Phase 1 Clinical Study of Mgta-145 in Combination with Plerixafor Shows Rapid Single-Day Mobilization and Collection of CD34+ HSCs without G-CSF

Abstract

<h3>Background</h3> G-CSF mobilization of hematopoietic stem cells (HSCs) requires 4-7 days of injections that provide unreliable collections. G-CSF is associated with significant side effects and potential for fatal complications in some patient populations (e.g. sickle cell disease, multiple sclerosis). MGTA-145 is an analog of the chemokine GROβ that activates CXCR2 and with plerixafor rapidly mobilizes HSCs in mice and non-human primates. The combination promises to be a same-day mobilization regimen that does not require G-CSF. <h3>Methods</h3> This phase 1 study consisted of four parts in healthy volunteers- Part A: single-agent doses of 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, at the start of apheresis cell collection. <h3>Results</h3> 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. Monotherapy of MGTA-145 led to an immediate mobilization of CD34+ cells within minutes that peaked within 1-hour post MGTA-145 and yielded a median peak of 11 CD34+ cells/µL (7-fold increase vs baseline) at the optimal single-agent dose of 0.03 mg/kg. White blood cells and neutrophils followed a similar pattern. Importantly, markers of neutrophil activation were relatively unchanged (≤2-fold vs baseline). MGTA-145 combined with plerixafor increased CD34+ cell mobilization, whether given simultaneously or 2h after plerixafor (Fig. 1A, 0.03 mg/kg dose shown). Mobilization was highly enriched for CD34+CD90+CD45RA- HSCs, which tracked closely with the total CD34 count (Fig. 1B). Mobilization efficacy was assessed by achievement of thresholds of peak peripheral blood CD34+ cells/µL: ≥20 was achieved in 12/14 (86%) subjects, and a median of 40 was achieved with staggered dosing. This regimen has advanced to Part D where mobilization and CD34+ cell collection by apheresis will be performed. Results of Parts A-D and apheresis graft analysis will be presented. <h3>Conclusions</h3> CD34+ cell mobilization with plerixafor + MGTA-145 was immediate and superior to plerixafor alone. MGTA-145 monotherapy is safe, well tolerated, and induced rapid mobilization of significant numbers of HSCs. These data suggest that the combination can enable the collection of sufficient HSCs for transplant in a single day. Further clinical development as a first line mobilization product is warranted in hematologic malignancies, autoimmune diseases, and gene therapy.