Xolremdi (mavorixafor)

Thank to their particular pharmacokinetics, the use of small organic molecules can be a very promising alternative to macromolecular targeting biomolecules (i.e. antibodies, peptides…) for specific imaging of tumours. Herein, the potential of two AMD070-like inhibitors as CXCR4-targeting units for specific imaging of cancer cells, and the influence of chromophore-grafting on their recognition properties has been investigated.

P1/2, N=32, Completed, X4 Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Jul 2025 --> Aug 2024 | Trial primary completion date: Jun 2025 --> Aug 2024

P1, N=16, Completed, X4 Pharmaceuticals | Phase classification: P1b --> P1

In conclusion, we compared different 177Lu-radiolabelled CXCR4-targeting peptides for their binding potential in GBM, and demonstrated their varied cytotoxic action against GBM cells in vitro, with POL3026 being the most promising, causing considerable DNA damage. Though the peptide's systemic biodistribution remains to be improved, our data demonstrate the potential of [177Lu]Lu-DOTA-POL3026 for CXCR4-TRT in the context of GBM.

P3, N=150, Recruiting, X4 Pharmaceuticals | Not yet recruiting --> Recruiting | Trial completion date: Jul 2025 --> Aug 2026 | Initiation date: Mar 2024 --> Jul 2024 | Trial primary completion date: Jun 2025 --> Jul 2026

P3, N=31, Active, not recruiting, X4 Pharmaceuticals | Trial primary completion date: Oct 2022 --> Dec 2024

P1/2, N=43, Active, not recruiting, X4 Pharmaceuticals | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

P3, N=150, Not yet recruiting, X4 Pharmaceuticals | Trial completion date: Apr 2025 --> Jul 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

These treatments include neutrophil elastase inhibitors, SGLT-2 inhibitors, mavorixafor - an oral CXCR4 inhibitor, gene therapy and gene editing. All of these alternatives to G-CSF are promising. The risks, relative benefits and costs are yet to be determined.

A biomarker-driven phase Ib study (NCT02823405) was conducted in 16 patients with melanoma to investigate the hypothesis that mavorixafor favorably modulates immune cell profiles in the tumor microenvironment (TME) and to evaluate the safety of mavorixafor alone and in combination with pembrolizumab. Despite survival improvements in patients with melanoma treated with checkpoint inhibitor therapy, a significant unmet medical need exists for therapies that enhance effectiveness. We propose that mavorixafor sensitizes the melanoma tumor microenvironment and enhances the activity of checkpoint inhibitors, and thereby may translate to a promising treatment for broader patient populations.

Our study provides supporting evidence for further exploration of mavorixafor alone or in combination with other B-cell-targeted therapies in the treatment of lymphomas and leukemias. Further studies using additional LC lines and/or primary patient cells are warranted to support these findings.

Methods WM cells (MWCL-1 cell line, MYD88 L265P CXCR4 WT ) pretreated with mavorixafor and B-cell targeted therapies (BTK antagonists: ibrutinib, zanubrutinib, evobrutinib, pirtobrutinib, nemtabrutinib; or BCL2 inhibitor venetoclax) were co-cultured with established BMSCs (HS27a cells). Conclusion Our studies provide preliminary evidence for the potential use of mavorixafor in disrupting the interaction of WM cells with the BMSC-based microenvironment, enhancing the efficacy of B-cell targeted therapies in the treatment of WM and potentially other lymphomas. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.

Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (eg, bendamustine, cyclophosphamide), nucleoside analogs (eg, fludarabine, cladribine), or proteasome inhibitors (eg, bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (eg, tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (eg, pirtobrutinib, ARQ531), BCL-2 antagonists (eg, venetoclax), and CXCR4-targeted agents (eg, mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost.

WM cells (MWCL-1 cell line, MYD88L265PCXCR4WT) pretreated with mavorixafor and BTK inhibitors (ibrutinib, zanubrutinib, evobrutinib, LOXO-305, ARQ 531) were co-cultured with established BMSCs (HS27a cells). Mavorixafor addition enhanced the efficacy of not only ibrutinib but the other BTK inhibitors tested, supporting the greater potential of this combination therapeutic strategy in WM patients with or without CXCR4WHIM mutations. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.

Second, nude male mice bearing intratibial, luciferase-expressing human PC-3 prostate cancer xenografts were treated with vehicle (p.o., q.d.), docetaxel (10 mg/kg i.p. weekly), X4P-001 (10 or 30 mg/kg p.o., q.d.), EMU-116 (10 or 30 mg/kg p.o., q.d.), X4P + axitinib, or EMU + axitinib. EMU-116, at the same or lower dose, was more efficacious than X4P-001 in these models. These results highlight EMU-116 as a clinical candidate with significant therapeutic potential to synergize with chemotherapeutics, targeted therapies, and immuno-oncology agents.

