CR, 7 (50%) continue to receive therapy; median age was 68 years (range, 50–76); IPSS was Int-1 (n=3), Int-2 (n=9), and High (n=2); WHO was RAEB-1 (n=5) and RAEB-2 (n=9); cytogenetic profiles were: 9 (64%) normal; 1 (7%) del (5q); 1 (7%) +8, 1 (7%) −7, 1 (7%) complex, and 1 (7%) unknown; median CR duration at last study assessment was 16 months (range, 3–36) and median OS at last assessment among CR pts was 27 months (range, 7–55). Seven CR pts (50%) evolved to AML a median of 20 months from achieving CR (range, 9–31); 10 (71%) remain alive at last study assessment. Conclusions: The LEN/AZA combination is well-tolerated and highly active in treating higher-risk MDS. The ORR seen in the Phase 1 study was supported by Phase 2 data, with good OS, even among progressing pts. Subsequent randomized studies will compare the LEN/AZA combination to AZA monotherapy and other AZA-based combinations. Disclosures: Sekeres: Celgene: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of lenalidomide, wapproved for lower-risk del(5q), will be discussed in higher-risk patients with MDS. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy. Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Fractionated Dosing of CLR 131 in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-131014 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 144-144 ◽

Cited By ~ 1

Author(s):

Sikander Ailawadhi ◽

Patrick J. Stiff ◽

Emad Ibrahim ◽

Anusha Vallurupalli ◽

Elizabeth H. Cull ◽

...

Keyword(s):

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

External Beam Radiation ◽

Cell Transplant ◽

Phase 2 ◽

Eligibility Criteria ◽

Beam Radiation ◽

Phase 1 Trial ◽

Phase 2 Trial

Background: CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the radiosensitivity of MM, fractionated dosing of CLR 131 is being examined in RRMM in a Phase 1 trial (NCT02278315) and a Phase 2 trial, CLOVER-1 (NCT02952508). Methods: Both the Phase 1 and Phase 2 trials of CLR 131 aim to determine efficacy and safety in RRMM. Eligibility criteria include progressive or relapsed MM that is refractory to at least 1 proteasome inhibitor (PI) and 1 immunomodulatory (IMiD) drug with no upper limit to the number of prior lines of therapy. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (< 20% of total marrow irradiated). The Phase 1 trial was a single and fractionated ascending dose escalation safety study and the Phase 2 trial is evaluating 3 doses: a bolus dose and 2 fractionated doses. The fractionated doses of CLR 131 included infusion of either 31.25 mCi/m2 CLR 131 or 37.5 mCi/m2 CLR 131 (administered as 15.625 mCi/m2 or 18.75 mCi/m2, respectively, on day 1 and day 7 (± 1 day)) administered as a 30-minute intravenous infusion is reported here. Adverse events (AEs) are graded by NCI-CTCAE v4.03. Responses were determined using IMWG criteria as assessed by the investigator. Results: As of 30Jul2019, 10 subjects have received fractionated 31.25 mCi/m2 and 6 subjects fractionated 37.5 mCi/m2 CLR 131. In addition, 1 subject was scheduled to receive fractionated 37.5 mCi/m2 CLR 131 but died due to progressive disease prior to administration of the second dose; this subject is not included in the analyses below as they did not receive both fractionated doses. There is no upper age limit for enrollment and the median age for the 16 RRMM patients was 71 (range 51-83), including 6 females and 10 males with a median of 4 prior therapies (range 2 to 13). Seven patients had prior ASCT. CLR 131 demonstrated 100% disease control rate in subjects receiving either fractionated dose of CLR 131. The overall response rate (ORR) in the fractionated 37.5 mCi/m2 cohort is 50%. Three subjects in the cohort experienced a partial responses (PR), median time to response 43 days, and the other three had minimal responses (MR) with an average 39% reduction in m-protein. In this cohort, 80% of the subjects were either quad- or penta-refractory; all 80% were refractory to daratumumab. There were two subjects in the 31.25 mCi/m2 cohort with non-secretory disease and their status was followed by FDG-PET imaging. Both have been excluded from the evaluation of efficacy as their disease does not meet with IMWG criteria for response. No patients in this cohort achieved a PR or better however a majority of the subjects experienced a minimal response. The primary AEs include thrombocytopenia, anemia, neutropenia, and fatigue (Table 2). The hematologic AEs were expected, manageable and followed a predictable timeline to nadir (average. 40 days) and subsequent recovery (average 17 days post nadir). Conclusions: CLR 131 is a unique, first in class targeted radiotherapeutic for RRMM. Preliminary data for CLR 131 administered as a fractionated dose shows an acceptable and expected safety profile in this patient population. Fractionated dosing at 37.5 mCi/m2 has shown an efficacy signal and has been adopted as the standard for CLR 131 dosing in ongoing and future trials. Dose escalation to determine the highest tolerated dose is ongoing in the Phase 1 study and is currently examining a fractionated infusion of 40 mCi/m2 administered as 20 mCi/m2 CLR 131 on day 1 and day 7 (± 1 day). Based upon these data enrollment to the fractionated 37.5 mCi/m2 cohort of the Phase 2 trial continues. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Stiff:Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Ibrahim:Cellectar: Honoraria, Research Funding; Incyte: Research Funding; Pfeizer: Research Funding; Puma: Research Funding; Eli Lilly: Research Funding; Hoffman-LaRoche: Research Funding; Spectrum: Research Funding; Takeda: Research Funding. Cull:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding. Green:GSK: Consultancy; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Oliver:Cellectar Biosciences: Employment. Longcor:Cellectar Biosciences: Employment, Equity Ownership.

