ACE-041
for Advanced / Metastatic Cancer
ACE-041 is an investigational protein therapeutic that inhibits angiogenesis by preventing BMP-9 and BMP-10, proteins in the TGF-β superfamily, from interacting with activin receptor-like kinase 1 (ALK1), a cell-surface receptor found on proliferating endothelial cells. ACE-041 inhibits ALK1 signaling, which is required for the development of mature, functional vasculature. Acceleron is developing ACE-041 for the treatment of patients with advanced cancer who have failed prior therapy.
Mechanism of Action
| Many types of tumors depend on the growth of new blood vessels, a process called angiogenesis, to supply nutrients and oxygen that allows cancer cells to grow, invade nearby tissue, and spread to other parts of the body. Angiogenesis inhibition is a widely-used approach to cancer treatment. Several angiogenesis inhibitors that work by blocking the vascular endothelial growth factor (VEGF) pathway are approved or are in development. ACE-041 is a first-in-class angiogenesis inhibitor with a mechanism distinct from VEGF inhibition. ACE-041 is a soluble form of the activin receptor-like kinase 1 (ALK1) that binds to the TGF-β superfamily members BMP-9 and BMP-10 and prevents these proteins from signaling through ALK1. ALK1 is expressed on activated blood vessel cells and plays critical roles in the formation and maturation of blood vessels. Acceleron and independent academic collaborators have conducted studies with ACE-041 in animal models, demonstrating robust anti-angiogenic and anti-tumor properties in a range of tumor types, including those resistant to VEGF inhibitors. |
Disease Overview
| Cancer is a leading cause of death and is characterized by the uncontrolled growth and spread of abnormal cells. Many types of tumors depend on the growth of new blood vessels (angiogenesis) to supply adequate nutrients and oxygen, allowing cancer cells to grow, invade nearby tissue, and spread to other parts of the body. Several angiogenesis inhibitors that work by inhibiting the vascular endothelial growth factor (VEGF) pathway are approved or are in development. These therapies, given alone or in combination with chemotherapy and/or radiation, can significantly improve survival. Accordingly, they play an important role in the treatment of advanced solid tumors, including those occurring in the lung, colon/rectum, liver and kidney. |
Clinical Need
| Despite their clinical utility, there are several limitations to approved angiogenesis inhibitors that target VEGF. Most patients with advanced cancers who are treated with VEGF-targeting therapies eventually develop resistance and experience tumor progression, often within several months of initiating therapy. Moreover, some patients are poor candidates for these therapies or must discontinue treatment because of side effects. There is a need for novel therapies that utilize alternative strategies to target the tumor blood supply. ACE-041 represents a new approach to angiogenesis inhibition. Clinical trials are underway to study its potential as a safe and effective treatment for patients with advanced cancer. |
Clinical Trials
Acceleron has conducted a multiple ascending dose Phase 1 clinical study in which 37 patients with advanced-stage tumors were treated to evaluate the safety, pharmacokinetics and antitumor activity of ACE-041. For information on the study design, click here. Preliminary results from this study presented at the American Society of Clinical Oncology 2011 Conference demonstrated:
- Pharmacokinetic profile supports dosing by subcutaneous injection once every three weeks.
- ACE-041 was generally well-tolerated. Common AEs included peripheral edema, fatigue, anemia, dyspnea, anorexia, nausea and headache. Possibly or probably related SAEs in 5 patients included fluid overload (2), fatigue, CHF, and LV dysfunction. No hypertension, proteinuria, GI perforations, or hemorrhage have been observed in the study to date.
- Through 11 May 2011, one patient (squamous cell cancer of the head and neck) had a partial response (target lesion best response % change from baseline: -33%) and eight patients had prolonged periods of stable disease (> 4 cycles / 12 weeks of ACE-041 with no evidence of disease progression)
- Decline > 20% in tumor metabolic activity seen in 35% of patients by FDG-PET imaging.
Combined with results from preclinical pharmacology studies, these data suggest that ACE-041 has significant potential as an anti-cancer therapy. A Phase 2 clinical study of ACE-041 in patients with advanced head and neck cancer is ongoing in the United States. For information about this study, click here . Additional studies in NSCLC, endometrial and ovarian cancer are also planned.