Alpha-9 Begins First-in-Human Trial of MC1R-Targeted Radiotherapeutic

Alpha-9 Oncology has initiated first-in-human dosing of A9-3408, an Actinium-225 (Ac-225)–based radiotherapeutic designed to target melanocortin 1 receptor (MC1R) in patients with advanced melanoma. For clinicians treating melanoma in an era of increasingly complex treatment algorithms, this early-phase trial represents a potentially important step in diversifying therapeutic mechanisms beyond immunotherapy and targeted kinase inhibition.¹

The A9-3408 Program

A9-3408 is built on this principle, pairing Ac-225 with an optimized MC1R-targeting ligand. The newly launched phase 1 study is a multi-center, open-label trial designed to evaluate safety, dosimetry, pharmacokinetics, and dose escalation. Eligible patients must have MC1R-positive melanoma and evidence of progression after standard therapies, including immunotherapy, reflecting a real-world population where therapeutic innovation is urgently needed.

This therapeutic program is enabled by Alpha-9’s precursor diagnostic agent, A9-3202, a Ga-68–based PET tracer used to image MC1R expression. The company reported that in its imaging study, 92% of patients who had progressed on immunotherapy demonstrated strong MC1R expression, supporting the feasibility of a radiotheranostic approach.

Robert Meehan, MD, chief medical officer at Alpha-9, emphasized the rationale:

“MC1R is an ideal target due to its high expression in melanoma and limited presence in healthy tissue.” He adds that unmet need remains substantial: “Despite advances in immunotherapy, significant unmet needs remain for patients who progress on current standard of care.”

Trial Significance for Clinicians

From a clinical perspective, the importance of this study lies in 3 major areas:

Novel Mechanism of Action:
Alpha-particle therapeutics deliver high-linear energy transfer radiation, producing double-strand DNA breaks that are largely insensitive to traditional resistance pathways. For patients who have exhausted immunotherapy and targeted agents, this could represent a mechanistically distinct treatment class.

Precision Targeting and Theranostics:
Radiotheranostic platforms enable selection of patients most likely to benefit while providing real-time biological confirmation of target expression. This stands in contrast to systemic therapies whose efficacy may depend on variable tumor microenvironment or immune responsiveness.

Safety and Tolerability Questions:
A primary focus of early-phase evaluation will be establishing dose-limiting toxicities, particularly given Ac-225’s potency. The short path length of alpha particles may reduce off-target effects, but radiopharmaceutical safety profiles depend heavily on biodistribution and retention, which the study aims to quantify.

Platform Development

The initiation of dosing follows the company’s broader push to expand its radiotherapeutics pipeline. Alpha-9 describes its platform as a systematic approach to optimizing binders, linkers, and chelators to improve tumor uptake and retention while minimizing exposure to normal tissues.

Paul Blanchfield, Alpha-9’s CEO, highlighted the milestone by stating, “Dosing the first patient with our MC1R radiotherapeutic marks an important milestone for the company and validates our internal R&D platform.”

The company has also strengthened its clinical leadership with the addition of Meehan, whose background encompasses roles at Dragonfly Therapeutics, Moderna, and the National Cancer Institute. His experience in early-phase drug development may support efficient progression of this and other upcoming programs.

Background and Rationale

Despite clear survival gains with immune checkpoint inhibitors and BRAF/MEK–directed therapies, a substantial subset of melanoma patients—particularly those with primary or acquired resistance—face limited treatment options. Novel approaches are needed for patients progressing on standard-of-care regimens, especially when disease biology provides exploitable molecular targets.²

MC1R is one such target. Highly expressed in most melanoma tumors with limited expression in healthy tissue, the receptor has emerged as an attractive anchor for radiotheranostic strategies. Radiotherapeutics using isotopes such as Ac-225 allow for localized alpha-particle emission, delivering high-energy, short-range cytotoxic effects directly to cancer cells while minimizing systemic toxicity.

Clinical Outlook

While outcomes from this phase 1 study remain several years away, the development of A9-3408 signals momentum in radiotheranostics for solid tumors—a field that has expanded beyond neuroendocrine tumors and prostate cancer into broader oncology settings. For clinicians managing refractory melanoma, the prospect of a new class of precision radiotherapeutics offers a welcome direction for future treatment paradigms.

As molecular imaging and targeted isotopes continue to advance, MC1R-directed radiotherapy may eventualmente become an important complement to established systemic therapies, pending further clinical validation.

References

1. Phase 1 study advances A9-3408, an Actinium-225-based radiotherapeutic, building on the progress of the company’s imaging agent, A9-3202, which entered the clinic last year. News release. Alpha 9 Oncology. Published December 4, 2025. Accessed December 4, 2025. https://www.a9oncology.com/phase-1-study-advances-a9-3408-an-actinium-225-based-radiotherapeutic-building-on-the-progress-of-the-companys-imaging-agent-a9-3202-which-entered-the-clinic-last-year/
2. Patel H, Yacoub N, Mishra R, White A, Long Y, Alanazi S, Garrett JT. Current advances in the treatment of BRAF-mutant melanoma. Cancers (Basel). 2020 Feb 19;12(2):482. doi: 10.3390/cancers12020482.