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Mavorixafor, an Oral CXCR4 Antagonist, for Treatment of Patients with WHIM Syndrome: Results from the Long-Term Extension of the Open-Label Phase 2 Study

Blood ◽

10.1182/blood-2021-145759 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1121-1121

Author(s):

David C. Dale ◽

Frank Caleb Firkin ◽

Audrey Anna Bolyard ◽

Weihua Tang ◽

Honghua Jiang ◽

...

Keyword(s):

Research Funding ◽

Term Treatment ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Whim Syndrome ◽

Patient Interviews ◽

Phase 2 Study ◽

Long Term Treatment

Abstract Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare, autosomal-dominant primary immunodeficiency. Gain-of-function (GOF) mutations in the CXCR4 gene are the most common cause of WHIM syndrome, manifesting as panleukopenia with severe neutropenia, lymphopenia, and monocytopenia, recurrent bacterial infections, unusual susceptibility to human papillomavirus infections with intractable mucocutaneous warts, and increased risk of malignancy (McDermott DH, et al. Immunol Rev. 2019;2878:91-102). Mavorixafor is an investigational, small-molecule, selective antagonist of the CXCR4 receptor being developed as an oral, once-daily (QD) treatment for patients with WHIM syndrome (Dale DC, et al. Blood. 2020;136(26):2994-3003). Objective: We present an update on the clinical outcomes of patients with WHIM syndrome who continued in the long-term extension of the phase 2 study, highlighting long-term safety and efficacy. Methods: A long-term extension is ongoing as part of the open-label, prospective, dose-escalation, phase 2 study evaluating the safety and efficacy of mavorixafor (NCT03005327) in adults with WHIM syndrome. Individuals with a pathogenic GOF CXCR4 mutation and absolute neutrophil count ≤400/μL and/or absolute lymphocyte count ≤650/μL were included. All provided written informed consent. The primary objectives were to evaluate safety and tolerability and assess safe dosage. Exploratory efficacy end points included changes in infection rates, number of cutaneous warts, and white blood cell counts, compared to baseline. Researchers completed detailed interviews of 4 participants continuing in the study to assess their overall study experience and perceived treatment effects. Results: Five of 8 patients in the dose-finding phase 2 study entered into the long-term extension (LTE); median treatment duration was 148.4 weeks. One patient left the LTE because of study fatigue, and all 5 patients had dose escalation to 400 mg oral QD as of May 2021. As of the November 2020 data cutoff, annualized infection rates decreased from 5.6/year at study baseline to 2.2/year at 40 months' treatment, providing evidence of persistent reduction of infections over time. At doses of 300 and 400mg QD (n=7), the mean time above threshold for ANC and ALC were 12.7 hours (SD ± 9.8) and 16.9 hours (SD ± 5.9) compared to 2.1 hours (SD ± 3.3) and 11.5 hours (SD ± 5.9) at doses ≤200 mg QD, respectively. One patient experienced a 79% reduction in warts. Safety data review at May 2021 showed that there were 12 minor treatment-emergent adverse events (grade 1) with long-term treatment (46 months), no treatment-related infections of grade 3 or higher, no treatment-related serious adverse events, and no clinically significant laboratory abnormalities with mavorixafor treatment. Patient interviews revealed that all 4 LTE participants experienced good tolerability of mavorixafor and decreased frequency, severity, and duration of infections and decreased hospital/doctor visits. Three of 4 participants reported previous need for prophylactic treatment to prevent infection of minor wounds, but with mavorixafor, minor wounds healed without infection or need for prophylaxis. The mechanism of action of mavorixafor was of interest to 3 of 4 participants, who found it important that treatment address the underlying cause of disease, not simply the symptoms. Two participants reported a QOL improvement, and the other 2 reported that WHIM syndrome never affected their QOL Conclusion: Ongoing long-term treatment of adults with WHIM syndrome with mavorixafor 300 to 400mg shows durable increase in neutrophils and lymphocytes and sustained improvements in infections and warts. Detailed patient interviews for patient global impression of changes are consistent with sustained clinical benefit of long-term treatment. Mavorixafor has the potential to be a safe, effective, and long-term therapy targeting the underlying cause of WHIM syndrome. A global phase 3 registrational study is ongoing. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Firkin: X4 Pharmaceuticals: Research Funding. Bolyard: X4 Pharmaceuticals: Research Funding. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. MacLeod: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hu: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

