Dalantercept

Summary

Dalantercept (also known as ACE‑041 or ALK1‑Fc) is an investigational fusion protein that combines the extracellular domain of activin receptor‑like kinase‑1 (ALK1) with an Fc fragment. By acting as a soluble “ligand trap” for the vascular growth factors BMP‑9 and BMP‑10, it aims to inhibit abnormal blood‑vessel formation that supports tumor growth. Clinical development has focused on solid tumours such as renal cell carcinoma and ovarian cancer, where it is being evaluated as a novel anti‑angiogenic strategy.

Mechanism of Action

ALK1 is a type I receptor of the TGF‑β superfamily that is highly expressed on proliferating endothelial cells. Its natural ligands, BMP‑9 and BMP‑10, bind ALK1 and trigger downstream SMAD‑dependent signaling that promotes vessel maturation and sprouting. Dalantercept consists of the soluble extracellular ALK1 domain fused to an IgG Fc region, allowing it to bind BMP‑9/10 in circulation with high affinity. By sequestering these ligands, the drug blocks ALK1‑mediated signaling, thereby disrupting endothelial cell proliferation, migration, and new‑vessel formation that tumors rely on for growth and metastasis.

What the Research Shows

Pre‑clinical work identified BMP‑9/10‑ALK1 signaling as a key regulator of angiogenesis, and recombinant BMP‑9 can reverse pulmonary hypertension in rodent models. Dalantercept entered phase II trials as a ligand trap for BMP‑9/10, aiming to inhibit tumor angiogenesis. In a phase II ovarian cancer study, subcutaneous dosing (1.2 mg/kg q3 weeks) was well tolerated but produced no objective responses and modest 6‑month progression‑free rates (20%). A randomized phase II trial in previously treated clear‑cell renal cell carcinoma combined dalantercept with axitinib; the addition did not improve progression‑free or overall survival and yielded a lower objective response rate than axitinib alone. Across studies, grade 3 adverse events occurred in roughly 60 % of patients, with no grade 4 events reported in the ovarian trial and similar safety to placebo in the renal trial. Reviews highlight dalantercept’s distinct safety profile compared with VEGF inhibitors and note its potential to address resistance mechanisms, but clinical efficacy remains unproven.

Reported Benefits

Dalantercept targets a non‑VEGF angiogenic pathway, offering a theoretical advantage in tumors that have become resistant to VEGF‑directed therapies. By trapping BMP‑9 and BMP‑10, it may reduce abnormal vascular remodeling without the hypertension and proteinuria commonly seen with VEGF inhibitors. Early-phase studies report a tolerable safety profile, with few severe toxicities and no dose‑limiting events, suggesting it could be combined with other agents such as axitinib. The distinct mechanism also provides a valuable tool for exploring ALK1 biology in cancer.

Limitations of the Evidence

Clinical data to date show limited antitumor activity; the ovarian cancer phase II trial reported no objective responses, and the renal cell carcinoma trial found no improvement in progression‑free or overall survival when dalantercept was added to axitinib. Sample sizes have been modest, and the trials have not demonstrated a clear benefit over existing standards of care. As an investigational agent, dalantercept remains unapproved, and its optimal dosing, patient selection criteria, and long‑term outcomes are still undefined.

Safety Considerations

Across studies, dalantercept was generally well tolerated. In the ovarian cancer trial, six grade 3 treatment‑related adverse events occurred, with no grade 4 events. The renal cell carcinoma study reported grade ≥ 3 adverse events in 59 % of dalantercept‑treated patients, a rate comparable to the placebo arm, and no new safety signals emerged. Reported toxicities have included hypertension and proteinuria, similar to other anti‑angiogenic agents, but at lower frequencies. Ongoing monitoring for vascular and bleeding complications is advised in future trials.

How It Is Administered

Dalantercept is formulated as a protein suitable for parenteral delivery. Clinical studies have employed subcutaneous injections (e.g., 1.2 mg/kg every three weeks) and intravenous infusions, reflecting its classification as a fusion protein with an Fc fragment. The drug is supplied as a sterile solution for injection, and dosing schedules are adjusted based on trial protocols and patient tolerance.

Routes of Administration

Goals & Uses

• solid tumor therapyOncologyModerate
• Hepatocellular carcinoma treatmentOncologyLow
• Renal cell carcinoma treatmentOncologyModerate
• Anti-tumor angiogenesisOncologyModerate
• Head and neck squamous cell carcinoma treatmentOncologyLow

Contraindications

• hypersensitivity to the drug or its excipientsAllergyHigh
• Severe hepatic impairmentOrganModerateLiver function concerns
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Hereditary hemorrhagic telangiectasia (HHT)Genetic Vascular DisorderHigh

Adverse Effects

• TelangiectasiasDermatologic/vascularCommon
• Peripheral edemaFluid BalanceCommonSwelling of the arms or legs
• HypertensionCardiovascularCommonHigh blood pressure
• EpistaxisVascular/bleedingCommon
• FatigueGeneralCommonLow energy or tiredness
• Pulmonary hypertensionCardiovascular/pulmonaryRare

Drug Interactions

• AxitinibModerate
• none identifiedLow
• Antihypertensive agentsModerate

Population Constraints

• PregnancyReproductive SafetyRelative
• Patients with pre-existing vascular malformationsVascularRelative
• Pediatric patientsAgeRelative
• Pregnant womenReproductiveAbsolute

Regulatory Status

• European UnionInvestigationalClinical trials ongoing; not authorized.
• United StatesInvestigationalUnder IND; no FDA approval.

No regulatory approval in any jurisdiction as of 2026; studied in phase I/II clinical trials.

Evidence & Sources

• New agents and new targets for renal cell carcinoma
  Journal ArticleModeratePhilips GK, Atkins MB2014-01-01T00:00:00.000000Z
• Regulation of the ALK1 ligands, BMP9 and BMP10
  Journal ArticleModerateLi W, et al.2016-01-01T00:00:00.000000Z
• Activin receptor inhibitors--dalantercept
  Journal ArticleModerateGupta S, et al.2015-01-01T00:00:00.000000Z
• Phase II evaluation of dalantercept in the treatment of persistent or recurrent epithelial ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study
  Journal ArticleModerateBurger RA, et al.2018-01-01T00:00:00.000000Z
• A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma
  Journal ArticleModerateVoss MH, et al.2019-01-01T00:00:00.000000Z
• Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function
  Journal ArticleModeratede Vinuesa AG, et al.2016-01-01T00:00:00.000000Z

Frequently Asked Questions