POL6326 – Balixafortide

Antagonist of chemokine receptor CXCR4 for combination treatment in oncology

Balixafortide (POL6326)

A potent blocker of CXCR4, a key passway involved in tumor growth and metastasis
Phase 1

Breast cancer therapy

Breast cancer is the most common cancer in women, having caused an estimated 500,000 deaths in 2011 (Global Health Estimates, WHO 2013). Despite advances in targeted hormonal and cytotoxic therapies, the overall survival in metastatic breast cancer remains poor, in particular in breast cancer resistant to chemotherapy and hormonal therapy.

Cancer drugs are usually most effective when given in combination. The rationale for combining different anticancer agents is to use drugs that work via different mechanisms, thereby decreasing the likelihood that resistant cancer cells will develop.

Blockade of the CXCR4 pathway by Balixafortide represents a novel combination treatment approach for patients with breast cancer.

A potent, selective CXCR4 antagonist

Candidate combination product for breast cancer and other cancer indications

Balixafortide is a potent and highly selective blocker of CXCR4, a G-protein coupled receptor (GPCR) that regulates the trafficking and homing of both cancer cells and cells of the patient’s immune system. It is expressed in a variety of cancer types, and additionally, locally in the tumor micro-environment 1, 2, 3.

CXCR4 also plays a critical role in tumor growth, survival, angiogenesis and metastasis 4. High CXCR4 levels have been detected in almost all human tumor types, including breast cancer. High CXCR4 expression is known to correlate with aggressive metastatic behavior of cancer cells and a poor prognosis 5.

The anti-cancer effects of Balixafortide are thought to include direct suppression of metastatic spread, sensitization of tumor cells to chemotherapy, and activation of the immune system 6.

Based on its multifaceted modes of action, it is anticipated that Balixafortide could enhance the activity of a range of other therapies including chemotherapy and immunotherapies.

Clinical proof-of-concept has been achieved in a Phase 1/2 study in patients with metastatic HER2-negative breast cancer. Balixafortide in combination with eribulin produced a higher response rate than published data for eribulin alone in a similar patient population 7.

References

1. Burger JA, Kipps TJ. Blood. 2006;107(5):1761-1767

2. Liotta LA. Nature. 2001;410(6824):24-25

3. Balkwill F. Semin Cancer Biol. 2004;14(3):171-179

4. Otsuka S, Bebb G. J Thorac Oncol. 2008;3(12):1379-1383

5. Chatterjee S, Behnam Azad B, Nimmagadda S. Adv Cancer Res. 2014; 124:31-82.

6. Scala S. Clin Cancer Res. 2015;21(19):4278-85

7. Gil-Martin M. et al. Phase 1 study of the combination of balixafortide (CXCR4 inhibitor) and eribulin in HER2-negative metastatic breast cancer (MBC) patients. J Clin Oncol. 2017;35(15_suppl):2555-2555

Preclinical summary

A highly potent and selective CXCR4 inhibitor*

Balixafortide’s key attributes*:

  • Potent CXCR4 inhibitor
  • Highly selective over a broad panel of GPCRs and ion channels
  • No CYP or HERG inhibition up to the maximum tested doses
  • Favorable physicochemical properties enabling exploration of various formulations

The receptor CXCR4 and its soluble ligand CXCL12 (also known as stromal-derived factor 1a [SDF-1a]) are key factors in the cross-talk between cancer cells and their tumor microenvironment.

CXCR4 belongs to the transmembrane receptor class of G-coupled protein receptors (GPCR). CXCR4 plays an important role in the metastatic process and allows tumor cells to migrate to sites where CXCL12 is expressed, for example, into the bone marrow of breast cancer patients.

CXCR4 overexpression has been detected in more than 23 different human cancer types and correlates with a poor prognosis. CXCL12 activates distinct intracellular signaling pathways in tumor cells and stimulates proliferation, migration and invasion. However, CXCR4 is also expressed in multiple normal cells, including lymphocytes, hematopoietic stem cells, and endothelial and epithelial cells, where it contributes to the regular functioning of organs and tissue.

It is hypothesized that reversible CXCR4 inhibition by selective, potent and CXCL12-competitive antagonists such as Balixafortide could have advantages compared to long-term blockade by therapeutic antibodies.

* Data on file

Designing new medicines from a natural product

The starting point for the design of novel CXCR4 antagonists was polyphemusin, a naturally occurring peptide from the horseshoe crab (Limulus polyphemus).

Polyphor has applied its PEM Technology to the discovery and optimization of fully synthetic cyclopeptide CXCR4 antagonists. This has led to Balixafortide, now in clinical development, amongst other candidate CXCR4 antagonists.

Structural models indicate that balixafortide occupies a large part of the receptor pocket when complexed with human CXCR4 (see illustration).

Illustration: Surface representation of the binary complex of human CXCR4 with Balixafortide*

Clinical studies

As a result of its pharmacological profile, Balixafortide has the potential to enhance the anti-tumor efficacy of chemotherapy

Results from a Phase 1 study in heavily pretreated metastatic breast cancer patients with the combination of Balixafortide and eribulin (Halaven®), an approved non-taxane inhibitor of microtubule dynamics 8, 9 :

  • Balixafortide shows a good safety profile, with transient and mainly mild to moderate histamine-like reactions or infusion-related reactions easily manageable with anti-histaminic agents or with a reduced infusion rate
  • The addition of Balixafortide to eribulin was well tolerated without the need to reduce the dose of eribulin
  • In the expanded dose cohort (n=24) the majority of patients were on treatment for 6 months or longer (up to >1 year)
  • Pharmacokinetic data showed consistently reproducible dose-linear exposure with low inter-subject variability
  • Balixafortide produced high tumor response rates in late stage and heavily pretreated metastatic breast cancer patients when used in combination with eribulin
  • The combination of Balixafortide and eribulin resulted in a response rate of 38%. This compares favorably with published data for eribulin alone in similar patient populations (response rate 12-14%)

References

8. Pernas Simon S. et al. J Clin Oncol. 2016;34(15_suppl):2548-2548

9. Gil-Martin M et al. J Clin Oncol. 2017;35(15_suppl):2555-2555