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Phase 1/2 Study of Oral TP-0184 for the Treatment of Anemia in Adults with Low- or Intermediate-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-147594 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1534-1534

Author(s):

Amit Verma ◽

Andrew M. Brunner ◽

Gregory Pennock ◽

Dragana McMullen ◽

Mark Wade ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Research Funding ◽

Group Performance ◽

Phase 1 ◽

Inadequate Response ◽

Cell Transplant ◽

Intermediate Risk ◽

Phase 2 ◽

Publicly Traded ◽

Downstream Signaling

Abstract Patients with anemia due to lower-risk myelodysplastic syndromes (MDS) have limited treatment options. The transforming growth factor β (TGF-β) pathway has been implicated in contributing to ineffective hematopoiesis in patients with MDS. Members of the TGF-β superfamily include activin receptor-like kinase 2 (ALK2) and ALK5. ALK2 signaling plays a key role in modulating hepcidin, an important regulator of iron homeostasis (and thus erythropoiesis). Increased levels of hepcidin have been linked to anemia in patients with chronic inflammation and cancer, including multiple myeloma (Maes K, et al. Blood. 2010;116:3635-44). The role of hepcidin in MDS-related anemia is unknown and needs to be explored. ALK5 signaling through SMAD2/3 phosphorylation is constitutively active in bone marrow precursor cells from patients with MDS (Zhou L, et al. Blood. 2008;112:3434-43). Inhibition of ALK5 suppresses phosphorylation of SMAD2 in MDS hematopoietic progenitor cells and stimulates hematopoiesis in cells derived from patients with MDS. Collectively, these data suggest that blockade of the TGF-β-SMAD2/3 signaling pathway with an ALK5 inhibitor has the potential to benefit patients with anemia due to MDS. TP-0184 is a small-molecule, dual inhibitor of ALK2 and ALK5. In vitro, TP-0184 inhibits downstream signaling from ALK2 by reducing the phosphorylation of SMAD1/5/8 and blocks hepcidin expression (Peterson PW, et al. Blood. 2017;130 [suppl_1]: 937). Ex vivo, TP-0184 inhibits downstream signaling from ALK5 by reducing SMAD2/3 phosphorylation (data on file). By inhibiting both the ALK2 and ALK5 signaling pathways, TP-0184 may reduce ineffective erythropoiesis in patients with MDS. An open-label, single-arm, phase 1/2 study (NCT04623996) is being undertaken to evaluate the preliminary safety and efficacy of TP-0184 in treating anemia in adults (aged ≥18 years) with MDS. To be eligible, patients must have low- or intermediate-risk MDS (de novo or secondary) per the Revised International Prognostic Scoring System and have relapsed, exhibited an inadequate response to, or been refractory, resistant, or intolerant to treatment with an erythropoiesis-stimulating agent. Patients may have low or high red blood cell transfusion burden, must exhibit adequate major organ function, and must have an Eastern Cooperative Oncology Group performance status of 0-2. Key exclusion criteria include the presence of concomitant severe cardiovascular disease, such as congestive heart failure, myocardial infarction, angina, and/or uncontrolled cardiac arrhythmia; history of stroke, deep venous thrombosis, or pulmonary or arterial embolism; presence of clinically significant anemia due to iron, vitamin B12, or folate deficiencies, autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding; and prior allogeneic or autologous stem cell transplant. In this study, TP-0184 will be administered orally once daily for 24 weeks. The primary and secondary endpoints of each study phase are summarized in the table. Recruitment is ongoing, with approximately 30 patients targeted for enrollment in phase 1 and 10-60 patients targeted for enrollment in phase 2. In phase 1, increasing dose levels of TP-0184 ranging from 20 to 270 mg will be evaluated, with 1-6 patients dosed at each level. Dose escalation will be performed using a two-parameter Bayesian logistic regression model. Determination of the recommended phase 2 dose (RP2D) will be informed by the maximum tolerated or maximum administered dose in phase 1. In phase 2, the efficacy of TP-0184 at the RP2D will be monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Figure 1 Figure 1. Disclosures Verma: Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding. Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Pennock: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. McMullen: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wade: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Yang: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Xie: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Whatcott: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Foulks: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Melear: Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau.

