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Abstract Number: 0386

Phase 1 Clinical Study of MGTA-145 in Combination with Plerixafor Shows Rapid Single-Day Mobilization and Collection of CD34+ Hematopoietic Stem Cells Without G-CSF

John DiPersio1, Jonathan Hoggatt2, Steven Devine3, David Scadden2, Haley Howell4, Veit Schmelmer4, Glen Raffel4, Pat Falahee4, Kevin Goncalves4, William Savage4 and John Davis4, 1Washington University, Saint Louis, 2Massachusetts General Hospital, Boston, 3National Marrow Donor Program, Minneapolis, 4Magenta Therapeutics, Cambridge

Meeting: ACR Convergence 2020

Keywords: chemokines, clinical trial, Scleroderma

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Session Information

Date: Friday, November 6, 2020

Title: Systemic Sclerosis & Related Disorders – Clinical Poster I

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Autologous hematopoietic stem cell (HSC) transplantation is a recommended therapeutic option for selected patients with scleroderma and other autoimmune diseases. HSC transplant requires collection of HSCs via mobilization by G-CSF, which consists of 4-7 days of injections that are associated with significant side effects and potential for severe complications including disease flares (e.g., scleroderma and multiple sclerosis). MGTA-145 is a biologic that activates CXCR2 on neutrophils, and with plerixafor (a CXCR4 antagonist) rapidly mobilizes HSCs in mice and non-human primates. The combination promises to be a same-day, G-CSF-free mobilization regimen.

Methods: This healthy volunteer study consisted of four parts- Part A: single-agent MGTA-145 or placebo; Part B: MGTA-145 or placebo given immediately or 2 hours after plerixafor; Part C: MGTA-145 or placebo given 2 hours after plerixafor on 2 consecutive days; Part D: MGTA-145 given 2 hours after plerixafor, just prior to apheresis cell collection.

Results: Monotherapy of MGTA-145 mobilized CD34+ cells within minutes and peaked within 1-hour post MGTA-145 (median 11 CD34+ cells/µL, a 7-fold increase vs baseline). White blood cells and neutrophils followed a similar pattern. Importantly, markers of neutrophil activation were relatively unchanged (≤2-fold vs baseline, Fig 1).

MGTA-145 combined with plerixafor increased CD34+ cell mobilization, whether given simultaneously or 2h after plerixafor (Fig. 2). Mobilization was highly enriched for CD34+CD90+CD45RA- HSCs. At the 0.03 mg/kg dose with 2h stagger, median peak CD34+ peripheral blood mobilization was ≥40 cells/µL in Part B. On a second consecutive day of dosing, MGTA-145 + plerixafor mobilized HSCs to levels comparable to day 1. Apheresis cell collection yields in Part D showed that sufficient numbers of cells (median 4.3 x 10^6 CD34+ cells/kg) for transplant were collected in a single day. Notably, MGTA-145 + plerixafor mobilized 3-fold higher numbers of CD34+CD90+CD45RA- HSCs and demonstrated >10-fold higher engraftment in NSG mice compared to cells mobilized by G-CSF.

MGTA-145 monotherapy was well tolerated with no significant adverse events (AEs). Grade 1, transient lower back pain that dissipated within minutes was reported. The combination of MGTA-145 with plerixafor was well tolerated, with some subjects experiencing grade 1/2 gastrointestinal AEs commonly observed with plerixafor and one grade 2 back pain with MGTA-145 at 0.075 mg/kg that resolved within minutes.

Conclusion: MGTA-145 was well-tolerated and induced rapid mobilization of significant numbers of HSCs. CD34+ cell mobilization with MGTA-145 + plerixafor was immediate and superior to plerixafor alone. These data suggest that the combination enables the collection of sufficient HSCs for transplant in one day without the need for G-CSF. Further clinical development as a first line mobilization agent is warranted in scleroderma and other autoimmune diseases, as well as in gene therapy and hematologic malignancies.

Figure 1: MGTA-145 has rapid, on-target neutrophil pharmacodynamics with minimal activation. (A) A single dose of MGTA-145 elicits dose-dependent mobilization of neutrophils into peripheral blood. (B) MGTA-145 monotherapy leads to rapid downregulation of its target receptor, CXCR2, on peripheral blood neutrophils. (C) MGTA-145 monotherapy leads to an increase in the molar ratio of the neutrophil protease, MMP-9, to its inhibitor, TIMP-1, in plasma. (D) MGTA-145 monotherapy elicits only modest changes in peripheral blood neutrophil activation markers (median ≤ 2-fold) after administration. Data represent at least 4 subjects per dose level and are expressed as mean ± SEM (A-C) or median + 10-90 percentile range (D). The shaded region in (A) represents the normal reference range for healthy subjects. The dotted line in (D) represents the anticipated effect of 5 days of G-CSF based on published data (Falanga et al, Blood. 1999).

Figure 2. Peripheral blood mobilization after plerixafor + 0.03 mg/kg MGTA-145 in healthy subjects with simultaneous and 2h stagger dosing after plerixafor. Dotted line: previously reported CD34+ counts with plerixafor alone mobilization (Chen et al, Blood Advances. 2018).

Table. Single-day Mobilization and Apheresis Cell Yields in Part D


Disclosure: J. DiPersio, Magenta Therapuetics, 1, 2, Wugen, 1, Incyte, 1, BioLineRx, 1; J. Hoggatt, Magenta Therapeutics, 1, 2; S. Devine, Bristol Myers, 1, Magenta Therapeutics, 1; D. Scadden, Magenta Therapeutics, 1; H. Howell, Magenta Therapeutics, 1, 2; V. Schmelmer, Magenta Therapeutics, 1, 2; G. Raffel, Magenta Therapeutics, 1, 2; P. Falahee, Magenta Therapeutics, 1, 2, 3; K. Goncalves, Magenta Therapeutics, 1, 2, 3; W. Savage, Magenta Therapeutics, 1, 2; J. Davis, Magenta Therapeutics, 1, 2, 3.

To cite this abstract in AMA style:

DiPersio J, Hoggatt J, Devine S, Scadden D, Howell H, Schmelmer V, Raffel G, Falahee P, Goncalves K, Savage W, Davis J. Phase 1 Clinical Study of MGTA-145 in Combination with Plerixafor Shows Rapid Single-Day Mobilization and Collection of CD34+ Hematopoietic Stem Cells Without G-CSF [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/phase-1-clinical-study-of-mgta-145-in-combination-with-plerixafor-shows-rapid-single-day-mobilization-and-collection-of-cd34-hematopoietic-stem-cells-without-g-csf/. Accessed .
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