Aphexda (motixafortide)

Utilizing anti-tumor chemokines or blocking pro-tumor chemokines may provide new therapeutic strategies for managing MM. Inspired by developed CXCR4 antagonists, including plerixafor, ulocuplumab, and motixafortide, more small molecular antagonists or antibodies for pro-tumor chemokine ligands and their receptors can be developed and used in clinical practice. Along with inhibiting pro-tumor chemokines, studies suggest combining chemokines with chimeric antigen receptor (CAR)-T therapy is promising and efficient.

P1, N=5, Recruiting, Washington University School of Medicine | Trial completion date: Jan 2024 --> Dec 2024 | Trial primary completion date: Jan 2024 --> Dec 2024

P3, N=180, Active, not recruiting, BioLineRx, Ltd. | Trial completion date: Dec 2025 --> Sep 2029

P2, N=18, Completed, M.D. Anderson Cancer Center | Phase classification: P2b --> P2

On 11 September 2023, motixafortide was approved in the USA for use in combination with filgrastim [granulocyte colony stimulating factor (G-CSF)] to mobilize HSCs to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma. Clinical development is ongoing for the mobilization of CD34 HSCs for gene therapy in patients with sickle cell disease. This article summarizes the milestones in the development of motixafortide leading to this first approval.

P1/2, N=340, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P3, N=180, Active, not recruiting, BioLineRx, Ltd. | N=136 --> 180

Motixafortide was safe and well tolerated with no episodes of anaphylaxis, no Grade 4 AEs and no deaths. Following implementation of a protocol amendment using combination pre-medication with an antihistamine H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen, the frequency and severity of hypersensitivity and injection site AEs associated with motixafortide were markedly improved.

Sponsored by BioLineRx, Inc.

P1/2, N=410, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P2b, N=18, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed

P2b, N=18, Active, not recruiting, M.D. Anderson Cancer Center | Suspended --> Active, not recruiting

P1/2, N=340, Recruiting, Hoffmann-La Roche | Trial completion date: Jun 2024 --> Oct 2026 | Trial primary completion date: Jun 2024 --> Oct 2025

P2b, N=18, Suspended, M.D. Anderson Cancer Center | Trial completion date: May 2023 --> Dec 2023 | Trial primary completion date: May 2023 --> Dec 2023

P2, N=50, Completed, Washington University School of Medicine | Active, not recruiting --> Completed

In conclusion, motixafortide + G-CSF mobilized significantly greater CD34 HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529.

Furthermore, two synthetic bulky chemical moieties of motixafortide work in tandem to restrict the conformations of important residues associated with CXCR4 activation. Our results not only elucidate the molecular mechanism by which motixafortide interacts with the CXCR4 receptor and stabilizes its inactive states, but also provide essential information to rationally design CXCR4 inhibitors that preserve the outstanding pharmacological features of motixafortide.

P2b, N=18, Suspended, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> May 2023 | Active, not recruiting --> Suspended | Trial primary completion date: Dec 2022 --> May 2023

However, the anti-tumor effects of Cim were not significantly different from the BL8040 treated groups (P<0.001, respectively). In conclusion Cim decreased acute myeloid leukemia cells protected by BMSCs through the CXCR4/SDF-1α pathway.

Notably, prior lenalidomide use was markedly lower in AMD-3102 (<10%) than in GENESIS (70%), which likely contributed to the higher mobilization rates in the AMD‑3102 PBO+G arm than in the GENESIS PBO+G arm. The results of this analysis show that the use of M+G was associated with significantly lower HRU relative to P+G for the mobilization of HSCs prior to ASCT in patients with MM, as well as significantly greater successful mobilization of ≥6x106 CD34+ cells/kg within 1 apheresis day. Cost-effectiveness analysis results showed that M+G was dominant to P+G, yielding additional QALYs and net cost savings over a lifetime horizon from a US healthcare payer perspective.

Adult patients ≥ 18 years with documented 1st CR/CRi/CRp, after induction therapy with cytarabine and an anthracycline, and not scheduled for allogeneic stem cell transplantation were randomized in a 1:1 ratio to receive two cycles (≥ 60 years) or three cycles (<60 years) of high-dose cytarabine plus BL-8040 or placebo as consolidation therapy. The addition of BL-8040 to intensive consolidation therapy did not improve RFS or OS. Although more side effects were noted, no differences in serious adverse events were observed.