The invasion ability of radiation‑resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and coculture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070...In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. These findings may facilitate the development of novel treatments for PaCa.

Several compounds exhibiting excellent in vitro activity profiles further demonstrated superior mouse pharmacokinetic properties to Mavorixafor, a small molecule CXCR4 antagonist under clinical development. These improved pharmacokinetic properties translated to significantly enhanced anticancer activity in mouse models of renal cell carcinoma. These efforts ultimately led to the identification of EMU-116 as a clinical candidate with robust therapeutic potential against various tumor types.

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. 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.

Our findings as of June 2021 in patients with WM carrying both MYD88 and CXCR4 WHIM mutations show that mavorixafor in combination with ibrutinib is well tolerated. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug–drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. All evaluable patients demonstrated at least a minor response.

P1/2, N=24, Enrolling by invitation, Abbisko Therapeutics Co, Ltd

The INNOVATE study randomized 150 patients with WM to either the combination of ibrutinib plus rituximab or placebo plus rituximab.2 The combination of ibrutinib plus rituximab was associated with a higher major response rate (72% versus 32%) and a higher 30-month PFS rate (82% versus 28%) than the combination of placebo plus rituximab, prompting the approval of the combination of ibrutinib plus rituximab for WM by the FDA in 2018...Three novel covalent BTK inhibitors are under active investigation for WM: zanubrutinib, acalabrutinib and tirabrutinib...The non-covalent BTK inhibitor pirtobrutinib was evaluated in a multicenter phase Iistudy in 26 patients with WM of whom 18 (12 had progressed and 6 were intolerant) were previously exposed to a covalent BTK inhibitor.6 The ORR to pirtobrutinib was 69%...A study evaluating the combination of ibrutinib and venetoclax in treatment-naïve patients with WM is ongoing...The CXCR4 inhibitor mavorixafor is being evaluated in combination with ibrutinib in WM patients who carry CXCR4 mutations. The PI3K inhibitor idelalisib show early efficacy in patients with WM but it seems to be associated with a high rate of liver toxicity.8 A multicenter study evaluating umbralisib in patients with WM has stopped accrual. The anti-CD38 monoclonal antibody daratumumab had a lower-than-expected efficacy rate in WM.9 Dasatanib is an HCK inhibitor being studied in patients with WM progressing on covalent BTK inhibitors. The phospholipid-drug conjugate CLR-131 was recently granted a Fast- Track Designation for WM patients having received two or more prior treatment regimens. In all, the treatment of patients with WM continues evolving. There are many reasons to be optimistic about the future of the treatment landscape of patients with WM.

For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the non-covalent BTK inhibitors pirtobrutinib and ARQ-531.

Our findings to date in patients with WM carrying both MYD88 and CXCR4 mutations show that mavorixafor in combination with ibrutinib is well tolerated at doses ≤400 mg QD. Unaltered mavorixafor and ibrutinib exposures suggest no apparent drug–drug interaction, and mavorixafor exposures tracked with increased WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM, suggesting mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.

Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug–drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM levels, suggesting that mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.

Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.

Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.

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.

Inspired by the benzimidazole-like inhibitors that are similar to the organic ligand of ZIF-7, a chemokine (C-X-C motif) receptor 4 (CXCR4) inhibitor AMD-070 (AMD) and magnesium ions (Mn2+) were successfully tandem exchanged to the ZIF-7 framework, forming an active-targeting framework AMD-ZIF-7(Mn) for CXCR4-overexpressed esophageal squamous cell cancer. With 5-Fu loading, AMD-ZIF-7(Mn)/5-Fu showed a synergistic therapeutic effect in DNA damage and CXCR4 inhibition of esophageal squamous cell cancer. Therefore, we propose a structural reconstruction method to effectively explore and improve the biomedical application of ZIFs in esophageal squamous cell cancer theranostics.

To construct nanobubbles (PTX-AMD070 NBs) for targeted delivery of paclitaxel (PTX) and AMD070, examine their performance in ultrasound molecular imaging of breast cancer and cervical cancer and their therapeutic effect combined with ultrasound targeted nanobubble destruction (UTND). PTX-AMD070 NBs improved the ultrasound imaging effect in CXCR4 xenograft tumors and facilitated targeted therapy combined with UTND. Therefore, this study provides an effective method for the integration of ultrasound molecular imaging and targeted therapy of malignant tumors.

ICG-TNBs can specifically bind to CXCR4 positive breast cancer cells, furthermore inhibit growth and promote apoptosis of breast cancer cells combined with ultrasonic irradiation by blocking the SDF-1/CXCR4 pathway. This study introduces a novel concept, method and mechanism for integration of targeted diagnosis and treatment of breast cancer.

Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.