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Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00603-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Huijie Bian ◽

Zhao-Hui Zheng ◽

Ding Wei ◽

Aidong Wen ◽

Zheng Zhang ◽

...

Keyword(s):

Healthy Volunteers ◽

Lung Tissue ◽

Phase 1 ◽

Area Under The Curve ◽

Blood Pool ◽

Control Group ◽

Phase 2 ◽

Phase 2 Trial ◽

Phase 2 Study

AbstractsRecent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood–pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

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PTG-300 Eliminates the Need for Therapeutic Phlebotomy in Both Low and High-Risk Polycythemia Vera Patients

Blood ◽

10.1182/blood-2020-137285 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-35 ◽

Cited By ~ 2

Author(s):

Marina Kremyanskaya ◽

Yelena Ginzburg ◽

Andrew T. Kuykendall ◽

Abdulraheem Yacoub ◽

Jay Yang ◽

...

Keyword(s):

High Risk ◽

Iron Deficiency ◽

Board Of Directors ◽

Research Funding ◽

Dose Finding ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Phase 2 Trial

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels <45% in an effort to reduce the incidence of thrombotic events [Marchioli NEJM 2013]. Since, they are seen periodically, PV patients likely spend significant time with hematocrit levels >45%, thereby potentially increasing their risk of thrombosis. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis [Ginzburg Leukemia 2018] and worsens after repeated and/or frequent TP, and often symptomatic from their iron deficiency. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in preclinical studies. In a phase 2 trial in β-thalassemia, PTG-300 leads to a sustained (3-7 days) decrease in serum iron and transferrin saturation (TSAT) but did not demonstrate off-target effects. The current study aims to compare the iron status and phlebotomy requirements in high TP-requiring PV patients before and during treatment with PTG-300 (Figure 1). Methods. PTG-300-04 is a 3-part Phase 2 trial consisting of (1) a 28-week dose-finding; (2) a 12-week blinded randomized withdrawal (1:1) PTG-300 vs placebo; and (3) a 52-week open label extension (Figure 1). Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit ≤45% in the 24 weeks prior to enrollment. PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly were adjusted to maintain hematocrit <45%. Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. After instruction, each of the patients self-administered the drug at home. Eight subjects have been treated for ≥3 months with PTG-300 (Figure 2a). Three subjects have been randomized. During the open label dose finding portion of the study, all subjects were phlebotomy-free with the exception of one subject. Three subjects completed part 1 (28 weeks) with no TP as compared to 3-5 TP required in a similar period prior to study initiation. During the 28-week dose-finding period, the hematocrit was continuously controlled below 45% in all but two subjects' (Figure 2b). Two subjects had hematocrits transiently >45% but remained below 45% after phlebotomy in one and dose increase in both. Furthermore, erythrocyte numbers decreased (Figure 2c) and MCV increased in all but two subjects. These findings suggest a redistribution of iron within erythropoiesis. Lastly, prior to treatment, mean iron-related parameters were consistent with systemic iron deficiency while serum ferritin increased progressively toward normal range. Most frequent adverse events were injection site reaction (ISR) reported by three patients. Most of the reactions were grade 1-2 and were transient in nature and no patient discontinued the drug. Conclusions. The current results indicate that PTG-300 is an effective agent for the treatment of PV, reversing iron deficiency and eliminating the need for TP in PV patients. Elimination of TP requirements for 7 months in TP-dependent PV patients is significant and unexpected. The effect of PTG-300 on PV-related symptoms is also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. PTG-300 looks very promising in eliminating the therapeutic phlebotomies in both low and high-risk patients. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Dynavax: Current equity holder in publicly-traded company. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding; Protagonist: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding. Hoffman:Forbius: Consultancy; Dompe: Research Funding; Protagonist: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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