Therefore, CXCR4 is considered a potential therapeutic target in cancer therapy, and CXCR4 antagonists, including AMD3100, MSX-122, BPRCX807, WZ811, Motixafortide, TN14003, AMD3465, and AMD1170, have been employed in experimental and clinical studies to enhance cancer therapy. Studies have shown that MSX-122 is particularly important in treating metastatic cancers and has great therapeutic potential. Accordingly, this review summarized the characteristics of MSX-122 and its effects on the CXCL12/CXCR4 axis as well as cancer therapy.

P1/2, N=290, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

Plerixafor, BKT140, LY2510924, PF-06747143, ulocuplumab, and NOX-A12 are among the most well-known CXCR4 and CXCL12 modulators that their therapeutic efficacies have been evaluated in different pre-clinical and clinical studies of hematologic malignancies. To have an overview of the importance of CXCL12/CXCR4 and CXCL12/CXCR7 axes in the pathogenesis of leukemia and to gather information about the latest advances as well as challenges in targeting these axes in clinical settings, the present review has begun with a discussion about how aberrant expression of CXCL12/CXCR4 and CXCL12/CXCR7 pathways might regulate leukemogenesis and ended by outlining the key news of preclinical and clinical investigations in leukemia treatment.

P1/2, N=410, Recruiting, Hoffmann-La Roche | Trial primary completion date: Feb 2025 --> Aug 2024

P3, N=136, Active, not recruiting, BioLineRx, Ltd. | Recruiting --> Active, not recruiting | N=207 --> 136 | Trial completion date: Sep 2019 --> Dec 2025

P1/2, N=290, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Nov 2022 --> Jun 2024 | Trial primary completion date: Nov 2022 --> Jun 2024

P2b, N=18, Active, not recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Dec 2021 --> Dec 2022

Extended CXCR4i with M+G mobilized significantly higher #s of combined CD34+ HSCs, MPPs and CMPs vs Px+G and P+G (p-values <0.05). Additionally, M+G mobilized a 10.5 fold higher # of immunophenotypically primitive CD34+ HSCs capable of broad multilineage hematopoietic reconstitution vs P+G (p<0.0001) and similar #s vs Px+G. CXCR4 expression on CD34+ HSPCs by 1D9 binding was similar across all arms.

M+G mobilization enabled significantly more CD34+ cells to be collected in 1 apheresis (median 10.8x10 6 CD34+ cells/kg) vs P+G (2.3x10 6 CD34+ cells/kg), as well as 3.5-5.6 fold higher #s of HSCs, MPPs, CMPs and GMPs (all p-values <0.0004). This high # of CD34+ cells/kg mobilized with M+G enables the potential infusion of ≥6x10 6 CD34+ cells/kg and cryopreservation of cells for later use. A dose response was observed with significant correlation between faster TPE and infusion of higher #s of total CD34+ HSPC doses (³6x10 6 CD34+ cells/kg) and combined HSC, MPP, CMP and GMP subsets.

A single injection of M on top of G significantly increased the proportion of patients mobilizing ≥6x10 6 CD34+ cells/kg for ASCT (92.5%) vs G (26.2%) in up to 2 apheresis days (p<0.0001), while enabling 88.8% to collect ≥6x10 6 CD34+ cells/kg in just 1 apheresis (p<0.0001, Figure 1A). Despite the higher # of cells mobilized by M+G, the # of CD34+ cells/kg infused was determined independently by each investigator according to local practice with comparable engraftment kinetics and graft durability between the 2 arms. Finally, M+G mobilized 10.5x more immunophenotypically primitive CD34+ HSCs capable of durable multilineage hematopoietic engraftment vs P+G (p<0.0001, Figure 1B).

P1/2, N=290, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

Triple combination of motixafortide, pembrolizumab and chemotherapy was safe, well tolerated and showed signs of efficacy in a population with poor prognosis and aggressive disease.

P1/2, N=410, Recruiting, Hoffmann-La Roche | Trial completion date: Feb 2023 --> Feb 2025 | Trial primary completion date: Feb 2023 --> Feb 2025

P1/2, N=290, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2021 --> Nov 2022 | Trial primary completion date: Nov 2021 --> Nov 2022

In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W... The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study.

To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization)...These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb)...Biol. xx: xx-xx; 2020.